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Front Immunol

2023 Jan 9

Wijewardana V, Ulbert S, Cattoli G.

2. Pre-clinical models for evaluating glioma targeted immunotherapies.

Front Immunol

2023 Jan 9

Frederico SC, Zhang X, Hu B

3. Natural biomolecules and derivatives as anticancer immunomodulatory agents.

Front Immunol

2023 Jan 9

Bernitsa S, Dayan R, Stephanou A

4. Crosstalk between fibroblasts and T cells in immune networks.

Front Immunol

2023 Jan 9

Lee B, Lee SH, Shin K.

5. Editorial: Recent advances and challenges in cancer immunotherapies for patients with autoimmune diseases.

Front Immunol

2023 Jan 9

Saleh R.

6. Editorial: Role of lung and gut microbiota in the immune response against respiratory viral infections.

Front Immunol

2023 Jan 9

de Souza APD, Singanayagam A, Porto BN.

7. Polyvalent human immunoglobulin for infectious diseases: Potential to circumvent antimicrobial resistance.

Front Immunol

2023 Jan 9

Pedraza-Sánchez S, Cruz-González A, Palmeros-Rojas O

8. Immune microenvironment infiltration landscape and immune-related subtypes in prostate cancer.

Front Immunol

2023 Jan 9

Wu W, Wang X, Le W

9. The role of Th17 cells in inflammatory bowel disease and the research progress.

Front Immunol

2023 Jan 9

Chen L, Ruan G, Cheng Y

10. Updates on immunological mechanistic insights and targeting of the oral lichen planus microenvironment.

Front Immunol

2023 Jan 9

Deng X, Wang Y, Jiang L

11. The therapeutic potential of non-invasive brain stimulation for the treatment of Long-COVID-related cognitive fatigue.

Front Immunol

2023 Jan 9

Linnhoff S, Koehler L, Haghikia A

12. Insights into the immunomodulatory regulation of matrix metalloproteinase at the maternal-fetal interface during early pregnancy and pregnancy-related diseases.

Front Immunol

2023 Jan 9

Jing M, Chen X, Qiu H

13. The other immuno-PET: Metabolic tracers in evaluation of immune responses to immune checkpoint inhibitor therapy for solid tumors.

Front Immunol

2023 Jan 9

Levi J, Song H.

14. Computationally profiling peptide:MHC recognition by T-cell receptors and T-cell receptor-mimetic antibodies.

Front Immunol

2023 Jan 9

Raybould MIJ, Nissley DA, Kumar S

15. Identification and comprehensive analysis of circRNA-miRNA-mRNA regulatory networks in osteoarthritis.

Front Immunol

2023 Jan 9

Liu X, Xiao H, Peng X

16. Beta 2 glycoprotein I and neutrophil extracellular traps: Potential bridge between innate and adaptive immunity in anti-phospholipid syndrome.

Front Immunol

2023 Jan 9

Grossi C, Capitani N, Benagiano M

17. Immunogenic self-peptides - the great unknowns in autoimmunity: Identifying T-cell epitopes driving the autoimmune response in autoimmune diseases.

Front Immunol

2023 Jan 9

Prinz JC.

HLA-associated autoimmune diseases likely arise from T-cell-mediated autoimmune responses against certain self-peptides from the broad HLA-presented immunopeptidomes. The limited knowledge of the autoimmune target peptides has so far compromised the basic understanding of autoimmune pathogenesis. This is due to the complexity of antigen processing and presentation as well as the polyspecificity of T-cell receptors (TCRs), which pose high methodological challenges on the discovery of immunogenic self-peptides. HLA-class I molecules present peptides to CD8+ T cells primarily derived from cytoplasmic proteins. Therefore, HLA-class I-restricted autoimmune responses should be directed against target cells expressing the corresponding parental protein. In HLA-class II-associated diseases, the origin of immunogenic peptides is not pre-specified, because peptides presented by HLA-class II molecules to CD4+ T cells may originate from both extracellular and cellular self-proteins. The different origins of HLA-class I and class II presented peptides determine the respective strategy for the discovery of immunogenic self-peptides in approaches based on the TCRs isolated from clonally expanded pathogenic T cells. Both involve identifying the respective restricting HLA allele as well as determining the recognition motif of the TCR under investigation by peptide library screening, which is required to search for homologous immunogenic self-peptides. In HLA-class I-associated autoimmune diseases, identification of the target cells allows for defining the restricting HLA allotype from the 6 different HLA-class I alleles of the individual HLA haplotype. It furthermore limits the search for immunogenic self-peptides to the transcriptome or immunopeptidome of the target cells, although neoepitopes generated by peptide splicing or translational errors may complicate identification. In HLA class II-associated autoimmune diseases, the lack of a defined target cell and differential antigen processing in different antigen-presenting cells complicate identification of the HLA restriction of autoreactive TCRs from CD4+ T cells. To avoid that all corresponding HLA-class II allotypes have to be included in the peptide discovery, autoantigens defined by autoantibodies can guide the search for immunogenic self-peptides presented by the respective HLA-class II risk allele. The objective of this article is to highlight important aspects to be considered in the discovery of immunogenic self-peptides in autoimmune diseases.

18. CAR T cell therapy becomes CHIC: "cytokine help intensified CAR" T cells.

Front Immunol

2023 Jan 9

Thomas S, Abken H.

19. Retrospective analysis on the immunopotentiating mechanism of an emulsion-based vaccine adjuvant on human antigen presenting cells.

Front Immunol

2023 Jan 9

Bonam SR, Platenburg PP, Bayry J.

20. Conversion therapy for advanced intrahepatic cholangiocarcinoma with lenvatinib and pembrolizumab combined with gemcitabine plus cisplatin: A case report and literature review.

Front Immunol

2023 Jan 9

Zhang W, Luo C, Zhang ZY

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant biliary tumor. Patients with unresectable and advanced ICC have a poor prognosis with current gemcitabine-based chemotherapy. Combination therapy strategies based on immunotherapy have achieved promising results in various tumor types. CASE PRESENTATION: We reported a patient with unresectable ICC who received lenvatinib and pembrolizumab in combination with gemcitabine plus cisplatin (GP) chemotherapy and subsequently underwent radical liver resection. A 46-year-old male with a history of chronic hepatitis B and hypertension was diagnosed with ICC. Multiple liver tumors with ring-like enhancement were detected on abdominal contrast-enhanced CT and MRI. Enlarged lymph nodes were found in the hilar and retroperitoneal areas. The tumor was clinically staged as T2N1M0 (stage IIIB). Lenvatinib and pembrolizumab in combination with GP chemotherapy were adopted as first-line treatments for the patient. After six cycles of scheduled treatment, the diameter of the largest liver lesion and the number of liver lesions were markedly reduced. The level of the tumor marker CA19-9 decreased to a normal range. A partial response according to the mRECIST criteria was achieved without severe toxicities. Non-anatomical liver resection (segment 4b, 5,6 + segment 7 + segment 8), cholecystectomy and hilar lymph node dissection were performed one month after stopping combination therapy. Pathological examination confirmed a diagnosis of moderate-to-poorly differentiated ICC with lymph node metastasis. The patient has survived 15 months following resection of the tumors, with no evidence of local recurrence or distant metastasis. CONCLUSION: Lenvatinib and anti-PD1 antibody pembrolizumab in combination with GP chemotherapy provided promising antitumor efficacy with reasonable tolerability, which may be a potentially feasible and safe conversion therapy strategy for patients with initially unresectable and advanced ICC.

21. Intratumoral STING activation causes durable immunogenic tumor eradication in the KP soft tissue sarcoma model.

Front Immunol

2023 Jan 9

Marritt KL, Hildebrand KM, Hildebrand KN

22. Huwe1 supports B-cell development, B-cell-dependent immunity, somatic hypermutation and class switch recombination by regulating proliferation.

Front Immunol

2023 Jan 9

Spanjaard A, Stratigopoulou M, de Groot D

23. A highly efficient indirect ELISA and monoclonal antibody established against African swine fever virus pK205R.

Front Immunol

2023 Jan 9

Li L, Qiao S, Liu J

24. Distinct systemic immune networks define severe vs. mild COVID-19 in hematologic and solid cancer patients.

Front Immunol

2023 Jan 9

Pignataro-Oshiro F, Figueiredo AB, Galdino NAL

INTRODUCTION: The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, has impacted health across all sectors of society. A cytokine-release syndrome, combined with an inefficient response of innate immune cells to directly combat the virus, characterizes the severe form of COVID-19. While immune factors involved in the development of severe COVID-19 in the general population are becoming clearer, identification of the immune mechanisms behind severe disease in oncologic patients remains uncertain. METHODS: Here we evaluated the systemic immune response through the analysis of soluble blood immune factors and anti-SARS-CoV-2 antibodies within the early days of a positive SARS-CoV-2 diagnostic in oncologic patients. RESULTS: Individuals with hematologic malignancies that went on to die from COVID-19 displayed at diagnosis severe leukopenia, low antibody production against SARS-CoV-2 proteins, and elevated production of innate immune cell recruitment and activation factors. These patients also displayed correlation networks in which IL-2, IL-13, TNF-alpha, IFN-gamma, and FGF2 were the focal points. Hematologic cancer patients that showed highly networked and coordinated anti-SARS-CoV-2 antibody production, with central importance of IL-4, IL-5, IL-12A, IL-15, and IL-17A, presented only mild COVID-19. Conversely, solid tumor patients that had elevated levels of inflammatory cytokines IL-6, CXCL8, and lost the coordinate production of anti-virus antibodies developed severe COVID-19 and died. Patients that displayed positive correlation networks between anti-virus antibodies, and a regulatory axis involving IL-10 and inflammatory cytokines recovered from the disease. We also provided evidence that CXCL8 is a strong predictor of death for oncologic patients and could be an indicator of poor prognosis within days of the positive diagnostic of SARS-CoV-2 infection. CONCLUSION: Our findings defined distinct systemic immune profiles associated with COVID-19 clinical outcome of patients with cancer and COVID-19. These systemic immune networks shed light on potential immune mechanisms involved in disease outcome, as well as identify potential clinically useful biomarkers.

25. Six-month longitudinal immune kinetics after mRNA-1273 vaccination: Correlation of peak antibody response with long-term, cross-reactive immunity.

Front Immunol

2023 Jan 9

Choi MJ, Heo JY, Seo YB

26. S100A8 alarmin supports IL-6 and metalloproteinase-9 production by fibroblasts in the synovial microenvironment of peripheral spondyloarthritis.

Front Immunol

2023 Jan 9

Arias JL, Funes SC, Blas R

27. Immunity against Delta and Omicron variants elicited by homologous inactivated vaccine booster in kidney transplant recipients.

Front Immunol

2023 Jan 9

Zhang L, Yang J, Lai C

BACKGROUND: A third mRNA vaccine booster is recommended to improve immunity against SARS-CoV-2 in kidney transplant recipients (KTRs). However, the immunity against SARS-CoV-2 Ancestral strain and Delta and Omicron variants elicited by the third dose of inactivated booster vaccine in KTRs remains unknown. METHODS: The blood parameters related to blood cells count, hepatic function, kidney function, heart injury and immunity were explored clinically from laboratory examinations. SARS-CoV-2 specific antibody IgG titer was detected using an enzyme-linked immunosorbent assay. Cellular immunity was analyzed using interferon-γ enzyme-linked immunospot assay. RESULTS: The results showed that there were no severe adverse effects and apparent changes of clinical laboratory biomarkers in KTRs and healthy volunteers (HVs) after homologous inactivated vaccine booster. A third dose of inactivated vaccine booster significantly increased anti-Ancestral-spike-trimer-IgG and anti-Ancestral-receptor binding domain (RBD)-IgG titers in KTRs and HVs compared with the second vaccination. However, the anti-Delta-RBD-IgG and anti-Omicron-RBD-IgG titers were significantly lower than anti-Ancestral-RBD-IgG titer in KTRs and HVs after the third dose. Notably, only 25.6% (10/39) and 10.3% (4/39) of KTRs had seropositivity for anti-Delta-RBD-IgG and anti-Omicron-RBD-IgG after booster, which were significantly lower than HVs (anti-Delta-RBD-IgG: 100%, anti-Omicron-RBD-IgG: 77.8%). Ancestral strain nucleocapsid protein and spike specific T cell frequency after booster was not significantly increased in KTRs compared with the second dose, significantly lower than that in HVs. Moreover, 33.3% (12/36), 14.3% (3/21) and 14.3% (3/21) of KTRs were positive for the Ancestral strain and Delta and Omicron spike-specific T cells, which were significantly lower than HVs (Ancestral: 80.8%, Delta: 53.8%, and Omicron: 57.7%). CONCLUSIONS: A third dose of inactivated booster vaccine may significantly increase humoral immunity against the Ancestral strain in KTRs, while humoral and cellular immunity against the Delta and Omicron variants were still poor in KTRs.

28. Partially replacing cyclophosphamide with bendamustine in combination with cyclosporine A improves survival and reduces xenogeneic graft-versus-host-disease.

Front Immunol

2023 Jan 9

Gilman KE, Cracchiolo MJ, Matiatos AP

INTRODUCTION: The use of allogeneic hematopoietic cell transplantation (allo-HCT) for treating hematological disorders is increasing, but the development of graft-versus-host disease (GvHD) remains a major cause of morbidity and mortality. The use of post-transplant cyclophosphamide (CY) has significantly improved outcomes following allo-HCT, but complications of viral reactivation due to delayed immune reconstitution or relapse remain. Other laboratories are evaluating the potential benefit of lowering the dose of CY given post-transplant, whereas our laboratory has been focusing on whether partially replacing CY with another DNA alkylating agent, bendamustine (BEN) may be advantageous in improving outcomes with allo-HCT. METHODS: Here, we utilized a xenogeneic GvHD (xGvHD) model in which immunodeficient NSG mice are infused with human peripheral blood mononuclear cells (PBMCs). RESULTS: We show that a lower dose of CY (25 mg/kg) given on days +3 and +4 or CY (75 mg/kg) given on only day +3 post-PBMC infusion is not sufficient for improving survival from xGvHD, but can be improved with the addition of BEN (15 mg/kg) on day +4 to day +3 CY (75 mg/kg). CY/BEN treated mice when combined with cyclosporine A (CSA) (10mg/kg daily from days +5 to +18 and thrice weekly thereafter), had improved outcomes over CY/CY +CSA treated mice. Infiltration of GvHD target organs was reduced in both CY/CY and CY/BEN treatment groups versus those receiving no treatment. CY/CY +CSA mice exhibited more severe xGvHD at day 10, marked by decreased serum albumin and increased intestinal permeability. CY/BEN treated mice had reductions in naïve, effector memory and Th17 polarized T cells. RNAseq analysis of splenocytes isolated from CY/CY and CY/BEN treated animals revealed increased gene set enrichment in multiple KEGG pathways related to cell migration, proliferation/differentiation, and inflammatory pathways, among others with CY/BEN treatment. CONCLUSION: Together, we illustrate that the use of CY/BEN is safe and shows similar control of xGvHD to CY/CY, but when combined with CSA, survival with CY/BEN is significantly prolonged compared to CY/CY.

29. Corrigendum: Effects of extracellular adhesion molecules on immune cell mediated solid tumor cell killing.

Front Immunol

2023 Jan 9

Kim SE, Yun S, Doh J.

30. Genomic and transcriptomic analysis of MSI-H colorectal cancer patients with targetable alterations identifies clinical implications for immunotherapy.

Front Immunol

2023 Jan 9

Hua H, He W, Chen N

INTRODUCTION: Targetable alterations such as BRAFV600E mutation and NTRK fusion are enriched in microsatellite instability-high (MSI-H) colorectal cancer (CRC). MSI-H with targetable alterations (MSI-H altered) might present unique opportunities for both targeted therapy and immunotherapy. We systematically evaluated the molecular characteristics and immune-related features of MSI-H altered and MSI-H without targetable alterations (MSI-H wt) CRC patients in our study. METHODS: Among 1938 continuously enrolled CRC patients, 126 patients with MSI-H status (6.50%) were included in this retrospective study. Genomic and transcriptomic data were investigated by next-generation sequencing (NGS) and gene expression profiling (GEP), respectively. RESULTS: BRAFV600E, NTRK1, and FGFR2 mutations were the most frequent targetable alterations in MSI-H CRC patients. The MSI-H altered phenotype was significantly associated with older age (p< 0.001), right side (p=0.024) and females (p= 0.036). No lynch syndrome (LS) patients were identified in MSI-H altered group. The tumor mutational burden (TMB), and tumor neoantigen burden (TNB) of MSI-H altered and wt subgroups were comparable (p<0.05). Subsequently, transcriptomic study analysis further revealed MSI-H altered CRC patients were linked to an immune-active tumor microenvironment with higher levels of Teff IFN-gamma, CYT, and MERCK 18 signatures, and lower levels of the IPRES gene signature, EMT and TGF Beta signatures. In addition, case study supported MSI-H CRC patient harboring targetable alterations might also achieved a long-term disease-free survival benefit from immunotherapy. DISCUSSION: Our study preliminary revealed MSI-H altered as a novel subtype of MSI-H CRC patients with unique molecular signatures and immune-active tumor microenvironment. Given the accessibility of immune checkpoint inhibitors (ICIs) treatment, our results might provide clinical evidence for immunotherapy in MSI-H CRC patients with targetable alterations.

31. The frequency of differentiated CD3(+)CD27(-)CD28(-) T cells predicts response to CART cell therapy in diffuse large B-cell lymphoma.

Front Immunol

2023 Jan 9

Worel N, Grabmeier-Pfistershammer K, Kratzer B

BACKGROUND: Chimeric antigen receptor T (CART) cell therapy targeting the B cell specific differentiation antigen CD19 has shown clinical efficacy in a subset of relapsed/refractory (r/r) diffuse large B cell lymphoma (DLBCL) patients. Despite this heterogeneous response, blood pre-infusion biomarkers predicting responsiveness to CART cell therapy are currently understudied. METHODS: Blood cell and serum markers, along with clinical data of DLBCL patients who were scheduled for CART cell therapy were evaluated to search for biomarkers predicting CART cell responsiveness. FINDINGS: Compared to healthy controls (n=24), DLBCL patients (n=33) showed significant lymphopenia, due to low CD3+CD4+ T helper and CD3-CD56+ NK cell counts, while cytotoxic CD3+CD8+ T cell counts were similar. Although lymphopenic, DLBCL patients had significantly more activated HLA-DR+ (P=0.005) blood T cells and a higher frequency of differentiated CD3+CD27-CD28- (28.7 ± 19.0% versus 6.6 ± 5.8%; P<0.001) T cells. Twenty-six patients were infused with CART cells (median 81 days after leukapheresis) and were analyzed for the overall response (OR) 3 months later. Univariate and multivariate regression analyses showed that low levels of differentiated CD3+CD27-CD28- T cells (23.3 ± 19.3% versus 35.1 ± 18.0%) were independently associated with OR. This association was even more pronounced when patients were stratified for complete remission (CR versus non-CR: 13.7 ± 11.7% versus 37.7 ± 17.4%, P=0.001). A cut-off value of ≤ 18% of CD3+CD27-CD28- T cells predicted CR at 12 months with high accuracy (P<0.001). In vitro, CD3+CD8+CD27-CD28- compared to CD3+CD8+CD27+CD28+ CART cells displayed similar CD19+ target cell-specific cytotoxicity, but were hypoproliferative and produced less cytotoxic cytokines (IFN-γ and TNF-α). CD3+CD8+ T cells outperformed CD3+CD4+ T cells 3- to 6-fold in terms of their ability to kill CD19+ target cells. INTERPRETATION: Low frequency of differentiated CD3+CD27-CD28- T cells at leukapheresis represents a novel pre-infusion blood biomarker predicting a favorable response to CART cell treatment in r/r DLBCL patients.

32. Secretomes derived from osteogenically differentiated jaw periosteal cells inhibit phenotypic and functional maturation of CD14(+) monocyte-derived dendritic cells.

Front Immunol

2023 Jan 9

Cen W, Umrath F, Salgado AJ

The jaw periosteal tissue is generally recognized as a suitable source for the isolation of mesenchymal stem cells (MSCs). In previous studies we showed evidence that two- and three-dimensionally cultured jaw periosteum-derived MSCs (JPCs) are able to induce a more immature phenotype of dendritic cells (DCs). To further expand our knowledge of JPCs' immunoregulative function, we investigated the effects of JPC secretomes derived from undifferentiated (CO) or osteogenically differentiated cells (treated with or without dexamethasone: OB+/-D) on CD14+ monocyte-derived DCs (MoDCs). We detected a remarkably reduced formation of MoDC homotypic clusters under the influence of secretomes from osteogenically induced JPCs. Further, significantly decreased numbers of CD83+ cells, up-regulated CD209 and down-regulated CD80, CD86 and CD197 expression levels were detected on the surface of MoDCs. Whereas secretomes from JPCs osteogenically stimulated with dexamethasone significantly enhanced FITC-dextran uptake capacity of MoDCs, the increase by secretomes of JPCs treated without dexamethasone did not reach significance. The analysis of mixed lymphocyte reactions revealed that OB+/-D secretomes were able to significantly reduce the numbers of proliferating CD14- peripheral blood mononuclear cells (PBMCs) and of proliferating CD4+ T cells. The OB-D secretome significantly promoted the expansion of regulatory CD25+ T cells. Regarding gene expression of MoDCs, remarkably up-regulated mRNA expression of CD209, HLA-DRA, CSF3, IL10 and IL8 was detected when DCs were cultured in the presence of OB+/-D secretomes. At the same time, secretomes seemed to have an impact in the down-regulation of IFNγ and IL12B gene expression. At protein level, OB+/-D secretomes significantly up-regulated IL-10 and IDO (indoleamine-pyrrole 2,3-dioxygenase) levels whereas IL-12/IL-23p40 levels were down-regulated in supernatants of MoDCs when cultured under the presence of OB+/-D secretomes. Taken together, while secretomes from untreated JPCs had only little effects on the process of maturation of MoDCs, secretomes derived from osteogenically induced JPCs were able to inhibit the phenotypic and functional maturation of MoDCs.

33. A retrospective clinical study of dolutegravir- versus efavirenz-based regimen in treatment-naïve patients with advanced HIV infection in Nanjing, China.

Front Immunol

2023 Jan 9

Zhong M, Li M, Qi M

Currently, there are limited data related to the efficacy and safety of ART regimens, as well as factors influencing immune recovery in antiretroviral therapy (ART)-naïve patients with advanced HIV infection, especially in China. We designed a single-center, retrospective cohort study from March 1, 2019, to May 31, 2022, at The Second Hospital of Nanjing, China. ART-naïve adults with advanced HIV infection (CD4+ T-cell count < 200 cells/μL) who met the study criteria were included. The plasma viral load (VL), CD4+ T-cell count, CD4/CD8 ratio, treatment discontinuation, and immune reconstitution inflammatory syndrome (IRIS) events were collected to compare the efficacy and safety of the dolutegravir (DTG) and the efavirenz (EFV) regimens. Factors of immune recovery were analyzed using the Cox regression model. Study enrolled 285 ART-naïve adults with advanced HIV-1 infection, of which 95 (33.3%) started regimens including DTG and 190 (66.7%) were treated with EFV. After ART initiation, the proportion of patients with HIV-1 RNA < 50 copies/mL was higher (22.5% versus 6.5%, P < 0.001) in those on DTG-based regimens at month 1, but no significant difference at other follow-up points. Compared to the baseline, the median CD4+ T-cell count and CD4/CD8 ratio increased significantly during follow-up both in the EFV and the DTG groups. However, the CD4+ T-cell count increased greater in patients on DTG-based regimens at months 6, 12, 24, and 36 (P < 0.05). A total of 52 (18.2%) patients discontinued treatment, with no significant difference between ART regimens in treatment discontinuation rates. Only 7 patients reported IRIS, without significant difference between ART regimens (P=0.224). Overall, 34.0% (97/285) achieved a CD4+ T-cell count ≥ 350 cells/μL during follow-up. Age (P < 0.001), baseline CD4+ T-cell count (P < 0.001), baseline VL (P < 0.001) and ART regimens (P = 0.019) were associated with the CD4+ T-cell count ≥ 350 cells/μL after adjusting for potential confounders. Among ART-naïve adults with advanced HIV infection, it appeared that DTG-based regimens were better options for initial therapy compared to regimens including EFV; in addition, ART regimens, age, baseline VL and CD4+ T-cell count were associated with immune recovery.

34. Identification of a CD4+ conventional T cells-related lncRNAs signature associated with hepatocellular carcinoma prognosis, therapy, and tumor microenvironment.

Front Immunol

2023 Jan 9

Zhu L, Zhang XP, Xu S

35. Cannabinoid receptor 2 plays a pro-tumorigenic role in non-small cell lung cancer by limiting anti-tumor activity of CD8(+) T and NK cells.

Front Immunol

2023 Jan 9

Sarsembayeva A, Kienzl M, Gruden E

36. The role of FOXO4/NFAT2 signaling pathway in dysfunction of human coronary endothelial cells and inflammatory infiltration of vasculitis in Kawasaki disease.

Front Immunol

2023 Jan 9

Huang H, Dong J, Jiang J

37. Distributions of the HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 alleles and haplotype frequencies of 1763 stem cell donors in the Colombian Bone Marrow Registry typed by next-generation sequencing.

Front Immunol

2023 Jan 9

Hernández-Mejía DG, Páez-Gutiérrez IA, Dorsant Ardón V

38. No difference in anti-spike antibody and surrogate viral neutralization following SARS-CoV-2 booster vaccination in persons with HIV compared to controls (CO-HIV Study).

Front Immunol

2023 Jan 9

Kling KD, Janulis P, Demonbreun AR

39. An advanced in vitro human mucosal immune model to predict food sensitizing allergenicity risk: A proof of concept using ovalbumin as model allergen.

Front Immunol

2023 Jan 9

Zuurveld M, Díaz CB, Redegeld F

40. Effect of early postnatal supplementation of newborns with probiotic strain E. coli O83:K24:H31 on allergy incidence, dendritic cells, and microbiota.

Front Immunol

2023 Jan 9

Súkeníková L, Černý V, Thon T

INTRODUCTION: Probiotic administration seems to be a rational approach to promote maturation of the neonatal immune system. Mutual interaction of the microbiota with the host immune system is critical for the setting of appropriate immune responses including a tolerogenic one and thevmaintenance of homeostasis. On the other hand, our knowledge on the modes of actions of probiotics is still scarce. METHODS: In our study, probiotic strain Escherichia coli O83:K24:H31 (EcO83) was administered to neonates of allergic mothers (AMs; neonates with increased risk for allergy development) within 48 h after the delivery, and the impact of this early postnatal supplementation on allergy incidence and selected immune markers has been analyzed 10 years after the primary EcO83 administration. RESULTS: We have observed decreased allergy incidence in 10-year-old children supplemented with EcO83 (13 of 52 children were allergic) in comparison with non-supplemented children of AMs (16 of 42 children were allergic). The early postnatal EcO83 supplementation appeared to limit the allergy in the high-risk group (children of AMs) compared to that in the low-risk group (children of healthy mothers). Dendritic cells (DCs) in the peripheral blood of EcO83-supplemented children do not differ significantly in cell surface presence of CD83. The immunomodulatory capacity of EcO83 on DCs was tested in vitro as well. Both directly isolated myeloid and in vitro monocyte-derived DCs from cord blood increased CD83 expression together with interleukin (IL)-10 secretion after EcO83 stimulation. The effect of early postnatal EcO83 supplementation on the microbiota composition of 10-year-old children was characterized by next-generation sequencing, and we have not observed significant changes in the microbiota composition of EcO83-supplemented and non-supplemented children at the age of 10 years. CONCLUSIONS: Early postnatal EcO83 supplementation appears to lower allergy incidence in children of AMs. It seems that the beneficial effect of EcO83 is mediated via modulation of DC functional capacities without impacting the microbiota composition. Larger-scale studies will be necessary to confirm these preliminary findings.

41. IP-score correlated to endogenous tumour antigen peptide processing: A candidate clinical response score algorithm of immune checkpoint inhibitors therapy in multiple cohorts.

Front Immunol

2023 Jan 9

Wang Y, Yan K, Guo Y

The processing of endogenous tumour antigen peptides was essential for anti-tumour immunity in the tumour microenvironment. A high degree of Endogenous tumour antigen peptide processing has been demonstrated to improve the prognosis of carcinoma patients. However, there is insufficient evidence to prove its effect on the clinical response to immune checkpoint inhibitor therapy. To undertake a more in-depth analysis of the effects of the aforementioned genes on immunotherapy, we constructed a gene set evaluation score system relevant to tumour endogenous antigen peptide therapy using the GSVA approach. This rating mechanism is known as IP score (IPs). Immediately afterwards, we used the TCGA pan-cancer cohorts to conduct a comprehensive analysis of 6 genes in the IPs, and the analysis results showed that these six genes were related to the proportion of CD8+ T lymphocytes in a variety of solid tumours. As a prognostic protective factor for solid tumours, patients had better prognosis outcomes in the group with high expression levels of the above genes. We analysed the differential expression of six genes between immune checkpoint inhibitor treatment response and disease progression groups using several treatment cohorts. The results revealed that after treatment with PD-1 or CTLA4 inhibitors, the expression levels of the above six genes were comparatively high in the effective group, but the expression of the signature genes was dramatically downregulated in the ICI-insensitive groups. This indicates that the 6 genes are related to the clinical response to ICI treatment. Finally, we used the GSVA method to evaluate the above signatures, and the results showed that PDCD1, CTAL4, CD274 and LAG3 were significantly higher expressed in the IPs high-expression group; therefore, based on the processing of endogenous antigenic peptides in tumours, a predictive score of clinical response to immune checkpoint inhibitor therapy composed of 6 genes(PSMB8/PSMB9/PSMB10/PSME1/PSME2/IRF1) was constructed, and the role of each independent variable in the signature in the solid tumour microenvironment and the impact on ICI treatment were comprehensively analysed. This study provides a candidate evaluation score for predicting clinical response to immune checkpoint inhibitor therapy.

42. Combination of GD2-directed bispecific trifunctional antibody therapy with Pd-1 immune checkpoint blockade induces anti-neuroblastoma immunity in a syngeneic mouse model.

Front Immunol

2023 Jan 9

Ivasko SM, Anders K, Grunewald L

INTRODUCTION: Despite advances in treating high-risk neuroblastoma, 50-60% of patients still suffer relapse, necessitating new treatment options. Bispecific trifunctional antibodies (trAbs) are a promising new class of immunotherapy. TrAbs are heterodimeric IgG-like molecules that bind CD3 and a tumor-associated antigen simultaneously, whereby inducing a TCR-independent anti-cancer T cell response. Moreover, via their functional Fc region they recruit and activate cells of the innate immune system like antigen-presenting cells potentially enhancing induction of adaptive tumor-specific immune responses. METHODS: We used the SUREK trAb, which is bispecific for GD2 and murine Cd3. Tumor-blind trAb and the monoclonal ch14.18 antibody were used as controls. A co-culture model of murine dendritic cells (DCs), T cells and a neuroblastoma cell line was established to evaluate the cytotoxic effect and the T cell effector function in vitro. Expression of immune checkpoint molecules on tumor-infiltrating T cells and the induction of an anti-neuroblastoma immune response using a combination of whole cell vaccination and trAb therapy was investigated in a syngeneic immunocompetent neuroblastoma mouse model (NXS2 in A/J background). Finally, vaccinated mice were assessed for the presence of neuroblastoma-directed antibodies. We show that SUREK trAb-mediated effective killing of NXS2 cells in vitro was strictly dependent on the combined presence of DCs and T cells. RESULTS: Using a syngeneic neuroblastoma mouse model, we showed that vaccination with irradiated tumor cells combined with SUREK trAb treatment significantly prolonged survival of tumor challenged mice and partially prevent tumor outgrowth compared to tumor vaccination alone. Treatment led to upregulation of programmed cell death protein 1 (Pd-1) on tumor infiltrating T cells and combination with anti-Pd-1 checkpoint inhibition enhanced the NXS2-directed humoral immune response. CONCLUSION: Here, we provide first preclinical evidence that a tumor vaccination combined with SUREK trAb therapy induces an endogenous anti-neuroblastoma immune response reducing tumor recurrence. Furthermore, a combination with anti-Pd-1 immune checkpoint blockade might even further improve this promising immunotherapeutic concept in order to prevent relapse in high-risk neuroblastoma patients.

43. Global trends in research of immune cells associated with hypertensive disorders of pregnancy: A 20-year bibliometric analyses (from 2001 to 2021).

Front Immunol

2023 Jan 9

Wang Y, Li B, Tong F.

BACKGROUND: A growing evidence suggests that immune cells play a significant role in the pathogenesis of hypertensive disorders of pregnancy (HDP).Over the past 20 years, several studies have been conducted on the role of immune cells in hypertensive disorders of pregnancy. This study used bibliometric analysis to assess research hotspots and future trends in studies on immune cells in hypertensive disorders of pregnancy. METHODS: We extracted all relevant literature on immune cells and hypertensive disorders of pregnancy from the Web of Science core collection for the period of 2001 to 2021. We used VOS Viewer, CiteSpace, R-bibliometrix and Python for bibliometric analysis. RESULTS: We identified 2,388 records published in 593 journals by 9,886 authors from 2,174 universities/institutions in 91 countries/regions. The number of publications tended to increase over time, with the highest number of publications in 2021, up to 205. The USA was the country with the most publications. UNIVERSITY OF MISSISSIPPI was the most influential institution. Lamarca B, Romero R, and Saito S were the most prolific authors. Finally, three research hotspot clusters were identified based on keywords, which reflected the role of immune cells in the development of hypertensive disorders of pregnancy, the current research status,and predicted hot spots for future research. CONCLUSIONS: Our study systematically analyzed the role of immune cells in the pathogenesis of hypertensive disorders of pregnancy in the last 20 years. Our results indicated that immune cells, such as T cells, natural killer (NK) cells,and macrophages, and the cytokines released such as TNF-α, IFN-γ in the maternal circulation and at the maternal-fetal interface would influence the development of hypertensive disorders of pregnancy and we need further investigate the role of individual immune cells and translational studies to provide new therapeutic perspectives to mitigate adverse perinatal outcomes due to hypertensive disorders of pregnancy. In conclusion, bibliometric studies provide a general overview of immune cells in the study of hypertensive disorders of pregnancy.

44. Metabolic syndrome in antiphospholipid syndrome versus rheumatoid arthritis and diabetes mellitus: Association with arterial thrombosis, cardiovascular risk biomarkers, physical activity, and coronary atherosclerotic plaques.

Front Immunol

2023 Jan 9

Bolla E, Tentolouris N, Sfikakis PP

BACKGROUND: Cardiovascular disease (CVD) is the foremost cause of morbidity and deaths in antiphospholipid syndrome (APS), driven by thrombo-inflammation and atherothrombosis mechanisms. Metabolic syndrome (MetS) is a proinflammatory and prothrombotic state characterized by increased CVD risk. We aimed to evaluate the prevalence of MetS in APS patients compared to rheumatoid arthritis (RA) and diabetes mellitus (DM) and its associations with clinical and laboratory patient characteristics and vascular ultrasound (US) markers of subclinical atherosclerosis. METHODS: We included 414 patients in our study: 138 patients with APS (median age: 44.9 years, females 70%) and matched 1:1 for age and sex RA and DM subjects. Three sets of criteria were used for MetS diagnosis: Joint Interim Statement (JIS), International Diabetes Federation (IDF) and modified National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII). The demographic, clinical and laboratory characteristics of all participants were recorded and carotid and femoral US was performed in patients with APS. Multivariate regression models were applied. RESULTS: Prevalence of MetS was 23.9%, 23.2%, 20.3% (based on JIS, IDF, modified NCEP-ATPIII criteria, respectively) in APS versus 17.4%, 17.4%, 13% in RA (p=0.181, p=0.231, p=0.106, respectively), and 44.2%, 44.2%, 40.6% in DM patients. In multivariate analysis, patients with systemic lupus erythematosus- related APS had an approximately 2.5-fold higher risk of MetS versus RA patients. MetS in APS was independently associated with arterial thrombosis (Odds ratio 3.5, p=0.030). Odds ratio for MetS was 1.16 for each one unit increase in C-reactive protein levels according to JIS and IDF criteria, and 1.49 and 1.47 for each one unit increase in uric acid levels using the IDF and modified NCEP-ATPIII models, respectively. APS patients with atherosclerotic carotid plaques had 4 to 6.5-fold increased risk of MetS. Odds for MetS were decreased by 26% with an increase in physical activity by one hour per week. CONCLUSIONS: MetS is present in approximately one-fourth of APS patients at a comparable prevalence to that observed in patients with RA. MetS in APS is associated with arterial thrombosis, cardiovascular risk biomarkers, physical activity, and subclinical atherosclerosis, supporting its role in cardiovascular risk stratification and management in APS.

45. Systemic immune inflammation index and peripheral blood carbon dioxide concentration at admission predict poor prognosis in patients with severe traumatic brain injury.

Front Immunol

2023 Jan 9

Chen L, Xia S, Zuo Y

BACKGROUND: Recent studies have shown that systemic inflammation responses and hyperventilation are associated with poor outcomes in patients with severe traumatic brain injury (TBI). The aim of this retrospective study was to investigate the relationships between the systemic immune inflammation index (SII = platelet × neutrophil/lymphocyte) and peripheral blood CO2 concentration at admission with the Glasgow Outcome Score (GOS) at 6 months after discharge in patients with severe TBI. METHODS: We retrospectively analyzed the clinical data for 1266 patients with severe TBI at three large medical centers from January 2016 to December 2021, and recorded the GOS 6 months after discharge. The receiver operating characteristic (ROC) curve was used to determine the best cutoff values for SII, CO2, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio (LMR), and chi-square tests were used to evaluate the relationships among SII, CO2 and the basic clinical characteristics of patients with TBI. Multivariate logistic regression analysis was used to determine the independent prognostic factors for GOS in patients with severe TBI. Finally, ROC curve, nomogram, calibration curve and decision curve analyses were used to evaluate the value of SII and coSII-CO2 in predicting the prognosis of patients with severe TBI. And we used the multifactor regression analysis method to build the CRASH model and the IMPACT model. The CRASH model included age, GCS score (GCS, Glasgow Coma Scale) and Pupillary reflex to light: one, both, none. The IMPACT model includes age, motor score and Pupillary reflex to light: one, both, none. RESULTS: The ROC curves indicated that the best cutoff values of SII, CO2, PLR, NLR and LMR were 2651.43×109, 22.15mmol/L, 190.98×109, 9.66×109 and 1.5×109, respectively. The GOS at 6 months after discharge of patients with high SII and low CO2 were significantly poorer than those with low SII and high CO2. Multivariate logistic regression analysis revealed that age, systolic blood pressure (SBP), pupil size, subarachnoid hemorrhage (SAH), SII, PLR, serum potassium concentration [K+], serum calcium concentration [Ca2+], international normalized ratio (INR), C-reactive protein (CRP) and co-systemic immune inflammation index combined with carbon dioxide (coSII-CO2) (P < 0.001) were independent prognostic factors for GOS in patients with severe TBI. In the training group, the C-index was 0.837 with SII and 0.860 with coSII-CO2. In the external validation group, the C-index was 0.907 with SII and 0.916 with coSII-CO2. Decision curve analysis confirmed a superior net clinical benefit with coSII-CO2 rather than SII in most cases. Furthermore, the calibration curve for the probability of GOS 6 months after discharge showed better agreement with the observed results when based on the coSII-CO2 rather than the SII nomogram. According to machine learning, coSII-CO2 ranked first in importance and was followed by pupil size, then SII. CONCLUSIONS: SII and CO2 have better predictive performance than NLR, PLR and LMR. SII and CO2 can be used as new, accurate and objective clinical predictors, and coSII-CO2, based on combining SII with CO2, can be used to improve the accuracy of GOS prediction in patients with TBI 6 months after discharge.

46. The role of pyroptosis in endothelial dysfunction induced by diseases.

Front Immunol

2023 Jan 9

Ju J, Liu Y, Liang H

47. CCL2: An important cytokine in normal and pathological pregnancies: A review.

Front Immunol

2023 Jan 6

Lin Z, Shi JL, Chen M

48. Immune response following traumatic spinal cord injury: Pathophysiology and therapies.

Front Immunol

2023 Jan 6

Sterner RC, Sterner RM.

49. The role of Akkermansia muciniphila in inflammatory bowel disease: Current knowledge and perspectives.

Front Immunol

2023 Jan 6

Zheng M, Han R, Yuan Y

50. Clinical effect and biological mechanism of exercise for rheumatoid arthritis: A mini review.

Front Immunol

2023 Jan 6

Li Z, Wang XQ.

Front Immunol

2023 Jan 6

Li J, Yu YF, Qi XW

52. Duck TRIM29 negatively regulates type I IFN production by targeting MAVS.

Front Immunol

2023 Jan 6

Li W, Song Y, Du Y

53. Increased Myosin light chain 9 expression during Kawasaki disease vasculitis.

Front Immunol

2023 Jan 6

Kobayashi H, Kimura MY, Hasegawa I

54. IgE-dependent human basophil responses are inversely associated with the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA).

Front Immunol

2023 Jan 6

Selnø ATH, Sumbayev VV, Gibbs BF.

55. National experience with adenosine deaminase deficiency related SCID in Polish children.

Front Immunol

2023 Jan 6

Dąbrowska-Leonik N, Piątosa B, Słomińska E

INTRODUCTION: Deficiency of adenosine deaminase (ADA) manifests as severe combined immunodeficiency (SCID), caused by accumulation of toxic purine degradation by-products. Untreated patients develop immune and non-immune symptoms with fatal clinical course. According to ESID and EBMT recommendations enzyme replacement therapy (ERT) should be implemented as soon as possible to stabilize the patient's general condition, normalize transaminases, treat pulmonary proteinosis, bone dysplasia, and protect from neurological damage. Hematopoietic stem cell transplantation (HSCT) from a matched related donor (MRD) is a treatment of choice. In absence of such donor, gene therapy (GT) should be considered. HSCT from a matched unrelated donor (MUD) and haploidentical hematopoietic stem cell transplantation (hHSCT) are associated with worse prognosis. MATERIAL AND METHODS: We retrospectively evaluated the clinical course and results of biochemical, immunological and genetic tests of 7 patients diagnosed in Poland with ADA deficiency since 2010 to 2022. RESULTS: All patients demonstrated lymphopenia affecting of T, B and NK cells. Diagnosis was made on the basis of ADA activity in red blood cells and/or genetic testing. Patients manifested with various non-immunological symptoms including: lung proteinosis, skeletal dysplasia, liver dysfunction, atypical hemolytic-uremic syndrome, and psychomotor development disorders. Five patients underwent successful HSCT: 3 patients from matched unrelated donor, 2 from matched sibling donor, and 1 haploidentical from a parental donor. In 4 patients HSCT was preceded by enzyme therapy (lasting from 2 to 5 months). One patient with multiple organ failure died shortly after admission, before the diagnosis was confirmed. None of the patients had undergone gene therapy. CONCLUSIONS: It is important to diagnose ADA SCID as early as possible, before irreversible multi-organ failure occurs. In Poland HSCT are performed according to international immunological societies recommendations, while ERT and GT are less accessible. Implementation of Newborn Screening (NBS) for SCID in Poland could enable recognition of SCID, including ADA-SCID.

56. Neutrophils drive pulmonary vascular leakage in MHV-1 infection of susceptible A/J mice.

Front Immunol

2023 Jan 6

Gong HH, Worley MJ, Carver KA

57. A new natural killer cell-specific gene signature predicting recurrence in colorectal cancer patients.

Front Immunol

2023 Jan 6

Shembrey C, Foroutan M, Hollande F.

58. Inflammatory markers and pulmonary function in adolescents and young adults 6 months after mild COVID-19.

Front Immunol

2023 Jan 6

Sommen SL, Havdal LB, Selvakumar J

INTRODUCTION: Both public and scientific attention have shifted from the acute COVID-19 illness to the chronic disability experienced by a proportion of COVID-19 convalescents. Post COVID-19 condition, a term used for long-lasting symptoms after COVID-19, can affect individuals across all disease severity and age groups. Data on post-COVID-19 symptomatology, epidemiology and pathophysiology in adolescents and young adults are scarce. To date, little is known on the immunological and pulmonary trends in these patients after COVID-19. This study investigated immunological markers and pulmonary function in non-hospitalized patients in this group at 6 months after initial mild COVID-19 infection. METHODS: Non-hospitalized SARS-CoV-2 positive (n = 405) and SARS-CoV-2 negative (n = 111) adolescents and young adults (aged 12-25 years) were followed prospectively for six months after SARS-CoV-2 PCR testing. At baseline and at six months follow-up, all participants underwent an assessment including clinical examination, questionnaires, spirometry, and blood sampling. Cross-sectional comparisons of blood biomarkers; including white blood cell counts, CRP, GDF-15, a 27-multiplex cytokine assay, complement activation products and SARS-CoV-2 antibodies; and spirometry measures were performed after classification of all participants according to their COVID-19 status and adherence to post-COVID-19 case criteria. Associations between biomarkers and COVID-19 symptoms were explored. RESULTS: No difference in pulmonary function was detected between the groups. COVID-19 convalescents had higher levels of chemokines eotaxin, MCP-1 and IP-10 than non-infected controls. The increase was modest and not associated with long-lasting COVID-19 symptoms. DISCUSSION: Elevated inflammatory mediators were found in adolescents and young adults six months after mild COVID-19, but there was no association with post-COVID-19 condition.

59. Type 2 cytokine genes as allergic asthma risk factors after viral bronchiolitis in early childhood.

Front Immunol

2023 Jan 6

Dong Z, Myklebust Å, Johnsen IB

BACKGROUND: Genome-wide association studies of asthma have identified associations with variants in type-2 related genes. Also, specific interactions between genetic variants and viral bronchiolitis in the development of asthma has been suggested. OBJECTIVE: To conduct a gene-based analysis of genetic variants in type 2 cytokine related genes as risk factors for allergic asthma at school age, and further, to study their interaction with specific viral infections in early childhood. METHODS: A prospectively investigated cohort of children with previous bronchiolitis and controls came for follow-up at school age. The research visit, blinded to viral exposure, included detailed lung function tests, laboratory investigation, and questionnaires. Allergic asthma was defined as typical symptoms plus objective variable airway obstruction, in addition to laboratory verified atopy (elevated eosinophil count or sensitization to an allergen). Targeted and complete sequencing was performed for nine type 2 cytokine candidate genes: IL4, 5, 13, 25, 33 and 37, IL17RB, CRLF2 and TSLP. RESULTS: At follow-up, there were 109 children with genetic data, 91 with a history of bronchiolitis (46% respiratory syncytial virus, 24% human rhinovirus, 15% human metapneumovirus and 14% mixed viral etiology) and 18 without. The median age was 9.4 years (range 6-13) and 41 (38%) had laboratory verified atopy. Twenty-one children (19%) met the definition of allergic asthma. After adjusting for age, sex and five viral categories, IL33 achieved nominal significance (p = 0.017) for a positive association with allergic asthma development. In the gene-virus interaction analysis, the variant set in IL17RB demonstrated a nominally significant positive interaction with human metapneumovirus infection (p=0.05). CONCLUSION: The results highlight the multifactorial nature of allergic asthma risk, with both viral infection and inherited genetic variants contributing to increasing risk. Results for IL33 and IL17RB were nominally significant and are potential candidate targets for designing therapeutics and early screening, but these results must be replicated in an independent study.

60. Single-cell transcriptomics reveals striking heterogeneity and functional organization of dendritic and monocytic cells in the bovine mesenteric lymph node.

Front Immunol

2023 Jan 6

Barut GT, Kreuzer M, Bruggmann R

61. Bispecific killer cell engager with high affinity and specificity toward CD16a on NK cells for cancer immunotherapy.

Front Immunol

2023 Jan 6

Nikkhoi SK, Li G, Eleya S

INTRODUCTION: The Fc region of monoclonal antibodies (mAbs) interacts with the CD16a receptor on natural killer (NK) cells with "low affinity" and "low selectivity". This low affinity/selectivity interaction results in not only suboptimal anticancer activity but also induction of adverse effects. CD16a on NK cells binds to the antibody-coated cells, leading to antibody-dependent cell-mediated cytotoxicity (ADCC). Recent clinical data have shown that the increased binding affinity between mAb Fc region and CD16a receptor is responsible for significantly improved therapeutic outcomes. Therefore, the objective of this study was to develop a bispecific killer cell engager (BiKE) with high affinity and specificity/selectivity toward CD16a receptor for NK cell-based cancer immunotherapy. METHODS: To engineer BiKE, a llama was immunized, then high binding anti-CD16a and anti-HER2 VHH clones were isolated using phage display. ELISA, flow cytometry, and biolayer interferometry (BLI) data showed that the isolated anti-CD16a VHH has high affinity (sub-nanomolar) toward CD16a antigen without cross-reactivity with CD16b-NA1 on neutrophils or CD32b on B cells. Similarly, the data showed that the isolated anti-HER2 VHH has high affinity/specificity toward HER2 antigen. Using a semi-flexible linker, anti-HER2 VHH was recombinantly fused with anti-CD16a VHH to create BiKE:HER2/CD16a. Then, the ability of BiKE:HER2/CD16a to activate NK cells to release cytokines and kill HER2+ cancer cells was measured. As effector cells, both high-affinity haNK92 (CD16+, V176) and low-affinity laNK92 (CD16+, F176) cells were used. RESULTS AND DISCUSSION: The data showed that the engineered BiKE:HER2/CD16a activates haNK92 and laNK92 cells to release cytokines much greater than best-in-class mAbs in the clinic. The cytotoxicity data also showed that the developed BiKE induces higher ADCC to both ovarian and breast cancer cells in comparison to Trazimera™ (trastuzumab). According to the BLI data, BiKE:HER2/CD16 recognizes a different epitope on CD16a antigen than IgG-based mAbs; thus, it provides the opportunity for not only monotherapy but also combination therapy with other antibody drugs such as checkpoint inhibitors and antibody-drug conjugates. Taken together, the data demonstrate the creation of a novel BiKE with high affinity and specificity toward CD16a on NK cells with the potential to elicit a superior therapeutic response in patients with HER2+ cancer than existing anti-HER2 mAbs.

62. Impact of the flame retardant 2,2'4,4'-tetrabromodiphenyl ether (PBDE-47) in THP-1 macrophage-like cell function via small extracellular vesicles.

Front Immunol

2023 Jan 6

Longo V, Aloi N, Lo Presti E

2,2'4,4'-tetrabromodiphenyl ether (PBDE-47) is one of the most widespread environmental brominated flame-retardant congeners which has also been detected in animal and human tissues. Several studies have reported the effects of PBDEs on different health issues, including neurobehavioral and developmental disorders, reproductive health, and alterations of thyroid function. Much less is known about its immunotoxicity. The aim of our study was to investigate the effects that treatment of THP-1 macrophage-like cells with PBDE-47 could have on the content of small extracellular vesicles' (sEVs) microRNA (miRNA) cargo and their downstream effects on bystander macrophages. To achieve this, we purified sEVs from PBDE-47 treated M(LPS) THP-1 macrophage-like cells (sEVsPBDE+LPS) by means of ultra-centrifugation and characterized their miRNA cargo by microarray analysis detecting the modulation of 18 miRNAs. Furthermore, resting THP-1 derived M(0) macrophage-like cells were cultured with sEVsPBDE+LPS, showing that the treatment reshaped the miRNA profiles of 12 intracellular miRNAs. This dataset was studied in silico, identifying the biological pathways affected by these target genes. This analysis identified 12 pathways all involved in the maturation and polarization of macrophages. Therefore, to evaluate whether sEVsPBDE+LPS can have some immunomodulatory activity, naïve M(0) THP-1 macrophage-like cells cultured with purified sEVsPBDE+LPS were studied for IL-6, TNF-α and TGF-β mRNAs expression and immune stained with the HLA-DR, CD80, CCR7, CD38 and CD209 antigens and analyzed by flow cytometry. This analysis showed that the PBDE-47 treatment does not induce the expression of specific M1 and M2 cytokine markers of differentiation and may have impaired the ability to make immunological synapses and present antigens, down-regulating the expression of HLA-DR and CD209 antigens. Overall, our study supports the model that perturbation of miRNA cargo by PBDE-47 treatment contributes to the rewiring of cellular regulatory pathways capable of inducing perturbation of differentiation markers on naïve resting M(0) THP-1 macrophage-like cells.

63. Type 2 and type 17 effector cells are increased in the duodenal mucosa but not peripheral blood of patients with functional dyspepsia.

Front Immunol

2023 Jan 6

Burns GL, Bruce JK, Minahan K

64. Identification of the osteoarthritis signature gene PDK1 by machine learning and its regulatory mechanisms on chondrocyte autophagy and apoptosis.

Front Immunol

2023 Jan 6

Meng J, Du H, Lv H

BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease frequently diagnosed in the elderly and middle-aged population. However, its specific pathogenesis has not been clarified. This study aimed to identify biomarkers for OA diagnosis and elucidate their potential mechanisms for restoring OA-dysregulated autophagy and inhibiting chondrocyte apoptosis in vitro. MATERIAL AND METHODS: Two publicly available transcriptomic mRNA OA-related datasets (GSE10575 and GSE51588) were explored for biomarker identification by least absolute shrinkage and selection operator (LASSO) regression, weighted gene co-expression network analysis (WGCNA), and support vector machine recursive feature elimination (SVM-RFE). We applied the GSE32317 and GSE55457 cohorts to validate the markers' efficacy for diagnosis. The connections of markers to chondrocyte autophagy and apoptosis in OA were also comprehensively explored in vitro using molecular biology approaches, including qRT-PCR and Western blot. RESULTS: We identified 286 differentially expressed genes (DEGs). These DEGs were enriched in the ECM-receptor interaction and PI3K/AKT signaling pathway. After external cohort validation and protein-protein interaction (PPI) network construction, PDK1 was finally identified as a diagnostic marker for OA. The pharmacological properties of BX795-downregulated PDK1 expression inhibited LPS-induced chondrocyte inflammation and apoptosis and rescued OA-dysregulated autophagy. Additionally, the phosphorylation of the mediators associated with the MAPK and PI3K/AKT pathways was significantly downregulated, indicating the regulatory function of PDK1 in apoptosis and autophagy via MAPK and PI3K/AKT-associated signaling pathways in chondrocytes. A significantly positive association between the PDK1 expression and Neutrophils, Eosinophils, Plasma cells, and activated CD4 memory T cells, as well as an evident negative correlation between T cells follicular helper and CD4 naive T cells, were detected in the immune cell infiltration analysis. CONCLUSIONS: PDK1 can be used as a diagnostic marker for OA. Inhibition of its expression can rescue OA-dysregulated autophagy and inhibit apoptosis by reducing the phosphorylation of PI3K/AKT and MAPK signaling pathways.

65. Phenotypic and functional alteration of CD45+ immune cells in the decidua of preeclampsia patients analyzed by mass cytometry (CyTOF).

Front Immunol

2023 Jan 6

Fu M, Zhang X, Liu C

Preeclampsia (PE) is a severe placenta-related pregnancy disease that has been associated with maternal systemic inflammation and immune system disorders. However, the distribution and functional changes in immune cells of the maternal-placental interface have not been well characterized. Herein, cytometry by time-of-flight mass spectrometry (CyTOF) was used to investigate the immune atlas at the decidua, which was obtained from four PE patients and four healthy controls. Six superclusters were identified, namely, T cells, B cells, natural killer (NK) cells, monocytes, granulocytes, and others. B cells were significantly decreased in the PE group, among which the reduction in CD27+CD38+ regulatory B cell (Breg)-like cells may stimulate immune activation in PE. The significantly increased migration of B cells could be linked to the significantly overexpressed chemokine C-X-C receptor 5 (CXCR5) in the PE group, which may result in the production of excessive autoantibodies and the pathogenesis of PE. A subset of T cells, CD11c+CD8+ T cells, was significantly decreased in PE and might lead to sustained immune activation in PE patients. NK cells were ultimately separated into four subsets. The significant reduction in a novel subset of NK cells (CD56-CD49a-CD38+) in PE might have led to the failure to suppress inflammation at the maternal-fetal interface during PE progression. Moreover, the expression levels of functional markers were significantly altered in the PE group, which also inferred that shifts in the decidual immune state contributed to the development of PE and might serve as potential treatment targets. This is a worthy attempt to elaborate the differences in the phenotype and function of CD45+ immune cells in the decidua between PE and healthy pregnancies by CyTOF, which contributes to understand the pathogenesis of PE, and the altered cell subsets and markers may inspire the immune modulatory therapy for PE.

66. CcGSDMEa functions the pore-formation in cytomembrane and the regulation on the secretion of IL-lβ in common carp (Cyprinus carpio haematopterus).

Front Immunol

2023 Jan 6

Zhao Y, Zhang J, Qiao D

67. Comparing the pertussis antibody levels of healthy children immunized with four doses of DTap-IPV/Hib (Pentaxim) combination vaccine and DTaP vaccine in Quzhou, China.

Front Immunol

2023 Jan 6

Yin Z, Zheng C, Fang Q

68. Breakthrough of glycobiology in the 21st century.

Front Immunol

2023 Jan 5

Mahara G, Tian C, Xu X

69. Editorial: T cell exhaustion; mechanisms of induction, modulation, and recovery.

Front Immunol

2023 Jan 5

Abdel-Hakeem MS.

70. Editorial: Regulation of osteoclast differentiation in autoimmune and inflammatory diseases.

Front Immunol

2023 Jan 5

Lee SK, Inforzato A, Sobacchi C.

71. Neuroinflammation and brain-peripheral interaction in ischemic stroke: A narrative review.

Front Immunol

2023 Jan 5

Cheng W, Zhao Q, Li C

72. The emerging role of Th1 cells in atherosclerosis and its implications for therapy.

Front Immunol

2023 Jan 5

Chen J, Xiang X, Nie L

73. A novel mRNA vaccine, SYS6006, against SARS-CoV-2.

Front Immunol

2023 Jan 5

Xu K, Lei W, Kang B

74. Paradoxical phenomena of bullous pemphigoid induced and treated by identical biologics.

Front Immunol

2023 Jan 5

Zhang J, Wang SH, Zuo YG.

75. The roles of long noncoding RNA-mediated macrophage polarization in respiratory diseases.

Front Immunol

2023 Jan 5

Qiao X, Ding Y, Wu D

76. Recombinant GM-CSF for diseases of GM-CSF insufficiency: Correcting dysfunctional mononuclear phagocyte disorders.

Front Immunol

2023 Jan 5

Lazarus HM, Pitts K, Wang T

INTRODUCTION: Endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of myeloid cells, is now known to support maturation and maintain the metabolic capacity of mononuclear phagocytes including monocytes, macrophages, and dendritic cells. These cells sense and attack potential pathogens, present antigens to adaptive immune cells, and recruit other immune cells. Recombinant human (rhu) GM-CSF (e.g., sargramostim [glycosylated, yeast-derived rhu GM-CSF]) has immune modulating properties and can restore the normal function of mononuclear phagocytes rendered dysfunctional by deficient or insufficient endogenous GM-CSF. METHODS: We reviewed the emerging biologic and cellular effects of GM-CSF. Experts in clinical disease areas caused by deficient or insufficient endogenous GM-CSF examined the role of GM-CSF in mononuclear phagocyte disorders including autoimmune pulmonary alveolar proteinosis (aPAP), diverse infections (including COVID-19), wound healing, and anti-cancer immune checkpoint inhibitor therapy. RESULTS: We discuss emerging data for GM-CSF biology including the positive effects on mitochondrial function and cell metabolism, augmentation of phagocytosis and efferocytosis, and immune cell modulation. We further address how giving exogenous rhu GM-CSF may control or treat mononuclear phagocyte dysfunction disorders caused or exacerbated by GM-CSF deficiency or insufficiency. We discuss how rhu GM-CSF may augment the anti-cancer effects of immune checkpoint inhibitor immunotherapy as well as ameliorate immune-related adverse events. DISCUSSION: We identify research gaps, opportunities, and the concept that rhu GM-CSF, by supporting and restoring the metabolic capacity and function of mononuclear phagocytes, can have significant therapeutic effects. rhu GM-CSF (e.g., sargramostim) might ameliorate multiple diseases of GM-CSF deficiency or insufficiency and address a high unmet medical need.

77. The diverse roles of miRNAs in HIV pathogenesis: Current understanding and future perspectives.

Front Immunol

2023 Jan 5

Rashid F, Zaongo SD, Song F

78. Disordered T cell-B cell interactions in autoantibody-positive inflammatory arthritis.

Front Immunol

2023 Jan 5

Julé AM, Lam KP, Taylor M

79. The role of immune cells and associated immunological factors in the immune response to spinal cord injury.

Front Immunol

2023 Jan 5

Tang H, Gu Y, Jiang L

80. The emerging role of TET enzymes in the immune microenvironment at the maternal-fetal interface during decidualization and early pregnancy.

Front Immunol

2023 Jan 5

Jin M, Ji J, Chen X

81. The challenges of Plasmodium vivax human malaria infection models for vaccine development.

Front Immunol

2023 Jan 5

Roobsoong W, Yadava A, Draper SJ

82. A CRISPR/Cas9-mediated screen identifies determinants of early plasma cell differentiation.

Front Immunol

2023 Jan 5

Xiong E, Popp O, Salomon C

INTRODUCTION: The differentiation of B cells into antibody-secreting plasma cells depends on cell division-coupled, epigenetic and other cellular processes that are incompletely understood. METHODS: We have developed a CRISPR/Cas9-based screen that models an early stage of T cell-dependent plasma cell differentiation and measures B cell survival or proliferation versus the formation of CD138+ plasmablasts. Here, we refined and extended this screen to more than 500 candidate genes that are highly expressed in plasma cells. RESULTS: Among known genes whose deletion preferentially or mostly affected plasmablast formation were the transcription factors Prdm1 (BLIMP1), Irf4 and Pou2af1 (OBF-1), and the Ern1 gene encoding IRE1a, while deletion of XBP1, the transcriptional master regulator that specifies the expansion of the secretory program in plasma cells, had no effect. Defective plasmablast formation caused by Ern1 deletion could not be rescued by the active, spliced form of XBP1 whose processing is dependent on and downstream of IRE1a, suggesting that in early plasma cell differentiation IRE1a acts independently of XBP1. Moreover, we newly identified several genes involved in NF-kB signaling (Nfkbia), vesicle trafficking (Arf4, Preb) and epigenetic regulators that form part of the NuRD complex (Hdac1, Mta2, Mbd2) to be required for plasmablast formation. Deletion of ARF4, a small GTPase required for COPI vesicle formation, impaired plasmablast formation and blocked antibody secretion. After Hdac1 deletion plasmablast differentiation was consistently reduced by about 50%, while deletion of the closely related Hdac2 gene had no effect. Hdac1 knock-out led to strongly perturbed protein expression of antagonistic transcription factors that govern plasma cell versus B cell identity (by decreasing IRF4 and BLIMP1 and increasing BACH2 and PAX5). DISCUSSION: Taken together, our results highlight specific and non-redundant roles for Ern1, Arf4 and Hdac1 in the early steps of plasma cell differentiation.

83. The making of multivalent gamma delta TCR anti-CD3 bispecific T cell engagers.

Front Immunol

2023 Jan 5

van Diest E, Nicolasen MJT, Kramer L

INTRODUCTION: We have recently developed a novel T cell engager concept by utilizing γ9δ2TCR as tumor targeting domain, named gamma delta TCR anti-CD3 bispecific molecule (GAB), targeting the phosphoantigen-dependent orchestration of BTN2A1 and BTN3A1 at the surface of cancer cells. GABs are made by the fusion of the ectodomains of a γδTCR to an anti-CD3 single chain variable fragment (scFv) (γδECTO-αCD3), here we explore alternative designs with the aim to enhance GAB effectivity. METHODS: The first alternative design was made by linking the variable domains of the γ and δ chain to an anti-CD3 scFv (γδVAR-αCD3). The second alternative design was multimerizing γδVAR-αCD3 proteins to increase the tumor binding valency. Both designs were expressed and purified and the potency to target tumor cells by T cells of the alternative designs was compared to γδECTO-αCD3, in T cell activation and cytotoxicity assays. RESULTS AND DISCUSSION: The γδVAR-αCD3 proteins were poorly expressed, and while the addition of stabilizing mutations based on finding for αβ single chain formats increased expression, generation of meaningful amounts of γδVAR-αCD3 protein was not possible. As an alternative strategy, we explored the natural properties of the original GAB design (γδECTO-αCD3), and observed the spontaneous formation of γδECTO-αCD3-monomers and -dimers during expression. We successfully enhanced the fraction of γδECTO-αCD3-dimers by shortening the linker length between the heavy and light chain in the anti-CD3 scFv, though this also decreased protein yield by 50%. Finally, we formally demonstrated with purified γδECTO-αCD3-dimers and -monomers, that γδECTO-αCD3-dimers are superior in function when compared to similar concentrations of monomers, and do not induce T cell activation without simultaneous tumor engagement. In conclusion, a γδECTO-αCD3-dimer based GAB design has great potential, though protein production needs to be further optimized before preclinical and clinical testing.

84. CD25 as a unique marker on human basophils in stable-mildly symptomatic allergic asthma.

Front Immunol

2023 Jan 5

Iype J, Rohner L, Bachmann S

85. Lisinopril prevents bullous pemphigoid induced by dipeptidyl peptidase 4 inhibitors via the Mas receptor pathway.

Front Immunol

2023 Jan 5

Nozawa K, Suzuki T, Kayanuma G

86. Ruxolitinib does not completely abrogate the functional capabilities of TLR4/9 ligand-activated NK cells.

Front Immunol

2023 Jan 5

Mestre-Durán C, Martín-Cortázar C, García-Solís B

INTRODUCTION: Natural killer (NK) cells are lymphocytes from the innate immune system part of the first defense barrier against infected and transformed cells, representing 5%-15% of peripheral blood lymphocytes. The cytotoxic capacity of NK cells is controlled by a balance between inhibitory and activating NK receptors expressed on their surface, which recognize and interact with the ligands on stressed cells. The cytokines involved in NK cell activation, proliferation, survival, and cytotoxicity are signaled mainly through the Janus kinase and signal transducer and activator of transcription proteins (JAK/STAT) pathway. NK cells are also activated in response to pathogens through Toll-like receptors (TLRs) expressed on their surface. Ruxolitinib is a specific JAK1/2 inhibitor approved for treating myelofibrosis and for steroid-refractory acute and chronic graft-versus-host disease (SR-GvHD). METHODS: Purified NK cells from healthy donors were stimulated with two TOLL-like receptor ligands, LPS and CpG, in the presence of different concentrations of Ruxolitinib. RESULTS: This study showed the effects of ruxolitinib on TLR4 and TLR9 ligand-activated NK cells from healthy donors. Ruxolitinib did not completely inhibit STAT3 phosphorylation and had a moderate effect on NK cell cytokine activation via the TLR pathway. Only the highest doses of ruxolitinib led to a decrease in the pro-inflammatory cytokines tumor necrosis factor α, interferon-γ, interleukin-6, and interleukin-1β. The cytotoxic capacity of stimulated NK cells versus K562, SEM, and MV-4-11 cell lines was reduced by increasing doses of ruxolitinib, but it was not completely abolished and we observed no major changes in degranulation capacity. Phenotypic changes were observed in activated NK cells in the presence of ruxolitinib. In a small cohort of pediatric patients treated with ruxolitinib for SR-GvHD, we observed no decrease in NK cell counts; however, further prospective studies with larger cohorts are necessary to confirm this finding. DISCUSSION: In summary, our results showed that the functional capabilities and phenotype of NK cells activated through TLR4/9 agonists were not completely abolished by the inhibition of the JAK-STAT pathway by ruxolitinib.

87. Standard immunosuppressive treatment reduces regulatory B cells in children with autoimmune liver disease.

Front Immunol

2023 Jan 5

Yuksel M, Nazmi F, Wardat D

INTRODUCTION: Autoimmune hepatitis (AIH) is a chronic liver disease caused by a perturbed immune system. The scarcity of short- and long-term immune monitoring of AIH hampered us to comprehend the interaction between immunosuppressive medication and immune homeostasis. METHODS AND PATIENTS: We recruited children with AIH at the time of diagnosis and at the 1st, 3rd, 6th, 12th, 18th, and 24th months of immunosuppression (IS). We also enrolled children with AIH being on IS for >2 years. Children with drug-induced liver injury (DILI), and those receiving tacrolimus after liver transplantation (LT), were enrolled as disease/IS control subjects. Healthy children (HC) were also recruited. Peripheral blood mononuclear cells (PBMCs) were isolated from all participants. Healthy liver tissue from adult donors and from livers without inflammation were obtained from children with hepatoblastoma. By using flow cytometry, we performed multi-parametric immune profiling of PBMCs and intrahepatic lymphocytes. Additionally, after IS with prednisolone, tacrolimus, rapamycin, or 6-mercaptopurine, we carried out an in vitro cytokine stimulation assay. Finally, a Lifecodes SSO typing kit was used to type HLA-DRB1 and Luminex was used to analyze the results. RESULTS: Untreated AIH patients had lower total CD8 T-cell frequencies than HC, but these cells were more naïve. While the percentage of naïve regulatory T cells (Tregs) (CD4+FOXP3lowCD45RA+) and regulatory B cells (Bregs, CD20+CD24+CD38+) was similar, AIH patients had fewer activated Tregs (CD4+FOXP3highCD45RA - ) compared to HC. Mucosal-associated-invariant-T-cells (MAIT) were also lower in these patients. Following the initiation of IS, the immune profiles demonstrated fluctuations. Bregs frequency decreased substantially at 1 month and did not recover anymore. Additionally, the frequency of intrahepatic Bregs in treated AIH patients was lower, compared to control livers, DILI, and LT patients. Following in vitro IS drugs incubation, only the frequency of IL-10-producing total B-cells increased with tacrolimus and 6MP. Lastly, 70% of AIH patients possessed HLA-DR11, whereas HLA-DR03/DR07/DR13 was present in only some patients. CONCLUSION: HLA-DR11 was prominent in our AIH cohort. Activated Tregs and MAIT cell frequencies were lower before IS. Importantly, we discovered a previously unrecognized and long-lasting Bregs scarcity in AIH patients after IS. Tacrolimus and 6MP increased IL-10+ B-cells in vitro.

88. IFI27 transcription is an early predictor for COVID-19 outcomes, a multi-cohort observational study.

Front Immunol

2023 Jan 5

Shojaei M, Shamshirian A, Monkman J

89. CHI3L1 in the CSF is a potential biomarker for anti-leucine-rich glioma inactivated 1 encephalitis.

Front Immunol

2023 Jan 5

Li J, Li H, Wang Y

OBJECTIVE: Anti-leucine-rich glioma inactivated 1(LGI1) encephalitis is one rare autoimmune encephalitis which is accompanied by inflammatory responses. (Anti-leucine-rich glioma inactivated 1 (anti-LGI1) encephalitis is an autoimmune disease mediated by inflammatory responses.)This study aimed to investigate the Chitinase 3-like 1(CHI3L1) in anti-LGI1encephalitis patients and evaluate its association with modified Rankin Scale (mRS) score in anti-LGI1 encephalitis at admission and 6 months follow-up.(This study looked into the relationship between Chitinase 3-like 1 (CHI3L1) and the modified Ranking Scale (mRS) score in anti-LGI1 encephalitis patients at admission and 6 months later.). METHODS: Thirty-five patients with anti-LGI1 encephalitis and 22 patients with non-inflammatory neurological disease were enrolled in this study. (We enrolled 35 patients with anti-LGI1 encephalitis and 22 patients with non-inflammatory neurological disease.)Cerebrospinal fluid (CSF) and serum levels of CHI3L1 were measured by enzyme-linked immunosorbent assay. (We quantified CHI3L1 in the serum and cerebrospinal fluid (CSF) by performing an enzyme-linked immunosorbent assay.)Patients were evaluated for mRS score at admission and at 6 months follow-up.(We recorded the mRS score of the patients at admission and 6 months later.). RESULTS: CHI3L1 levels in CSF and serum were highly elevated in patients with anti-LGI1 encephalitis at admission compared those with the controls.(At admission, patients with anti-LGI1 encephalitis had elevated CHI3L1 levels in the CSF and serum.) Additionally, patients presenting with cognitive impairment had significantly higher CSF CHI3L1 levels and mRS scores than those without cognitive impairment symptoms. Patients presenting with only faciobrachial dystonic seizures at admission had lower CSF CHI3L1 levels than those with other symptoms. Finally, CSF CHI3L1 levels were positively correlated with CSF lactate levels. CONCLUSION: CHI3L1 level in CSF is correlated with the severity and prognosis of anti-LGI1 encephalitis. (CSF CHI3L1 levels are correlated with the severity and prognosis of anti-LGI1 encephalitis.).

90. Immunodominant antibody responses directed to SARS-CoV-2 hotspot mutation sites and risk of immune escape.

Front Immunol

2023 Jan 5

Oliveira JR, Ruiz CMR, Machado RRG

91. Transcriptome and single-cell analysis reveal the contribution of immunosuppressive microenvironment for promoting glioblastoma progression.

Front Immunol

2023 Jan 5

Ni L, Sun P, Zhang S

92. Investigating regulatory patterns of NLRP3 Inflammasome features and association with immune microenvironment in Crohn's disease.

Front Immunol

2023 Jan 5

Wu H, Zeng R, Qiu X

93. Corrigendum: Intraocular human cytomegaloviruses of ocular diseases are distinct from those of viremia and are capable of escaping from innate and adaptive immunity by exploiting HLA-E-mediated peripheral and central tolerance.

Front Immunol

2023 Jan 5

Shirane M, Yawata N, Motooka D

94. Corrigendum: Immunogenicity and protective efficacy of the recombinant Pasteurella multocida lipoproteins VacJ and PlpE, and outer membrane protein H from P. multocida A:1 in ducks.

Front Immunol

2023 Jan 5

Li Y, Xiao J, Chang YF

95. Routine laboratory parameters predict intensive care unit admission and hospitalization in patients suffering stab injuries.

Front Immunol

2023 Jan 5

Maleitzke T, Zhou S, Zocholl D

BACKGROUND: Knife crime has increased considerably in recent years in Northern Europe. Affected patients often require immediate surgical care due to traumatic organ injury. Yet, little is known about clinically relevant routine laboratory parameters in stab injury patients and how these are associated with intensive care unit (ICU) admission, hospitalization and number of surgeries. METHODS: We retrospectively analyzed 258 stab injury cases between July 2015 and December 2021 at an urban Level I Trauma Center. Annual and seasonal incidences, injury site, injury mechanism, Injury Severity Score (ISS), and surgical management were evaluated. First, correlations between routine laboratory parameters for hematology, coagulation, and serum biochemistry (peak, and Δ (change from admission to peak within 3 days following admission)) and length of hospital stay, ICU stay, and number of surgeries were assessed using Spearman's rank correlation coefficients. Second, multivariable Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were conducted to identify parameters predictive of clinical outcomes. Third, longitudinal developments of routine laboratory parameters were assessed during hospital admission. RESULTS: In 2021, significantly more stab injuries were recorded compared with previous years and occurred less during winter compared with other seasons. Mean ISS was 8.3 ± 7.3, and ISS was positively correlated with length of hospital and ICU stay (r = 0.5-0.8, p < 0.001). Aspartate transaminase (AST) (Δ) (r = 0.690), peak C-reactive protein (CrP) (r = 0.573), and erythrocyte count (Δ) (r = 0.526) showed the strongest positive correlations for length of ICU stay for penetrating, thoracoabdominal, and organ injuries, respectively. No correlations were observed between routine laboratory parameters and number of surgeries. For patients with penetrating injuries, LASSO-selected predictors of ICU admission included ISS, pH and lactate at admission, and Δ values for activated partial thromboplastin time (aPTT), K+, and erythrocyte count. CrP levels on day 3 were significantly higher in patients with penetrating (p = 0.005), thoracoabdominal (p = 0.041), and organ injuries (p < 0.001) compared with those without. CONCLUSION: Our data demonstrate an increase in stab injury cases in 2021 and an important link between changes in routine laboratory parameters and ICU admission and hospitalization. Monitoring ISS and changes in AST, CrP, erythrocyte count, pH, lactate, aPTT, and K+ may be useful to identify patients at risk and adjust surgical and ICU algorithms early on.

96. BNT162b2 COVID-19 vaccination elicited protective robust immune responses in pediatric patients with inborn errors of metabolism.

Front Immunol

2023 Jan 5

Zubarioglu T, Dinc HO, Hopurcuoglu D

97. Virome and metagenomic analysis reveal the distinct distribution of microbiota in human fetal gut during gestation.

Front Immunol

2023 Jan 5

Liu X, He G, Lan Y

98. A novel model of urosepsis in rats developed by injection of Escherichia coli into the renal pelvis.

Front Immunol

2023 Jan 5

Cao Y, Bai C, Si P

99. Serum IL-5 levels predict HBsAg seroclearance in patients treated with Nucleos(t)ide analogues combined with pegylated interferon.

Front Immunol

2023 Jan 5

Wang P, Mo Z, Zhang Y

100. A high interferon gamma signature of CD8(+) T cells predicts response to neoadjuvant immunotherapy plus chemotherapy in gastric cancer.

Front Immunol

2023 Jan 5

Li S, Li K, Tian F

101. Comprehensive bulk and single-cell transcriptome profiling give useful insights into the characteristics of osteoarthritis associated synovial macrophages.

Front Immunol

2023 Jan 5

Liao S, Yang M, Li D

BACKGROUND: Osteoarthritis (OA) is a common chronic joint disease, but the association between molecular and cellular events and the pathogenic process of OA remains unclear. OBJECTIVE: The study aimed to identify key molecular and cellular events in the processes of immune infiltration of the synovium in OA and to provide potential diagnostic and therapeutic targets. METHODS: To identify the common differential expression genes and function analysis in OA, we compared the expression between normal and OA samples and analyzed the protein-protein interaction (PPI). Additionally, immune infiltration analysis was used to explore the differences in common immune cell types, and Gene Set Variation Analysis (GSVA) analysis was applied to analyze the status of pathways between OA and normal groups. Furthermore, the optimal diagnostic biomarkers for OA were identified by least absolute shrinkage and selection operator (LASSO) models. Finally, the key role of biomarkers in OA synovitis microenvironment was discussed through single cell and Scissor analysis. RESULTS: A total of 172 DEGs (differentially expressed genes) associated with osteoarticular synovitis were identified, and these genes mainly enriched eight functional categories. In addition, immune infiltration analysis found that four immune cell types, including Macrophage, B cell memory, B cell, and Mast cell were significantly correlated with OA, and LASSO analysis showed that Macrophage were the best diagnostic biomarkers of immune infiltration in OA. Furthermore, using scRNA-seq dataset, we also analyzed the cell communication patterns of Macrophage in the OA synovial inflammatory microenvironment and found that CCL, MIF, and TNF signaling pathways were the mainly cellular communication pathways. Finally, Scissor analysis identified a population of M2-like Macrophages with high expression of CD163 and LYVE1, which has strong anti-inflammatory ability and showed that the TNF gene may play an important role in the synovial microenvironment of OA. CONCLUSION: Overall, Macrophage is the best diagnostic marker of immune infiltration in osteoarticular synovitis, and it can communicate with other cells mainly through CCL, TNF, and MIF signaling pathways in microenvironment. In addition, TNF gene may play an important role in the development of synovitis.

102. The diagnostic and prognostic value of IgG and IgA anti-citrullinated protein antibodies in patients with early rheumatoid arthritis.

Front Immunol

2023 Jan 5

Sieghart D, Konrad C, Swiniarski S

103. Safety and efficacy of plasma exchange treatment in children with AQP4-IgG positive neuromyelitis optica spectrum disorder.

Front Immunol

2023 Jan 5

Li Z, Wan L, Liu X

104. Tumor-infiltrating lymphocyte enrichment predicted by CT radiomics analysis is associated with clinical outcomes of non-small cell lung cancer patients receiving immune checkpoint inhibitors.

Front Immunol

2023 Jan 5

Park C, Jeong DY, Choi Y

BACKGROUND: Enrichment of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment (TME) is a reliable biomarker of immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). Phenotyping through computed tomography (CT) radiomics has the overcome the limitations of tissue-based assessment, including for TIL analysis. Here, we assess TIL enrichment objectively using an artificial intelligence-powered TIL analysis in hematoxylin and eosin (H&E) image and analyze its association with quantitative radiomic features (RFs). Clinical significance of the selected RFs is then validated in the independent NSCLC patients who received ICI. METHODS: In the training cohort containing both tumor tissue samples and corresponding CT images obtained within 1 month, we extracted 86 RFs from the CT images. The TIL enrichment score (TILes) was defined as the fraction of tissue area with high intra-tumoral or stromal TIL density divided by the whole TME area, as measured on an H&E slide. From the corresponding CT images, the least absolute shrinkage and selection operator model was then developed using features that were significantly associated with TIL enrichment. The CT model was applied to CT images from the validation cohort, which included NSCLC patients who received ICI monotherapy. RESULTS: A total of 220 NSCLC samples were included in the training cohort. After filtering the RFs, two features, gray level variance (coefficient 1.71 x 10-3) and large area low gray level emphasis (coefficient -2.48 x 10-5), were included in the model. The two features were both computed from the size-zone matrix, which has strength in reflecting intralesional texture heterogeneity. In the validation cohort, the patients with high predicted TILes (≥ median) had significantly prolonged progression-free survival compared to those with low predicted TILes (median 4.0 months [95% CI 2.2-5.7] versus 2.1 months [95% CI 1.6-3.1], p = 0.002). Patients who experienced a response to ICI or stable disease with ICI had higher predicted TILes compared with the patients who experienced progressive disease as the best response (p = 0.001, p = 0.036, respectively). Predicted TILes was significantly associated with progression-free survival independent of PD-L1 status. CONCLUSIONS: In this CT radiomics model, predicted TILes was significantly associated with ICI outcomes in NSCLC patients. Analyzing TME through radiomics may overcome the limitations of tissue-based analysis and assist clinical decisions regarding ICI.

105. SARS-CoV-2 antibody response after mRNA vaccination in healthcare workers with and without previous COVID-19, a follow-up study from a university hospital in Poland during 6 months 2021.

Front Immunol

2023 Jan 5

Owsianka I, Pac A, Jachowicz E

106. Comprehensive comparative analysis of prognostic value of serum systemic inflammation biomarkers for colorectal cancer: Results from a large multicenter collaboration.

Front Immunol

2023 Jan 5

Xie H, Ruan G, Wei L

107. Cardiac involvement in a patient with B-cell lymphoblastic lymphoma/acute lymphoblastic leukemia and a history of allogeneic hematopoietic stem cell transplantation and CAR T-cell therapy: A case report.

Front Immunol

2023 Jan 5

Cao Y, Liu Y, Zhang R

108. Editorial: Immune interactions with pathogenic and commensal fungi.

Front Immunol

2023 Jan 4

Fang W, Coelho C, Cao C

109. Corrigendum: Mind the "vaccine fatigue".

Front Immunol

2023 Jan 4

Su Z, Cheshmehzangi A, McDonnell D

110. Editorial: Modulation of the immune system by bacteria: From evasion to therapy.

Front Immunol

2023 Jan 4

de Bernard M, Kaparakis-Liaskos M, D'Elios MM.

111. Apoptosis in megakaryocytes: Safeguard and threat for thrombopoiesis.

Front Immunol

2023 Jan 4

Yang S, Wang L, Wu Y

112. Modulating the tumor immune microenvironment with locoregional image-guided interventions.

Front Immunol

2023 Jan 4

Jain S, Sheth RA.

113. Advances in artificial intelligence to predict cancer immunotherapy efficacy.

Front Immunol

2023 Jan 4

Xie J, Luo X, Deng X

114. Host-parasite interactions during Plasmodium infection: Implications for immunotherapies.

Front Immunol

2023 Jan 4

Chandley P, Ranjan R, Kumar S

115. Immunomodulatory role of mesenchymal stem cell therapy in liver fibrosis.

Front Immunol

2023 Jan 4

Liu P, Qian Y, Liu X

116. Corrigendum: Role of endothelial cells in graft-versus-host disease.

Front Immunol

2023 Jan 4

Neidemire-Colley L, Robert J, Ackaoui A

117. Remodeling the tumor immune microenvironment with oncolytic viruses expressing miRNAs.

Front Immunol

2023 Jan 4

St-Cyr G, Penarroya D, Daniel L

118. Epigenetic modification-related mechanisms of hepatocellular carcinoma resistance to immune checkpoint inhibition.

Front Immunol

2023 Jan 4

Tao S, Liang S, Zeng T

119. Postpartum hepatitis and host immunity in pregnant women with chronic HBV infection.

Front Immunol

2023 Jan 4

Zhang L, Jiang T, Yang Y

In order to develop immune tolerant to the fetal, maternal immune system will have some modification comparing to the time before pregnancy. Immune tolerance starts and develops at the maternal placental interface. In innate immunity, decidual natural killer (dNK) cells, macrophages and dendritic cells play a key role in immue tolerance. In adaptive immunity, a moderate increase of number and immune inhibition function of regulatory T cells (Treg) are essential for immune tolerance. The trophoblast cells and immune cells expressing indoleamine 2,3-dioxygenase (IDO), the trophoblast cells expressing HLA-G, and Th1/Th2 shifting to Th2 dominant and Th17/Treg shifting to Treg domiant are in favor of maternal fetal immune tolerance. Steroids (estrogen and progesterone) and human chorionic gonadotropin (HCG) also participate in immune tolerance by inducing Treg cells or upregulating immunosuppressive cytokines. Most of the patients with chronic HBV infection are in the "HBV immune tolerance period" before pregnancy, and the liver disease is relatively stable during pregnancy. In chronic HBV infection women, after delivery, the relative immunosuppression in vivo is reversed, and Th1 is dominant in Th1/Th2 and Th17 is dominant in Th17/Treg balance. After delivery, the number of Treg decrease and NK cells increase in quantity and cytotoxicity in peripheral blood. Liver NK cells may cause liver inflammation through a non-antigen specific mechanism. After delivery, the number of CD8+ T cells will increase and HBV specific T cell response recovers from the disfunction in pregnancy. Under the background of postpartum inflammation, the rapid decrease of cortisol after delivery, and especially the enhancement of HBV specific T cell response induced by HBV DNA and cytokines, are the main reasons for postpartum hepatitis. HBeAg positive, especially HBeAg<700 S/CO, and HBV DNA>3-5Log10IU/ml are risk factors for postpartum hepatitis. Antiviral treatment in late pregnancy can reduce the incidence of mother to child transmission (MTCT) in chronic HBV infection women. Chronic HBV infection women have hepatitis both during pregnancy and more often in 12 weeks postpartum. It is generally agreed that postpartum hepatitis is mild symptoms and self-limited. Delaying drug withdrawal to 48 weeks can increase the seroconversion rate of HBeAg in delivery women with elevated alanine aminotransferase (ALT) in pregnancy.

120. Drastic transformation of visceral adipose tissue and peripheral CD4 T cells in obesity.

Front Immunol

2023 Jan 4

Shirakawa K, Sano M.

Obesity has a pronounced effect on the immune response in systemic organs that results in not only insulin resistance but also altered immune responses to infectious diseases and malignant tumors. Obesity-associated microenvironmental changes alter transcriptional expression and metabolism in T cells, leading to alterations in T-cell differentiation, proliferation, function, and survival. Adipokines, cytokines, and lipids derived from obese visceral adipose tissue (VAT) may also contribute to the systemic T-cell phenotype, resulting in obesity-specific pathogenesis. VAT T cells, which have multiple roles in regulating homeostasis and energy utilization and defending against pathogens, are most susceptible to obesity. In particular, many studies have shown that CD4 T cells are deeply involved in the homeostasis of VAT endocrine and metabolic functions and in obesity-related chronic inflammation. In obesity, macrophages and adipocytes in VAT function as antigen-presenting cells and contribute to the obesity-specific CD4 T-cell response by inducing CD4 T-cell proliferation and differentiation into inflammatory effectors via interactions between major histocompatibility complex class II and T-cell receptors. When obesity persists, prolonged stimulation by leptin and circulating free fatty acids, repetitive antigen stimulation, activating stress responses, and hypoxia induce exhaustion of CD4 T cells in VAT. T-cell exhaustion is characterized by restricted effector function, persistent expression of inhibitory receptors, and a transcriptional state distinct from functional effector and memory T cells. Moreover, obesity causes thymic regression, which may result in homeostatic proliferation of obesity-specific T-cell subsets due to changes in T-cell metabolism and gene expression in VAT. In addition to causing T-cell exhaustion, obesity also accelerates cellular senescence of CD4 T cells. Senescent CD4 T cells secrete osteopontin, which causes further VAT inflammation. The obesity-associated transformation of CD4 T cells remains a negative legacy even after weight loss, causing treatment resistance of obesity-related conditions. This review discusses the marked transformation of CD4 T cells in VAT and systemic organs as a consequence of obesity-related microenvironmental changes.

121. Current knowledge of targeted-release budesonide in immunoglobulin A nephropathy: A comprehensive review.

Front Immunol

2023 Jan 4

Liao J, Zhou Y, Xu X

122. Differential regulation of lineage-determining transcription factor expression in innate lymphoid cell and adaptive T helper cell subsets.

Front Immunol

2023 Jan 4

Fang D, Healy A, Zhu J.

123. Comprehensive autoantibody profiles in systemic sclerosis: Clinical cluster analysis.

Front Immunol

2023 Jan 4

Höppner J, Tabeling C, Casteleyn V

BACKGROUND: Systemic sclerosis (SSc) belongs to the group of connective tissue diseases and is associated with the occurrence of disease-specific autoantibodies. Although it is still controversial whether these antibodies contribute to pathogenesis, there are new insights into the development of these specific antibodies and their possible pathophysiological properties. Interestingly, they are associated with specific clinical manifestations, but for some rarer antibodies this association is not fully clarified. The aim of this study is a comprehensive analysis of the serum autoantibody status in patients with SSc followed by correlation analyses of autoantibodies with the clinical course of the disease. METHODS: Serum from SSc patients was analyzed using a line blot (EUROLINE, EUROIMMUN AG) for SSc-related autoantibodies. Autoantibodies to centromere, Topo-1, antimitochondrial antibodies (AMA) M2 subunit, angiotensin II type 1 receptors (AT1R) and endothelin-1 type-A-receptors (ETAR) were also determined by ELISA. We formed immunological clusters and used principal components analysis (PCA) to assign specific clinical characteristics to these clusters. RESULTS: A total of 372 SSc patients were included. 95.3% of the patients were antinuclear antibody positive and in 333 patients at least one SSc specific antibody could be detected. Four immunological clusters could be found by PCA. Centromere, Topo-1 and RP3 all formed own clusters, which are associated with distinct clinical phenotypes. We found that patients with an inverted phenotype, such as limited cutaneous SSc patients within the Topo-1 cluster show an increased risk for interstital lung disease compared to ACA positive patients. Anti-AT1R and anti-ETAR autoantibodies were measured in 176 SSc patients; no association with SSc disease manifestation was found. SSc patients with AMA-M2 antibodies showed an increased risk of cardiovascular events. CONCLUSION: In our in large cluster analysis, which included an extended autoantibody profile, we were able to show that serologic status of SSc patients provides important clues to disease manifestation, co-morbidities and complications. Line blot was a reliable technique to detect autoantibodies in SSc and detected rarer autoantibodies in 42% of our patients.

124. Increase of ALCAM and VCAM-1 in the plasma predicts the Alzheimer's disease.

Front Immunol

2023 Jan 4

Chen J, Dai AX, Tang HL

125. Immunoinformatics design of B and T-cell epitope-based SARS-CoV-2 peptide vaccination.

Front Immunol

2023 Jan 4

Khan MS, Khan IM, Ahmad SU

126. Functional changes in cytotoxic CD8+ T-cell cross-reactivity against the SARS-CoV-2 Omicron variant after mRNA vaccination.

Front Immunol

2023 Jan 4

Nogimori T, Suzuki K, Masuta Y

127. Single-cell computational machine learning approaches to immune-mediated inflammatory disease: New tools uncover novel fibroblast and macrophage interactions driving pathogenesis.

Front Immunol

2023 Jan 4

Fritz D, Inamo J, Zhang F.

Recent advances in single-cell sequencing technologies call for greater computational scalability and sensitivity to analytically decompose diseased tissues and expose meaningful biological relevance in individual cells with high resolution. And while fibroblasts, one of the most abundant cell types in tissues, were long thought to display relative homogeneity, recent analytical and technical advances in single-cell sequencing have exposed wide variation and sub-phenotypes of fibroblasts of potential and apparent clinical significance to inflammatory diseases. Alongside anticipated improvements in single cell spatial sequencing resolution, new computational biology techniques have formed the technical backbone when exploring fibroblast heterogeneity. More robust models are required, however. This review will summarize the key advancements in computational techniques that are being deployed to categorize fibroblast heterogeneity and their interaction with the myeloid compartments in specific biological and clinical contexts. First, typical machine-learning-aided methods such as dimensionality reduction, clustering, and trajectory inference, have exposed the role of fibroblast subpopulations in inflammatory disease pathologies. Second, these techniques, coupled with single-cell predicted computational methods have raised novel interactomes between fibroblasts and macrophages of potential clinical significance to many immune-mediated inflammatory diseases such as rheumatoid arthritis, ulcerative colitis, lupus, systemic sclerosis, and others. Third, recently developed scalable integrative methods have the potential to map cross-cell-type spatial interactions at the single-cell level while cross-tissue analysis with these models reveals shared biological mechanisms between disease contexts. Finally, these advanced computational omics approaches have the potential to be leveraged toward therapeutic strategies that target fibroblast-macrophage interactions in a wide variety of inflammatory diseases.

128. Narciclasine inhibits phospholipase A2 and regulates phospholipid metabolism to ameliorate psoriasis-like dermatitis.

Front Immunol

2023 Jan 4

Kong Y, Jiang J, Huang Y

INTRODUCTION: Psoriasis is a common inflammatory skin disease recognized by the World Health Organization as "an incurable chronic, noninfectious, painful, disfiguring and disabling disease." The fact that metabolic syndrome (MetS) is the most common and important comorbidities of psoriasis suggests an important role of lipid metabolism in the pathogenesis of psoriasis. Narciclasine (Ncs) is an alkaloid isolated from the Amaryllidaceae plants. Its biological activities include antitumor, antibacterial, antiinflammatory, anti-angiogenic and promoting energy expenditure to improve dietinduced obesity. Here, we report that Ncs may be a potential candidate for psoriasis, acting at both the organismal and cellular levels. METHODS: The therapeutic effect of Ncs was assessed in IMQ-induced psoriasis-like mouse model. Then, through in vitro experiments, we explored the inhibitory effect of Ncs on HaCaT cell proliferation and Th17 cell polarization; Transcriptomics and lipidomics were used to analyze the major targets of Ncs; Single-cell sequencing data was used to identify the target cells of Ncs action. RESULTS: Ncs can inhibit keratinocyte proliferation and reduce the recruitment of immune cells in the skin by inhibiting psoriasis-associated inflammatory mediators. In addition, it showed a direct repression effect on Th17 cell polarization. Transcriptomic and lipidomic data further revealed that Ncs extensively regulated lipid metabolismrelated genes, especially the Phospholipase A2 (PLA2) family, and increased antiinflammatory lipid molecules. Combined with single-cell data analysis, we confirmed that keratinocytes are the main cells in which Ncs functions. DISCUSSION: Taken together, our findings indicate that Ncs alleviates psoriasiform skin inflammation in mice, which is associated with inhibition of PLA2 in keratinocytes and improved phospholipid metabolism. Ncs has the potential for further development as a novel anti-psoriasis drug.

129. Characterization of natural killer and T cells in bronchoalveolar lavage and peripheral blood of sarcoidosis patients.

Front Immunol

2023 Jan 4

Bergantini L, d'Alessandro M, Del Zotto G

130. Genetic analysis of potential biomarkers and therapeutic targets in ferroptosis from psoriasis.

Front Immunol

2023 Jan 4

Wu MN, Zhou DM, Jiang CY

131. Depressive symptoms predict longitudinal changes of chronic inflammation at the transition to adulthood.

Front Immunol

2023 Jan 4

Zhai S, Qu Y, Zhang D

BACKGROUND: Inflammation is closely related to poor mental and physical health, including depressive symptoms and its specific symptoms. To reveal the linear and nonlinear relationships between depressive symptoms and chronic inflammation levels, and perform further analysis of the associations between symptom-specificity of depressive symptoms and inflammation among young adults by using a prospective design. METHODS: In this longitudinal study, we examined college students recruited from two universities in China, who were examined at baseline and 2-years follow-up. Depressive symptoms were measured by applying the Patient Health Questionnaire 9 (PHQ-9) at baseline. Plasma levels of four inflammatory biomarkers, including interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and C reactive protein (CRP) were assayed at baseline and 2-year follow-up. In addition to the conventional generalized linear models, as well as restricted cubic splines were innovatively used to analyze the cross-sectional and longitudinal nonlinear relationships between depressive symptoms and inflammatory biomarkers. RESULTS: Generalized linear model analysis revealed that there were no statistical associations between depressive symptoms and any inflammatory biomarker levels. The results of the restricted cubic spline demonstrated a U-shaped nonlinear association between depressive symptoms and ΔIL-1β or ΔTNF-α (changes in baseline and 2-year follow-up), but these associations disappeared after adjusting the confounders. Symptom-specificity of depressive symptoms such as sleeping problems and suicidal ideation were associated with lower IL-1β at baseline or changes in IL-1β levels. Sleeping problems and psychomotor changes at baseline were associated with higher CRP at 2-year follow-up. Suicidal ideation at baseline was associated with changes in TNF-α levels. CONCLUSION: Our findings suggested that symptom-specificity of depressive symptoms was associated with inflammation during a 2-year follow-up at the transition to adulthood. Simultaneously, more research is warranted to seek the directionality of depressive symptoms and chronic inflammation.

132. Deep dive into the immune response against murine mesothelioma permits design of novel anti-mesothelioma therapeutics.

Front Immunol

2023 Jan 4

Stern E, Caruso S, Meiller C

133. Case report: Amphiphysin-IgG autoimmunity: a paraneoplastic presentation of appendiceal goblet cell carcinoma.

Front Immunol

2023 Jan 4

Lin J, Yu T, Wang M

134. Serplulimab plus chemotherapy as first-line treatment for extensive-stage small-cell lung cancer: A cost-effectiveness analysis.

Front Immunol

2023 Jan 4

Zhu Y, Liu K, Qin Q

135. Single-cell transcriptome analysis reveals heterogeneity and convergence of the tumor microenvironment in colorectal cancer.

Front Immunol

2023 Jan 4

Xie S, Cai Y, Chen D

136. The impact of supervised physical exercise on chemokines and cytokines in recovered COVID-19 patients.

Front Immunol

2023 Jan 4

Filgueira TO, Carvalho PRC, de Sousa Fernandes MS

COVID-19 is an infectious disease caused by the SARS-CoV-2 virus, which induces a high release of pro-inflammatory chemokines and cytokines, leading to severe systemic disorders. Further, evidence has shown that recovered COVID-19 patients still have some symptoms and disorders from COVID-19. Physical exercise can have many health benefits. It is known to be a potent regulator of the immune system, which includes frequency, intensity, duration, and supervised by a professional. Given the confinement and social isolation or hospitalization of COVID-19 patients, the population became sedentary or opted for physical exercise at home, assuming the guarantee of the beneficial effects of physical exercise and reducing exposure to SARS-CoV-2. This study aimed to investigate the effects of a supervised exercise protocol and a home-based unsupervised exercise protocol on chemokine and cytokine serum levels in recovered COVID-19 patients. This study was a prospective, parallel, two-arm clinical trial. Twenty-four patients who had moderate to severe COVID-19 concluded the intervention protocols of this study. Participants were submitted to either supervised exercise protocol at the Clinical Hospital of the Federal University of Pernambuco or home-based unsupervised exercise for 12 weeks. We analyzed serum levels of chemokines (CXCL8/IL-8, CCL5/RANTES, CXCL9/MIG, CCL2/MCP-1, and CXCL10/IP-10) and cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, TNF-α, and IFN-γ). Before the interventions, no significant differences were observed in the serum levels of chemokines and cytokines between the supervised and home-based unsupervised exercise groups. The CXCL8/IL-8 (p = 0.04), CCL2/MCP-1 (p = 0.03), and IFN-γ (p = 0.004) levels decreased after 12 weeks of supervised exercise. In parallel, an increase in IL-2 (p = 0.02), IL-6 (p = 0.03), IL-4 (p = 0.006), and IL-10 (p = 0.04) was observed after the supervised protocol compared to pre-intervention levels. No significant differences in all the chemokines and cytokines were found after 12 weeks of the home-based unsupervised exercise protocol. Given the results, the present study observed that supervised exercise was able to modulate the immune response in individuals with post-COVID-19, suggesting that supervised exercise can mitigate the inflammatory process associated with COVID-19 and its disorders. CLINICAL TRIAL REGISTRATION: https://ensaiosclinicos.gov.br/rg/RBR-7z3kxjk, identifier U1111-1272-4730.

137. The potential role of cfDNA-related innate immune responses in postoperative bone loss after alveolar bone grafting.

Front Immunol

2023 Jan 4

Huang H, Yang R, Shi B.

138. A case report of steroid-refractory bullous pemphigoid induced by immune checkpoint inhibitor therapy.

Front Immunol

2023 Jan 4

Guan S, Zhang L, Zhang J

139. Causal association between celiac disease and inflammatory bowel disease: A two-sample bidirectional Mendelian randomization study.

Front Immunol

2023 Jan 4

Yuan S, Kim JH, Xu P

140. CRISPR-Cas9-AAV versus lentivector transduction for genome modification of X-linked severe combined immunodeficiency hematopoietic stem cells.

Front Immunol

2023 Jan 4

Brault J, Liu T, Liu S

INTRODUCTION: Ex vivo gene therapy for treatment of Inborn errors of Immunity (IEIs) have demonstrated significant clinical benefit in multiple Phase I/II clinical trials. Current approaches rely on engineered retroviral vectors to randomly integrate copy(s) of gene-of-interest in autologous hematopoietic stem/progenitor cells (HSPCs) genome permanently to provide gene function in transduced HSPCs and their progenies. To circumvent concerns related to potential genotoxicities due to the random vector integrations in HSPCs, targeted correction with CRISPR-Cas9-based genome editing offers improved precision for functional correction of multiple IEIs. METHODS: We compare the two approaches for integration of IL2RG transgene for functional correction of HSPCs from patients with X-linked Severe Combined Immunodeficiency (SCID-X1 or XSCID); delivery via current clinical lentivector (LV)-IL2RG versus targeted insertion (TI) of IL2RG via homology-directed repair (HDR) when using an adeno-associated virus (AAV)-IL2RG donor following double-strand DNA break at the endogenous IL2RG locus. RESULTS AND DISCUSSION: In vitro differentiation of LV- or TI-treated XSCID HSPCs similarly overcome differentiation block into Pre-T-I and Pre-T-II lymphocytes but we observed significantly superior development of NK cells when corrected by TI (40.7% versus 4.1%, p = 0.0099). Transplants into immunodeficient mice demonstrated robust engraftment (8.1% and 23.3% in bone marrow) for LV- and TI-IL2RG HSPCs with efficient T cell development following TI-IL2RG in all four patients' HSPCs. Extensive specificity analysis of CRISPR-Cas9 editing with rhAmpSeq covering 82 predicted off-target sites found no evidence of indels in edited cells before (in vitro) or following transplant, in stark contrast to LV's non-targeted vector integration sites. Together, the improved efficiency and safety of IL2RG correction via CRISPR-Cas9-based TI approach provides a strong rationale for a clinical trial for treatment of XSCID patients.

141. Comprehensive analysis of cuproptosis-related lncRNAs for prognostic significance and immune microenvironment characterization in hepatocellular carcinoma.

Front Immunol

2023 Jan 4

Li D, Jin S, Chen P

Cuproptosis was characterized as a novel type of programmed cell death. Recently, however, the role of cuproptosis-related long noncoding RNAs (CRLs) in tumors has not yet been studied. Identifying a predictive CRL signature in hepatocellular carcinoma (HCC) and investigating its putative molecular function were the goals of this work. Initially, Pearson's test was used to assess the relationship between lncRNAs and cuproptosis-associated genes obtained from HCC data of The Cancer Genome Atlas (TCGA). By implementing differential expression and univariate Cox analysis, 61 prognostic CRLs were subsequent to the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. A prognostic risk score model was then constructed to evaluate its ability to predict patients' survival when combined with clinicopathological parameters in HCC. The five-lncRNA prognostic signature categorized the HCC patients into high- and low-risk groups. The low-risk group exhibited more sensitivity to elesclomol than the high-risk one. Surprisingly, distinct mitochondrial metabolism pathways connected to cuproptosis and pivotal immune-related pathways were observed between the two groups via gene set enrichment analysis (GSEA). Meanwhile, there were substantial differences between the high-risk group and the low-risk group in terms of tumor-infiltrating immune cells (TIICs). Furthermore, a positive relationship was shown between the risk score and the expression of immune checkpoints. Additionally, differential expression of the five lncRNAs was confirmed in our own HCC samples and cell lines via RT-qPCR. Finally, in vitro assays confirmed that WARS2-AS1 and MKLN1-AS knockdown could sensitize HCC cells to elesclomol-induced cuproptosis. Overall, our predictive signature may predict the prognosis of HCC patients in an independent manner, give a better understanding of how CRLs work in HCC, and offer therapeutic reference for patients with HCC.

142. Transfer factors peptides (Imuno TF(®)) modulate the lung inflammation and airway remodeling in allergic asthma.

Front Immunol

2023 Jan 4

Oliveira CR, Carvalho J, Olímpio F

BACKGROUND: Allergic asthma is a chronic lung disease in which the lung inflammation and airway remodeling are orchestrated by both the inflammatory and the immune cells that creates a lung millieu that favors the perpetuation of clinical symptoms. The cell signaling in asthma involves the mast cells activation during initial contact with the allergen and, principally, the participation of eosinophils as well as Th2 cells which determine increased levels of IgE, exaggerated secretion of mucus and collagen, and bronchial hyperreactivity. Moreover, allergic asthma presents lower level of cytokines associated to the both Th1 and Treg cells response, and it implies in deficiency of anti-inflammatory response to counterregulate the exaggerated inflammation against allergen. Therefore, the equilibrium between cytokines as well as transcription factors associated to Th2, Th1, and Treg cells is compromised in allergic asthma. Imuno TF® is a food supplement with ability to interfere in immune system pathways. It has been previously demonstrated that Imuno TF® upregulated Th1 cell response whilst downregulated Th2 cell response in human lymphocytes. OBJECTIVE: For this reason, we hypothesized that the Imuno TF effect could be restore the balance between Th1/Th2 CD4 T cells response in murine allergic asthma. METHODS: Initially, animals were sensitized with OVA via i.p. and challenged with OVA i.n. on days 14, 15 and 16. Treatment with Imuno TF once a day was performed via orogastric from day 17 to day 20. Mice were euthanized on day 21. RESULTS: The Imuno TF reduced eosinophilia, mucus production, and airway remodeling (collagen deposition) in asthma mice. Imuno TF influenced cellular signaling associated to allergic asthma once downregulated STAT6 expression as well as decreased IL-4, IL-5, and IL-13 in lung and serum. In addition, Imuno TF restored T-bet and Foxp3 expression as well as increased IL-12, IFN-ɣ, and IL-10. CONCLUSION: Ultimately, Imuno TF mitigated the allergic asthma due to the restoration of balance between the responses of Th1/Th2 as well as Treg cells, and their respective transcription factors the T-bet/STAT6 and Foxp3.

143. m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis.

Front Immunol

2023 Jan 4

Yang Y, Li Q, Ling Y

144. The relevance between hypoxia-dependent spatial transcriptomics and the prognosis and efficacy of immunotherapy in claudin-low breast cancer.

Front Immunol

2023 Jan 4

Sun H, Li Y, Zhang Y

INTRODUCTION: Hypoxia is an important characteristic of solid tumors. However, spatial transcriptomics (ST) of hypoxia-associated heterogeneity is not clear. METHODS: This study integrated Spatial Transcriptomics (ST) with immunofluorescence to demonstrate their spatial distribution in human claudin-low breast cancer MDA-MB-231 engraft. ST spots were clustered with differentially expression genes. The data were combined with hypoxia-specific marker and angiogenesis marker-labeled serial sections to indicate the spatial distribution of hypoxia and hypoxia-inducted transcriptional profile. Moreover, marker genes, cluster-specific hypoxia genes, and their co-essential relationship were identified and mapped in every clusters. The clinicopathological association of marker genes of hypoxia-dependent spatial clusters was explored in 1904 breast cancers from METABRIC database. RESULTS: The tumor from center to periphery were enriched into five hypoxia-dependent subgroups with differentially expressed genes, which were matched to necrosis, necrosis periphery, hypoxic tumor, adaptive survival tumor, and invasive tumor, respectively. Different subgroups demonstrated distinct hypoxia condition and spatial heterogeneity in biological behavior and signaling pathways. Cox regression analysis showed that the invasive tumor (cluster 0) and hypoxic tumor (cluster 6) score could be served as independent prognostic factors in claudin-low patients. KM analysis indicated that high invasive tumor (cluster 0) and hypoxic tumor (cluster 6) score was associated with poor prognoses of claudin-low patients. Further analysis showed that hypoxia-induced immune checkpoints, such as CD276 and NRP1, upregulation in invasive tumor to block infiltration and activation of B cells and CD8+ T cells to change tumor immune microenvironment. DISCUSSION: This study reveals hypoxia-dependent spatial heterogeneity in claudin-low breast cancer and highlights its potential value as a predictive biomarker of clinical outcomes and immunotherapy response. The molecules found in this study also provided potential molecular mechanisms and therapeutic targets for subsequent studies.

145. Conventional dendritic cells type 1 are strongly enriched, quiescent and relatively tolerogenic in local inflammatory arthritis.

Front Immunol

2023 Jan 4

Boltjes A, Samat AAK, Plantinga M

INTRODUCTION: Dendritic cells (DC) are crucial for initiating and shaping immune responses. So far, little is known about the functional specialization of human DC subsets in (local) inflammatory conditions. We profiled conventional (c)DC1, cDC2 and monocytes based on phenotype, transcriptome and function from a local inflammatory site, namely synovial fluid (SF) from patients suffering from a chronic inflammatory condition, Juvenile Idiopathic Arthritis (JIA) as well as patients with rheumatoid arthritis (RA). METHODS: Paired PB and SF samples from 32 JIA and 4 RA patients were collected for mononuclear cell isolation. Flow cytometry was done for definition of antigen presenting cell (APC) subsets. Cell sorting was done on the FACSAria II or III. RNA sequencing was done on SF APC subsets. Proliferation assays were done on co-cultures after CD3 magnetic activated cell sorting (MACS). APC Toll-like receptor (TLR) stimulation was done using Pam3CSK4, Poly(I:C), LPS, CpG-A and R848. Cytokine production was measured by Luminex. RESULTS: cDC1, a relatively small DC subset in blood, are strongly enriched in SF, and showed a quiescent immune signature without a clear inflammatory profile, low expression of pathogen recognition receptors (PRRs), chemokine and cytokine receptors, and poor induction of T cell proliferation and cytokine production, but selective production of IFNλ upon polyinosinic:polycytidylic acid exposure. In stark contrast, cDC2 and monocytes from the same environment, showed a pro-inflammatory transcriptional profile, high levels of (spontaneous) pro-inflammatory cytokine production, and strong induction of T cell proliferation and cytokine production, including IL-17. Although the cDC2 and monocytes showed an overlapping transcriptional core profile, there were clear differences in the transcriptional landscape and functional features, indicating that these cell types retain their lineage identity in chronic inflammatory conditions. DISCUSSION: Our findings suggest that at the site of inflammation, there is specific functional programming of human DCs, especially cDC2. In contrast, the enriched cDC1 remain relatively quiescent and seemingly unchanged under inflammatory conditions, pointing to a potentially more regulatory role.

146. Major alterations to monocyte and dendritic cell subsets lasting more than 6 months after hospitalization for COVID-19.

Front Immunol

2023 Jan 4

Hopkins FR, Govender M, Svanberg C

147. Combination of transcriptional biomarkers and clinical parameters for early prediction of sepsis indued acute respiratory distress syndrome.

Front Immunol

2023 Jan 4

Yao RQ, Shen Z, Ma QM

OBJECTIVE: As a common yet intractable complication of severe sepsis, acute respiratory distress syndrome (ARDS) is closely associated with poor clinical outcomes and elevated medical expenses. The aim of the current study is to generate a model combining transcriptional biomarkers and clinical parameters to alarm the development of ARDS in septic patients. METHODS: Gene expression profile (GSE66890) was downloaded from the Gene Expression Omnibus database and clinical data were extracted. Differentially expressed genes (DEGs) from whole blood leukocytes were identified between patients with sepsis alone and septic patients who develop ARDS. ARDS prediction model was constructed using backward stepwise regression and Akaike Information Criterion (AIC). Meanwhile, a nomogram based on this model was established, with subsequent internal validation. RESULTS: A total of 57 severe septic patients were enrolled in this study, and 28 (49.1%) developed ARDS. Based on the differential expression analysis, six DEGs (BPI, OLFM4, LCN2, CD24, MMP8 and MME) were screened. According to the outcome prediction model, six valuable risk factors (direct lung injury, shock, tumor, BPI, MME and MMP8) were incorporated into a nomogram, which was used to predict the onset of ARDS in septic patients. The calibration curves of the nomogram showed good consistency between the probabilities and observed values. The decision curve analysis also revealed the potential clinical usefulness of the nomogram. The area under the receiver operating characteristic (AUROC) for the prediction of ARDS occurrence in septic patients by the nomogram was 0.86 (95% CI = 0.767-0.952). A sensitivity analysis showed that the AUROC for the prediction of ARDS development in septic patients without direct lung injury was 0.967 (95% CI = 0.896-1.0). CONCLUSIONS: The nomogram based on transcriptional biomarkers and clinical parameters showed a good performance for the prediction of ARDS occurrence in septic patients.

148. Viral load and its relationship with the inflammatory response and clinical outcomes in hospitalization of patients with COVID-19.

Front Immunol

2023 Jan 4

Kuri-Ayache M, Rivera-Cavazos A, Pérez-Castillo MF

149. Serum organic acid metabolites can be used as potential biomarkers to identify prostatitis, benign prostatic hyperplasia, and prostate cancer.

Front Immunol

2023 Jan 4

He J, Han Z, Luo W

BACKGROUND: Noninvasive methods for the early identify diagnosis of prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer (PCa) are current clinical challenges. METHODS: The serum metabolites of 20 healthy individuals and patients with prostatitis, BPH, or PCa were identified using untargeted liquid chromatography-mass spectrometry (LC-MS). In addition, targeted LC-MS was used to verify the organic acid metabolites in the serum of a validation cohort. RESULTS: Organic acid metabolites had good sensitivity and specificity in differentiating prostatitis, BPH, and PCa. Three diagnostic models identified patients with PROSTATITIS: phenyllactic acid (area under the curve [AUC]=0.773), pyroglutamic acid (AUC=0.725), and pantothenic acid (AUC=0.721). Three diagnostic models identified BPH: citric acid (AUC=0.859), malic acid (AUC=0.820), and D-glucuronic acid (AUC=0.810). Four diagnostic models identified PCa: 3-hydroxy-3-methylglutaric acid (AUC=0.804), citric acid (AUC=0.918), malic acid (AUC=0.862), and phenyllactic acid (AUC=0.713). Two diagnostic models distinguished BPH from PCa: phenyllactic acid (AUC=0.769) and pyroglutamic acid (AUC=0.761). Three diagnostic models distinguished benign BPH from PROSTATITIS: citric acid (AUC=0.842), ethylmalonic acid (AUC=0.814), and hippuric acid (AUC=0.733). Six diagnostic models distinguished BPH from prostatitis: citric acid (AUC=0.926), pyroglutamic acid (AUC=0.864), phenyllactic acid (AUC=0.850), ethylmalonic acid (AUC=0.843), 3-hydroxy-3-methylglutaric acid (AUC=0.817), and hippuric acid (AUC=0.791). Three diagnostic models distinguished PCa patients with PROSTATITISA < 4.0 ng/mL from those with PSA > 4.0 ng/mL: 5-hydromethyl-2-furoic acid (AUC=0.749), ethylmalonic acid (AUC=0.750), and pyroglutamic acid (AUC=0.929). Conclusions: These results suggest that serum organic acid metabolites can be used as biomarkers to differentiate prostatitis, BPH, and PCa.

150. Ferric carboxymaltose and SARS-CoV-2 vaccination-induced immunogenicity in kidney transplant recipients with iron deficiency: The COVAC-EFFECT randomized controlled trial.

Front Immunol

2023 Jan 4

Vinke JSJ, Altulea DHA, Eisenga MF

151. Clinical response trajectories and drug persistence in systemic lupus erythematosus patients on belimumab treatment: A real-life, multicentre observational study.

Front Immunol

2023 Jan 4

Nikoloudaki M, Nikolopoulos D, Koutsoviti S

OBJECTIVE: To obtain real-world data on outcomes of belimumab treatment and respective prognostic factors in patients with systemic lupus erythematosus (SLE). METHODS: Observational study of 188 active SLE patients (median disease duration 6.2 years, two previous immunosuppressive/biological agents) treated with belimumab, who were monitored for SLEDAI-2K, Physician Global Assessment (PGA), LLDAS (lupus low disease activity state), remission (DORIS/Padua definitions), SELENA-SLEDAI Flare Index, SLICC/ACR damage index and treatment discontinuations. Group-based disease activity trajectories were modelled followed by multinomial regression for predictive variables. Drug survival was analysed by Cox-regression. RESULTS: At 6, 12 and 24 months, LLDAS was attained by 36.2%, 36.7% and 33.5%, DORIS-remission by 12.3%, 11.6% and 17.8%, and Padua-remission by 21.3%, 17.9% and 29.0%, respectively (attrition-corrected). Trajectory analysis of activity indices classified patients into complete (25.5%), partial (42.0%) and non-responder (32.4%) groups, which were predicted by baseline PGA, inflammatory rash, leukopenia and prior use of mycophenolate. During median follow-up of 15 months, efficacy-related discontinuations occurred in 31.4% of the cohort, especially in patients with higher baseline PGA (hazard ratio [HR] 2.78 per 1-unit; 95% CI 1.32-5.85). Conversely, PGA improvement at 3 months predicted longer drug retention (HR 0.57; 95% CI 0.33-0.97). Use of hydroxychloroquine was associated with lower risk for safety-related drug discontinuation (HR 0.33; 95% CI 0.13-0.85). Although severe flares were reduced, flares were not uncommon (58.0%) and contributed to treatment stops (odds ratio [OR] 1.73 per major flare; 95% CI 1.09-2.75) and damage accrual (OR 1.83 per mild/moderate flare; 95% CI 1.15-2.93). CONCLUSIONS: In a real-life setting with predominant long-standing SLE, belimumab was effective in the majority of patients, facilitating the achievement of therapeutic targets. Monitoring PGA helps to identify patients who will likely benefit and stay on the treatment. Vigilance is required for the prevention and management of flares while on belimumab.

152. Maternal Lactobacillus rhamnosus administration impacts neonatal CD4 T-cell activation and prevents murine T helper 2-type allergic airways disease.

Front Immunol

2023 Jan 4

Smout J, Valentin C, Delbauve S

153. Desmosterol: A natural product derived from macroalgae modulates inflammatory response and oxidative stress pathways in intestinal epithelial cells.

Front Immunol

2023 Jan 4

Qu H, Zong Q, Hu P

154. Associations of cord blood meta-inflammation and vitamin D with neurodevelopmental delay: A prospective birth cohort study in China.

Front Immunol

2023 Jan 4

Wang P, Wu L, Yin WJ

155. Using two-step cluster analysis to classify inpatients with primary biliary cholangitis based on autoantibodies: A real-world retrospective study of 537 patients in China.

Front Immunol

2023 Jan 4

Zhao DT, Yan HP, Liao HY

BACKGROUND: A variety of autoantibodies have been detected in primary biliary cholangitis (PBC), while the presence of autoantibody clusters and their clinical significance have not been fully understood. We aimed at defining autoantibody clusters and to better understand the clinical features and prognosis of PBC patients based on autoantibody clusters under real-world conditions. METHODS: We retrospectively analyzed 788 inpatients with PBC evaluated between October 2008 and July 2019, and included 537 patients. Nineteen autoantibodies which were measured routinely were investigated for cluster analysis. Two-step clustering, Kaplan-Meier survival, and Cox regression analyses were used. RESULTS: Five clusters were defined. A cluster of antinuclear antibodies (ANA) and anti-gp210 positive patients were identified with a high rate of cirrhosis at baseline and low survival rate; a cluster of ANA, anti-centromere antibodies (ACA) and/or anti-CENP-B female dominant patients with older disease onset, low level of platelet count at baseline, high rate of hepatic decompensation, and low survival rate was also characterized; and another cluster of anti-mitochondrial antibodies (AMA) and/or AMA-M2, anti-Ro52 and a high rate of anti-gp210 positive patients were identified with a high proportion of male patients and low survival rate. A subgroup of patients with anti-SSA and/or anti-SSB coexists with SjS was also identified; patients with only AMA and/or AMA-M2-positive with a benign clinical outcome and relatively high complication of non-alcoholic fatty liver disease (NAFLD) were also identified. Only anti-gp210 was considered as a significant predictor for poor outcomes especially in patients with cirrhosis. CONCLUSION: Clustering methods allow the identification of distinct autoantibody profiles of PBC that form clinical subsets and can be useful for personalized approaches to diagnosis, clinical management, and the prediction of clinical outcomes. Anti-gp210 was the strongest predictive factor for poor outcomes especially in PBC patients with cirrhosis under real-world conditions.

156. Spatial genomics reveals a high number and specific location of B cells in the pancreatic ductal adenocarcinoma microenvironment of long-term survivors.

Front Immunol

2023 Jan 4

Aziz HM, Saida L, de Koning W

157. Glioma-derived CCL2 and CCL7 mediate migration of immune suppressive CCR2(+)/CX3CR1(+) M-MDSCs into the tumor microenvironment in a redundant manner.

Front Immunol

2023 Jan 4

Takacs GP, Kreiger CJ, Luo D

158. Comparison of first-line treatments for elderly patients with diffuse large B-cell lymphoma: A systematic review and network meta-analysis.

Front Immunol

2023 Jan 4

Wang Y, Ren X, Huang K

159. Granulocytic myeloid-derived suppressor cells increase infection risk via the IDO/IL-10 pathway in patients with hepatitis B virus-related liver failure.

Front Immunol

2023 Jan 4

Yu X, Sun J, Yang F

160. Osteopontin contributes to virus resistance associated with type I IFN expression, activation of downstream ifn-inducible effector genes, and CCR2(+)CD115(+)CD206(+) macrophage infiltration following ocular HSV-1 infection of mice.

Front Immunol

2023 Jan 4

Filiberti A, Gmyrek GB, Berube AN

Ocular pathology is often associated with acute herpes simplex virus (HSV)-1 infection of the cornea in mice. The present study was undertaken to determine the role of early T lymphocyte activation 1 protein or osteopontin (OPN) in corneal inflammation and host resistance to ocular HSV-1 infection. C57BL/6 wild type (WT) and osteopontin deficient (OPN KO) mice infected in the cornea with HSV-1 were evaluated for susceptibility to infection and cornea pathology. OPN KO mice were found to possess significantly more infectious virus in the cornea at day 3 and day 7 post infection compared to infected WT mice. Coupled with these findings, HSV-1-infected OPN KO mouse corneas were found to express less interferon (IFN)-α1, double-stranded RNA-dependent protein kinase, and RNase L compared to infected WT animals early post infection that likely contributed to decreased resistance. Notably, OPN KO mice displayed significantly less corneal opacity and neovascularization compared to WT mice that paralleled a decrease in expression of vascular endothelial growth factor (VEGF) A within 12 hr post infection. The change in corneal pathology of the OPN KO mice aligned with a decrease in total leukocyte infiltration into the cornea and specifically, in neutrophils at day 3 post infection and in macrophage subpopulations including CCR2+CD115+CD206+ and CD115+CD183+CD206+ -expressing cells. The infiltration of CD4+ and CD8+ T cells into the cornea was unaltered comparing infected WT to OPN KO mice. Likewise, there was no difference in the total number of HSV-1-specific CD4+ or CD8+ T cells found in the draining lymph node with both sets functionally competent in response to virus antigen comparing WT to OPN KO mice. Collectively, these results demonstrate OPN deficiency directly influences the host innate immune response to ocular HSV-1 infection reducing some aspects of inflammation but at a cost with an increase in local HSV-1 replication.

161. Functional status and spatial interaction of T cell subsets driven by specific tumor microenvironment correlate with recurrence of non-small cell lung cancer.

Front Immunol

2023 Jan 4

Yang L, Zhang W, Sun J

BACKGROUND: The anti-tumoral or pro-tumoral roles of CD4+ and CD8+ T cells typify the complexity of T cell subsets function in cancer. In the non-small cell lung cancer (NSCLC), the density and topology of distinct T cell phenotypes at the tumor center (TC) versus the invasive margin (IM) are largely unknown. Here, we investigated T cell subsets density and distribution within TC and IM regions in NSCLC and its impact on the prognosis. METHODS: We performed multiplex immunofluorescence using a tissue microarray of samples from 99 patients with locally advanced NSCLC to elucidate the distributions of tumor cell, T cell subpopulations (CD4/conventional CD4/regulatory CD4/CD8/cytotoxic CD8/pre-dysfunctional CD8/dysfunctional CD8), microvessel density (MVD), cancer-associated fibroblasts (CAFs) and hypoxia-inducible factor-1α (HIF-1α) in TC and IM tissues. Cell-to-cell nearest neighbor distances and interactions were analyzed using the phenoptrreports R package. Cox regression was used to evaluate the associations between T cell subsets density and proximity to tumor cells and recurrence-free survival (RFS). Correlations between different cell subsets were examined by Spearman's or Kruskal-Wallis tests. RESULTS: In the locally advanced NSCLC, the proportion of tumor cells and CAFs in IM is lower than in the TC, while MVD, CD4+, and CD8+ T lymphocytes were increased, and tumor cells were closer to T lymphocytes and their subsets. The density and proximity of CD4+ and CD8+ T cells in the TC and IM regions were not associated with RFS, but in the IM area, increased density of dysfunctional CD8 and closer regulatory CD4 to tumor cells were independent risk factors for recurrence (HR were 3.536 and 2.884, respectively), and were positively correlated with HIF-1α+CD8 (r = 0.41, P = 0.000) and CAFs (P = 0.017), respectively.s. CONCLUSIONS: In locally advanced NSCLC, the functional status of T cells in the IM region is closely related to recurrence. The density of dysfunctional CD8 and the proximity of regulatory CD4 to tumor cells were independent risk factors for recurrence, and are positively correlated with the hypoxia response of CD8+ T cells and CAFs. Targeting hypoxia or CAFs is expected to further sensitize therapy.

162. Safety and efficacy of dual PI3K-δ, γ inhibitor, duvelisib in patients with relapsed or refractory lymphoid neoplasms: A systematic review and meta-analysis of prospective clinical trials.

Front Immunol

2023 Jan 4

Wang Z, Zhou H, Xu J

BACKGROUND: Duvelisib is the first FDA-approved oral dual inhibitor of phosphatidylinositol-3-kinase PI3K-delta (PI3K-δ) and PI3K-gamma (PI3K-γ). Although many clinical studies support the efficacy of duvelisib, the safety of duvelisib remains with great attention. This systematic review and meta-analysis aimed to evaluate the safety and efficacy of duvelisib in treating different relapsed or refractory (RR) lymphoid neoplasm types. METHODS: We searched prospective clinical trials from PUBMED, EMBASE, Cochrane Library, and ClinicalTrials.gov. For efficacy analysis, Overall response rate (ORR), complete response rate (CR), partial response rate (PR), rate of stable disease (SDR), rate of progressive disease (PDR), median progression-free survival (mPFS), 12-/24-month PFS, and 12-month overall survival (OS) were assessed. For safety analysis, the incidences of any grade and grade ≥3 adverse events (AEs), serious AEs, and treatment-related discontinuation and death were evaluated. Subgroup analysis based on the disease type was performed. RESULTS: We included 11 studies and 683 patients, including 305 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 187 B-cell indolent non-Hodgkin lymphoma (iNHL), 39 B-cell aggressive non-Hodgkin lymphoma (aNHL), and 152 T-cell non-Hodgkin lymphoma (T-NHL) patients. The pooled ORR in CLL/SLL, iNHL, aNHL and T-NHL was 70%, 70%, 28% and 47%, respectively. Additionally, the pooled ORR in CLL/SLL patients with or without TP53 mutation/17p-deletion (62% vs. 74%, p=0.45) and in follicular lymphoma (FL) or other iNHL (69% vs. 57%, p=0.38) had no significant differences. Mantle cell lymphoma (MCL) patients had higher pooled ORR than other aNHL (68% vs. 17%, p=0.04). Angioimmunoblastic TCL (AITL) patients had higher pooled ORR than other PTCL patients (67% vs. 42%, p=0.01). The pooled incidence of any grade, grade ≥3, serious AEs, treatment-related discontinuation and death was 99%, 79%, 63%, 33% and 3%, respectively. The most frequent any-grade AEs were diarrhea (47%), ALT/AST increase (39%), and neutropenia (38%). The most frequent grade ≥3 AEs were neutropenia (25%), ALT/AST increased (16%), diarrhea (12%), and anemia (12%). CONCLUSION: Generally, duvelisib could offer favorable efficacy in patients with RR CLL/SLL, iNHL, MCL, and AITL. Risk and severity in duvelisib treatment may be mitigated through proper identification and management.

163. Case report: Pneumocystis jirovecii pneumonia in a severe case of Aicardi-Goutières syndrome with an IFIH1 gain-of-function mutation mimicking combined immunodeficiency.

Front Immunol

2023 Jan 4

Železnik M, Soltirovska Šalamon A, Debeljak M

164. Prognostic factors of second hematopoietic allogeneic stem cell transplantation among hematological malignancy patients relapsed after first hematopoietic stem cell transplantation: A single center study.

Front Immunol

2023 Jan 4

Lu Y, Zhang JP, Zhao YL

INTRODUCTION: We aimed to evaluate prognostic factors of a second allogeneic stem cell transplantation (allo-HSCT2) among hematological malignancy patients who have relapsed after the first allo-HSCT(allo-HSCT1). METHODS: We retrospectively analyzed 199 hematological malignancy patients who received allo-HSCT2 as a salvage treatment post allo-HSCT1 relapse between November 2012 and October 2021. RESULTS: The median age at allo-HSCT2 was 23 (range: 3-60) years. The median time to relapse after HSCT1 was 9 (range: 1-72) months. Prior to allo-HSCT2, patients had the following hematopoietic cell transplantation-comorbidity indexes (HCT-CI): 127 with a score of 0, 52 with a score of 1, and 20 with a score of 2 or greater. Fifty percent of patients received chimeric antigen receptor (CAR) T-cell therapy following HSCT1 relapse. Disease status was minimal residual disease (MRD)-negative complete remission (CR) among 119 patients, MRD-positive CR among 37 patients and non-remission (NR) for 43 patients prior to allo-HSCT2. Allo-HSCT2 was performed from a new donor in 194 patients (97.4%) and 134 patients (67.3%) received a graft with a new mismatched haplotype. The median follow-up time was 24 months (range: 6-98 months), and the 2-year OS and LFS were 43.8% ± 4.0% and 42.1% ± 4.1%, respectively. The 2-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) was 30.0%±4.8% and 38.5%±3.8%, respectively. Cox regression multivariate analysis showed that disease statusof MRD-negative CR, HCT-CI score of 0 prior to allo-HSCT2, and new mismatched haplotype donor were predictive factors of improved OS and LFS compared to patients without these characteristics. Based on these three favorable factors, we developed a predictive scoring system for patients who received allo-HSCT2. Patients with a prognostic score of 3 who had the three factors showed a superior 2-year OS of 63.3% ± 6.7% and LFS of 63.3% ± 6.7% and a lower CIR of 5.5% ± 3.1% than patients with a prognostic score of 0. Allo-HSCT2 is feasible and patients with good prognostic features prior to allo-HSCT2 -disease status of CR/MRD- and HCT-CI score of 0 as well as a second donor with a new mismatched haplotype could have the maximal benefit from the second allo-HSCT. CONCLUSIONS: Allo-HSCT2 is feasible and patients with good prognostic features prior to allo-HSCT2 -disease status of CR/MRD- and HCT-CI score of 0 as well as a second donor with a new mismatched haplotype could have the maximal benefit from the second allo-HSCT.

165. Mannose-modified erythrocyte membrane-encapsulated chitovanic nanoparticles as a DNA vaccine carrier against reticuloendothelial tissue hyperplasia virus.

Front Immunol

2023 Jan 4

Feng Y, Tang F, Li S

166. Corrigendum: Reliable estimation of CD8 T cell inhibition of in vitro HIV-1 replication.

Front Immunol

2023 Jan 3

Xu Y, Weideman AM, Abad-Fernandez M

167. The endoplasmic reticulum stress sensor IRE1α modulates macrophage metabolic function during Brucella abortus infection.

Front Immunol

2023 Jan 3

Guimarães ES, Gomes MTR, Sanches RCO

168. Stimulation of the farnesoid X receptor promotes M2 macrophage polarization.

Front Immunol

2023 Jan 27

Jaroonwitchawan T, Arimochi H, Sasaki Y

169. Suppression of microRNA-222-3p ameliorates ulcerative colitis and colitis-associated colorectal cancer to protect against oxidative stress via targeting BRG1 to activate Nrf2/HO-1 signaling pathway.

Front Immunol

2023 Jan 27

Wang XJ, Zhang D, Yang YT

Oxidative stress is an important pathogenic factor in ulcerative colitis (UC) and colitis-associated colorectal cancer (CAC), further impairing the entire colon. Intestinal epithelial cells (IECs) are crucial components of innate immunity and play an important role in maintaining intestinal barrier function. Recent studies have indicated that microRNA-222-3p (miR-222-3p) is increased in colon of UC and colorectal cancer (CRC) patients, and miR-222-3p is a crucial regulator of oxidative stress. However, whether miR-222-3p influences IEC oxidative stress in UC and CAC remains unknown. This study investigated the effect of miR-222-3p on the regulation of IEC oxidative stress in UC and CAC. An in vitro inflammation model was established in NCM460 colonic cells, mouse UC and CAC models were established in vivo, and IECs were isolated. The biological role and mechanism of miR-222-3p-mediated oxidative stress in UC and CAC were determined. We demonstrated that miR-222-3p expression was notably increased in dextran sulfate sodium (DSS)-induced NCM460 cells and IECs from UC and CAC mice. In vitro, these results showed that the downregulation of miR-222-3p reduced oxidative stress, caspase-3 activity, IL-1β and TNF-α in DSS-induced NCM460 cells. We further identified BRG1 as the target gene of miR-222-3p, and downregulating miR-222-3p alleviated DSS-induced oxidative injury via promoting BRG1-mediated activation Nrf2/HO-1 signaling in NCM460 cells. The in vivo results demonstrated that inhibiting miR-222-3p in IECs significantly relieved oxidative stress and inflammation in the damaged colons of UC and CAC mice, as evidenced by decreases in ROS, MDA, IL-1β and TNF-α levels and increases in GSH-Px levels. Our study further demonstrated that inhibiting miR-222-3p in IECs attenuated oxidative damage by targeting BRG1 to activate the Nrf2/HO-1 signaling. In summary, inhibiting miR-222-3p in IECs attenuates oxidative stress by targeting BRG1 to activate the Nrf2/HO-1 signaling, thereby reducing colonic inflammation and tumorigenesis.

170. Neutralizing antibodies to Omicron after the fourth SARS-CoV-2 mRNA vaccine dose in immunocompromised patients highlight the need of additional boosters.

Front Immunol

2023 Jan 27

Rescigno M, Agrati C, Salvarani C

Author information: (1)Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy. (2)Mucosal Immunology and Microbiota Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Rozzano, Milano, Italy. (3)Cellular Immunology Laboratory, National Institute for Infectious Diseases (INMI) L Spallanzani - Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy. (4)Department of Hematology and Oncology and Cell and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Bambino Gesù Children Hospital , Roma, Italy. (5)Unità di Reumatologia, Azienda Unità Sanitaria Locale-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) di Reggio Emilia, Reggio Emilia, Italy. (6)Unità di Reumatologia, Università degli Studi di Modena e Reggio Emilia, Reggio Emilia, Italy. (7)Facility di Epidemiologia e Biostatistica, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Roma, Italy. (8)Scientific Directorate, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori di Milano, Milano, Italy. (9)Humanitas Scientific Directorate, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Rozzano, Milan, Italy. (10)William Harvey Research Institute, Queen Mary University, London, United Kingdom. (11)Vice Scientific Directorate, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo II", Bari, Italy. (12)Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy. (13)Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy. (14)Scientific Directorate, San Gallicano Dermatological Institute Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Roma, Italy. (15)Virology Laboratory, INMI L Spallanzani - Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Roma, Italy. (16)Scientific Directorate, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Neurologico Carlo Besta, Milano, Italy. (17)Department of Medical Biotechnology and Translational Medicine, University of Milan, Milano, Italy. (18)Scientific Directorate, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale Policlinico San Martino, Genoa, Italy. (19)Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy. (20)Scientific Directorate, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Regina Elena, National Cancer Institute, Istituti Fisioterapici Ospitalieri (IFO), Roma, Italy. (21)Microbiology and Virology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy. (22)Department of Clinical, Surgical, Diagnostics and Pediatric Sciences, University of Pavia, Pavia, Italy. (23)Department of Pediatrics, Catholic University of the Sacred Heart, Roma, Italy. (24)Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Messina, Italy. (25)Department of Oncology and Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori di Milano, Milano, Italy. (26)Infrastruttura Ricerca e Statistica, Azienda Unità Sanitaria Locale-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) di Reggio Emilia, Reggio Emilia, Italy. (27)Hematology and BMT Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milano, Italy.

171. Medium chain fatty acid supplementation improves animal metabolic and immune status during the transition period: A study on dairy cattle.

Front Immunol

2023 Jan 27

Wang Z, Wang Q, Tang C

The transition period is the stage of the high incidence of metabolic and infectious diseases in dairy cows. Improving transition dairy cows' health is crucial for the industry. This study aimed to determine the effects of dietary supplementation medium-chain fatty acids (MCFAs) on immune function, metabolic status, performance of transition dairy cows. Twenty multiparous Holstein cows randomly assigned to two treatments at 35 d before calving. 1) CON (fed the basal 2) MCFA treatment (basal diet was supplemented at an additional 20 g MCFAs mixture every day) until 70 d after calving. The results showed that the serum amyloid A myeloperoxidase concentrations in the blood of cows in MCFA treatment significantly decreased during the early lactation (from 1 d to 28 d after calving) 0.03, 0.04, respectively) compared with the CON, while the tumor necrosis factor concentration was significantly decreased at 56 d after calving (P = 0.02). In addition, the concentration of insulin in the pre-calving (from 21 d before calving to calving) blood of cows in MCFA treatment was significantly decreased (P = 0.04), and concentration of triglyceride also showed a downward trend at 28 d after calving 0.07). Meanwhile, MCFAs supplementation significantly decreased the concentrations of lithocholic acid, hyodeoxycholic acid, and hyocholic acid in the blood at 1 d calving (P = 0.02, < 0.01, < 0.01, respectively), and the level of hyocholic acid taurocholic acid concentrations (P < 0.01, = 0.01, respectively) decreased dramatically at 14 d after calving. However, compared with the CON, the pre-calving dry matter intake and the early lactation milk yield in MCFA treatment were significantly decreased (P = 0.05, 0.02, respectively). In conclusion, MCFAs supplementation transition diet could improve the immune function and metabolic status of dairy cows, and the health of transition cows might be beneficial from the endocrine status.

172. Case report: Advanced primary squamous cell carcinoma in the periampullary area with upregulation of programmed cell death-ligand 1 expression and response to sintilimab immunotherapy.

Front Immunol

2023 Jan 27

Wang B, Li D, Zeng D

173. RUNX1/CD44 axis regulates the proliferation, migration, and immunotherapy of gliomas: A single-cell sequencing analysis.

Front Immunol

2023 Jan 26

Zhang H, Cao H, Luo H

174. TLQP-21 is a low potency partial C3aR activator on human primary macrophages.

Front Immunol

2023 Jan 26

Li XX, Lee JD, Lee HS

175. The roles of fungus in CNS autoimmune and neurodegeneration disorders.

Front Immunol

2023 Jan 26

Wu C, Jiang ML, Jiang R

176. Mapping of DNA methylation-sensitive cellular processes in gingival and periodontal ligament fibroblasts in the context of periodontal tissue homeostasis.

Front Immunol

2023 Jan 26

Lagosz-Cwik KB, Melnykova M, Nieboga E

177. Unequal distribution of genetically-intact HIV-1 proviruses in cells expressing the immune checkpoint markers PD-1 and/or CTLA-4.

Front Immunol

2023 Jan 26

Fisher K, Schlub TE, Boyer Z

INTRODUCTION: HIV-1 persists in resting CD4+ T-cells despite antiretroviral therapy (ART). Determining the cell surface markers that enrich for genetically-intact HIV-1 genomes is vital in developing targeted curative strategies. Previous studies have found that HIV-1 proviral DNA is enriched in CD4+ T-cells expressing the immune checkpoint markers programmed cell death protein-1 (PD-1) or cytotoxic T-lymphocyte associated protein-4 (CTLA-4). There has also been some success in blocking these markers in an effort to reverse HIV-1 latency. However, it remains unclear whether cells expressing PD-1 and/or CTLA-4 are enriched for genetically-intact, and potentially replication-competent, HIV-1 genomes. METHODS: We obtained peripheral blood from 16 HIV-1-infected participants, and paired lymph node from four of these participants, during effective ART. Memory CD4+ T-cells from either site were sorted into four populations: PD-1-CTLA-4- (double negative, DN), PD-1+CTLA-4- (PD-1+), PD-1-CTLA-4+ (CTLA-4+) and PD-1+CTLA-4+ (double positive, DP). We performed an exploratory study using the full-length individual proviral sequencing (FLIPS) assay to identify genetically-intact and defective genomes from each subset, as well as HIV-1 genomes with specific intact open reading frames (ORFs). RESULTS AND DISCUSSION: In peripheral blood, we observed that proviruses found within PD-1+ cells are more likely to have intact ORFs for genes such as tat, rev and nef compared to DN, CTLA-4+ and DP cells, all of which may contribute to HIV-1 persistence. Conversely, we observed that CTLA-4 expression is a marker for cells harbouring HIV-1 provirus that is more likely to be defective, containing low levels of these intact ORFs. In the lymph node, we found evidence that CTLA-4+ cells contain lower levels of HIV-1 provirus compared to the other cell subsets. Importantly, however, we observed significant participant variation in the enrichment of HIV-1 proviruses with intact genomes or specific intact ORFs across these memory CD4+ T-cell subsets, and therefore consideration of additional cellular markers will likely be needed to consistently identify cells harbouring latent, and potentially replication-competent, HIV-1.

178. Emerging predictive biomarkers for novel therapeutics in peripheral T-cell and natural killer/T-cell lymphoma.

Front Immunol

2023 Jan 26

Yap DRY, Lim JQ, Huang D

179. Decreased monocyte-to-lymphocyte ratio was associated with satisfied outcomes of first-line PD-1 inhibitors plus chemotherapy in stage IIIB-IV non-small cell lung cancer.

Front Immunol

2023 Jan 26

Zheng L, Xiong A, Wang S

OBJECTIVES: Immune-checkpoint inhibitors (ICIs) combined with chemotherapy are more widely used than monotherapy and have shown better survival in patients with advanced non-small cell lung cancer (NSCLC) without oncogenic driver alterations. The monocyte-to-lymphocyte ratio (MLR) might predict the treatment outcomes of ICI therapy in advanced NSCLC patients but has not yet been investigated. In addition, the cutoff of MLR is controversial. Therefore, the present study aimed to explore the associations between changes in MLR at the initial stage of treatment and clinical outcomes in stage IIIB-IV NSCLC patients receiving first-line PD-1 inhibitor combined with chemotherapy. METHODS: The present study included 139 stage IIIB-IV NSCLC patients treated with first-line PD-1 inhibitor combined with chemotherapy. The blood results were assessed 10 days before initiation of PD-1 inhibitor-based combination therapy (time point 1, baseline) and before the third cycle of combined therapy (time point 2). Compared to altered MLR, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in baseline and in time point 2, patients were divided into decreased MLR/NLR/PLR and increased MLR/NLR/PLR groups. The objective response rate (ORR), progression-free survival (PFS), and the association with the changes in blood indicators were analyzed. RESULTS: A total of 48 patients were categorized in the decreased MLR group and 91 in the increased MLR group. Patients with decreased MLR had a significantly higher ORR in the univariate (P<0.001) and multivariate (P<0.001) Cox proportional hazards models. On the other hand, decreased MLR was significantly associated with prolonged PFS in the univariate (P=0.007) and multivariate (P=0.016) analyses. Next, 91 patients comprised the decreased NLR group and 48 as the increased NLR group. Patients with decreased NLR exhibited high ORR (P=0.001) and prolonged PFS in univariate analysis (P=0.033). Then, 64 patients comprised the decreased PLR group and 75 the increased PLR group. Decreased PLR was significantly associated with high ORR in univariate (P<0.001) and multivariate (P=0.017) analyses. The subgroup analyses showed that decreased MLR was significantly associated with satisfactory outcomes in patients with all PD-L1 expressions. CONCLUSION: Decreased MLR was associated with high ORR and long PFS and might have a potential predictive value in patients with stage IIIB-IV NSCLC treated with first-line PD-1 inhibitor combined with chemotherapy. In addition, changes in MLR might have predictive value in all PD-L1-expressing populations. Decreased NLR and PLR also showed improved survival, suggesting that changes in NLR and PLR may be complementary to predicting prognosis.

180. RAGE contributes to allergen driven severe neutrophilic airway inflammation via NLRP3 inflammasome activation in mice.

Front Immunol

2023 Jan 26

Killian KN, Kosanovich JL, Lipp MA

181. T cells and their products in diabetic kidney disease.

Front Immunol

2023 Jan 26

Liu Y, Lv Y, Zhang T

182. Smoking and coronary artery disease risk in patients with diabetes: A Mendelian randomization study.

Front Immunol

2023 Jan 26

Chen S, Yang F, Xu T

183. gC1qR: A New Target for Cancer Immunotherapy.

Front Immunol

2023 Jan 26

Lei Y, Li X, Qin D

184. Quantitative plasma proteomics identifies metallothioneins as a marker of acute-on-chronic liver failure associated acute kidney injury.

Front Immunol

2023 Jan 26

Acharya P, Saha R, Quadri JA

185. IgD shapes the pre-immune naïve B cell compartment in humans.

Front Immunol

2023 Jan 26

Dirks J, Andres O, Paul L

186. DOG1 as a novel antibody-drug conjugate target for the treatment of multiple gastrointestinal tumors and liver metastasis.

Front Immunol

2023 Jan 26

Wu Y, Li W, Chen X

187. Resistance to immune checkpoint inhibitors in advanced lung cancer: Clinical characteristics, potential prognostic factors and next strategy.

Front Immunol

2023 Jan 26

Zhou J, Lu X, Zhu H

BACKGROUND: Immune checkpoint inhibitors (ICIs) have shown unprecedented clinical benefit in cancer immunotherapy and are rapidly transforming the practice of advanced lung cancer. However, resistance routinely develops in patients treated with ICIs. We conducted this retrospective study to provide an overview on clinical characteristics of ICI resistance, optimal treatment beyond disease progression after prior exposure to immunotherapy, as well as potential prognostic factors of such resistance. METHODS: 190 patients diagnosed with unresectable lung cancer who received at least one administration of an anti-programmed cell death 1 (PD-1)/anti-programmed cell death-ligand 1(PD-L1) at any treatment line at Zhongshan Hospital Fudan University between Sep 2017 and December 2019 were enrolled in our study. Overall survival (OS) and progression-free survival (PFS) were analyzed. Levels of plasma cytokines were evaluated for the prognostic value of ICI resistance. RESULTS: We found that EGFR/ALK/ROS1 mutation and receiving ICI treatment as second-line therapy were risk factors associated with ICI resistance. Patients with bone metastasis at baseline had a significantly shorter PFS1 time when receiving initial ICI treatment. Whether or not patients with oligo-progression received local treatment seemed to have no significant effect on PFS2 time. Systemic therapies including chemotherapy and anti-angiogenic therapy rather than continued immunotherapy beyond ICI resistance had significant effect on PFS2 time. TNF, IL-6 and IL-8 were significantly elevated when ICI resistance. Lower plasma TNF level and higher plasma IL-8 level seemed to be significantly associated with ICI resistance. A nomogram was established to prognosis the clinical outcome of patients treated with ICIs. CONCLUSION: Patients with EGFR/ALK/ROS1 mutation, or those receiving ICI treatment as second-line therapy had higher risk of ICI resistance. Patients with bone metastasis had poor prognosis during immunotherapy. For those patients with oligo-progression after ICI resistance, combination with local treatment did not lead to a significantly longer PFS2 time. Chemotherapy and anti-angiogenic therapy rather than continued immunotherapy beyond ICI resistance had significant effect on PFS2 time. Levels of plasma cytokines including TNF, IL-6 and IL-8 were associated with ICI resistance.

188. JAK inhibitors differentially modulate B cell activation, maturation and function: A comparative analysis of five JAK inhibitors in an in-vitro B cell differentiation model and in patients with rheumatoid arthritis.

Front Immunol

2023 Jan 26

Frede N, Lorenzetti R, Hüppe JM

BACKGROUND: Janus kinase (JAK) inhibitors have been approved for the treatment of several immune-mediated diseases (IMIDs) including rheumatoid arthritis (RA) and psoriatic arthritis and are in clinical trials for numerous other IMIDs. However, detailed studies investigating the effects of different JAK inhibitors on B cells are missing. Within this study, we therefore aimed to characterize the effect of JAK inhibition on the B cell compartment. METHODS: To this end, we investigated the B cell compartment under JAK inhibition and compared the specific effects of the different JAK inhibitors tofacitinib (pan-JAK), baricitinib (JAK1/2), ruxolitinib (JAK1/2), upadacitinib (JAK1/2) as well as filgotinib (selective JAK1) on in-vitro B cell activation, proliferation, and class switch recombination and involved pathways. RESULTS: While B cell phenotyping of RA patients showed an increase in marginal zone (MZ) B cells under JAK inhibition, comparison with healthy donors revealed that the relative frequency of MZ B cells was still lower compared to healthy controls. In an in-vitro model of T-cell-independent B cell activation we observed that JAK1/2 and selective JAK1 inhibitor treatment led to a dose-dependent decrease of total B cell numbers. We detected an altered B cell differentiation with a significant increase in MZ-like B cells and an increase in plasmablast differentiation in the first days of culture, most pronounced with the pan-JAK inhibitor tofacitinib, although there was no increase in immunoglobulin secretion in-vitro. Notably, we further observed a profound reduction of switched memory B cell formation, especially with JAK1/2 inhibition. JAK inhibitor treatment led to a dose-dependent reduction of STAT3 expression and phosphorylation as well as STAT3 target gene expression and modulated the secretion of pro- and anti-inflammatory cytokines by B cells. CONCLUSION: JAK inhibition has a major effect on B cell activation and differentiation, with differential outcomes between JAK inhibitors hinting towards distinct and unique effects on B cell homeostasis.

189. Rapid screening and scaled manufacture of immunogenic virus-like particles in a tobacco BY-2 cell-free protein synthesis system.

Front Immunol

2023 Jan 26

Armero-Gimenez J, Wilbers R, Schots A

Several vaccine platforms have been developed to fight pathogenic threats, with Virus-Like Particles (VLPs) representing a very promising alternative to traditional platforms. VLPs trigger strong and lasting humoral and cellular immune responses with fewer safety concerns and higher stability than other platforms. The use of extensively characterized carrier VLPs modified with heterologous antigens was proposed to circumvent the viral complexity of specific viruses that could lead to poor VLP assembly and yields. Although carrier VLPs have been successfully produced in a wide variety of cell-based systems, these are limited by low protein yields and protracted clone selection and optimization workflows that limit VLP screening approaches. In response, we have demonstrated the cell-free protein synthesis (CFPS) of several variants of the hepatitis B core (HBc) carrier VLP using a high-yielding tobacco BY-2 lysate (BYL). High VLP yields in the BYL system allowed in-depth characterization of HBc variants. Insertion of heterologous sequences at the spike region of the HBc monomer proved more structurally demanding than at the N-terminus but removal of the C-terminal domain allowed higher particle flexibility and insert acceptance, albeit at the expense of thermal and chemical stability. We also proved the possibility to scale the CFPS reaction up to 1L in batch mode to produce 0.45 grams of the native HBc VLP within a 48-hour reaction window. A maximum yield of 820 µg/ml of assembled VLP particles was observed at the 100µl scale and most remarkably the CFPS reaction was successfully scaled from 50µl to 1L without any reduction in protein yield across this 20,000-fold difference in reaction volumes. We subsequently proved the immunogenicity of BYL-derived VLPs, as flow cytometry and microscopy clearly showed prompt recognition and endocytosis of fluorescently labelled VLPs by human dendritic cells. Triggering of inflammatory cytokine production in human peripheral blood mononuclear cells was also quantitated using a multiplex assay. This research establishes BYL as a tool for rapid production and microscale screening of VLP variants with subsequent manufacturing possibilities across scales, thus accelerating discovery and implementation of new vaccine candidates using carrier VLPs.

190. A novel interleukin-2-based fusion molecule, HCW9302, differentially promotes regulatory T cell expansion to treat atherosclerosis in mice.

Front Immunol

2023 Jan 25

Zhu X, Li Q, George V

191. The helminth derived peptide FhHDM-1 redirects macrophage metabolism towards glutaminolysis to regulate the pro-inflammatory response.

Front Immunol

2023 Jan 25

Quinteros SL, von Krusenstiern E, Snyder NW

192. Human antibodies targeting ENPP1 as candidate therapeutics for cancers.

Front Immunol

2023 Jan 25

Chu X, Baek DS, Li W

193. Dendritic cell phenotype and function in a 3D co-culture model of patient-derived metastatic colorectal cancer organoids.

Front Immunol

2023 Jan 25

Subtil B, Iyer KK, Poel D

Colorectal cancer (CRC) remains one of the most aggressive and lethal cancers, with metastasis accounting for most deaths. As such, there is an unmet need for improved therapies for metastatic CRC (mCRC). Currently, the research focus is shifting towards the reciprocal interactions within the tumor microenvironment (TME), which prevent tumor clearance by the immune system. Dendritic cells (DCs) play a key role in the initiation and amplification of anti-tumor immune responses and in driving the clinical success of immunotherapies. Dissecting the interactions between DCs and CRC cells may open doors to identifying key mediators in tumor progression, and possible therapeutic targets. This requires representative, robust and versatile models and tools. Currently, there is a shortage of such in vitro systems to model the CRC TME and its tumor-immune cell interactions. Here we develop and establish a dynamic organotypic 3D co-culture system to recapitulate and untangle the interactions between DCs and patient-derived mCRC tumor organoids. To our knowledge, this is the first study investigating human DCs in co-culture with tumor organoids in a 3D, organotypic setting. This system reveals how mCRC organoids modulate and shape monocyte-derived DCs (MoDCs) behavior, phenotype, and function, within a collagen matrix, using techniques such as brightfield and fluorescence microscopy, flow cytometry, and fluorescence-activated cell sorting. Our 3D co-culture model shows high viability and extensive interaction between DCs and tumor organoids, and its structure resembles patient tissue sections. Furthermore, it is possible to retrieve DCs from the co-cultures and characterize their phenotypic and functional profile. In our study, the expression of activation markers in both mature and immature DCs and their ability to activate T cells were impacted by co-culture with tumor organoids. In the future, this direct co-culture platform can be adapted and exploited to study the CRC-DC interplay in more detail, enabling novel and broader insights into CRC-driven DC (dys)function.

194. Alkaline phosphatase combined with γ-glutamyl transferase is an independent predictor of prognosis of hepatocellular carcinoma patients receiving programmed death-1 inhibitors.

Front Immunol

2023 Jan 25

Xu L, Chen L, Zhang B

195. Adenovirus vector-mediated single chain variable fragments target the nucleocapsid protein of porcine epidemic diarrhea virus and protect against viral infection in piglets.

Front Immunol

2023 Jan 24

Wang F, Zhang Q, Zhang F

Porcine epidemic diarrhea virus (PEDV) mainly infects the intestinal epithelial cells of pigs, causing porcine epidemic diarrhea (PED). In particular, the virus causes severe diarrhea, dehydration, and death in neonatal piglets. Maternal immunity effectively protects neonatal piglets from PEDV infection; however, maternal antibodies can only prevent PEDV attachment and entry into target cells, but have no effects on intracellular viruses. Intracellular antibodies targeting virus-encoded proteins are effective in preventing viral infection. We previously identified four single chain variable fragments (scFvs), ZW1-16, ZW3-21, ZW1-41, and ZW4-16, which specifically targeted the PEDV N protein and significantly inhibited PEDV replication and up-regulated interferon-λ1 (IFN-λ1) expression in host cells. In our current study, the four scFvs were subcloned into replication-defective adenovirus vectors to generate recombinant adenoviruses rAdV-ZW1-16, rAdV-ZW3-21, rAdV-ZW1-41, and rAdV-ZW4-16. ScFvs were successfully expressed in Human Embryonic Kidney 293 (HEK293) cells and intestinal porcine epithelial cell line J2 (IPEC-J2) and were biosafe for piglets as indicated by body temperature and weight, scFv excretion in feces, IFN-γ and interleukin-4 (IL-4) expression in jejunum, and pathological changes in porcine tissue after oral administration. Western blotting, immunofluorescence, and immunohistochemical analyses showed that scFvs were expressed in porcine jejunum. The prophylactic effects of rAdV-ZW, a cocktail of the four rAdV-scFvs, on piglet diarrhea caused by PEDV was investigated. Clinical symptoms in piglets orally challenged with PEDV, following a two-time treatment with rAdV-ZW, were significantly reduced when compared with PEDV-infected piglets treated with phosphate buffered saline (PBS) or rAdV-wild-type. Also, no death and jejunal lesions were observed. ScFv co-localization with the PEDV N protein in vivo was also observed. Next, the expression of pro-inflammatory serum cytokines such as tumor necrosis factor-α (TNF-α), IL-6, IL-8, IL-12, and IFN-λ was assessed by enzyme-linked immunosorbent assay (ELISA), which showed that scFvs significantly suppressed PEDV-induced pro-inflammatory cytokine expression and restored PEDV-inhibited IFN-λ expression. Therefore, our study supported a promising role for intracellular scFvs targeting the PEDV N protein to prevent and treat diarrhea in PEDV-infected piglets.

196. 25-hydroxyvitamin D(3) generates immunomodulatory plasticity in human periodontal ligament-derived mesenchymal stromal cells that is inflammatory context-dependent.

Front Immunol

2023 Jan 24

Behm C, Blufstein A, Gahn J

INTRODUCTION: Human periodontal ligament-derived mesenchymal stromal cells (hPDL-MSCs) exhibit a tight bi-directional interaction with CD4+ T lymphocytes. The hPDL-MSCs' immunomodulatory abilities are drastically enhanced by pro-inflammatory cytokines via boosting the expression of various immunomediators. 25-hydroxyvitamin D3 (25(OH)D3), the major metabolite of vitamin D3 in the blood, affects both hPDL-MSCs and CD4+ T lymphocytes, but its influence on their interaction is unknown. METHODS: Therefore, primary hPDL-MSCs were stimulated in vitro with tumor necrosis factor (TNF)-α a or interleukin (IL)-1β in the absence and presence of 25(OH)D3 followed by an indirect co-culture with phytohemagglutinin-activated CD4+ T lymphocytes. The CD4+ T lymphocyte proliferation, viability, and cytokine secretion were analyzed. Additionally, the expression of various immunomediators in hPDL-MSCs was investigated, and their implication was verified by using pharmacological inhibitors. RESULTS: 25(OH)D3 significantly counteracted the suppressive effects of IL-1β-treated hPDL-MSCs on CD4+ T lymphocyte proliferation, whereas no effects were observed in the presence of TNF-α. Additionally, 25(OH)D3 significantly increased the percentage of viable CD4+ T lymphocytes via TNF-α- or IL-1β-treated hPDL-MSCs. It also caused a significant decrease in interferon-γ, IL-17A, and transforming growth factor-β productions, which were triggered by TNF-α-treated hPDL-MSCs. 25(OH)D3 significantly decreased the production of various immunomediators in hPDL-MSCs. Inhibition of two of them, prostaglandin E2 and indoleamine-2,3-dioxygenase-1, partially abolished some of the hPDL-MSCs-mediated effects of 25(OH)D3 on CD4+ T lymphocytes. CONCLUSION: These data indicate that 25(OH)D3 influences the immunomodulatory activities of hPDL-MSCs. This modulatory potential seems to have high plasticity depending on the local cytokine conditions and may be involved in regulating periodontal tissue inflammatory processes.

197. Kinetics of SARS-CoV-2 neutralizing antibodies in Omicron breakthrough cases with inactivated vaccination: Role in inferring the history and duration of infection.

Front Immunol

2023 Jan 24

Simayi A, Li C, Chen C

BACKGROUND: The quantitative level and kinetics of neutralizing antibodies (NAbs) in individuals with Omicron breakthrough infections may differ from those of vaccinated individuals without infection. Therefore, we aimed to evaluate the difference in NAb levels to distinguish the breakthrough cases from the post-immunized population to identify early infected person in an outbreak epidemic when nasal and/or pharyngeal swab nucleic acid real-time PCR results were negative. METHODS: We collected 1077 serum samples from 877 individuals, including 189 with Omicron BA.2 breakthrough infection and 688 post-immunized participants. NAb titers were detected using the surrogate virus neutralization test, and were log(2)-transformed to normalize prior to analysis using Student's unpaired t-tests. Geometric mean titers (GMT) were calculated with 95% confidence intervals (CI). Linear regression models were used to identify factors associated with NAb levels. We further conducted ROC curve analysis to evaluate the NAbs' ability to identify breakthrough infected individuals in the vaccinated population. RESULTS: The breakthrough infection group had a consistently higher NAb levels than the post-immunized group according to time since the last vaccination. NAb titers in the breakthrough infection group were 6.4-fold higher than those in the post-immunized group (GMT: 40.72 AU/mL and 6.38 AU/mL, respectively; p<0.0001). In the breakthrough infection group, the NAbs in the convalescent phase were 10.9-fold higher than in the acute phase (GMT: 200.48 AU/mL and 18.46 AU/mL, respectively; p<0.0001). In addition, the time since infection, booster vaccination, and the time since last vaccination were associated with log(2)-transformed NAb levels in the breakthrough infection group. ROC curve analysis showed that ROC area was largest (0.728) when the cut-off value of log(2)-transformed NAb was 6, which indicated that NAb levels could identify breakthrough infected individuals in the vaccinated population. CONCLUSION: Our study demonstrates that the NAb titers of Omicron BA.2 variant breakthrough cases are higher than in the post-immunized group. The difference in NAb levels could be used to identify cases of breakthrough infection from the post-immunized population in an outbreak epidemic.

198. Quantitative fluorescence resonance energy transfer-based immunoassay for activated complement C1s.

Front Immunol

2023 Jan 24

Ye J, Xu J, Zhang C

OBJECTIVES: C1s activation is associated with the pathogenesis of various diseases, indicating the potential value of C1s activation detection in clinic. Here we aimed to establish fluorescence resonance energy transfer (FRET)-based immunoassay for the quantitative detection of activated C1s in serum. METHODS: FRET-based fluorogenic peptides, sensitive to the enzymatic activity of activated C1s, were prepared and labeled with the fluorophore ortho-aminobenzoic acid (Abz) and quencher 2,4-dinitrophenyl (Dnp), and then were further selected depending on its Kcat/Km value. C1s in the samples was captured and separated using anti-C1s-conjugated magnetic microbeads. Next, enzymatic activity of activated C1s in samples and standards was examined using fluorescent quenched substrate assays. Limit of detection (LOD), accuracy, precision, and specificity of FRET-based immunoassay were also investigated. RESULTS: This method presented a linear quantification range for the enzymatic activity of activated C1s up to 10 μmol min-1 mL-1 and LOD of 0.096 μmol·min-1·mL-1 for serum samples. The recovery of the method was in the range of 90% ~ 110%. All CV values of the intra-analysis and inter-analysis of three levels in samples were less than 10%. The cross-reaction rates with C1r enzyme, MASP1, and MASP2 were less than 0.5%. No significant interferences were found with bilirubin (0.2 mg mL-1), Chyle (2000 FTU), and haemoglobin (5 mg mL-1), but anticoagulants (EDTA, citrate and heparin) inhibited the enzymatic ability of activated C1s. Thus, this established method can be used for the determination of active C1s in human serum samples in the concentration interval of 0.096-10.000 μmol min-1 mL-1. CONCLUSIONS: One anti-C1s-based FRET immunoassay for activated C1s detection in serum samples were established, and it will be useful to explore the role of C1s activation in the pathogenesis, diagnosis and treatment in complement-related diseases.

199. An integrative systems biology view of host-pathogen interactions: The regulation of immunity and homeostasis is concomitant, flexible, and smart.

Front Immunol

2023 Jan 24

Grossman Z, Meyerhans A, Bocharov G.

The systemic bio-organization of humans and other mammals is essentially "preprogrammed", and the basic interacting units, the cells, can be crudely mapped into discrete sets of developmental lineages and maturation states. Over several decades, however, and focusing on the immune system, we and others invoked evidence - now overwhelming - suggesting dynamic acquisition of cellular properties and functions, through tuning, re-networking, chromatin remodeling, and adaptive differentiation. The genetically encoded "algorithms" that govern the integration of signals and the computation of new states are not fully understood but are believed to be "smart", designed to enable the cells and the system to discriminate meaningful perturbations from each other and from "noise". Cellular sensory and response properties are shaped in part by recurring temporal patterns, or features, of the signaling environment. We compared this phenomenon to associative brain learning. We proposed that interactive cell learning is subject to selective pressures geared to performance, allowing the response of immune cells to injury or infection to be progressively coordinated with that of other cell types across tissues and organs. This in turn is comparable to supervised brain learning. Guided by feedback from both the tissue itself and the neural system, resident or recruited antigen-specific and innate immune cells can eradicate a pathogen while simultaneously sustaining functional homeostasis. As informative memories of immune responses are imprinted both systemically and within the targeted tissues, it is desirable to enhance tissue preparedness by incorporating attenuated-pathogen vaccines and informed choice of tissue-centered immunomodulators in vaccination schemes. Fortunately, much of the "training" that a living system requires to survive and function in the face of disturbances from outside or within is already incorporated into its design, so it does not need to deep-learn how to face a new challenge each time from scratch. Instead, the system learns from experience how to efficiently select a built-in strategy, or a combination of those, and can then use tuning to refine its organization and responses. Efforts to identify and therapeutically augment such strategies can take advantage of existing integrative modeling approaches. One recently explored strategy is boosting the flux of uninfected cells into and throughout an infected tissue to rinse and replace the infected cells.

200. Corrigendum: Bullous pemphigoid IgG induces cell dysfunction and enhances the motility of epidermal keratinocytes via Rac1/proteasome activation.

Front Immunol

2023 Jan 24

Tie D, Da X, Natsuga K

201. Association of iKIR-mismatch model and donor aKIRs with better outcome in haploidentical hematopoietic stem cell transplantation for acute myeloid leukemia.

Front Immunol

2023 Jan 24

Zhang Y, Ye C, Zhu H

202. Novel pre-clinical mouse models for chronic Graft-versus-Host Disease.

Front Immunol

2023 Jan 24

Verlaat L, Riesner K, Kalupa M

203. Dendritic cells in inborn errors of immunity.

Front Immunol

2023 Jan 23

Gupta S, Agrawal A.

204. Tissue-resident memory T cells in renal autoimmune diseases.

Front Immunol

2023 Jan 23

Ginsberg P, Panzer U, Asada N.

205. STAT5b: A master regulator of key biological pathways.

Front Immunol

2023 Jan 23

Smith MR, Satter LRF, Vargas-Hernández A.

206. Immunogenic cell death: The cornerstone of oncolytic viro-immunotherapy.

Front Immunol

2023 Jan 23

Palanivelu L, Liu CH, Lin LT.

207. Immunologic, metabolic and genetic impact of diabetes on tuberculosis susceptibility.

Front Immunol

2023 Jan 23

Ssekamatte P, Sande OJ, van Crevel R

208. Advances in CT features and radiomics of checkpoint inhibitor-related pneumonitis: A short review.

Front Immunol

2023 Jan 23

Huang J, Chen X, Xia B

209. The microbiota as a modulator of mucosal inflammation and HIV/HPV pathogenesis: From association to causation.

Front Immunol

2023 Jan 23

Moreno E, Ron R, Serrano-Villar S.

210. Biomaterials delivery strategies to repair degenerated intervertebral discs by regulating the inflammatory microenvironment.

Front Immunol

2023 Jan 23

Xia Y, Wang H, Yang R

Intervertebral disc degeneration (IVDD) is one of the leading causes of lower back pain. Although IVDD cannot directly cause death, it can cause pain, psychological burdens, and economic burdens to patients. Current conservative treatments for IVDD can relieve pain but cannot reverse the disease. Patients who cannot tolerate pain usually resort to a strategy of surgical resection of the degenerated disc. However, the surgical removal of IVDD can affect the stability of adjacent discs. Furthermore, the probability of the reherniation of the intervertebral disc (IVD) after surgery is as high as 21.2%. Strategies based on tissue engineering to deliver stem cells for the regeneration of nucleus purposes (NP) and annulus fibrosus (AF) have been extensively studied. The developed biomaterials not only locally withstand the pressure of the IVD but also lay the foundation for the survival of stem cells. However, the structure of IVDs does not provide sufficient nutrients for delivered stem cells. The role of immune mechanisms in IVDD has recently become clear. In IVDD, the IVD that was originally in immune privilege prevents the attack of immune cells (mainly effector T cells and macrophages) and aggravates the disease. Immune regulatory and inflammatory factors released by effector T cells, macrophages, and the IVD further aggravate IVDD. Reversing IVDD by regulating the inflammatory microenvironment is a potential approach for the treatment of the disease. However, the biological factors modulating the inflammatory microenvironment easily degrade in vivo. It makes it possible for different biomaterials to modulate the inflammatory microenvironment to repair IVDD. In this review, we have discussed the structures of IVDs and the immune mechanisms underlying IVDD. We have described the immune mechanisms elicited by different biological factors, including tumor necrosis factors, interleukins, transforming growth factors, hypoxia-inducible factors, and reactive oxygen species in IVDs. Finally, we have discussed the biomaterials used to modulate the inflammatory microenvironment to repair IVDD and their development.

211. Transcription factor TFII-I fine tunes innate properties of B lymphocytes.

Front Immunol

2023 Jan 23

Singh A, Kaileh M, De S

212. Autophagy-related IFNG is a prognostic and immunochemotherapeutic biomarker of COAD patients.

Front Immunol

2023 Jan 23

Yue T, Cai Y, Zhu J

BACKGROUND: Numerous studies have shown autophagy affects cellular immune responses. This study aims to explore prognosis and immunotherapeutic biomarkers related to autophagy in colon adenocarcinoma (COAD). METHODS: Based on R software, we performed the ssGSEA, differential expression analysis, Kaplan-Meier survival analysis, correlation analysis, and enrichment analysis. For wet experiment, we did qRT-PCR, immunohistochemistry and CCK-8 experiments. RESULTS: Using autophagy-related genes (ARGs) and the ssGSEA, COAD patients were divided into low and high autophagy groups. For immune score, stromal score, tumor purity, tumor infiltrating immune cells, co-signaling molecules, tumor mutational burden, microsatellite instability, mismatch repair, immune-related pathways, immune signatures, somatic mutations and subtype analysis, high autophagy group might benefit more from immunotherapy. Among 232 ARGs, IFNG was generally significantly correlated with tumor immunotherapy biomarkers (PD-L1, CD8A and cytotoxic T lymphocytes (CTL)). The disease-free survival of high IFNG group was significantly longer than that of low group. On above-mentioned immune-related research, the high IFNG group reached the same conclusion. The qRT-PCR and IHC analysis confirmed that IFNG was significantly higher expressed in dMMR samples compared to pMMR samples. For chemotherapy, the autophagy and IFNG were significantly negatively related to the chemosensitivity to cisplatin; IFNG inhibitor glucosamine increased cisplatin chemoresistance while IFNG increased cisplatin chemosensitivity; IFNG could reverse glucosamine induced chemoresistance. The functional enrichment analysis of IFNG, PD-L1, CD8A and 20 similar proteins were related to the activation of the immune system. The GSEA and ceRNA network partly described interaction mechanisms of IFNG with PD-L1 and CD8A. CONCLUSION: Autophagy score and IFNG expression were novel immunotherapy predictive biomarkers, which might play predictive effects through the JAK-STAT signaling pathway. IFNG might be a potential targeted therapy for cisplatin resistant colon cancer. Besides, IFNG was also a prognostic indicator.

213. Clostridium butyricum alleviates LPS-induced acute immune stress in goats by regulating bacterial communities and blood metabolites.

Front Immunol

2023 Jan 23

Zhang C, Hou T, Wang J

The mitigation and prevention of acute immune stress are essential for livestock production. Clostridium butyricum (C. butyricum) has shown positive effects in stabilizing intestinal microbiota disorders, improving immune function and inhibiting disease development, but its effects on ruminants are unclear. Therefore, the current trial hypothesized that C. butyricum could improve goats' immune function and antioxidant capacity by regulating bacterial communities and blood metabolism and effectively alleviating the acute immune stress induced by Lipopolysaccharides (LPS). Sixteen healthy goats were fed C. butyricum for 70 days, and the goats were challenged with LPS on day 71. Blood and feces were collected at 0 h and 6 h after the challenge to evaluate the effects of C. butyricum on their intestinal microbiota, immune function, antioxidant function, and plasma metabolites. The results showed that C. butyricum had no significant effect on plasma biochemical parameters at the beginning of the LPS challenge. However, supplementation with C. butyricum increased plasma levels of IgA, IgG, T-SOD, and T-AOC (P < 0.05), but TNF-α, IL-6, and MDA were decreased (P < 0.05). In contrast, IL-10 showed an increasing trend (P < 0.10). Rectal microbiota analysis showed that C. butyricum significantly increased the relative abundance of Epsilonbacteraeota at the phylum level of goats; at the genus level, the relative abundances of Campylobacter and Anaerorhabdus]_furcosa_group were also significantly increased (P < 0.05). Christensenellaceae_R-7_group as the dominant microbiota also showed a significant increase in their abundance values, while Clostridium and Lachnospiraceae_UCG-001 were significantly lower (P < 0.05). When the LPS challenge continued up to 6 h, dietary supplementation with C. butyricum still resulted in significantly higher plasma concentrations of IgA, IL-10, and T-SOD in goats than in the control group, reducing TNF-α levels (P < 0.05). In addition, plasma levels of T-CHOL and LDL were significantly reduced, and the expression of d-proline was significantly upregulated according to metabolomic analysis (P < 0.05). In conclusion, dietary supplementation with C. butyricum helped optimize the expression of bacterial communities and plasma metabolites to enhance the ability of goats to alleviate acute immune stress.

214. Iripin-1, a new anti-inflammatory tick serpin, inhibits leukocyte recruitment in vivo while altering the levels of chemokines and adhesion molecules.

Front Immunol

2023 Jan 23

Chlastáková A, Kaščáková B, Kotál J

Serpins are widely distributed and functionally diverse inhibitors of serine proteases. Ticks secrete serpins with anti-coagulation, anti-inflammatory, and immunomodulatory activities via their saliva into the feeding cavity to modulate host's hemostatic and immune reaction initiated by the insertion of tick's mouthparts into skin. The suppression of the host's immune response not only allows ticks to feed on a host for several days but also creates favorable conditions for the transmission of tick-borne pathogens. Herein we present the functional and structural characterization of Iripin-1 (Ixodes ricinus serpin-1), whose expression was detected in the salivary glands of the tick Ixodes ricinus, a European vector of tick-borne encephalitis and Lyme disease. Of 16 selected serine proteases, Iripin-1 inhibited primarily trypsin and further exhibited weaker inhibitory activity against kallikrein, matriptase, and plasmin. In the mouse model of acute peritonitis, Iripin-1 enhanced the production of the anti-inflammatory cytokine IL-10 and chemokines involved in neutrophil and monocyte recruitment, including MCP-1/CCL2, a potent histamine-releasing factor. Despite increased chemokine levels, the migration of neutrophils and monocytes to inflamed peritoneal cavities was significantly attenuated following Iripin-1 administration. Based on the results of in vitro experiments, immune cell recruitment might be inhibited due to Iripin-1-mediated reduction of the expression of chemokine receptors in neutrophils and adhesion molecules in endothelial cells. Decreased activity of serine proteases in the presence of Iripin-1 could further impede cell migration to the site of inflammation. Finally, we determined the tertiary structure of native Iripin-1 at 2.10 Å resolution by employing the X-ray crystallography technique. In conclusion, our data indicate that Iripin-1 facilitates I. ricinus feeding by attenuating the host's inflammatory response at the tick attachment site.

215. Cost-effectiveness of sintilimab plus chemotherapy versus chemotherapy alone as first-line treatment of locally advanced or metastatic oesophageal squamous cell carcinoma.

Front Immunol

2023 Jan 23

Liu L, Wang L, Chen L

BACKGROUND: Sintilimab plus chemotherapy significantly prolongs overall survival (OS) for patients with advanced or metastatic oesophageal squamous cell carcinoma (OSCC). However, the cost-effectiveness of this high-priced therapy is currently unknown. We evaluated the cost-effectiveness of sintilimab plus chemotherapy vs chemotherapy alone as fist-line therapy in patients with advanced or metastatic OSCC from the perspective of Chinese healthcare system. METHODS: A partitioned survival model consisting of 3 discrete health states was constructed to assess the cost and effectiveness of sintilimab plus chemotherapy vs chemotherapy as first-line treatment of OSCC. Key clinical data in the model came from the ORIENT-15 trial. Costs and utilities were collected from published sources. Life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), incremental net health benefits (INHB), and incremental net monetary benefits (INMB) were calculated for the two treatment strategies. One-way and probabilistic sensitivity analyses were conducted to account for uncertainty and model stability. Additional subgroup and scenario analyses were performed. RESULTS: Treatment with sintilimab plus chemotherapy provided an additional 0.37 QALYs and an incremental cost of $8,046.58 compared with chemotherapy, which resulted in an ICER of $21,782.24 per QALY gained. One-way sensitivity analysis revealed that the model was most sensitive to utility of progression-free survival (PFS) and the cost of sintilimab. The probabilistic sensitivity analysis indicated that the probability of sintilimab plus chemotherapy being cost-effective was 0.01%, 76.80% and 98.60% at the threshold of 1, 2 or 3 times GDP per capita per QALY, respectively. Subgroup analysis found that all subgroups other than PD-L1 expression combined positive scores < 1 subgroup favored sintilimab plus chemotherapy treatment due to its association with positive INHBs by varying the hazard ratios for OS and PFS. The scenario analyses showed altering the time horizon of the model or fitting survival curves separately did not reverse results of the model. CONCLUSION: Sintilimab plus chemotherapy was associated with improved QALYs and an additional cost but was estimated to be cost-effective compared with chemotherapy alone as a first-line treatment for patients with advanced or metastatic OSCC at the commonly adopted willingness-to-pay threshold of 3 times GDP per capita per QALY in China.

216. Cytokine/chemokine levels in the CSF and serum of anti-NMDAR encephalitis: A systematic review and meta-analysis.

Front Immunol

2023 Jan 23

Ma Y, Wang J, Guo S

OBJECTIVES: To summarize the cytokine/chemokine levels of anti-N-methyl-Daspartate receptor encephalitis (NMDAR-E) and explore the potential role of these molecules and immune cells in the pathogenic mechanism. METHODS: The PubMed, Cochrane Library, Embase, and Web of Science databases were searched for various articles that assessed the concentrations of cytokines/chemokines in the unstimulated cerebrospinal fluid (CSF) or serum of patients with NMDAR-E in this systematic review and meta-analysis. The standardized mean difference (SMD) and 95% confidence interval (CI) were calculated by Stata17.0. RESULTS: A total of 19 articles were included in the systematic review from 260 candidate papers, and cytokine/chemokine levels reported in the CSF/serum were examined in each article. This meta-analysis included 17 eligible studies comprising 579 patients with NMDAR-E, 367 patients with noninflammatory neurological disorders, and 42 healthy controls from China, Spain, South Korea, Australia, Czechia, and Sweden. The results indicated that the levels of different cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-10, IL-13, IL-1β, IL-12, and IL-17 and chemokine C-X-C motif ligand (CXCL)10 in the CSF were significantly higher in NMDAR-E patients with a large effect size. In addition, B cell activating factor (BAFF), CXCL13, and interferon (IFN)-γ levels in the CSF were higher in NMDAR-E patients with a middle effect size. In contrast, levels of IL-2 and IL-4 in the CSF and CXCL13 and BAFF in the serum did not show a significant difference between cases and controls. CONCLUSIONS: These analyses showed that the central immune response in NMDAR-E is a process that involves multiple immune cell interactions mediated by cytokines/chemokines, and T cells play an important role in the pathogenesis of immunity. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier (CRD42022342485).

217. Serum cytokine change profile associated with HBsAg loss during combination therapy with PEG-IFN-α in NAs-suppressed chronic hepatitis B patients.

Front Immunol

2023 Jan 23

Wang WX, Jia R, Jin XY

218. Counting is almost all you need.

Front Immunol

2023 Jan 20

Akerman O, Isakov H, Levi R

219. NK cell education: Physiological and pathological influences.

Front Immunol

2023 Jan 20

Rascle P, Woolley G, Jost S

220. IgY antibodies: The promising potential to overcome antibiotic resistance.

Front Immunol

2023 Jan 20

El-Kafrawy SA, Abbas AT, Oelkrug C

221. Targeting HIV-1 reservoirs in T cell subsets.

Front Immunol

2023 Jan 20

Li M, Budai MM, Chen M

222. Free complement and complement containing extracellular vesicles as potential biomarkers for neuroinflammatory and neurodegenerative disorders.

Front Immunol

2023 Jan 20

Burgelman M, Dujardin P, Vandendriessche C

223. A potential area of use for immune checkpoint inhibitors: Targeting bone marrow microenvironment in acute myeloid leukemia.

Front Immunol

2023 Jan 20

Aru B, Pehlivanoğlu C, Dal Z

224. The potential role of short chain fatty acids improving ex vivo T and CAR-T cell fitness and expansion for cancer immunotherapies.

Front Immunol

2023 Jan 20

González-Brito A, Uribe-Herranz M.

225. Multimodal human thymic profiling reveals trajectories and cellular milieu for T agonist selection.

Front Immunol

2023 Jan 20

Heimli M, Flåm ST, Hjorthaug HS

226. Blood transcriptome responses in patients correlate with severity of COVID-19 disease.

Front Immunol

2023 Jan 20

Wang Y, Schughart K, Pelaia TM

Author information: (1)Department of Intensive Care Medicine, Nepean Hospital, Penrith, NSW, Australia. (2)Centre for Immunology and Allergy Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia. (3)Faculty of Medicine and Health, Sydney Medical School Nepean, Nepean Hospital, University of Sydney, Penrith, NSW, Australia. (4)Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, United States. (5)Institute of Molecular Virology, University of Münster, Münster, Germany. (6)Sydney Informatics Hub, Core Research Facilities, The University of Sydney, Sydney, NSW, Australia. (7)Medical ICU, 1st Department of Internal Medicine, Charles University and Teaching Hospital, Pilsen, Czechia. (8)Department of Microbiology. St George Hospital, Kogarah, NSW, Australia. (9)Research and Education Network, Western Sydney Local Health District, Westmead Hospital, NSW, Westmead, Australia. (10)Faculty of Medicine and Health, Sydney Medical School Westmead, Westmead Hospital, University of Sydney, NSW, Westmead, Australia. (11)School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia. (12)Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, Westmead, NSW, Australia. (13)Faculty of Medicine and Health, School of Medical Sciences, The University of Sydney, Sydney, NSW, Australia. (14)Westmead Hospital, Western Sydney Local Health District, Westmead, NSW, Australia. (15)Sydney Institute for Infectious Disease, The University of Sydney, Sydney, NSW, Australia. (16)Victorian Infectious Disease Service, The Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. (17)Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. (18)Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute of Medical Research, Royal Perth Hospital, Perth, WA, Australia. (19)Medical School, University of Western Australia, Perth, WA, Australia. (20)Emergency Department, Royal Perth Hospital, Perth, WA, Australia. (21)Centre for Clinical Research in Emergency Medicine, Royal Perth Bentley Group, Perth, WA, Australia.

227. Exposure to solar ultraviolet radiation establishes a novel immune suppressive lipidome in skin-draining lymph nodes.

Front Immunol

2023 Jan 20

Tse BCY, Ferguson AL, Koay YC

228. Assessment of the longitudinal humoral response in non-hospitalized SARS-CoV-2-positive individuals at decentralized sites: Outcomes and concordance.

Front Immunol

2023 Jan 20

Djaïleb A, Lavallée É, Parker MF

229. LAG3 genotype of the donor and clinical outcome after allogeneic transplantation from HLA-identical sibling donors.

Front Immunol

2023 Jan 20

Cruz D, Rodríguez-Romanos R, González-Bartulos M

230. High levels of kappa free light chain synthesis predict cognitive decline in relapsing-remitting multiple sclerosis.

Front Immunol

2023 Jan 20

Rosenstein I, Axelsson M, Novakova L

231. Corrigendum: Immunogenomic landscape in breast cancer reveals immunotherapeutically relevant gene signatures.

Front Immunol

2023 Jan 20

Wang T, Li T, Li B

232. Acute and long-term immune responses to SARS-CoV-2 infection in unvaccinated children and young adults with inborn errors of immunity.

Front Immunol

2023 Jan 20

García-García A, Fortuny C, Fumadó V

PURPOSE: To describe SARS-CoV-2 infection outcome in unvaccinated children and young adults with inborn errors of immunity (IEI) and to compare their specific acute and long-term immune responses with a sex-, age-, and severity-matched healthy population (HC). METHODS: Unvaccinated IEI patients up to 22 years old infected with SARS-CoV-2 were recruited along with a cohort of HC. SARS-CoV-2 serology and ELISpot were performed in the acute phase of infection (up to 6 weeks) and at 3, 6, 9, and 12 months. RESULTS: Twenty-five IEI patients (median age 14.3 years, min.-max. range 4.5-22.8; 15/25 males; syndromic combined immunodeficiencies: 48.0%, antibody deficiencies: 16.0%) and 17 HC (median age 15.3 years, min.-max. range 5.4-20.0; 6/17 males, 35.3%) were included. Pneumonia occurred in 4/25 IEI patients. In the acute phase SARS-CoV-2 specific immunoglobulins were positive in all HC but in only half of IEI in whom it could be measured (n=17/25): IgG+ 58.8% (10/17) (p=0.009); IgM+ 41.2% (7/17)(p<0.001); IgA+ 52.9% (9/17)(p=0.003). Quantitative response (index) was also lower compared with HC: IgG IEI (3.1 ± 4.4) vs. HC (3.5 ± 1.5)(p=0.06); IgM IEI (1.9 ± 2.4) vs. HC (3.9 ± 2.4)(p=0.007); IgA IEI (3.3 ± 4.7) vs. HC (4.6 ± 2.5)(p=0.04). ELISpots positivity was qualitatively lower in IEI vs. HC (S-ELISpot IEI: 3/11, 27.3% vs. HC: 10/11, 90.9%; p=0.008; N-ELISpot IEI: 3/9, 33.3% vs. HC: 11/11, 100%; p=0.002) and also quantitatively lower (S-ELISpot IEI: mean index 3.2 ± 5.0 vs. HC 21.2 ± 17.0; p=0.001; N-ELISpot IEI: mean index 9.3 ± 16.6 vs. HC: 39.1 ± 23.7; p=0.004). As for long term response, SARS-CoV-2-IgM+ at 6 months was qualitatively lower in IEI(3/8, 37.5% vs. 9/10 HC: 90.0%; p=0.043), and quantitatively lower in all serologies IgG, M, and A (IEI n=9, 1.1 ± 0.9 vs. HC n=10, 2.1 ± 0.9, p=0.03; IEI n=9, 1.3 ± 1.5 vs. HC n=10, 2.9 ± 2.8, p=0.02; and IEI n=9, 0.6 ± 0.5 vs. HC n=10, 1.7 ± 0.8, p=0.002 -respectively) but there were no differences at remaining time points. CONCLUSIONS: Our IEI pediatric cohort had a higher COVID-19 pneumonia rate than the general age-range population, with lower humoral and cellular responses in the acute phase (even lower compared to the reported IEI serological response after SARS-CoV-2 vaccination), and weaker humoral responses at 6 months after infection compared with HC.

233. The adjuvants dmLT and mmCT enhance humoral immune responses to a pneumococcal conjugate vaccine after both parenteral or mucosal immunization of neonatal mice.

Front Immunol

2023 Jan 20

Molina Estupiñan JL, Aradottir Pind AA, Foroutan Pajoohian P

234. Identification of a forkhead box protein transcriptional network induced in human neutrophils in response to inflammatory stimuli.

Front Immunol

2023 Jan 20

Ismailova A, Salehi-Tabar R, Dimitrov V

235. Editorial: The role of hematopoietic and immune microenvironment in hematopoietic stem cell transplantation.

Front Immunol

2023 Jan 19

Wang X, Liu Q, Zhang X.

236. The role of major immune cells in myocardial infarction.

Front Immunol

2023 Jan 19

Feng Q, Li Q, Zhou H

237. Longitudinal monitoring of mRNA-vaccine-induced immunity against SARS-CoV-2.

Front Immunol

2023 Jan 19

Monzon-Posadas WO, Zorn J, Peters K

238. Review: Current trends, challenges, and success stories in adjuvant research.

Front Immunol

2023 Jan 19

Singleton KL, Joffe A, Leitner WW.

239. Maternal synapsin autoantibodies are associated with neurodevelopmental delay.

Front Immunol

2023 Jan 19

Bünger I, Makridis KL, Kreye J

240. A review of TSHR- and IGF-1R-related pathogenesis and treatment of Graves' orbitopathy.

Front Immunol

2023 Jan 19

Cui X, Wang F, Liu C.

241. Clinical application and prospect of immune checkpoint inhibitors for CAR-NK cell in tumor immunotherapy.

Front Immunol

2023 Jan 19

Yang K, Zhao Y, Sun G

242. Virus induced dysbiosis promotes type 1 diabetes onset.

Front Immunol

2023 Jan 19

Morse ZJ, Simister RL, Crowe SA

243. MAITabolism(2) - the emerging understanding of MAIT cell metabolism and their role in metabolic disease.

Front Immunol

2023 Jan 19

Kedia-Mehta N, Hogan AE.

244. Single-cell analysis of myeloid cells in HPV(+) tonsillar cancer.

Front Immunol

2023 Jan 19

Jimenez DG, Altunbulakli C, Swoboda S

245. New methods for the quantification of mixed chimerism in transplantation.

Front Immunol

2023 Jan 19

Picard C, Frassati C, Cherouat N

246. Lysine methyltransferase Kmt2d regulates naive CD8(+) T cell activation-induced survival.

Front Immunol

2023 Jan 19

Kim J, Nguyen T, Cifello J

247. The Vacc-SeqQC project: Benchmarking RNA-Seq for clinical vaccine studies.

Front Immunol

2023 Jan 19

Goll JB, Bosinger SE, Jensen TL

INTRODUCTION: Over the last decade, the field of systems vaccinology has emerged, in which high throughput transcriptomics and other omics assays are used to probe changes of the innate and adaptive immune system in response to vaccination. The goal of this study was to benchmark key technical and analytical parameters of RNA sequencing (RNA-seq) in the context of a multi-site, double-blind randomized vaccine clinical trial. METHODS: We collected longitudinal peripheral blood mononuclear cell (PBMC) samples from 10 subjects before and after vaccination with a live attenuated Francisella tularensis vaccine and performed RNA-Seq at two different sites using aliquots from the same sample to generate two replicate datasets (5 time points for 50 samples each). We evaluated the impact of (i) filtering lowly-expressed genes, (ii) using external RNA controls, (iii) fold change and false discovery rate (FDR) filtering, (iv) read length, and (v) sequencing depth on differential expressed genes (DEGs) concordance between replicate datasets. Using synthetic mRNA spike-ins, we developed a method for empirically establishing minimal read-count thresholds for maintaining fold change accuracy on a per-experiment basis. We defined a reference PBMC transcriptome by pooling sequence data and established the impact of sequencing depth and gene filtering on transcriptome representation. Lastly, we modeled statistical power to detect DEGs for a range of sample sizes, effect sizes, and sequencing depths. RESULTS AND DISCUSSION: Our results showed that (i) filtering lowly-expressed genes is recommended to improve fold-change accuracy and inter-site agreement, if possible guided by mRNA spike-ins (ii) read length did not have a major impact on DEG detection, (iii) applying fold-change cutoffs for DEG detection reduced inter-set agreement and should be used with caution, if at all, (iv) reduction in sequencing depth had a minimal impact on statistical power but reduced the identifiable fraction of the PBMC transcriptome, (v) after sample size, effect size (i.e. the magnitude of fold change) was the most important driver of statistical power to detect DEG. The results from this study provide RNA sequencing benchmarks and guidelines for planning future similar vaccine studies.

248. Endoplasmic reticulum-associated protein degradation contributes to Toll innate immune defense in Drosophila melanogaster.

Front Immunol

2023 Jan 19

Zhu Y, Liu L, Zhang C

249. Vam6 reduces iNKT cell function in tumor via modulating AMPK/mTOR pathways.

Front Immunol

2023 Jan 19

Bai S, Wu Q, Zhu S

250. Age-adjusted impact of prior COVID-19 on SARS-CoV-2 mRNA vaccine response.

Front Immunol

2023 Jan 19

Nakagama S, Nakagama Y, Komase Y

251. The adjuvant effect of bacterium-like particles depends on the route of administration.

Front Immunol

2023 Jan 19

Sudo H, Tokunoh N, Tsujii A

252. Corrigendum: Suitability of potyviral recombinant virus-like particles bearing a complete food allergen for immunotherapy vaccines.

Front Immunol

2023 Jan 19

Pazos-Castro D, Margain C, Gonzalez-Klein Z

253. Alkaline sphingomyelinase (NPP7) impacts the homeostasis of intestinal T lymphocyte populations.

Front Immunol

2023 Jan 19

Alyamani M, Kadivar M, Erjefält J

254. Identification and classification of distinct surface markers of T regulatory cells.

Front Immunol

2023 Jan 19

Wegrzyn AS, Kedzierska AE, Obojski A.

BACKGROUND: Regulatory T (Treg) cells have emerged as key players in the maintenance of immune homeostasis. Although significant progress has been made in recent years to define the Treg surface markers involved with or identifying their suppressive function, there remains much to be elucidated, and many questions persist. This study determined the expression of surface markers on human peripheral Treg cells and conventional T (Tconv) cells in a steady state and after activation to gain insight into their mechanism of action and more precisely characterize this regulatory population in humans. METHODS: To screen Treg and Tconv cells, peripheral blood mononuclear cells (PBMCs) were isolated from volunteers, stained with a commercially available lyophilized antibody array comprising 371 surface antigens, and analyzed by flow cytometry. To compare Treg cells with activated Tconv cells, PBMCs were stimulated with PMA and further stained similar to freshly isolated cells. RESULTS: Treg and Tconv cells were positive for 135 and 168 of the 371 antigens, respectively. Based on the frequency distribution, all of the most highly expressed markers identified were shared by both Treg and Tconv cells and participate in T cell activation, act as costimulatory and signaling molecules, or exhibit adhesion and migratory functions. Additionally, we identified several differences in marker expression between Treg and Tconv cells, with most found in the expression of co-stimulatory (ICOS, GITR, 4-1BB) and co-inhibitory (TIGIT, CTLA-4) molecules, as well as chemokine receptors (CXCR4, CXCR5, CCR4, CCR5, CCR7, CCR8, and CXCR7). Furthermore, post-activation expression of surface molecules identified molecules capable of discriminating Treg cells from activated Tconv cells (GITR, 4-1BB, TIGIT, CD120b, and CD39); however, almost all of these markers were also expressed in a small fraction of activated Tconv cells. CONCLUSIONS: These results offer insight into the biology of Tregs and contribute to their accurate identification and characterization in variety of immunological diseases as well as physiological processes.

255. Protective effects of dietary grape against atopic dermatitis-like skin lesions in NC/NgaTndCrlj mice.

Front Immunol

2023 Jan 19

Singh CK, Mintie CA, Ndiaye MA

256. Exploring causal correlations between inflammatory cytokines and systemic lupus erythematosus: A Mendelian randomization.

Front Immunol

2023 Jan 19

Xiang M, Wang Y, Gao Z

257. Cassane diterpenoid ameliorates dextran sulfate sodium-induced experimental colitis by regulating gut microbiota and suppressing tryptophan metabolism.

Front Immunol

2023 Jan 19

Liu T, Ning Z, Liu P

258. Prediction and validation of murine MHC class I epitopes of the recombinant virus VSV-GP.

Front Immunol

2023 Jan 19

Vijver SV, Danklmaier S, Pipperger L

Oncolytic viruses are currently tested as a novel platform for cancer therapy. These viruses preferentially replicate in and kill malignant cells. Due to their microbial origin, treatment with oncolytic viruses naturally results in anti-viral responses and general immune activation. Consequently, the oncolytic virus treatment also induces anti-viral T cells. Since these can constitute the dominant activated T cell pool, monitoring of the anti-viral T cell response may aid in better understanding of the immune responses post oncolytic virotherapy. This study aimed to identify the anti-viral T cells raised by VSV-GP virotherapy in C57BL/6J mice, one of the most widely used models for preclinical studies. VSV-GP is a novel oncolytic agent that recently entered a clinical phase I study. To identify the VSV-GP epitopes to which mouse anti-viral T cells react, we used a multilevel adapted bioinformatics viral epitope prediction approach based on the tools netMHCpan, MHCflurry and netMHCstabPan, which are commonly used in neoepitope identification. Predicted viral epitopes were ranked based on consensus binding strength categories, predicted stability, and dissimilarity to the mouse proteome. The top ranked epitopes were selected and included in the peptide candidate matrix in order to use a matrix deconvolution approach. Using ELISpot, we showed which viral epitopes presented on C57BL/6J mouse MHC-I alleles H2-Db and H2-Kb trigger IFN-γ secretion due to T cell activation. Furthermore, we validated these findings using an intracellular cytokine staining. Collectively, identification of the VSV-GP T cell epitopes enables monitoring of the full range of anti-viral T cell responses upon VSV-GP virotherapy in future studies with preclinical mouse models to more comprehensively delineate anti-viral from anti-tumor T cell responses. These findings also support the development of novel VSV-GP variants expressing immunomodulatory transgenes and can improve the assessment of anti-viral immunity in preclinical models.

259. The antitumor activity of human Vγ9Vδ2 T cells is impaired by TGF-β through significant phenotype, transcriptomic and metabolic changes.

Front Immunol

2023 Jan 19

Rafia C, Loizeau C, Renoult O

260. Corrigendum: Development of a phagocytosis- dependent gene signature to predict prognosis and response to checkpoint inhibition in clear-cell renal cell carcinoma.

Front Immunol

2023 Jan 19

Li K, Li Y, Lyu Y

261. Airway epithelial cell-specific deletion of HMGB1 exaggerates inflammatory responses in mice with muco-obstructive airway disease.

Front Immunol

2023 Jan 19

Mao Y, Patial S, Saini Y.

262. The association of BTLA gene polymorphisms with non-small lung cancer risk in smokers and never-smokers.

Front Immunol

2023 Jan 19

Andrzejczak A, Partyka A, Wiśniewski A

INTRODUCTION: Lung cancer is the predominant cause of death among cancer patients and non-small cell lung cancer (NSCLC) is the most common type. Cigarette smoking is the prevailing risk factor for NSCLC, nevertheless, this cancer is also diagnosed in never-smokers. B and T lymphocyte attenuator (BTLA) belongs to immunological checkpoints which are key regulatory molecules of the immune response. A growing body of evidence highlights the important role of BTLA in cancer. In our previous studies, we showed a significant association between BTLA gene variants and susceptibility to chronic lymphoblastic leukemia and renal cell carcinoma in the Polish population. The present study aimed to analyze the impact of BTLA polymorphic variants on the susceptibility to NSCLC and NSCLC patients' overall survival (OS). METHODS: Using TaqMan probes we genotyped seven BTLA single-nucleotide polymorphisms (SNPs): rs2705511, rs1982809, rs9288952, rs9288953, rs1844089, rs11921669 and rs2633582 with the use of ViiA 7 Real-Time PCR System. RESULTS: We found that rs1982809 within BTLA is associated with NSCLC risk, where carriers of rs1982809G allele (AG+GG genotypes) were more frequent in patients compared to controls. In subgroup analyses, we also noticed that rs1982809G carriers are significantly overrepresented in never-smokers, but not in smokers compared to controls. Additionally, the global distribution of the haplotypes differed between the never-smokers and smokers, where haplotypes A G G C A, C G A C G, and C G A T G were more frequent in never-smoking patients. Furthermore, the presence rs1982809G (AG+GG genotypes) allele as well as the presence of rs9288953T allele (CT+TT genotypes) increased NSCLC risk in females' patients. After stratification by histological type, we noticed that rs1982809G and rs2705511C carriers were more frequent among adenocarcinoma patients. Moreover, rs1982809G and rs2705511C correlated with the more advanced stages of NSCLC (stage II and III), but not with stage IV. Furthermore, we showed that rs2705511 and rs1982809 significantly modified OS, while rs9288952 tend to be associated with patients' survival. CONCLUSION: Our results indicate that BTLA polymorphic variants may be considered low penetrating risk factors for NSCLC especially in never-smokers, and in females, and are associated with OS of NSCLC patients.

263. Impact of ankylosing spondylitis on stroke limited to specific subtypes: Evidence from Mendelian randomization study.

Front Immunol

2023 Jan 19

Mei J, Wei P, Zhang L

BACKGROUND: The relationship between Ankylosing Spondylitis (AS) and the risk of stroke is complex. Therefore, we utilized Two-Sample Mendelian randomization to examine the probable causal link between these two features. METHODS: The genetic instruments linked to AS were chosen from a summary-level genetic data set from the FinnGen consortium in people of European ancestry (1462 cases and 164,682 controls). Stroke and its subtypes were selected as outcomes, and the MEGASTROKE consortium population was used to identify the genetic associations of AS on stroke (40,585 cases and 406,111 controls), ischemic stroke (IS) (34,217 cases and 406,111 controls), and its subtypes including large artery stroke (LAS) (4373 cases and 146,392 controls), small vessel stroke (SVS) (5386 cases and 192,662 controls), and cardioembolic stroke (CES) (7193 cases and 204,570 controls). Intracerebral hemorrhage (ICH) (1687 cases and 201,146 controls) data set from the FinnGen consortium was also used. To obtain the casual estimates, the inverse variant weighted (IVW) method was mainly used. By examining the heterogeneity and pleiotropy of particular single nucleotide polymorphisms (SNPs), the robustness of the results was also examined. RESULTS: There was no evidence found to prove the correlation between genetically predicted AS and stroke (odds ratio [OR] 1.014; 95% confidence interval [CI] 0.999-1.031; P = 0.063), ICH (OR 1.030; 95% CI 0.995-1.067; P = 0.090), and IS (OR 1.013; 95% CI 0. 998-1.030; P = 0.090). In terms of the different subtypes of IS, there was strong evidence of positive causal inferences on CES (OR 1.051; 95% CI 1.022-1.081; P = 0.001), and suggestive evidence of positive causal inferences on LAS (OR 1.042; 95% CI 1.003-1.082; P = 0.033), while it was not significant for SVS (OR 1.010; 95% CI 0.975-1.047; P = 0.563). CONCLUSION: This study suggests that the possible causative impact of genetically predicted AS on stroke may be restricted to the CES and LAS subtypes.

264. Olive leaves extract alleviates inflammation and modifies the intrinsic apoptotic signal in the leukemic bone marrow.

Front Immunol

2023 Jan 19

Nath P, Modak S, Aktar T

265. Identification of gene signatures associated with ulcerative colitis and the association with immune infiltrates in colon cancer.

Front Immunol

2023 Jan 19

Pan Z, Lin H, Fu Y

BACKGROUND: Inflammatory bowel diseases, including ulcerative colitis (UC) and Crohn's disease, are some of the most common inflammatory disorders of the gastrointestinal tract. The dysfunction of the immune system in the intestines is suggested to be the underlying cause of the pathogenesis of UC. However, the mechanisms regulating these dysfunctional immune cells and inflammatory phenotypes are still unclear. METHODS: The differential expression analysis on microarray datasets were performed including GSE24287, GSE87466, GSE102133, and GSE107499, including 376 samples. "Gene Ontology" and "Kyoto Encyclopedia of Genes and Genomes" pathway enrichment analyses were conducted to identify the common differentially expressed genes (DEGs) in these datasets and explore their underlying biological mechanisms. Further algorithms like "Cell-type Identification by Estimating Relative Subsets of RNA Transcripts" were used to determine the infiltration status of immune cells in patients with UC. "Cytoscape" and "Gene Set Enrichment Analysis" were used to screen for hub genes and to investigate their biological mechanisms. The Tumor Immune Estimation Resource database was used to study the correlation between hub genes and infiltrating immune cells in patients with UC. A total of three hub genes, CCL3, MMP3, and TIMP1, were identified using Cytoscape. RESULTS: A positive correlation was observed between these hub genes and patients with active UC. These genes served as a biomarker for active UC. Moreover, a decrease in CCL3, MMP3, and TIMP1 expression was observed in the mucosa of the intestine of patients with active UC who responded to Golimumab therapy. In addition, results show a significant positive correlation between CCL3, MMP3, and TIMP1 expression and different immune cell types including dendritic cells, macrophages, CD8+ T cells, and neutrophils in patients with colon cancer. Moreover, CCL3, MMP3, and TIMP1 expression were strongly correlated with different immune cell markers. CONCLUSION: Study results show the involvement of hub genes like CCL3, MMP3, and TIMP1 in the pathogenesis of UC. These genes could serve as a novel pharmacological regulator of UC. These could be used as a therapeutic target for treating patients with UC and may serve as biomarkers for immune cell infiltration in colon cancer.

266. NK cell-derived exosomes enhance the anti-tumor effects against ovarian cancer by delivering cisplatin and reactivating NK cell functions.

Front Immunol

2023 Jan 19

Luo H, Zhou Y, Zhang J

267. A 31-plex panel for high-dimensional single-cell analysis of murine preclinical models of solid tumors by imaging mass cytometry.

Front Immunol

2023 Jan 19

Glasson Y, Chépeaux LA, Dumé AS

268. The survival outcomes of neoadjuvant sintilimab combined with chemotherapy in patients with locally advanced esophageal squamous cell carcinoma.

Front Immunol

2023 Jan 19

Lv H, Huang C, Li J

269. Comprehensive analysis of the immune pattern of T cell subsets in chronic myeloid leukemia before and after TKI treatment.

Front Immunol

2023 Jan 19

Yao D, Lai J, Lu Y

270. Staining of activated ß(2)-integrins in combination with CD137 and CD154 for sensitive identification of functional antigen-specific CD4(+) and CD8(+) T cells.

Front Immunol

2023 Jan 19

Schöllhorn A, Maia A, Kimmerle F

271. A nomogram based on HBeAg, AST, and age to predict non-minimal liver inflammation in CHB patients with ALT <80 U/L.

Front Immunol

2023 Jan 19

Zhang L, Bi X, Chen X

272. IFNα and 5-Aza-2'-deoxycytidine combined with a dendritic-cell targeting DNA vaccine alter tumor immune cell infiltration in the B16F10 melanoma model.

Front Immunol

2023 Jan 19

Gordy JT, Sandhu AK, Fessler K

INTRODUCTION: DNA vaccines containing a fusion of the gene encoding chemokine MIP-3α (CCL20), the ligand for CCR6 on immature dendritic cells (DCs), to melanoma-associated antigen genes have enhanced anti-tumor immunity and efficacy compared to those lacking the chemokine gene. Previous work has shown that type-I interferon (IFNα or IFN) and 5-Aza-2'-deoxycytidine (5Aza) significantly enhance the therapeutic benefit of DNA vaccines as measured by reduced tumor burden and improved mouse survival. METHODS: Here, we explored mouse intratumoral immune correlates underlying the therapeutic benefit of this combination regimen (vaccine, IFN, and 5Aza) as compared to vaccine alone and IFN and 5Aza without vaccine, focusing on chemokine mRNA expression by qRT-PCR and inflammatory cellular infiltration into the tumor microenvironment (TME) by flow cytometry and immunohistochemistry (IHC). RESULTS: The combination group significantly upregulated intratumoral mRNA expression of key immune infiltration chemokines XCL1 and CXCL10. Flow cytometric analyses of tumor suspensions exhibited greater tumor infiltration of CD8+ DCs, CCR7+ DCs, and NK cells in the combination group, as well as reduced levels of myeloid-derived suppressor cells (MDSCs) in vaccinated groups. The mice receiving combination therapy also had greater proportions of effector/memory T-cells (Tem), in addition to showing an enhanced infiltration of Tem and central memory CD8+ T-cells, (Tcm). Tem and Tcm populations both correlated with smaller tumor size. Immunohistochemical analysis of tumors confirmed that CD8+ cells were more abundant overall and especially in the tumor parenchyma with combination therapy. DISCUSSION: Efficient targeting of antigen to immature DCs with a chemokine-fusion vaccine offers a potential alternative approach to classic and dendritic cell-based vaccines. Combining this approach with IFNα and 5Aza treatments significantly improved vaccine efficacy. This treatment creates an environment of increased inflammatory chemokines that facilitates the trafficking of CD8+ DCs, NK cells, and CD8+ T-cells, especially memory cells, while reducing the number of MDSCs. Importantly, in the combination group, CD8+ cells were more able to penetrate the tumor mass in addition to being more numerous. Further analysis of the pathways engaged by our combination therapy is expected to provide additional insights into melanoma pathogenesis and facilitate the development of novel treatment strategies.

273. Combination of single-cell and bulk RNA seq reveals the immune infiltration landscape and targeted therapeutic drugs in spinal cord injury.

Front Immunol

2023 Jan 19

Zhang Q, Yu B, Zhang Y

BACKGROUND: In secondary spinal cord injury (SCI), the immune microenvironment of the injured spinal cord plays an important role in spinal regeneration. Among the immune microenvironment components, macrophages/microglia play a dual role of pro-inflammation and anti-inflammation in the subacute stage of SCI. Therefore, discovering the immune hub genes and targeted therapeutic drugs of macrophages/microglia after SCI has crucial implications in neuroregeneration. This study aimed to identify immune hub genes and targeted therapeutic drugs for the subacute phase of SCI. METHODS: Bulk RNA sequencing (bulk-RNA seq) datasets (GSE5296 and GSE47681) and single-cell RNA sequencing (scRNA-seq) dataset (GSE189070) were obtained from the Gene Expression Omnibus database. In the bulk RNA-seq, the R package 'limma,' 'WGCNA,' and 'CIBERSORT' were used to jointly screen key immune genes. Subsequently, the R package 'Seurat' and the R package 'celldex' were used to divide and annotate the cell clusters, respectively. After using the Autodock software to dock immune hub genes and drugs that may be combined, the effectiveness of the drug was verified using an in vivo experiment with the T9 SCI mouse model. RESULTS: In the bulk-RNA seq, B2m, Itgb5, and Vav1 were identified as immune hub genes. Ten cell clusters were identified in scRNA-seq, and B2m and Itgb5 were mainly located in the microglia, while Vav1 was mainly located in macrophages. Molecular docking results showed that the proteins corresponding to these immune genes could accurately bind to decitabine. In decitabine-treated mice, the pro-inflammatory factor (TNF-α, IL-1β) levels were decreased while anti-inflammatory factor (IL-4, IL-10) levels were increased at 2 weeks post-SCI, and macrophages/microglia transformed from M1 to M2. At 6 weeks post-SCI, the neurological function score and electromyography of the decitabine treatment group were also improved. CONCLUSION: In the subacute phase of SCI, B2m, Itgb5, and Vav1 in macrophages/microglia may be key therapeutic targets to promote nerve regeneration. In addition, low-dose decitabine may promote spinal cord regeneration by regulating the polarization state of macrophages/microglia.

274. Leukocyte cell population data in patients with cardiac surgery and cardiopulmonary bypass: A potential readily available tool to monitor immunity.

Front Immunol

2023 Jan 19

Nguyen M, Stiel L, Guilloteau A

PURPOSE: Cardiac surgery with cardiopulmonary bypass triggers sterile inflammation that is responsible for post-operative morbidity. Automated flow cytometry devices used for leucocyte count provide cell population data (CPD) regarding fluorescence intensity, size and granularity of leukocytes that have never been studied in the context of sterile inflammation. Our objective was to explore leukocyte cell population data in patients undergoing cardiac surgery with cardiopulmonary bypass in order to determine whether CPD could be used to monitor immune cell activation. METHODS: This is an ancillary study of a cohort of patients undergoing cardiac surgery with cardiopulmonary bypass. Cell population data (CPD) extracted from a routine automated flow cytometer were analyzed (Fluorescence targeted to nucleic acids). The time points of interest were: pre-operative, postoperative and 5 days after surgery. The variations in those parameters were studied. Data were then compared between patients according to the occurrence of a composite criteria (supra-ventricular arrythmia, stroke, acute renal failure, and/or death). RESULTS: Data from 1453 patients were analyzed. The neutrophil count, fluorescence granularity (NE-SCC), intensity (NE-SFL) and size (NE-FSC) increased with surgery. Heterogeneity of neutrophils decreased in terms of fluorescence granularity (NE-WX) and size (NE-WZ) but increased in terms of intensity (NE-WY). The lymphocyte count decreased with surgery. While fluorescence granularity (LY-X) and size increased (LY-Z), Lymphocyte intensity decreased (LY-Y). Lymphocytes were less heterogeneous in terms of their granularity, size and intensity after surgery (LY-WX, LY-WY, LY-WZ). Patients who developed the composite complication criteria had a higher pre-operative neutrophil count (5.08 [3.89;6.95] vs 4.76 [3.60;6.13], p = 0.02; AUC = 0.56 [0.51;0.60]), and more heterogeneous neutrophils in terms of fluorescence granularity (NE-WX, AUC = 0.57 [0.52;0.62]) and intensity (NE-WY, AUC 0.61 [0.56;0.65]). Those patients also had lower pre-operative lymphocyte count (1.49 [1.10;1.14] vs 1.81 [1.39;2.39], p<0.01, AUC = 0.61 [0.57;0.66]) and fluorescence granularity (LY-X, AUC = 0.57 [0.53;0.62]). NE-WX, NE-WY and LY-X were associated with post-operative complications after adjustment on the EuroSCORE 2 (adjusted odd ratio of 1.01 [1.00;1.02]; 1.01 [1.00;1.01] and 1.08 [1.02;1.15] respectively). CONCLUSION: Cardiac surgery with cardiopulmonary bypass was associated with substantial alterations of CPD probably reflecting leukocytes activation in sterile inflammation. Pre-operative NE-WX, NE-WY and LY-X biomarkers levels were associated with post-operative complications, independently of the EuroSCORE 2. Such routine, unexploited and low cost parameters might represent useful tools likely to monitor immune function and predict outcomes for patients undergoing cardiac surgery. Our findings requires validation on a larger external cohort.

275. Eomes is sufficient to regulate IL-10 expression and cytotoxic effector molecules in murine CD4(+) T cells.

Front Immunol

2023 Jan 19

Thelen B, Schipperges V, Knörlein P

276. The immunomodulatory role of matrix metalloproteinases in colitis-associated cancer.

Front Immunol

2023 Jan 19

He L, Kang Q, Chan KI

277. Hepatocytes: A key role in liver inflammation.

Front Immunol

2023 Jan 18

Gong J, Tu W, Liu J

278. Transient autoantibodies to danger signals.

Front Immunol

2023 Jan 18

Shaw ER, Matzinger P.

279. Metabolism of NK cells during viral infections.

Front Immunol

2023 Jan 18

Osuna-Espinoza KY, Rosas-Taraco AG.

280. CD8(+) T-cell immunity orchestrated by iNKT cells.

Front Immunol

2023 Jan 18

Qin Y, Bao X, Zheng M.

281. Targeting STING: From antiviral immunity to treat osteoporosis.

Front Immunol

2023 Jan 18

Gao Z, Gao Z, Zhang H

282. Cancer-associated pyroptosis: A new license to kill tumor.

Front Immunol

2023 Jan 18

Kong Q, Zhang Z.

283. The mechanism of NLRP3 inflammasome activation and its pharmacological inhibitors.

Front Immunol

2023 Jan 18

Zhan X, Li Q, Xu G

284. Exosomes: A potential tool for immunotherapy of ovarian cancer.

Front Immunol

2023 Jan 18

Gong X, Chi H, Strohmer DF

285. The hypoxic tissue microenvironment as a driver of mucosal inflammatory resolution.

Front Immunol

2023 Jan 18

Cartwright IM, Colgan SP.

286. Programmed cell death and lipid metabolism of macrophages in NAFLD.

Front Immunol

2023 Jan 18

Xiao Z, Liu M, Yang F

287. Manipulation of metabolic pathways to promote stem-like and memory T cell phenotypes for immunotherapy.

Front Immunol

2023 Jan 18

Claiborne MD.

288. Anti-IL-17A antibody-associated de novo vitiligo: Case report and review of literature.

Front Immunol

2023 Jan 18

Su HJ, Chan YP, Shen PC

289. Vesicular traffic-mediated cell-to-cell signaling at the immune synapse in Ankylosing Spondylitis.

Front Immunol

2023 Jan 18

Tavasolian F, Pastrello C, Ahmed Z

290. Engineered soluble ACE2 receptor: Responding to change with change.

Front Immunol

2023 Jan 18

Li G, Qian K, Zhang S

291. C-reactive protein isoforms as prognostic markers of COVID-19 severity.

Front Immunol

2023 Jan 18

Molins B, Figueras-Roca M, Valero O

292. Patients with IBD have a more cautious attitude towards COVID-19 vaccination.

Front Immunol

2023 Jan 18

Hu S, Liu J, Li S

293. Nr4a1-dependent non-classical monocytes are important for macrophage-mediated wound healing in the large intestine.

Front Immunol

2023 Jan 18

Heidbreder K, Sommer K, Wiendl M

294. Specificity of the innate immune responses to different classes of non-tuberculous mycobacteria.

Front Immunol

2023 Jan 18

Hu W, Koch BEV, Lamers GEM

295. Docosahexaenoic acid inhibits TNF-α-induced osteoclast formation and orthodontic tooth movement through GPR120.

Front Immunol

2023 Jan 18

Ma J, Kitaura H, Ogawa S

296. The genetic and epigenetic regulation of CD55 and its pathway analysis in colon cancer.

Front Immunol

2023 Jan 18

Liu J, Fu N, Yang Z

BACKGROUND: CD55 plays an important role in the development of colon cancer. This study aims to evaluate the expression of CD55 in colon cancer and discover how it is regulated by transcriptional factors and miRNA. METHODS: The expression of CD55 was explored by TIMER2.0, UALCAN, and Human Protein Atlas (HPA) databases. TRANSFAC and Contra v3 were used to predict the potential binding sites of transcription factors in the CD55 promoter. TargetScan and starBase v2.0 were used to predict the potential binding ability of miRNAs to the 3' untranslated region (3'UTR) of CD55. SurvivalMeth was used to explore the differentially methylated sites in the CD55 promoter. Western blotting was used to detect the expression of TFCP2 and CD55. Dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were performed to determine the targeting relationship of TFCP2, NF-κB, or miR-27a-3p with CD55. CD55-related genes were explored by constructing a protein-protein interaction (PPI) network and performing pathway analysis by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). RESULTS: CD55 was highly expressed in colon cancer tissues. The mRNA and protein expression levels of TFCP2 were reduced by si-TFCP2. NF-κB mRNA was obviously reduced by NF-κB inhibitor and increased by NF-κB activator. CD55 protein was also inhibited by miR-27a-3p. Dual-luciferase reporter assays showed that after knocking down TFCP2 or inhibiting NF-κB, the promoter activity of CD55 was decreased by 21% and 70%, respectively; after activating NF-κB, the promoter activity of CD55 increased by 2.3 times. As TFCP2 or NF-κB binding site was mutated, the transcriptional activity of CD55 was significantly decreased. ChIP assay showed that TFCP2 and NF-κB combined to the promoter of CD55. The luciferase activity of CD55 3'UTR decreased after being co-transfected with miR-27a-3p mimics and increased by miR-27a-3p antagomir. As the miR-27a-3p binding site was mutated, we did not find any significant effect of miR-27a-3p on reporter activity. PPI network assay revealed a set of CD55-related genes, which included CFP, CFB, C4A, and C4B. GO and KEGG analyses revealed that the target genes occur more frequently in immune-related pathways. CONCLUSION: Our results indicated that CD55 is regulated by TFCP2, NF-κB, miR-27a-3p, and several immune-related genes, which in turn affects colon cancer.

297. Knowledge landscape of tumor-associated macrophage research: A bibliometric and visual analysis.

Front Immunol

2023 Jan 18

Zhou F, Liu Y, Liu C

298. Single-cell atlas reveals different immune environments between stable and vulnerable atherosclerotic plaques.

Front Immunol

2023 Jan 18

Ge P, Li H, Ya X

299. The dietary inflammatory index and its association with the prevalence of hypertension: A cross-sectional study.

Front Immunol

2023 Jan 18

Zhou N, Xie ZP, Liu Q

AIMS: We aim to investigate the association of the Dietary Inflammatory Index (DII) with the prevalence of hypertension in a large multiracial population in the United States. METHODS: Participants from the National Health and Nutrition Examination Survey (NHANES) (1999-2018) were included in this cross-sectional study. Dietary information was obtained and used to calculate DII. Blood pressures of participants were measured by experienced examiners. The NHANES used the method of "stratified multistage probability sampling," and this study is a weight analysis following the NHANES analytic guidance. Weight logistic regression analysis was adopted to investigate the association of hypertension with DII. Least Absolute Shrinkage and Selection Operator (LASSO) regression was carried out to screen the most important dietary factors associated with the risk of hypertension. Moreover, a nomogram model based on key dietary factors was established; the receiver operating characteristic (ROC) curve was used to evaluate the diagnostic power of the nomogram model for screening hypertension risk. RESULTS: A total of 45,023 participants were included in this study, representing 191 million residents in the United States. Participants with hypertension had an elevated DII compared with those without hypertension. Weight logistic regression showed that an increment of DII was strongly associated with hypertension after adjusting for confounding factors. The nomogram model, based on key dietary factors screened by LASSO regression, showed a favorable discriminatory power with an area under the curve (AUC) of 78.5% (95% CI: 78.5%-79.3%). Results of the sensitivity analysis excluding participants who received any drug treatment were consistent with those in the main analysis. CONCLUSION: An increment of DII is associated with the risk of hypertension. For better prevention and treatment of hypertension, more attention should be paid to controlling dietary inflammation.

300. HLA and Non-HLA gene polymorphisms in autoimmune hepatitis patients of North Indian adults.

Front Immunol

2023 Jan 18

Ahuja N, Singh J, Minz RW

301. Dual targeting of mTOR/IL-17A and autophagy by fisetin alleviates psoriasis-like skin inflammation.

Front Immunol

2023 Jan 18

Roy T, Banang-Mbeumi S, Boateng ST

Psoriasis is a chronic autoimmune inflammatory skin disorder characterized by epidermal hyperplasia and aberrant immune response. In addition to aberrant cytokine production, psoriasis is associated with activation of the Akt/mTOR pathway. mTOR/S6K1 regulates T-lymphocyte activation and migration, keratinocytes proliferation and is upregulated in psoriatic lesions. Several drugs that target Th1/Th17 cytokines or their receptors have been approved for treating psoriasis in humans with variable results necessitating improved therapies. Fisetin, a natural dietary polyphenol with anti-oxidant and anti-proliferative properties, covalently binds mTOR/S6K1. The effects of fisetin on psoriasis and its underlying mechanisms have not been clearly defined. Here, we evaluated the immunomodulatory effects of fisetin on Th1/Th17-cytokine-activated adult human epidermal keratinocytes (HEKa) and anti-CD3/CD28-stimulated inflammatory CD4+ T cells and compared these activities with those of rapamycin (an mTOR inhibitor). Transcriptomic analysis of HEKa revealed 12,713 differentially expressed genes (DEGs) in the fisetin-treated group compared to 7,374 DEGs in the rapamycin-treated group, both individually compared to a cytokine treated group. Gene ontology analysis revealed enriched functional groups related to PI3K/Akt/mTOR signaling pathways, psoriasis, and epidermal development. Using in silico molecular modeling, we observed a high binding affinity of fisetin to IL-17A. In vitro, fisetin significantly inhibited mTOR activity, increased the expression of autophagy markers LC3A/B and Atg5 in HEKa cells and suppressed the secretion of IL-17A by activated CD4+ T lymphocytes or T lymphocytes co-cultured with HEKa. Topical administration of fisetin in an imiquimod (IMQ)-induced mouse psoriasis model exhibited a better effect than rapamycin in reducing psoriasis-like inflammation and Akt/mTOR phosphorylation and promoting keratinocyte differentiation and autophagy in mice skin lesions. Fisetin also significantly inhibited T-lymphocytes and F4/80+ macrophage infiltration into skin. We conclude that fisetin potently inhibits IL-17A and the Akt/mTOR pathway and promotes keratinocyte differentiation and autophagy to alleviate IMQ-induced psoriasis-like disease in mice. Altogether, our findings suggest fisetin as a potential treatment for psoriasis and possibly other inflammatory skin diseases.

302. Single-cell RNA-seq reveals cellular heterogeneity from deep fascia in patients with acute compartment syndrome.

Front Immunol

2023 Jan 18

Wang T, Long Y, Ma L

303. Five genes as diagnostic biomarkers of dermatomyositis and their correlation with immune cell infiltration.

Front Immunol

2023 Jan 18

Zhao X, Si S.

BACKGROUND: Dermatomyositis (DM) is a rare autoimmune disease characterized by severe muscle dysfunction, and the immune response of the muscles plays an important role in the development of DM. Currently, the diagnosis of DM relies on symptoms, physical examination, and biopsy techniques. Therefore, we used machine learning algorithm to screen key genes, and constructed and verified a diagnostic model composed of 5 key genes. In terms of immunity, The relationship between 5 genes and immune cell infiltration in muscle samples was analyzed. These diagnostic and immune-cell-related genes may contribute to the diagnosis and treatment of DM. METHODS: GSE5370 and GSE128470 datasets were utilised from the Gene Expression Omnibus database as DM test sets. And we also used R software to merge two datasets and to analyze the results of differentially expressed genes (DEGs) and functional correlation analysis. Then, we could detect diagnostic genes adopting least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine recursive feature elimination (SVM-RFE) analyses. The validity of putative biomarkers was assessed using the GSE1551 dataset, and we confirmed the area under the receiver operating characteristic curve (AUC) values. Finally, CIBERSORT was used to evaluate immune cell infiltration in DM muscles and the correlations between disease-related biomarkers and immune cells. RESULTS: In this study, a total of 414 DEGs were screened. ISG15, TNFRSF1A, GUSBP11, SERPINB1 and PTMA were identified as potential DM diagnostic biomarkers(AUC > 0.85),and the expressions of 5 genes in DM group were higher than that in healthy group (p < 0.05). Immune cell infiltration analyses indicated that identified DM diagnostic biomarkers may be associated with M1 macrophages, activated NK cells, Tfh cells, resting NK cells and Treg cells. CONCLUSION: The study identified that ISG15, TNFRSF1A, GUSBP11, SERPINB1 and PTMA as potential diagnostic biomarkers of DM and these genes were closely correlated with immune cell infiltration.This will contribute to future studies in diagnosis and treatment of DM.

304. Corrigendum: rAAV immunogenicity, toxicity, and durability in 255 clinical trials: A meta-analysis.

Front Immunol

2023 Jan 18

Shen W, Liu S, Ou L.

305. Protective effects of blocking PD-1 pathway on retinal ganglion cells in a mouse model of chronic ocular hypertension.

Front Immunol

2023 Jan 18

Sheng S, Ma Y, Zou Y

306. Efficacy and safety of lenvatinib combined with PD-1/PD-L1 inhibitors plus Gemox chemotherapy in advanced biliary tract cancer.

Front Immunol

2023 Jan 18

Zhu C, Xue J, Wang Y

307. Analysis of neutralizing antibodies to COVID-19 inactivated or subunit recombinant vaccines in hospitalized patients with liver dysfunction.

Front Immunol

2023 Jan 18

Li H, Li S, Xu P

308. Gut bacterial species in late trimester of pregnant sows influence the occurrence of stillborn piglet through pro-inflammation response.

Front Immunol

2023 Jan 18

Chen Z, Yang H, Fu H

Maternal gut microbiota is an important regulator for the metabolism and immunity of the fetus during pregnancy. Recent studies have indicated that maternal intestinal microbiota is closely linked to the development of fetus and infant health. Some bacterial metabolites are considered to be directly involved in immunoregulation of fetus during pregnancy. However, the detailed mechanisms are largely unknown. In this study, we exploited the potential correlation between the gut microbiota of pregnant sows and the occurrence of stillborn piglets by combining the 16S rRNA gene and metagenomic sequencing data, and fecal metabolome in different cohorts. The results showed that several bacterial species from Bacteroides, potential pathogens, and LPS-producing bacteria exhibited significantly higher abundances in the gut of sows giving birth to stillborn piglets. Especially, Bacteroides fragilis stood out as the key driver in both tested cohorts and showed the most significant association with the occurrence of stillborn piglets in the DN1 cohort. However, several species producing short-chain fatty acids (SCFAs), such as Prevotella copri, Clostridium butyricum and Faecalibacterium prausnitzii were enriched in the gut of normal sows. Functional capacity analysis of gut microbiome revealed that the pathways associated with infectious diseases and immune diseases were enriched in sows giving birth to stillborn piglets. However, energy metabolism had higher abundance in normal sows. Fecal metabolome profiling analysis found that Lysophosphatidylethanolamine and phosphatidylethanolamine which are the main components of cell membrane of Gram-negative bacteria showed significantly higher concentration in stillbirth sows, while SCFAs had higher concentration in normal sows. These metabolites were significantly associated with the stillborn-associated bacterial species including Bacteroides fragilis. Lipopolysaccharide (LPS), IL-1β, IL-6, FABP2, and zonulin had higher concentration in the serum of stillbirth sows, indicating increased intestinal permeability and pro-inflammatory response. The results from this study suggested that certain sow gut bacterial species in late trimester of pregnancy, e.g., an excess abundance of Bacteroides fragilis, produced high concentration of LPS which induced sow pro-inflammatory response and might cause the death of the relatively weak piglets in a farrow. This study provided novel evidences about the effect of maternal gut microbiota on the fetus development and health.

309. Exploration of the shared pathways and common biomarker PAN3 in ankylosing spondylitis and ulcerative colitis using integrated bioinformatics analysis.

Front Immunol

2023 Jan 18

Zhang M, Zhou J, Wang H

BACKGROUND: Ulcerative colitis (UC) is a chronic autoimmune-related disease that causes inflammation of the intestine. Ankylosing spondylitis (AS) is a common extraintestinal complication of UC involving the sacroiliac joint. However, the pathogenesis of AS secondary to UC has not been studied. This study aimed to investigate the shared pathways and potential common biomarkers of UC and AS. METHODS: Microarray data downloaded from the Gene Expression Omnibus (GEO) database were used to screen differentially expressed genes (DEGs) in the UC and AS datasets. Weighted gene co-expression network analysis (WGCNA) was performed to identify co-expression modules related to UC and AS. Shared genes were then further analyzed for functional pathway enrichment. Next, the optimal common biomarker was selected using SVM-RFF and further validated using two independent GEO datasets. Finally, immune infiltration analysis was used to investigate the correlation of immune cell infiltration with common biomarkers in UC and AS. RESULTS: A total of 4428 and 2438 DEGs in UC and AS, respectively, were screened. Four modules were identified as significant for UC and AS using WGCNA. A total of 25 genes overlapped with the strongest positive and negative modules of UC and AS. KEGG analysis showed these genes may be involved in the mitogen-activated protein kinase (MAPK) signaling pathway. GO analysis indicated that these genes were significantly enriched for RNA localization. PAN3 was selected as the optimal common biomarker for UC and AS. Immune infiltration analysis showed that the expression of PAN3 was correlated with changes in immune cells. CONCLUSION: This study first explored the common pathways and genetic diagnostic markers involved in UC and AS using bioinformatic analysis. Results suggest that the MAPK signaling pathway may be associated with both pathogeneses and that PAN3 may be a potential diagnostic marker for patients with UC complicated by AS.

310. Mycobacterium avium subsp. paratuberculosis antigens induce cellular immune responses in cattle without causing reactivity to tuberculin in the tuberculosis skin test.

Front Immunol

2023 Jan 18

Gupta SK, Wilson T, Maclean PH

Mycobacterium avium subspecies paratuberculosis (MAP) causes chronic progressive granulomatous enteritis leading to diarrhea, weight-loss, and eventual death in ruminants. Commercially available vaccine provides only partial protection against MAP infection and can interfere with the use of current diagnostic tests for bovine tuberculosis in cattle. Here, we characterized immune responses in calves to vaccines containing four truncated MAP antigens as a fusion (Ag85A202-347-SOD1-72-Ag85B173-330-74F1-148+669-786), either displayed on protein particles, or expressed as a soluble recombinant MAP (rMAP) fusion protein as well as to commercially available Silirum® vaccine. The rMAP fusion protein elicited the strongest antigen-specific antibody responses to both PPDA and recombinant antigen and strong and long-lasting T-cell immune responses to these antigens, as indicated by increased production of IFN-γ and IL-17A in antigen-stimulated whole blood cultures. The MAP fusion protein particle vaccine induced minimal antibody responses and weak IFN-γ responses but stimulated IL-17A responses to recombinant antigen. The immune response profile of Silirum® vaccine was characterized by weak antibodies and strong IFN-γ and IL-17A responses to PPDA. Transcription analysis on antigen-stimulated leukocytes from cattle vaccinated with rMAP fusion protein showed differential expression of several immune response genes and genes involved in costimulatory signaling, TLR4, TLR2, PTX3, PTGS2, PD-L1, IL1B, IL2, IL6, IL12B, IL17A, IL22, IFNG, CD40, and CD86. Moreover, the expression of several genes of immune pathways correlated with cellular immune responses in the rMAP fusion protein vaccinated group. These genes have key roles in pathways of mycobacterial immunity, including autophagy, manipulation of macrophage-mediated killing, Th17- and regulatory T cells- (Treg) mediated responses. Calves vaccinated with either the rMAP fusion protein or MAP fusion protein particle vaccine did not induce reactivity to PPDA and PPDB in a comparative cervical skin test, whereas Silirum® induced reactivity to these tuberculins in most of the vaccinated animals. Overall, our results suggest that a combination of recombinant MAP antigens in the form of a soluble fusion protein vaccine are capable of inducing strong antigen-specific humoral and a balanced Th1/Th17-cell immune response. These findings, together with the absence of reactivity to tuberculin, suggest this subunit vaccine could provide protective immunity against intracellular MAP infection in cattle without compromising the use of current bovine tuberculosis surveillance test.

311. Loss of CFTR function is associated with reduced bitter taste receptor-stimulated nitric oxide innate immune responses in nasal epithelial cells and macrophages.

Front Immunol

2023 Jan 18

Carey RM, Palmer JN, Adappa ND

INTRODUCTION: Bitter taste receptors (T2Rs) are G protein-coupled receptors identified on the tongue but expressed all over the body, including in airway cilia and macrophages, where T2Rs serve an immune role. T2R isoforms detect bitter metabolites (quinolones and acyl-homoserine lactones) secreted by gram negative bacteria, including Pseudomonas aeruginosa, a major pathogen in cystic fibrosis (CF). T2R activation by bitter bacterial products triggers calcium-dependent nitric oxide (NO) production. In airway cells, the NO increases mucociliary clearance and has direct antibacterial properties. In macrophages, the same pathway enhances phagocytosis. Because prior studies linked CF with reduced NO, we hypothesized that CF cells may have reduced T2R/NO responses, possibly contributing to reduced innate immunity in CF. METHODS: Immunofluorescence, qPCR, and live cell imaging were used to measure T2R localization, calcium and NO signaling, ciliary beating, and antimicrobial responses in air-liquid interface cultures of primary human nasal epithelial cells and immortalized bronchial cell lines. Immunofluorescence and live cell imaging was used to measure T2R signaling and phagocytosis in primary human monocyte-derived macrophages. RESULTS: Primary nasal epithelial cells from both CF and non-CF patients exhibited similar T2R expression, localization, and calcium signals. However, CF cells exhibited reduced NO production also observed in immortalized CFBE41o- CF cells and non-CF 16HBE cells CRISPR modified with CF-causing mutations in the CF transmembrane conductance regulator (CFTR). NO was restored by VX-770/VX-809 corrector/potentiator pre-treatment, suggesting reduced NO in CF cells is due to loss of CFTR function. In nasal cells, reduced NO correlated with reduced ciliary and antibacterial responses. In primary human macrophages, inhibition of CFTR reduced NO production and phagocytosis during T2R stimulation. CONCLUSIONS: Together, these data suggest an intrinsic deficiency in T2R/NO signaling caused by loss of CFTR function that may contribute to intrinsic susceptibilities of CF patients to P. aeruginosa and other gram-negative bacteria that activate T2Rs.

312. The imbalance in the relationship between inflammatory and regulatory cytokines during gestational toxoplasmosis can be harmful to fetuses: A systematic review.

Front Immunol

2023 Jan 18

Dos Santos PV, de Toledo DNM, de Souza DMS

313. Airway microbiome-immune crosstalk in chronic obstructive pulmonary disease.

Front Immunol

2023 Jan 17

Kayongo A, Robertson NM, Siddharthan T

314. Exosomes as smart drug delivery vehicles for cancer immunotherapy.

Front Immunol

2023 Jan 17

Zhang H, Wang S, Sun M

315. The lung, the niche, and the microbe: Exploring the lung microbiome in cancer and immunity.

Front Immunol

2023 Jan 17

Huynh M, Crane MJ, Jamieson AM.

316. The E3 ubiquitin ligases regulate PD-1/PD-L1 protein levels in tumor microenvironment to improve immunotherapy.

Front Immunol

2023 Jan 17

Hou B, Chen T, Zhang H

317. A multi-epitope vaccine GILE against Echinococcus Multilocularis infection in mice.

Front Immunol

2023 Jan 17

Zhou P, Zhou Z, Huayu M

INTRODUCTION: The objective of this study is to construct a multi-epitope vaccine GILE containing B-cell and T-cell epitopes against Echinococcus Multilocularis (E. multilocularis) infection based on the dominant epitopes of E. multilocularis EMY162, LAP, and GLUT1. METHODS: The structure and hydrophobicity of GILE were predicted by SWISSMODEL, pyMOL, SOPMA and VMD, and its sequence was optimized by Optimum™ Codon. The GILE gene was inserted into pCzn1 and transformed into Escherichia coli Arctic express competent cells. IPTG was added to induce the expression of recombinant proteins. High-purity GILE recombinant protein was obtained by Ni-NTA Resin. BALB/c mice were immunized with GILE mixed with Freund's adjuvant, and the antibody levels and dynamic changes in the serum were detected by ELISA. Lymphocyte proliferation was detected by MTS. The levels of IFN-g and IL-4 were detected by ELISpot and flow cytometry (FCM). T cells were detected by FCM. The growth of hepatic cysts was evaluated by Ultrasound and their weights were measured to evaluate the immune protective effect of GILE. RESULTS: The SWISS-MODEL analysis showed that the optimal model was EMY162 95-104-LAP464-479-LAP495-510-LAP396-410-LAP504-518-EMY162112-126. The SOPMA results showed that there were Alpha helix (14.88%), Extended strand (26.25%), Beta turn (3.73%) and Random coil (45.82%) in the secondary structure of GILE. The restriction enzyme digestion and sequencing results suggested that the plasmid pCzn1-GILE was successfully constructed. The SDSPAGE results indicated that the recombinant protein was 44.68 KD. The ELISA results indicated that mice immunized with GILE showed higher levels of serum antibodies compared to the PBS group. The FCM and ELISpot results indicated that mice immunized with GILE secreted more IFN-g and IL-4. Immunization with GILE also led to a significant decrease in the maximum diameter and weight of cysts and stimulated the production of CD4+ and CD8+ T Cell. DISCUSSION: A multi-epitope vaccine GILE with good immunogenicity and antigenicity has been successfully constructed in this study, which may provide important theoretical and experimental bases for the prevention and treatment of E. multilocularis infection.

318. Safety and feasibility of toripalimab plus lenvatinib with or without radiotherapy in advanced BTC.

Front Immunol

2023 Jan 17

Wang Y, Zhang N, Xue J

319. Natural killer cells suppress cancer metastasis by eliminating circulating cancer cells.

Front Immunol

2023 Jan 17

Vyas M, Requesens M, Nguyen TH

320. Bone-marrow derived cells do not contribute to new beta-cells in the inflamed pancreas.

Front Immunol

2023 Jan 17

Jiang Y, Wiersch J, Wu W

321. Immunogenicity and reactogenicity of accelerated regimens of fractional intradermal COVID-19 vaccinations.

Front Immunol

2023 Jan 17

Niyomnaitham S, Atakulreka S, Wongprompitak P

322. Imidazolium salts as an alternative for anti-Leishmania drugs: Oxidative and immunomodulatory activities.

Front Immunol

2023 Jan 17

Baldissera FG, Fazolo T, da Silva MB

323. The role of intestinal immune cells and matrix metalloproteinases in inflammatory bowel disease.

Front Immunol

2023 Jan 17

Mei K, Chen Z, Wang Q

324. Enhanced glaucomatous damage accompanied by glial response in a new multifactorial mouse model.

Front Immunol

2023 Jan 17

Reinehr S, Girbig RM, Schulte KK

INTRODUCTION: Glaucoma is a complex, multifactorial neurodegenerative disease, which can lead to blindness if left untreated. It seems that, among others, immune processes, elevated intraocular pressure (IOP), or a combination of these factors are responsible for glaucomatous damage. Here, we combined two glaucoma models to examine if a combination of risk factors (IOP and immune response) results in a more severe damage of retinal ganglion cells (RGCs) and the optic nerves as well as an additional glia activation. METHODS: Six-week-old wildtype (WT+ONA) and βB1-Connective Tissue Growth Factor (CTGF) mice (CTGF+ONA) were immunized with 1 mg ONA (optic nerve antigen). A WT and a CTGF control group (CTGF) received sodium chloride instead. IOP was measured before and every two weeks after immunization. After six weeks, electroretinogram (ERG) measurements were performed. Then, retinae and optic nerves were processed for (immuno-) histology. Further, mRNA levels of corresponding genes in optic nerve and retina were analyzed via RT-qPCR. RESULTS: Six weeks after immunization, the IOP in CTGF and CTGF+ONA mice was increased. The optic nerve of CTGF+ONA animals displayed the most severe cell inflammation, demyelination, and macroglia activation. Fewer numbers of oligodendrocytes were only observed in WT+ONA optic nerves, while more apoptotic cells triggered by the extrinsic pathway could be revealed in all three glaucoma groups. The number of microglia/macrophages was not altered within the optic nerves of all groups. The loss of neuronal cells, especially RGCs was most pronounced in CTGF+ONA retinae in the central part and this was accompanied by an enhanced activation of microglia/macrophages. Also, Müller cell activation could be noted in CTGF and CTGF+ONA retinae. DISCUSSION: In this new model, an additive degeneration could be noted in optic nerves as well as in the number of RGCs. These results suggest a potential additive role of high IOP and immune factors in glaucoma development, which will aid for understanding this multifactorial disease more precisely in the future.

325. Duck cGAS inhibits DNA and RNA virus replication by activating IFNs and antiviral ISGs.

Front Immunol

2023 Jan 17

Lin C, Zheng M, Xiao S

326. The need and benefit of immune monitoring to define patient and disease heterogeneity, mechanisms of therapeutic action and efficacy of intervention therapy for precision medicine in type 1 diabetes.

Front Immunol

2023 Jan 17

Roep BO.

327. Association of low ficolin-2 concentration in cord serum with respiratory distress syndrome in preterm newborns.

Front Immunol

2023 Jan 17

Gajek G, Świerzko AS, Jarych D

INTRODUCTION: Ficolin-2 is a serum pattern recognition molecule, involved in complement activation via the lectin pathway. This study aimed to investigate the association of ficolin-2 concentration in cord blood serum with complications related to premature birth. METHODS: 546 premature neonates were included. The concentration of ficolin-2 in cord blood serum was determined by a sandwich TRIFMA method. FCN2 genetic variants were analysed with RFLP-PCR, allele-specific PCR, Sanger sequencing or allelic discrimination using TaqMan probes method. FINDINGS: Cord blood serum ficolin-2 concentration correlated positively with Apgar score and inversely with the length of hospitalisation and stay at Neonatal Intensive Care Unit (NICU). Multivariate logistic regression analysis indicated that low ficolin-2 increased the possibility of respiratory distress syndrome (RDS) diagnosis [OR=2.05, 95% CI (1.24-3.37), p=0.005]. Median ficolin-2 concentration was significantly lower in neonates with RDS than in premature babies without this complication, irrespective of FCN2 gene polymorphisms localised to promoter and 3'untranslated regions: for patients born <33 GA: 1471 ng/ml vs. 2115 ng/ml (p=0.0003), and for patients born ≥33 GA 1610 ng/ml vs. 2081 ng/ml (p=0.012). Ficolin-2 level was also significantly lower in neonates requiring intubation in the delivery room (1461 ng/ml vs. 1938 ng/ml, p=0.023) and inversely correlated weakly with the duration of respiratory support (R=-0.154, p<0.001). Interestingly, in the neonates born at GA <33, ficolin-2 concentration permitted differentiation of those with/without RDS [AUC=0.712, 95% CI (0.612-0.817), p<0.001] and effective separation of babies with mild RDS from those with moderate/severe form of the disease [AUC=0.807, 95% CI (0.644-0.97), p=0.0002]. CONCLUSION: Low cord serum ficolin-2 concentration (especially in neonates born at GA <33 weeks) is associated with a higher risk of developing moderate/severe RDS, requiring respiratory support and intensive care.

328. Transcriptomic analysis of asthma and allergic rhinitis reveals CST1 as a biomarker of unified airways.

Front Immunol

2023 Jan 17

Wang M, Gong L, Luo Y

BACKGROUND: Allergic rhinitis (AR) is an important risk factor for the development of asthma. The "unified airway" theory considers the upper and lower airways as a morphological and functional whole. However, studies exploring biomarkers linking the upper and lower airways in allergic disease are lacking, which may provide insight into the mechanisms underlying AR comorbid asthma. PURPOSE: To integrate bioinformatics techniques to explore biomarkers in airway allergic diseases, and to provide a molecular etiology profile for preventing the development of asthma in AR patients. METHODS: Biomarkers were screened by identifying key genes common between AR and asthma through WGCNA and differential gene analysis. GO and KEGG analyses were performed using DAVID. Immuno-infiltration analysis was performed by CIBERSORTx. The predictive value of CST1 to distinguish Th2-high asthma was determined by ROC curves. GSEA was used to analyze the signaling pathways involved in CST1. TargetScan and miRNet were combined with GSE142237 to construct ceRNA network. CMap was used to explore potential therapeutic drugs. RESULTS: Validation of datasets showed that CST1 was the only gene that was up-regulated in both upper and lower airways in patients with AR and asthma, and correlation heatmaps showed that CST1 was the gene with the highest sum of correlation coefficients. GO and KEGG analysis demonstrated that the lower airways of AR patients were mainly involved in inflammatory and immune responses, similar to asthma. Immune infiltration showed that CST1 was mainly positively correlated with activated CD4 memory T cells. According to the ROC curve, CST1 showed excellent diagnostic efficiency for Th2-high asthma. GSEA indicated that CST1 was involved in the FcϵRI signaling pathway and O-glycan biosynthesis. A ceRNA network including the lncRNAs KCNQ1OT1 and NEAT1 was constructed. Four drugs, including verrucarin-A, had the potential to prevent the development of asthma in AR patients. In addition, corticosteroids were found to downregulate CST1 expression. CONCLUSION: CST1 plays a key role in the development of AR comorbid asthma and may be a biomarker for airway allergic diseases. Targeted treatment of CST1 has the potential to prevent the development of asthma in AR patients and deserves further study.

329. Exploring the pathogenesis and immune infiltration in dilated cardiomyopathy complicated with atrial fibrillation by bioinformatics analysis.

Front Immunol

2023 Jan 17

Gan T, Hu J, Aledan AKO

BACKGROUND: Atrial fibrillation (AF) is a serious complication of dilated cardiomyopathy (DCM), which increases the risk of thromboembolic events and sudden death in DCM patients. However, the common mechanism of DCM combined with AF remains unclear. This study aims to explore the molecular mechanism and analyze immune infiltration in DCM complicated with AF through comprehensive bioinformatics analysis. METHODS: The gene expression datasets of DCM (GSE141910) and AF (GSE41177 and GSE79768) were obtained from the Gene Expression Omnibus database. Gene enrichment analyses were performed after screening the common differentially expressed genes (DEGs) of DCM and AF. Protein-protein interaction network was constructed in the STRING database and visualized in Cytoscape software, which helped to further screen the central functional modules of DEGs and hub genes. In addition, ImmuCellAI algorithm was performed to estimate immune infiltration patterns, and Spearman correlation was conducted to investigate the correlation between the abundance of multiple immune cells and the expression levels of hub immune-related genes after obtaining hub immune-related genes from the ImmPort database. The hub immune-related genes expression and immune infiltration patterns were additionally verified in the validation datasets (GSE57338, GSE115574, and GSE31821). The diagnostic effectiveness of hub immune-related genes was evaluated through Receiver Operator Characteristic Curve analysis. RESULTS: A total of 184 common DEGs in DCM and AF were identified for subsequent analyses. The functions of hub genes were significantly associated with immune responses. We identified 7 hub immune-related genes (HLA-DRA, LCK, ITK, CD48, CD247, CD3D, and IL2RG) and a spectrum of immune cell subsets including Monocyte, Neutrophil, and follicular helper T (Tfh) cells were found to be concurrently dysregulated in both DCM and AF. 7 hub immune-related genes were predominantly favorably correlated with Tfh cells and were primarily negatively correlated with Neutrophil infiltrations in DCM and AF. CD48+CD3D were verified to diagnose DCM and AF with excellent sensitivity and specificity, showing favorable diagnostic value. CONCLUSIONS: Our study reveals that immune cells (Tfh cells) disorders caused by hub immune-related genes (CD48 and CD3D) may be the common pathogenesis of DCM combined with AF, which lays a foundation for further immune mechanism research.

330. Cross-talk between cuproptosis and ferroptosis regulators defines the tumor microenvironment for the prediction of prognosis and therapies in lung adenocarcinoma.

Front Immunol

2023 Jan 17

Shen Y, Li D, Liang Q

331. Identification and validation of a novel ferroptosis-related gene signature for prognosis and potential therapeutic target prediction in cholangiocarcinoma.

Front Immunol

2023 Jan 17

Sae-Fung A, Mutirangura A, Jitkaew S.

Cholangiocarcinoma (CCA) is a highly heterogeneous and aggressive malignancy of the bile ducts with a poor prognosis and high mortality rate. Effective targeted therapy and accurate prognostic biomarkers are still lacking. Ferroptosis is a form of regulated cell death implicated in cancer progression and has emerged as a potential therapeutic target in various cancers. However, a comprehensive analysis of ferroptosis-related genes (FRGs) for predicting CCA prognosis and therapeutic targets and determining the role of ferroptosis in CCA remain to be performed. Here, we developed a prognostic FRG signature using a least absolute shrinkage and selection operator Cox regression analysis in a training cohort. We then validated it using four independent public datasets. The six-FRG signature was developed to predict CCA patient survival, stratifying them into low-risk and high-risk groups based on survival time. Significantly, the high-risk CCA patients had shorter overall survival. A receiver operating characteristic curve analysis further confirmed the prognostic FRG signature's strong predictive ability, indicating that it was an independent prognostic indicator for CCA patients. Furthermore, the high-risk group was associated with fluke infection and high clinical stages. Cancer-associated fibroblast (CAF) score and CAF markers were significantly higher in the high-risk group than the low-risk group. Moreover, our FRG signature could predict immune checkpoint markers for immunotherapy and drug sensitivity. The mRNA expression levels of the six-FRG signature was validated in 10 CCA cell lines and dividing them into low-risk and high-risk groups using the FRG signature. We further showed that high-risk CCA cell lines were more resistant to ferroptosis inducers, including erastin and RSL3, than the low-risk CCA cell lines. Our study constructed a novel FRG signature model to predict CCA prognoses which might provide prognostic biomarkers and potential therapeutic targets for CCA patients. Ferroptosis sensitivity in high-risk and low-risk CCA cell lines suggests that ferroptosis resistance is associated with high-risk group CCA. Therefore, ferroptosis could be a promising therapeutic target for precision therapy in CCA patients.

332. Neonatal NET-Inhibitory Factor improves survival in the cecal ligation and puncture model of polymicrobial by inhibiting neutrophil extracellular traps.

Front Immunol

2023 Jan 17

de Araujo CV, Denorme F, Stephens WZ

INTRODUCTION: Neutrophil extracellular traps (NETs) clear pathogens but may contribute Q8 pathogenically to host inflammatory tissue damage during sepsis. Innovative therapeutic agents targeting NET formation and their potentially harmful collateral effects remain understudied. METHODS: We investigated a novel therapeutic agent, neonatal NET-Inhibitory Factor (nNIF), in a mouse model of experimental sepsis - cecal ligation and puncture (CLP). We administered 2 doses of nNIF (1 mg/ kg) or its scrambled peptide control intravenously 4 and 10 hours after CLP treatment and assessed survival, peritoneal fluid and plasma NET formation using the MPO-DNA ELISA, aerobic bacterial colony forming units (CFU) using serial dilution and culture, peritoneal fluid and stool microbiomes using 16S rRNA gene sequencing, and inflammatory cytokine levels using a multiplexed cytokine array. Meropenem (25 mg/kg) treatment served as a clinically relevant treatment for infection. RESULTS: We observed increased 6-day survival rates in nNIF (73%) and meropenem (80%) treated mice compared to controls (0%). nNIF decreased NET formation compared to controls, while meropenem did not impact NET formation. nNIF treatment led to increased peritoneal fluid and plasma bacterial CFUs consistent with loss of NET-mediated extracellular microbial killing, while nNIF treatment alone did not alter the peritoneal fluid and stool microbiomes compared to vehicle-treated CLP mice. nNIF treatment also decreased peritoneal TNF-a inflammatory cytokine levels compared to scrambled peptide control. Furthermore, adjunctive nNIF increased survival in a model of sub-optimal meropenem treatment (90% v 40%) in CLP-treated mice. DISCUSSION: Thus, our data demonstrate that nNIF inhibits NET formation in a translationally relevant mouse model of sepsis, improves survival when given as monotherapy or as an adjuvant with antibiotics, and may play an important protective role in sepsis.

333. Development of a prognostic model to identify the metastatic nasopharyngeal carcinoma patients who may benefit from chemotherapy combination PD-1 inhibitor.

Front Immunol

2023 Jan 17

Liu GY, Lu N, Bei WX

334. PFKFB3 overexpression in monocytes of patients with colon but not rectal cancer programs pro-tumor macrophages and is indicative for higher risk of tumor relapse.

Front Immunol

2023 Jan 17

Larionova I, Patysheva M, Iamshchikov P

335. Identification and validation of a muscle failure index to predict prognosis and immunotherapy in lung adenocarcinoma through integrated analysis of bulk and single-cell RNA sequencing data.

Front Immunol

2023 Jan 17

Gu X, Cai L, Luo Z

BACKGROUND: It was previously reported that the production of exerkines is positively associated with the beneficial effects of exercise in lung adenocarcinoma (LUAD) patients. This study proposes a novel scoring system based on muscle failure-related genes, to assist in clinical decision making. METHODS: A comprehensive analysis of bulk and single cell RNA sequencing (scRNA-seq) of early, advanced and brain metastatic LUAD tissues and normal lung tissues was performed to identify muscle failure-related genes in LUAD and to determine the distribution of muscle failure-related genes in different cell populations. A novel scoring system, named MFI (Muscle failure index), was developed and validated. The differences in biological functions, immune infiltration, genomic alterations, and clinical significance of different subtypes were also investigated. RESULTS: First, we conducted single cell analysis on the dataset GSE131907 and identified eight cell subpopulations. We found that four muscle failure-related genes (BDNF, FNDC5, IL15, MSTN) were significantly increased in tumor cells. In addition, IL15 was widely distributed in the immune cell population. And we have validated it in our own clinical cohort. Then we created the MFI model based on 10 muscle failure-related genes using the LASSO algorithm, and MFI remained an independent prognostic factor of OS in both the training and validation cohorts. Moreover, we generated MFI in the single-cell dataset, in which cells with high MFI received and sent more signals compared to those with low MFI. Biological function analysis of both subtypes revealed stronger anti-tumor immune activity in the low MFI group, while tumor cells with high MFI had stronger metabolic and proliferative activity. Finally, we systematically assessed the immune cell activity and immunotherapy responses in LUAD patients, finding that the low MFI group was more sensitive to immunotherapy. CONCLUSION: Overall, our study can improve the understanding of the role of muscle failure-related genes in tumorigenesis and we constructed a reliable MFI model for predicting prognosis and guiding future clinical decision making.

336. Efficacy of chimeric antigen receptor T cell therapy and autologous stem cell transplant in relapsed or refractory diffuse large B-cell lymphoma: A systematic review.

Front Immunol

2023 Jan 17

Tian L, Li C, Sun J

337. Effect of immunostimulation with bacterial lysate on the clinical course of allergic rhinitis and the level of γδT, iNKT and cytotoxic T cells in children sensitized to grass pollen allergens: A randomized controlled trial.

Front Immunol

2023 Jan 17

Janeczek K, Kowalska W, Zarobkiewicz M

BACKGROUND: There are many drugs for allergic rhinitis (AR), however, these drugs show variable clinical effectiveness and some side effects. Therefore, new methods of AR pharmacotherapy are being sought. OBJECTIVES: The objectives of this study were to evaluate the efficacy of polyvalent mechanical bacterial lysate (PMBL) therapy in improving the clinical course of grass pollen-induced AR (seasonal AR, SAR) in children and its effect on changes in the blood level of the γδT, iNKT and cytotoxic T cell subsets. METHODS: Fifty children with SAR were enrolled in this study and were randomly assigned to either the PMBL group or the placebo group. The severity of SAR symptoms was assessed using the total nasal symptom score (TNSS) and visual analogue scale (VAS). During two visits (V1, V2), peak nasal inspiratory flow (PNIF) was measured and peripheral blood was collected for immunological analyses. The study also included 2 telephone contacts (TC1, TC2). RESULTS: The severity of the nasal symptoms of SAR on the TNSS scale was revealed to have a significantly lower impact in the PMBL group vs the placebo group at measuring points TC1 and V2 (p = 0.01, p = 0.009, respectively). A statistically significantly lower mean severity of nasal symptoms of SAR on the VAS scale was recorded for children in the PMBL group compared to the placebo group at measuring points TC1, V2 and TC2 (p = 0.04, p = 0.04, p = 0.03, respectively). The compared groups do not show significant differences in terms of PNIF values at individual measuring points. There were no statistically significant changes in immune variables. For both groups, there was a statistically significant association between the level of Th1-like γδT cells and the severity of SAR symptoms expressed on the TNSS scale (p = 0.03) - the lower the level of Th1-like γδT cells, the higher the TNSS value. CONCLUSION: Administration of sublingual PMBL tablets during the grass pollen season proves to have a high efficacy in alleviating SAR symptoms in children sensitized to grass pollen allergens. Th1-like γδT cells may be used as potential markers for SAR severity in children. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier (NCT04802616).

338. Traffic jam within lymphocytes: A clinician's perspective.

Front Immunol

2023 Jan 16

Hosahalli Vasanna S, Dalal J.

339. Editorial: Non-lymphoid functions of regulatory T cells in health and disease.

Front Immunol

2023 Jan 16

Bos PD, Yoshimura A, Rudra D.

340. Innate immunity in pancreatic cancer: Lineage tracing and function.

Front Immunol

2023 Jan 16

Ye L, Shi S, Chen W.

341. Editorial: Gut microbiome, metabolites, and immune response in lupus, rheumatoid arthritis, and Sjögren syndrome.

Front Immunol

2023 Jan 16

Zhao L, Kostic AD, Zhang X.

342. Plasmodium vivax vaccine: What is the best way to go?

Front Immunol

2023 Jan 16

da Veiga GTS, Moriggi MR, Vettorazzi JF

343. The emerging role of exosomes in innate immunity, diagnosis and therapy.

Front Immunol

2023 Jan 16

Gangadaran P, Madhyastha H, Madhyastha R

344. Dysregulated B cell function and disease pathogenesis in systemic sclerosis.

Front Immunol

2023 Jan 16

Beesley CF, Goldman NR, Taher TE

345. The immune suppressive tumor microenvironment in multiple myeloma: The contribution of myeloid-derived suppressor cells.

Front Immunol

2023 Jan 16

Giannotta C, Autino F, Massaia M.

346. The role of Th17 cells in endocrine organs: Involvement of the gut, adipose tissue, liver and bone.

Front Immunol

2023 Jan 16

Zi C, Wang D, Gao Y

347. The crosstalk between the gut microbiota and tumor immunity: Implications for cancer progression and treatment outcomes.

Front Immunol

2023 Jan 16

Wang M, Zhang L, Chang W

348. Chronic exposure to low-level lipopolysaccharide dampens influenza-mediated inflammatory response via A20 and PPAR network.

Front Immunol

2023 Jan 16

Gu Y, Hsu AC, Zuo X

349. The circadian rhythms regulated by Cx43-signaling in the pathogenesis of Neuromyelitis Optica.

Front Immunol

2023 Jan 16

Xue H, Wu M, Wang Y

350. Inflammatory and deleterious role of gut microbiota-derived trimethylamine on colon cells.

Front Immunol

2023 Jan 16

Jalandra R, Makharia GK, Sharma M

351. Different sea urchin RAG-like genes were domesticated to carry out different functions.

Front Immunol

2023 Jan 16

Yakovenko I, Tobi D, Ner-Gaon H

Front Immunol

2023 Jan 16

Toscano A, Elst J, Van Gasse AL

353. Neuronal surface antigen-specific immunostaining pattern on a rat brain immunohistochemistry in autoimmune encephalitis.

Front Immunol

2023 Jan 16

Nagata N, Kanazawa N, Mitsuhata T

A variety of neuronal surface (NS) antibodies (NS-Ab) have been identified in autoimmune encephalitis (AE). Tissue-based assay (TBA) using a rodent brain immunohistochemistry (IHC) is used to screen NS-Ab, while cell-based assay (CBA) to determine NS antigens. Commercial rat brain IHC is currently available but its clinical relevance remains unclear. Immunostaining patterns of NS antigens have not been extensively studied yet. To address these issues, we assessed a predictive value of "neuropil pattern" and "GFAP pattern" on commercial IHC in 261 patients, and characterized an immunostaining pattern of 7 NS antigens (NMDAR, LGI1, GABAaR, GABAbR, AMPAR, Caspr2, GluK2). Sensitivity and specificity of "neuropil pattern" for predicting NS-Ab were 66.0% (95% CI 55.7-75.3), and 98.2% (95% CI 94.8-99.6), respectively. False-positive rate was 1.8% (3/164) while false-negative rate was 34.0% (33/97). In all 3 false-positive patients, neuropil-like staining was attributed to high titers of GAD65-Ab. In 33 false-negative patients, NMDAR was most frequently identified (n=18 [54.5%], 16/18 [88.9%] had low titers [< 1:32]), followed by GABAaR (n=5). Of 261 patients, 25 (9.6%) had either GFAP (n=21) or GFAP-mimicking pattern (n=4). GFAP-Ab were identified in 21 of 31 patients examined with CBA (20 with GFAP pattern, 1 with GFAP-mimicking pattern). Immunostaining pattern of each NS antigen was as follows: 1) NMDAR revealed homogenous reactivity in the dentate gyrus molecular layer (DG-ML) with less intense dot-like reactivity in the cerebellar granular layer (CB-GL); 2) both GABAaR and GluK2 revealed intense dot-like reactivity in the CB-GL, but GABAaR revealed homogenous reactivity in the DG-ML while GluK2 revealed intense reactivity along the inner layer of the DG-ML; and 3) LGI1, Caspr2, GABAbR, and AMPAR revealed intense reactivity in the cerebellar ML (CB-ML) but LGI1 revealed intense reactivity along the middle layer of the DG-ML. Whereas, Caspr2, GABAbR, and AMPAR revealed similar reactivity in the DG-ML but some difference in other regions. TBA is useful not only for screening NS- or GFAP-Ab but also for estimating NS antigens; however, negative results should be interpreted cautiously because "neuropil pattern" may be missed on commercial IHC when antibody titers are low. Antigen-specific immunoreactivity is a useful biomarker of AE.

354. Peripheral blood cellular profile at pre-lymphodepletion is associated with CD19-targeted CAR-T cell-associated neurotoxicity.

Front Immunol

2023 Jan 16

De Matteis S, Dicataldo M, Casadei B

BACKGROUND: Infusion of second generation autologous CD19-targeted chimeric antigen receptor (CAR) T cells in patients with R/R relapsed/refractory B-cell lymphoma (BCL) is affected by inflammatory complications, such as Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Current literature suggests that the immune profile prior to CAR-T infusion modifies the chance to develop ICANS. METHODS: This is a monocenter prospective study on 53 patients receiving approved CAR T-cell products (29 axi-cel, 24 tisa-cel) for R/R-BCL. Clinical, biochemical, and hematological variables were analyzed at the time of pre-lymphodepletion (pre-LD). In a subset of 21 patients whose fresh peripheral blood sample was available, we performed cytofluorimetric analysis of leukocytes and extracellular vesicles (EVs). Moreover, we assessed a panel of soluble plasma biomarkers (IL-6/IL-10/GDF-15/IL-15/CXCL9/NfL) and microRNAs (miR-146a-5p, miR-21-5p, miR-126-3p, miR-150-5p) which are associated with senescence and inflammation. RESULTS: Multivariate analysis at the pre-LD time-point in the entire cohort (n=53) showed that a lower percentage of CD3+CD8+ lymphocytes (38.6% vs 46.8%, OR=0.937 [95% CI: 0.882-0.996], p=0.035) and higher levels of serum C-reactive protein (CRP, 4.52 mg/dl vs 1.00 mg/dl, OR=7.133 [95% CI: 1.796-28], p=0.005) are associated with ICANS. In the pre-LD samples of 21 patients, a significant increase in the percentage of CD8+CD45RA+CD57+ senescent cells (median % value: 16.50% vs 9.10%, p=0.009) and monocytic-myeloid derived suppressor cells (M-MDSC, median % value: 4.4 vs 1.8, p=0.020) was found in ICANS patients. These latter also showed increased levels of EVs carrying CD14+ and CD45+ myeloid markers, of the myeloid chemokine CXCL-9, as well of the MDSC-secreted cytokine IL-10. Notably, the serum levels of circulating neurofilament light chain, a marker of neuroaxonal injury, were positively correlated with the levels of senescent CD8+ T cells, M-MDSC, IL-10 and CXCL-9. No variation in the levels of the selected miRNAs was observed between ICANS and no-ICANS patients. DISCUSSION: Our data support the notion that pre-CAR-T systemic inflammation is associated with ICANS. Higher proportion of senescence CD8+ T cells and M-MDSC correlate with early signs of neuroaxonal injury at pre-LD time-point, suggesting that ICANS may be the final event of a process that begins before CAR-T infusion, consequence to patient clinical history.

355. Increased expression of long-isoform thymic stromal lymphopoietin is associated with rheumatoid arthritis and fosters inflammatory responses.

Front Immunol

2023 Jan 16

Li W, Liao C, Du J

356. Impact of SIV infection on mycobacterial lipid-reactive T cell responses in Bacillus Calmette-Guérin (BCG) inoculated macaques.

Front Immunol

2023 Jan 16

Walker EM, Merino KM, Slisarenko N

BACKGROUND: Although BCG vaccine protects infants from tuberculosis (TB), it has limited efficacy in adults against pulmonary TB. Further, HIV coinfection significantly increases the risk of developing active TB. In the lack of defined correlates of protection in TB disease, it is essential to explore immune responses beyond conventional CD4 T cells to gain a better understanding of the mechanisms of TB immunity. METHODS: Here, we evaluated unconventional lipid-reactive T cell responses in cynomolgus macaques following aerosol BCG inoculation and examined the impact of subsequent SIV infection on these responses. Immune responses to cellular lipids of M. bovis and M. tuberculosis were examined ex vivo in peripheral blood and bronchioalveolar lavage (BAL). RESULTS: Prior to BCG inoculation, innate-like IFN-γ responses to mycobacterial lipids were observed in T cells. Aerosol BCG exposure induced an early increase in frequencies of BAL γδT cells, a dominant subset of lipid-reactive T cells, along with enhanced IL-7R and CXCR3 expression. Further, BCG exposure stimulated greater IFN-γ responses to mycobacterial lipids in peripheral blood and BAL, suggesting the induction of systemic and local Th1-type response in lipid-reactive T cells. Subsequent SIV infection resulted in a significant loss of IL-7R expression on blood and BAL γδT cells. Additionally, IFN-γ responses of mycobacterial lipid-reactive T cells in BAL fluid were significantly lower in SIV-infected macaques, while perforin production was maintained through chronic SIV infection. CONCLUSIONS: Overall, these data suggest that despite SIV-induced decline in IL-7R expression and IFN-γ production by mycobacterial lipid-reactive T cells, their cytolytic potential is maintained. A deeper understanding of anti-mycobacterial lipid-reactive T cell functions may inform novel approaches to enhance TB control in individuals with or without HIV infection.

357. Virotherapy combined with anti-PD-1 transiently reshapes the tumor immune environment and induces anti-tumor immunity in a preclinical PDAC model.

Front Immunol

2023 Jan 16

Veinalde R, Pidelaserra-Martí G, Moulin C

358. Adenosine receptors differentially mediate enteric glial cell death induced by Clostridioides difficile Toxins A and B.

Front Immunol

2023 Jan 16

Costa DVS, Shin JH, Goldbeck SM

Increased risk of intestinal dysfunction has been reported in patients after Clostridioides difficile infection (CDI). Enteric glial cells (EGCs), a component of the enteric nervous system (ENS), contribute to gut homeostasis. Previous studies showed that adenosine receptors, A2A and A2B, modulate inflammation during CDI. However, it is unknown how these receptors can modulate the EGC response to the C. difficile toxins (TcdA and TcdB). We investigated the effects of these toxins on the expression of adenosine receptors in EGCs and the role of these receptors on toxin-induced EGC death. Rat EGCs line were incubated with TcdA or TcdB alone or in combination with adenosine analogues 1h prior to toxins challenge. After incubation, EGCs were collected to evaluate gene expression (adenosine receptors and proinflammatory markers) and cell death. In vivo, WT, A2A, and A2B KO mice were infected with C. difficile, euthanized on day 3 post-infection, and cecum tissue was processed. TcdA and TcdB increased A2A and A3 transcripts, as well as decreased A2B. A2A agonist, but not A2A antagonist, decreased apoptosis induced by TcdA and TcdB in EGCs. A2B blocker, but not A2B agonist, diminished apoptosis in EGCs challenged with both toxins. A3 agonist, but not A3 blocker, reduced apoptosis in EGCs challenged with TcdA and TcdB. Inhibition of protein kinase A (PKA) and CREB, both involved in the main signaling pathway driven by activation of adenosine receptors, decreased EGC apoptosis induced by both toxins. A2A agonist and A2B antagonist decreased S100B upregulation induced by C. difficile toxins in EGCs. In vivo, infected A2B KO mice, but not A2A, exhibited a decrease in cell death, including EGCs and enteric neuron loss, compared to infected WT mice, reduced intestinal damage and decreased IL-6 and S100B levels in cecum. Our findings indicate that upregulation of A2A and A3 and downregulation of A2B in EGCs and downregulation of A2B in intestinal tissues elicit a protective response against C. difficile toxins. Adenosine receptors appear to play a regulatory role in EGCs death and proinflammatory response induced by TcdA and TcdB, and thus may be potential targets of intervention to prevent post-CDI intestinal dysmotility.

359. Positive regulators of T cell functions as predictors of prognosis and microenvironment characteristics of low-grade gliomas.

Front Immunol

2023 Jan 16

Li Y, Feng Y, Luo F

BACKGROUND: Low-grade gliomas (LGG) are one of the most prevalent types of brain cancers. The efficacy of immunotherapy in LGG is limited compared to other cancers. Immunosuppression in the tumor microenvironment (TME) of LGG is one of the main reasons for the low efficacy of immunotherapy. Recent studies have identified 33 positive regulators of T cell functions (TPRs) that play a critical role in promoting the proliferation, activity, and functions of multiple immunocytes. However, their role in the TME of LGG has not been investigated. This study aimed to construct a risk model based on these TPRs and to detect the significance of immunotypes in predicting LGG prognosis and immunotherapy efficacy. METHODS: A total of 688 LGGs and 202 normal brain tissues were extracted from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Genotype-Tissue Expression (GTEx) databases. The NMF R package was used to identify TRP-related subtypes. The TPR prognostic model was established using the least absolute shrinkage and selection operator (LASSO) algorithm to predict the overall survival of LGG samples. RESULTS: The Subtype 2 patients had worse survival outcomes, suppressed immune function, and higher immune cell infiltration. A risk regression model consisting of 14 TPRs was established, and its performance was validated in CGGA325 cohorts. The low-risk group exhibited better overall survival, immune microenvironment, and immunotherapy response, as determined via the TIDE algorithm, indicating that increasing the level of immune infiltration can effectively improve the response to immunotherapy in the low-risk group. The risk score was determined to be an independent hazard factor (p<0.001) although other clinical features (age, sex, grade, IDH status, 1p19q codel status, MGMT status, and accepted radiotherapy) were considered. Lastly, high-risk groups in both cohorts revealed optimal drug responses to rapamycin, paclitaxel, JW-7-52-1, and bortezomib. CONCLUSIONS: Our study identified two distinct TPR subtypes and built a TPR signature to elucidate the characteristics of T cell proliferation in LGG and its association with immune status and prognosis. These findings shed light on possible immunotherapeutic strategies for LGGs.

360. Gardnerella subgroup dominant microbiomes are associated with divergent cervicovaginal immune responses in a longitudinal cohort of Kenyan women.

Front Immunol

2023 Jan 16

Shvartsman E, Perciani CT, Richmond MEI

361. Exploring the causality and pathogenesis of systemic lupus erythematosus in breast cancer based on Mendelian randomization and transcriptome data analyses.

Front Immunol

2023 Jan 16

Li W, Wang R, Wang W.

362. Successful treatment of a pure red-cell aplasia patient with γδT cells and clonal TCR gene rearrangement: A case report.

Front Immunol

2023 Jan 16

Li X, Zhu X, Zhang X

363. Corrigendum: Investigation of the association between the genetic polymorphisms of co-stimulatory system and systemic lupus erythematosus.

Front Immunol

2023 Jan 16

Chen DP, Lin WT, Yu KH.

364. Corrigendum: Increased levels of interleukin-36 in obesity and type 2 diabetes fuels adipose tissue inflammation by inducing its own expression and release by adipocytes and macrophages.

Front Immunol

2023 Jan 16

Frühbeck G, Gómez-Ambrosi J, Ramírez B

365. Inflammation and histone modification in chronic pain.

Front Immunol

2023 Jan 13

Jiang W, Zhang LX, Tan XY

366. Protein post-translational modification in SARS-CoV-2 and host interaction.

Front Immunol

2023 Jan 13

Cheng N, Liu M, Li W

SARS-CoV-2 can cause lung diseases, such as pneumonia and acute respiratory distress syndrome, and multi-system dysfunction. Post-translational modifications (PTMs) related to SARS-CoV-2 are conservative and pathogenic, and the common PTMs are glycosylation, phosphorylation, and acylation. The glycosylation of SARS-CoV-2 mainly occurs on spike (S) protein, which mediates the entry of the virus into cells through interaction with angiotensin-converting enzyme 2. SARS-CoV-2 utilizes glycans to cover its epitopes and evade the immune response through glycosylation of S protein. Phosphorylation of SARS-CoV-2 nucleocapsid (N) protein improves its selective binding to viral RNA and promotes viral replication and transcription, thereby increasing the load of the virus in the host. Succinylated N and membrane(M) proteins of SARS-CoV-2 synergistically affect virus particle assembly. N protein regulates its affinity for other proteins and the viral genome through acetylation. The acetylated envelope (E) protein of SARS-CoV-2 interacts with bromodomain-containing protein 2/4 to influence the host immune response. Both palmitoylation and myristoylation sites on S protein can affect the virus infectivity. Papain-like protease is a domain of NSP3 that dysregulates host inflammation by deubiquitination and impinges host IFN-I antiviral immune responses by deISGylation. Ubiquitination of ORF7a inhibits host IFN-α signaling by blocking STAT2 phosphorylation. The methylation of N protein can inhibit the formation of host stress granules and promote the binding of N protein to viral RNA, thereby promoting the production of virus particles. NSP3 macrodomain can reverse the ADP-ribosylation of host proteins, and inhibit the cascade immune response with IFN as the core, thereby promoting the intracellular replication of SARS-CoV-2. On the whole, PTMs have fundamental roles in virus entry, replication, particle assembly, and host immune response. Mutations in various SARS-CoV-2 variants, which lead to changes in PTMs at corresponding sites, cause different biological effects. In this paper, we mainly reviewed the effects of PTMs on SARS-CoV-2 and host cells, whose application is to inform the strategies for inhibiting viral infection and facilitating antiviral treatment and vaccine development for COVID-19.

367. Releasing the restraints of Vγ9Vδ2 T-cells in cancer immunotherapy.

Front Immunol

2023 Jan 13

Ridgley LA, Caron J, Dalgleish A

OBJECTIVES: Vγ9Vδ2 T-cells are a subset of T-cells with a crucial role in immunosurveillance which can be activated and expanded by multiple means to stimulate effector responses. Little is known about the expression of checkpoint molecules on this cell population and whether the ligation of these molecules can regulate their activity. The aim of this study was to assess the expression of both activatory and inhibitory receptors on Vγ9Vδ2 T-cells to assess potential avenues of regulation to target with immunotherapy. METHODS: Expression of various activatory and inhibitory receptors was assessed on Vγ9Vδ2 T-cells by flow cytometry following activation and expansion using zoledronic acid (ZA) and Bacillus Calmette-Guérin (BCG). Expression of these markers and production of effector molecules was also examined following co-culture with various tumour cell targets. The effect of immune checkpoint blockade on Vγ9Vδ2 T-cells was also explored. RESULTS: Vγ9Vδ2 T-cells expressed high levels of activatory markers both at baseline and following stimulation. Vγ9Vδ2 T-cells expressed variable levels of inhibitory checkpoint receptors with many being upregulated following stimulation. Expression of these markers is further modulated upon co-culture with tumour cells with changes reflecting activation and effector functions. Despite their high expression of inhibitory receptors when cultured with tumour cells expressing cognate ligands there was no effect on Vδ2+ T-cell cytotoxic capacity or cytokine production with immune checkpoint blockade. CONCLUSIONS: Our work suggests the expression of checkpoint receptors present on Vγ9Vδ2 T-cells which may provide a mechanism with the potential to be utilised by tumour cells to subvert Vγ9Vδ2 T-cell cytotoxicity. This work suggests important candidates for blockade by ICI therapy in order to increase the successful use of Vγ9Vδ2 T-cells in immunotherapy.

368. Metabolic effects of CCL5 deficiency in lean and obese mice.

Front Immunol

2023 Jan 13

Zhou H, Liao X, Zeng Q

369. Effect of GnRH immunocastration on immune function in male rats.

Front Immunol

2023 Jan 13

Pan F, Du H, Tian W

370. Design and immunological evaluation of two-component protein nanoparticle vaccines for East Coast fever.

Front Immunol

2023 Jan 13

Lacasta A, Kim HC, Kepl E

371. Uterine NK cells underexpress KIR2DL1/S1 and LILRB1 in reproductive failure.

Front Immunol

2023 Jan 13

Woon EV, Nikolaou D, MacLaran K

372. Secondary myeloid neoplasms after CD19 CAR T therapy in patients with refractory/relapsed B-cell lymphoma: Case series and review of literature.

Front Immunol

2023 Jan 13

Zhao A, Zhao M, Qian W

BACKGROUND: Several chimeric antigen receptor T cells (CAR T) targeting CD19 have induced profound and prolonged remission for refractory/relapsed (R/R) B-cell lymphoma. The risk of secondary malignancies, especially myeloid neoplasms, is of particular concern in the CAR T community, which still remains unclear. METHODS: Four patients with R/R B-cell lymphoma after CD19 CAR T therapy diagnosed with secondary myeloid neoplasms (SMN) from 2 hospitals in eastern China were presented, including 3 with myelodysplastic syndrome (MDS) and 1 with acute myeloid leukemia (AML). Using single-cell RNA sequencing (scRNA-seq), we compared the cellular components of bone marrow (BM) samples obtained from one of these MDS patients and a health donor. We also provided a review of recently published literature concerning SMN risk of CAR T therapy. RESULTS: Relevant demographic, clinical, laboratory, therapeutic and outcome data were collected and presented by chart review. In our case series, the male-female ratio was 3.0 and the median age at MDS onset was 61.25 years old (range, 50-78). Median number of previous systemic therapies was 4.5 (range, 4-5), including autologous hematopoietic stem cell transplantation (auto-HSCT) in one patient. BM assessments prior to CAR T therapy confirmed normal hematopoiesis without myeloid neoplasms. Moreover, for 3 patients with SMN in our series, cytogenetic analysis predicted a relatively adverse outcome. In our experience and in the literature, treatment choices for the patients with SMN included allogeneic hematopoietic stem cell transplantation (allo-HSCT), hypomethylating agent (HMA), period filgrastim, transfusions and other supportive care. Finally, treatment responses of lymphoma, together with SMN, directly correlated with the overall survival of this community. Of note, it appeared that pathogenesis of MDS wasn't associated with the CAR T toxicities, since all 4 patients experienced a pretty mild CRS of grade 1-2. Additionally, scRNA-seq analysis described the transcriptional alteration of CD34+ cells, identified 13 T/NK clusters, and also indicated increased cytotoxic T cells in MDS BM. CONCLUSION: Our study illustrated the onset and progression of SMN after CD19 CAR T therapy in patients with R/R B-cell lymphoma, which provides useful information of this uncommon later event.

373. CRISPR-mediated rapid arming of poxvirus vectors enables facile generation of the novel immunotherapeutic STINGPOX.

Front Immunol

2023 Jan 13

Whelan JT, Singaravelu R, Wang F

374. A modifiable universal cotinine-chimeric antigen system of NK cells with multiple targets.

Front Immunol

2023 Jan 13

Kang HY, Lee SY, Kim HM

375. Case report: Scleromyxedema associated with a monoclonal gammapathy: Successful treatment with intravenous immunoglobulins.

Front Immunol

2023 Jan 13

Wang SS, Chen QY, Xiang LH.

376. Robust humoral and cellular recall responses to AZD1222 attenuate breakthrough SARS-CoV-2 infection compared to unvaccinated.

Front Immunol

2023 Jan 13

Maaske J, Sproule S, Falsey AR

377. Persistent humoral and CD4(+) T(H) cell immunity after mild SARS-COV-2 infection-The CoNAN long-term study.

Front Immunol

2023 Jan 13

Schnizer C, Andreas N, Vivas W

378. Shifting gears: Study of immune system parameters of male habitual marathon runners.

Front Immunol

2023 Jan 13

Panagoulias I, Charokopos N, Thomas I

AIM: Marathon is a running event in which athletes must cover a distance of 42.195 km. In addition to participating in marathons, marathoners have incorporated extensive running into their lifestyle. In the present study, we investigated the effect of long-term strenuous exercise in the form of marathon running on the immune system. METHODS & RESULTS: We collected peripheral blood samples from 37 male marathoners before/after a race and 37 age/sex/body mass index (BMI)-matched healthy sedentary controls. Hematological and biochemical tests revealed race-induced leukocytosis attributable to neutrophilia and significant increases in plasma lactate dehydrogenase (LDH), creatine phosphokinase (CPK), and cortisol concentrations. Phenotypic analysis of lymphocytes revealed race-induced significant decrease in the number of lymphocytes, memory helper T (Th) cells, naive, memory and activated cytotoxic T (Tc) cells, natural killer (NK), NKT, and B1 cells, and a significant increase in the number of activated Th and regulatory Th cells (Tregs). Compared with controls, marathoners maintained significantly lower levels of memory and activated Th cells and higher levels of activated Tc and B1 cells. Measurement of plasma cytokine levels revealed a pro-inflammatory cytokine polarization that increased after the race. Examination of gene expression of cytokines and Th-cell signature transcription factors in peripheral blood mononuclear cells revealed a significant decrease in tumor necrosis factor α (TNF-α) and interleukin (IL)-17, and a significant increase in IL-6, IL-10 and forkhead box P3 (FoxP3) after the race. Compared with controls, marathoners maintained significantly higher levels of TNF-α. Assessment of the suppressive capacity of Tregs in co-cultures of isolated effector Th cells and Tregs showed significantly increased suppressive capacity of marathoners' Tregs after the race. CONCLUSIONS: Compared with controls, marathoners live with permanent changes in certain immune parameters. Marathoners exhibit a stable pro-inflammatory cytokine polarization that increases after the race and is counterbalanced by increased numbers of Tregs overexpressing FoxP3 and having increased suppressive capacity.

379. Pre-clinical efficacy evaluation of human umbilical cord mesenchymal stem cells for ischemic stroke.

Front Immunol

2023 Jan 13

Shen D, Wang H, Zhu H

OBJECTIVE: This study explored the underlying therapeutic mechanism of human umbilical cord mesenchymal stem cells (hUCMSCs) for ischemic stroke (IS), and determined the optimal administration time windows and dose-effect relationship. METHODS: The levels of SDF-1α, IL-10, IL-6, TNF-α, BDNF, IL-1β, and VEGF-A factors in serum and brain tissue lysate were measured by ELISA. The pathological status of brain tissues was evaluated by Hematoxylin-Eosin (HE) staining, and apoptosis of nerve cells was detected by tunel. The protein expression of CXCR-4, NeuN, and Nestin in the brain tissues was assessed through immunofluorescence. The balance beam, forelimb muscle strength, and limb placement were tested on MCAO rats at different time points and doses. The infarct area of the rat brain tissues was measured at the end of the experiment. RESULTS: The hUCMSC treatment during the acute phase of MCAO significantly reduced the secretion of IL-6, TNF-α, IL-1β but increased IL-10 in serum, and the levels of SDF-α and BDNF in serum and brain tissues lysate were also increased. The pathological results showed that there were more neurons in the treatment group compared to the model group. Immunofluorescence assays showed that the expression of CXCR4、Nestin、NeuN was relatively higher than that in the model group. The d4 and d7 treatment significantly improves the motor function, promotes the recovery of forelimb muscle strength, increases the forelimb placement rate and reduces the scope of cerebral infarction, but the d14 treatment group has less therapeutic effect compared to the d4 and d7 treatment. The 2×107/kg treatment showed the best therapeutic effect, followed by the 1×107/kg treatment, and the worst is 0.5×107/kg treatment from the test of balance beam, forelimb muscle strength, limb placement and the infarct area of the rat brain tissues. CONCLUSION: The hUCMSCs can inhibit the infiltration of inflammatory cells in the brain tissue, and promote the repair of brain tissue structure and function. Early intervention by injecting high-dose of hUCMSCs can significantly improve the recovery of neurological/motor function and reduce the size of cerebral infarction in rats.

380. CRISPR interference for sequence-specific regulation of fibroblast growth factor receptor A in Schistosoma mansoni.

Front Immunol

2023 Jan 13

Du X, McManus DP, French JD

381. SARM suppresses TRIF, TRAF3, and IRF3/7 mediated antiviral signaling in large yellow croaker Larimichthys crocea.

Front Immunol

2023 Jan 13

Zhang JX, Li Y, Tang JC

382. The association between sedentary behavior, exercise, and sleep disturbance: A mediation analysis of inflammatory biomarkers.

Front Immunol

2023 Jan 13

You Y, Chen Y, Fang W

BACKGROUND: Two related lifestyle behaviors associated with sleep disturbance are sedentary behavior and physical exercise participation. We aimed to use a population-based study to disentangle the relationships between sedentary behavior, exercise, and sleep disturbance based on blood-cell-based inflammatory biomarkers. METHODS: A total of 22,599 participants from the National Health and Nutrition Examination Survey (NHANES) were included in the analyses. Sleep disturbance was assessed according to the NHANES questionnaire. Exercise participation ansd sedentary behavior were evaluated by the global physical activity questionnaire. The inflammatory biomarkers in the examination were white blood cell (WBC) count, neutrophil count (NEU), neutrophil-to-lymphocyte ratio (NLR), and systemic immune inflammation index (SII). A complex multistage sampling design and weighted multivariable logistic regression were applied for further analysis. Mediation models were constructed to figure out the mediating role of inflammatory biomarkers. RESULTS: The weighted prevalence of sleep disturbance was 24.17%. Sedentary behavior and exercise were associated with sleep disturbance after full adjustment [for sedentary behavior, OR (95% CI): 1.261 (1.154, 1.377); for exercise, OR (95% CI): 0.849 (0.757, 0.953)]. In severe sedentary behavior groups, the mitigation effect of exercise on sleep disturbance was observed [OR (95% CI): 0.687 (0.551, 0.857)]. For the mechanism, strong associations were detected between inflammatory biomarkers and sleep disturbance. Mediation analysis showed that WBC, NEU, NLR, and SII mediated the statistical association between sedentary behavior and sleep disturbance with proportions (%) of 2.09, 2.27, 1.76, and 0.82, respectively. CONCLUSIONS: Our data suggested that sedentary behavior was a risk factor for sleep disturbance. Blood-cell-based inflammatory biomarkers were an easily accessible and cost-effective strategy for identifying sleep disturbance and also significantly mediated the association between sedentary behavior and sleep disturbance. Exercise was proved to be effective in severe sedentary behavior groups to improve sleep disturbance symptoms, while the internal mechanism needed further exploration.

383. Differential expression of nuclear hormone receptors by dendritic cell subsets in human vaginal mucosa and skin.

Front Immunol

2023 Jan 13

Joo H, Gu C, Wiest M

384. Distinct SARS-CoV-2 RNA fragments activate Toll-like receptors 7 and 8 and induce cytokine release from human macrophages and microglia.

Front Immunol

2023 Jan 13

Wallach T, Raden M, Hinkelmann L

385. Comprehensive characteristics of pathological subtypes in testicular germ cell tumor: Gene expression, mutation and alternative splicing.

Front Immunol

2023 Jan 13

Yao X, Zhou H, Duan C

BACKGROUND: Testicular germ cell tumor (TGCT) is the most common tumor in young men, but molecular signatures, especially the alternative splicing (AS) between its subtypes have not yet been explored. METHODS: To investigate the differences between TGCT subtypes, we comprehensively analyzed the data of gene expression, alternative splicing (AS), and somatic mutation in TGCT patients from the TCGA database. The gene ontology (GO) enrichment analyses were used to explore the function of differentially expressed genes and spliced genes respectively, and Spearman correlation analysis was performed to explore the correlation between differential genes and AS events. In addition, the possible patterns in which AS regulates gene expression were elaborated by the ensemble database transcript atlas. And, we identified important transcription factors that regulate gene expression and AS and functionally validated them in TGCT cell lines. RESULTS: We found significant differences between expression and AS in embryonal carcinoma and seminoma, while mixed cell tumors were in between. GO enrichment analyses revealed that both differentially expressed and spliced genes were enriched in transcriptional regulatory pathways, and obvious correlation between expression and AS events was determined. By analyzing the transcript map and the sites where splicing occurs, we have demonstrated that AS regulates gene expression in a variety of ways. We further identified two pivot AS-related molecules (SOX2 and HDAC9) involved in AS regulation, which were validated in embryonal carcinoma and seminoma cell lines. Differences in somatic mutations between subtypes are also of concern, with our results suggesting that mutations in some genes (B3GNT8, CAPN7, FAT4, GRK1, TACC2, and TRAM1L1) occur only in embryonal carcinoma, while mutations in KIT, KARS, and NRAS are observed only in seminoma. CONCLUSIONS: In conclusion, our analysis revealed the differences in gene expression, AS and somatic mutation among TGCT subtypes, providing a molecular basis for clinical diagnosis and precise therapy of TGCT patients.

386. Subjective sleep quality and fatigue assessment in Polish adult patients with primary immunodeficiencies: A pilot study.

Front Immunol

2023 Jan 13

Grochowalska K, Ziętkiewicz M, Więsik-Szewczyk E

387. The non-oral infection of larval Echinococcus granulosus induces immune and metabolic reprogramming in the colon of mice.

Front Immunol

2023 Jan 13

Zhou Y, Luo T, Gong Y

388. Diagnostic and prognostic value of STAP1 and AHNAK methylation in peripheral blood immune cells for HBV-related hepatopathy.

Front Immunol

2023 Jan 13

Sun L, Lu J, Li K

389. Protective effects of conditioned media of immortalized stem cells from human exfoliated deciduous teeth on pressure ulcer formation.

Front Immunol

2023 Jan 13

Katahira Y, Murakami F, Inoue S

390. Fourteen-day vonoprazan and low- or high-dose amoxicillin dual therapy for eradicating Helicobacter pylori infection: A prospective, open-labeled, randomized non-inferiority clinical study.

Front Immunol

2023 Jan 13

Hu Y, Xu X, Liu XS

391. Humoral and T-cell response 12 months after the first BNT162b2 vaccination in solid organ transplant recipients and controls: Kinetics, associated factors, and role of SARS-CoV-2 infection.

Front Immunol

2023 Jan 13

Rezahosseini O, Hamm SR, Heftdal LD

392. Heterodimeric IL-15 (hetIL-15) reduces circulating tumor cells and metastasis formation improving chemotherapy and surgery in 4T1 mouse model of TNBC.

Front Immunol

2023 Jan 13

Stravokefalou V, Stellas D, Karaliota S

393. Pre-transplant CD69+ extracellular vesicles are negatively correlated with active ATLG serum levels and associate with the onset of GVHD in allogeneic HSCT patients.

Front Immunol

2023 Jan 13

Storci G, Barbato F, Ricci F

Graft versus host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Rabbit anti-T lymphocyte globulin (ATLG) in addition to calcineurin inhibitors and antimetabolites is a suitable strategy to prevent GVHD in several transplant settings. Randomized studies already demonstrated its efficacy in terms of GVHD prevention, although the effect on relapse remains the major concern for a wider use. Tailoring of ATLG dose on host characteristics is expected to minimize its side effects (immunological reconstitution, relapse, and infections). Here, day -6 to day +15 pharmacokinetics of active ATLG serum level was first assayed in an explorative cohort of 23 patients by testing the ability of the polyclonal serum to bind antigens on human leukocytes. Significantly lower levels of serum active ATLG were found in the patients who developed GVHD (ATLG_AUCCD45: 241.52 ± 152.16 vs. 766.63 +/- 283.52 (μg*day)/ml, p = 1.46e-5). Consistent results were obtained when the ATLG binding capacity was assessed on CD3+ and CD3+/CD4+ T lymphocytes (ATLG_AUCCD3: 335.83 ± 208.15 vs. 903.54 ± 378.78 (μg*day)/ml, p = 1.92e-4; ATLG_AUCCD4: 317.75 ± 170.70 vs. 910.54 ± 353.35 (μg*day)/ml, p = 3.78e-5. Concomitantly, at pre-infusion time points, increased concentrations of CD69+ extracellular vesicles (EVs) were found in patients who developed GVHD (mean fold 9.01 ± 1.33; p = 2.12e-5). Consistent results were obtained in a validation cohort of 12 additional ATLG-treated HSCT patients. Serum CD69+ EVs were mainly represented in the nano (i.e. 100 nm in diameter) EV compartment and expressed the leukocyte marker CD45, the EV markers CD9 and CD63, and CD103, a marker of tissue-resident memory T cells. The latter are expected to set up a host pro-inflammatory cell compartment that can survive in the recipient for years after conditioning regimen and contribute to GVHD pathogenesis. In summary, high levels of CD69+ EVs are significantly correlated with an increased risk of GVHD, and they may be proposed as a tool to tailor ATLG dose for personalized GVHD prevention.

394. A diet enriched in omega-3 PUFA and inulin prevents type 1 diabetes by restoring gut barrier integrity and immune homeostasis in NOD mice.

Front Immunol

2023 Jan 13

Lo Conte M, Antonini Cencicchio M, Ulaszewska M

INTRODUCTION: The integrity of the gut barrier (GB) is fundamental to regulate the crosstalk between the microbiota and the immune system and to prevent inflammation and autoimmunity at the intestinal level but also in organs distal from the gut such as the pancreatic islets. In support to this idea, we recently demonstrated that breakage of GB integrity leads to activation of islet-reactive T cells and triggers autoimmune Type 1 Diabetes (T1D). In T1D patients as in the NOD mice, the spontaneous model of autoimmune diabetes, there are alterations of the GB that specifically affect structure and composition of the mucus layer; however, it is yet to be determined whether a causal link between breakage of the GB integrity and occurrence of autoimmune T1D exists. METHODS: Here we restored GB integrity in the NOD mice through administration of an anti-inflammatory diet (AID- enriched in soluble fiber inulin and omega 3-PUFA) and tested the effect on T1D pathogenesis. RESULTS: We found that the AID prevented T1D in NOD mice by restoring GB integrity with increased mucus layer thickness and higher mRNA transcripts of structural (Muc2) and immunoregulatory mucins (Muc1 and Muc3) as well as of tight junction proteins (claudin1). Restoration of GB integrity was linked to reduction of intestinal inflammation (i.e., reduced expression of IL-1β, IL-23 and IL-17 transcripts) and expansion of regulatory T cells (FoxP3+ Treg cells and IL-10+ Tr1 cells) at the expenses of effector Th1/Th17 cells in the intestine, pancreatic lymph nodes (PLN) and intra-islet lymphocytes (IIL) of AID-fed NOD mice. Importantly, the restoration of GB integrity and immune homeostasis were associated with enhanced concentrations of anti-inflammatory metabolites of the ω3/ω6 polyunsaturated fatty acids (PUFA) and arachidonic pathways and modifications of the microbiome profile with increased relative abundance of mucus-modulating bacterial species such as Akkermansia muciniphila and Akkermansia glycaniphila. DISCUSSION: Our data provide evidence that the restoration of GB integrity and intestinal immune homeostasis through administration of a tolerogenic AID that changed the gut microbial and metabolic profiles prevents autoimmune T1D in preclinical models.

395. Editorial: Effector functions of therapeutic antibodies.

Front Immunol

2023 Jan 12

Boross P, Peipp M, Nimmerjahn F.

396. Research progress on circular RNA vaccines.

Front Immunol

2023 Jan 12

Bai Y, Liu D, He Q

397. Subunit vaccines for Acinetobacter baumannii.

Front Immunol

2023 Jan 12

Yang N, Jin X, Zhu C

398. Immunological consequences of microbiome-based therapeutics.

Front Immunol

2023 Jan 12

Alam MZ, Maslanka JR, Abt MC.

399. Editorial: Identification, function and mechanisms of interferon induced genes associated with viruses.

Front Immunol

2023 Jan 12

Ren L, Bai J, Li C.

400. Editorial: Combining chemo/radio therapy and immunotherapy for cancers-perfect mix of old and new.

Front Immunol

2023 Jan 12

Slaney CY, Luo P, Kong FM

401. Review: The role of HMGB1 in spinal cord injury.

Front Immunol

2023 Jan 12

Mo Y, Chen K.

402. Chemo-immunoablation of solid tumors: A new concept in tumor ablation.

Front Immunol

2023 Jan 12

Meng L, Wei Y, Xiao Y.

403. Cancer organoid co-culture model system: Novel approach to guide precision medicine.

Front Immunol

2023 Jan 12

Yuan J, Li X, Yu S.

404. Application of individualized multimodal radiotherapy combined with immunotherapy in metastatic tumors.

Front Immunol

2023 Jan 12

Ji X, Jiang W, Wang J

405. ACKR3 promotes CXCL12/CXCR4-mediated cell-to-cell-induced lymphoma migration through LTB4 production.

Front Immunol

2023 Jan 12

Antonello P, Pizzagalli DU, Foglierini M

406. Current experimental methods to investigate the impact of specialized pro-resolving lipid mediators on Sjögren's syndrome.

Front Immunol

2023 Jan 12

Dos Santos HT, Nam K, Gil D

407. Sinonasal diffuse large B-cell lymphoma in a patient with Wiskott-Aldrich syndrome: A case report and literature review.

Front Immunol

2023 Jan 12

Sun X, Luo C, Tang R

408. TERT promoter mutations and methylation for telomerase activation in urothelial carcinomas: New mechanistic insights and clinical significance.

Front Immunol

2023 Jan 12

Liu T, Li S, Xia C

409. Walk on the wild side: SIV infection in African non-human primate hosts-from the field to the laboratory.

Front Immunol

2023 Jan 12

Jasinska AJ, Apetrei C, Pandrea I.

HIV emerged following cross-species transmissions of simian immunodeficiency viruses (SIVs) that naturally infect non-human primates (NHPs) from Africa. While HIV replication and CD4+ T-cell depletion lead to increased gut permeability, microbial translocation, chronic immune activation, and systemic inflammation, the natural hosts of SIVs generally avoid these deleterious consequences when infected with their species-specific SIVs and do not progress to AIDS despite persistent lifelong high viremia due to long-term coevolution with their SIV pathogens. The benign course of natural SIV infection in the natural hosts is in stark contrast to the experimental SIV infection of Asian macaques, which progresses to simian AIDS. The mechanisms of non-pathogenic SIV infections are studied mainly in African green monkeys, sooty mangabeys, and mandrills, while progressing SIV infection is experimentally modeled in macaques: rhesus macaques, pigtailed macaques, and cynomolgus macaques. Here, we focus on the distinctive features of SIV infection in natural hosts, particularly (1): the superior healing properties of the intestinal mucosa, which enable them to maintain the integrity of the gut barrier and prevent microbial translocation, thus avoiding excessive/pathologic immune activation and inflammation usually perpetrated by the leaking of the microbial products into the circulation; (2) the gut microbiome, the disruption of which is an important factor in some inflammatory diseases, yet not completely understood in the course of lentiviral infection; (3) cell population shifts resulting in target cell restriction (downregulation of CD4 or CCR5 surface molecules that bind to SIV), control of viral replication in the lymph nodes (expansion of natural killer cells), and anti-inflammatory effects in the gut (NKG2a/c+ CD8+ T cells); and (4) the genes and biological pathways that can shape genetic adaptations to viral pathogens and are associated with the non-pathogenic outcome of the natural SIV infection. Deciphering the protective mechanisms against SIV disease progression to immunodeficiency, which have been established through long-term coevolution between the natural hosts and their species-specific SIVs, may prompt the development of novel therapeutic interventions, such as drugs that can control gut inflammation, enhance gut healing capacities, or modulate the gut microbiome. These developments can go beyond HIV infection and open up large avenues for correcting gut damage, which is common in many diseases.

Front Immunol

2023 Jan 12

Webster SE, Tsuji NL, Clemente MJ

INTRODUCTION: Natural antibody (NAb) derived from CD5+ B-1 cells maintains tissue homeostasis, controls inflammation, aids in establishing long-term protective responses against pathogens, and provides immediate protection from infection. CD5+ B-1 cell NAbs recognize evolutionarily fixed epitopes, such as phosphatidylcholine (PtC), found on bacteria and senescent red blood cells. Anti-PtC antibodies are essential in protection against bacterial sepsis. CD5+ B-1 cell-derived NAbs have a unique germline-like structure that lacks N-additions, a feature critical for providing protection against infection. Previously, we demonstrated the repertoire and germline status of PtC+CD5+ B-1 cell IgM obtained from male mice changes with age depending on the anatomical location of the B-1 cells. More recently, we demonstrated serum antibody from aged female mice maintains protection against pneumococcal infection, whereas serum antibody from male mice does not provide protection. RESULTS: Here, we show that aged female mice have significantly more splenic PtC+CD5+ B-1 cells and more PtC specific serum IgM than aged male mice. Furthermore, we find both age and biological sex related repertoire differences when comparing B cell receptor (BCR) sequencing results of PtC+CD5+ B-1 cells. While BCR germline status of PtC+CD5+ B-1 cells from aged male and female mice is similar in the peritoneal cavity, it differs significantly in the spleen, where aged females retain germline configuration and aged males do not. Nucleic acid sensing toll-like receptors are critical in the maintenance of PtC+ B-1 cells; therefore, to begin to understand the mechanism of differences observed between the male and female PtC+CD5+ B-1 cell repertoire, we analyzed levels of cell-free nucleic acids and found increases in aged females. CONCLUSION: Our results suggest the antigenic milieu differs between aged males and females, leading to differential selection of antigen-specific B-1 cells over time. Further elucidation of how biological sex differences influence the maintenance of B-1 cells within the aging environment will be essential to understand sex and age-related disparities in the susceptibility to bacterial infection and will aid in the development of more effective vaccination and/or therapeutic strategies specific for males and females.

411. Overview of the effect of rumen-protected limiting amino acids (methionine and lysine) and choline on the immunity, antioxidative, and inflammatory status of periparturient ruminants.

Front Immunol

2023 Jan 12

Khan MZ, Liu S, Ma Y

412. The antihypertensive effect of remote ischemic conditioning in spontaneously hypertensive rats.

Front Immunol

2023 Jan 12

Li X, Ren C, Li S

413. Akkermansia and its metabolites play key roles in the treatment of campylobacteriosis in mice.

Front Immunol

2023 Jan 12

Jiang L, Yuan C, Ye W

INTRODUCTION: Campylobacter jejuni (C. jejuni) is a common food-borne bacterial pathogen that can use the host's innate immune response to induce the development of colitis. There has been some research on the role of normal intestinal flora in C. jejuni-induced colitis, but the mechanisms that play a central role in resistance to C. jejuni infection have not been explored. METHODS: We treated Campylobacter jejuni-infected mice with fecal microbiota transplantation (FMT), oral butyric acid and deoxycholic acid in a controlled trial and analyzed the possible mechanisms of treatment by a combination of chromatography, immunohistochemistry, fluorescence in situ hybridization, 16s rRNA gene, proteomics and western blot techniques. RESULTS: We first investigated the therapeutic effect of FMT on C. jejuni infection. The results showed that FMT significantly reduced the inflammatory response and blocked the invasion of C.jejuni into the colonic tissue. We observed a significant increase in the abundance of Akkermansia in the colon of mice after FMT, as well as a significant increase in the levels of butyric acid and deoxycholic acid. We next demonstrated that oral administration of sodium butyrate or deoxycholic acid had a similar therapeutic effect. Further proteomic analysis showed that C.jejuni induced colitis mainly through activation of the PI3K-AKT signaling pathway and MAPK signaling pathway, whereas Akkermansia, the core flora of FMT, and the gut microbial metabolites butyric acid and deoxycholic acid both inhibited these signaling pathways to counteract the infection of C. jejuni and alleviate colitis. Finally, we verified the above idea by in vitro cellular assays. In conclusion, FMT is highly effective in the treatment of colitis caused by C. jejuni, with which Akkermansia and butyric and deoxycholic acids are closely associated.The present study demonstrates that Akkermansia and butyric and deoxycholic acids are effective in the treatment of colitis caused by C. jejuni. DISCUSSION: This is the first time that Akkermansia has been found to be effective in fighting pathogens, which provides new ideas and insights into the use of FMT to alleviate colitis caused by C. jejuni and Akkermansia as a treatment for intestinal sexually transmitted diseases caused by various pathogens.

414. Susceptibility identification for seasonal influenza A/H3N2 based on baseline blood transcriptome.

Front Immunol

2023 Jan 12

Tang J, Xu Q, Tang K

415. Spleen tyrosine kinase mediates the γδTCR signaling required for γδT cell commitment and γδT17 differentiation.

Front Immunol

2023 Jan 12

Muro R, Narita T, Nitta T

416. MSI2 deficiency in ILC3s attenuates DSS-induced colitis by affecting the intestinal microbiota.

Front Immunol

2023 Jan 12

Li N, Xu S, Zhang S

BACKGROUND: The etiology and pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are generally believed to be related to immune dysfunction and intestinal microbiota disorder. However, the exact mechanism is not yet fully understood. The pathological changes associated with dextran sodium sulfate (DSS)-induced colitis are similar to those in human UC. As a subgroup of the innate immune system, group 3 innate lymphoid cells (ILC3s) are widely distributed in the lamina propria of the intestinal mucosa, and their function can be regulated by a variety of molecules. Musashi2 (MSI2) is a type of evolutionarily conserved RNA-binding protein that maintains the function of various tissue stem cells and is essential for postintestinal epithelial regeneration. The effect of MSI2 deficiency in ILC3s on IBD has not been reported. Thus, mice with conditional MSI2 knockout in ILC3s were used to construct a DSS-induced colitis model and explore its effects on the pathogenesis of IBD and the species, quantity and function of the intestinal microbiota. METHODS: Msi2flox/flox mice (Msi2fl/fl ) and Msi2flox/floxRorcCre mice (Msi2ΔRorc ) were induced by DSS to establish the IBD model. The severity of colitis was evaluated by five measurements: body weight percentage, disease activity index, colon shortening degree, histopathological score and routine blood examination. The species, quantity and function of the intestinal microbiota were characterized by high-throughput 16S rRNA gene sequencing of DNA extracted from fecal samples. RESULTS: MSI2 was knocked out in the ILC3s of Msi2ΔRorc mice. The Msi2ΔRorc mice exhibited reductions in body weight loss, the disease activity index, degree of colon shortening, tissue histopathological score and immune cells in the peripheral blood compared to those of Msi2fl/fl mice after DSS administration. The 16S rRNA sequencing results showed that the diversity of the intestinal microbiota in DSS-treated Msi2ΔRorc mice changed, with the abundance of Firmicutes increasing and that of Bacteroidetes decreasing. The linear discriminant analysis effect size (LEfSe) approach revealed that Lactobacillaceae could be the key bacteria in the Msi2ΔRorc mouse during the improvement of colitis. Using PICRUST2 to predict the function of the intestinal microbiota, it was found that the functions of differential bacteria inferred by modeling were mainly enriched in infectious diseases, immune system and metabolic functions. CONCLUSIONS: MSI2 deficiency in ILC3s attenuated DSS-induced colonic inflammation in mice and affected intestinal microbiota diversity, composition, and function, with Lactobacillaceae belonging to the phylum Firmicutes possibly representing the key bacteria. This finding could contribute to our understanding of the pathogenesis of IBD and provide new insights for its clinical diagnosis and treatment.

417. Differential expression profiles and functional prediction of circRNA in mice with traumatic heterotopic ossification.

Front Immunol

2023 Jan 12

Wang Z, Yi X, Liu Y

BACKGROUND: Traumatic heterotopic ossification (HO) is an intractable sequela incited by inflammatory insult. To date, the exact molecular mechanisms of traumatic HO formation remain unclear. Recent studies have indicated that circular RNAs (circRNAs) participate in various human skeletal diseases. Although the formation of HO recapitulates many programs during bone development and remodeling, few data are available concerning whether circRNAs could participate in this pathological osteogenesis. METHODS: To investigate the differentially expressed circRNAs (DE-circRNAs) in HO formation, microarray assay was performed to analyze the circRNA expression profile in four pairs of mice HO tissues and normal tissues. Then, qRT-PCR was applied to verify the microarray data. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed the biological functions of the differentially expressed circRNAs target genes. Cytoscape software was used to construct the circRNA-miRNA-mRNA network for circRNAs with different expression levels as well as the target genes. RESULTS: We demonstrated that 491 circRNAs were significantly differentially expressed in mouse HO tissues by a fold-change ≥ 2 and p-value ≤ 0.05. Among them, the expressions of 168 circRNAs were increased, while 323 were decreased. The expression levels of 10 selected circRNAs were verified successfully by qRT-PCR. GO analysis exhibited that these DE-circRNAs participated in a series of cellular processes. KEGG pathway analysis revealed that multiple upregulated and downregulated pathways were closely related to the DE-circRNAs in HO mice. The circRNA-miRNA-mRNA networks demonstrated that DE-circRNAs may be involved in the pathological osteogenesis of HO through the circRNA-targeted miRNA-mRNA axis. CONCLUSION: Our study first demonstrated the expression profiles and predicted the potential functions of DE-circRNAs in mice traumatic HO, which may shed new light on the elucidation of mechanisms as well as provide novel potential peripheral biological diagnostic markers and therapeutic targets for traumatic HO.

418. Activated autophagy of innate immune cells during the early stages of major trauma.

Front Immunol

2023 Jan 12

Chen D, Zhang C, Luo J

BACKGROUND: Trauma-induced immune dysfunction has been a major barrier to achieving reduced mortality, which is poorly understood. Autophagy is a crucial catabolic mechanism of immune cells during times of stress. Few studies have investigated the immune regulatory effects induced by autophagy after trauma. Here, we use single-cell transcriptomics analysis in a major trauma cohort to demonstrate the dominant role of autophagy in innate immune cells during the early stages of major trauma. METHOD: Single-cell transcriptional profiling of peripheral blood mononuclear cells (PBMCs) was performed, which were sampled from three control participants and five major trauma patients within 6 hours of injury. In detail, after single-cell RNA-sequence data processing, cell type annotation and cluster marker identification were performed. A genetic toolbox with 604 autophagy-related genes was used to monitor the autophagy levels in immune cells. In addition, all transcriptome RNA sequencing data obtained from PBMCs in a cohort of 167 major trauma patients were downloaded from gene expression omnibus (GEO) datasets (GSE36809). Key deregulated biological processes and important autophagic hub genes involved in immune cells were identified by weighted gene co-expression network analysis and gene ontology enrichment analysis. RESULTS: A total of 20,445 differentially expressed genes were identified and five co-expression modules were constructed. Enrichment analysis indicated that activated autophagy is the most important biological process during the early stages of major trauma, and JMY (autophagy-related genes) were identified as hub genes. The single-cell transcriptional profiling of PBMCs demonstrated that all components of adaptive immune cells were significantly decreased, whereas components of innate immune cells (monocytes and neutrophils) were significantly increased in major trauma patients compared with control participants. Activated autophagy was detected in monocytes and neutrophils by monitoring the dynamic transcriptional signature of the autophagy-related genetic toolbox. Biological process analysis shows that antigen uptake, processing presentation, and major histocompatibility complex (MHC) class II protein complex assembly pathways were up-regulated in autophagy-positive monocytes, whereas antigen processing and presentation of endogenous antigen and type I interferon signaling pathways were up-regulated in autophagy-positive neutrophils during the early stages of major trauma. CONCLUSION: Our study demonstrated that autophagy is a biological process crucial to the development of immune disorders in the early stages of major trauma. Furthermore, the results of our study generated a comprehensive single-cell immune landscape for major trauma patients, in which we determined that autophagy profoundly affects the main functions of innate immune cells and provides insight into the cellular basis of immune dysregulation after major trauma.

419. Recombinant GMA56 and ROP17 of Eimeria magna conferred protection against infection by homologous species.

Front Immunol

2023 Jan 12

Xiao J, Chen H, Zheng R

One of the most common rabbits coccidia species, Eimeria magna is mainly parasitic in the ileal and jejunal epithelial cells. E. magna infection can affect the growth performance of rabbits or cause other secondary diseases. Traditional methods of anticoccidial treatment typically result in drug resistance and drug residue. Therefore, vaccination is a promising alternative. Gametocyte antigen 56 (GAM56) and rhoptry kinase family proteins (ROPs) are involved in oocyst wall formation and parasite invasion, respectively. A virulence factor, ROP17 contains a serine/threonine kinase catalytic domain. In this study, recombinant E. magna GAM56 (rEmGAM56) and ROP17 (rEmROP17) proteins were obtained from a prokaryotic expression system and their reactogenicity was investigated with immunoblotting. To assess the potential of rEmGAM56 and rEmROP17 as coccidiosis vaccines, New Zealand White rabbits were subcutaneously immunized with 100 μg rEmGAM56 (rGC group) or rEmROP17 (rRC group) twice at 2-week intervals followed by homologous oocyst challenge. The rabbit serum was collected weekly to detect the specific antibody levels. The cytokine levels of pre-challenge serum were measured by enzyme-linked immunosorbent assay and the rabbits were observed and recorded post-challenge for the onset of clinical symptoms. The weight gain, oocyst output, and feed conversion ratio were calculated at the end of the experiment. The results showed that both rEmGAM56 and rEmROP17 had good reactogenicity. The rEmGAM56- or rEmROP17-immunized rabbits had milder clinical symptoms and feed conversion ratios of 3.27:1 and 3.37:1, respectively. The rEmGAM56-immunized rabbits had 81.35% body weight gain and 63.85% oocyst output reduction; the rEmROP17-immunized rabbits had 79.03% body weight gain and 80.10% oocyst output reduction. The ACI of rGC and rRC groups were 162.35 and 171.03, respectively. The specific antibody levels increased rapidly after immunization. Significantly increased interleukin (IL)-2, interferon (IFN)-γ, and IL-17 levels were evident in the rGC and rRC groups (p < 0.05). The rEmGAM56 and rEmROP17 elicited humoral and cellular responses, which protected against E. magna infection in rabbits. Thus, rEmGAM56 and rEmROP17 are potential vaccine candidates against E. magna, and rEmROP17 performed better than rEmGAM56.

420. Longitudinal white matter alterations in SIVmac239-infected rhesus monkeys with and without regular cART treatment.

Front Immunol

2023 Jan 12

Liu J, Nguchu BA, Liu D

OBJECTIVE: To use SIV-mac239-infected Chinese rhesus monkeys to study white matter changes with and without regular combined antiretroviral therapy (cART) and the relationships between the changes and clinical results. METHODS: Diffusion tensor imaging (DTI) data were collected at baseline and 10 days, 4 weeks, 12 weeks, 24 weeks, and 36 weeks after viral inoculation. Plasma CD4 T cell counts, CD4/CD8 ratio, plasma viral load, and cerebrospinal fluid (CSF) viral load were collected at baseline and 1 week, 5 weeks, 12 weeks, 24 weeks, and 36 weeks after viral inoculation. Microstructural characteristics were examined within 76 white matter areas defined by the DTI-white matter (WM) atlas for rhesus macaques. Corrections for multiple comparisons were performed using a false discovery rate (p < 0.05, FDR). Correlation analyzes between imaging markers and clinical markers (plasma CD4 T cell counts, CD4/CD8 ratio, plasma viral load, and cerebral spinal fluid viral load) were performed using Pearson correlations. RESULTS: White matter changes in SIV-infected macaques were detected in different brain regions as early as 4 weeks after inoculation. As time progressed, cART reversed, ameliorated, or even enhanced the effects. The CD4 T cell count was mainly associated with DTI metrics before cART, while the CD4/CD8 ratio was associated with white matter changes with and without cART. Viral load was positively associated with mean diffusivity in HIV patients without cART, and the opposite results were seen in HIV patients with cART. CONCLUSION: SIV-mac239 infection may be an ideal tool for studying HIV-induced changes in the brain. The first white matter changes appeared in a structure adjacent to the periventricular area as early as 4 weeks after inoculation. As time progressed, cART had different effects on different regions, reversing, attenuating, or even progressing the pathology. Moreover, these changes were closely related to the CD4/CD8 ratio and viral load, even after cART.

421. Identifying and validating molecular subtypes of biliary atresia using multiple high-throughput data integration analysis.

Front Immunol

2023 Jan 12

Wang D, Yang S, Zhao Y

BACKGROUND: Biliary atresia (BA) is the most common form of severe neonatal obstructive jaundice. The etiology and pathogenesis of BA are multifactorial, and different factors may interact to produce heterogeneous pathological features and clinical outcomes. Despite different pathological features, all patients received the same treatment strategy. This study performed integrative clustering analysis based on multiple high-throughput datasets to identify the molecular subtypes of BA and provide a new treatment strategy for personalized treatment of the different subtypes of BA. METHODS: The RNA sequence dataset GSE122340 in the Gene Expression Omnibus (GEO) database was downloaded; 31 BA and 20 control normal liver tissues were collected at our center for transcriptome sequencing, and clinical and follow-up data of BA patients were available. Molecular subtypes were identified using integrated unsupervised cluster analysis involving gene expression, biliary fibrosis, and immune enrichment scores based on the transcriptome dataset, and the results were validated using independent datasets. RESULTS: Based on the results of the integrated unsupervised clustering analysis, four molecular subtypes were identified: autoimmune, inflammatory, virus infection-related, and oxidative stress. The autoimmune subtype with a moderate prognosis was dominated by autoimmune responses and morphogenesis, such as the Fc-gamma receptor and Wnt signaling pathway. The biological process of the inflammatory subtype was mainly the inflammatory response, with the best prognosis, youngest age at surgery, and lowest liver stiffness. The virus infection-related subtype had the worst prognosis and was enriched for a variety of biological processes such as viral infection, immunity, anatomical morphogenesis, and epithelial mesenchymal transition. The oxidative stress subtype was characterized by the activation of oxidative stress and various metabolic pathways and had a poor prognosis. The above results were verified independently in the validation sets. CONCLUSIONS: This study identified four molecular subtypes of BA with distinct prognosis and biological processes. According to the pathological characteristics of the different subtypes, individualized perioperative and preoperative treatment may be a new strategy to improve the prognosis of BA.

422. Low circulatory Fe and Se levels with a higher IL-6/IL-10 ratio provide nutritional immunity in tuberculosis.

Front Immunol

2023 Jan 12

Kaushik SR, Sahu S, Guha H

423. Placental macrophages present distinct polarization pattern and effector functions depending on clinical onset of preeclampsia.

Front Immunol

2023 Jan 12

Mercnik MH, Schliefsteiner C, Fluhr H

Hofbauer cells (HBCs) are resident macrophages of the human placenta, regulating immune tolerance and tissue homeostasis. HBCs of a normal placenta (CTR) exhibit mainly an anti-inflammatory M2 phenotype. Under exaggerated chronic inflammation during pregnancy, as in preeclampsia (PE), a phenotypic switch towards M1 polarization has been proposed. PE, defined as maternally derived syndrome can be distinguished into two different entities: early-onset (EO) preeclampsia and late-onset (LO) preeclampsia. Although the clinical presenting characteristics overlap, both can be identified by biochemical markers, heritability, and different maternal and fetal outcomes. To date, no study has specifically investigated polarization and phenotype of EO- and LO-PE HBCs and looked at possible changes in HBC functionality. Primary HBCs were isolated from CTR and PE placentae. First, in vitro morphological differences were observed between CTR and PE HBCs, with both PE groups exhibiting features of M1 macrophages alongside M2 forms. Interestingly, a different polarization pattern was observed between EO- and LO-PE HBCs. EO-PE HBCs develop a tissue remodeling M2 phenotype that is strongly shifted toward M1 polarization and showed a significant upregulation of CD86, TLR4, and HLA-DR. Furthermore, this pro-inflammatory signature is corroborated by higher expression of IRF5 and of NOS2 (p ≤ 0.05). However, their M2 characteristics is reflected by significant TGF-β secretion and ARG1 expression. In contrast, LO-PE HBCs developed a phagocytic CD209-low M2 phenotype in which the M1 pattern was not as pronounced as they downregulated the NOS2 gene, but expressed increased levels of pro-inflammatory CD80 and TLR1 (p ≤ 0.05). The enhanced phagocytosis and MMP-9 secretion alongside the increased secretion of anti-inflammatory IL -4, IL -13 and TGF-β in both EO- and LO-PE HBCs suggests their adaptive role and plasticity in resolving inflammation and tissue homeostasis.

424. A novel assay that characterizes properdin function shows neutrophil-derived properdin has a distinct oligomeric distribution.

Front Immunol

2023 Jan 12

Moore SR, Menon SS, Galwankar NS

Properdin acts as an essential positive regulator of the alternative pathway of complement by stabilizing enzymatic convertases. Identical properdin monomers form head-to-tail associations of oligomers in a reported 20:54:26 ratio (most often described as an approximate 1:2:1 ratio) of tetramers (P4), trimers (P3), and dimers (P2), in blood, under normal physiological conditions. Oligomeric size is proportional to properdin function with tetramers being more active, followed by trimers and dimers. Neutrophils are the most abundant granulocyte, are recruited to inflammatory microenvironments, and are a significant source of properdin, yet the ratio of properdin oligomers released from neutrophils is unknown. The oligomer ratio of neutrophil-derived properdin could have functional consequences in local microenvironments where neutrophils are abundant and complement drives inflammation. We investigated the oligomer properties of neutrophil-derived properdin, as compared to that of normal human sera, using a novel ELISA-based method that detects function of properdin in a way that was proportional to the oligomeric size of properdin (i.e., the larger the oligomer, the higher the detected function). Unexpectedly, neutrophil-derived properdin had 5-fold lower function than donor-matched serum-derived properdin. The lower function was due to a lower percentage of tetramers/trimers and more dimers, indicating a significantly different P4:P3:P2 ratio in neutrophil-derived properdin (18:34:48) as compared to donor-matched serum (29:43:29). Release of lower-order oligomers by neutrophils may constitute a novel regulatory mechanism to control the rate of complement activation in cellular microenvironments. Further studies to determine the factors that affect properdin oligomerization and whether, or how, the predominant dimers in neutrophil-derived properdin, assimilate to the ~1:2:1 ratio found in serum are warranted.

425. Integrated analysis of transcription factor-mRNA-miRNA regulatory network related to immune characteristics in medullary thyroid carcinoma.

Front Immunol

2023 Jan 12

Weng D, He L, Chen X

BACKGROUND: Medullary thyroid carcinoma (MTC), a thyroid C cell-derived malignancy, is poorly differentiated and more aggressive than papillary, follicular and oncocytic types of thyroid cancer. The current therapeutic options are limited, with a third of population suffering resistance. The differential gene expression pattern among thyroid cancer subtypes remains unclear. This study intended to explore the exclusive gene profile of MTC and construct a comprehensive regulatory network via integrated analysis, to uncover the potential key biomarkers. METHODS: Multiple datasets of thyroid and other neuroendocrine tumors were obtained from GEO and TCGA databases. Differentially expressed genes (DEGs) specific in MTC were identified to construct a transcription factor (TF)-mRNA-miRNA network. The impact of the TF-mRNA-miRNA network on tumor immune characteristics and patient survival was further explored by single-sample GSEA (ssGSEA) and ESTIMATE algorithms, as well as univariate combined with multivariate analyses. RT-qPCR, cell viability and apoptosis assays were performed for in vitro validation. RESULTS: We identified 81 genes upregulated and 22 downregulated in MTC but not in other types of thyroid tumor compared to the normal thyroid tissue. According to the L1000CDS2 database, potential targeting drugs were found to reverse the expressions of DEGs, with panobinostat (S1030) validated effective for tumor repression in MTC by in vitro experiments. The 103 DEGs exclusively seen in MTC were involved in signal release, muscle contraction, pathways of neurodegeneration diseases, neurotransmitter activity and related amino acid metabolism, and cAMP pathway. Based on the identified 15 hub genes, a TF-mRNA-miRNA linear network, as well as REST-cored coherent feed-forward loop networks, namely REST-KIF5C-miR-223 and REST-CDK5R2-miR-130a were constructed via online prediction and validation by public datasets and our cohort. Hub-gene, TF and miRNA scores in the TF-mRNA-miRNA network were related to immune score, immune cell infiltration and immunotherapeutic molecules in MTC as well as in neuroendocrine tumor of lung and neuroblastoma. Additionally, a high hub-gene score or a low miRNA score indicated good prognoses of neuroendocrine tumors. CONCLUSION: The present study uncovers underlying molecular mechanisms and potential immunotherapy-related targets for the pathogenesis and drug discovery of MTC.

426. Clinical characteristics and long-term outcome of patients with gastrointestinal involvement in eosinophilic granulomatosis with polyangiitis.

Front Immunol

2023 Jan 12

Li R, Chen Y, Zhang S

OBJECTIVE: This study aims to investigate clinical characteristics, potential risk factors, as well as long-term outcome in EGPA patients with GI involvement. METHODS: A total of 94 EGPA patients were included in this cohort study. We retrospectively reviewed the clinical data, treatment, and outcome of 21 EGPA patients with GI involvement and compared them with other 73 EGPA patients without GI involvement. Multivariate logistic regression was used to find potential risk factors associated with GI involvement in EGPA patients. RESULTS: Compared with EGPA patients without GI involvement, EGPA patients with GI involvement had higher level of hs-CRP (65.1 (24.5-138.9) vs. 21.3 (5.7-39.1) mg/L, p=0.005), higher grades of Birmingham vasculitis activity score (BVAS) (20 (13-29.5) vs. 12 (16-19), p=0.022), higher Five Factor Score (FFS) (1 (1-2) vs. 0 (0-1), p<0.001), and were more likely to have weight loss (66.7% vs. 38.4%, p=0.021) at baseline. In EGPA patients with GI involvement, the most common gastrointestinal symptoms were abdominal pain (90.5%) and diarrhea (42.9%). Weight loss was identified as a potential risk factor for GI involvement in EGPA patients (OR = 4.304, 95% CI 1.339-13.841). During follow-up, EGPA patients with GI involvement showed lower 1-year cumulative survival rate (75.2% vs. 100.0%, P <0.0001) and 3-year cumulative survival rate (67.7% vs. 100.0%, P<0.0001), lower long-term remission rate (33.3% vs. 86.3%, P<0.001), but higher 1-year cumulative relapse rate (19.2% vs. 3.8%, P=0.03) and 3-year cumulative relapse rate (54.6% vs. 13.1%, P<0.001) compared with patients without GI involvement. CONCLUSION: EGPA patients with GI involvement had distinct features from those without GI involvement, including higher hs-CRP level, higher BVAS and FFS scores. EGPA patients with GI involvement showed lower cumulative survival rate, lower long-term remission rate and higher cumulative relapse rate compared with those without GI involvement.

427. Inhibition of complement activation by CD55 overexpression in human induced pluripotent stem cell derived kidney organoids.

Front Immunol

2023 Jan 12

Gaykema LH, van Nieuwland RY, Dekkers MC

428. Identification of EMT-related alternative splicing event of TMC7 to promote invasion and migration of pancreatic cancer.

Front Immunol

2023 Jan 12

Weng Y, Qian H, Hong L

OBJECTIVE: Epithelial-to-mesenchymal transition (EMT) is tightly associated with the invasion and metastasis of pancreatic cancer with rapid progression and poor prognosis. Notably, gene alternative splicing (AS) event plays a critical role in regulating the progression of pancreatic cancer. Therefore, this study aims to identify the EMT-related AS event in pancreatic cancer. METHODS: The EMT-related gene sets, transcriptomes, and matched clinical data were obtained from the MSigDB, The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases. Key gene AS events associated with liver metastasis were identified by prognostic analysis, gene set variation analysis (GSVA), and correlation analysis in pancreatic cancer. The cell line and organoid model was constructed to evaluate these key gene AS events in regulating pancreatic cancer in vitro. Furthermore, we established an EMT-related gene set consisting of 13 genes by prognostic analysis, the role of which was validated in two other databases. Finally, the human pancreatic cancer tissue and organoid model was used to evaluate the correlation between the enrichment of this gene set and liver metastasis. RESULTS: Prognostic analysis and correlation analysis revealed that eight AS events were closely associated with the prognosis of pancreatic cancer. Furthermore, the expression of TMC7 and CHECK1 AS events was increased in the metastatic lesions of the human tissue and organoid model. Additionally, the knockdown of exon 17 of TMC7 significantly inhibited the proliferation, invasion, and migration of pancreatic cancer cells in 2D and 3D cell experiments. Finally, the expression of exon 17 of TMC17 exhibited a significant correlation with the poor prognosis in pancreatic ductal adenocarcinoma (PDAC). CONCLUSION: The AS events of TMC7 and CHECK1 were associated with liver metastasis in pancreatic cancer. Moreover, exon 17 of TMC7 could be a potential therapeutic target in pancreatic cancer.

429. GM-CSF, Flt3-L and IL-4 affect viability and function of conventional dendritic cell types 1 and 2.

Front Immunol

2023 Jan 12

Lellahi SM, Azeem W, Hua Y

Conventional type 1 dendritic cells (cDC1) and conventional type 2 dendritic cells (cDC2) have attracted increasing attention as alternatives to monocyte-derived dendritic cells (moDCs) in cancer immunotherapy. Use of cDCs for therapy has been hindered by their low numbers in peripheral blood. In the present study, we found that extensive spontaneous apoptosis and cDC death in culture within 24hrs represent an additional challenge. Different media conditions that maintain cDC viability and function were investigated. CD141+ cDC1 and CD1c+ cDC2 were isolated from healthy blood donor buffy coats. Low viabilities were found with CellGenix DC, RPMI-1640, and X-VIVO 15 standard culture media and with several supplements at 24hrs and 48hrs. Among multiple factors it was found that GM-CSF improved both cDC1 and cDC2 viability, whereas Flt3-L and IL-4 only increased viability of cDC1 and cDC2, respectively. Combinations of these three cytokines improved viability of both cDCs further, both at 24hrs and 48hrs time points. Although these cytokines have been extensively investigated for their role in myeloid cell differentiation, and are also used clinically, their effects on mature cDCs remain incompletely known, in particular effects on pro-inflammatory or tolerogenic cDC features. HLA-DR, CD80, CD83, CD86, PD-L1 and PD-L2 cDC membrane expressions were relatively little affected by GM-CSF, IL-4 and Flt3-L cytokine supplements compared to the strong induction following Toll-like receptor (TLR) stimulation for 24hrs. With minor exceptions the three cytokines appeared to be permissive to the TLR-induced marker expression. Allogeneic mixed leukocyte reaction showed that the cytokines promoted T-cell proliferation and revealed a potential to boost both Th1 and Th2 polarizing cytokines. GM-CSF and Flt3-L and their combination improved the capability of cDC1 for dextran uptake, while in cDC2, dextran capture was improved by GM-CSF. The data suggest that GM-CSF, IL-4 and Flt3-L and combinations might be beneficial for DC viability and function in vitro. Limited viability of cDCs could be a confounding variable experimentally and in immunotherapy.

430. A novel TBK1/IKKϵ is involved in immune response and interacts with MyD88 and MAVS in the scallop Chlamys farreri.

Front Immunol

2023 Jan 12

Liu W, Ma J, Chen J

431. Recombinant full-length Bacillus Anthracis protective antigen and its 63 kDa form elicits protective response in formulation with addavax.

Front Immunol

2023 Jan 12

Sharma S, Bahl V, Srivastava G

INTRODUCTION: Bacillus anthracis is the causative agent for the lethal disease anthrax, primarily affecting animals and humans in close contact with an infected host. The pathogenicity of B. anthracis is attributed to the secreted exotoxins and their outer capsule. The host cell-binding exotoxin component "protective antigen" (PA) is reported to be a potent vaccine candidate. The aim of our study is to produce several PA constructs and analyze their vaccine potential. METHODS: We have designed the various subunit, PA-based recombinant proteins, i.e., full-length Protective antigen (PA-FL), C-terminal 63 kDa fragment (PA63), Protective antigen domain 1-domain 4 chimeras (PA-D1-4) and protective antigen domain 4 (PA-D4) and analyzed their vaccine potential with different human-compatible adjuvants in the mouse model. We have optimized the process and successfully expressed our recombinant antigens as soluble proteins, except full-length PA. All the recombinant antigen formulations with three different adjuvants i.e., Addavax, Alhydrogel, and Montanide ISA 720, were immunized in different mouse groups. The vaccine efficacy of the formulations was analyzed by mouse serum antigen-specific antibody titer, toxin neutralization assay, and survival analysis of mouse groups challenged with a lethal dose of B. anthracis virulent spores. RESULTS: We have demonstrated that the PA-FL addavax and PA63 addavax formulations were most effective in protecting spore-challenged mice and serum from the mice immunized with PAFL addavax, PA-FL alhydrogel, PA63 addavax, and PA63 alhydrogel formulations were equivalently efficient in neutralizing the anthrax lethal toxin. The higher levels of serum Th1, Th2, and Th17 cytokines in PA-FL addavax immunized mice correspond to the enhanced protection provided by the formulation in challenged mice. DISCUSSION: We have demonstrated that the PA-FL addavax and PA63 addavax formulations exhibit equivalent efficiency as vaccine formulation both in a mouse model of anthrax and mammalian cell lines. However, PA63 is a smaller antigen than PA-FL and more importantly, PA63 is expressed as a soluble protein in E. coli, which imparts a translational advantage to PA63-based formulation. Thus, the outcome of our study has significant implications for the development of protective antigen-based vaccine formulations for human use against the lethal disease anthrax.

432. An environmentally relevant concentration of antibiotics impairs the immune system of zebrafish (Danio rerio) and increases susceptibility to virus infection.

Front Immunol

2023 Jan 12

Pereiro P, Rey-Campos M, Figueras A

433. Human and mouse TLR2 results in different activation of p38 and JNK signal pathway in HaCaT infected by Trichophyton rubrum and Microsporum canis.

Front Immunol

2023 Jan 12

Su Z, Deng W, Zhan S

INTRODUCTION: It has long been recognized that inflammation to dermatophyte infection is different among various hosts, but the mechanism underlying is still not well understood. Toll-like receptor (TLR2), mediates the innate immune response against dermatophyte infection and is very important to trigger the inflammatory response to dermatophytes. Considering the different amino acid sequences and structures of TLR2, we speculated that TLR2 from different hosts will activate the downstream signal pathways to varying degrees, resulting in different inflammatory responses to dermatophytes. METHODS: In this study, we constructed the mice-human fusion TLR2 expressed HaCaT (mhTLR2-HaCaT) by replacing the extracellular ligand recognition region of human TLR2 with that of the mouse. Then hTLR2-HaCaT cells and mhTLR2-HaCaT cells were infected with T. rubrum and M. canis for 24 h followed by immunoblotting to asses associated proteins of p38 and JNK signal pathway. RESULTS: Compared with that of human TLR2 expressed HaCaT (hTLR2-HaCaT), levels of phosphorylated p38 protein were increased in mhTLR2-HaCaT cells stimulated by T. rubrum for 24 h, and levels of phosphorylatedJNK and c-Jun protein were increased in mhTLR2-HaCaT cells whenstimulated with M. canis for 24 h. DISCUSSION: Compared with hTLR2-HaCaT cells, p38 and JNK signal pathwayswere activated in mhTLR2-HaCaT after being infected by Trichophyton rubrumand Microsporum canis, respectively. Since p38 and JNK are the mainpathways that transduce the signal for host recognition of dermatophytes andmediate the downstream inflammatory response, it suggested that theinterspecific difference of TLR2 ectodomain may be one of the reasons for thedifferent inflammatory manifestations between humans and mice infected bythese two dermatophytes. Quite especially, the mouse-derived TLR2extracellular recognition region is more effective in recognizing T. rubrum andM. canis to activate the downstream signal pathways, resulting in a tenserinflammatory response against these two dermatophytes.

434. Case report: Autoimmune encephalitis with multiple auto-antibodies with reversible splenial lesion syndrome and bilateral ovarian teratoma.

Front Immunol

2023 Jan 12

Li Y, Zhang M, Liu D

BACKGROUND: Reversible splenial lesion syndrome (RESLES) is a spectrum of disease radiologically characterized by reversible lesions caused by multiple factors, primarily involving the splenium of the corpus callosum (SCC). The most common causes of RESLES include infection, antiepileptic drug use and withdrawal, and severe metabolic disorders. Nevertheless, cases of autoimmune encephalitis (AE) are uncommon. CASE PRESENTATION: A 26-year-old female computer programming engineer with no previous medical or psychiatric history reported to the psychiatric hospital due to a 3-day episode of irritability, babbling, limb stiffness, sleepwalking, hallucinations, and paroxysmal mania. Brain MRI revealed abnormal signals of the SCC. Lumbar puncture was performed and further testing for auto-antibodies was conducted in both the CSF and serum. CSF of the patient was positive for anti-NMDAR (titer of 1:3.2) antibodies, and serum was also positive for anti-NMDAR (titer of 1:32) as well as mGluR5 (titer of 1:10) antibodies. Enhanced CT of the pelvis showed an enlarged pelvic mass; bilateral ovarian teratomas (mature teratoma and immature teratoma) were evaluated, which were pathologically confirmed after transabdominal left adnexal resection, right ovarian biopsy, and ovarian cystectomy. The patient considerably improved after intravenous administration of steroids, immunoglobulin, oral prednisone, surgical treatment, and chemotherapy. A follow-up MRI revealed completely resolved lesions. During a 3-month follow-up, the patient experienced complete resolution of symptoms without any sign of recurrence and tumors. The titer of the anti-NMDAR antibody decreased to 1:10 in serum. CONCLUSION: Herein, we report a rare case of AE with overlapping auto-antibodies, along with RESLES and bilateral ovarian teratomas. The current case provides the possibility of the concurrence of mGluR5 antibodies in anti-NMDAR encephalitis. However, the underlying mechanism remains elusive. Furthermore, we provide additional evidence that overlapping antibodies-related pathology may be one of the many causes of RESLES. Nonetheless, caution should be observed in interpreting the observation, considering that this is a single-case study.

435. mRNA vaccines against SARS-CoV-2 induce comparably low long-term IgG Fc galactosylation and sialylation levels but increasing long-term IgG4 responses compared to an adenovirus-based vaccine.

Front Immunol

2023 Jan 12

Buhre JS, Pongracz T, Künsting I

BACKGROUND: The new types of mRNA-containing lipid nanoparticle vaccines BNT162b2 and mRNA-1273 and the adenovirus-based vaccine AZD1222 were developed against SARS-CoV-2 and code for its spike (S) protein. Several studies have investigated short-term antibody (Ab) responses after vaccination. OBJECTIVE: However, the impact of these new vaccine formats with unclear effects on the long-term Ab response - including isotype, subclass, and their type of Fc glycosylation - is less explored. METHODS: Here, we analyzed anti-S Ab responses in blood serum and the saliva of SARS-CoV-2 naïve and non-hospitalized pre-infected subjects upon two vaccinations with different mRNA- and adenovirus-based vaccine combinations up to day 270. RESULTS: We show that the initially high mRNA vaccine-induced blood and salivary anti-S IgG levels, particularly IgG1, markedly decrease over time and approach the lower levels induced with the adenovirus-based vaccine. All three vaccines induced, contrary to the short-term anti-S IgG1 response with high sialylation and galactosylation levels, a long-term anti-S IgG1 response that was characterized by low sialylation and galactosylation with the latter being even below the corresponding total IgG1 galactosylation level. Instead, the mRNA, but not the adenovirus-based vaccines induced long-term IgG4 responses - the IgG subclass with inhibitory effector functions. Furthermore, salivary anti-S IgA levels were lower and decreased faster in naïve as compared to pre-infected vaccinees. Predictively, age correlated with lower long-term anti-S IgG titers for the mRNA vaccines. Furthermore, higher total IgG1 galactosylation, sialylation, and bisection levels correlated with higher long-term anti-S IgG1 sialylation, galactosylation, and bisection levels, respectively, for all vaccine combinations. CONCLUSION: In summary, the study suggests a comparable "adjuvant" potential of the newly developed vaccines on the anti-S IgG Fc glycosylation, as reflected in relatively low long-term anti-S IgG1 galactosylation levels generated by the long-lived plasma cell pool, whose induction might be driven by a recently described TH1-driven B cell response for all three vaccines. Instead, repeated immunization of naïve individuals with the mRNA vaccines increased the proportion of the IgG4 subclass over time which might influence the long-term Ab effector functions. Taken together, these data shed light on these novel vaccine formats and might have potential implications for their long-term efficacy.

436. Relative adrenal insufficiency is a risk factor and endotype of sepsis - A proof-of-concept study to support a precision medicine approach to guide glucocorticoid therapy for sepsis.

Front Immunol

2023 Jan 12

Wu CH, Guo L, Hao D

437. Immunotherapeutic approaches in EBV-associated nasopharyngeal carcinoma.

Front Immunol

2023 Jan 11

Li W, Duan X, Chen X

438. Editorial: Crosstalk between innate and adaptive immunity in colorectal cancer: Implications for immunotherapy.

Front Immunol

2023 Jan 11

Jarry A, Gervois N, Bossard C

439. Tertiary lymphoid structures are critical for cancer prognosis and therapeutic response.

Front Immunol

2023 Jan 11

Zhang Q, Wu S.

440. The role of histone methylase and demethylase in antitumor immunity: A new direction for immunotherapy.

Front Immunol

2023 Jan 11

Zhang Y, Chen J, Liu H

441. Perspectives of ERCC1 in early-stage and advanced cervical cancer: From experiments to clinical applications.

Front Immunol

2023 Jan 11

Du P, Li G, Wu L

442. Fire in the belly: A scoping review of the immunopathological mechanisms of acute pancreatitis.

Front Immunol

2023 Jan 11

Venkatesh K, Glenn H, Delaney A

INTRODUCTION: Acute pancreatitis (AP) is characterised by an inflammatory response that in its most severe form can cause a systemic dysregulated immune response and progression to acute multi-organ dysfunction. The pathobiology of the disease is unclear and as a result no targeted, disease-modifying therapies exist. We performed a scoping review of data pertaining to the human immunology of AP to summarise the current field and to identify future research opportunities. METHODS: A scoping review of all clinical studies of AP immunology was performed across multiple databases. Studies were included if they were human studies of AP with an immunological outcome or intervention. RESULTS: 205 studies met the inclusion criteria for the review. Severe AP is characterised by significant immune dysregulation compared to the milder form of the disease. Broadly, this immune dysfunction was categorised into: innate immune responses (including profound release of damage-associated molecular patterns and heightened activity of pattern recognition receptors), cytokine profile dysregulation (particularly IL-1, 6, 10 and TNF-α), lymphocyte abnormalities, paradoxical immunosuppression (including HLA-DR suppression and increased co-inhibitory molecule expression), and failure of the intestinal barrier function. Studies including interventions were also included. Several limitations in the existing literature have been identified; consolidation and consistency across studies is required if progress is to be made in our understanding of this disease. CONCLUSIONS: AP, particularly the more severe spectrum of the disease, is characterised by a multifaceted immune response that drives tissue injury and contributes to the associated morbidity and mortality. Significant work is required to develop our understanding of the immunopathology of this disease if disease-modifying therapies are to be established.

443. CK2β-regulated signaling controls B cell differentiation and function.

Front Immunol

2023 Jan 11

Quotti Tubi L, Mandato E, Canovas Nunes S

444. β-hydroxybutyrate enhances bovine neutrophil adhesion by inhibiting autophagy.

Front Immunol

2023 Jan 11

He J, Wang K, Liu M

INTRODUCTION: Subclinical ketosis (SCK) in dairy cows, a common metabolic disorder during the perinatal period, is accompanied by systemic inflammation and a high concentration of blood β-hydroxybutyrate (BHB). BHB induced adhesion of neutrophils may play a crucial role in the development of systemic inflammation in SCK cows. Autophagy, an intracellular degradation system, regulates the recycling of membrane adhesion molecules and may be involved in BHB regulating adhesion and pro-inflammatory activation of bovine neutrophils. Thus, the objective of this study was to determine the relationship between BHB, autophagy, and neutrophil adhesion. RESULTS AND DISCUSSION: Here, elevated abundance of serum amyloid A, haptoglobin, C-reactive protein, interleukin-1β, interleukin-6, and tumor necrosis factor-α were found in SCK cows, and all these pro-inflammatory factors had a strong positive correlation with serum BHB. After BHB treatment, the number of adherent neutrophils and the adhesion associated protein abundance of both total and membrane CD11a, CD11b, and CD18 was greater, confirming that BHB promoted the adhesion of bovine neutrophils. However, the mRNA abundance of ITGAL (CD11a), ITGAM (CD11b), and ITGB2 (CD18) did not show a significant difference, suggesting that the degradation of adhesion molecules may be impaired. Transmission electron microscopy revealed a decreased number of autophagosomes and a decrease in mRNA abundance of SQSTM1 (p62) and MAP1LC3B (LC3) after BHB treatment. In parallel, protein abundance of p62 increased while the ratio of protein LC3 II to LC3 I decreased after BHB treatment, indicating that BHB inhibits autophagy of bovine neutrophils. To confirm the regulatory role of autophagy in BHB promoting neutrophil adhesion, we used an autophagy activator rapamycin (RAPA). Data showed that RAPA relieved the inhibitory effect on autophagy and the promotive effect on cell adhesion induced by BHB. Importantly, BHB inhibited the colocalization of LC3 and CD11b, which was relieved by RAPA, further confirming the regulatory role of autophagy in the recycling of the above adhesion molecules. Furthermore, BHB treatment increased the mRNA abundance and the release of pro-inflammatory factors IL-1B, IL-6, and TNF of bovine neutrophils, and these effects were attenuated by RAPA. Overall, the present study revealed that BHB promotes the adhesion of bovine neutrophils by inhibiting autophagy.

445. The impact of cross-reactive immunity on the emergence of SARS-CoV-2 variants.

Front Immunol

2023 Jan 11

Thompson RN, Southall E, Daon Y

INTRODUCTION: A key feature of the COVID-19 pandemic has been the emergence of SARS-CoV-2 variants with different transmission characteristics. However, when a novel variant arrives in a host population, it will not necessarily lead to many cases. Instead, it may fade out, due to stochastic effects and the level of immunity in the population. Immunity against novel SARS-CoV-2 variants may be influenced by prior exposures to related viruses, such as other SARS-CoV-2 variants and seasonal coronaviruses, and the level of cross-reactive immunity conferred by those exposures. METHODS: Here, we investigate the impact of cross-reactive immunity on the emergence of SARS-CoV-2 variants in a simplified scenario in which a novel SARS-CoV-2 variant is introduced after an antigenically related virus has spread in the population. We use mathematical modelling to explore the risk that the novel variant invades the population and causes a large number of cases, as opposed to fading out with few cases. RESULTS: We find that, if cross-reactive immunity is complete (i.e. someone infected by the previously circulating virus is not susceptible to the novel variant), the novel variant must be more transmissible than the previous virus to invade the population. However, in a more realistic scenario in which cross-reactive immunity is partial, we show that it is possible for novel variants to invade, even if they are less transmissible than previously circulating viruses. This is because partial cross-reactive immunity effectively increases the pool of susceptible hosts that are available to the novel variant compared to complete cross-reactive immunity. Furthermore, if previous infection with the antigenically related virus assists the establishment of infection with the novel variant, as has been proposed following some experimental studies, then even variants with very limited transmissibility are able to invade the host population. DISCUSSION: Our results highlight that fast assessment of the level of cross-reactive immunity conferred by related viruses against novel SARS-CoV-2 variants is an essential component of novel variant risk assessments.

446. Weight cycling induces innate immune memory in adipose tissue macrophages.

Front Immunol

2023 Jan 11

Caslin HL, Cottam MA, Piñon JM

447. Checkpoint inhibitor immune-related adverse events: A focused review on autoantibodies and B cells as biomarkers, advancements and future possibilities.

Front Immunol

2023 Jan 11

Taylor J, Gandhi A, Gray E

448. Three-phase extraction of polysaccharide from Stropharia rugosoannulata: Process optimization, structural characterization and bioactivities.

Front Immunol

2023 Jan 11

Li X, Zhang Z, Wang L

449. Alterations of the gut virome in patients with systemic lupus erythematosus.

Front Immunol

2023 Jan 11

Chen C, Yan Q, Yao X

BACKGROUND: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that has been linked to the dysbiosis of the gut microbiome and virome. However, the potential characterization of the gut virome in SLE patients needs to be explored more extensively. METHODS: Herein, we analyzed the gut viral community of 16 SLE patients and 31 healthy controls using both bulk and virus-like particle (VLP)-based metagenomic sequencing of their fecal samples. A total of 15,999 non-redundant viral operational taxonomic units (vOTUs) were identified from the metagenomic assembled contigs and used for gut virome profiling. RESULTS: SLE patients exhibited a significant decrease in gut viral diversity in the bulk metagenome dataset, but this change was not significant in the VLP metagenome dataset. Also, considerable alterations of the overall gut virome composition and remarkable changes in the viral family compositions were observed in SLE patients compared with healthy controls, as observed in both two technologies. We identified 408 vOTUs (177 SLE-enriched and 231 control-enriched) with significantly different relative abundances between patients and controls in the bulk virome, and 18 vOTUs (17 SLE-enriched in 1 control-enriched) in the VLP virome. The SLE-enriched vOTUs included numerous Siphoviridae, Microviridae, and crAss-like viruses and were frequently predicted to infect Bacteroides, Parabacteroides, and Ruminococcus_E, while the control-enriched contained numerous members of Siphoviridae and Myoviridae and were predicted to infect Prevotella and Lachnospirales_CAG-274. We explored the correlations between gut viruses and bacteria and found that some Lachnospirales_CAG-274 and Hungatella_A phages may play key roles in the virus-bacterium network. Furthermore, we explored the gut viral signatures for disease discrimination and achieved an area under the receiver operator characteristic curve (AUC) of above 0.95, suggesting the potential of the gut virome in the prediction of SLE. CONCLUSION: Our findings demonstrated the alterations in viral diversity and taxonomic composition of the gut virome of SLE patients. Further research into the etiology of SLE and the gut viral community will open up new avenues for treating and preventing SLE and other autoimmune diseases.

450. TREM2 is associated with tumor immunity and implies poor prognosis in glioma.

Front Immunol

2023 Jan 11

Yu M, Chang Y, Zhai Y

451. The involvement of the primo vascular system in local enteritis and its modification by electroacupuncture.

Front Immunol

2023 Jan 11

Nan S, Wan J, Lei Q

452. Human pegivirus-1 replication influences NK cell reconstitution after allogeneic haematopoietic stem cell transplantation.

Front Immunol

2023 Jan 11

Pradier A, Cordey S, Zanella MC

INTRODUCTION: Human pegivirus-1 (HPgV-1) is a so-called commensal virus for which no known associated organ disease has been found to date. Yet, it affects immune-reconstitution as previously studied in the HIV population, in whom active co-infection with HPgV-1 can modulate T and NK cell activation and differentiation leading to a protective effect against the evolution of the disease. Little is known on the effect of HPgV-1 on immune-reconstitution in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients, a patient population in which we and others have previously reported high prevalence of HPgV-1 replication. The aim of this study was to compare the immune reconstitution after allo-HSCT among HPgV-1-viremic and HPgV-1-non-viremic patients. METHODS: Within a cohort study of 40 allo-HSCT patients, 20 allo-HSCT recipients positive in plasma sample for HPgV-1 by rRT-PCR during the first year (1, 3, 6, 12 months) after transplantation were matched with 20 allo-HSCT recipients negative for HPgV-1. T and NK cell reconstitution was monitored by flow cytometry in peripheral blood samples from allo-HSCT recipients at the same time points. RESULTS: We observed no significant difference in the absolute number and subsets proportions of CD4 and CD8 T cells between patient groups at any analysed timepoint. We observed a significantly higher absolute number of NK cells at 3 months among HPgV-1-viremic patients. Immunophenotypic analysis showed a significantly higher proportion of CD56bright NK cells mirrored by a reduced percentage of CD56dim NK cells in HPgV-1-positive patients during the first 6 months after allo-HSCT. At 6 months post-allo-HSCT, NK cell phenotype significantly differed depending on HPgV-1, HPgV-1-viremic patients displaying NK cells with lower CD16 and CD57 expression compared with HPgV-1-negative patients. In accordance with their less differentiated phenotype, we detected a significantly reduced expression of granzyme B in NK cells in HPgV-1-viremic patients at 6 months. DISCUSSION: Our study shows that HPgV-1-viremic allo-HSCT recipients displayed an impaired NK cell, but not T cell, immune-reconstitution compared with HPgV-1-non-viremic patients, revealing for the first time a potential association between replication of the non-pathogenic HPgV-1 virus and immunomodulation after allo-HSCT.

453. PRKX down-regulates TAK1/IRF7 signaling in the antiviral innate immunity of black carp Mylopharyngodon piceus.

Front Immunol

2023 Jan 11

Yang X, Ai Y, Chen L

454. Single-cell profiling reveals distinct subsets of CD14+ monocytes drive blood immune signatures of active tuberculosis.

Front Immunol

2023 Jan 11

Hillman H, Khan N, Singhania A

455. Safety of COVID-19 vaccination in women undergoing IVF/ICSI treatment - Clinical study and systematic review.

Front Immunol

2023 Jan 11

Chen H, Zhang X, Lin G

456. Fecal microbiota transplantation and short-chain fatty acids reduce sepsis mortality by remodeling antibiotic-induced gut microbiota disturbances.

Front Immunol

2023 Jan 11

Lou X, Xue J, Shao R

OBJECTIVE: Sepsis is the leading cause of death in critically ill patients. The gastrointestinal tract has long been thought to play an important role in the pathophysiology of sepsis. Antibiotic therapy can reduce a patient's commensal bacterial population and raise their risk of developing subsequent illnesses, where gut microbiota dysbiosis may be a key factor. METHODS: In this study, we analyzed the 16S rRNA of fecal samples from both healthy people and patients with sepsis to determine if alterations in gut bacteria are associated with sepsis. Then, we developed a mouse model of sepsis using cecal ligation and puncture (CLP) in order to examine the effects of fecal microbiota transplantation (FMT) and short-chain fatty acids (SCFAs) on survival rate, systemic inflammatory response, gut microbiota, and mucosal barrier function. RESULTS: Sepsis patients' gut microbiota composition significantly differed from that of healthy people. At the phylum level, the amount of Proteobacteria in the intestinal flora of sepsis patients was much larger than that of the control group, whereas the number of Firmicutes was significantly lower. Mice with gut microbiota disorders (ANC group) were found to have an elevated risk of death, inflammation, and organ failure as compared to CLP mice. However, all of these could be reversed by FMT and SCFAs. FMT and SCFAs could regulate the abundance of bacteria such as Firmicutes, Proteobacteria, Escherichia Shigella, and Lactobacillus, restoring them to levels comparable to those of healthy mice. In addition, they increased the expression of the Occludin protein in the colon of mice with sepsis, downregulated the expression of the NLRP3 and GSDMD-N proteins, and reduced the release of the inflammatory factors IL-1β and IL-18 to inhibit cell pyroptosis, ultimately playing a protective role in sepsis. DISCCUSION: FMT and SCFAs provide a microbe-related survival benefit in a mouse model of sepsis, suggesting that they may be a viable treatment for sepsis.

457. DNA methylation regulatory patterns and underlying pathways behind the co-pathogenesis of allergic rhinitis and chronic spontaneous urticaria.

Front Immunol

2023 Jan 11

Yang Z, Wen P, Chen J

BACKGROUND: Allergic rhinitis (AR) and chronic spontaneous urticaria (CSU) are often concurrent in patients. Changes in DNA methylation affect T cell biological processes, which may explain the occurrence and progression of comorbidity. However, downstream regulatory pathways of DNA methylation in two diseases and the underlying mechanisms have not been fully elucidated. METHODS: The GSE50101, GSE72541, GSE50222 and OEP002482 were mined for the identification of differentially expressed genes (DEGs) or co-expressed genes and differentially methylated genes (DMGs) in AR and CSU patients. We applied GO analysis and consensus clustering to study the potential functions and signal pathways of selected genes in two diseases. GSVA and logistic regression analysis were used to find the regulatory pathway between DNA methylation and activation patterns of CD4+ T cells. Besides, we used the Illumina 850k chip to detect DNA methylation expression profiles and recognize the differentially methylated CpG positions (DMPs) on corresponding genes. Finally, we annotated the biological process of these genes using GO and KEGG pathway analysis. RESULT: The AR-related DEGs were found closely related to the differentiation and activation of CD4+ T cells. The DEGs or co-expressed genes of CD4+ T cells in AR and CSU patients were also clustered using GO and KEGG analysis and we got 57 co-regulatory pathways. Furthermore, logistic regression analysis showed that the regulation of cellular component size was closely related to the activation of CD4+ T cells regulated by DNA methylation. We got self-tested data using the Illumina 850k chip and identified 98 CpGs that were differentially methylated in patients. Finally, we mapped the DMPs to 15 genes and found that they were mainly enriched in the same CD4+T cell regulating pathway. CONCLUSION: Our study indicated that DNA methylation affected by pollen participated in the activation patterns of CD4 + T cells, providing a novel direction for the symptomatic treatment of the co-occurrence of AR and CSU.

458. Statins change the cytokine profile in Trypanosoma cruzi-infected U937 macrophages and murine cardiac tissue through Rho-associated kinases inhibition.

Front Immunol

2023 Jan 11

González-Herrera F, Clayton NS, Guzmán-Rivera D

INTRODUCTION: Chronic Chagasic cardiomyopathy (CCC), caused by the protozoan Trypanosoma cruzi, is the most severe manifestation of Chagas disease.CCC is characterized by cardiac inflammation and fibrosis caused by a persistent inflammatory response. Following infection, macrophages secrete inflammatory mediators such as IL-1β, IL-6, and TNF-α to control parasitemia. Although this response contains parasite infection, it causes damage to the heart tissue. Thus, the use of immunomodulators is a rational alternative to CCC. Rho-associated kinase (ROCK) 1 and 2 are RhoA-activated serine/threonine kinases that regulate the actomyosin cytoskeleton. Both ROCKs have been implicated in the polarization of macrophages towards an M1 (pro-inflammatory) phenotype. Statins are FDA-approved lipid-lowering drugs that reduce RhoA signaling by inhibiting geranylgeranyl pyrophosphate (GGPP) synthesis. This work aims to identify the effect of statins on U937 macrophage polarization and cardiac tissue inflammation and its relationship with ROCK activity during T. cruzi infection. METHODS: PMA-induced, wild-type, GFP-, CA-ROCK1- and CA-ROCK2-expressing U937 macrophages were incubated with atorvastatin, or the inhibitors Y-27632, JSH-23, TAK-242, or C3 exoenzyme incubated with or without T. cruzi trypomastigotes for 30 min to evaluate the activity of ROCK and the M1 and M2 cytokine expression and secretion profiling. Also, ROCK activity was determined in T. cruzi-infected, BALB/c mice hearts. RESULTS: In this study, we demonstrate for the first time in macrophages that incubation with T. cruzi leads to ROCK activation via the TLR4 pathway, which triggers NF-κB activation. Inhibition of ROCKs by Y-27632 prevents NF-κB activation and the expression and secretion of M1 markers, as does treatment with atorvastatin. Furthermore, we show that the effect of atorvastatin on the NF-kB pathway and cytokine secretion is mediated by ROCK. Finally, statin treatment decreased ROCK activation and expression, and the pro-inflammatory cytokine production, promoting anti-inflammatory cytokine expression in chronic chagasic mice hearts. CONCLUSION: These results suggest that the statin modulation of the inflammatory response due to ROCK inhibition is a potential pharmacological strategy to prevent cardiac inflammation in CCC.

459. Case report: Dupilumab treatment improved type 2 disorders in a patient with IPEX syndrome diagnosis.

Front Immunol

2023 Jan 11

Caruso C, Laterza L, Settanni CR

We described a case of IPEX syndrome successfully controlled with dupilumab, an anti-IL4 receptor alpha subunit inhibitor. IPEX syndrome is a rare and generally fatal genetic disorder characterized by immune dysregulation, polyendocrinopathy and enteropathy, mostly diagnosed in early childhood. Nonetheless, cases reported in the last 20 years demonstrated that IPEX clinical spectrum encompasses more than the classical triad of early-onset intractable diarrhea, type 1 diabetes and eczema. Atypical cases of IPEX include patients with late-onset of symptoms, single-organ involvement, mild disease phenotypes or rare clinical features. A 21-year-old caucasian man presented with immune dysregulation (hypereosinophilia and elevated IgE), protein-losing enteropathy, polyendocrinopathy (thyroiditis, osteoporosis, delayed puberty), weight loss, eczema manifestations and celiac disease. IPEX syndrome was diagnosed because of the presence of a hemizygous mutation in FOXP3 gene (c.543C>T (p.S181S) in the exon 5). During the course of the disease, the patient developed erosive proctitis, pyoderma gangrenosum, and erythema nodosum. Symptoms improved only after enteral and parenteral corticosteroid therapy and the patient soon developed steroid-dependence. Notwithstanding various therapies including azathioprine, sirolimus, tacrolimus, adalimumab, vedolizumab, the patient failed to achieve a good control of symptoms without steroids. Almost exclusive enteral nutrition with a hypoallergenic, milk-protein free, amino acid-based food for special medical purposes. He continued to lose weight (BMI 14.5 kg/m2) with a consequent high limitation of physical activity and a progressive worsening of the quality of life. In consideration of the poor response to conventional immunosuppressants and the presence of type 2 inflammatory manifestations, treatment with dupilumab at an initial dose of 600 mg, followed by a maintenance dose of 300 mg every other week, according to atopic dermatitis labeled dose, was started and combined to oral budesonide 6 mg/day and 6-mercaptopurine 75 mg/day. The patient experienced a rapid improvement in bowel and skin symptoms, leading to a progressive tapering of steroids. By our knowledge, this is the first report of IPEX syndrome successfully treated by antiIL-4/IL-13 therapy. In this case dupilumab demonstrated to be an effective, safe and steroid-sparing option.

460. Immunotherapy or targeted therapy as the first-line strategies for unresectable hepatocellular carcinoma: A network meta-analysis and cost-effectiveness analysis.

Front Immunol

2023 Jan 11

Liu K, Zhu Y, Zhu H.

INTRODUCTION: The existence of many phase III randomized controlled trials (RCTs) of first-line treatment for unresectable hepatocellular carcinoma (HCC) puzzle doctors and patients in choosing the most effective treatment strategies. We aimed to assess the efficacy, safety, and cost-effectiveness of immunotherapy or targeted therapy as the first-line strategy for unresectable HCC. METHODS: The included clinical trials were retrieved from PubMed, Embase, the Cochrane library, and Web of Science databases, in which immunotherapy or targeted therapy was regarded as the first-line treatment for unresectable HCC, published in English between January 1, 2010, and September 20, 2022. We conducted a network meta-analysis (NMA) and cost-effectiveness analysis (CEA) from the Chinese payer's perspective. Overall survival (OS), progression-free survival (PFS), the ranks of different treatments using P-score, and adverse events (AEs) were evaluated by NMA. Total costs, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-benefit ratio (ICER) were estimated from 15-year Markov models developed by CEA. RESULTS: We identified 2,825 records, including 11,796 patients, from 15 RCTs. The NMA revealed that sintilimab plus a bevacizumab biosimilar (HR, 0.57; 95% CI, 0.43 to 0.75; P = 0.96) and camrelizumab plus rivoceranib (HR, 0.56; 95% CI, 0.41 to 0.66; P = 0.94) could lead to great improvements in OS and PFS compared with sorafenib-related survival. The CEA indicated that tislelizumab increased by 0.220 QALYs (0.312 LYs) and decreased by $1,938 compared with sorafenib, which yielded ICERs of -$8,809/QALY (-$2,612/LY). Sensitivity analysis showed that the model was stable. CONCLUSION: Sintilimab plus a bevacizumab biosimilar and camrelizumab plus rivoceranib significantly prolonged OS and PFS, respectively. Further considering the pharmacoeconomics factors, tislelizumab is the most cost-effective first-line treatment strategy for unresectable HCC in China.

461. Host blood-based biosignatures for subclinical TB and incipient TB: A prospective study of adult TB household contacts in Southern India.

Front Immunol

2023 Jan 11

Sivakumaran D, Jenum S, Srivastava A

462. Temporal trends of COVID-19 antibodies in vaccinated healthcare workers undergoing repeated serological sampling: An individual-level analysis within 13 months in the ORCHESTRA cohort.

Front Immunol

2023 Jan 11

Collatuzzo G, De Palma G, Violante FS

SHORT SUMMARY: We investigated changes in serologic measurements after COVID-19 vaccination in 19,422 subjects. An individual-level analysis was performed on standardized measurements. Age, infection, vaccine doses, time between doses and serologies, and vaccine type were associated with changes in serologic levels within 13 months. BACKGROUND: Persistence of vaccine immunization is key for COVID-19 prevention. METHODS: We investigated the difference between two serologic measurements of anti-COVID-19 S1 antibodies in an individual-level analysis on 19,422 vaccinated healthcare workers (HCW) from Italy, Spain, Romania, and Slovakia, tested within 13 months from first dose. Differences in serologic levels were divided by the standard error of the cohort-specific distribution, obtaining standardized measurements. We fitted multivariate linear regression models to identify predictors of difference between two measurements. RESULTS: We observed a progressively decreasing difference in serologic levels from <30 days to 210-240 days. Age was associated with an increased difference in serologic levels. There was a greater difference between the two serologic measurements in infected HCW than in HCW who had never been infected; before the first measurement, infected HCW had a relative risk (RR) of 0.81 for one standard deviation in the difference [95% confidence interval (CI) 0.78-0.85]. The RRs for a 30-day increase in time between first dose and first serology, and between the two serologies, were 1.08 (95% CI 1.07-1.10) and 1.04 (95% CI 1.03-1.05), respectively. The first measurement was a strong predictor of subsequent antibody decrease (RR 1.60; 95% CI 1.56-1.64). Compared with Comirnaty, Spikevax (RR 0.83, 95% CI 0.75-0.92) and mixed vaccines (RR 0.61, 95% CI 0.51-0.74) were smaller decrease in serological level (RR 0.46; 95% CI 0.40-0.54). CONCLUSIONS: Age, COVID-19 infection, number of doses, time between first dose and first serology, time between serologies, and type of vaccine were associated with differences between the two serologic measurements within a 13-month period.

463. MRI/PET multimodal imaging of the innate immune response in skeletal muscle and draining lymph node post vaccination in rats.

Front Immunol

2023 Jan 11

Madi S, Xie F, Farhangi K

The goal of this study was to utilize a multimodal magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging approach to assess the local innate immune response in skeletal muscle and draining lymph node following vaccination in rats using two different vaccine platforms (AS01 adjuvanted protein and lipid nanoparticle (LNP) encapsulated Self-Amplifying mRNA (SAM)). MRI and 18FDG PET imaging were performed temporally at baseline, 4, 24, 48, and 72 hr post Prime and Prime-Boost vaccination in hindlimb with Cytomegalovirus (CMV) gB and pentamer proteins formulated with AS01, LNP encapsulated CMV gB protein-encoding SAM (CMV SAM), AS01 or with LNP carrier controls. Both CMV AS01 and CMV SAM resulted in a rapid MRI and PET signal enhancement in hindlimb muscles and draining popliteal lymph node reflecting innate and possibly adaptive immune response. MRI signal enhancement and total 18FDG uptake observed in the hindlimb was greater in the CMV SAM vs CMV AS01 group (↑2.3 - 4.3-fold in AUC) and the MRI signal enhancement peak and duration were temporally shifted right in the CMV SAM group following both Prime and Prime-Boost administration. While cytokine profiles were similar among groups, there was good temporal correlation only between IL-6, IL-13, and MRI/PET endpoints. Imaging mass cytometry was performed on lymph node sections at 72 hr post Prime and Prime-Boost vaccination to characterize the innate and adaptive immune cell signatures. Cell proximity analysis indicated that each follicular dendritic cell interacted with more follicular B cells in the CMV AS01 than in the CMV SAM group, supporting the stronger humoral immune response observed in the CMV AS01 group. A strong correlation between lymph node MRI T2 value and nearest-neighbor analysis of follicular dendritic cell and follicular B cells was observed (r=0.808, P<0.01). These data suggest that spatiotemporal imaging data together with AI/ML approaches may help establish whether in vivo imaging biomarkers can predict local and systemic immune responses following vaccination.

464. Duration of immunity to SARS-CoV-2 in children after natural infection or vaccination in the omicron and pre-omicron era: A systematic review of clinical and immunological studies.

Front Immunol

2023 Jan 11

Buonsenso D, Cusenza F, Passadore L

465. Case report: Daratumumab for treatment of refractory late or chronic active antibody-mediated rejection in renal allograft recipients with high levels of de novo donor-specific antibodies.

Front Immunol

2023 Jan 11

Zhu L, Guo Z, Zhao D

466. Editorial: SARS-CoV-2 variants, B lymphocytes, and autoreactivity.

Front Immunol

2023 Jan 10

Radic MZ, Zouali M.

467. Editorial: Updates on the pathogenesis of common variable immunodeficiency (CVID).

Front Immunol

2023 Jan 10

Martelius T, Seppänen MRJ, Warnatz K.

468. γδT cells in oral tissue immune surveillance and pathology.

Front Immunol

2023 Jan 10

Chen Y, Du J, Liu Y

469. Inhibition of galectins in cancer: Biological challenges for their clinical application.

Front Immunol

2023 Jan 10

Laderach DJ, Compagno D.

470. The application basis of immuno-checkpoint inhibitors combined with chemotherapy in cancer treatment.

Front Immunol

2023 Jan 10

Shi MY, Liu HG, Chen XH

471. Intestinal and blood lymphograms as new diagnostic tests for celiac disease.

Front Immunol

2023 Jan 10

Roy G, Fernández-Bañares F, Corzo M

472. Role of inflammation, immunity, and oxidative stress in hypertension: New insights and potential therapeutic targets.

Front Immunol

2023 Jan 10

Zhang Z, Zhao L, Zhou X

473. Dendritic cells and natural killer cells: The road to a successful oncolytic virotherapy.

Front Immunol

2023 Jan 10

Ghasemi M, Abbasi L, Ghanbari Naeini L

474. Corrigendum: Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2.

Front Immunol

2023 Jan 10

Wines BD, Kurtovic L, Trist HM

475. Generation of bispecific antibodies by structure-guided redesign of IgG constant regions.

Front Immunol

2023 Jan 10

Iwasaki YW, Tharakaraman K, Subramanian V

476. Characterizing T cell responses to enzymatically modified beta cell neo-epitopes.

Front Immunol

2023 Jan 10

Nguyen H, Arribas-Layton D, Chow IT

INTRODUCTION: Previous studies verify the formation of enzymatically post-translationally modified (PTM) self-peptides and their preferred recognition by T cells in subjects with type 1 diabetes (T1D). However, questions remain about the relative prevalence of T cells that recognize PTM self-peptides derived from different antigens, their functional phenotypes, and whether their presence correlates with a specific disease endotype. METHODS: To address this question, we identified a cohort of subjects with T1D who had diverse levels of residual beta cell function. Using previously developed HLA class II tetramer reagents, we enumerated T cells that recognize PTM GAD epitopes in the context of DRB1*04:01 or PTM IA2 epitopes in the context of DQB1*03:02 (DQ8). RESULTS: Consistent with prior studies, we observed higher overall frequencies and a greater proportion of memory T cells in subjects with T1D than in HLA matched controls. There were significantly higher numbers of GAD specific T cells than IA2 specific T cells in subjects with T1D. T cells specific for both groups of epitopes could be expanded from the peripheral blood of subjects with established T1D and at-risk subjects. Expanded neo-epitope specific T cells primarily produced interferon gamma in both groups, but a greater proportion of T cells were interferon gamma positive in subjects with T1D, including some poly-functional cells that also produced IL-4. Based on direct surface phenotyping, neo-epitope specific T cells exhibited diverse combinations of chemokine receptors. However, the largest proportion had markers associated with a Th1-like phenotype. Notably, DQ8 restricted responses to PTM IA2 were over-represented in subjects with lower residual beta cell function. Neo-epitope specific T cells were present in at-risk subjects, and those with multiple autoantibodies have higher interferon gamma to IL-4 ratios than those with single autoantibodies, suggesting a shift in polarization during progression. DISCUSSION: These results reinforce the relevance of PTM neo-epitopes in human disease and suggest that distinct responses to neo-antigens promote a more rapid decline in beta cell function.

477. Duck gasdermin E is a substrate of caspase-3/-7 and an executioner of pyroptosis.

Front Immunol

2023 Jan 10

Li H, Wang X, Yu L

478. Leukemia-associated truncation of granulocyte colony-stimulating factor receptor impacts granulopoiesis throughout the life-course.

Front Immunol

2023 Jan 10

Bulleeraz V, Goy M, Basheer F

479. Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function.

Front Immunol

2023 Jan 10

Hudock KM, Collins MS, Imbrogno MA

480. Long-term benefit of immunotherapy in a patient with squamous lung cancer exhibiting mismatch repair deficient/high microsatellite instability/high tumor mutational burden: A case report and literature review.

Front Immunol

2023 Jan 10

Li N, Wan Z, Lu D

481. Impact of mouse model tumor implantation site on acquired resistance to anti-PD-1 immune checkpoint therapy.

Front Immunol

2023 Jan 10

Denis M, Mathé D, Micoud M

482. Nintedanib in an elderly non-small-cell lung cancer patient with severe steroid-refractory checkpoint inhibitor-related pneumonitis: A case report and literature review.

Front Immunol

2023 Jan 10

Pan L, Meng F, Wang W

483. The multifactorial complexities of autoimmune development in Pemphigus vulgaris: Critical evaluation of the role of environmental and lifestyle "exposome" factors.

Front Immunol

2023 Jan 10

Adebiyi OT, Galloway DF, Augustin MS

484. Diagnostic challenge in a series of eleven patients with hyper IgE syndromes.

Front Immunol

2023 Jan 10

Yaakoubi R, Mekki N, Ben-Mustapha I

485. Construction of ceRNA and m6A-related lncRNA networks associated with anti-inflammation of AdipoAI.

Front Immunol

2023 Jan 10

Yu H, Wu H, Xie Q

BACKGROUND: Adiponectin (APN) is an endogenous adipokine secreted from adipocytes that exerts anti-inflammatory properties. AdipoAI is an orally active adiponectin receptor agonist identified by our group that can emulate APN's anti-inflammatory properties through mechanisms that are not fully understood. LncRNAs, a type of noncoding RNA more than 200 bp in length, have been demonstrated to have abundant biological functions, including in anti-inflammatory responses. MATERIALS AND RESULT: In the current study, we performed a lncRNA microarray in LPS-induced Raw264.7 cells that were prestimulated with AdipoAI and screened 110 DElncRNAs and 190 DEmRNAs. Enrichment analyses were conducted on total mRNAs and DEmRNAs, including GSVA, ssGSEA, GO/KEGG, GSEA, and PPI analysis. Among all these processes, endocytosis was significantly enriched. A coexpression analysis was built based on DElncRNAs and DEmRNAs. Then, using TargetScan and miRwalk to predict related microRNAs of DElncRNAs and DEmRNAs, respectively, we established competing endogenous RNA (ceRNA) networks including 54 mRNAs from 8 GO items. Furthermore, 33 m6A methylation-related marker genes were obtained from a previous study and used for the construction of an m6A-related lncRNA network by coexpression analysis. We identified FTO as the hub gene of the network and 14 lncRNAs that interacted with it. The expression levels of 10 lncRNAs selected from ceRNA and FTO-related lncRNA networks were validated with qRT‒PCR. Finally, macrophage phenotype scores showed that AdipoAI could attenuate the M2b and M2c polarization of macrophages and correlate with the above lncRNAs. CONCLUSION: Our work reveals that lncRNAs might be involved in the anti-inflammation process of AdipoAI in LPS-induced macrophages through the ceRNA network and the epigenetic regulation of m6A. Mechanistically, these lncRNAs associated with AdipoAI might be related to endocytosis and polarization in macrophages and provide new candidates for the anti-inflammatory application of APN and its receptor agonist.

486. Differentially expressed genes in head kidney of Pelteobagrus fulvidraco following Vibrio cholerae challenge.

Front Immunol

2023 Jan 10

Jiang SH, Wu LX, Cai YT

487. Perioperative corticosteroid treatment impairs tumor-infiltrating dendritic cells in patients with newly diagnosed adult-type diffuse gliomas.

Front Immunol

2023 Jan 10

Carenza C, Franzese S, Castagna A

488. DNA methylation change of HIPK3 in Chinese rheumatoid arthritis and its effect on inflammation.

Front Immunol

2023 Jan 10

Jiang P, Wei K, Xu L

489. Patient genetics shape the autoimmune response in the blistering skin disease pemphigus vulgaris.

Front Immunol

2023 Jan 10

Baker J, Seiffert-Sinha K, Sinha AA.

BACKGROUND AND AIM: Pemphigus vulgaris (PV) is known to have one of the strongest HLA associations among autoimmune diseases. DRB1*0402 and DQB1*0503 in particular are significantly overrepresented in PV patients in certain worldwide populations. Yet, there remain significant gaps in our understanding regarding the precise link between PV-associated HLA molecules, the specificity of the autoimmune response, and clinical expression. In this study we assessed correlations between factors including HLA genotype, ethnicity, autoantibody levels, and lesion distribution in a cohort of 293 patients. METHODS AND POPULATION: Participants were recruited from multiple outpatient dermatology clinic settings and patient support meetings in the USA. On intake, patients provided venous blood samples and answered questionnaires regarding their current disease activity. RESULTS: Eighty-one percent of patients typed as either DRB1*0402 or DQB1*0503 with a high prevalence of DRB1*0402 in patients of Ashkenazi Jewish or Caucasian (non-Jewish) descent (86% and 42%, respectively) and DQB1*0503 in patients of Southeast Asian descent (78%). Patients typing as HLA DRB1*0402 had higher levels of anti-desmoglein (Dsg)3 antibodies (204.6 +/- 340.5 IU/ml) than patients without DRB1*0402 (138.5 +/- 236.4 IU/ml) (p=0.03) and had mucosal only lesions more often than cutaneous only or mucocutaneous lesions. Patients typing as DQB1*0503 had higher levels of anti-Dsg1 antibodies (47.3 +/- 59.8 IU/ml) compared to other groups (27.8 +/- 43.7 IU/ml) (p=0.06) and higher rates of mucocutaneous disease than other lesion types. We also report an unexpected HLA association of DRB1*0804 in PV patients of African descent. Sixty-four percent of this population carried the DRB1*0804 allele, and presented with highly elevated levels of anti-Dsg3 (p=0.02). However, neither African heritage nor the presence of DRB1*0804 correlated with a predilection to any specific lesion morphology. Patients that carried neither DRB1*0402, nor DQB1*0503 or DRB1*0804 had the lowest levels of anti-Dsg3 antibodies (60.0 +/- 80.0 IU/ml) and the highest rate of solely cutaneous disease compared to carriers of these alleles. CONCLUSION: Our data illuminate the broader impact of genetic factors on disease development by showing that differences in HLA expression among patients and ethnicities play a large role in driving distinct patterns of antibody selection and disease phenotype in PV. These findings provide insights regarding clinical heterogeneity, and are relevant to developing improved, patient tailored management strategies.

490. Machine learning for screening and predicting the risk of anti-MDA5 antibody in juvenile dermatomyositis children.

Front Immunol

2023 Jan 10

Xue Y, Zhang J, Li C

OBJECTIVE: The anti-MDA5 (anti-melanoma differentiation associated gene 5) antibody is often associated with a poor prognosis in juvenile dermatomyositis (JDM) patients. In many developing countries, there is limited ability to access myositis- specific antibodies due to financial and technological issues, especially in remote regions. This study was performed to develop a prediction model for screening anti-MDA5 antibodies in JDM patients with commonly available clinical findings. METHODS: A cross-sectional study was undertaken with 152 patients enrolled from the inpatient wards of Beijing Children's Hospital between June 2018 and September 2021. Stepwise logistic regression, least absolute shrinkage and selection operator (LASSO) regression, and the random forest (RF) method were used to fit the model. Model discrimination, calibration, and decision curve analysis were performed for validation. RESULTS: The final prediction model included eight clinical variables (gender, fever, alopecia, periungual telangiectasia, digital ulcer, interstitial lung disease, arthritis/arthralgia, and Gottron sign) and four auxiliary results (WBC, CK, CKMB, and ALB). An anti-MDA5 antibody risk probability-predictive nomogram was established with an AUC of 0.975 predicted by the random forest algorithm. The model was internally validated by Harrell's concordance index (0.904), the Brier score (0.052), and a 500 bootstrapped satisfactory calibration curve. According to the net benefit and predicted probability thresholds of decision curve analysis, the established model showed a significantly higher net benefit than the traditional logistic regression model. CONCLUSION: We developed a prediction model using routine clinical assessments to screen for JDM patients likely to be anti-MDA5 positive. This new tool may effectively predict the detection of anti-MDA5 in these patients using a non-invasive and efficient way.

491. Immune escaping of the novel genotypes of human respiratory syncytial virus based on gene sequence variation.

Front Immunol

2023 Jan 10

Zhou X, Jiang M, Wang F

492. PD-1 expression in transbronchial biopsies of lung transplant recipients is a possible early predictor of rejection.

Front Immunol

2023 Jan 10

Righi I, Vaira V, Morlacchi LC

493. T cell activation profiles can distinguish gram negative/positive bacterial sepsis and are associated with ICU discharge.

Front Immunol

2023 Jan 10

Huang C, Xiong H, Li W

494. Single-cell RNA sequencing reveals the molecular features of peripheral blood immune cells in children, adults and centenarians.

Front Immunol

2023 Jan 10

Zhong J, Ding R, Jiang H

495. Three doses of BNT162b2 COVID-19 mRNA vaccine establish long-lasting CD8(+) T cell immunity in CLL and MDS patients.

Front Immunol

2023 Jan 10

Hernandez SPA, Hersby DS, Munk KK

496. Natural killer cell therapy potentially enhances the antitumor effects of bevacizumab plus irinotecan in a glioblastoma mouse model.

Front Immunol

2023 Jan 10

Tran TA, Kim YH, Duong TH

Various combination treatments have been considered to attain the effective therapy threshold by combining independent antitumor mechanisms against the heterogeneous characteristics of tumor cells in malignant brain tumors. In this study, the natural killer (NK) cells associated with bevacizumab (Bev) plus irinotecan (Iri) against glioblastoma multiforme (GBM) were investigated. For the experimental design, NK cells were expanded and activated by K562 cells expressing the OX40 ligand and membrane-bound IL-18 and IL-21. The effects of Bev and Iri on the proliferation and NK ligand expression of GBM cells were evaluated through MTT assay and flow cytometry. The cytotoxic effects of NK cells against Bev plus Iri-treated GBM cells were also predicted via the LDH assay in vitro. The therapeutic effect of different injected NK cell routes and numbers combined with the different doses of Bev and Iri was confirmed according to tumor size and survival in the subcutaneous (s.c) and intracranial (i.c) U87 xenograft NOD/SCID IL-12Rγnull mouse model. The presence of injected-NK cells in tumors was detected using flow cytometry and immunohistochemistry ex vivo. As a result, Iri was found to affect the proliferation and NK ligand expression of GBM cells, while Bev did not cause differences in these cellular processes. However, the administration of Bev modulated Iri efficacy in the i.c U87 mouse model. NK cells significantly enhanced the cytotoxic effects against Bev plus Iri-treated GBM cells in vitro. Although the intravenous (IV) injection of NK cells in combination with Bev plus Iri significantly reduced the tumor volume in the s.c U87 mouse model, only the direct intratumorally (IT) injection of NK cells in combination with Bev plus Iri elicited delayed tumor growth in the i.c U87 mouse model. Tumor-infiltrating NK cells were detected after IV injection of NK cells in both s.c and i.c U87 mouse models. In conclusion, the potential therapeutic effect of NK cells combined with Bev plus Iri against GBM cells was limited in this study. Accordingly, further research is required to improve the accessibility and strength of NK cell function in this combination treatment.

497. Melanocortin receptor agonist NDP-α-MSH improves cognitive deficits and microgliosis but not amyloidosis in advanced stages of AD progression in 5XFAD and 3xTg mice.

Front Immunol

2023 Jan 10

Daini E, Vandini E, Bodria M

498. A single-cell atlas reveals the heterogeneity of meningeal immunity in a mouse model of Methyl CpG binding protein 2 deficiency.

Front Immunol

2023 Jan 10

Li H, Hu M, Huang Z

499. Microwave ablation and synchronous transarterial chemoembolization combined with PD-1 inhibitor in patients with hepatocellular carcinoma following tyrosine kinase inhibitor intolerance.

Front Immunol

2023 Jan 10

Shi Q, Zhou X, Zhang Z

500. Persistence of salivary antibody responses after COVID-19 vaccination is associated with oral microbiome variation in both healthy and people living with HIV.

Front Immunol

2023 Jan 10

Ghorbani M, Al-Manei K, Naud S

501. Identification and validation of a prognostic signature of autophagy, apoptosis and pyroptosis-related genes for head and neck squamous cell carcinoma: to imply therapeutic choices of HPV negative patients.

Front Immunol

2023 Jan 10

Nan Z, Dou Y, Chen A

INTRODUCTION: An effective tool is needed to predict the prognosis of head and neck squamous cell carcinoma (HNSCC). Human papillomavirus (HPV) positive HNSCC patients generally have a favorable survival and a promising responsiveness to radiotherapy, chemoradiotherapy and checkpoint blockades. However, HPV negative patients, the majority of HNSCC patients, have been largely overlooked. Cell death has been involved in the therapeutic resistance of cancers. To this end, we aimed to identify the association of autophagy, apoptosis and pyroptosis-related genes with the prognosis of HNSCC, and construct a prognostic signature to predict the prognosis for HNSCC, especially for HPV negative HNSCC. METHODS: Autophagy and apoptosis-related genes were obtained from Gene Set Enrichment Analysis (GSEA) website, and pyroptosis-related genes were obtained from GSEA and Gene Ontology (GO) database. We established the cell death index (CDI) based on RNA sequencing (RNA-seq) data and clinicopathological information from The Cancer Genome Atlas (TCGA) dataset. The prognostic value of CDI was verified by Kaplan-Meier, receiver operating characteristic (ROC) and univariate and multivariate Cox regression analyses in TCGA dataset, and validated with the datasets from Gene Expression Omnibus (GEO) and Qilu Hospital of Shandong University. We further assessed the immune microenvironment of patients with high and low CDI scores. Moreover, the expression of the signature genes in HNSCC cell lines were explored. RESULTS: We found that CDI was an independent prognostic indicator for overall survival (hazard ratio 3.80, 95% confidential interval: 2.70-5.40, P < 0.001). Furthermore, HNSCC patients with high CDI scores obtained increased overall survival post radiation indicating benefits from radiotherapy of this subgroup. On the other hand, HPV negative HNSCC patients with low CDI exhibited increased checkpoint gene expressions, an inflamed tumor microenvironment and an enriched immune response-related functions, suggesting the potential benefits from checkpoint immunotherapies of this subgroup. Moreover, we validated the baseline and induced expressions of above 16 genes in two HPV negative HNSCC cell lines, CAL27 and SCC-15. DISCUSSION: We established a prognostic signature and emphasized its implements in the therapeutic choices of HPV negative HNSCC patients, the majority and the poor outcome population of HNSCC.

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