生信网-文献期刊

Front Immunol

2022 Aug 9

Zhang C, Liu H, Tan Y

2. Enhanced immunogenicity of a positively supercharged archaeon thioredoxin scaffold as a cell-penetrating antigen carrier for peptide vaccines.

Front Immunol

2022 Aug 9

Cavazzini D, Spagnoli G, Mariz FC

3. Dietary selenium sources alleviate immune challenge induced by Salmonella Enteritidis potentially through improving the host immune response and gut microbiota in laying hens.

Front Immunol

2022 Aug 9

Kang R, Wang W, Liu Y

The aim of this study was to evaluate the effects of different selenium (Se) sources on the immune responses and gut microbiota of laying hens challenged with Salmonella enteritidis (S. Enteritidis). A total of 240 45-week-old layers were randomly divided into eight groups with six replicates per group according to a 4 × 2 factorial design, including a blank diet without Se supplementation (CON group) and three diets with 0.3 mg/kg Se supplementation from sodium selenite (IS group), yeast Se (YS group), and selenium-enriched yeast culture (SYC group), respectively. After 8 weeks of feeding, half of them were orally challenged with 1.0 ml suspension of 109 colony-forming units per milliliter of S. Enteritidis daily for 3 days. The serum was collected on days 3, 7, and 14, and the cecum content was collected on day 14 after challenge. There was no significant difference in laying performance among the eight groups before challenge. The S. Enteritidis challenge significantly decreased the laying performance, egg quality, GSH-Px, IgG, and IgM and increased the ratio of feed and egg, malondialdehyde (MDA), Salmonella-specific antibody (SA) titers, IL-6, IL-2, IL-1β, and INF-γ. However, SYC increased the level of GSH-Px and IgG and decreased IL-6, while YS decreased the level of IL-2 and IL-1β. What is more, Se supplementation decreased the SA titers to varying degrees and reduced the inflammatory cell infiltration in the lamina propria caused by S. Enteritidis infection. In addition, the S. Enteritidis challenge disrupted the intestinal flora balance by reducing the abundance of the genera Clostridium innocuum, Lachnospiraceae, and Bifidobacterium and increasing the genera Butyricimonas and Brachyspira, while Se supplementation increased the gut microbial alpha diversity whether challenged or not. Under the S. Enteritidis challenge condition, the alteration of microbial composition by the administration of different Se sources mainly manifested as IS increased the relative abundance of the genera Lachnospiraceae and Christensenellaceae, YS increased the relative abundance of the genera Megamonas and Sphingomonas, and SYC increased the genera Fusobacterium and Lactococcus. The alteration of gut microbial composition had a close relationship with antioxidant or immune response. To summarize, different Se sources can improve the egg quality of layers challenged by S. Enteritidis that involves elevating the immunity level and regulating the intestinal microbiota.

4. Monoclonal antibody therapy of herpes simplex virus: An opportunity to decrease congenital and perinatal infections.

Front Immunol

2022 Aug 9

Backes IM, Leib DA, Ackerman ME.

5. The difference in CD4(+) T cell immunity between high- and low-virulence Tembusu viruses is mainly related to residues 151 and 304 in the envelope protein.

Front Immunol

2022 Aug 9

Meng R, Yang B, Feng C

6. Migration and homeostasis of regulatory T cells in rheumatoid arthritis.

Front Immunol

2022 Aug 9

Kotschenreuther K, Yan S, Kofler DM.

7. Protective antigenic epitopes revealed by immunosignatures after three doses of inactivated SARS-CoV-2 vaccine.

Front Immunol

2022 Aug 9

Peng M, Dou X, Zhang X

8. Polygenic Innate Immunity Score to Predict the Risk of Cytomegalovirus Infection in CMV D+/R- Transplant Recipients. A Prospective Multicenter Cohort Study.

Front Immunol

2022 Aug 9

Bodro M, Cervera C, Linares L

9. Characterization and validation of a ferroptosis-related LncRNA signature as a novel prognostic model for lung adenocarcinoma in tumor microenvironment.

Front Immunol

2022 Aug 9

Wang Y, Lu G, Xue X

10. Neutrophil to lymphocyte ratio predicting poor outcome after aneurysmal subarachnoid hemorrhage: A retrospective study and updated meta-analysis.

Front Immunol

2022 Aug 9

Guo Y, Liu J, Zeng H

BACKGROUND: The relationship between neutrophil to lymphocyte ratio (NLR) and poor outcome of aneurysmal subarachnoid hemorrhage (aSAH) is controversial. We aim to evaluate the relationship between NLR on admission and the poor outcome after aSAH. METHOD: Part I: Retrospective analysis of aSAH patients in our center. Baseline characteristics of patients were collected and compared. Multivariate analysis was used to evaluate parameters independently related to poor outcome. Receiver operating characteristic (ROC) curve analysis was used to determine the best cut-off value of NLR. Part II: Systematic review and meta-analysis of relevant literature. Related literature was selected through the database. The pooled odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated to evaluate the correlation between NLR and outcome measures. RESULTS: Part I: A total of 240 patients with aSAH were enrolled, and 52 patients had a poor outcome. Patients with poor outcome at 3 months had a higher admission NLR, Hunt & Hess score, Barrow Neurological Institute (BNI) scale score, Subarachnoid Hemorrhage Early Brain Edema Score (SEBES), and proportion of hypertension history. After adjustment, NLR at admission remained an independent predictor of poor outcome in aSAH patients (OR 0.76, 95% CI 0.69-0.83; P < 0.001). The best cut-off value of NLR in ROC analysis is 12.03 (area under the curve 0.805, 95% CI 0.735 - 0.875; P < 0.001). Part II: A total of 16 literature were included. Pooled results showed that elevated NLR was significantly associated with poor outcome (OR 1.31, 95% CI 1.14-1.49; P < 0.0001) and delayed cerebral ischemia (DCI) occurrence (OR 1.32, 95% CI 1.11-1.56; P = 0.002). The results are more reliable in large sample sizes, low NLR cut-off value, multicenter, or prospective studies. CONCLUSION: Elevated NLR is an independent predictor of poor outcome and DCI occurrence in aSAH.

11. Estrogen mediates inflammatory role of mast cells in endometriosis pathophysiology.

Front Immunol

2022 Aug 9

McCallion A, Nasirzadeh Y, Lingegowda H

Endometriosis is an estrogen dependent, chronic inflammatory disease characterized by the growth of endometrial lining outside of the uterus. Mast cells have emerged as key players in regulating not only allergic responses but also other mechanisms such as angiogenesis, fibrosis, and pain. The influence of estrogen on mast cell function has also been recognized as a potential factor driving disease pathophysiology in number of allergic and chronic inflammatory conditions. However, precise information is lacking on the cross talk between endocrine and immune factors within the endometriotic lesions and whether that contributes to the involvement of mast cells with disease pathophysiology. In this study, we observed a significant increase in mast cell numbers within endometriotic lesions compared to matched eutopic endometrium from the same patients. Compared to eutopic endometrium, endometriotic lesions had significantly higher levels of stem cell factor (SCF), a potent growth factor critical for mast cell expansion, differentiation, and survival for tissue resident mast cells. Targeted mRNA Q-PCR array revealed that the endometriotic lesions harbour microenvironment (upregulation of CPA3, VCAM1, CCL2, CMA1, CCR1, and KITLG) that is conducive to mast cells recruitment and subsequent differentiation. To examine cross-talk of mast cells within the endometriotic lesion microenvironment, endometriotic epithelial cells (12Z) and endometrial stromal cells (hESC) incubated with mast cell-conditioned media showed significantly increased production of pro-inflammatory and chemokinetic cytokines. To further understand the impact of estrogen on mast cells in endometriosis, we induced endometriosis in C57BL/6 mice. Mature mast cells were significantly higher in peritoneal fluid of estrogen-treated mice compared to untreated mice within the sham operated groups. Mouse endometriotic lesion tissue revealed several genes (qRT-PCR) relevant in mast cell biology significantly upregulated in the estrogen treated, endometriosis-induced group compared to control endometrium. The endometriotic lesions from estrogen treated mice also had significantly higher density of Alcian blue stained mast cells compared to untreated lesions or control endometrium. Collectively, these findings suggest that endometriotic lesions provide a microenvironment necessary for recruitment and differentiation of mast cells. In turn, mast cells potentially release pro-inflammatory mediators that contribute to chronic pelvic pain and endometriosis disease progression.

12. Circulating interleukin-38 concentrations in healthy adults.

Front Immunol

2022 Aug 9

Teufel LU, de Graaf DM, Netea MG

13. Black raspberry extract inhibits regulatory T-cell activity in a murine model of head and neck squamous cell carcinoma chemoprevention.

Front Immunol

2022 Aug 9

Ryan NM, Lamenza FF, Upadhaya P

Head and neck squamous cell carcinomas (HNSCC) are one of the most diagnosed malignancies globally, with a 5-year survival rate of approximately 40% to 50%. Current therapies are limited to highly invasive surgery, aggressive radiation, and chemotherapies. Recent reports have demonstrated the potential phytochemical properties of black raspberries in inhibiting the progression of various cancers including HNSCCs. However, the effects of black raspberry extracts on immune cells of the tumor microenvironment, specifically regulatory T cells during HNSCC, have not been investigated. We used a mouse model of 4-nitroquinoline-1-oxide (4NQO) chemically induced HNSCC carcinogenesis to determine these effects. C57BL/6 mice were exposed to 4NQO for 16 weeks and regular water for 8 weeks. 4NQO-exposed mice were fed the AIN-76A control mouse diet or the AIN76 diet supplemented with black raspberry extract. At terminal sacrifice, tumor burdens and immune cell recruitment and activity were analyzed in the tumor microenvironment, draining lymph nodes, and spleens. Mice fed the BRB extract-supplemented diet displayed decreased tumor burden compared to mice provided the AIN-76A control diet. Black raspberry extract administration did not affect overall T-cell populations as well as Th1, Th2, or Th17 differentiation in spleens and tumor draining lymph nodes. However, dietary black raspberry extract administration inhibited regulatory T-cell recruitment to HNSCC tumor sites. This was associated with an increased cytotoxic immune response in the tumor microenvironment characterized by increased CD8+ T cells and enhanced Granzyme B production during BRB extract-mediated HNSCC chemoprevention. Interestingly, this enhanced CD8+ T-cell antitumoral response was localized at the tumor sites but not at spleens and draining lymph nodes. Furthermore, we found decreased levels of PD-L1 expression by myeloid populations in draining lymph nodes of black raspberry-administered carcinogen-induced mice. Taken together, our findings demonstrate that black raspberry extract inhibits regulatory T-cell recruitment and promotes cytotoxic CD8 T-cell activity at tumor sites during HNSCC chemoprevention. These results demonstrate the immunomodulatory potential of black raspberry extracts and support the use of black raspberry-derived phytochemicals as a complementary approach to HNSCC chemoprevention and treatment.

14. Development of RAG2 (-/-) IL2Rγ (-/Y) immune deficient FAH-knockout miniature pig.

Front Immunol

2022 Aug 9

Zhao H, Ye W, Guo J

15. Coagulation and complement: Key innate defense participants in a seamless web.

Front Immunol

2022 Aug 9

Pryzdial ELG, Leatherdale A, Conway EM.

16. MR1-dependence of unmetabolized folic acid side-effects.

Front Immunol

2022 Aug 9

Tang JS, Cait A, White RM

17. Identification of nine signature proteins involved in periodontitis by integrated analysis of TMT proteomics and transcriptomics.

Front Immunol

2022 Aug 9

Liu W, Qiu W, Huang Z

18. PD-L1 maintains neutrophil extracellular traps release by inhibiting neutrophil autophagy in endotoxin-induced lung injury.

Front Immunol

2022 Aug 9

Zhu CL, Xie J, Zhao ZZ

19. The cytoplasmic LSm1-7 and nuclear LSm2-8 complexes exert opposite effects on Hepatitis B virus biosynthesis and interferon responses.

Front Immunol

2022 Aug 9

Rahman N, Sun J, Li Z

20. N(6)-Methyladenosine regulator RBM15B acts as an independent prognostic biomarker and its clinical significance in uveal melanoma.

Front Immunol

2022 Aug 8

Wang T, Bai J, Zhang Y

21. Response to apatinib and camrelizumab combined treatment in a radioiodine refractory differentiated thyroid cancer patient resistant to prior anti-angiogenic therapy: A case report and literature review.

Front Immunol

2022 Aug 8

Li J, Zhang X, Mu Z

22. Detailed spatial immunophenotyping of primary melanomas reveals immune cell subpopulations associated with patient outcome.

Front Immunol

2022 Aug 8

Attrill GH, Lee H, Tasker AT

While the tumor immune microenvironment (TIME) of metastatic melanoma has been well characterized, the primary melanoma TIME is comparatively poorly understood. Additionally, although the association of tumor-infiltrating lymphocytes with primary melanoma patient outcome has been known for decades, it is not considered in the current AJCC melanoma staging system. Detailed immune phenotyping of advanced melanoma has revealed multiple immune biomarkers, including the presence of CD8+ T-cells, for predicting response to immunotherapies. However, in primary melanomas, immune biomarkers are lacking and CD8+ T-cells have yet to be extensively characterized. As recent studies combining immune features and clinicopathologic characteristics have created more accurate predictive models, this study sought to characterize the TIME of primary melanomas and identify predictors of patient outcome. We first phenotyped CD8+ T cells in fresh stage II primary melanomas using flow cytometry (n = 6), identifying a CD39+ tumor-resident CD8+ T-cell subset enriched for PD-1 expression. We then performed Opal multiplex immunohistochemistry and quantitative pathology-based immune profiling of CD8+ T-cell subsets, along with B cells, NK cells, Langerhans cells and Class I MHC expression in stage II primary melanoma specimens from patients with long-term follow-up (n = 66), comparing patients based on their recurrence status at 5 years after primary diagnosis. A CD39+CD103+PD-1- CD8+ T-cell population (P2) comprised a significantly higher proportion of intratumoral and stromal CD8+ T-cells in patients with recurrence-free survival (RFS) ≥5 years vs those with RFS <5 years (p = 0.013). Similarly, intratumoral B cells (p = 0.044) and a significantly higher B cell density at the tumor/stromal interface were associated with RFS. Both P2 and B cells localized in significantly closer proximity to melanoma cells in patients who remained recurrence-free (P2 p = 0.0139, B cell p = 0.0049). Our results highlight how characterizing the TIME in primary melanomas may provide new insights into how the complex interplay of the immune system and tumor can modify the disease outcomes. Furthermore, in the context of current clinical trials of adjuvant anti-PD-1 therapies in high-risk stage II primary melanoma, assessment of B cells and P2 could identify patients at risk of recurrence and aid in long-term treatment decisions at the point of primary melanoma diagnosis.

23. Editorial: Novel treatments for diffuse large B-cell lymphoma: The post-CART era.

Front Immunol

2022 Aug 8

Mussetti A, Derenzini E, Clementine S

24. Post-translational changes in Phialophora verrucosa via lysine lactylation during prolonged presence in a patient with a CARD9-related immune disorder.

Front Immunol

2022 Aug 8

Song Y, Liu X, Stielow JB

CARD9-related inherited immune disorders are a major risk factor for chronic disseminated fungal infection. In addition to pathogens of Candida and dermatophytes, the environmental opportunists of the black yeast-like fungi are relatively frequent in this patient cohort. Particularly the genus Phialophora is overrepresented. We investigated two isolates of a strain of P. verrucosa residing in a CARD9 patient, sampled with a period of ten years apart. Genomes, melanization and antifungal susceptibility of progenitor and derived strains were compared, and potential adaptation to the host habitat was investigated with proteomic techniques using post-translational modification as a proxy. Global lactylation analysis was performed using high accuracy nano-LC-MS/MS in combination with enrichment of lactylated peptides from digested cell lysates, and subsequent peptide identification. The genome of the derived isolate had accumulated 6945 SNPs, of which 31 were detected in CDS. A large number of identified proteins were significantly enriched, e.g. in melanin biosynthesis. A total of 636 lactylation sites on 420 lactylated proteins were identified, which contained in 26 types of modification motifs. Lysine lactylation (Kla) was found in 23 constituent proteins of the ribosome, indicating an impact of Kla in protein synthesis. Twelve lactylated proteins participated in pathogenicity. A protein-protein interaction (PPI) network analysis suggested that protein lactylations are widely distributed influencing various biological processes. Our findings reveal widespread roles for lysine lactylation in regulating metabolism and melanin biosynthesis in black fungi. Several large rearrangements and inversions were observed in the genome, but genomic changes could not be linked to adaptation or to known clinically relevant properties of progenitor to derived isolate; in vitro antifungal susceptibility had largely remained unaltered.

25. Colon metastasis from lung adenocarcinoma with BRAF V600E mutation: A case report.

Front Immunol

2022 Aug 8

Luo Y, Mou K, Wang J

26. Microbiome in cancer: An exploration of carcinogenesis, immune responses and immunotherapy.

Front Immunol

2022 Aug 8

Zhou P, Hu Y, Wang X

27. Substratum interactions determine immune response to allogeneic transplants of endothelial cells.

Front Immunol

2022 Aug 8

Wilcox EC, Edelman ER.

Endothelial cells (ECs) are central to vascular health but also interact with and regulate the immune system. Changes in endothelial state enable immune cells to migrate into the tissue to facilitate repair and fight infection. ECs modulate the function of immune cells through the expression of adhesion molecules, chemokines, major histocompatibility complex (MHC), and an array of co-stimulatory and inhibitor molecules. These interactions allow ECs to act as antigen presenting cells (APCs) and influence the outcome of immune recognition. This study elucidates how EC microenvironment, vascular cell biology, and immune response are not only connected but interdependent. More specifically, we explored how cell-substratum interactions influence EC antigen presentation and co-stimulation, and how these differences affect allorecognition in animal models of cell transplantation. Investigation of EC state was carried out using RNA sequencing while assessment of the allogeneic response includes measurements of immune cell cytotoxic ability, T cell proliferation, cytokine release, serum antibodies, and histological staining. Differences in substratum led to divergent EC phenotypes which in turn influenced immune response to transplanted cells, both due to the physical barrier of matrix-adhesion and differences in expression of surface markers. ECs grown in 2D on tissue culture plastic or in 3D on collagen scaffolds had significantly different basal levels of MHC expression, co-stimulatory and adhesion molecules. When treated with cytokines to mimic an inflammatory state, ECs did not converge to a single phenotype but rather responded differently based on their substratum. Generally, 3D ECs were more responsive to inflammatory stimuli than 2D ECs. These unique expression patterns measured in vitro also influence immune recognition in vivo. ECs grown in 2D were more likely to provoke a cytotoxic response while 3D ECs induced T cell proliferation. ECs are uniquely configured to sense not only local flow and mechanical forces but a range of markers related to systemic state, including immune function. ECs interact with immune cells with differing results depending on the environment in which the EC-lymphocyte interaction occurs. Therefore, understanding this relationship is essential to predicting and modifying the outcome of EC-immune interacts. We specifically examined the relationship between EC substratum and allorecognition.

28. The significance of preclinical anti-BP180 autoantibodies.

Front Immunol

2022 Aug 8

Mai Y, Izumi K, Mai S

29. Metabolic rewiring directs melanoma immunology.

Front Immunol

2022 Aug 8

Sun N, Tian Y, Chen Y

30. Transcriptional patterns reveal tumor histologic heterogeneity and immunotherapy response in lung adenocarcinoma.

Front Immunol

2022 Aug 8

Jiao M, Liu H, Liu X.

31. Roles and functions of SARS-CoV-2 proteins in host immune evasion.

Front Immunol

2022 Aug 8

Rashid F, Xie Z, Suleman M

32. A novel tumor mutational burden-based risk model predicts prognosis and correlates with immune infiltration in ovarian cancer.

Front Immunol

2022 Aug 8

Wang H, Liu J, Yang J

Tumor mutational burden (TMB) has been reported to determine the response to immunotherapy, thus affecting the patient's prognosis in many cancers. However, it is unclear whether TMB or TMB-related signature could be used as prognostic indicators for ovarian cancer (OC), as its potential association with immune infiltration remains poorly understood. Therefore, this study aimed to develop a novel TMB-related risk model (TMBrisk) to predict the prognosis of OC patients on the basis of exploring TMB-related genes, and to explore the potential association between TMB/TMBrisk and immune infiltration. The mutational landscape, TMB scores, and correlations between TMB and clinical characteristics and immune infiltration were investigated in The Cancer Genome Atlas (TCGA)-OV cohort. Differentially expressed gene (DEG) analyses and weighted gene co-expression network analysis (WGCNA) were performed to derive TMB-related genes. TMBrisk was constructed by Cox regression and further validated in Gene Expression Omnibus (GEO) datasets. The mRNA and protein expression levels and biological functions of TMBrisk hub genes were verified through Gene Expression Profiling Interactive Analysis (GEPIA), GSCA Lite, the Human Protein Atlas (HPA) database, and RT-qPCR. TMBrisk-related biological phenotypes were analyzed in function enrichment and tumor immune infiltration signature. Potential therapeutic regimens were inferred utilizing the Genomics of Drug Sensitivity in Cancer (GDSC) database and connectivity map (CMap). According to our results, higher TMB was associated with better survival and higher CD8+ T cell, regulatory T cell, and NK cell infiltration. TMBrisk was developed based on CBWD1, ST7L, RFX5-AS1, C3orf38, LRFN1, LEMD1, and HMGB1. High TMBrisk was identified as a poor factor for prognosis in TCGA and GEO datasets; the high-TMBrisk group comprised more higher-grade (G2 and G3) and advanced clinical stage (stage III/IV) tumors. Meanwhile, higher TMBrisk was associated with an immunosuppressive phenotype, with less infiltration of a majority of immunocytes and less expression of several genes of the human leukocyte antigen (HLA) family. Moreover, a nomogram containing TMBrisk showed a strong predictive ability demonstrated by time-dependent ROC analysis. Overall, this novel TMB-related risk model (TMBrisk) could predict prognosis, evaluate immune infiltration, and discover new therapeutic regimens in OC, which is very promising in clinical promotion.

33. Human leukocyte antigen class II gene diversity tunes antibody repertoires to common pathogens.

Front Immunol

2022 Aug 8

Khan T, Rahman M, Ahmed I

34. Serum amyloid A, a host-derived DAMP in pregnancy?

Front Immunol

2022 Aug 5

Lin YK, Zhu P, Wang WS

35. Connective tissue growth factor-targeting DNA aptamer suppresses pannus formation as diagnostics and therapeutics for rheumatoid arthritis.

Front Immunol

2022 Aug 5

Wu G, Liu C, Cao B

36. Ferroptosis in sepsis: The mechanism, the role and the therapeutic potential.

Front Immunol

2022 Aug 5

Xl L, Gy Z, R G

37. Corrigendum: Potential gut microbiota features for non-invasive detection of schistosomiasis.

Front Immunol

2022 Aug 5

Lin D, Song Q, Liu J

38. Screening of crosstalk and pyroptosis-related genes linking periodontitis and osteoporosis based on bioinformatics and machine learning.

Front Immunol

2022 Aug 5

Liu J, Zhang D, Cao Y

BACKGROUND AND OBJECTIVE: This study aimed to identify crosstalk genes between periodontitis (PD) and osteoporosis (OP) and potential relationships between crosstalk and pyroptosis-related genes. METHODS: PD and OP datasets were downloaded from the GEO database and were performed differential expression analysis to obtain DEGs. Overlapping DEGs got crosstalk genes linking PD and OP. Pyroptosis-related genes were obtained from literature reviews. Pearson coefficients were used to calculate crosstalk and pyroptosis-related gene correlations in the PD and OP datasets. Paired genes were obtained from the intersection of correlated genes in PD and OP. PINA and STRING databases were used to conduct the crosstalk-bridge-pyroptosis genes PPI network. The clusters in which crosstalk and pyroptosis-related genes were mainly concentrated were defined as key clusters. The key clusters' hub genes and the included paired genes were identified as key crosstalk-pyroptosis genes. Using ROC curve analysis and XGBoost screened key genes. PPI subnetwork, gene-biological process and gene-pathway networks were constructed based on key genes. In addition, immune infiltration was analyzed on the PD dataset using the CIBERSORT algorithm. RESULTS: A total of 69 crosstalk genes were obtained. 13 paired genes and hub genes TNF and EGFR in the key clusters (cluster2, cluster8) were identified as key crosstalk-pyroptosis genes. ROC and XGBoost showed that PRKCB, GSDMD, ARMCX3, and CASP3 were more accurate in predicting disease than other key crosstalk-pyroptosis genes while better classifying properties as a whole. KEGG analysis showed that PRKCB, GSDMD, ARMCX3, and CASP3 were involved in neutrophil extracellular trap formation and MAPK signaling pathway pathways. Immune infiltration results showed that all four key genes positively correlated with plasma cells and negatively correlated with T cells follicular helper, macrophages M2, and DCs. CONCLUSION: This study shows a joint mechanism between PD and OP through crosstalk and pyroptosis-related genes. The key genes PRKCB, GSDMD, ARMCX3, and CASP3 are involved in the neutrophil extracellular trap formation and MAPK signaling pathway, affecting both diseases. These findings may point the way to future research.

39. Mice with humanized immune system as novel models to study HIV-associated pulmonary hypertension.

Front Immunol

2022 Aug 5

Rodriguez-Irizarry VJ, Schneider AC, Ahle D

40. Multifunctional regulation of VAMP3 in exocytic and endocytic pathways of RBL-2H3 cells.

Front Immunol

2022 Aug 5

Mishima S, Sakamoto M, Kioka H

Mast cells (MCs) are inflammatory cells involved in allergic reactions. Crosslinking of the high-affinity receptor for IgE (FcϵRI) with multivalent antigens (Ags) induces secretory responses to release various inflammatory mediators. These responses are largely mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Vesicle-associated membrane protein 3 (VAMP3) is a vesicular-SNARE that interacts with targeted SNARE counterparts, driving the fusion of MC secretory granules with the membrane and affecting subsequent assembly of the plasma membrane. However, the role of VAMP3 in FcϵRI-mediated MC function remains unclear. In this study, we comprehensively examined the role of VAMP3 and the molecular mechanisms underlying VAMP3-mediated MC function upon FcϵRI activation. VAMP3 shRNA transduction considerably decreased VAMP3 expression compared with non-target shRNA-transduced (NT) cells. VAMP3 knockdown (KD) cells were sensitized with an anti-DNP IgE antibody and subsequently stimulated with Ag. The VAMP3 KD cells showed decreased degranulation response upon Ag stimulation. Next, we observed intracellular granule formation using CD63-GFP fluorescence. The VAMP3 KD cells were considerably impaired in their capacity to increase the size of granules when compared to NT cells, suggesting that VAMP3 mediates granule fusion and therefore promotes granule exocytosis in MCs. Analysis of FcϵRI-mediated activation of signaling events (FcϵRI, Lyn, Syk, and intracellular Ca2+ response) revealed that signaling molecule activation was enhanced in VAMP3 KD cells. We also found that FcϵRI expression on the cell surface decreased considerably in VAMP3 KD cells, although the amount of total protein did not vary. VAMP3 KD cells also showed dysregulation of plasma membrane homeostasis, such as endocytosis and lipid raft formation. The difference in the plasma membrane environment in VAMP3 KD cells might affect FcϵRI membrane dynamics and the subsequent signalosome formation. Furthermore, IgE/Ag-mediated secretion of TNF-α and IL-6 is oppositely regulated in the absence of VAMP3, which appears to be attributed to both the activation of FcϵRI and defects in VAMP3-mediated membrane fusion. Taken together, these results suggest that enhanced FcϵRI-mediated signal transduction in VAMP3 KD cells occurs due to the disruption of plasma membrane homeostasis. Hence, a multifunctional regulation of VAMP3 is involved in complex secretory responses in MCs.

41. Case report: A colorectal cancer patient with microsatellite instability-high and MSH2 germline mutation failed to respond to anti-PD-1 immunotherapy.

Front Immunol

2022 Aug 5

Zhang Q, Hu J, Zhang Y

42. A novel monoclonal IgG1 antibody specific for Galactose-alpha-1,3-galactose questions alpha-Gal epitope expression by bacteria.

Front Immunol

2022 Aug 5

Kreft L, Schepers A, Hils M

43. Kinetics of severe acute respiratory syndrome coronavirus 2 infection antibody responses.

Front Immunol

2022 Aug 5

Lin Y, Zhu J, Liu Z

44. Roles, detection, and visualization of neutrophil extracellular traps in acute pancreatitis.

Front Immunol

2022 Aug 5

Li H, Zhao L, Wang Y

45. Strong T-cell activation in response to COVID-19 vaccination in multiple sclerosis patients receiving B-cell depleting therapies.

Front Immunol

2022 Aug 5

Alfonso-Dunn R, Lin J, Kirschner V

46. CRISPR screening identifies T cell-intrinsic regulators of CD3-bispecific antibody responses.

Front Immunol

2022 Aug 5

Molony RD, Funk T, Trabucco G

47. Case report: Cellular therapy for hydroa vacciniforme-like lymphoproliferative disorder in pediatric common variable immunodeficiency with chronic active Epstein-Barr virus infection.

Front Immunol

2022 Aug 5

Grześk E, Kołtan S, Dąbrowska A

48. Donor specific HLA antibody in hematopoietic stem cell transplantation: Implications for donor selection.

Front Immunol

2022 Aug 5

Krummey SM, Gareau AJ.

49. Inhibition of IL1R1 or CASP4 attenuates spinal cord injury through ameliorating NLRP3 inflammasome-induced pyroptosis.

Front Immunol

2022 Aug 5

Wang C, Ma H, Zhang B

50. Corrigendum: Patients with myeloproliferative neoplasms harbor high frequencies of CD8 T cell-platelet aggregates associated with T cell suppression.

Front Immunol

2022 Aug 5

Simões AMC, Holmström MO, Aehnlich P

51. The role of the macrophage-to-myofibroblast transition in renal fibrosis.

Front Immunol

2022 Aug 5

Wei J, Xu Z, Yan X.

52. Heat shock proteins and viral infection.

Front Immunol

2022 Aug 5

Zhang X, Yu W.

53. CAR T cells targeting the ganglioside NGcGM3 control ovarian tumors in the absence of toxicity against healthy tissues.

Front Immunol

2022 Aug 5

Cribioli E, Giordano Attianese GMP, Coukos G

54. The versatility of macrophage heterogeneity in liver fibrosis.

Front Immunol

2022 Aug 5

Gao CC, Bai J, Han H

55. Modified combination of anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) as compared with standard ATG protocol in haploidentical peripheral blood stem cell transplantation for acute leukemia.

Front Immunol

2022 Aug 5

Barkhordar M, Kasaeian A, Janbabai G

In haploidentical peripheral blood stem cell transplantation (haplo-PBSCT), the combination of anti-thymocyte globulin and post-transplant cyclophosphamide (ATG/PTCy) has a synergistic impact in preventing graft-versus-host disease (GvHD). However, little is known about the long-term consequences of the new combination approach. Our goal is to evaluate the efficacy of ATG/PTCy versus a standard ATG regimen by focusing at long-term outcomes in a more homogeneous group of patients. We retrospectively included 118 adult patients up to 60 years with acute leukemia who underwent haplo-PBSCT at our single institution, following the same myeloablative conditioning regimen. From 2010 to 2020, 78 patients received a modified combination of ATG (2.5 mg/kg/day, on days -3, -2, and -1) and PTCy (40 mg/kg/day on days +3 and +4) compared to 40 patients who had a standard ATG-based regimen (2.5 mg/kg/day from days -4 to -1) from 2008 to 2015. The median follow-up time for all patients was 5.36 years, respectively. The cumulative incidence (CI) of neutrophil and platelet engraftment, as well as CMV reactivation, did not differ statistically between the two groups. The CI of the acute GvHD of grades II-IV and III-IV and extensive chronic GvHD were considerably lower in the ATG/PTCy (34.6%, 8.97%, and 13.63%) than in the ATG cohort (57.5%, 30%, and 38.23%) as validated by multivariable modeling. Additionally, compared to the ATG arm, the ATG/PTCy was a hazard factor associated with a higher risk of relapse (HR = 2.23, p = 0.039). The probability of 5-year overall survival, disease-free survival, and GvHD-free relapse-free survival in the ATG/PTCy group (53.34%, 49.77%, and 36.04%) was comparable with the ATG group (47.5%, 42.5%, and 22.5%), respectively. Our finding suggested that a modified ATG/PTCy combination resulted in a lower risk of acute and chronic GvHD and a higher risk of relapse than the standard ATG-based protocol but had no effect on long-term outcomes. However, certain adjustments in the immunosuppression protocol are warranted to improve the outcome.

56. Cuproptosis and cuproptosis-related genes in rheumatoid arthritis: Implication, prospects, and perspectives.

Front Immunol

2022 Aug 4

Zhao J, Guo S, Schrodi SJ

57. Editorial: Glycoconjugates in vaccines and immunotherapeutics.

Front Immunol

2022 Aug 4

Shivatare S, Sanjiv K, Kikkeri R

58. Integration of transcriptomics, proteomics, and metabolomics data to reveal HER2-associated metabolic heterogeneity in gastric cancer with response to immunotherapy and neoadjuvant chemotherapy.

Front Immunol

2022 Aug 4

Yuan Q, Deng D, Pan C

BACKGROUND: Currently available prognostic tools and focused therapeutic methods result in unsatisfactory treatment of gastric cancer (GC). A deeper understanding of human epidermal growth factor receptor 2 (HER2)-coexpressed metabolic pathways may offer novel insights into tumour-intrinsic precision medicine. METHODS: The integrated multi-omics strategies (including transcriptomics, proteomics and metabolomics) were applied to develop a novel metabolic classifier for gastric cancer. We integrated TCGA-STAD cohort (375 GC samples and 56753 genes) and TCPA-STAD cohort (392 GC samples and 218 proteins), and rated them as transcriptomics and proteomics data, resepectively. 224 matched blood samples of GC patients and healthy individuals were collected to carry out untargeted metabolomics analysis. RESULTS: In this study, pan-cancer analysis highlighted the crucial role of ERBB2 in the immune microenvironment and metabolic remodelling. In addition, the metabolic landscape of GC indicated that alanine, aspartate and glutamate (AAG) metabolism was significantly associated with the prevalence and progression of GC. Weighted metabolite correlation network analysis revealed that glycolysis/gluconeogenesis (GG) and AAG metabolism served as HER2-coexpressed metabolic pathways. Consensus clustering was used to stratify patients with GC into four subtypes with different metabolic characteristics (i.e. quiescent, GG, AAG and mixed subtypes). The GG subtype was characterised by a lower level of ERBB2 expression, a higher proportion of the inflammatory phenotype and the worst prognosis. However, contradictory features were found in the mixed subtype with the best prognosis. The GG and mixed subtypes were found to be highly sensitive to chemotherapy, whereas the quiescent and AAG subtypes were more likely to benefit from immunotherapy. CONCLUSIONS: Transcriptomic and proteomic analyses highlighted the close association of HER-2 level with the immune status and metabolic features of patients with GC. Metabolomics analysis highlighted the co-expressed relationship between alanine, aspartate and glutamate and glycolysis/gluconeogenesis metabolisms and HER2 level in GC. The novel integrated multi-omics strategy used in this study may facilitate the development of a more tailored approach to GC therapy.

59. Genetic dissection of innate immune memory in Drosophila melanogaster.

Front Immunol

2022 Aug 4

Tang C, Kurata S, Fuse N.

60. Editorial: Extracellular vesicles in cancer immunosurveillance.

Front Immunol

2022 Aug 4

Moloudizargari M, Asghari MH, Jørgensen MM

61. Mesenchymal stem/stromal cells in the pathogenesis and regenerative therapy of inflammatory bowel diseases.

Front Immunol

2022 Aug 4

Che Z, Ye Z, Zhang X

62. Oncogenic signaling pathway-related long non-coding RNAs for predicting prognosis and immunotherapy response in breast cancer.

Front Immunol

2022 Aug 4

Li H, Liu H, Hao Q

BACKGROUND: The clinical outcomes of breast cancer (BC) are unpredictable due to the high level of heterogeneity and complex immune status of the tumor microenvironment (TME). When set up, multiple long non-coding RNA (lncRNA) signatures tended to be employed to appraise the prognosis of BC. Nevertheless, predicting immunotherapy responses in BC is still essential. LncRNAs play pivotal roles in cancer development through diverse oncogenic signal pathways. Hence, we attempted to construct an oncogenic signal pathway-based lncRNA signature for forecasting prognosis and immunotherapy response by providing reliable signatures. METHODS: We preliminarily retrieved RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) database and extracted lncRNA profiles by matching them with GENCODE. Following this, Gene Set Variation Analysis (GSVA) was used to identify the lncRNAs closely associated with 10 oncogenic signaling pathways from the TCGA-BRCA (breast-invasive carcinoma) cohort and was further screened by the least absolute shrinkage and selection operator Cox regression model. Next, an lncRNA signature (OncoSig) was established through the expression level of the final 29 selected lncRNAs. To examine survival differences in the stratification described by the OncoSig, the Kaplan-Meier (KM) survival curve with the log-rank test was operated on four independent cohorts (n = 936). Subsequently, multiple Cox regression was used to investigate the independence of the OncoSig as a prognostic factor. With the concordance index (C-index), the time-dependent receiver operating characteristic was employed to assess the performance of the OncoSig compared to other publicly available lncRNA signatures for BC. In addition, biological differences between the high- and low-risk groups, as portrayed by the OncoSig, were analyzed on the basis of statistical tests. Immune cell infiltration was investigated using gene set enrichment analysis (GSEA) and deconvolution tools (including CIBERSORT and ESTIMATE). The combined effect of the Oncosig and immune checkpoint genes on prognosis and immunotherapy was elucidated through the KM survival curve. Ultimately, a pan-cancer analysis was conducted to attest to the prevalence of the OncoSig. RESULTS: The OncoSig score stratified BC patients into high- and low-risk groups, where the latter manifested a significantly higher survival rate and immune cell infiltration when compared to the former. A multivariate analysis suggested that OncoSig is an independent prognosis predictor for BC patients. In addition, compared to the other four publicly available lncRNA signatures, OncoSig exhibited superior predictive performance (AUC = 0.787, mean C-index = 0.714). The analyses of the OncoSig and immune checkpoint genes clarified that a lower OncoSig score meant significantly longer survival and improved response to immunotherapy. In addition to BC, a high OncoSig score in several other cancers was negatively correlated with survival and immune cell infiltration. CONCLUSIONS: Our study established a trustworthy and discriminable prognostic signature for BC patients with similar clinical profiles, thus providing a new perspective in the evaluation of immunotherapy responses. More importantly, this finding can be generalized to be applicable to the vast majority of human cancers.

63. Cuproptosis scoring system to predict the clinical outcome and immune response in bladder cancer.

Front Immunol

2022 Aug 4

Song Q, Zhou R, Shu F

Cuproptosis is a novel copper ion-dependent cell death type being regulated in cells, and this is quite different from the common cell death patterns such as apoptosis, pyroptosis, necroptosis, and ferroptosis. Interestingly, like with death patterns, cuproptosis-related genes have recently been reported to regulate the occurrence and progression of various tumors. However, in bladder cancer, the link between cuproptosis and clinical outcome, tumor microenvironment (TME) modification, and immunotherapy is unknown. To determine the role of cuprotosis in the tumor microenvironment, we systematically examined the characteristic patterns of 10 cuproptosis-related genes in bladder cancer (BLCA). By analyzing principal component data, we established a cuproptosis score to determine the degree of cuproptosis among patients. Finally, we evaluated the potential of these values in predicting BLCA prognosis and treatment responses. A comprehensive study of the mutations of cuproptosis-related genes in BLCA specimens was conducted at the genetic level, and their expression and survival patterns were evaluated using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Two cuproptosis patterns were constructed based on the transcription level of 10 cuproptosis-related genes, featuring differences in the prognosis and the infiltrating landscape of immune cells (especially T and dendritic cells) with interactions between cuproptosis and the TME. Our study further demonstrated that cuproptosis score may predict prognosis, immunophenotype sensitivity to chemotherapy, and immunotherapy response among bladder cancer patients. The development and progression of bladder cancer are likely to be influenced by cuproptosis, which may involve a diverse and complex TME. The cuproptosis pattern evaluated in our study may enhance understanding of immune infiltrations and guide more potent immunotherapy interventions.

64. Efficacy and safety of ruxolitinib in steroid-refractory graft-versus-host disease: A meta-analysis.

Front Immunol

2022 Aug 4

Fan S, Huo WX, Yang Y

Ruxolitinib is an important treatment for steroid refractory graft-versus-host disease (SR-GVHD). Therefore, we reported the updated results of a systematic review and meta-analysis of ruxolitinib as treatment for SR-GVHD. In addition, we wanted to compare the efficacy and safety between children and adults with SR-GVHD. Overall response rate (ORR) after ruxolitinib treatment was chosen as the primary end point. Complete response rate (CRR), infection, myelosuppression, and overall survival (OS) were chosen as secondary end points. A total of 37 studies were included in this meta-analysis, and 1,580 patients were enrolled. ORR at any time after ruxolitinib treatment was 0.77 [95% confidence interval (CI): 0.68-0.84] and 0.78 (95% CI: 0.74-0.81), respectively, for SR-aGVHD and SR-cGVHD. CRR at any time after ruxolitinib treatment was 0.49 (95% CI: 0.40-0.57) and 0.15 (95% CI: 0.10-0.23), respectively, for SR-aGVHD and SR-cGVHD. The ORRs at any time after treatment was highest in mouth SR-cGVHD, followed by skin, gut, joints and fascia, liver, eyes, esophagus, and lung SR-cGVHD. The incidence rate of infections after ruxolitinib treatment was 0.61 (95% CI: 0.45-0.76) and 0.47 (95% CI: 0.31-0.63), respectively, for SR-aGVHD and SR-cGVHD. The incidence rates of overall (grades I-IV) and severe (grades III-IV) cytopenia were 53.2% (95% CI: 16.0%-90.4%) and 31.0% (95% CI: 0.0-100.0%), respectively, for SR-aGVHD, and were 28.8% (95% CI:13.0%-44.6%) and 10.4% (95% CI: 0.0-27.9%), respectively, for SR-cGVHD. The probability rate of OS at 6 months after treatment was 63.9% (95% CI: 52.5%-75.2%) for SR-aGVHD. The probability rates of OS at 6 months, 1 year, and 2 years after treatment were 95% (95% CI: 79.5%-100.0%), 78.7% (95% CI: 67.2%-90.1%), and 75.3% (95% CI: 68.0%-82.7%), respectively, for SR-cGVHD. The ORR, CRR, infection events, and myelosuppression were all comparable between children and adults with SR-GVHD. In summary, this study suggests that ruxolitinib is an effective and safe treatment for SR-GVHD, and both children and adults with SR-GVHD could benefit from ruxolitinib treatment.

65. Coelomocyte populations in the sea urchin, Strongylocentrotus purpuratus, undergo dynamic changes in response to immune challenge.

Front Immunol

2022 Aug 31

Barela Hudgell MA, Grayfer L, Smith LC.

The sea urchin, Strongylocentrotus purpuratus has seven described populations of distinct coelomocytes in the coelomic fluid that are defined by morphology, size, and for some types, by known functions. Of these subtypes, the large phagocytes are thought to be key to the sea urchin cellular innate immune response. The concentration of total coelomocytes in the coelomic fluid increases in response to pathogen challenge. However, there is no quantitative analysis of how the respective coelomocyte populations change over time in response to immune challenge. Accordingly, coelomocytes collected from immunoquiescent, healthy sea urchins were evaluated by flow cytometry for responses to injury and to challenge with either heat-killed Vibrio diazotrophicus, zymosan A, or artificial coelomic fluid, which served as the vehicle control. Responses to the initial injury of coelomic fluid collection or to injection of V. diazotrophicus show significant increases in the concentration of large phagocytes, small phagocytes, and red spherule cells after one day. Responses to zymosan A show decreases in the concentration of large phagocytes and increases in the concentration of small phagocytes. In contrast, responses to injections of vehicle result in decreased concentration of large phagocytes. When these changes in coelomocytes are evaluated based on proportions rather than concentration, the respective coelomocyte proportions are generally maintained in response to injection with V. diazotrophicus and vehicle. However, this is not observed in response to zymosan A and this lack of correspondence between proportions and concentrations may be an outcome of clearing these large particles by the large phagocytes. Variations in coelomocyte populations are also noted for individual sea urchins evaluated at different times for their responses to immune challenge compared to the vehicle. Together, these results demonstrate that the cell populations in sea urchin immune cell populations undergo dynamic changes in vivo in response to distinct immune stimuli and to injury and that these changes are driven by the responses of the large phagocyte populations.

66. Profiling the serum proteome during Schistosoma mansoni infection in the BALB/c mice: A focus on the altered lipid metabolism as a key modulator of host-parasite interactions.

Front Immunol

2022 Aug 31

Gonçalves-Silva G, Vieira LGMDS, Cosenza-Contreras M

Schistosomiasis represents a condition in which every aspect of the disease, starting from skin invasion of the cercariae to egg laying by adult worms, incites a tissue response from the vertebrate host. This response, whether acute or chronic, leads to the appearance of reporter molecules of tissue injury in bodily fluids that could be surveyed as markers for disease diagnosis, status and prognosis. In this scenario, the serum proteome associated with a schistosome infection remains poorly explored; particularly by the use of high-throughput mass spectrometric instrumentation. In this study, we aimed to comparatively examine the serum proteome of control versus infected BALB/c mice, spanning the interval between the onset of egg laying and the peak of the acute phase of infection. Compositional analysis of the sera, using one dimensional reversed-phase fractionation of tryptic peptides coupled to mass spectrometry, allowed identification of 453 constituents. Among these, over 30% (143 molecules) were differentially present comparing sera from infected and non-infected mice, as revealed by quantitative label-free shotgun approach. The majority of proteins exhibiting altered levels was categorised as belonging to immune response (acute phase-related proteins) followed by those linked to lipid transport and metabolism. Inspection of the lipid profile from control and infected individuals demonstrated more pronounced and significant alterations in triglycerides, VLDL and HDL fractions (p<0,001), attesting for a disturbance in circulating lipid molecules, and suggesting a key role in host-parasite interactions. Our findings provide a global view of the serum proteome in the context of experimental schistosomiasis during the acute phase of infection. It contributes by listing key molecules that could be monitored to inform on the associated inflammatory disease status. We hope it will shed light into uncovered aspects of the Schistosoma mansoni parasitism in the vertebrate host, particularly those related to modulation of the lipid metabolism mediating immune responses.

67. Lipopolysaccharide sensitizes the therapeutic response of breast cancer to IAP antagonist.

Front Immunol

2022 Aug 31

Liu X, Yao JJ, Chen Z

Inhibitor of apoptosis protein (IAP) is a class of E3 ubiquitin ligases functioning to support cancer survival and growth. Many small-molecule IAP antagonists have been developed, aiming to degrade IAP proteins to kill cancer. We have evaluated the effect of lipopolysaccharide (LPS), a component of the bacterial outer membrane, on IAP antagonists in treating breast cancer in a mouse model to guide future clinical trials. We show that LPS promotes IAP antagonist-induced regression of triple-negative breast cancer (TNBC) from MDA-MB-231 cells in immunodeficient mice. IAP antagonists such as SM-164, AT-406, and BV6, do not kill MDA-MB-231 cells alone, but allow LPS to induce cancer cell apoptosis rapidly. The apoptosis caused by LPS plus SM-164 is blocked by toll-like receptor 4 (TLR4) or MyD88 inhibitor, which inhibits LPS-induced TNFα production by the cancer cells. Consistent with this, MDA-MB-231 cell apoptosis induced by LPS plus SM-164 is also blocked by the TNF inhibitor. LPS alone does not kill MDA-MB-231 cells because it markedly increases the protein level of cIAP1/2, which is directly associated with and stabilized by MyD88, an adaptor protein of TLR4. ER+ MCF7 breast cancer cells expressing low levels of cIAP1/2 undergo apoptosis in response to SM-164 combined with TNFα but not with LPS. Furthermore, TNFα but not LPS alone inhibits MCF7 cell growth in vitro. Consistent with these, LPS combined with SM-164, but not either of them alone, causes regression of ER+ breast cancer from MCF7 cells in immunodeficient mice. In summary, LPS sensitizes the therapeutic response of both triple-negative and ER+ breast cancer to IAP antagonist therapy by inducing rapid apoptosis of the cancer cells through TLR4- and MyD88-mediated production of TNFα. We conclude that antibiotics that can reduce microbiota-derived LPS should not be used together with an IAP antagonist for cancer therapy.

68. The role of helminths in the development of non-communicable diseases.

Front Immunol

2022 Aug 31

Wu Y, Duffey M, Alex SE

69. Emerging innovations on exosome-based onco-therapeutics.

Front Immunol

2022 Aug 31

Dai X, Ye Y, He F.

70. Pulse corticosteroid therapy in the treatment of steroid-refractory immune checkpoint inhibitor-related pneumonitis: Case report and review.

Front Immunol

2022 Aug 31

Lai KC, Hsiao YH, Chen SC.

71. Cryoablation reshapes the immune microenvironment in the distal tumor and enhances the anti-tumor immunity.

Front Immunol

2022 Aug 31

Wu Y, Cao F, Zhou D

72. Serum soluble Fas ligand is a severity and mortality prognostic marker for COVID-19 patients.

Front Immunol

2022 Aug 31

Saleki K, Shirzad M, Javanian M

73. Case report: Primary hepatocellular carcinoma with portal vein tumor thrombus characterized by active tumor immune microenvironment achieving a complete response following treatment of combined immunotherapy.

Front Immunol

2022 Aug 31

Zhong K, Xu Y, Cheng Y

74. Safety and immunogenicity of BK-SE36 in a blinded, randomized, controlled, age de-escalating phase Ib clinical trial in Burkinabe children.

Front Immunol

2022 Aug 31

Bougouma EC, Palacpac NMQ, Tiono AB

BACKGROUND: A blood-stage vaccine targeting the erythrocytic-stages of the malaria parasite Plasmodium falciparum could play a role to protect against clinical disease. Antibodies against the P. falciparum serine repeat antigen 5 (SE47 and SE36 domains) correlate well with the absence of clinical symptoms in sero-epidemiological studies. A previous phase Ib trial of the recombinant SE36 antigen formulated with aluminum hydroxyl gel (BK-SE36) was promising. This is the first time the vaccine candidate was evaluated in young children below 5 years using two vaccination routes. METHODS: Safety and immunogenicity of BK-SE36 was assessed in a double-blind, randomized, controlled, age de-escalating phase Ib trial. Fifty-four Burkinabe children in each age cohort, 25-60 or 12-24 months, were randomized in a 1:1:1 ratio to receive three doses of BK-SE36 either by intramuscular (BK IM) or subcutaneous (BK SC) route on Day 0, Week 4, and 26; or the control vaccine, Synflorix® via IM route on Day 0, Week 26 (and physiological saline on Week 4). Safety data and samples for immunogenicity analyses were collected at various time-points. RESULTS: Of 108 subjects, 104 subjects (96.3%) (Cohort 1: 94.4%; Cohort 2: 98.1%) received all three scheduled vaccine doses. Local reactions, mostly mild or of moderate severity, occurred in 99 subjects (91.7%). The proportion of subjects that received three doses without experiencing Grade 3 adverse events was similar across BK-SE36 vaccines and control arms (Cohort 1: 100%, 89%, and 89%; and Cohort 2: 83%, 82%, and 83% for BK IM, BK SC, and control, respectively). BK-SE36 vaccine was immunogenic, inducing more than 2-fold change in antibody titers from pre-vaccination, with no difference between the two vaccination routes. Titers waned before the third dose but in both cohorts titers were boosted 6 months after the first vaccination. The younger cohort had 2-fold and 4-fold higher geometric mean titers compared to the 25- to 60-month-old cohort after 2 and 3 doses of BK-SE36, respectively. CONCLUSION: BK-SE36 was well tolerated and immunogenic using either intramuscular or subcutaneous routes, with higher immune response in the younger cohort. CLINICAL TRIAL REGISTRATION: https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=934, identifier PACTR201411000934120.

75. Immune response in ofatumumab treated multiple sclerosis patients after SARS-CoV-2 vaccination.

Front Immunol

2022 Aug 31

Faissner S, Heitmann N, Plaza-Sirvent C

76. Editorial: The bone/bone marrow microenvironment: A hub for immune regulation of the tumor cells fate.

Front Immunol

2022 Aug 31

Horas K, Menale C, Maurizi A.

77. Editorial: Future challenges and directions in determining allo-immunity in kidney transplantation.

Front Immunol

2022 Aug 31

Lim WH, Ho J, Kosmoliaptsis V

78. Risk of HBV reactivation in relapsed or refractory diffuse large B-cell lymphoma patients receiving Bruton tyrosine kinase inhibitors therapy.

Front Immunol

2022 Aug 31

Ni Y, Gao L, Lu Y

79. Discovering common pathogenetic processes between COVID-19 and sepsis by bioinformatics and system biology approach.

Front Immunol

2022 Aug 31

Lu L, Liu LP, Gui R

Corona Virus Disease 2019 (COVID-19), an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread rapidly worldwide, resulting in a pandemic with a high mortality rate. In clinical practice, we have noted that many critically ill or critically ill patients with COVID-19 present with typical sepsis-related clinical manifestations, including multiple organ dysfunction syndrome, coagulopathy, and septic shock. In addition, it has been demonstrated that severe COVID-19 has some pathological similarities with sepsis, such as cytokine storm, hypercoagulable state after blood balance is disrupted and neutrophil dysfunction. Considering the parallels between COVID-19 and non-SARS-CoV-2 induced sepsis (hereafter referred to as sepsis), the aim of this study was to analyze the underlying molecular mechanisms between these two diseases by bioinformatics and a systems biology approach, providing new insights into the pathogenesis of COVID-19 and the development of new treatments. Specifically, the gene expression profiles of COVID-19 and sepsis patients were obtained from the Gene Expression Omnibus (GEO) database and compared to extract common differentially expressed genes (DEGs). Subsequently, common DEGs were used to investigate the genetic links between COVID-19 and sepsis. Based on enrichment analysis of common DEGs, many pathways closely related to inflammatory response were observed, such as Cytokine-cytokine receptor interaction pathway and NF-kappa B signaling pathway. In addition, protein-protein interaction networks and gene regulatory networks of common DEGs were constructed, and the analysis results showed that ITGAM may be a potential key biomarker base on regulatory analysis. Furthermore, a disease diagnostic model and risk prediction nomogram for COVID-19 were constructed using machine learning methods. Finally, potential therapeutic agents, including progesterone and emetine, were screened through drug-protein interaction networks and molecular docking simulations. We hope to provide new strategies for future research and treatment related to COVID-19 by elucidating the pathogenesis and genetic mechanisms between COVID-19 and sepsis.

80. Extracellular matrix metalloproteinase inducer in brain ischemia and intracerebral hemorrhage.

Front Immunol

2022 Aug 31

Liu Y, Mu Y, Li Z

81. New insights on the role of human leukocyte antigen complex in primary biliary cholangitis.

Front Immunol

2022 Aug 31

Mulinacci G, Palermo A, Gerussi A

82. Inflammatory perturbations in early life long-lastingly shape the transcriptome and TCR repertoire of the first wave of regulatory T cells.

Front Immunol

2022 Aug 31

Yang J, Zou M, Chu X

The first wave of Foxp3+ regulatory T cells (Tregs) generated in neonates is critical for the life-long prevention of autoimmunity. Although it is widely accepted that neonates are highly susceptible to infections, the impact of neonatal infections on this first wave of Tregs is completely unknown. Here, we challenged newborn Treg fate-mapping mice (Foxp3eGFPCreERT2xROSA26STOP-eYFP) with the Toll-like receptor (TLR) agonists LPS and poly I:C to mimic inflammatory perturbations upon neonatal bacterial or viral infections, respectively, and subsequently administrated tamoxifen during the first 8 days of life to selectively label the first wave of Tregs. Neonatally-tagged Tregs preferentially accumulated in non-lymphoid tissues (NLTs) when compared to secondary lymphoid organs (SLOs) irrespective of the treatment. One week post challenge, no differences in the frequency and phenotypes of neonatally-tagged Tregs were observed between challenged mice and untreated controls. However, upon aging, a decreased frequency of neonatally-tagged Tregs in both NLTs and SLOs was detected in challenged mice when compared to untreated controls. This decrease became significant 12 weeks post challenge, with no signs of altered Foxp3 stability. Remarkably, this late decrease in the frequency of neonatally-tagged Tregs only occurred when newborns were challenged, as treating 8-days-old mice with TLR agonists did not result in long-lasting alterations of the first wave of Tregs. Combined single-cell T cell receptor (TCR)-seq and RNA-seq revealed that neonatal inflammatory perturbations drastically diminished TCR diversity and long-lastingly altered the transcriptome of neonatally-tagged Tregs, exemplified by lower expression of Tigit, Foxp3, and Il2ra. Together, our data demonstrate that a single, transient encounter with a pathogen in early life can have long-lasting consequences for the first wave of Tregs, which might affect immunological tolerance, prevention of autoimmunity, and other non-canonical functions of tissue-resident Tregs in adulthood.

83. Alpha-D-glucan-based vaccine adjuvants: Current status and future perspectives.

Front Immunol

2022 Aug 31

Patil V, Hernandez-Franco JF, HogenEsch H

84. A robust CD8(+) T cell-related classifier for predicting the prognosis and efficacy of immunotherapy in stage III lung adenocarcinoma.

Front Immunol

2022 Aug 31

Feng J, Xu L, Zhang S

85. The impact of Rituximab administered before transplantation in patients undergoing allogeneic hematopoietic stem cell transplantation: A real-world study.

Front Immunol

2022 Aug 31

Wei X, Xie Y, Jiang R

86. Astrocytes regulate vascular endothelial responses to simulated deep space radiation in a human organ-on-a-chip model.

Front Immunol

2022 Aug 30

Verma SD, Passerat de la Chapelle E, Malkani S

87. Immunoinformatic analysis of the whole proteome for vaccine design: An application to Clostridium perfringens.

Front Immunol

2022 Aug 30

Soto LF, Romaní AC, Jiménez-Avalos G

88. The imbalance between Type 17 T-cells and regulatory immune cell subsets in psoriasis vulgaris.

Front Immunol

2022 Aug 30

Kim J, Moreno A, Krueger JG.

89. An overview of JAK/STAT pathways and JAK inhibition in alopecia areata.

Front Immunol

2022 Aug 30

Lensing M, Jabbari A.

Alopecia Areata (AA) is a common autoimmune disease characterized by non-scarring hair loss ranging from patches on the scalp to complete hair loss involving the entire body. Disease onset is hypothesized to follow the collapse of immune privilege of the hair follicle, which results in an increase in self-peptide/MHC expression along the follicular epithelium. Hair loss is associated with infiltration of the hair follicle with putatively self-reactive T cells. This process is thought to skew the hair follicle microenvironment away from a typically homeostatic immune state towards one of active inflammation. This imbalance is mediated in part by the dominating presence of specific cytokines. While interferon-γ (IFNγ) has been identified as the key player in AA pathogenesis, many other cytokines have also been shown to play pivotal roles. Mechanistic studies in animal models have highlighted the contribution of common gamma chain (γc) cytokines such as IL-2, IL-7, and IL-15 in augmenting disease. IFNγ and γc cytokines signal through pathways involving receptor activation of Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). Based on these findings, JAK/STAT pathways have been targeted for the purposes of therapeutic intervention in the clinical setting. Case reports and series have described use of small molecule JAK inhibitors leading to hair regrowth among AA patients. Furthermore, emerging clinical trial results show great promise and position JAK inhibitors as a treatment strategy for patients with severe or recalcitrant disease. Demonstrated efficacy from large-scale clinical trials of the JAK inhibitor baricitinib led to the first-in-disease FDA-approved treatment for AA in June of 2022. This review aims to highlight the JAK/STAT signaling pathways of various cytokines involved in AA and how targeting those pathways may impact disease outcomes in both laboratory and clinical settings.

90. The multifaceted roles of NLRP3-modulating proteins in virus infection.

Front Immunol

2022 Aug 30

Harris J, Borg NA.

91. The cuproptosis-related signature associated with the tumor environment and prognosis of patients with glioma.

Front Immunol

2022 Aug 30

Wang W, Lu Z, Wang M

BACKGROUND: Copper ions are essential for cellular physiology. Cuproptosis is a novel method of copper-dependent cell death, and the cuproptosis-based signature for glioma remains less studied. METHODS: Several glioma datasets with clinicopathological information were collected from TCGA, GEO and CGGA. Robust Multichip Average (RMA) algorithm was used for background correction and normalization, cuproptosis-related genes (CRGs) were then collected. The TCGA-glioma cohort was clustered using ConsensusClusterPlus. Univariate Cox regression analysis and the Random Survival Forest model were performed on the differentially expressed genes to identify prognostic genes. The cuproptosis-signature was constructed by calculating CuproptosisScore using Multivariate Cox regression analysis. Differences in terms of genomic mutation, tumor microenvironment, and enrichment pathways were evaluated between high- or low-CuproptosisScore. Furthermore, drug response prediction was carried out utilizing pRRophetic. RESULTS: Two subclusters based on CRGs were identified. Patients in cluster2 had better clinical outcomes. The cuproptosis-signature was constructed based on CuproptosisScore. Patients with higher CuproptosisScore had higher WHO grades and worse prognosis, while patients with lower grades were more likely to develop IDH mutations or MGMT methylation. Univariate and Multivariate Cox regression analysis demonstrated CuproptosisScore was an independent prognostic factor. The accuracy of the signature in prognostic prediction was further confirmed in 11 external validation datasets. In groups with high-CuproptosisScore, PIK3CA, MUC16, NF1, TTN, TP53, PTEN, and EGFR showed high mutation frequency. IDH1, TP53, ATRX, CIC, and FUBP1 demonstrated high mutation frequency in low-CuproptosisScore group. The level of immune infiltration increased as CuproptosisScore increased. SubMap analysis revealed patients with high-CuproptosisScore may respond to anti-PD-1 therapy. The IC50 values of Bexarotene, Bicalutamide, Bortezomib, and Cytarabine were lower in the high-CuproptosisScore group than those in the low-CuproptosisScore group. Finally, the importance of IGFBP2 in TCGA-glioma cohort was confirmed. CONCLUSION: The current study revealed the novel cuproptosis-based signature might help predict the prognosis, biological features, and appropriate treatment for patients with glioma.

92. CRX-527 induced differentiation of HSCs protecting the intestinal epithelium from radiation damage.

Front Immunol

2022 Aug 30

Liu D, Dong S, Liu C

93. Pharmacological modulation of myeloid-derived suppressor cells to dampen inflammation.

Front Immunol

2022 Aug 30

van Geffen C, Heiss C, Deißler A

94. A high-throughput screening RT-qPCR assay for quantifying surrogate markers of immunity from PBMCs.

Front Immunol

2022 Aug 30

Browne DJ, Kelly AM, Brady JL

95. Case Report: Possible autoimmune obsessive-compulsive disorder with postpartum onset.

Front Immunol

2022 Aug 30

Endres D, Hannibal L, Zaltenbach B

96. The key player in the pathogenesis of environmental influence of systemic lupus erythematosus: Aryl hydrocarbon receptor.

Front Immunol

2022 Aug 30

Wu J, Pang T, Lin Z

97. An optimized Factor H-Fc fusion protein against multidrug-resistant Neisseria gonorrhoeae.

Front Immunol

2022 Aug 30

Shaughnessy J, Chabeda A, Tran Y

Novel therapeutics against the global threat of multidrug-resistant Neisseria gonorrhoeae are urgently needed. Gonococci evade killing by complement by binding factor H (FH), a key inhibitor of the alternative pathway. FH comprises 20 short consensus repeat (SCR) domains organized as a single chain. Gonococci bind FH through domains 6 and 7, and C-terminal domains 18 through 20. Previously, we showed that a chimeric protein comprising (from the N- to C-terminus) FH domains 18-20 (containing a point mutation in domain 19 to prevent lysis of host cells) fused to human IgG1 Fc (called FH*/Fc1) killed gonococci in a complement-dependent manner and reduced the duration and bacterial burden in the mouse vaginal colonization model of gonorrhea. Considering the N. gonorrhoeae-binding FH domains 18-20 are C-terminal in native FH, we reasoned that positioning Fc N-terminal to FH* (Fc1/FH*) would improve binding and bactericidal activity. Although both molecules bound gonococci similarly, Fc1/FH* displayed a 5-fold lower IC50 (the concentration required for 50% killing in complement-dependent bactericidal assays) than FH*/Fc1. To further increase complement activation, we replaced human IgG1 Fc in Fc1/FH* with Fc from human IgG3, the most potent complement-activating IgG subclass, to obtain Fc3/FH*. Bactericidal activity was further increased ~2.3-fold in Fc3/FH* compared to Fc1/FH*. Fc3/FH* killed (defined by <50% survival) 45/45 (100%) diverse PorB1B-expessing gonococci, but only 2/15 PorB1A-expressing isolates, in a complement-dependent manner. Decreased Fc3/FH* binding accounted for the limited activity against PorB1A strains. Fc3/FH* was efficacious against all four tested PorB1B gonococcal strains in the mouse vaginal colonization model when administered at a dose of 5 µg intravaginally, daily. Furthermore, Fc3/FH* retained bactericidal activity when reconstituted following lyophilization or spray-drying, suggesting feasibility for formulation into intravaginal rings. In conclusion, Fc3/FH* represents a promising prophylactic immunotherapeutic against multidrug-resistant gonococci.

98. A comparative study of adjuvants effects on neonatal plasma cell survival niche in bone marrow and persistence of humoral immune responses.

Front Immunol

2022 Aug 3

Aradottir Pind AA, Thorsdottir S, Magnusdottir GJ

The neonatal immune system is distinct from the immune system of older individuals rendering neonates vulnerable to infections and poor responders to vaccination. Adjuvants can be used as tools to enhance immune responses to co-administered antigens. Antibody (Ab) persistence is mediated by long-lived plasma cells that reside in specialized survival niches in the bone marrow, and transient Ab responses in early life have been associated with decreased survival of plasma cells, possibly due to lack of survival factors. Various cells can secrete these factors and which cells are the main producers is still up for debate, especially in early life where this has not been fully addressed. The receptor BCMA and its ligand APRIL have been shown to be important in the maintenance of plasma cells and Abs. Herein, we assessed age-dependent maturation of a broad range of bone marrow accessory cells and their expression of the survival factors APRIL and IL-6. Furthermore, we performed a comparative analysis of the potential of 5 different adjuvants; LT-K63, mmCT, MF59, IC31 and alum, to enhance expression of survival factors and BCMA following immunization of neonatal mice with tetanus toxoid (TT) vaccine. We found that APRIL expression was reduced in the bone marrow of young mice whereas IL-6 expression was higher. Eosinophils, macrophages, megakaryocytes, monocytes and lymphocytes were important secretors of survival factors in early life but undefined cells also constituted a large fraction of secretors. Immunization and adjuvants enhanced APRIL expression but decreased IL-6 expression in bone marrow cells early after immunization. Furthermore, neonatal immunization with adjuvants enhanced the proportion of plasmablasts and plasma cells that expressed BCMA both in spleen and bone marrow. Enhanced BCMA expression correlated with enhanced vaccine-specific humoral responses, even though the effect of alum on BCMA was less pronounced than those of the other adjuvants at later time points. We propose that low APRIL expression in bone marrow as well as low BCMA expression of plasmablasts/plasma cells in early life together cause transient Ab responses and could represent targets to be triggered by vaccine adjuvants to induce persistent humoral immune responses in this age group.

99. Recent malaria does not substantially impact COVID-19 antibody response or rates of symptomatic illness in communities with high malaria and COVID-19 transmission in Mali, West Africa.

Front Immunol

2022 Aug 3

Woodford J, Sagara I, Diawara H

100. Spatial localization of cathepsins: Implications in immune activation and resolution during infections.

Front Immunol

2022 Aug 3

Anes E, Pires D, Mandal M

101. Microneedling combined with compound betamethasone in treatment of severe alopecia areata: A case report.

Front Immunol

2022 Aug 3

Pei D, Chen L, Yao Y

102. Homologous recombination repair gene mutations as a predictive biomarker for immunotherapy in patients with advanced melanoma.

Front Immunol

2022 Aug 3

You Z, Lv M, He X

BACKGROUND: Nowadays, immunotherapy targeting immune checkpoint receptors is one of the cornerstones of systemic treatment in melanoma. Homologous recombination repair (HRR) is one of the DNA damage response (DDR) pathways, which has been proved to correlate with the efficacy of platinum-based chemotherapy, PARP inhibitor therapy, and immunotherapy in a variety of cancers. However, their predictive value of HRR remained unknown in patients with advanced melanoma. METHODS: Data of advanced melanoma patients from an independent cohort (Samstein2018) were used to analyze the correlation with immunogenic markers and the prognostic effect of HRR on immunotherapy, and another four cohorts (pooled cohort: Miao2018, Allen 2015, Hugo2016, and Synder2014) were used for validation. Immune infiltration cell scores analyzed by TCGA-SKCM cohort were used to explore potential mechanisms related to the immune microenvironment. RESULTS: Compared to patients with an HRR wild type (HRRwt), those with HRR mutations (HRRmut) in anti-CTLA-4-treated patients of the Samstein2018 cohort had higher tumor mutation burden (TMB; P = 0.0041) and longer median overall survival (mOS; P = 0.0094). In terms of results validation, it was also confirmed that the mOS (P = 0.0014) of HRRmut patients receiving anti-CTLA-4 therapy was significantly better than that of HRRwt patients in the pooled cohort, and objective response rates (ORR; P = 0.0053) were also found to be significant. However, there was no significant difference in mOS between HRRmut patients who received anti-PD-1/L1 therapy and HRRwt patients in either the discovery (Samstein2018 cohort, P = 0.94) or validation (pooled cohort, P = 0.96) set. Exploratory analysis found that although HRRmut patients showed no significant difference in mOS between anti-CTLA-4 and anti-PD-1/L1 therapy (P = 0.79), the mOS value of the anti-CTLA-4 therapy group (31.7 months) in HRRmut patients was numerically superior to the anti-PD-1/L1 therapy group (27.5 months). In contrast, the mOS of the anti-CTLA-4 therapy group was significantly lower than that of the anti-PD-1/L1 therapy group (12.4 vs. 32.0 months) in HRRwt patients. In addition, transcriptome profiling analysis revealed that the 29 (65.9%)-gene mutation of the HRR pathway associated with reshaping of the immunological microenvironment in melanoma. CONCLUSIONS: HRR mutations were associated with a higher TMB level, and better anti-CTLA-4 therapy outcomes. HRR may serve as an independent predictor of anti-CTLA-4 therapy efficacy in patients with advanced melanoma and their clinical value warrants further investigation.

103. Single-cell RNA sequencing reveals distinct immunology profiles in human keloid.

Front Immunol

2022 Aug 3

Feng C, Shan M, Xia Y

104. Erratum: Clinical significance of shared T cell epitope analysis in early de novo donor-specific anti-HLA antibody production after kidney transplantation and comparison with shared B cell epitope analysis.

Front Immunol

2022 Aug 3

Frontiers Production Office.

105. Factors that predict severity of infection and seroconversion in immunocompromised children and adolescents with COVID-19 infection.

Front Immunol

2022 Aug 3

Abu Shanap M, Sughayer M, Alsmadi O

OBJECTIVES: We aimed to study the outcomes, severity, and seroconversion post SARS-CoV-2 infection in immunocompromised children and adolescents treated at our center. METHOD: For this observational study, all pediatric patients who had COVID-19 infection from Sep-22-2020 to Nov-10-2021were identified by reviewing our laboratory records. Their charts were reviewed to determine clinical severity and outcome. Blood samples were drawn for anti-SARS-CoV-2 antibody assay. Serious COVID-19 infection (SVI) was defined if the patient had moderate, severe, or critical illness. A cutoff of 100 U/mL anti-SARS-CoV-2 antibodies was used to categorize low and high titer seroconversion. RESULTS: We identified 263 pediatric patients with COVID-19; most (68%) were symptomatic: 5% had severe or critical infection, 25% were hospitalized, 12 required respiratory support, 12 were admitted to the ICU, and five patients (2%) died. Multivariable analysis revealed several factors that predict SVI: Age above 12 years (p=0.035), body mass index above 95th percentile (p=0.034), comorbid conditions (p=0.025), absolute neutrophil count ≤500(p=0.014) and absolute lymphocyte count ≤300 (p=0.022). Levels of anti-SARS-CoV-2 spike antibodies were obtained for 173 patients at a median of 94 days (range, 14-300) after PCR diagnosis; of them 142 (82%) patients seroconverted; the lowest seroconversion rate was observed in patients with hematological malignancies (79%). Our univariable model showed that the following factors were predictive of low titer: lower ANC, p=0.01; hematologic malignancy, p=0.023; receiving steroids in the last 14 days, p=0.032; time since last chemotherapy or immunosuppressive therapy less than 30 days, p=0.002; and being on active chemotherapy in the last 3 months prior to infection, p<0.001. CONCLUSIONS: SARS-CoV-2 antibodies developed in most immunocompromised patients with COVID-19 infection in our study. Mortality was relatively low in our patients. Our univariable and multivariable models showed multiple variables that predict severity of infections and antibody response post COVID-19 infection. These observations may guide choice of active therapy during infection and the best timing of vaccination in this high-risk population.

106. Case report and analysis: Behçet's disease with lower extremity vein thrombosis and pseudoaneurysm.

Front Immunol

2022 Aug 29

Wang HL, Zhang JH, Wu YC

BACKGROUND: Behçet's disease (BD) is a unique autoimmune chronic systemic vasculitis that affects veins and arteries of all sizes. BD can lead to recurrent vascular events, especially venous thrombosis, with an incidence rate of 40%, or pseudoaneurysms formed under long-term inflammatory reaction or iatrogenic stimulation. BD-related risk factors promote endothelial dysfunction, platelet activation and overactivation of tissue factors leading to mural inflammatory thrombi. Thrombosis may be the first clinical manifestation of BD. CASE PRESENTATION: A 32-year-old man complaining of progressive swelling and pain in the right lower extremity for 30 days was initially diagnosed with "venous thrombosis of the right lower extremity," using color Doppler ultrasonography. Patient underwent inferior vena cava filter placement combined with deep vein angioplasty of the right lower extremity and catheter-directed urokinase thrombolysis. Postoperative oral anticoagulant therapy was administered. However, the patient was readmitted 20 days later for pulsatile pain in the right groin. Prior medical history included 4 years of repeated oral and perineal ulcers, and 2 months of blurred vision. Abdominal computed tomography angiography (CTA) revealed rupture of the right common iliac artery (CIA) and left internal iliac artery (IIA), complicated by a pseudoaneurysm. Based on the clinical manifestations and other auxiliary examination results, the patient was re-diagnosed with "BD combined with deep venous thrombosis of the right lower extremity and an iliac artery pseudoaneurysm." Stent implantation was performed for iliac artery pseudoaneurysm after symptoms were controlled with timely immunosuppressive therapy. After endovascular treatment, the patient underwent continued immunosuppressive therapy and dynamic reexaminations of abdominal CTA, which revealed that a small amount of contrast agent at the stent in the right CIA continued to flow into the cavity of the pseudoaneurysm; in addition, the size of the pseudoaneurysm was gradually increasing. Therefore, the patient underwent a second stent implantation for iliac artery pseudoaneurysm, and the condition improved further. CONCLUSION: The importance of early diagnosis of BD should be recognized, and the choice of interventional and surgical procedures should be carefully evaluated, as this may trigger further damage to vascular access in BD patients with aneurysm.

107. Gut microbiota on admission as predictive biomarker for acute necrotizing pancreatitis.

Front Immunol

2022 Aug 29

Zou M, Yang Z, Fan Y

BACKGROUND: Acute necrotizing pancreatitis (NP), a severe form of acute pancreatitis (AP), has higher mortality and worse outcome than non-necrotizing pancreatitis (non-NP). Infected NP is a devastating subgroup of NP. To date neither NP nor infected NP has robust prediction strategies, which may delay early recognition and timely intervention. Recent studies revealed correlations between disturbed gut microbiota and AP severity. Some features of intestinal microbiota have the potential to become biomarkers for NP prediction. METHODS: We performed 16S rRNA sequencing to analyze gut microbiota features in 20 healthy controls (HC), and 58 AP patients on hospital admission. The AP patients were later classified into NP and non-NP groups based on subsequent diagnostic imaging features. Random forest regression model and ROC curve were applied for NP and infected NP prediction. PIRCUSt2 was used for bacterial functional pathway prediction analysis. RESULTS: We found that the three groups (HC, NP, and non-NP) had distinct microorganism composition. NP patients had reduced microbial diversity, higher abundance of Enterobacteriales, but lower abundance of Clostridiales and Bacteroidales compared with the non-NP group. Correlation analyses displayed that intestine bacterial taxonomic alterations were related to severity, ICU admission, and prognosis. By pathway prediction, species more abundant in NP patients had positive correlation with synthesis and degradation of ketone bodies, and benzoate degradation. Enterococcus faecium (ASV2) performed best in discriminating NP and non-NP patients. Finegoldia magna (ASV3) showed the maximal prediction capacity among all ASVs and had comparable accuracy with Balthazar CT to detect patients with infected NP. CONCLUSIONS: Our study suggests that NP patients have distinct intestinal microbiota on admission compared to non-NP patients. Dysbiosis of intestinal microbiota might influence NP progression through ketone body or benzoate metabolism. Enterococcus faecium and Finegoldia magna are potential predictors for NP and infected NP. Our findings explore biomarkers which may inform clinical decision-making in AP and shed light on further studies on NP pathophysiology and management.

108. Immunogenicity of COVID-19 vaccines in patients with diabetes mellitus: A systematic review.

Front Immunol

2022 Aug 29

Boroumand AB, Forouhi M, Karimi F

PURPOSE: To evaluate the immunogenicity of COVID-19 vaccines in patients with diabetes mellitus (DM) through a systematic approach. METHOD: A comprehensive search was conducted in PubMed, Scopus, and Web of Science with no time restrictions. The search was based on the three main concepts: Covid-19, Vaccine immunogenicity and Diabetes Mellitus. RESULTS: After excluding irrelevant studies, 16 studies remained for the quantitative assay. Among the sixteen studies, eleven had controls. Type of diabetes was specifically mentioned in six studies (T2DM; n=4, T1DM and T2DM; n=2). Twelve of the included studies were conducted on the immunogenicity of vaccines that included mRNA vaccines (i.e. BNT162b2 and mRNA-1273) in DM, five studies included vector-based vaccines (i.e. Ad5-nCoV and ChAdOx1-S), and five studies assessed the immunogenicity of vaccines in DM, including inactivated vaccines (i.e. BBV-152, CoronaVac, Sinopharm or SinoVac). Most of the current studies indicate lower antibody response in patients with DM compared to individuals without DM, after the second dose of vaccine and irrespective of vaccine type. Several studies have shown that higher age and higher BMI are associated with lower antibody response, while optimum glycemic control and higher GFR are associated with higher antibody response among patients with DM. CONCLUSION: Immunogenicity of the vaccines has mostly been reported to be lower among patients with DM compared to healthy controls. There are also few studies assessing variables that significantly affect this association, including age, type of diabetes, BMI, glycemic control and eGFR. Investigating these associations could help us provide the most advantageous condition for patients with DM before, during and after vaccination for optimum antibody response. Many unresolved issues concerning potential factors affecting vaccine immunogenicity, including type of vaccine, numbers of administered doses, re-vaccination intervals and hyperglycemia in patients with DM need to be addressed through future research.

109. Investigation of the risk factors to predict cytokine release syndrome in relapsed or refractory B-cell acute lymphoblastic leukemia patients receiving IL-6 knocking down anti-CD19 chimeric antigen receptor T-cell therapy.

Front Immunol

2022 Aug 29

Gong WJ, Qiu Y, Li MH

110. The parasitic worm product ES-62 protects the osteoimmunology axis in a mouse model of obesity-accelerated ageing.

Front Immunol

2022 Aug 29

Harnett MM, Doonan J, Lumb FE

Despite significant increases in human lifespan over the last century, adoption of high calorie diets (HCD) has driven global increases in type-2 diabetes, obesity and cardiovascular disease, disorders precluding corresponding improvements in healthspan. Reflecting that such conditions are associated with chronic systemic inflammation, evidence is emerging that infection with parasitic helminths might protect against obesity-accelerated ageing, by virtue of their evolution of survival-promoting anti-inflammatory molecules. Indeed, ES-62, an anti-inflammatory secreted product of the filarial nematode Acanthocheilonema viteae, improves the healthspan of both male and female C57BL/6J mice undergoing obesity-accelerated ageing and also extends median lifespan in male animals, by positively impacting on inflammatory, adipose metabolic and gut microbiome parameters of ageing. We therefore explored whether ES-62 affects the osteoimmunology axis that integrates environmental signals, such as diet and the gut microbiome to homeostatically regulate haematopoiesis and training of immune responses, which become dysregulated during (obesity-accelerated) ageing. Of note, we find sexual dimorphisms in the decline in bone health, and associated dysregulation of haematopoiesis and consequent peripheral immune responses, during obesity-accelerated ageing, highlighting the importance of developing sex-specific anti-ageing strategies. Related to this, ES-62 protects trabecular bone structure, maintaining bone marrow (BM) niches that counter the ageing-associated decline in haematopoietic stem cell (HSC) functionality highlighted by a bias towards myeloid lineages, in male but not female, HCD-fed mice. This is evidenced by the ability of ES-62 to suppress the adipocyte and megakaryocyte bias and correspondingly promote increases in B lymphocytes in the BM. Furthermore, the consequent prevention of ageing-associated myeloid/lymphoid skewing is associated with reduced accumulation of inflammatory CD11c+ macrophages and IL-1β in adipose tissue, disrupting the perpetuation of inflammation-driven dysregulation of haematopoiesis during obesity-accelerated ageing in male HCD-fed mice. Finally, we report the ability of small drug-like molecule analogues of ES-62 to mimic some of its key actions, particularly in strongly protecting trabecular bone structure, highlighting the translational potential of these studies.

111. Advances in the study of HLA class Ib in maternal-fetal immune tolerance.

Front Immunol

2022 Aug 29

Yang Y, Wang W, Weng J

112. Characterization of a novel cysteine protease inhibitor in Baylisascaris schroederi migratory larvae and its role in regulating mice immune cell response.

Front Immunol

2022 Aug 29

Xu J, Gu X, Xie Y

Baylisascaris schroederi (B. schroederi) is a severe threat to the survival of giant pandas. Currently, the immune regulation mechanism of B. schroederi is poorly understood. Cysteine protease inhibitors (CPI) play important roles in the regulation of host immune responses against certain nematodes. In this study, a recombinant CPI of B. schroederi migratory larvae (rBsCPI-1) was cloned and expressed, and the effects of rBsCPI-1 on the physiological activities and antigen presentation of monocyte-derived macrophages (MDMs) were analyzed. We also analyzed the regulatory effects of rBsCPI-1 on the proliferation and differentiation of CD4+ T cells. And further identified the signaling pathways which play important roles in this process. The results showed that rBsCPI-1 activated the TLR2/4-small Rho GTPases-PAK1 pathway. On the one hand, it increased the phagocytosis and migration of MDMs. On the other hand, it activated downstream MAPK and NF-κB signaling pathways to induce apoptosis of MDMs. rBsCPI-1 also induced MDMs to polarize to the M2 subtype, thereby exerting an immunosuppressive effect. Meanwhile, rBsCPI-1 inhibited the antigen presentation process by decreasing the expression of MHC-II molecules, further inhibiting the proliferation of CD4+ T cells and inducing a Th1/Th2 mixed immune response. Treg cells with immunosuppressive effects were increased. The PD-L2/PD-1 and CD80/CTLA-4 signaling pathways between MDMs and CD4+ T cells were also activated by rBsCPI-1. In conclusion, this study preliminarily confirmed that rBsCPI-1 affects the physiological activities and polarization of MDMs through the TLR2/4 signaling pathway, and further interferes with antigen presentation response, inducing CD4+ T cells to play an immunosuppressive cellular response during the migratory process of B. schroederi. Thus, this study will provide a reference for elucidating the immune evasion mechanism of B. schroederi and developing new drugs and protective vaccines against B. schroederi.

113. Detrimental NFKB1 missense variants affecting the Rel-homology domain of p105/p50.

Front Immunol

2022 Aug 29

Fliegauf M, Kinnunen M, Posadas-Cantera S

Most of the currently known heterozygous pathogenic NFKB1 (Nuclear factor kappa B subunit 1) variants comprise deleterious defects such as severe truncations, internal deletions, and frameshift variants. Collectively, these represent the most frequent monogenic cause of common variable immunodeficiency (CVID) identified so far. NFKB1 encodes the transcription factor precursor p105 which undergoes limited proteasomal processing of its C-terminal half to generate the mature NF-κB subunit p50. Whereas p105/p50 haploinsufficiency due to devastating genetic damages and protein loss is a well-known disease mechanism, the pathogenic significance of numerous NFKB1 missense variants still remains uncertain and/or unexplored, due to the unavailability of accurate test procedures to confirm causality. In this study we functionally characterized 47 distinct missense variants residing within the N-terminal domains, thus affecting both proteins, the p105 precursor and the processed p50. Following transient overexpression of EGFP-fused mutant p105 and p50 in HEK293T cells, we used fluorescence microscopy, Western blotting, electrophoretic mobility shift assays (EMSA), and reporter assays to analyze their effects on subcellular localization, protein stability and precursor processing, DNA binding, and on the RelA-dependent target promoter activation, respectively. We found nine missense variants to cause harmful damage with intensified protein decay, while two variants left protein stability unaffected but caused a loss of the DNA-binding activity. Seven of the analyzed single amino acid changes caused ambiguous protein defects and four variants were associated with only minor adverse effects. For 25 variants, test results were indistinguishable from those of the wildtype controls, hence, their pathogenic impact remained elusive. In summary, we show that pathogenic missense variants affecting the Rel-homology domain may cause protein-decaying defects, thus resembling the disease-mechanisms of p105/p50 haploinsufficiency or may cause DNA-binding deficiency. However, rare variants (with a population frequency of less than 0.01%) with minor abnormalities or with neutral tests should still be considered as potentially pathogenic, until suitable tests have approved them being benign.

114. Corrigendum: Urine soluble CD163 is a promising biomarker for the diagnosis and evaluation of lupus nephritis.

Front Immunol

2022 Aug 29

Huang YJ, Lin CH, Yang HY

115. The collectin SP-A and its trimeric recombinant fragment protect alveolar epithelial cells from the cytotoxic and proinflammatory effects of human cathelicidin in vitro.

Front Immunol

2022 Aug 29

de Tapia L, García-Fojeda B, Kronqvist N

116. Innate lymphocytes: Role in alcohol-induced immune dysfunction.

Front Immunol

2022 Aug 29

Ruiz-Cortes K, Villageliu DN, Samuelson DR.

117. Global research trends on precision cancer medicine-related rashes (2008-2021): A bibliographic study.

Front Immunol

2022 Aug 26

Zhao F, Yu R, Chen S

118. Structural and functional analysis of the small GTPase ARF1 reveals a pivotal role of its GTP-binding domain in controlling of the generation of viral inclusion bodies and replication of grass carp reovirus.

Front Immunol

2022 Aug 26

Zhang J, Li P, Lu R

119. Pharmacological activation of the C5a receptor leads to stimulation of the β-adrenergic receptor and alleviates cognitive impairment in a murine model of familial Alzheimer's disease.

Front Immunol

2022 Aug 26

Fella E, Papacharalambous R, Kynigopoulos D

120. A century of BCG vaccination: Immune mechanisms, animal models, non-traditional routes and implications for COVID-19.

Front Immunol

2022 Aug 26

Singh S, Saavedra-Avila NA, Tiwari S

Bacillus Calmette-Guerin (BCG) has been used as a vaccine against tuberculosis since 1921 and remains the only currently approved vaccine for this infection. The recent discovery that BCG protects against initial infection, and not just against progression from latent to active disease, has significant implications for ongoing research into the immune mechanisms that are relevant to generate a solid host defense against Mycobacterium tuberculosis (Mtb). In this review, we first explore the different components of immunity that are augmented after BCG vaccination. Next, we summarize current efforts to improve the efficacy of BCG through the development of recombinant strains, heterologous prime-boost approaches and the deployment of non-traditional routes. These efforts have included the development of new recombinant BCG strains, and various strategies for expression of important antigens such as those deleted during the M. bovis attenuation process or antigens that are present only in Mtb. BCG is typically administered via the intradermal route, raising questions about whether this could account for its apparent failure to generate long-lasting immunological memory in the lungs and the inconsistent level of protection against pulmonary tuberculosis in adults. Recent years have seen a resurgence of interest in the mucosal and intravenous delivery routes as they have been shown to induce a better immune response both in the systemic and mucosal compartments. Finally, we discuss the potential benefits of the ability of BCG to confer trained immunity in a non-specific manner by broadly stimulating a host immunity resulting in a generalized survival benefit in neonates and the elderly, while potentially offering benefits for the control of new and emerging infectious diseases such as COVID-19. Given that BCG will likely continue to be widely used well into the future, it remains of critical importance to better understand the immune responses driven by it and how to leverage these for the design of improved vaccination strategies against tuberculosis.

121. Etanercept/celecoxib on improving MRI inflammation of active ankylosing spondylitis: A multicenter, open-label, randomized clinical trial.

Front Immunol

2022 Aug 26

Tu L, Zhao M, Wang X

122. Plasma exosomal IRAK1 can be a potential biomarker for predicting the treatment response to renin-angiotensin system inhibitors in patients with IgA nephropathy.

Front Immunol

2022 Aug 26

Wu J, Wei X, Li J

123. Characterization of the immune related lncRNAs in bladder cancer to aid immunotherapy.

Front Immunol

2022 Aug 26

Xiao Y, Dong Y, Yu T

124. Characterization of disease flares and impact of mepolizumab in patients with hypereosinophilic syndrome.

Front Immunol

2022 Aug 26

Pane F, Lefevre G, Kwon N

125. Sintilimab combined with apatinib plus capecitabine in the treatment of unresectable hepatocellular carcinoma: A prospective, open-label, single-arm, phase II clinical study.

Front Immunol

2022 Aug 26

Li D, Xu L, Ji J

126. Arabinogalactan enhances Mycobacterium marinum virulence by suppressing host innate immune responses.

Front Immunol

2022 Aug 26

Li YY, Liu HM, Wang D

Arabinogalactan (AG) participates in forming the cell wall core of mycobacteria, a structure known as the mAGP complex. Few studies have reported the virulence of inartificial AG or its interaction with the host immune system. Using clustered regularly interspaced short palindromic repeats interference gene editing technology, conditional Mycobacterium marinum mutants were constructed with a low expression of embA or glfT2 (EmbA_KD or GlfT2_KD), which are separately involved in the biosynthesis of AG arabinose and galactose domains. High-performance gel permeation chromatography and high-performance liquid chromatography assays confirmed that the EmbA_KD strain showed a remarkable decrease in AG content with fragmentary arabinose chains, and the GlfT2_KD strain displayed less reduction in content with cut-down galactose chains. Based on transmission and scanning electron microscopy observations, the cell walls of the two mutants were found to be dramatically thickened, and the boundaries of different layers were more distinct. Phenotypes including the over-secretion of extracellular substances and enhanced spreading motility with a concomitant decreased resistance to ethambutol appeared in the EmbA_KD strain. The EmbA_KD and GlfT2_KD strains displayed limited intracellular proliferation after infecting murine J774A.1 macrophages. The disease progression infected with the EmbA_KD or GlfT2_KD strain significantly slowed down in zebrafish/murine tail infection models as well. Through transcriptome profiling, macrophages infected by EmbA_KD/GlfT2_KD strains showed enhanced oxidative metabolism. The cell survival measured using the CCK8 assay of macrophages exposed to the EmbA_KD strain was upregulated and consistent with the pathway enrichment analysis of differentially expressed genes in terms of cell cycle/apoptosis. The overexpression of C/EBPβ and the increasing secretion of proinflammatory cytokines were validated in the macrophages infected by the EmbA_KD mutant. In conclusion, the AG of Mycobacterium appears to restrain the host innate immune responses to enhance intracellular proliferation by interfering with oxidative metabolism and causing macrophage death. The arabinose chains of AG influence the Mycobacterium virulence and pathogenicity to a greater extent.

127. Sintilimab induced ICIAM in the treatment of advanced HCC: A case report and analysis of research progress.

Front Immunol

2022 Aug 26

Ji H, Wen Z, Liu B

128. Precise somatic genome editing for treatment of inborn errors of immunity.

Front Immunol

2022 Aug 26

Meng Q, Sun H, Liu J.

129. Systemic consequences of abnormal cholesterol handling: Interdependent pathways of inflammation and dyslipidemia.

Front Immunol

2022 Aug 26

O'Hagan R, Berg AR, Hong CG

130. Lactate: A regulator of immune microenvironment and a clinical prognosis indicator in colorectal cancer.

Front Immunol

2022 Aug 26

Zhu D, Jiang Y, Cao H

131. Construction of an easily detectable transgenic Synechococcus elongatus PCC 7942 against White Spot Syndrome Virus using vp28 and mOrange Gene and its metabolism in shrimp.

Front Immunol

2022 Aug 26

Peng W, Bao Q, Jia R

White spot syndrome is an epidemic disease caused by the highly contagious and lethal white spot syndrome virus (WSSV), resulting in huge economic losses to the global aquaculture industry. VP28 is the main structural protein in the capsule of WSSV and is important in the early stage of infection. Under an excitation wavelength of 548 nm, the mOrange fluorescent protein releases a 562 nm emission wavelength, which is different from the autofluorescence of cyanobacteria. Therefore, using this characteristic combined with the receptor system of Synechococcus elongatus PCC 7942, we constructed transgenic S. elongatus to express the recombinant protein VP28-mOrange. In addition, PCR and western blotting were used to confirm the stable expression of the target gene in cyanobacteria. Using mOrange tracer features, we explored the recombinant protein VP28-mOrange in the metabolic cycle of young Litopenaeus Vannamei after feeding. After the young shrimp had stopped consuming transgenic cyanobacteria, the 24 to 33 h fluorescence signal in the intestine was very weak, and almost disappeared after 36 h. We explored the protective effect of transgenic vp28-mOrange S. elongatus within 48 h of being ingested by L. vannamei and set WSSV challenges at 2, 12, 24, and 48 h post-immunization. However, the survival rate of L. vannamei decreased as the time of the WSSV challenge increased. The survival rate on the seventh day was 81%, 52%, 45.5%, and 33.3% for shrimps challenged for 2, 12, 24, and 48 h, respectively. Enzyme activity can also support this conjecture, the enzyme activity indexes of the experimental groups were significantly reduced compared to positive and wild-type controls. Therefore, this immune agent functioned as a preventive agent. Compared with the traditional method, this method was easy to detect and can visualize the digestion of transgenic cyanobacteria in the Litopenaeus vannamei intestine.

132. Transcriptome profiles of latently- and reactivated HIV-1 infected primary CD4(+) T cells: A pooled data-analysis.

Front Immunol

2022 Aug 26

Inderbitzin A, Loosli T, Opitz L

The main obstacle to cure HIV-1 is the latent reservoir. Antiretroviral therapy effectively controls viral replication, however, it does not eradicate the latent reservoir. Latent CD4+ T cells are extremely rare in HIV-1 infected patients, making primary CD4+ T cell models of HIV-1 latency key to understanding latency and thus finding a cure. In recent years several primary CD4+ T cell models of HIV-1 latency were developed to study the underlying mechanism of establishing, maintaining and reversing HIV-1 latency. In the search of biomarkers, primary CD4+ T cell models of HIV-1 latency were used for bulk and single-cell transcriptomics. A wealth of information was generated from transcriptome analyses of different primary CD4+ T cell models of HIV-1 latency using latently- and reactivated HIV-1 infected primary CD4+ T cells. Here, we performed a pooled data-analysis comparing the transcriptome profiles of latently- and reactivated HIV-1 infected cells of 5 in vitro primary CD4+ T cell models of HIV-1 latency and 2 ex vivo studies of reactivated HIV-1 infected primary CD4+ T cells from HIV-1 infected individuals. Identifying genes that are differentially expressed between latently- and reactivated HIV-1 infected primary CD4+ T cells could be a more successful strategy to better understand and characterize HIV-1 latency and reactivation. We observed that natural ligands and coreceptors were predominantly downregulated in latently HIV-1 infected primary CD4+ T cells, whereas genes associated with apoptosis, cell cycle and HLA class II were upregulated in reactivated HIV-1 infected primary CD4+ T cells. In addition, we observed 5 differentially expressed genes that co-occurred in latently- and reactivated HIV-1 infected primary CD4+ T cells, one of which, MSRB2, was found to be differentially expressed between latently- and reactivated HIV-1 infected cells. Investigation of primary CD4+ T cell models of HIV-1 latency that mimic the in vivo state remains essential for the study of HIV-1 latency and thus providing the opportunity to compare the transcriptome profile of latently- and reactivated HIV-1 infected cells to gain insights into differentially expressed genes, which might contribute to HIV-1 latency.

133. Immune responses in COVID-19 and tuberculosis coinfection: A scoping review.

Front Immunol

2022 Aug 26

Flores-Lovon K, Ortiz-Saavedra B, Cueva-Chicaña LA

134. Targeting the Cbl-b-Notch1 axis as a novel immunotherapeutic strategy to boost CD8+ T-cell responses.

Front Immunol

2022 Aug 26

Monticone G, Huang Z, Csibi F

135. Lipid nanoparticle-based mRNA vaccines in cancers: Current advances and future prospects.

Front Immunol

2022 Aug 26

Huang T, Peng L, Han Y

136. The association between peritraumatic distress, perceived stress, depression in pregnancy, and NR3C1 DNA methylation among Chinese pregnant women who experienced COVID-19 lockdown.

Front Immunol

2022 Aug 25

Wei L, Ying X, Zhai M

137. Anti-CD40 predominates over anti-CTLA-4 to provide enhanced antitumor response of DC-CIK cells in renal cell carcinoma.

Front Immunol

2022 Aug 25

Zhang Y, Wu X, Sharma A

138. Identification and validation of an anoikis-associated gene signature to predict clinical character, stemness, IDH mutation, and immune filtration in glioblastoma.

Front Immunol

2022 Aug 25

Sun Z, Zhao Y, Wei Y

BACKGROUND: Glioblastoma (GBM) is the most prominent and aggressive primary brain tumor in adults. Anoikis is a specific form of programmed cell death that plays a key role in tumor invasion and metastasis. The presence of anti-anoikis factors is associated with tumor aggressiveness and drug resistance. METHODS: The non-negative matrix factorization algorithm was used for effective dimension reduction for integrated datasets. Differences in the tumor microenvironment (TME), stemness indices, and clinical characteristics between the two clusters were analyzed. Difference analysis, weighted gene coexpression network analysis (WGCNA), univariate Cox regression, and least absolute shrinkage and selection operator regression were leveraged to screen prognosis-related genes and construct a risk score model. Immunohistochemistry was performed to evaluate the expression of representative genes in clinical specimens. The relationship between the risk score and the TME, stemness, clinical traits, and immunotherapy response was assessed in GBM and pancancer. RESULTS: Two definite clusters were identified on the basis of anoikis-related gene expression. Patients with GBM assigned to C1 were characterized by shortened overall survival, higher suppressive immune infiltration levels, and lower stemness indices. We further constructed a risk scoring model to quantify the regulatory patterns of anoikis-related genes. The higher risk score group was characterized by a poor prognosis, the infiltration of suppressive immune cells and a differentiated phenotype, whereas the lower risk score group exhibited the opposite effects. In addition, patients in the lower risk score group exhibited a higher frequency of isocitrate dehydrogenase (IDH) mutations and a more sensitive response to immunotherapy. Drug sensitivity analysis was performed, revealing that the higher risk group may benefit more from drugs targeting the PI3K/mTOR signaling pathway. CONCLUSION: We revealed potential relationships between anoikis-related genes and clinical features, TME, stemness, IDH mutation, and immunotherapy and elucidated their therapeutic value.

139. Long noncoding RNA profiling reveals that LncRNA BTN3A2 inhibits the host inflammatory response to Eimeria tenella infection in chickens.

Front Immunol

2022 Aug 25

Yu H, Mi C, Wang Q

140. Host and bacterial factors linking periodontitis and rheumatoid arthritis.

Front Immunol

2022 Aug 25

Krutyhołowa A, Strzelec K, Dziedzic A

141. PHACTR1, a coronary artery disease risk gene, mediates endothelial dysfunction.

Front Immunol

2022 Aug 25

Ma X, Su M, He Q

Genome-wide association studies (GWAS) have recently identified phosphatase and actin regulator-1 (PHACTR1) as a critical risk gene associated with polyvascular diseases. However, it remains largely unclear how PHACTR1 is involved in endothelial dysfunction. Here, by mining published datasets of human stable and vulnerable/ruptured plaque tissues, we observed upregulated expression of PHACTR1 in vulnerable/ruptured plaques. Congruent with these data, we demonstrated increased Phactr1 gene expression in aortic endothelium from ApoE-/- mice fed a western type diet compared with that in normal C57BL/6J mice. Relevantly, PHACTR1 gene expression was upregulated by pro-inflammatory and pro-atherogenic stimuli, including TNF-α, IL-1β and oxidized LDL (oxLDL). By employing next-generation RNA sequencing, we demonstrate that PHACTR1 overexpression disrupts pathways associated with endothelial homeostasis. Cell biological studies unravel that PHACTR1 mediates endothelial inflammation and monocyte adhesion by activating NF-κB dependent intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) expression. In addition, overexpression of PHACTR1 also reduces the generation of nitric oxide (NO) by inhibiting Akt/eNOS activation. In-house compound screening of vasoprotective drugs identifies several drugs, including lipid-lowering statins, decreases PHACTR1 gene expression. However, PHACTR1 gene expression was not affected by another lipid-lowering drug-fenofibrate. We also performed a proteomic study to reveal PHACTR1 interacting proteins and validated that PHACTR1 can interact with heat shock protein A8 (HSPA8) which was reported to be associated with coronary artery disease and eNOS degradation. Further studies are warranted to confirm the precise mechanism of PHACTR1 in driving endothelial dysfunction. In conclusion, by using systems biology approach and molecular validation, we disclose the deleterious effects of PHACTR1 on endothelial function by inducing endothelial inflammation and reducing NO production, highlighting the potential to prevent endothelial dysfunction and atherosclerosis by targeting PHACTR1 expression. The precise role of endothelial cell PHACTR1 in polyvascular diseases remains to be validated in diseased conditions.

142. An immunotherapy response prediction model derived from proliferative CD4(+) T cells and antigen-presenting monocytes in ccRCC.

Front Immunol

2022 Aug 25

Zheng K, Gao L, Hao J

143. Cuproptosis-related gene index: A predictor for pancreatic cancer prognosis, immunotherapy efficacy, and chemosensitivity.

Front Immunol

2022 Aug 25

Huang X, Zhou S, Tóth J

AIM: The term "Cuproptosis" was coined to describe a novel type of cell death triggered by intracellular copper buildup that is fundamentally distinct from other recognized types such as autophagy, ferroptosis, and pyroptosis in recent days. As the underlying mechanism was newly identified, its potential connection to pancreatic adenocarcinoma (PAAD) is still an open issue. METHODS: A set of machine learning algorithms was used to develop a Cuproptosis-related gene index (CRGI). Its immunological characteristics were studied by exploring its implications on the expression of the immunological checkpoints, prospective immunotherapy responses, etc. Moreover, the sensitivity to chemotherapeutic drugs was predicted. Unsupervised consensus clustering was performed to more precisely identify different CRGI-based molecular subtypes and investigate the immunotherapy and chemotherapy efficacy. The expression of DLAT, LIPT1 and LIAS were also investigated, through real-time quantitative polymerase chain reaction (RT-qPCR), western blot, and immunofluorescence staining (IFS). RESULTS: A novel CRGI was identified and validated. Additionally, correlation analysis revealed major changes in tumor immunology across the high- and low-CRGI groups. Through an in-depth study of each medication, it was determined that the predictive chemotherapeutic efficacy of 32 regularly used anticancer drugs differed between high- and low-CRGI groups. The results of the molecular subtyping provided more support for such theories. Expressional assays performed at transcriptomic and proteomic levels suggested that the aforementioned Cuproptosis-related genes might serve as reliable diagnostic biomarkers in PAAD. SIGNIFICANCE: This is, to the best of our knowledge, the first study to examine prognostic prediction in PAAD from the standpoint of Cuproptosis. These findings may benefit future immunotherapy and chemotherapeutic therapies.

144. The gamble between oncolytic virus therapy and IFN.

Front Immunol

2022 Aug 25

Li Q, Tan F, Wang Y

145. Regulated necrosis in COVID-19: A double-edged sword.

Front Immunol

2022 Aug 25

Sun C, Han Y, Zhang R

146. Comprehensive analysis of pyroptotic gene prognostic signatures associated with tumor immune microenvironment and genomic mutation in breast cancer.

Front Immunol

2022 Aug 25

Zhang H, Yu X, Yang J

BACKGROUND: Breast cancer is becoming a tumor with the highest morbidity rate, and inflammation-induced cell death namely pyroptosis reportedly plays dual roles in cancers. However, the specific mechanism between pyroptosis and the clinical prognosis of breast cancer patients is indistinct. Hence, novel pyroptosis-related biomarkers and their contributing factors deserve further exploration to predict the prognosis in breast cancer. METHODS: Pearson's correlation analysis, and univariate and multivariate Cox regression analysis were utilized to obtain six optimal pyroptosis-related gene prognostic signatures (Pyro-GPS). The risk score of each breast cancer patient was calculated. Next, a Pyro-GPS risk model was constructed and verified in TCGA cohort (n=1,089) and GSE20711 cohort (n=88). Then analyses of immune microenvironment, genomic variation, functional enrichment, drug response and clinicopathologic feature stratification associated with the risk score of Pyro-GPS were performed. Subsequently, a nomogram based on the risk score and several significant clinicopathologic features was established. Ultimately, we further investigated the role of CCL5 in the biological behavior of MDA-MB-231 cell line. RESULTS: The low-risk breast cancer patients have better survival outcomes than the high-risk patients. The low-risk patients also show higher immune cell infiltration levels and immune-oncology target expression levels. There is no significant difference in genetic variation between the two risk groups, but the frequency of gene mutations varies. Functional enrichment analysis shows that the low-risk patients are prominently correlated with immune-related pathways, whereas the high-risk patients are enriched in cell cycle, ubiquitination, mismatch repair, homologous recombination and biosynthesis-related pathways. Pyro-GPS is positively correlated with the IC50 of anti-tumor drugs. Furthermore, comprehensive analyses based on risk score and clinicopathological features were performed to predict the prognosis of breast cancer patients. Additionally, in vitro experiments confirmed that breast cancer cells with high expression of CCL5 had weaker proliferation, invasion and metastasis abilities as well as stronger apoptosis and cell cycle arrest abilities. CONCLUSIONS: The risk score of Pyro-GPS can serve as a promising hallmark to predict the prognosis of BRCA patients. Risk score evaluation may assist to acquire relevant information of tumor immune microenvironment, genomic mutation status, functional pathways and drug sensitivity, and thus provide more effective personalized strategies.

147. Latent autoimmune diabetes in adults in China.

Front Immunol

2022 Aug 25

Qiu J, Xiao Z, Zhang Z

148. Blockade of Mbd2 by siRNA-loaded liposomes protects mice against OVA-induced allergic airway inflammation via repressing M2 macrophage production.

Front Immunol

2022 Aug 25

Wu GR, Zhou M, Wang Y

149. Suppression of FOXP3 expression by the AP-1 family transcription factor BATF3 requires partnering with IRF4.

Front Immunol

2022 Aug 25

Arnold PR, Wen M, Zhang L

150. The antimicrobial peptides secreted by the chromaffin cells of the adrenal medulla link the neuroendocrine and immune systems: From basic to clinical studies.

Front Immunol

2022 Aug 25

Scavello F, Kharouf N, Lavalle P

151. Role of the hedgehog signaling pathway in rheumatic diseases: An overview.

Front Immunol

2022 Aug 25

Su Y, Xing H, Kang J

152. Pulmonary infection and baseline mRS scores predict poor prognosis in anti-GABA(B)R encephalitis.

Front Immunol

2022 Aug 25

Ding J, Xu D, Lv J

PURPOSE: Anti-gamma-aminobutyric-acid type B receptor (anti-GABABR) encephalitis is a rare autoimmune condition caused by the presence of GABABR antibodies in the limbic system. However, its clinical features and prognostic factors are poorly understood. In this study, we aimed to explore factors that affect the response to first-line treatment in patients with anti-GABABR encephalitis. METHODS: Thirty-four patients with an initial diagnosis of anti-GABABR encephalitis were retrospectively enrolled from December 2015 to June 2021. Clinical features and experimental data recorded within 24 h of admission were extracted from the patients' medical records. The modified Rankin Scale (mRS) was utilized to assess disease severity at admission and functional recovery after immunotherapy. Independent prognostic factors were determined by ordinal logistic regression analysis. RESULTS: Of the 34 anti-GABABR encephalitis patients, 12 (35%) presented with cancer; all of these patients had lung cancer. According to multivariate regression analysis, the cancer group exhibited a decrease in the peripheral blood absolute lymphocyte count (ALC) (odds ratio [OR]: 0.063, 95% confidence interval [CI]: 0.006-0.639, P=0.019) and hyponatremia (OR: 9.268, 95% CI: 1.054-81.502, 0.045). In addition, the neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR) and platelet/lymphocyte ratio (PLR) did not significantly differ according to mRS scores in patients receiving first-line treatment. No patients with mild or moderate mRS scores (0-2) at admission developed symptoms after treatment; in contrast, only 11 patients with a severe mRS scores (≥3, 11/18) experienced symptom alleviation. Ordinal regression analysis indicated that worse prognosis was associated with pulmonary infection (OR=9.885, 95% CI: 1.106-88.323, P=0.040) and baseline mRS scores (OR= 24.047, 95% CI: 3.294-175.739, P=0.002) in the adjusted model. CONCLUSION: Our findings demonstrate that pulmonary infection and baseline mRS scores are independent risk factors for poor prognosis in patients with anti-GABABR encephalitis after first-line treatment. ALC and hyponatremia are potential biomarkers for anti-GABABR encephalitis cases accompanied by lung cancer.

153. CD4(+)CD8(+) T follicular helper cells regulate humoral immunity in chronic inflammatory lesions.

Front Immunol

2022 Aug 25

Murayama K, Ikegami I, Kamekura R

154. Serum cytokine levels are associated with tumor progression during FOLFIRINOX chemotherapy and overall survival in pancreatic cancer patients.

Front Immunol

2022 Aug 25

van der Sijde F, Dik WA, Mustafa DAM

155. Liver sinusoidal endothelial cell expressed vascular cell adhesion molecule 1 promotes liver fibrosis.

Front Immunol

2022 Aug 25

Guo Q, Furuta K, Islam S

BACKGROUND: During liver injury, liver sinusoidal endothelial cells (LSECs) dysfunction and capillarization promote liver fibrosis. We have previously reported that the LSEC vascular cell adhesion molecule 1 (VCAM1) plays a key role in liver inflammation in nonalcoholic steatohepatitis (NASH) and we now aim to uncover its role in LSEC capillarization and liver fibrosis. METHODS: Wild-type C57BL/6J mice were fed either chow or high fat, fructose and cholesterol diet to induce NASH and treated with either anti-VCAM1 neutralizing antibody or control isotype antibody. Inducible endothelial cell-specific Vcam1 deleted mice (Vcam1Δend ) and control mice (Vcam1fl/fl ) were fed choline-deficient high-fat diet (CD-HFD) to induce NASH or injected with carbon tetrachloride to induce liver fibrosis. LSECs isolated from Vcam1fl/fl or Vcam1Δend and hepatic stellate cells (HSCs) isolated from wild-type mice were cocultured in a 3-D system or a μ-Slide 2 well co-culture system. RESULTS: Immunostaining for Lyve1 (marker of differentiated LSECs) was reduced in Vcam1fl/fl mice and restored in Vcam1Δend mice in both NASH and liver fibrosis models. Co-immunostaining showed increased α-smooth muscle actin in the livers of Vcam1fl/fl mice in areas lacking Lyve1. Furthermore, scanning electron microscopy showed reduced LSEC fenestrae in the Vcam1fl/fl mice but not Vcam1Δend mice in both injury models, suggesting that VCAM1 promotes LSEC capillarization during liver injury. HSCs profibrogenic markers were reduced when cocultured with LSECs from CD-HFD fed Vcam1Δend mice compared to Vcam1fl/fl mice. Furthermore, recombinant VCAM1 activated the Yes-associated protein 1 pathway and induced a fibrogenic phenotype in HSCs in vitro, supporting the profibrogenic role of LSEC VCAM1. CONCLUSION: VCAM1 is not just a scaffold for leukocyte adhesion during liver injury, but also a modulator of LSEC capillarization and liver fibrosis.

156. The effects of nutrition bio-shield superfood powder on immune system function: A clinical trial study among patients with COVID-19.

Front Immunol

2022 Aug 25

Azizi Jalilian F, Keshavarz G, Khazaei S

The present study aimed to evaluate the effects of Nutrition Bio-shield Superfood (NBS) powder on the immune system function and clinical manifestations in patients with COVID-19. We compare the effects of NBS powder on the immune system function and clinical manifestations among two different groups: 1) intervention group receiving standard treatment scheduled according to treatment guidelines plus NBS powder, and 2) control group receiving only the same standard treatment. The serum levels of IL-2, IL-6, IL-17, IFNγ, and TNFα were determined after four weeks of treatment by specific ELISA kits according to the manufacturer's instructions. Finally, the level of immune system stimulation and inflammatory markers were compared at baseline and after intervention in both groups. Data were analyzed using SPSS (version 22). A p-value of ≤ 0.05 was set as significant. A total of 47 patients with COVID-19 (24 patients in the intervention group and 23 patients in the control group) were included in this study. Results showed that the differences in the mean decrease of IL-2, IL-6, and TNF-α in the intervention group in comparison to the control group were 0.93, 10.28, and 8.11 pg/ml, respectively (P<0.001). On the other hand, there was no difference in IL-17, IFNγ, monocytes, eosinophil, and other inflammatory indices between the intervention and control groups. Although NBS powder was able to significantly decrease the levels of some proinflammatory cytokines in patients with COVID-19, however, it is noteworthy that the course of the disease was to large part unaffected by NBS power and there was a reduction independent of treatment. The present study indicates that NBS powder could provide a beneficial anti-inflammatory effect in patients with COVID-19. Hence, NBS in treating patients with COVID-19 shows promise as an adjuvant to the current standard antiviral treatment of such patients. CLINICAL TRIAL REGISTRATION: https://www.irct.ir, identifier IRCT20200426047206N1.

157. Fibrosis in fat: From other diseases to Crohn's disease.

Front Immunol

2022 Aug 25

Xiong S, Tan J, Wang Y

158. IL-22 regulates endometrial regeneration by enhancing tight junctions and orchestrating extracellular matrix.

Front Immunol

2022 Aug 25

Ganieva U, Schneiderman S, Bu P

The uterine endometrium uniquely regenerates after menses, postpartum, or after breaks in the uterine layer integrity throughout women's lives. Direct cell-cell contacts ensured by tight and adherens junctions play an important role in endometrial integrity. Any changes in these junctions can alter the endometrial permeability of the uterus and have an impact on the regeneration of uterine layers. Interleukin 22 (IL-22) is a cytokine that is recognized for its role in epithelial regeneration. Moreover, it is crucial in controlling the inflammatory response in mucosal tissues. Here, we studied the role of IL-22 in endometrial recovery after inflammation-triggered abortion. Fecundity of mice was studied in consecutive matings of the same animals after lipopolysaccharide (LPS) (10 µg per mouse)-triggered abortion. The fecundity rate after the second mating was substantially different between IL-22 knockout (IL-22-/-) (9.1%) and wild-type (WT) (71.4%) mice (p < 0.05), while there was no difference between the groups in the initial mating, suggesting that IL-22 deficiency might be associated with secondary infertility. A considerable difference was observed between IL-22-/- and WT mice in the uterine clearance following LPS-triggered abortion. Gross examination of the uteri of IL-22-/- mice revealed non-viable fetuses retained inside the horns (delayed clearance). In contrast, all WT mice had completed abortion with total clearance after LPS exposure. We also discovered that IL-22 deficiency is associated with a decreased expression of tight junctions (claudin-2 and claudin-10) and cell surface pathogen protectors (mucin-1). Moreover, IL-22 has a role in the remodeling of the uterine tissue in the inflammatory environment by regulating epithelial-mesenchymal transition markers called E- and N-cadherin. Therefore, IL-22 contributes to the proper regeneration of endometrial layers after inflammation-triggered abortion. Thus, it might have a practical significance to be utilized as a treatment option postpartum (enhanced regeneration function) and in secondary infertility caused by inflammation (enhanced barrier/protector function).

159. Identify metabolism-related genes IDO1, ALDH2, NCOA2, SLC7A5, SLC3A2, LDHB, and HPRT1 as potential prognostic markers and correlate with immune infiltrates in head and neck squamous cell carcinoma.

Front Immunol

2022 Aug 25

Li C, Chen S, Jia W

160. Case report: A case of acute mastitis associated with reactive cutaneous capillary endothelial proliferation after camrelizumab treatment: A new immune-related adverse event.

Front Immunol

2022 Aug 25

Wu PS, Xiong D, Feng YB

161. Schlafen family is a prognostic biomarker and corresponds with immune infiltration in gastric cancer.

Front Immunol

2022 Aug 25

Xu J, Chen S, Liang J

The Schlafen (SLFN) gene family plays an important role in immune cell differentiation and immune regulation. Previous studies have found that the increased SLFN5 expression in patients with intestinal metaplasia correlates with gastric cancer (GC) progression. However, no investigation has been conducted on the SLFN family in GC. Therefore, we systematically explore the expression and prognostic value of SLFN family members in patients with GC, elucidating their possible biological function and its correlation with tumor immune cells infiltration. TCGA database results indicated that the SLFN5, SLFN11, SLFN12, SLFN12L, and SLFN13 expression was significantly higher in GC. The UALCAN and KM plotter databases indicated that enhanced the SLFN family expression was associated with lymph node metastasis, tumor stage, and tumor grade and predicted an adverse prognosis. cBioportal database revealed that the SLFN family had a high frequency of genetic alterations in GC (about 12%), including mutations and amplification. The GeneMANIA and STRING databases identified 20 interacting genes and 16 interacting proteins that act as potential targets of the SLFN family. SLFN5, SLFN11, SLFN12, SLFN12L, and SLFN14 may be implicated in the immunological response, according to Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Additionally, Timer and TISIDB databases indicate that SLFN5, SLFN11, SLFN12, SLFN12L, and SLFN14 are involved in the immune response. Furthermore, Timer, TCGA, and TISIDB databases suggested that the SLFN5, SLFN11, SLFN12, SLFN12L, and SLFN14 expression in GC is highly linked with immune cell infiltration levels, immune checkpoint, and the many immune cell marker sets expression. We isolated three samples of peripheral blood mononuclear cell (PBMC) and activated T cells; the results showed the expression of SLFN family members decreased significantly when T cell active. In conclusion, the SLFN family of proteins may act as a prognostic indicator of GC and is associated with immune cell infiltration and immune checkpoint expression in GC. Additionally, it may be involved in tumor immune evasion by regulating T cell activation.

162. Gonadal bacterial community composition is associated with sex-specific differences in swamp eels (Monopterus albus).

Front Immunol

2022 Aug 24

Meng K, Lin X, Liu H

163. Molecular characterization and functional analysis of DIGIRR from golden pompano (Trachinotus ovatus).

Front Immunol

2022 Aug 24

Xie Y, Gao S, Cao Y

164. Facing the Omicron variant-how well do vaccines protect against mild and severe COVID-19? Third interim analysis of a living systematic review.

Front Immunol

2022 Aug 24

Külper-Schiek W, Piechotta V, Pilic A

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is currently the dominant variant globally. This third interim analysis of a living systematic review summarizes evidence on the effectiveness of the coronavirus disease 2019 (COVID-19) vaccine (vaccine effectiveness, VE) and duration of protection against Omicron. METHODS: We systematically searched literature on COVID-19 for controlled studies, evaluating the effectiveness of COVID-19 vaccines approved in the European Union up to 14/01/2022, complemented by hand searches of websites and metasearch engines up to 11/02/2022. We considered the following comparisons: full primary immunization vs. no vaccination, booster immunization vs. no vaccination, and booster vs. full primary immunization. VE against any confirmed SARS-CoV-2 infection, symptomatic, and severe COVID-19 (i.e., COVID-19-related hospitalization, ICU admission, or death) was indicated, providing estimate ranges. Meta-analysis was not performed due to high study heterogeneity. The risk of bias was assessed with ROBINS-I, and the certainty of the evidence was evaluated using GRADE. RESULTS: We identified 26 studies, including 430 to 2.2 million participants, which evaluated VE estimates against infections with the SARS-CoV-2 Omicron variant. VE against any confirmed SARS-CoV-2 infection ranged between 0-62% after full primary immunization and between 34-66% after a booster dose compared to no vaccination. VE range for booster vs. full primary immunization was 34-54.6%. After full primary immunization VE against symptomatic COVID-19 ranged between 6-76%. After booster immunization VE ranged between 3-84% compared to no vaccination and between 56-69% compared to full primary immunization. VE against severe COVID-19 ranged between 3-84% after full primary immunization and between 12-100% after booster immunization compared to no vaccination, and 100% (95% CI 71.4-100) compared to full primary immunization (data from only one study). VE was characterized by a moderate to strong decline within 3-6 months for SARS-CoV-2 infections and symptomatic COVID-19. Against severe COVID-19, protection remained robust for at least up to 6 months. Waning immunity was more profound after primary than booster immunization. The risk of bias was moderate to critical across studies and outcomes. GRADE certainty was very low for all outcomes. CONCLUSIONS: Under the Omicron variant, the effectiveness of EU-licensed COVID-19 vaccines in preventing any SARS-CoV-2 infection is low and only short-lasting after full primary immunization, but can be improved by booster vaccination. VE against severe COVID-19 remains high and is long-lasting, especially after receiving the booster vaccination.

165. Immunological balance between Treg and Th17 lymphocytes as a key element of type 1 diabetes progression in children.

Front Immunol

2022 Aug 24

Starosz A, Jamiołkowska-Sztabkowska M, Głowińska-Olszewska B

Front Immunol

2022 Aug 24

Hornigold K, Chu JY, Chetwynd SA

Host defense against bacterial and fungal infections diminishes with age. In humans, impaired neutrophil responses are thought to contribute to this decline. However, it remains unclear whether neutrophil responses are also impaired in old mice. Here, we investigated neutrophil function in old mice, focusing on responses primed by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria like E. coli, which signals through toll-like receptor (TLR) 4. We show that old mice have a reduced capacity to clear pathogenic E. coli during septic peritonitis. Neutrophil recruitment was elevated during LPS-induced but not aseptic peritonitis. Neutrophils from old mice showed reduced killing of E. coli. Their reactive oxygen species (ROS) production was impaired upon priming with LPS but not with GM-CSF/TNFα. Phagocytosis and degranulation were reduced in a partially LPS-dependent manner, whereas impairment of NET release in response to S. aureus was independent of LPS. Unexpectedly, chemotaxis was normal, as were Rac1 and Rac2 GTPase activities. LPS-primed activation of Erk and p38 Mapk was defective. PIP3 production was reduced upon priming with LPS but not with GM-CSF/TNFα, whereas PIP2 levels were constitutively low. The expression of 5% of neutrophil proteins was dysregulated in old age. Granule proteins, particularly cathepsins and serpins, as well as TLR-pathway proteins and membrane receptors were upregulated, whereas chromatin and RNA regulators were downregulated. The upregulation of CD180 and downregulation of MyD88 likely contribute to the impaired LPS signaling. In summary, all major neutrophil responses except chemotaxis decline with age in mice, particularly upon LPS priming. This LPS/TLR4 pathway dependence resolves previous controversy regarding effects of age on murine neutrophils and confirms that mice are an appropriate model for the decline in human neutrophil function.

167. Lung cancer in never smokers: Tumor immunology and challenges for immunotherapy.

Front Immunol

2022 Aug 24

de Alencar VTL, Figueiredo AB, Corassa M

168. C5a elevation in convalescents from severe COVID-19 is not associated with early complement activation markers C3bBbP or C4d.

Front Immunol

2022 Aug 24

Kowalska D, Kuźniewska A, Senent Y

169. The deficiency in Th2-like Tfh cells affects the maturation and quality of HIV-specific B cell response in viremic infection.

Front Immunol

2022 Aug 24

Noto A, Suffiotti M, Joo V

170. Multimerization of Ebola GPΔmucin on protein nanoparticle vaccines has minimal effect on elicitation of neutralizing antibodies.

Front Immunol

2022 Aug 24

Powell AE, Xu D, Roth GA

171. Inactivated tick-borne encephalitis vaccine elicits several overlapping waves of T cell response.

Front Immunol

2022 Aug 24

Sycheva AL, Komech EA, Pogorelyy MV

172. Global scientific trends on the immunomodulation of mesenchymal stem cells in the 21st century: A bibliometric and visualized analysis.

Front Immunol

2022 Aug 24

Wang Z, Sun Y, Shen R

173. Immunologic phenotype of patients with long-COVID syndrome of 1-year duration.

Front Immunol

2022 Aug 24

García-Abellán J, Fernández M, Padilla S

BACKGROUND: The pathophysiology of long-COVID remains unknown, and information is particularly limited for symptoms of very long duration. We aimed to assess the serological, T-cell immune responses and ANA titers of patients with long-COVID-19 syndrome of 1-year duration. METHODS: Prospective, longitudinal study of hospitalized COVID-19 patients followed-up for 12 months. Sequential blood samples and COVID-19 symptom questionnaires (CSQ) were obtained, and humoral and cellular immune responses, antinuclear antibodies (ANA) and inflammation biomarkers were analyzed. RESULTS: Of 154 patients discharged from hospital, 72 non-vaccinated with available CSQ in all visits were included. Of them, 14 (19.4%) reported persistent symptoms both at 6-months and 12-months, mainly asthenia (15.3%), myalgia (13.9%), and difficulty concentrating/memory loss (13.9%). Symptomatic patients were more frequently women, smokers, showed higher WHO severity score, and a trend to higher ICU admission. In the adjusted analysis, long-COVID syndrome was associated with lower frequency of detectable neutralizing antibodies (adjusted hazard ratio [aHR] 0.98; 95% confidence interval [CI], 0.97-0.99) and lower SARS-CoV-2-S1/S2 titers (aHR [95%CI] 0.14 [0.03-0.65]). T-cell immune response measured with a SARS-CoV-2-interferon-γ release assay was not different between groups. There was a higher frequency of positive ANA titers (≥160) in symptomatic patients (57.1% vs 29.3%, p=0.04), that was attenuated after adjustment aHR [95% CI] 3.37 [0.84-13.57], p=0.087. Levels of C-reactive protein and D-dimer were higher during follow-up in symptomatic patients, but with no differences at 12 months. CONCLUSION: Patients with 1-year duration long-COVID-19 syndrome exhibit a distinct immunologic phenotype that includes a poorer SARS-CoV-2 antibody response, low-degree chronic inflammation that tends to mitigate, and autoimmunity.

174. Robust pyroptosis risk score guides the treatment options and predicts the prognosis of bladder carcinoma.

Front Immunol

2022 Aug 24

Deng D, Liu F, Liu Z

BACKGROUND: Bladder carcinoma (BLCA) is a heterogeneous disease that makes it difficult to achieve proper individual treatment and predict prognosis. This study aimed to develop a risk score from a new perspective of pyroptosis and guide accurate treatment and prognosis prediction for BLCA. METHODS: The TCGA-BLCA cohort data were downloaded from The Cancer Genome Atlas database. Two external validation cohorts were collected from the Gene Expression Omnibus. Another independent validation cohort (the Xiangya cohort) was recruited from our hospital. The least absolute shrinkage and selector operation (LASSO) algorithm and Cox regression models were used to establish the pyroptosis risk score. Thereafter, we correlated the pyroptosis risk score with prognosis, tumor microenvironment (TME) immune hallmarks, and multiple treatments, including anticancer immunotherapy, chemotherapy, radiotherapy, and targeted therapy. RESULTS: The pyroptosis risk score was an independent prognostic predictor of BLCA. We found that the activities of multiple steps of the anticancer immune response cycle, such as the release of cancer cell antigens, CD8 T cell recruitment, and NK cell recruitment, were significantly higher in the high-risk score group than in the low-risk score group. In addition, the infiltration levels of the corresponding tumor-infiltrating immune cells (TIICs), such as CD8 T cells and NK cells, were positively correlated with the pyroptosis risk score. Thus, BLCA with a high-risk score may be associated with inflamed phenotypes. Simultaneously, the expression of multiple immune checkpoints (such as PD-L1, CTLA-4, and PD-1) and enrichment scores of gene signatures positively correlated with immunotherapy response were positively correlated with the pyroptosis risk score. Therefore, patients with a high pyroptosis risk score may be more sensitive to immunotherapy. In addition, patients with high pyroptosis risk scores may be more sensitive to chemotherapeutic drugs, such as cisplatin, docetaxel, and paclitaxel. In addition, the pyroptosis risk score accurately predicted the molecular subtypes of BLCA, which were cross-validated in several independent systems. CONCLUSIONS: This study developed and validated a robust pyroptosis risk score that can predict the clinical outcomes and TME immune phenotypes of BLCA. In summary, the pyroptosis risk score helps drive precision therapy in patients with BLCA.

175. Peripheral enthesitis assessed by whole-body MRI in axial spondyloarthritis: Distribution and diagnostic value.

Front Immunol

2022 Aug 23

Guo Z, Li B, Zhang Y

OBJECTIVE: To determine the distribution and diagnostic value of peripheral enthesitis detected by whole-body MRI (WBMRI) in axial spondyloarthritis (axSpA) diagnosis, and to determine the value of the peripheral enthesitis score in axSpA assessment. METHODS: Sixty axSpA patients [mean age of 33.2 (24.8-40.6) years] and 50 controls with chronic low back pain (LBP) [mean age of 34.7 (28.3-41.1) years] were enrolled. The gold standard was physician's comprehensive diagnosis based on current classification criteria and physical examination. All subjects underwent WBMRI, and 47 peripheral entheses were assessed for each patient with scores of 0-188. RESULTS: WBMRI identified 155 enthesitis sites in 78.3% (n = 47) patients with axSpA. Meanwhile, 23 enthesitis sites were identified in 32% (n = 16) controls. The pelvis had the maximum number of enthesitis sites (52, 33.5%) in axSpA patients. Pelvic and anterior chest wall enthesitis had the highest sensitivity (51.67%) and specificity (100%) in axSpA diagnosis, respectively. There were different manifestations of enthesitis subtypes between axSpA patients and the control group. Osteitis was more present than soft-tissue inflammation in axSpA patients. The AUC for the number of enthesitis sites was 0.819 (95% CI 0.739-0.899), and that for the enthesitis score was 0.833 (95% CI 0.755-0.910), indicating statistically significant differences (P = 0.025). Based on the Youden index and clinical need, three enthesitis sites (sensitivity of 53.33, specificity of 98, and Youden index of 0.51) and enthesitis score (sensitivity of 58.33, specificity of 98, and Youden index of 0.56) may have the greatest value for axSpA diagnosis. CONCLUSION: The distribution of peripheral enthesitis can be adequately assessed by whole-body MRI, which could help diagnose axial spondyloarthritis. The enthesitis score may provide a more accurate assessment and diagnostic tool in axSpA compared with enthesitis site counting.

176. A score of DNA damage repair pathway with the predictive ability for chemotherapy and immunotherapy is strongly associated with immune signaling pathway in pan-cancer.

Front Immunol

2022 Aug 23

Ding K, He Y, Wei J

177. Immune tolerance induced by hematopoietic stem cell infusion after HLA identical sibling kidney transplantation.

Front Immunol

2022 Aug 23

Huang H, Shen Q, Zhou J

178. Blockade of TMPRSS2-mediated priming of SARS-CoV-2 by lactoferricin.

Front Immunol

2022 Aug 23

Ohradanova-Repic A, Skrabana R, Gebetsberger L

179. The impact of pulmonary tuberculosis on immunological and metabolic features of diabetic patients.

Front Immunol

2022 Aug 23

Chen H, Su L, Bao J

180. Immune effector cell associated neurotoxicity syndrome in chimeric antigen receptor-T cell therapy.

Front Immunol

2022 Aug 23

Sterner RC, Sterner RM.

181. Research progress on the pathogenesis of Graves' ophthalmopathy: Based on immunity, noncoding RNA and exosomes.

Front Immunol

2022 Aug 23

Zheng J, Duan H, You S

182. FLT3LG and IFITM3P6 consolidate T cell activity in the bone marrow microenvironment and are prognostic factors in acute myelocytic leukemia.

Front Immunol

2022 Aug 23

Chen H, Wu M, Xia H

183. Mechanisms of extracellular vesicle-mediated immune evasion in melanoma.

Front Immunol

2022 Aug 23

Dieterich LC.

184. Combination strategies to optimize the efficacy of chimeric antigen receptor T cell therapy in haematological malignancies.

Front Immunol

2022 Aug 23

Xiao X, Wang Y, Zou Z

185. Anti-factor H antibody and its role in atypical hemolytic uremic syndrome.

Front Immunol

2022 Aug 23

Raina R, Mangat G, Hong G

186. Exploration of PDCoV-induced apoptosis through mitochondrial dynamics imbalance and the antagonistic effect of SeNPs.

Front Immunol

2022 Aug 23

Ren Z, Yu Y, Zhang X

187. Akt isoforms in the immune system.

Front Immunol

2022 Aug 23

Guerau-de-Arellano M, Piedra-Quintero ZL, Tsichlis PN.

188. Potential role of HTLV-1 Tax-specific cytotoxic t lymphocytes expressing a unique t-cell receptor to promote inflammation of the central nervous system in myelopathy associated with HTLV-1.

Front Immunol

2022 Aug 23

Tanaka Y, Sato T, Yagishita N

Human T-lymphotropic virus 1 (HTLV-1) infection causes two serious diseases: adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). Immunological studies have revealed that HTLV-1 Tax-specific CD8+ cytotoxic T-cells (Tax-CTLs) in asymptomatic carriers (ACs) and ATL patients play an important role in the elimination of HTLV-1-infected host cells, whereas Tax-CTLs in HAM patients trigger an excessive immune response against HTLV-1-infected host cells infiltrating the central nervous system (CNS), leading to local inflammation. Our previous evaluation of HTLV-1 Tax301-309 (SFHSLHLLF)-specific Tax-CTLs (Tax301-309-CTLs) revealed that a unique T-cell receptor (TCR) containing amino acid (AA)-sequence motif PDR, was shared among HLA-A*24:02+ ACs and ATL patients and behaved as an eliminator by strong activity against HTLV-1. However, it remains unclear whether PDR+Tax301-309-CTLs also exist in HLA-A*24:02+ HAM patients and are involved in the pathogenesis of HAM. In the present study, by high-throughput TCR repertoire analysis technology, we revealed TCR repertoires of Tax301-309-CTLs in peripheral blood (PB) of HLA-A*24:02+ HAM patients were skewed, and a unique TCR-motif PDR was conserved in HAM patients (10 of 11 cases). The remaining case dominantly expressed (-DR, P-R, and PD-), which differed by one AA from PDR. Overall, TCRs with unique AA-sequence motifs PDR, or (-DR, P-R, and PD-) accounted for a total of 0.3-98.1% of Tax301-309-CTLs repertoires of HLA-A*24:02+ HAM patients. Moreover, TCR repertoire analysis of T-cells in the cerebrospinal fluid (CSF) from four HAM patients demonstrated the possibility that PDR+Tax301-309-CTLs and (-DR, P-R, and PD-)+Tax301-309-CTLs efficiently migrated and accumulated in the CSF of HAM patients fostering increased inflammation, although we observed no clear significant correlation between the frequencies of them in PB and the levels of CSF neopterin, a known disease activity biomarker of HAM. Furthermore, to better understand the potential function of PDR+Tax301-309-CTLs, we performed immune profiling by single-cell RNA-sequencing of Tax301-309-CTLs, and the result showed that PDR+Tax301-309-CTLs up-regulated the gene expression of natural killer cell marker KLRB1 (CD161), which may be associated with T-cell activation and highly cytotoxic potential of memory T-cells. These findings indicated that unique and shared PDR+Tax301-309-CTLs have a potential role in promoting local inflammation within the CNS of HAM patients.

189. Neuromuscular junction dysfunctions due to immune checkpoint inhibitors therapy: An analysis of FAERS data in the past 15 years.

Front Immunol

2022 Aug 22

Zhang P, Lao D, Chen H

190. Interferon gamma as an immune modulating adjunct therapy for invasive mucormycosis after severe burn - A case report.

Front Immunol

2022 Aug 22

Tawfik DM, Dereux C, Tremblay JA

191. Innate immune responses to three doses of the BNT162b2 mRNA SARS-CoV-2 vaccine.

Front Immunol

2022 Aug 22

Saresella M, Piancone F, Marventano I

192. Cellular heterogeneity in disease severity and clinical outcome: Granular understanding of immune response is key.

Front Immunol

2022 Aug 22

Khare K, Pandey R.

193. Core immune cell infiltration signatures identify molecular subtypes and promote precise checkpoint immunotherapy in cutaneous melanoma.

Front Immunol

2022 Aug 22

Zhu Z, Li G, Li Z

194. Strategies to induce natural killer cell tolerance in xenotransplantation.

Front Immunol

2022 Aug 22

Lopez KJ, Cross-Najafi AA, Farag K

195. Novel insight on marker genes and pathogenic peripheral neutrophil subtypes in acute pancreatitis.

Front Immunol

2022 Aug 22

Zhang D, Wang M, Zhang Y

196. Identification of ISCA1 as novel immunological and prognostic biomarker for bladder cancer.

Front Immunol

2022 Aug 22

Zhou R, Peng N, Li W.

BACKGROUND: Iron-sulfur cluster assembly 1 (ISCA1) has a significant effect on respiratory complexes and energy metabolism. Although there is some evidence that ISCA1 gene expression impacts energy metabolism and consequently has a role in tumorigenesis and cancer metastasis in different types of malignancies, no systematic pan-cancer study of the ISCA1 has been conducted. As a result, we sought to investigate ISCA1's predictive value in 33 cancer types as well as its possible immunological function. METHODS: We included the pan-cancer expression profile dataset and clinical data from the public database. Firstly, the single-sample Gene Set Enrichment Analysis (ssGSEa) approach was employed for analyzing the immune link in pan-cancer, while the limma package was utilized for analyzing the differential expression in cancer species. Subsequently, ciberport, MCP-counter, TIMER2, quanTIseq, and xCELL were employed for analyzing bladder cancer (BLCA)'s immune infiltration. Least absolute shrinkage and selection operator (Lasso) were employed for choosing the best gene to develop the immune risk scoring model. RESULTS: ISCA1 gene expression was positively related to four immune signatures (chemokine, immunostimulator, MHC, and receptor) in BLCA. Samples of BLCA were sorted into two groups by the best cut-off of ISCA1 expression degree. The group with a high level of ISCA1 expression had a higher risk, suggesting that the ISCA1 gene was a risk factor in BLCA, and its high expression resulted in a poorer prognosis. Additionally, it was noted that ISCA1 was positively linked with these immune checkpoints. Moreover, there was a considerable positive link between ISCA1 and different immune properties in subgroups with different immune checkpoint inhibiting responses. Finally, an immune risk scoring model was made and it showed a better score in comparison to that of TIDE. CONCLUSION: ISCA1 can be a prognostic marker for a variety of cancers, particularly BLCA. Its high level of expression has a deleterious impact on the prognosis of BLCA patients. This strongly shows that ISCA1 is a significant prognostic factor for BLCA and that it could be used as a new prognostic detection target and treatment approach.

197. Role of Pannexin-1-P2X7R signaling on cell death and pro-inflammatory mediator expression induced by Clostridioides difficile toxins in enteric glia.

Front Immunol

2022 Aug 22

Loureiro AV, Moura-Neto LI, Martins CS

198. Identification of senescence-related subtypes, establishment of a prognosis model, and characterization of a tumor microenvironment infiltration in breast cancer.

Front Immunol

2022 Aug 22

Zhou Y, Xiao L, Long G

199. Peripheral cytokine levels as novel predictors of survival in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.

Front Immunol

2022 Aug 22

Mao XC, Yang CC, Yang YF

200. Nanomaterials: A powerful tool for tumor immunotherapy.

Front Immunol

2022 Aug 22

Chen Z, Yue Z, Wang R

201. The development and function of CD11c(+) atypical B cells - insights from single cell analysis.

Front Immunol

2022 Aug 22

Gao X, Cockburn IA.

202. Multiple myeloma metabolism - a treasure trove of therapeutic targets?

Front Immunol

2022 Aug 22

Roman-Trufero M, Auner HW, Edwards CM.

203. Trimethylamine-N-oxide (TMAO) mediates the crosstalk between the gut microbiota and hepatic vascular niche to alleviate liver fibrosis in nonalcoholic steatohepatitis.

Front Immunol

2022 Aug 22

Zhou D, Zhang J, Xiao C

204. Editorial: Epigenetics of the immune component of inflammation.

Front Immunol

2022 Aug 22

Liu YJ, Wang H, Zhong HJ

205. Chronic recurrent multifocal osteomyelitis. A narrative and pictorial review.

Front Immunol

2022 Aug 22

Sergi CM, Miller E, Demellawy DE

206. Shifting gears: Id3 enables recruitment of E proteins to new targets during T cell development and differentiation.

Front Immunol

2022 Aug 2

Anderson MK.

Shifting levels of E proteins and Id factors are pivotal in T cell commitment and differentiation, both in the thymus and in the periphery. Id2 and Id3 are two different factors that prevent E proteins from binding to their target gene cis-regulatory sequences and inducing gene expression. Although they use the same mechanism to suppress E protein activity, Id2 and Id3 play very different roles in T cell development and CD4 T cell differentiation. Id2 imposes an irreversible choice in early T cell precursors between innate and adaptive lineages, which can be thought of as a railway switch that directs T cells down one path or another. By contrast, Id3 acts in a transient fashion downstream of extracellular signals such as T cell receptor (TCR) signaling. TCR-dependent Id3 upregulation results in the dislodging of E proteins from their target sites while chromatin remodeling occurs. After the cessation of Id3 expression, E proteins can reassemble in the context of a new genomic landscape and molecular context that allows induction of different E protein target genes. To describe this mode of action, we have developed the "Clutch" model of differentiation. In this model, Id3 upregulation in response to TCR signaling acts as a clutch that stops E protein activity ("clutch in") long enough to allow shifting of the genomic landscape into a different "gear", resulting in accessibility to different E protein target genes once Id3 decreases ("clutch out") and E proteins can form new complexes on the DNA. While TCR signal strength and cytokine signaling play a role in both peripheral and thymic lineage decisions, the remodeling of chromatin and E protein target genes appears to be more heavily influenced by the cytokine milieu in the periphery, whereas the outcome of Id3 activity during T cell development in the thymus appears to depend more on the TCR signal strength. Thus, while the Clutch model applies to both CD4 T cell differentiation and T cell developmental transitions within the thymus, changes in chromatin accessibility are modulated by biased inputs in these different environments. New emerging technologies should enable a better understanding of the molecular events that happen during these transitions, and how they fit into the gene regulatory networks that drive T cell development and differentiation.

207. Myocardial involvement is not rare in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis/clinically amyopathic dermatomyositis: a retrospective study.

Front Immunol

2022 Aug 2

Zhou S, Lai J, Wu C

OBJECTIVES: Studies concerning myocardial involvement (MI) in patients with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis/clinically amyopathic dermatomyositis (anti-MDA5 Ab+ DM/CADM) are scarce. We aimed to characterize MI in our anti-MDA5 Ab+ DM/CADM cohort and to investigate its association with prognosis. METHODS: In this single-center retrospective study, anti-MDA5 Ab+ hospitalized DM/CADM patients who underwent transthoracic echocardiography (TTE) were enrolled. Myocardial involvement was diagnosed according to abnormal cardiac structure and function detected by TEE. Clinical features and cardiac examination findings of patients with MI were analyzed. Clinical features, laboratory findings, complications, and treatments were compared between MI and non-MI, deceased, and survival patients. Logistic regression analysis was used to explore the independent risk factors for the occurrence of MI and prognostic factors for these patients. RESULTS: Seventy-six hospitalized patients with anti-MDA5 Ab+ DM/CADM were enrolled. Twelve (15.8%) patients were diagnosed with MI. Of the 12 patients, three underwent cardiac magnetic resonance imaging (CMR) and late gadolinium enhancement (LGE) were noted for them. TEE revealed that eight (66.7%) patients had left atrial and/or ventricular enlargement, three (25.0%) had cardiac hypertrophy, six (50.0%) had diffuse ventricular wall dyskinesia, and seven (58.3%) had diastolic dysfunction. Six (50.0%) patients with MI developed heart failure (HF) during treatment. Of the 12 patients, one patient died of HF caused by myocarditis, three died of infection, and four died of exacerbation of rapidly progressive interstitial lung disease (RP-ILD). Logistic regression analysis revealed that dysphagia (OR 3.923, 95% CI 1.085, 14.181), NT-proBNP >600 pg/ml (OR 18.333, 95% CI 1.508, 222.875), and increased peripheral white blood cells (OR 1.201, 95% CI 1.003, 1.438) were risk factors for the occurrence of MI, but plasma albumin (OR 0.892, 95% CI 0.796, 0.999) was a protective factor. Both MI (OR 5.984, 95% CI 1.174, 30.496) and RP-ILD (OR 11.875, 95% CI 2.796, 50.411) were independent risk factors for the mortality of these anti-MDA5 Ab+ DM/CADM patients. CONCLUSION: Myocardial involvement is not rare and is an independent poor prognostic factor of anti-MDA5 Ab+ DM/CADM patients. Cardiac abnormality screening is necessary for them.

208. Pro-inflammatory cytokines and leukocyte integrins associated with chronic neuropathic pain in traumatic and inflammatory neuropathies: Initial observations and hypotheses.

Front Immunol

2022 Aug 2

Dong C, Ubogu EE.

Leukocyte infiltration and persistence within peripheral nerves have been implicated in chronic nociception pathogenesis in murine peripheral neuropathy models. Endoneurial cytokine and chemokine expression contribute to leukocyte infiltration and maintenance of a pro-inflammatory state that delays peripheral nerve recovery and promotes chronic pain behaviors in these mice. However, there has been a failure to translate murine model data into safe and effective treatments for chronic neuropathic pain in peripheral neuropathy patients, or develop reliable biomarkers that may help diagnose or determine treatment responses in affected patients. Initial work showed that persistent sciatic nerve CD11b+ CD45+ leukocyte infiltration was associated with disease severity in three mouse models of inflammatory and traumatic peripheral neuropathies, implying a direct contributing role in disease pathogenesis. In support of this, CD11b+ leukocytes were also seen in the sural nerve biopsies of chronic neuropathic pain patients with three different peripheral neuropathies. Systemic CD11b antagonism using a validated function-neutralizing monoclonal antibody effectively treated chronic nociception following unilateral sciatic nerve crush injury (a representative traumatic neuropathy model associated with axonal degeneration and increased blood-nerve barrier permeability) and does not cause drug addiction behaviors in adult mice. These data suggest that CD11b could be an effective molecular target for chronic neuropathic pain treatment in inflammatory and traumatic peripheral neuropathies. Despite known murine peripheral neuropathy model limitations, our initial work suggests that early expression of pro-inflammatory cytokines, such as tissue inhibitor of metalloproteinases-1 may predict subsequent chronic nociception development following unilateral sciatic nerve crush injury. Studies aligning animal model investigation with observational data from well-characterized human peripheral neuropathies, including transcriptomics and proteomics, as well as animal model studies using a human clinical trial design should foster the identification of clinically relevant biomarkers and effective targeted treatments with limited addiction potential for chronic neuropathic pain in peripheral neuropathy patients.

209. Inflammatory stimuli alter bone marrow composition and compromise bone health in the malnourished host.

Front Immunol

2022 Aug 2

Osorio EY, Gugala Z, Patterson GT

Inflammation has a role in the pathogenesis of childhood malnutrition. We investigated the effect of malnutrition and inflammatory challenge on bone marrow composition and bone health. We studied an established murine model of moderate acute malnutrition at baseline and after acute inflammatory challenge with bacterial lipopolysaccharide (LPS), a surrogate of Gram-negative bacterial sepsis, or Leishmania donovani, the cause of visceral leishmaniasis. Both of these infections cause significant morbidity and mortality in malnourished children. Of the 2 stimuli, LPS caused more pronounced bone marrow changes that were amplified in malnourished mice. LPS challenge led to increased inflammatory cytokine expression (Il1b, Il6, and Tnf), inflammasome activation, and inflammatory monocyte accumulation in the bone marrow of malnourished mice. Depletion of inflammatory monocytes in Csfr1-LysMcre-DT malnourished mice significantly reduced the inflammasome activation and IL1-ß production after LPS challenge. The inflammatory challenge also led to increased expansion of mesenchymal stem cells (MSCs), bone marrow adiposity, and expression of genes (Pparg, Adipoq, and Srbp1) associated with adipogenesis in malnourished mice. This suggests that inflammatory challenge promotes differentiation of BM MSCs toward the adipocyte lineage rather than toward bone-forming osteoblasts in the malnourished host. Concurrent with this reduced osteoblastic potential there was an increase in bone-resorbing osteoclasts, enhanced osteoclast activity, upregulation of inflammatory genes, and IL-1B involved in osteoclast differentiation and activation. The resulting weakened bone formation and increased bone resorption would contribute to the bone fragility associated with malnutrition. Lastly, we evaluated the effect of replacing lipid rich in omega-6 fatty acids (corn oil) with lipid-rich in omega-3 fatty acids (fish oil) in the nutrient-deficient diet. LPS-challenged malnourished mice that received dietary fish oil showed decreased expression of inflammatory cytokines and Rankl and reduced osteoclast differentiation and activation in the bone marrow. This work demonstrates that the negative effect of inflammatory challenge on bone marrow is amplified in the malnourished host. Increasing dietary intake of omega-3 fatty acids may be a means to reduce inflammation and improve bone health in malnourished children.

210. Level of interleukin-35 in patients with idiopathic membranous nephropathy and its predictive value for remission time.

Front Immunol

2022 Aug 2

Zhang N, Dai H, Dong X

OBJECTIVE: As a member of interleukin-12 family, interleukin-35 (IL-35) plays an important regulatory role in immune response. The relationship between IL-35 and idiopathic membranous nephropathy (IMN) is still unclear, and the purpose of this study is to clarify the relationship between IL-35 and disease activity and remission of IMN. METHODS: This study was a single-center, retrospective study in which all patients were diagnosed with IMN by renal biopsy or aPLA2R titer and treated with Mahuang Fuzi and Shenzhuo Decoction (MFSD). A follow-up was conducted with the endpoint of clinical complete or partial remission (CR+PR). Levels of serum IL-35 were measured and its relationship with IMN remission were analyzed. The regulatory T cell (Treg) and inducible IL-35 producing Tregs (iTR35) in peripheral blood of IMN patients were detected by flow cytometry. RESULTS: A total of 76 IMN patients (age 51.95 ± 13.29) were followed-up for 18 (12, 24) months. The level of serum IL-35 in all patients increased after treatment, but the degree of increase in remission group was significantly higher than that in no remission (NR) group (117.6% vs 83.7%, P<0.01). The baseline IL-35 level in remission group was higher than that in NR group (174.87 vs.151.87 pg/ml, P=0.016). Cox regression analysis showed that baseline IL-35 level was a independent risk factor for IMN remission (HR 1.081, 95%CI 1.048-1.116, P<0.001). Patients with baseline IL-35 lower than the lower quartile (≤145.49 pg/ml) had an average remission time twice as long as those with baseline IL-35 higher than the upper quartile (> 203.05 pg/ml) (12mon vs. 24mon, P<0.01). The baseline IL-35 can predict the remission time of IMN patients with either aPLA2R positive (AUC=0.673) or negative (AUC=0.745). Analysis of 18 patients with IMN showed that IL-35 level had a higher correlation with iTR35, but not Treg (r=0.613, P<0.05). CONCLUSIONS: The level of IL-35 in patients with IMN showed an increasing trend with the progress of treatment, and the baseline IL-35 could predict the remission time of IMN patients, including those patients with negative aPLA2R. The level of IL-35 is related to the number of iTR35 cells.

211. CpG content in the Zika virus genome affects infection phenotypes in the adult brain and fetal lymph nodes.

Front Immunol

2022 Aug 2

Udenze D, Trus I, Berube N

Increasing the number of CpG dinucleotides in RNA viral genomes, while preserving the original amino acid composition, leads to impaired infection which does not cause disease. Beneficially, impaired infection evokes antiviral host immune responses providing a cutting-edge vaccine approach. For example, we previously showed that CpG-enriched Zika virus variants cause attenuated infection phenotypes and protect against lethal challenge in mice. While CpG recoding is an emerging and promising vaccine approach, little is known about infection phenotypes caused by recoded viruses in vivo, particularly in non-rodent species. Here, we used well-established mouse and porcine models to study infection phenotypes of the CpG-enriched neurotropic and congenital virus-Zika virus, directly in the target tissues-the brain and placenta. Specifically, we used the uttermost challenge and directly injected mice intracerebrally to compare infection phenotypes caused by wild-type and two CpG-recoded Zika variants and model the scenario where vaccine strains breach the blood-brain barrier. Also, we directly injected porcine fetuses to compare in utero infection phenotypes and model the scenario where recoded vaccine strains breach the placental barrier. While overall infection kinetics were comparable between wild-type and recoded virus variants, we found convergent phenotypical differences characterized by reduced pathology in the mouse brain and reduced replication of CpG-enriched variants in fetal lymph nodes. Next, using next-generation sequencing for the whole virus genome, we compared the stability of de novo introduced CpG dinucleotides during prolonged virus infection in the brain and placenta. Most de novo introduced CpG dinucleotides were preserved in sequences of recoded Zika viruses showing the stability of vaccine variants. Altogether, our study emphasized further directions to fine-tune the CpG recoding vaccine approach for better safety and can inform future immunization strategies.

212. Autoreactive B cells recruited to lungs by silica exposure contribute to local autoantibody production in autoimmune-prone BXSB and B cell receptor transgenic mice.

Front Immunol

2022 Aug 2

Fee L, Kumar A, Tighe RM

Occupational exposure to inhaled crystalline silica dust (cSiO2) is linked to systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and anti-neutrophil cytoplasmic autoantibody vasculitis. Each disease has a characteristic autoantibody profile used in diagnosis and implicated in pathogenesis. A role for cSiO2 in modulating humoral autoimmunity in vivo is supported by findings in mice, where respirable cSiO2 induces ectopic lymphoid structures as well as inflammation in exposed lungs across genetically diverse backgrounds. In lupus-prone mice cSiO2 exposure also leads to early onset autoantibody production and accelerated disease. Elevated autoantibody levels in bronchoalveolar lavage fluid (BALF) and lung transcriptome analysis suggest that the lung is a hub of cSiO2-evoked autoimmune activity. However, mechanisms by which cSiO2 and lung microenvironments interact to promote autoantibody production remain unclear. We previously demonstrated elevated anti-DNA Ig in BALF but not in lung cell cultures from cSiO2-exposed C57BL/6 mice, suggesting that BALF autoantibodies did not arise locally in this non-autoimmune strain. Autoantibodies were also elevated in BALF of cSiO2-exposed lupus-prone BXSB mice. In this report we test the hypothesis that dysregulated autoreactive B cells recruited to cSiO2-exposed lungs in the context of autoimmune predisposition contribute to local autoantibody production. We found that anti-DNA and anti-myeloperoxidase (MPO) Ig were significantly elevated in cultures of TLR ligand-stimulated lung cells from cSiO2-exposed BXSB mice. To further explore the impact of strain genetic susceptibility versus B cell intrinsic dysfunction on cSiO2-recruited B cell fate, we used an anti-basement membrane autoantibody transgenic (autoAb Tg) mouse line termed M7. In M7 mice, autoAb Tg B cells are aberrantly regulated and escape from tolerance on the C57BL/6 background. Exposure to cSiO2 elicited prominent pulmonary B cell and T cell aggregates and autoAb Tg Ig were readily detected in lung cell culture supernatants. Taken together, diverse disease-relevant autoreactive B cells, including cells specific for DNA, MPO, and basement membrane, are recruited to lung ectopic lymphoid aggregates in response to cSiO2 instillation. B cells that escape tolerance can contribute to local autoantibody production. Our demonstration of significantly enhanced autoantibody induction by TLR ligands further suggests that a coordinated environmental co-exposure can magnify autoimmune vulnerability.

213. Critical roles of sepsis-reshaped fecal virota in attenuating sepsis severity.

Front Immunol

2022 Aug 2

Chancharoenthana W, Sutnu N, Visitchanakun P

214. Phosgene-Induced acute lung injury: Approaches for mechanism-based treatment strategies.

Front Immunol

2022 Aug 2

Cao C, Zhang L, Shen J.

215. Signaling networks controlling ID and E protein activity in T cell differentiation and function.

Front Immunol

2022 Aug 2

Hwang SM, Im SH, Rudra D.

216. Tissue specificity drives protective immunity against Staphylococcus aureus infection.

Front Immunol

2022 Aug 2

Beesetty P, Si Y, Li Z

217. Utomilumab in Patients With Immune Checkpoint Inhibitor-Refractory Melanoma and Non-Small-Cell Lung Cancer.

Front Immunol

2022 Aug 2

Hong DS, Gopal AK, Shoushtari AN

218. Sulforaphane diminishes moonlighting of pyruvate kinase M2 and interleukin 1β expression in M1 (LPS) macrophages.

Front Immunol

2022 Aug 2

Bahiraii S, Brenner M, Yan F

219. Editorial: Immune dysfunction in nephrotic syndrome - recent advances and new roads ahead.

Front Immunol

2022 Aug 2

Seitz-Polski B, Audard V, Ghiggeri GM

220. Dynamically upregulated mast cell CPA3 patterns in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.

Front Immunol

2022 Aug 2

Siddhuraj P, Jönsson J, Alyamani M

221. Exploration of the relationship between hippocampus and immune system in schizophrenia based on immune infiltration analysis.

Front Immunol

2022 Aug 2

Du Y, Gao Y, Wu G

Immune dysfunction has been implicated in the pathogenesis of schizophrenia (SZ). Despite previous studies showing a broad link between immune dysregulation and the central nervous system of SZ, the exact relationship has not been completely elucidated. With immune infiltration analysis as an entry point, this study aimed to explore the relationship between schizophrenia and the immune system in more detail from brain regions, immune cells, genes, and pathways. Here, we comprehensively analyzed the hippocampus (HPC), prefrontal cortex (PFC), and striatum (STR) between SZ and control groups. Differentially expressed genes (DEGs) and functional enrichment analysis showed that three brain regions were closely related to the immune system. Compared with PFC and STR, there were 20 immune-related genes (IRGs) and 42 immune pathways in HPC. The results of immune infiltration analysis showed that the differential immune cells in HPC were effector memory T (Tem) cells. The correlation of immune-related DEGs (IDEGs) and immune cells further analysis showed that NPY, BLNK, OXTR, and FGF12, were moderately correlated with Tem cells. Functional pathway analysis indicated that these four genes might affect Tem by regulating the PI3K-AKT pathway and the neuroactive ligand-receptor interaction pathway. The receiver operating characteristic curve (ROC) analysis results indicated that these four genes had a high diagnostic ability (AUC=95.19%). Finally, the disease animal model was successfully replicated, and further validation was conducted using the real-time PCR and the western blot. These results showed that these gene expression changes were consistent with our previous expression profiling. In conclusion, our findings suggested that HPC in SZ may be more closely related to immune disorders and modulate immune function through Tem, PI3K-Akt pathway, and neuroactive ligand-binding receptor interactions. To the best of our knowledge, the Immucell AI tool has been applied for the first time to analyze immune infiltration in SZ, contributing to a better understanding of the role of immune dysfunction in SZ from a new perspective.

222. Exploring the function of stromal cells in cholangiocarcinoma by three-dimensional bioprinting immune microenvironment model.

Front Immunol

2022 Aug 2

Li C, Jin B, Sun H

223. Neutrophil heterogeneity in complement C1q expression associated with sepsis mortality.

Front Immunol

2022 Aug 2

Trzeciak A, Mongre RK, Kim MR

224. Gut microbiota in systemic lupus erythematosus patients and lupus mouse model: a cross species comparative analysis for biomarker discovery.

Front Immunol

2022 Aug 2

Toumi E, Goutorbe B, Plauzolles A

225. Concurrence of leukocyte chemotactic factor 2-associated amyloidosis and autoimmune diseases: A case report.

Front Immunol

2022 Aug 19

Wang S, Yu XJ, Li DY

226. Neutrophil extracellular traps: New players in cancer research.

Front Immunol

2022 Aug 19

Zhao J, Jin J.

227. Centaur antibodies: Engineered chimeric equine-human recombinant antibodies.

Front Immunol

2022 Aug 19

Rosenfeld R, Alcalay R, Zvi A

228. Delineating the role of extracellular vesicles in cancer metastasis: A comprehensive review.

Front Immunol

2022 Aug 19

Majood M, Rawat S, Mohanty S.

229. Innate immunity to malaria: The good, the bad and the unknown.

Front Immunol

2022 Aug 19

Pohl K, Cockburn IA.

230. Drug-induced Fanconi syndrome in patients with kidney allograft transplantation.

Front Immunol

2022 Aug 19

Tang Z, Li T, Dai H

BACKGROUND: Patients after kidney transplantation need to take long-term immunosuppressive and other drugs. Some of these drug side effects are easily confused with the symptoms of Fanconi syndrome, resulting in misdiagnosis and missed diagnosis, and causing serious consequences to patients. Therefore, improving awareness, early diagnosis and treatment of Fanconi syndrome after kidney transplantation is critical. METHODS: This retrospective study analyzed 1728 cases of allogeneic kidney transplant patients admitted to the Second Xiangya Hospital of Central South University from July 2016 to January 2021. Two patients with Fanconi syndrome secondary to drugs, adefovir dipivoxil (ADV) and tacrolimus, were screened. We summarized the diagnostic process, clinical data, and prognosis. RESULTS: The onset of Fanconi syndrome secondary to ADV after renal transplantation was insidious, and the condition developed after long-term medication (>10 years). It mainly manifested as bone pain, osteomalacia, and scoliosis in the late stage and was accompanied by obvious proximal renal tubular damage (severe hypophosphatemia, hypokalemia, hypocalcemia, hypouricemia, glycosuria, protein urine, acidosis, etc.) and renal function damage (increased creatinine and azotemia). The pathological findings included mitochondrial swelling and deformity in renal tubular epithelial cells. The above symptoms and signs were relieved after drug withdrawal, but the scoliosis was difficult to rectify. Fanconi syndrome secondary to tacrolimus has a single manifestation, increased creatinine, which can be easily confused with tacrolimus nephrotoxicity. However, it is often ineffective to reduce the dose of tacrolomus, and proximal renal failure can be found in the later stage of disease development. There was no abnormality in the bone metabolism index and imageological examination findings. The creatinine level decreased rapidly, the proximal renal tubule function returned to normal, and no severe electrolyte imbalance or urinary component loss occurred when the immunosuppression was changed from tacrolimus to cyclosporine A. CONCLUSIONS: For the first time, drug-induced Fanconi syndrome after kidney transplantation was reported. These results confirmed that the long-term use of ADV or tacrolimus after kidney transplantation may have serious consequences, some of which are irreversible. Greater understanding of Fanconi syndrome after kidney transplantation is necessary in order to avoid incorrect and missed diagnosis.

231. Association of longitudinal platelet count trajectory with ICU mortality: A multi-cohort study.

Front Immunol

2022 Aug 19

Chen J, Gao X, Shen S

OBJECTIVE: Platelet (PLT) engages in immune and inflammatory responses, all of which are related to the prognosis of critically ill patients. Although thrombocytopenia at ICU admission contributes to in-hospital mortality, PLT is repeatedly measured during ICU hospitalization and the role of longitudinal PLT trajectory remains unclear. We aimed to identify dynamic PLT trajectory patterns and evaluate their relationships with mortality risk and thrombocytopenia. METHODS: We adopted a three-phase, multi-cohort study strategy. Firstly, longitudinal PLT trajectory patterns within the first four ICU days and their associations with 28-day survival were tested in the eICU Collaborative Research Database (eICU-CRD) and independently validated in the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Secondly, the relationships among PLT trajectory patterns, thrombocytopenia, and 28-day mortality were explored and validated. Finally, a Mortality GRade system for ICU dynamically monitoring patients (Mortality-GRID) was developed to quantify the mortality risk based on longitudinal PLT, which was further validated in the Molecular Epidemiology of Acute Respiratory Distress Syndrome (MEARDS) cohort. RESULTS: A total of 35,332 ICU patients were included from three cohorts. Trajectory analysis clustered patients into ascending (AS), stable (ST), or descending (DS) PLT patterns. DS patients with high baseline PLT decline quickly, resulting in poor prognosis. AS patients have low baseline PLT but recover quickly, favoring a better prognosis. ST patients maintain low PLT, having a moderate prognosis in between (HR ST vs AS = 1.26, 95% CI: 1.14-1.38, P = 6.15 × 10-6; HR DS vs AS = 1.58, 95% CI: 1.40-1.79, P = 1.41 × 10-13). The associations remained significant in patients without thrombocytopenia during the entire ICU hospitalization and were robust in sensitivity analyses and stratification analyses. Further, the trajectory pattern was a warning sign of thrombocytopenia, which mediated 27.2% of the effects of the PLT trajectory on 28-day mortality (HR indirect = 1.11, 95% CI: 1.06-1.17, P = 9.80 × 10-6). Mortality-GRID well predicts mortality risk, which is in high consistency with that directly estimated in MEARDS (r = 0.98, P = 1.30 × 10-23). CONCLUSION: Longitudinal PLT trajectory is a complementary predictor to baseline PLT for patient survival, even in patients without risk of thrombocytopenia. Mortality-GRID could identify patients at high mortality risk.

232. Pooled resequencing of larvae and adults reveals genomic variations associated with Ostreid herpesvirus 1 resistance in the Pacific oyster Crassostrea gigas.

Front Immunol

2022 Aug 19

Yao S, Li L, Guan X

233. Efficacy and safety of biological agents for the treatment of pediatric patients with psoriasis: A bayesian analysis of six high-quality randomized controlled trials.

Front Immunol

2022 Aug 19

Cai XC, Ru Y, Liu L

234. Time-resolved characterization of the innate immune response in the respiratory epithelium of human, porcine, and bovine during influenza virus infection.

Front Immunol

2022 Aug 19

Laloli L, Licheri MF, Probst L

Viral cross-species transmission is recognized to be a major threat to both human and animal health, however detailed information on determinants underlying virus host tropism and susceptibility is missing. Influenza C and D viruses (ICV, IDV) are two respiratory viruses that share up to 50% genetic similarity, and both employ 9-O-acetylated sialic acids to enter a host cell. While ICV infections are mainly restricted to humans, IDV possesses a much broader host tropism and has shown to have a zoonotic potential. This suggests that additional virus-host interactions play an important role in the distinct host spectrum of ICV and IDV. In this study, we aimed to characterize the innate immune response of the respiratory epithelium of biologically relevant host species during influenza virus infection to identify possible determinants involved in viral cross-species transmission. To this end, we performed a detailed characterization of ICV and IDV infection in primary airway epithelial cell (AEC) cultures from human, porcine, and bovine origin. We monitored virus replication kinetics, cellular and host tropism, as well as the host transcriptional response over time at distinct ambient temperatures. We observed that both ICV and IDV predominantly infect ciliated cells, independently from host and temperature. Interestingly, temperature had a profound influence on ICV replication in both porcine and bovine AEC cultures, while IDV replicated efficiently irrespective of temperature and host. Detailed time-resolved transcriptome analysis revealed both species-specific and species uniform host responses and highlighted 34 innate immune-related genes with clear virus-specific and temperature-dependent profiles. These data provide the first comprehensive insights into important common and species-specific virus-host dynamics underlying the distinct host tropism of ICV and IDV, as well as possible determinants involved in viral cross-species transmission.

235. Pooled human bone marrow-derived mesenchymal stromal cells with defined trophic factors cargo promote dermal wound healing in diabetic rats by improved vascularization and dynamic recruitment of M2-like macrophages.

Front Immunol

2022 Aug 19

Willer H, Spohn G, Morgenroth K

Human Mesenchymal Stromal Cells (hMSCs) are a promising source for cell-based therapies. Yet, transition to phase III and IV clinical trials is remarkably slow. To mitigate donor variabilities and to obtain robust and valid clinical data, we aimed first to develop a manufacturing concept balancing large-scale production of pooled hMSCs in a minimal expansion period, and second to test them for key manufacture and efficacy indicators in the clinically highly relevant indication wound healing. Our novel clinical-scale manufacturing concept is comprised of six single donor hMSCs master cell banks that are pooled to a working cell bank from which an extrapolated number of 70,000 clinical doses of 1x106 hMSCs/cm2 wound size can be manufactured within only three passages. The pooled hMSC batches showed high stability of key manufacture indicators such as morphology, immune phenotype, proliferation, scratch wound healing, chemotactic migration and angiogenic support. Repeated topical hMSCs administration significantly accelerated the wound healing in a diabetic rat model by delivering a defined growth factor cargo (specifically BDNF, EGF, G-CSF, HGF, IL-1α, IL-6, LIF, osteopontin, VEGF-A, FGF-2, TGF-β, PGE-2 and IDO after priming) at the specific stages of wound repair, namely inflammation, proliferation and remodeling. Specifically, the hMSCs mediated epidermal and dermal maturation and collagen formation, improved vascularization, and promoted cell infiltration. Kinetic analyses revealed transient presence of hMSCs until day (d)4, and the dynamic recruitment of macrophages infiltrating from the wound edges (d3) and basis (d9), eventually progressing to the apical wound on d11. In the wounds, the hMSCs mediated M2-like macrophage polarization starting at d4, peaking at d9 and then decreasing to d11. Our study establishes a standardized, scalable and pooled hMSC therapeutic, delivering a defined cargo of trophic factors, which is efficacious in diabetic wound healing by improving vascularization and dynamic recruitment of M2-like macrophages. This decision-making study now enables the validation of pooled hMSCs as treatment for impaired wound healing in large randomized clinical trials.

236. Palmitic acid induces intestinal lipid metabolism disorder, endoplasmic reticulum stress and inflammation by affecting phosphatidylethanolamine content in large yellow croaker Larimichthys crocea.

Front Immunol

2022 Aug 19

Fang W, Liu Y, Chen Q

237. CX3CL1-induced CD16(+) monocytes extravasation in myeloperoxidase-ANCA-associated vasculitis correlates with renal damage.

Front Immunol

2022 Aug 19

Tang J, Liao Z, Luo L

238. Differential proteome response to H5N1 highly pathogenic avian influenza (HPAI) viruses infection in duck.

Front Immunol

2022 Aug 19

Ye Y, Fan H, Li Q

239. Metabolic profiling reveals new serum signatures to discriminate lupus nephritis from systemic lupus erythematosus.

Front Immunol

2022 Aug 19

Zhang Y, Gan L, Tang J

BACKGROUND: Lupus nephritis (LN) occurs in 50% of patients with systemic lupus erythematosus (SLE), causing considerable morbidity and even mortality. Previous studies had shown the potential of metabolic profiling in the diagnosis of SLE or LN. However, few metabonomics studies have attempted to distinguish SLE from LN based on metabolic changes. The current study was designed to find new candidate serum signatures that could differentiate LN from SLE patients using a non-targeted metabonomics method based on ultra high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). METHOD: Metabolic profiling of sera obtained from 21 healthy controls, 52 SLE patients and 43 LN patients. We used SPSS 25.0 for statistical analysis. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and metabolic pathway analysis were used to analyze the metabolic data. RESULTS: Upon comparison of SLE and LN groups, 28 differential metabolites were detected, the majority of which were lipids and amino acids. Glycerolphospholipid metabolism, pentose and glucuronate interconversions and porphyrin and chlorophyll metabolism were obviously enriched in LN patients versus those with SLE. Among the 28 characteristic metabolites, five key serum metabolites including SM d34:2, DG (18:3(9Z,12Z,15Z)/20:5(5Z,8Z,11Z,14Z,17Z)/0:0), nervonic acid, Cer-NS d27:4, and PC (18:3(6Z,9Z,12Z)/18:3(6Z,9Z,12Z) performed higher diagnostic performance in discriminating LN from SLE (all AUC > 0.75). Moreover, combined analysis of neuritic acid, C1q, and CysC (AUC = 0.916) produced the best combined diagnosis. CONCLUSION: This study identified five serum metabolites that are potential indicators for the differential diagnosis of SLE and LN. Glycerolphospholipid metabolism may play an important role in the development of SLE to LN. The metabolites we screened can provide more references for the diagnosis of LN and more support for the pathophysiological study of SLE progressed to LN.

240. An open, observational, three-arm clinical study of 2-3 cycles of treatment as neoadjuvant therapy in operable locally advanced non-small cell lung cancer: An interim analysis.

Front Immunol

2022 Aug 19

Gu L, Wang X, Sun Y

BACKGROUND: An open, observational, three-arm clinical study aimed at investigating the efficacy of different neoadjuvant therapies (neoadjuvant immunotherapy with(out) chemotherapy, neoadjuvant chemotherapy, and neoadjuvant targeted therapy) in operable locally advanced non-small cell lung cancer (NSCLC) was conducted (NCT04197076). We report an interim analysis of 49 of 53 evaluable patients. METHODS: This study was conducted at Shanghai Chest Hospital and included eligible NSCLC patients who were 18 years old and had clinical stage IIB-IIIB disease. All 49 patients had surgical resection within 4-6 weeks after 2-3 cycles of neoadjuvant treatment consisting of immunotherapy (24 patients), chemotherapy (16 patients), and a targeted therapy (9 patients) regimen starting on the first day of each 21-day cycle. Pathologic complete response (pCR) was evaluated as the primary endpoint. Major pathological response (MPR) and tumor regression rate (TRR) were also evaluated. RESULTS: An improved pathologic complete response was achieved in the neoadjuvant immunotherapy arm compared with the neoadjuvant chemotherapy arm and neoadjuvant targeted therapy arm [20.8% (5/24) vs. 6.3% (1/16) vs. 0.0% (0/9); P = 0.089, 95% CI 0.138-0.151]. More importantly, we found that the curative effect of the neoadjuvant immunotherapy arm in pCR+MPR was better than that of the neoadjuvant chemotherapy arm and neoadjuvant targeted therapy arm [45.8% (11/24) vs. 18.8% (3/16) vs. 0.0% (0/9); P = 0.006, 95% confidence interval, 0.008-0.012]. Different neoadjuvant therapies had a statistically significant effect on postoperative pathological tumor downstaging (P = 0.017). CONCLUSIONS: Neoadjuvant immunotherapy was associated with a trend toward better pCR than the neoadjuvant chemotherapy arm and neoadjuvant targeted therapy. Curative effect (pCR + MPR) was significantly better with neoadjuvant immunotherapy (P = 0.006, 95% confidence interval, 0.008-0.012). CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT04197076?recrs=a&cond=NCT04197076&draw=2&rank=1.

241. Effects of ibrutinib on T-cell immunity in patients with chronic lymphocytic leukemia.

Front Immunol

2022 Aug 19

Liu Y, Song Y, Yin Q.

242. Evaluation of safety and immunogenicity of duck-plague virus gC/gE double gene deletion.

Front Immunol

2022 Aug 18

Ruan P, Feng X, Cheng A

243. Whole transcriptome sequencing reveals neutrophils' transcriptional landscape associated with active tuberculosis.

Front Immunol

2022 Aug 18

Geng X, Wu X, Yang Q

244. Neuroimaging and clinicopathological differences between tumefactive demyelinating lesions and sentinel lesions of primary central nervous system lymphoma.

Front Immunol

2022 Aug 18

Sun C, Han J, Lin Y

245. Burkholderia pseudomallei biofilm phenotypes confined but surviving in neutrophil extracellular traps of varying appearance.

Front Immunol

2022 Aug 18

Khamwong M, Phanthanawiboon S, Salao K

Melioidosis is a fatal infectious disease caused by Burkholderia pseudomallei. Complications following treatment are usually due to antibiotic resistance and relapse is mainly caused by B. pseudomallei biofilm. Although the release of neutrophil extracellular traps (NETs) is crucial to capture and eliminate bacterial pathogens, to date response of NETs to B. pseudomallei biofilm is poorly understood. Here we compare the NETs produced by neutrophils in response to B. pseudomallei H777 (a biofilm-producing strain containing the bpsl0618 gene), a biofilm-defect strain lacking this gene (B. pseudomallei M10) and a bpsl0618 biofilm-complemented strain, B. pseudomallei C17, in which function of bpsl0618 was restored. Co-cultivation of these strains with healthy human neutrophils at MOI 10 with or without cytochalasin D demonstrated that H777 significantly resisted neutrophil-mediated killing and non-phagocytotic mechanisms compared to M10 (p < 0.0001). Three distinct morphotypes of NETs were seen: "aggregated", "spiky" and "cloudy". These were induced in different proportions by the different bacterial strains. All types of NETs were shown to confine all B. pseudomallei strains. Strains H777 and C17 could stimulate production of twice as much extracellular DNA (234.62 ng/mL and 205.43 ng/mL, respectively) as did M10 (111.87 ng/mL). Cells of H777 and C17 were better able to survive in the presence of neutrophil killing mechanisms relative to M10 (p < 0.0001) and NET formation (p < 0.0001 and 0.05). These findings suggest that NET stimulation was insufficient to eradicate B. pseudomallei H777 and C17 despite their possession of bpsl0618, a sugar-transferase gene associated with biofilm formation ability. Our findings demonstrate that B. pseudomallei biofilm phenotype may be a key factor in assisting pathogens to escape killing by neutrophils. This work provides a better understanding of how B. pseudomallei biofilm-associated infections induce and survive NET formation, resulting in bacterial persistence and increased severity of disease.

246. Licensing microgels prolong the immunomodulatory phenotype of mesenchymal stromal cells.

Front Immunol

2022 Aug 18

Patrick MD, Annamalai RT.

Mesenchymal stromal cells (MSC) are sensors of inflammation, and they exert immunomodulatory properties through the secretion of cytokines and exosomes and direct cell-cell interactions. MSC are routinely used in clinical trials and effectively resolve inflammatory conditions. Nevertheless, inconsistent clinical outcomes necessitate the need for more robust therapeutic phenotypes. The immunomodulatory properties of MSC can be enhanced and protracted by priming (aka licensing) them with IFNγ and TNFα. Yet these enhanced properties rapidly diminish, and prolonged stimulation could tolerize their response. Hence a balanced approach is needed to enhance the therapeutic potential of the MSC for consistent clinical performance. Here, we investigated the concentration-dependent effects of IFNγ and TNFα and developed gelatin-based microgels to sustain a licensed MSC phenotype. We show that IFNγ treatment is more beneficial than TNFα in promoting an immunomodulatory MSC phenotype. We also show that the microgels possess integrin-binding sites to support adipose tissue-derived MSC (AD-MSC) attachment and a net positive charge to sequester the licensing cytokines electrostatically. Microgels are enzymatically degradable, and the rate is dependent on the enzyme concentration and matrix density. Our studies show that one milligram of microgels by dry mass can sequester up to 641 ± 81 ng of IFNγ. Upon enzymatic degradation, microgels exhibited a sustained release of IFNγ that linearly correlated with their degradation rate. The AD-MSC cultured on the IFNγ sequestered microgels displayed efficient licensing potential comparable to or exceeding the effects of bolus IFNγ treatment. When cultured with proinflammatory M1-like macrophages, the AD-MSC-seeded on licensing microgel showed an enhanced immunomodulatory potential compared to untreated AD-MSC and AD-MSC treated with bolus IFNγ treatment. Specifically, the AD-MSC seeded on licensing microgels significantly upregulated Arg1, Mrc1, and Igf1, and downregulated Tnfα in M1-like macrophages compared to other treatment conditions. These licensing microgels are a potent immunomodulatory approach that shows substantial promise in elevating the efficacy of current MSC therapies and may find utility in treating chronic inflammatory conditions.

247. Mechanism of selenomethionine inhibiting of PDCoV replication in LLC-PK1 cells based on STAT3/miR-125b-5p-1/HK2 signaling.

Front Immunol

2022 Aug 18

Ren Z, Ding T, He H

248. Editorial: Novel roles for tumor-associated neutrophils.

Front Immunol

2022 Aug 18

Mandruzzato S, Läubli H.

249. Dysregulation of neutrophil death in sepsis.

Front Immunol

2022 Aug 18

Zhu CL, Wang Y, Liu Q

250. Serum multi-cytokines screening identifies TRAIL and IL-10 as probable new biomarkers for prostate health index diagnostic utility adjustment in grey zone aggressive prostate cancer detection: A single-center data in China.

Front Immunol

2022 Aug 18

Chen H, Zhou J, Luo J

251. Role of released mitochondrial DNA in acute lung injury.

Front Immunol

2022 Aug 18

Long G, Gong R, Wang Q

252. Senescence of alveolar epithelial cells impacts initiation and chronic phases of murine fibrosing interstitial lung disease.

Front Immunol

2022 Aug 18

Yamada Z, Nishio J, Motomura K

Fibrosing interstitial lung disease (ILD) develops due to the impaired reparative processes following lung tissue damage. Cellular senescence has been reported to contribute to the progression of fibrosis. However, the mechanisms by which these senescent cells initiate and/or drive the progression of lung tissue fibrosis are not yet fully understood. We demonstrated that p21WAF1/CIP1- and p16INK4A-pathway-dependent senescence in type 2 alveolar epithelial cells (AEC2) were both involved in the initiation and progression of lung fibrosis in murine bleomycin (BLM)-induced ILD. p21WAF1/CIP1-senescent AEC2 emerged rapidly, as early as 1 day after the intratracheal instillation of BLM. Their number subsequently increased and persisted until the later fibrosis phase. Very few p16INK4A-senescent AEC2 emerged upon the instillation of BLM, and their increase was slower and milder than that of p21WAF1/CIP1+ AEC2. AEC2 enriched with senescent cells sorted from BLM-ILD lungs expressed senescence-associated secretory phenotype (SASP)-related genes, including Il6, Serpin1, Tnfa, Ccl2, Tgfb, and Pdgfa, at the initiation and chronic phases of fibrosis, exhibiting distinct expression patterns of magnitude that were dependent on the disease phase. Ly6C+ inflammatory monocytes increased in the lungs immediately after the instillation of BLM and interstitial macrophages increased from day 3. The expression of Acta2 and Col1a1 was upregulated as early as day 1, indicating the activation of fibroblasts. We speculated that IL-6, plasminogen activator inhibitor-1 (PAI-1), and TGF-β contributed to the accumulation of senescent cells during the progression of fibrosis in an autocrine and paracrine manner. In addition, CCL2, produced in large amounts by senescent AEC2, may have induced the infiltration of Ly6C+ inflammatory monocytes in the early phase, and TGF-β and PDGFa from senescent AEC2 may contribute to the activation of fibroblasts in the very early phases. Our study indicated that senescent AEC2 plays a role in the pathogenesis of fibrosing ILD throughout the course of the disease and provides insights into its pathogenesis, which may lead to the development of new therapeutic methods targeting senescent cells or SASP molecules.

253. Effects of TolC on the pathogenicity of porcine extraintestinal pathogenic Escherichia coli.

Front Immunol

2022 Aug 18

Hu J, Wang D, Huang X

254. Tas2R signaling enhances mouse neutrophil migration via a ROCK-dependent pathway.

Front Immunol

2022 Aug 18

Kobayashi D, Watarai T, Ozawa M

255. Cross-sectional analysis of the humoral response after SARS-CoV-2 vaccination in Sardinian multiple sclerosis patients, a follow-up study.

Front Immunol

2022 Aug 18

Idda ML, Pitzalis M, Lodde V

256. Progress in preclinical studies of macrophage autophagy in the regulation of ALI/ARDS.

Front Immunol

2022 Aug 18

Liu C, Xiao K, Xie L.

257. Thrombocytopenia in the first trimester predicts adverse pregnancy outcomes in obstetric antiphospholipid syndrome.

Front Immunol

2022 Aug 18

Jin J, Xu X, Hou L

BACKGROUND: Thrombocytopenia is a common manifestation of antiphospholipid syndrome (APS), and is a main concern for bleeding on the standard treatment of low dose aspirin (LDA) and low molecular weight heparin (LMWH) in obstetric APS (OAPS). OBJECTIVE: This study assesses the possible relationship between thrombocytopenia during the first trimester and adverse pregnancy outcomes (APOs) in OAPS patients. METHODS: A case-control study was conducted at Peking University People's Hospital, Beijing, China. The clinical, immunologic, and pregnancy outcomes of the OAPS patients were collected. Univariate and multivariate logistic regression analyses were applied to assess the relationship between APOs and thrombocytopenia in the first trimester. RESULTS: A total of 115 participants were included in the analysis. There were no difference on antepartum and postpartum hemorrhage between the two groups. The gestational age in the thrombocytopenia group was less than that in the control group (34.12 ± 8.44 vs. 37.44 ± 3.81 weeks, p = 0.002). Hypocomplementemia, double aPL positive, and high titers of anti-β2 glycoprotein I were more frequent in APS patients with thrombocytopenia (p < 0.05). Compared to the control group, thrombocytopenia in the first trimester was correlated with SGA (12.12% vs. 31.25%, p = 0.043), premature birth <37 weeks (16.16% vs 43.75%, p = 0.010) and intrauterine fetal death (2.02% vs 12.50%, p = 0.033). Thrombocytopenia in first-trimester independently increased the risk of preterm birth <37 weeks (OR = 5.40, 95% CI: 1.35-21.53, p = 0.02) after adjusting for demographic and laboratory factors. After adding medication adjustments, these factors above become insignificant (p > 0.05). Of note, the number of platelets increased after delivery in 14 thrombocytopenia patients with live fetuses (p = 0.03). CONCLUSION: This study demonstrates that thrombocytopenia in the first trimester increases the risks of preterm birth in women with APS. The effective OAPS treatments may improve pregnancy outcomes and not increase the risk of antepartum and postpartum hemorrhage.

258. Simultaneous C5 and CD14 inhibition limits inflammation and organ dysfunction in pig polytrauma.

Front Immunol

2022 Aug 18

Lupu L, Horst K, Greven J

259. Editorial: Adhesion molecules and autoimmune diseases.

Front Immunol

2022 Aug 18

Fan Z, Sun H.

260. The contribution of the intestinal microbiome to immune recovery after HCT.

Front Immunol

2022 Aug 18

Wolfe AE, Markey KA.

Allogenic hematopoietic stem-cell transplantation (allo-HCT) is a curative-intent immunotherapy for high-risk hematological malignancies and immune deficiencies. Allo-HCT carries a high risk of treatment-related mortality (TRM), largely due to infection or graft-versus-host disease (GVHD). Robust immune recovery is essential for optimal patient outcomes, given the immunologic graft-versus-leukemia effect prevents relapse, and functional innate and adaptive immunity are both needed for the prevention and control of infection. Most simply, we measure immune recovery by enumerating donor lymphocyte subsets in circulation. In functional terms, ideal immune recovery is more difficult to define, and current lab techniques are limited to the measurement of specific vaccine-responses or mitogens ex vivo. Clinically, poor immune function manifests as problematic infection with viral, bacterial and fungal organisms. Furthermore, the ideal recovering immune system is capable of exerting graft-versus-tumor effects to prevent relapse, and does not induce graft-versus-host disease. Large clinical observational studies have linked loss of diversity within the gut microbiome with adverse transplant outcomes including decreased overall survival and increased acute and chronic GVHD. Furthermore, the correlation between intestinal microbial communities and numeric lymphocyte recovery has now been reported using a number of approaches. Large sets of clinically available white blood cell count data, clinical flow cytometry of lymphocyte subsets and bespoke flow cytometry analyses designed to capture microbiota-specific T cells (e.g. Mucosal-associated invariant T cells, subsets of the gd T cells) have all been leveraged in an attempt to understand links between the microbiota and the recovering immune system in HCT patients. Additionally, preclinical studies suggest an immunomodulatory role for bacterial metabolites (including butyrate, secondary bile acids, and indole derivatives from tryptophan metabolism) in transplant outcomes, though further studies are needed to unravel mechanisms relevant to the post-HCT setting. An understanding of mechanistic relationships between the intestinal microbiome and post-transplant outcomes is necessary for reduction of risk associated with transplant, to inform prophylactic procedures, and ensure optimal immune reconstitution without alloreactivity. Here, we summarize the current understanding of the complex relationship between bacterial communities, their individual members, and the metabolites they produce with immune function in both the allo-HCT and steady-state setting.

261. Assessment of disease activity in patients with rheumatoid arthritis using plasma tumour M2-pyruvate kinase test.

Front Immunol

2022 Aug 18

Ahn SS, Kim HM, Park Y.

BACKGROUND: Pyruvate kinase M2 (PKM2) is an enzyme that regulates the final process of glycolysis and exists in tetrameric and dimeric forms. The dimeric form of PKM2, also known as tumour M2-PK, increases when aerobic glycolysis is augmented, a feature observed in rheumatoid arthritis (RA). We investigated whether plasma tumour M2-PK is elevated in patients with RA and whether its levels correlate with disease activity. METHODS: Plasma levels of tumour M2-PK were measured for patients with RA (n=151), those with osteoarthritis (OA) (n=37), and controls (n=37). We evaluated the association between plasma tumour M2-PK and continuous variables using Pearson's correlation analysis, and multivariate logistic regression analysis to determine the association between plasma tumour M2-PK and disease activity status. Knee synovial tissue blocks from patients with RA and OA were subjected to real-time quantitative PCR (qPCR) using two different primers for PKM2 and tumour M2-PK immunohistochemical (IHC) staining. RESULTS: The tumour M2-PK level significantly correlated with the disease activity score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) (r=0.546, p<0.001) and DAS28-C-reactive protein (CRP) (r=0.589, p<0.001). Moreover, repeat testing of tumour M2-PK levels in 20 patients revealed a significant decline in tumour M2-PK levels after reduction in inflammation (p<0.001). Area under the receiver operating characteristic curve (AUROC) analysis demonstrated that upon incorporation of tumour M2-PK, ESR, and CRP, the area under the curve was 0.962 for distinguishing moderate/high from remission/low disease activity. Adjusted logistic regression also revealed that a tumour M2-PK >43.9 U/mL (OR 3.672, p=0.042) independently predicted moderate/high disease activity status. Furthermore, tumour M2-PK levels in patients with RA were significantly higher than in those with OA and controls (all p<0.001). However, no differences were found in PKM2 expression in RA and OA synovial tissues as assessed by qPCR, and IHC analysis revealed negligible tumour M2-PK expression in the synovial tissues. CONCLUSION: Circulating plasma tumour M2-PK levels may be a clinically useful indicator for evaluating disease activity and RA diagnosis.

262. Biodegradable nanoparticles induce cGAS/STING-dependent reprogramming of myeloid cells to promote tumor immunotherapy.

Front Immunol

2022 Aug 18

Podojil JR, Cogswell AC, Chiang MY

263. Genome editing for primary immunodeficiencies: A therapeutic perspective on Wiskott-Aldrich syndrome.

Front Immunol

2022 Aug 18

Naseem A, Steinberg Z, Cavazza A.

264. Immunological signature of patients with thymic epithelial tumors and Good syndrome.

Front Immunol

2022 Aug 18

Malfitano AM, D'Esposito V, De Placido P

265. Comparison of non-criteria antiphospholipid syndrome with definite antiphospholipid syndrome: A systematic review.

Front Immunol

2022 Aug 18

Pires da Rosa G, Ferreira E, Sousa-Pinto B

OBJECTIVES: Patients with laboratory or clinical manifestations suggestive of antiphospholipid syndrome (APS) but not fulfilling the classification criteria constitute a clinical challenge. This study aims to compare non-criteria APS (NC-APS) with definite APS in terms of clinical manifestations, therapies, and outcomes. METHODS: A systematic review of observational studies comparing definite and NC-APS was performed searching four electronic databases. Data on clinical manifestations, therapies and clinical outcomes was extracted. RESULTS: Sixteen studies, assessing a total of 3,798 participants, were included. Seven out of 10 studies found no significant difference in the prevalence of arterial or venous thrombosis between definite and NC-APS, with two studies on seronegative APS also finding no difference in thrombosis recurrence. Seven out of 12 studies found no significant difference in the prevalence of obstetric manifestations between groups, with the remaining exhibiting conflicting results. In 9 studies comparing treatment frequency in obstetric patients, all but one described similar treatment frequency, with the percentage of NC-APS treated during pregnancy ranging from 26% to 100%. In 10 studies comparing pregnancy outcomes of NC-APS versus definite APS, 7 found similar successful pregnancies/live births. Additionally, 5 studies described improvement of live births in both groups with treatment, with three signalling aspirin monotherapy as efficacious as combination therapy in NC-APS. CONCLUSION: This review hints at an absence of marked differences in most evaluated parameters between definite and NC-APS, emphasizing the value of a more active follow-up of these patients. The low-quality available evidence highlights the need for well-defined NC-APS populations in future studies. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero, identifier CRD42020210674.

266. Host-microbiota interactions shaping T-cell response and tolerance in type 1 diabetes.

Front Immunol

2022 Aug 18

Majumdar S, Lin Y, Bettini ML.

267. CAR-T cell development for Cutaneous T cell Lymphoma: current limitations and potential treatment strategies.

Front Immunol

2022 Aug 18

To V, Evtimov VJ, Jenkin G

268. Fucose as a potential therapeutic molecule against the immune-mediated inflammation in IgA nepharopathy: An unrevealed link.

Front Immunol

2022 Aug 17

Qing J, Hu X, Li C

BACKGROUND: IgA nephropathy (IgAN) is an autoimmune disease that affects people of any age and is an important cause of end-stage renal disease. However, the pathogenesis and pathophysiology of IgAN is not clear. This article aimed to explore the immune-mediated inflammation and genetic mechanisms in IgAN. METHODS: The transcriptome sequencing data of IgAN glomeruli in the Gene Expression Omnibus database were downloaded. Single-sample gene set enrichment analysis was used to estimate the immune microenvironment of the merged microarray data and GSE141295. IgAN samples were divided into two clusters by cluster analysis. "limma" and "DEseq2" package in R were used to identify differentially expressed genes (DEGs). The weighted gene co-expression network analysis (WGCNA) was used to identify the co-expression modules related to inflammation in IgAN. R software package "clusterProfiler" was used for enrichment analysis, whereas Short Time-Series Expression Miner (STEM) analysis was used to identify the trend of gene expression. Machine-learn (ML) was performed using the shiny app. Finally, Drug Signatures Database (DSigDB) was used to identify potential molecules for treating IgAN. RESULTS: The infiltration of macrophages in IgAN glomeruli was increased, whereas CD4+ T cells, especially inducedregulatory T cells (iTregs) were decreased. A total of 1,104 common DEGs were identified from the merged data and GSE141295. Brown module was identified to have the highest inflammatory correlation with IgAN using WGCNA, and 15 hub genes were screened from this module. Among these 15 hub genes, 14 increased with the severity of IgAN inflammation based on STEM analysis. Neural network (nnet) is considered as the best model to predict the severity of IgAN. Fucose identified from DSigDB has a potential biological activity to treat IgAN. CONCLUSION: The increase of macrophages and the decrease of iTregs in glomeruli represent the immune-mediated inflammation of IgAN, and fucose may be a potential therapeutic molecule against IgAN because it affects genes involved in the severe inflammation of IgAN.

269. Key molecules associated with thyroid carcinoma prognosis: A study based on transcriptome sequencing and GEO datasets.

Front Immunol

2022 Aug 17

Bai M, Ke S, Yu H

BACKGROUND: Thyroid carcinoma (THCA) has a low mortality rate, but its incidence has been rising over the years. We need to pay attention to its progression and prognosis. In this study, a transcriptome sequencing analysis and bioinformatics methods were used to screen key genes associated with THCA development and analyse their clinical significance and diagnostic value. METHODS: We collected 10 pairs of THCA tissues and noncancerous tissues, these samples were used for transcriptome sequencing to identify disordered genes. The gene expression profiles were obtained from the Gene Expression Omnibus (GEO) database. Comprehensive analysis of thyroid clinicopathological data using The Cancer Genome Atlas (TCGA). R software was used to carry out background correction, normalization and log2 conversion. We used quantitative real-time PCR (qRT-PCR) and Western blot to determine differentially expressed genes (DEGs) expression in samples. We integrated the DEGs expression, clinical features and progression-free interval (PFI). The related functions and immune infiltration degree were established by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and single-sample Gene Set Enrichment Analysis (ssGSEA). The UALCAN database was used to analyse the methylation level. RESULTS: We evaluated DEGs between normal tissue and cancer. Three genes were identified: regulator of G protein signaling 8 (RGS8), diacylglycerol kinase iota (DGKI) and oculocutaneous albinism II (OCA2). The mRNA and protein expression levels of RGS8, DGKI and OCA2 in normal tissues were higher than those in THCA tissues. Better survival outcomes were associated with higher expression of RGS8 (HR=0.38, P=0.001), DGKI (HR=0.52, P=0.022), and OCA2 (HR=0.41, P=0.003). The GO analysis, KEGG analysis and GSEA proved that the coexpressed genes of RGS8, DGKI and OCA2 were related to thyroid hormone production and peripheral downstream signal transduction effects. The expression levels of RGS8, DGKI and OCA2 were linked to the infiltration of immune cells such as DC cells. The DNA methylation level of OCA2 in cancer tissues was higher than that in the normal samples. CONCLUSIONS: RGS8, DGKI and OCA2 might be promising prognostic molecular markers in patients with THCA and reveal the clinical significance of RGS8, DGKI and OCA2 in THCA.

270. The association between antibiotic use and outcomes of HCC patients treated with immune checkpoint inhibitors.

Front Immunol

2022 Aug 17

Zhang L, Chen C, Chai D

271. Differential gene expression profiling reveals potential biomarkers and pharmacological compounds against SARS-CoV-2: Insights from machine learning and bioinformatics approaches.

Front Immunol

2022 Aug 17

Hoque MN, Sarkar MMH, Khan MA

The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has created an urgent global situation. Therefore, it is necessary to identify the differentially expressed genes (DEGs) in COVID-19 patients to understand disease pathogenesis and the genetic factor(s) responsible for inter-individual variability and disease comorbidities. The pandemic continues to spread worldwide, despite intense efforts to develop multiple vaccines and therapeutic options against COVID-19. However, the precise role of SARS-CoV-2 in the pathophysiology of the nasopharyngeal tract (NT) is still unfathomable. This study utilized machine learning approaches to analyze 22 RNA-seq data from COVID-19 patients (n = 8), recovered individuals (n = 7), and healthy individuals (n = 7) to find disease-related differentially expressed genes (DEGs). We compared dysregulated DEGs to detect critical pathways and gene ontology (GO) connected to COVID-19 comorbidities. We found 1960 and 153 DEG signatures in COVID-19 patients and recovered individuals compared to healthy controls. In COVID-19 patients, the DEG-miRNA, and DEG-transcription factors (TFs) interactions network analysis revealed that E2F1, MAX, EGR1, YY1, and SRF were the highly expressed TFs, whereas hsa-miR-19b, hsa-miR-495, hsa-miR-340, hsa-miR-101, and hsa-miR-19a were the overexpressed miRNAs. Three chemical agents (Valproic Acid, Alfatoxin B1, and Cyclosporine) were abundant in COVID-19 patients and recovered individuals. Mental retardation, mental deficit, intellectual disability, muscle hypotonia, micrognathism, and cleft palate were the significant diseases associated with COVID-19 by sharing DEGs. Finally, the detected DEGs mediated by TFs and miRNA expression indicated that SARS-CoV-2 infection might contribute to various comorbidities. Our results provide the common DEGs between COVID-19 patients and recovered humans, which suggests some crucial insights into the complex interplay between COVID-19 progression and the recovery stage, and offer some suggestions on therapeutic target identification in COVID-19 caused by the SARS-CoV-2.

272. A Novel hepatocellular carcinoma specific hypoxic related signature for predicting prognosis and therapeutic responses.

Front Immunol

2022 Aug 17

Cai G, Zhu J, Ning D

273. Ezetimibe ameliorates clinical symptoms in a mouse model of ankylosing spondylitis associated with suppression of Th17 differentiation.

Front Immunol

2022 Aug 17

Moon J, Lee SY, Na HS

Ankylosing spondylitis (AS) is a chronic inflammatory disease that causes spinal inflammation and fusion. Although the cause of AS is unknown, genetic factors (e.g., HLA-B27) and environmental factors (e.g., sex, age, and infection) increase the risk of AS. Current treatments for AS are to improve symptoms and suppress disease progression. There is no way to completely cure it. High blood cholesterol and lipid levels aggravate the symptoms of autoimmune diseases. We applied hyperlipidemia drugs ezetimibe and rosuvastatin to AS mice and to PBMCs from AS patients. Ezetimibe and rosuvastatin was administered for 11 weeks to AS model mice on the SKG background. Then, the tissues and cells of mice were performed using flow cytometry, computed tomography, immunohistochemistry, and immunofluorescence. Also, the normal mouse splenocytes were cultured in Th17 differentiation conditions for in vitro analysis such as flow cytometry, ELISA and RNA sequencing. The 10 AS patients' PBMCs were treated with ezetimibe and rosuvastatin. The patients' PBMC were analyzed by flow cytometry and ELISA for investigation of immune cell type modification. Ezetimibe caused substantial inhibition for AS. The present study showed that ezetimibe inhibits Th17 cell function, thereby slowing the progression of AS. It is well known that statins are more effective in reducing blood lipid concentrations than ezetimibe, however, our results that ezetimibe had a better anti-inflammatory effect than rosuvastatin in AS. This data suggests that ezetimibe has an independent anti-inflammatory effect independent of blood lipid reduction. To investigate whether ezetimibe has its anti-inflammatory effect through which signaling pathway, various in vitro experiments and RNA sequencing have proceeded. Here, this study suggests that ezetimibe can be an effective treatment for AS patients by inhibiting Th17 differentiation-related genes such as IL-23R and IL-1R. Thus, this study suggests that ezetimibe has therapeutic potential for AS through inhibition of Th17 differentiation and the production of pro-inflammatory cytokines.

274. Involvement of Fusobacterium nucleatum in malignancies except for colorectal cancer: A literature review.

Front Immunol

2022 Aug 17

He Z, Tian W, Wei Q

275. Mucosal immunity: The missing link in comprehending SARS-CoV-2 infection and transmission.

Front Immunol

2022 Aug 17

Russell MW, Mestecky J.

276. Improved induced innate immune response after cART initiation in people with HIV.

Front Immunol

2022 Aug 17

Hove-Skovsgaard M, Møller DL, Hald A

INTRODUCTION: Impairment of the innate immune function may contribute to the increased risk of bacterial and viral infections in people with HIV (PWH). In this study we aimed to investigate the induced innate immune responses in PWH prior to and after initiation of combinational antiretroviral therapy (cART). Furthermore, we aimed to investigate if the induced innate immune responses before initiation of cART were associated with CD4+ T-cell recovery one year after initiating cART. MATERIAL AND METHOD: The induced innate immune response was assessed by the TruCulture® whole blood technique in 32 PWH before cART initiation and after 1, 6 and 12 months. To mimic bacterial and viral infections we used a panel of three stimuli (lipopolysaccharide (LPS), resiquimod (R848), and polyinosinic:polycytidylic acid (Poly I:C)) to stimulate the extracellular Toll-like receptor (TLR) 4 and the intracellular TLR7/8 and TLR3, respectively. The following cytokine responses were analyzed by Luminex 200: Tumor Necrosis Factor (TNF)-α, Interleukin (IL)-1b, IL-6, IL-8, IL-10, IL-12p40, IL17A, Interferon (IFN)-α, and IFN-γ. RESULTS: At baseline PWH with nadir CD4+ T-cell count <350 cell/µL had lower levels of LPS-, R848-, and Poly I:C-induced IL-6 and IFN-γ, LPS- and R848-induced TNF-α and IL-12, LPS induced IL-1b, and R848-induced IL-10 than PWH with nadir CD4+ T-cell count >350 cells/µL. The majority (>50%) had induced cytokine concentrations below the reference intervals at baseline which was most pronounced for the LPS- and Poly I:C-induced responses. The induced responses in the whole population improved after 12 months of cART, and more PWH had induced cytokine concentrations within the reference intervals after 12 months. However, the majority of PWH still had LPS-induced INF-α, INF-γ and Poly I:C-induced TNF-α and IL-6 below the reference interval. The induced innate immune responses before cART initiation were not associated with the CD4+ T-cell recovery after 12 months of cART. CONCLUSION: The innate immune response was impaired in PWH, with a more pronounced impairment in PWH with low nadir CD4+ T-cell count. Initiation of cART improved the innate immune response, but compared to the reference intervals, some impairment remained in PWH without viral replication.

277. Decreased CD57 expression of natural killer cells enhanced cytotoxicity in patients with primary sclerosing cholangitis.

Front Immunol

2022 Aug 17

Liu B, Yang GX, Sun Y

278. Layer-by-Layer Delivery of Multiple Antigens Using Trimethyl Chitosan Nanoparticles as a Malaria Vaccine Candidate.

Front Immunol

2022 Aug 17

Xu Y, Zhou Z, Brooks B

Developing a safe and effective malaria vaccine is critical to reducing the spread and resurgence of this deadly disease, especially in children. In recent years, vaccine technology has seen expanded development of subunit protein, peptide, and nucleic acid vaccines. This is due to their inherent safety, the ability to tailor their immune response, simple storage requirements, easier production, and lower expense compared to using attenuated and inactivated organism-based approaches. However, these new vaccine technologies generally have low efficacy. Subunit vaccines, due to their weak immunogenicity, often necessitate advanced delivery vectors and/or the use of adjuvants. A new area of vaccine development involves design of synthetic micro- and nano-particles and adjuvants that can stimulate immune cells directly through their physical and chemical properties. Further, the unique and complex life cycle of the Plasmodium organism, with multiple stages and varying epitopes/antigens presented by the parasite, is another challenge for malaria vaccine development. Targeting multistage antigens simultaneously is therefore critical for an effective malaria vaccine. Here, we rationally design a layer-by-layer (LbL) antigen delivery platform (we called LbL NP) specifically engineered for malaria vaccines. A biocompatible modified chitosan nanoparticle (trimethyl chitosan, TMC) was synthesized and utilized for LbL loading and release of multiple malaria antigens from pre-erythrocytic and erythrocytic stages. LbL NP served as antigen/protein delivery vehicles and were demonstrated to induce the highest Plasmodium falciparum Circumsporozoite Protein (PfCSP) specific T-cell responses in mice studies as compared to multiple controls. From immunogenicity studies, it was concluded that two doses of intramuscular injection with a longer interval (4 weeks) than traditional malaria vaccine candidate dosing would be the vaccination potential for LbL NP vaccine candidates. Furthermore, in PfCSP/Py parasite challenge studies we demonstrated protective efficacy using LbL NP. These LbL NP provided a significant adjuvant effect since they may induce innate immune response that led to a potent adaptive immunity to mediate non-specific anti-malarial effect. Most importantly, the delivery of CSP full-length protein stimulated long-lasting protective immune responses even after the booster immunization 4 weeks later in mice.

279. Investigating population-level immunosenescence: From bench to bedside.

Front Immunol

2022 Aug 17

Cunha LL, Valsecchi VADS, Ward LS.

The immune response is remodeled with aging in a process called immunosenescence. Some immunologists conceive immunosenescence as an adaptation of immunity to the aged immune-environment rather than a merely collapsed reactivity of immune cells against microbes and tumor cells. Others believe on an uninterrupted activation of the innate immune system with aging, leading to a low grade, sterile and chronic proinflammatory state called inflammaging. For instance, it is possible that chronic infection by cytomegalovirus leads to persistent production of viral load. This phenomenon offers periodic stimuli to the immune system that ultimately contribute to the remodeling of the immune response. If investigating immunosenescence at the cellular level is already a difficult task, considering the population level is much more complex. However, by studying immunosenescence at the population level, we can extract valuable results with viable applications. While studies with animal models allow scientists to deepen their understanding of the mechanisms of immunosenescence, studying large populations can bring practical innovations to medicine and the health system. Many researchers and funders have dedicated themselves to producing methods for the evaluation of immunosenescence on a large scale, aiming to elucidate new mechanisms by which diseases are established in the elderly. The description of how the immune response is remodeled with aging emerges as a new tool to identify the subset of subjects in which unhealthy aging is a matter of time, to help better individualize clinical management and select patients who may benefit. of early interventions. This review focuses on functional assays as valuable methods for measuring the remodeling of the immune response with aging and discuss their clinical impact. We also recall fundamental concepts for understanding the aging process of the immune response. In addition, we highlight future prospects for immunosenescence research.

280. PIRCHE-II scores prove useful as a predictive biomarker among kidney transplant recipients with rejection: An analysis of indication and follow-up biopsies.

Front Immunol

2022 Aug 17

Spitznagel T, Matter LS, Kaufmann YL

281. Cellular and humoral immune responses and breakthrough infections after three SARS-CoV-2 mRNA vaccine doses.

Front Immunol

2022 Aug 17

Almendro-Vázquez P, Chivite-Lacaba M, Utrero-Rico A

282. Regulatory T cells regulate blastemal proliferation during zebrafish caudal fin regeneration.

Front Immunol

2022 Aug 17

Hui SP, Sugimoto K, Sheng DZ

283. Immunosuppressant exposure confounds gene expression analysis in systemic lupus erythematosus.

Front Immunol

2022 Aug 17

Northcott M, Gearing LJ, Bonin J

284. Single-cell sequencing reveals heterogeneity between pancreatic adenosquamous carcinoma and pancreatic ductal adenocarcinoma with prognostic value.

Front Immunol

2022 Aug 16

Zhang D, Wu S, Pan S

285. Just one word, plastic!": Controversies and caveats in innate lymphoid cell plasticity.

Front Immunol

2022 Aug 16

Kabil A, Shin SB, Hughes MR

286. Mining the multifunction of mucosal-associated invariant T cells in hematological malignancies and transplantation immunity: A promising hexagon soldier in immunomodulatory.

Front Immunol

2022 Aug 16

Gao MG, Zhao XS.

287. Myeloid checkpoint blockade improves killing of T-acute lymphoblastic leukemia cells by an IgA2 variant of daratumumab.

Front Immunol

2022 Aug 16

Baumann N, Arndt C, Petersen J

288. A diversified role for γδT cells in vector-borne diseases.

Front Immunol

2022 Aug 16

Chen C, Chen A, Yang Y.

289. CDKN2A-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple-negative breast cancer.

Front Immunol

2022 Aug 16

Cheng T, Wu Y, Liu Z

290. Establishment of three heterogeneous subtypes and a risk model of low-grade gliomas based on cell senescence-related genes.

Front Immunol

2022 Aug 16

Chen J, Wu L, Yang H

BACKGROUND: Cellular senescence is a key element in the occurrence and progression of a variety of tumors. As a result, cellular senescence-related markers can be categorized based on the prognosis status of patients. Due to the heterogeneity and the complexity of the tumor microenvironment (TME), the long-term effectiveness of low-grade glioma (LGG) treatment remains a clinical challenge. Consequently, developing and refining effective treatment approaches to aid with LGG management is critical. METHODS: Based on the expressions of cell senescence-related genes (CSRGs) acquired from the cellAge database, consensus clustering was utilized to identify stable molecular subtypes. Clinical features, immune infiltration, route modifications, and genetic changes of various subtypes were also assessed. Following that, the least absolute shrinkage and selection operator (LASSO) regression and univariate Cox regression analysis were used for developing the cell senescence-related risk score (CSRS) model. Finally, a correlation study of the CSRS model with molecular, immunological, and immunotherapy parameters was performed. RESULTS: C1, C2, and C3, are the three senescence-related subtypes that were identified. Patients belonging to the C1 subtype had poor prognoses and a substantial proportion of them was in the grade G3. The differentially expressed genes (DEGs) among the three subtypes were used to develop the CSRS model. In both the training and independent validation cohort, the model had a high area under the receiver operating characteristic (ROC) curve in predicting the overall survival (OS) of patients. As a result, this model can predict clinical features and responses to immunotherapy in a variety of patients and it is a potential independent prognostic factor for LGG. CONCLUSION: This research discovered three LGG subtypes related to cell senescence and created a CSRS model for six genes. Cell senescence was highly associated with unfavorable prognosis in LGG. The CSRS model can be used to predict the prognosis of patients and identify patients who would benefit from immunotherapy.

291. Dissecting the dynamic transcriptional landscape of early T helper cell differentiation into Th1, Th2, and Th1/2 hybrid cells.

Front Immunol

2022 Aug 16

Burt P, Peine M, Peine C

292. The complex formation of MASP-3 with pattern recognition molecules of the lectin complement pathway retains MASP-3 in the circulation.

Front Immunol

2022 Aug 16

Kusakari K, Machida T, Ishida Y

The complement system plays an important role in host defense and is activated via three different activation pathways. We have previously reported that mannose-binding lectin-associated serine protease (MASP)-3, unlike its splicing variant MASP-1, circulates in an active form and is essential for the activation of the alternative pathway (AP) via the activation of complement factor D (FD). On the other hand, like MASP-1 and MASP-2 of the lectin pathway (LP), MASP-3 forms a complex with the pattern recognition molecules (PRMs) of the LP (LP-PRMs). Both MASP-1 and MASP-2 can be activated efficiently when the LP-PRMs complexed with them bind to their ligands. On the other hand, it remains unclear how MASP-3 is activated, or whether complex formation of MASP-3 with LP-PRMs is involved in activation of MASP-3 or its efficiency in the circulation. To address these issues, we generated wild-type (WT) and four mutant recombinant mouse MASP-3 proteins fused with PA (human podoplanin dodecapeptide)-tag (rmMASP-3-PAs), the latter of which have single amino acid substitution for alanine in the CUB1 or CUB2 domain responsible for binding to LP-PRMs. The mutant rmMASP-3-PAs showed significantly reduced in-vivo complex formation with LP-PRMs when compared with WT rmMASP-3-PA. In the in-vivo kinetic analysis of MASP-3 activation, both WT and mutant rmMASP-3-PAs were cleaved into the active forms as early as 30 minutes in the circulation of mice, and no significant difference in the efficiency of MASP-3 cleavage was observed throughout an observation period of 48 hours after intravenous administration. All sera collected 3 hours after administration of each rmMASP-3-PA showed full restoration of the active FD and AP activity in MASP-3-deficient mouse sera at the same levels as WT mouse sera. Unexpectedly, all mutant rmMASP-3-PAs showed faster clearance from the circulation than the WT rmMASP-3-PA. To our knowledge, the current study is the first to show in-vivo kinetics of MASP-3 demonstrating rapid activation and clearance in the circulation. In conclusion, our results demonstrated that the complex formation of MASP-3 with LP-PRMs is not required for in-vivo activation of MASP-3 or its efficiency, but may contribute to the long-term retention of MASP-3 in the circulation.

293. Protection against influenza-induced Acute Lung Injury (ALI) by enhanced induction of M2a macrophages: possible role of PPARγ/RXR ligands in IL-4-induced M2a macrophage differentiation.

Front Immunol

2022 Aug 16

Gopalakrishnan A, Joseph J, Shirey KA

Many respiratory viruses cause lung damage that may evolve into acute lung injury (ALI), a cytokine storm, acute respiratory distress syndrome, and ultimately, death. Peroxisome proliferator activated receptor gamma (PPARγ), a member of the nuclear hormone receptor (NHR) family of transcription factors, regulates transcription by forming heterodimers with another NHR family member, Retinoid X Receptor (RXR). Each component of the heterodimer binds specific ligands that modify transcriptional capacity of the entire heterodimer by recruiting different co-activators/co-repressors. However, the role of PPARγ/RXR ligands in the context of influenza infection is not well understood. PPARγ is associated with macrophage differentiation to an anti-inflammatory M2 state. We show that mice lacking the IL-4Rα receptor, required for M2a macrophage differentiation, are more susceptible to mouse-adapted influenza (A/PR/8/34; "PR8")-induced lethality. Mice lacking Ptgs2, that encodes COX-2, a key proinflammatory M1 macrophage mediator, are more resistant. Blocking the receptor for COX-2-induced Prostaglandin E2 (PGE2) was also protective. Treatment with pioglitazone (PGZ), a PPARγ ligand, increased survival from PR8 infection, decreased M1 macrophage gene expression, and increased PPARγ mRNA in lungs. Conversely, conditional knockout mice expressing PPARγ-deficient macrophages were significantly more sensitive to PR8-induced lethality. These findings were extended in cotton rats: PGZ blunted lung inflammation and M1 cytokine gene expression after challenge with non-adapted human influenza. To study mechanisms by which PPARγ/RXR transcription factors induce canonical M2a genes, WT mouse macrophages were treated with IL-4 in the absence or presence of rosiglitazone (RGZ; PPARγ ligand), LG100754 (LG; RXR ligand), or both. IL-4 dose-dependently induced M2a genes Arg1, Mrc1, Chil3, and Retnla. Treatment of macrophages with IL-4 and RGZ and/or LG differentially affected induction of Arg1 and Mrc1 vs. Chil3 and Retnla gene expression. In PPARγ-deficient macrophages, IL-4 alone failed to induce Arg1 and Mrc1 gene expression; however, concurrent treatment with LG or RGZ + LG enhanced IL-4-induced Arg1 and Mrc1 expression, but to a lower level than in WT macrophages, findings confirmed in the murine alveolar macrophage cell line, MH-S. These findings support a model in which PPARγ/RXR heterodimers control IL-4-induced M2a differentiation, and suggest that PPARγ/RXR agonists should be considered as important tools for clinical intervention against influenza-induced ALI.

294. Bioinformatics analysis of potential pathogenesis and risk genes of immunoinflammation-promoted renal injury in severe COVID-19.

Front Immunol

2022 Aug 16

Chen Z, Chen C, Chen F

Renal injury secondary to COVID-19 is an important factor for the poor prognosis of COVID-19 patients. The pathogenesis of renal injury caused by aberrant immune inflammatory of COVID-19 remains unclear. In this study, a total of 166 samples from 4 peripheral blood transcriptomic datasets of COVID-19 patients were integrated. By using the weighted gene co-expression network (WGCNA) algorithm, we identified key genes for mild, moderate, and severe COVID-19. Subsequently, taking these genes as input genes, we performed Short Time-series Expression Miner (STEM) analysis in a time consecutive ischemia-reperfusion injury (IRI) -kidney dataset to identify genes associated with renal injury in COVID-19. The results showed that only in severe COVID-19 there exist a small group of genes associated with the progression of renal injury. Gene enrichment analysis revealed that these genes are involved in extensive immune inflammation and cell death-related pathways. A further protein-protein interaction (PPI) network analysis screened 15 PPI-hub genes: ALOX5, CD38, GSF3R, LGR, RPR1, HCK, ITGAX, LYN, MAPK3, NCF4, SELP, SPI1, WAS, TLR2 and TLR4. Single-cell sequencing analysis indicated that PPI-hub genes were mainly distributed in neutrophils, macrophages, and dendritic cells. Intercellular ligand-receptor analysis characterized the activated ligand-receptors between these immune cells and parenchyma cells in depth. And KEGG enrichment analysis revealed that viral protein interaction with cytokine and cytokine receptor, necroptosis, and Toll-like receptor signaling pathway may be potentially essential for immune cell infiltration leading to COVID-19 renal injury. Finally, we validated the expression pattern of PPI-hub genes in an independent data set by random forest. In addition, we found that the high expression of these genes was correlated with a low glomerular filtration rate. Including them as risk genes in lasso regression, we constructed a Nomogram model for predicting severe COVID-19. In conclusion, our study explores the pathogenesis of renal injury promoted by immunoinflammatory in severe COVID-19 and extends the clinical utility of its key genes.

295. Nivolumab plus ipilimumab induced endocrinopathy and acute interstitial nephritis in metastatic sarcomatoid renal-cell carcinoma: A case report and review of literature.

Front Immunol

2022 Aug 16

Hino C, Nishino K, Pham B

296. Risk of primary Sjogren's Syndrome following human papillomavirus infections: a nationwide population-based cohort study.

Front Immunol

2022 Aug 16

Chen HH, Ma KS, Dong C

297. Targeted treatment of autoimmune cytopenias in primary immunodeficiencies.

Front Immunol

2022 Aug 16

Pacillo L, Giardino G, Amodio D

298. SIRGs score may be a predictor of prognosis and immunotherapy response for esophagogastric junction adenocarcinoma.

Front Immunol

2022 Aug 16

OuYang LY, Deng ZJ, You YF

299. The role of cell-mediated immunity against influenza and its implications for vaccine evaluation.

Front Immunol

2022 Aug 16

Janssens Y, Joye J, Waerlop G

300. The time window for the reversal of depigmentation from aggravation to recovery in a non-small-cell lung cancer patient with pre-existing vitiligo using anti-programmed cell death-1 therapy: A case report.

Front Immunol

2022 Aug 16

Gao Z, Xu Y, Zu J

301. A role for the nuclear receptor NR2F6 in peritoneal B cell homeostasis.

Front Immunol

2022 Aug 16

Olson WJ, Jakic B, Labi V

302. Extrahepatic factors in hepatic immune regulation.

Front Immunol

2022 Aug 16

Zhang S, Lu S, Li Z.

303. Bile acids in immunity: Bidirectional mediators between the host and the microbiota.

Front Immunol

2022 Aug 16

Godlewska U, Bulanda E, Wypych TP.

304. Four cases of cytokine storm after COVID-19 vaccination: Case report.

Front Immunol

2022 Aug 15

Murata K, Nakao N, Ishiuchi N

305. Immune responses in diabetic nephropathy: Pathogenic mechanisms and therapeutic target.

Front Immunol

2022 Aug 15

Chen J, Liu Q, He J

306. Human metapneumovirus M2-2 protein inhibits RIG-I signaling by preventing TRIM25-mediated RIG-I ubiquitination.

Front Immunol

2022 Aug 15

Tanaka Y, Morita N, Kitagawa Y

307. Translating extracellular vesicle packaging into therapeutic applications.

Front Immunol

2022 Aug 15

Ozkocak DC, Phan TK, Poon IKH.

308. Evasion of interferon-mediated immune response by arteriviruses.

Front Immunol

2022 Aug 15

Jian Z, Ma R, Zhu L

309. Hybrid antigens expressing surface loops of BauA from Acinetobacter baumannii are capable of inducing protection against infection.

Front Immunol

2022 Aug 15

Chaudhuri S, Rasooli I, Oskouei RH

Acinetobacter baumannii is a human bacterial pathogen of increasing concern in clinical settings due to the emergence of antibiotic resistant strains and the lack of effective therapeutics. Researchers have been exploring new treatment options such as novel drug candidates and vaccines to prevent severe infections and mortality. Bacterial surface antigens that are essential to A. baumannii for acquiring micronutrients (e.g. iron, zinc) from nutrient restricted environments are being considered as targets for vaccines or immunotherapy due to their crucial role for growth and pathogenesis in the human host. BauA, the outer membrane receptor for the siderophore acinetobactin was targeted for vaccine development in this study. Due to challenges in the commercial production of membrane proteins for vaccines, a novel hybrid antigen method developed by our group was used. Exposed loops of BauA were selected and displayed on a foreign scaffold to generate novel hybrid antigens designed to elicit an immune response against the native BauA protein. The potential epitopes were incorporated into a scaffold derived from the C-lobe of Neisseria meningitidis transferrin binding protein B (TbpB), named the loopless C-lobe (LCL). Hybrid proteins displaying three selected loops (5, 7 and 8) individually or in combination were designed and produced and evaluated in an A. baumannii murine sepsis model as vaccine antigens. Immunization with the recombinant BauA protein protected 100% of the mice while immunization with hybrid antigens displaying individual loops achieved between 50 and 100% protection. The LCL scaffold did not induce a protective immune response, enabling us to attribute the observed protection elicited by the hybrid antigens to the displayed loops. Notably, the mice immunized with the hybrid antigen displaying loop 7 were completely protected from infection. Taken together, these results suggest that our hybrid antigen approach is a viable method for generating novel vaccine antigens that target membrane surface proteins necessary for bacterial growth and pathogenesis and the loop 7 hybrid antigen can be a foundation for approaches to combat A. baumannii infections.

310. Prognostic impacts of soluble immune checkpoint regulators and cytokines in patients with SARS-CoV-2 infection.

Front Immunol

2022 Aug 15

Lee N, Jeong S, Jeon K

Coronavirus disease 2019 (COVID-19) has been a pandemic for the past two years. Predicting patient prognosis is critical. Although immune checkpoints (ICs) were shown to be involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, quantitative studies of ICs in clinical practice are limited. In this study, various soluble ICs (sICs) and cytokine levels in patients with SARS-CoV-2 infection at different time points were compared between survivors and deaths; we also examined whether sICs are useful for predicting prognosis. sICs and cytokines were measured in serum samples from 38 patients diagnosed with COVID-19 in the first and second week post-diagnosis. All assays were performed by bead-based multiplexed immunoassay system using Luminex Bio-Plex 200 system. The correlation of sICs and cytokines with laboratory markers was evaluated, and the levels of sICs in survivors were compared with those in deaths. Among the sICs, the second-week levels of soluble cluster of differentiation (sCD27, p = 0.012), sCD40 (p< 0.001), cytotoxic T-lymphocyte-associated protein 4 (sCTLA-4, p< 0.001), herpes virus entry mediator (sHVEM, p = 0.026), and T-cell immunoglobulin and mucin-domain containing-3 (sTIM-3, p = 0.002) were significantly higher in deaths than in survivors. The levels of nine cytokines assessed in the second week of deaths were significantly higher than those in survivors. The sICs sCD27, sCD40, sCTLA-4, and sTIM-3 and cytokines chemokine CC motif ligand 2 (CCL2), GM-CSF, IL-10, and IL-8 showed significant positive correlations with the levels of C-reactive protein (CRP) and procalcitonin and were negatively correlated with the absolute lymphocyte count and platelet values. Increased levels of sICs including sCD27, sCD40, sCTLA-4, and sTIM-3 and cytokines were significant factors for poor prognosis. sICs, together with cytokines and inflammatory markers, may be useful as prognostic stratification markers in SARS-CoV-2-infected patients.

311. Smad4-deficient T cells promote colitis-associated colon cancer via an IFN-γ-dependent suppression of 15-hydroxyprostaglandin dehydrogenase.

Front Immunol

2022 Aug 15

Choi SH, Huang AY, Letterio JJ

312. Host-microbiota interactions: The aryl hydrocarbon receptor in the acute and chronic phases of cerebral ischemia.

Front Immunol

2022 Aug 12

Fan X, Wang S, Hu S

313. Computational identification of immune-related lncRNA signature for predicting the prognosis and immune landscape of human glioblastoma multiforme.

Front Immunol

2022 Aug 12

Shi D, Zhong W, Liu D

314. Innate lymphoid cells in early tumor development.

Front Immunol

2022 Aug 12

Warner K, Ghaedi M, Chung DC

315. I've looked at gut from both sides now: Gastrointestinal tract involvement in the pathogenesis of SARS-CoV-2 and HIV/SIV infections.

Front Immunol

2022 Aug 12

Pandrea I, Brooks K, Desai RP

316. Hyperthermia combined with immune checkpoint inhibitor therapy in the treatment of primary and metastatic tumors.

Front Immunol

2022 Aug 12

Yang X, Gao M, Xu R

317. Immunogenicity and toxicity of AAV gene therapy.

Front Immunol

2022 Aug 12

Ertl HCJ.

318. Nature vs. nurture: FOXP3, genetics, and tissue environment shape Treg function.

Front Immunol

2022 Aug 12

Raugh A, Allard D, Bettini M.

319. Distinct spatial and temporal roles for Th1, Th2, and Th17 cells in asthma.

Front Immunol

2022 Aug 12

Luo W, Hu J, Xu W

320. A rapid method for isolation of bacterial extracellular vesicles from culture media using epsilon-poly-L-lysine that enables immunological function research.

Front Immunol

2022 Aug 12

Wei S, Jiao D, Xing W.

321. Chemerin plasma levels are increased in COVID-19 patients and are an independent risk factor of mortality.

Front Immunol

2022 Aug 12

Lavis P, Morra S, Orte Cano C

BACKGROUND: Chemerin is an extracellular protein with chemotactic activities and its expression is increased in various diseases such as metabolic syndrome and inflammatory conditions. Its role in lung pathology has not yet been extensively studied but both known pro- and anti-inflammatory properties have been observed. The aim of our study was to evaluate the involvement of the chemerin/ChemR23 system in the physiopathology of COVID-19 with a particular focus on its prognostic value. METHODS: Blood samples from confirmed COVID-19 patients were collected at day 1, 5 and 14 from admission to Erasme Hospital (Brussels - Belgium). Chemerin concentrations and inflammatory biomarkers were analyzed in the plasma. Blood cells subtypes and their expression of ChemR23 were determined by flow cytometry. The expression of chemerin and ChemR23 was evaluated on lung tissue from autopsied COVID-19 patients by immunohistochemistry (IHC). RESULTS: 21 healthy controls (HC) and 88 COVID-19 patients, including 40 in intensive care unit (ICU) were included. Plasma chemerin concentration were significantly higher in ICU patients than in HC at all time-points analyzed (p<0.0001). Moreover, they were higher in deceased patients compared to survivors (p<0.05). Logistic univariate regression and multivariate analysis demonstrated that chemerin level at day 14 of admission was an independent risk factor for death. Accordingly, chemerin levels correlated with inflammatory biomarkers such as C-reactive protein and tumor necrosis factor α. Finally, IHC analysis revealed a strong expression of ChemR23 on smooth muscle cells and chemerin on myofibroblasts in advanced acute respiratory distress syndrome (ARDS). DISCUSSION: Increased plasma chemerin levels are a marker of severity and may predict death of COVID-19 patients. However, multicentric studies are needed, before chemerin can be considered as a biomarker of severity and death used in daily clinical practice. Further studies are also necessary to identify the precise mechanisms of the chemerin/ChemR23 system in ARDS secondary to viral pneumonia.

322. Heterogeneity of tumor immune microenvironment and real-world analysis of immunotherapy efficacy in lung adenosquamous carcinoma.

Front Immunol

2022 Aug 12

Li C, Zheng X, Li P

323. NanoNet: Rapid and accurate end-to-end nanobody modeling by deep learning.

Front Immunol

2022 Aug 12

Cohen T, Halfon M, Schneidman-Duhovny D.

324. Ginsenoside Rg5 allosterically interacts with P2RY(12) and ameliorates deep venous thrombosis by counteracting neutrophil NETosis and inflammatory response.

Front Immunol

2022 Aug 12

Chen Z, Wang G, Xie X

325. Fecal microbiota transplantation treatment of autoimmune-mediated type 1 diabetes mellitus.

Front Immunol

2022 Aug 12

He L, Chen R, Zhang B

326. Impaired functionality of antigen presenting cells in HIV- exposed uninfected infants in the first six months of life.

Front Immunol

2022 Aug 12

Jalbert E, Ghosh T, Smith C

327. The potential role of exosomal miRNAs and membrane proteins in acute HIV-infected people.

Front Immunol

2022 Aug 12

Li X, Wang W, Chen J

328. Defying convention in the time of COVID-19: Insights into the role of γδ T cells.

Front Immunol

2022 Aug 11

Sanz M, Mann BT, Chitrakar A

329. ROCK inhibition with Y-27632 reduces joint inflammation and damage in serum-induced arthritis model and decreases in vitro osteoclastogenesis in patients with early arthritis.

Front Immunol

2022 Aug 11

Rodríguez-Trillo A, Pena C, García S

330. A promising antitumor method: Targeting CSC with immune cells modified with CAR.

Front Immunol

2022 Aug 11

Huang B, Miao L, Liu J

331. Circulating microRNA signatures associated with disease severity and outcome in COVID-19 patients.

Front Immunol

2022 Aug 11

Giannella A, Riccetti S, Sinigaglia A

BACKGROUND: SARS-CoV-2 induces a spectrum of clinical conditions ranging from asymptomatic infection to life threatening severe disease. Host microRNAs have been involved in the cytokine storm driven by SARS-CoV-2 infection and proposed as candidate biomarkers for COVID-19. METHODS: To discover signatures of circulating miRNAs associated with COVID-19, disease severity and mortality, small RNA-sequencing was performed on serum samples collected from 89 COVID-19 patients (34 severe, 29 moderate, 26 mild) at hospital admission and from 45 healthy controls (HC). To search for possible sources of miRNAs, investigation of differentially expressed (DE) miRNAs in relevant human cell types in vitro. RESULTS: COVID-19 patients showed upregulation of miRNAs associated with lung disease, vascular damage and inflammation and downregulation of miRNAs that inhibit pro-inflammatory cytokines and chemokines, angiogenesis, and stress response. Compared with mild/moderate disease, patients with severe COVID-19 had a miRNA signature indicating a profound impairment of innate and adaptive immune responses, inflammation, lung fibrosis and heart failure. A subset of the DE miRNAs predicted mortality. In particular, a combination of high serum miR-22-3p and miR-21-5p, which target antiviral response genes, and low miR-224-5p and miR-155-5p, targeting pro-inflammatory factors, discriminated severe from mild/moderate COVID-19 (AUROC 0.88, 95% CI 0.80-0.95, p<0.0001), while high leukocyte count and low levels of miR-1-3p, miR-23b-3p, miR-141-3p, miR-155-5p and miR-4433b-5p predicted mortality with high sensitivity and specificity (AUROC 0.95, 95% CI 0.89-1.00, p<0.0001). In vitro experiments showed that some of the DE miRNAs were modulated directly by SARS-CoV-2 infection in permissive lung epithelial cells. CONCLUSIONS: We discovered circulating miRNAs associated with COVID-19 severity and mortality. The identified DE miRNAs provided clues on COVID-19 pathogenesis, highlighting signatures of impaired interferon and antiviral responses, inflammation, organ damage and cardiovascular failure as associated with severe disease and death.

332. Characterization of CD41(+) cells in the lymph node.

Front Immunol

2022 Aug 11

Dai L, Uehara M, Li X

333. Glycolysis, monocarboxylate transport, and purinergic signaling are key events in Eimeria bovis-induced NETosis.

Front Immunol

2022 Aug 11

Conejeros I, López-Osorio S, Zhou E

The protozoan parasite Eimeria bovis is the causative agent of bovine coccidiosis, an enteric disease of global importance that significantly affects cattle productivity. Previous studies showed that bovine NETosis-an important early host innate effector mechanism of polymorphonuclear neutrophil (PMN)-is elicited by E. bovis stages. So far, the metabolic requirements of E. bovis-triggered NET formation are unknown. We here studied early glycolytic and mitochondrial responses of PMN as well as the role of pH, distinct metabolic pathways, P2 receptor-mediated purinergic signaling, and monocarboxylate transporters 1 and 2 (MCT1, MCT2) in E. bovis sporozoite-induced NET formation. Seahorse-based experiments revealed a rapid induction of both neutrophil oxygen consumption rate (OCR) and early glycolytic responses, thereby reflecting immediate PMN activation and metabolic changes upon confrontation with sporozoites. The impact of these metabolic changes on NET formation was studied via chemical inhibition experiments targeting glycolysis and energy generation by the use of 2-fluor-2-deoxy-D-glucose (FDG), 6-diazo-5-oxo-L-norleucin (DON), sodium dichloroacetate (DCA), oxythiamine (OT), sodium oxamate (OXA), and oligomycin A (OmA) to block glycolysis, glutaminolysis, pyruvate dehydrogenase kinase, pyruvate dehydrogenase, lactate dehydrogenase, and mitochondrial ATP-synthase, respectively. Overall, sporozoite-induced NET formation was significantly diminished via PMN pretreatments with OmA and OXA, thereby indicating a key role of ATP- and lactate-mediated metabolic pathways. Consequently, we additionally studied the effects of extracellular pH, MCT1, MCT2, and purinergic receptor inhibitors (AR-C141900, AR-C155858, theobromine, and NF449, respectively). Pretreatment with the latter inhibitors led to blockage of sporozoite-triggered DNA release from exposed bovine PMN. This report provides first evidence on the pivotal role of carbohydrate-related metabolic pathways and purinergic receptors being involved in E. bovis sporozoite-induced NETosis.

334. Identification of m6A- and ferroptosis-related lncRNA signature for predicting immune efficacy in hepatocellular carcinoma.

Front Immunol

2022 Aug 11

Xie H, Shi M, Liu Y

335. Identifying immune cells-related phenotype to predict immunotherapy and clinical outcome in gastric cancer.

Front Immunol

2022 Aug 11

Jiang S, Ding X, Wu Q

336. The relationship between dyslipidemia and inflammation among adults in east coast China: A cross-sectional study.

Front Immunol

2022 Aug 11

Hong N, Lin Y, Ye Z

OBJECTIVE: Dyslipidemia is one of the major public health problems in China. It is characterized by multisystem dysregulation and inflammation, and oxidant/antioxidant balance has been suggested as an important factor for its initiation and progression. The objective of this study was to determine the relationship between prevalence of dyslipidemia and measured changes in the levels of proinflammatory cytokines (IL-6, TNF-a, and MCP-1), thiobarbituric acid-reactant substances (TBARS), and serum total antioxidant capacity (TAC) in serum samples. STUDY DESIGN: A cross-sectional survey with a purposive sampling of 2,631 enrolled participants (age 18-85 years) was performed using the adult population of long-term residents of the municipality of east coast China in Fujian province between the years 2017 and 2019. Information on general health status, dyslipidemia prevalence, and selected mediators of inflammation was collected through a two-stage probability sampling design according to socioeconomic level, sex, and age. METHODS: The lipid profile was conducted by measuring the levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) with an autoanalyzer. Dyslipidemia was defined according to National Cholesterol Education Program Adult Treatment Panel III diagnostic criteria, and patients with it were identified by means of a computerized database. Serum parameters including IL-6/TNF-a/MCP-1, TBARS, and TAC were measured in three consecutive years. Familial history, education level, risk factors, etc. were determined. The association between dyslipidemia and serum parameters was explored using multivariable logistic regression models. Sociodemographic, age, and risk factors were also investigated among all participants. RESULTS: The mean prevalence of various dyslipidemia in the population at baseline (2017) was as follows: dyslipidemias, 28.50%; hypercholesterolemia, 26.33%; high LDL-C, 26.10%; low HDL-C, 24.44%; and hypertriglyceridemia, 27.77%. A significant effect of aging was found among all male and female participants. The mean levels of serum Il-6/TNF-a/MCP-1 were significantly higher in all the types of dyslipidemia among male participants. Female participants with all types of dyslipidemia but low HDL-C showed an elevation of IL-6 and MCP-1 levels, and those with dyslipidemias and hypercholesterolemia presented higher levels of TNF-a compared to the normal participants. The oxidative stress marker TBARS increased among all types of dyslipidemia except hypertriglyceridemia. All participants with different types of dyslipidemia had a lower total antioxidant capacity. Correlation analysis showed that cytokines and TBARS were positively associated with age, obesity, and diabetes mellitus, but not sex, sedentary leisure lifestyle, hypertension, and CVD/CHD history. The activity of TAC was negatively associated with the above parameters. CONCLUSIONS: The correlation between the prevalence of dyslipidemia and the modification of inflammation status was statistically significant. The levels of proinflammatory cytokines, oxidative stress, and antioxidant capacity in serum may reflect the severity of the lipid abnormalities. These promising results further warrant a thorough medical screening in enhanced anti-inflammatory and reduced oxidative stress to better diagnose and comprehensively treat dyslipidemia at an early stage.

337. Evasion of NK cell immune surveillance via the vimentin-mediated cytoskeleton remodeling.

Front Immunol

2022 Aug 11

Peng JM, Chiu CF, Cheng JH

Cancer immunotherapy uses the immune system to achieve therapeutic effects; however, its effect is still limited. Therefore, in addition to immune checkpoint-based treatment, the development of other strategies that can inhibit cancer cells from resisting immune cytotoxicity is important. There are currently few studies on the mechanism of tumors using cytoskeletal proteins reorganization to participate in immune escape. In this study, we identified cancer cell lines that were sensitive or resistant to natural killer cells in urothelial and lung cancer using the natural killer cell sensitivity assay. We found that immunoresistant cancer cells avoid natural killer cell-mediated cytotoxicity by upregulation of vimentin and remodeling of actin cytoskeleton. Immunofluorescence staining showed that immune cells promoted the formation of actin filaments at the immune synapse, which was not found in immunosensitive cancer cells. Pretreatment of the actin polymerization inhibitors latrunculin B increased the cytotoxicity of natural killer cells, suggesting that cytoskeleton remodeling plays a role in resisting immune cell attack. In addition, silencing of vimentin with shRNA potentiated the cytotoxicity of natural killer cells. Interestingly, the upregulation and extension of vimentin was found in tumor islands of upper tract urothelial carcinoma infiltrated by natural killer cells. Conversely, tumors without natural killer cell invasion showed less vimentin signal. The expression level of vimentin was highly correlated with natural killer cell infiltration. In summary, we found that when immune cells attack cancer cells, the cancer cells resist immune cytotoxicity through upregulated vimentin and actin reorganization. In addition, this immune resistance mechanism was also found in patient tumors, indicating the possibility that they can be applied to evaluate the immune response in clinical diagnosis.

338. Antibiotic-induced alternations in gut microflora are associated with the suppression of immune-related pathways in grass carp (Ctenopharyngodon idellus).

Front Immunol

2022 Aug 11

Shi F, Huang Y, Yang M

339. The role of inflammation in hematopoiesis and bone marrow failure: What can we learn from mouse models?

Front Immunol

2022 Aug 11

Wang J, Erlacher M, Fernandez-Orth J.

340. Metabolomics in rheumatoid arthritis: Advances and review.

Front Immunol

2022 Aug 11

Xu L, Chang C, Jiang P

341. Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment.

Front Immunol

2022 Aug 11

Ihim SA, Abubakar SD, Zian Z

342. An enhanced level of VCAM in transplant preservation fluid is an independent predictor of early kidney allograft dysfunction.

Front Immunol

2022 Aug 11

Baboudjian M, Gondran-Tellier B, Boissier R

343. Lacticaseibacillus rhamnosus alleviates intestinal inflammation and promotes microbiota-mediated protection against Salmonella fatal infections.

Front Immunol

2022 Aug 11

Peng X, Ed-Dra A, Song Y

The fatal impairment of the intestinal mucosal barrier of chicks caused by Salmonella significantly resulting economic losses in the modern poultry industry. Probiotics are recognized for beneficially influencing host immune responses, promoting maintenance of intestinal epithelial integrity, antagonistic activity against pathogenic microorganisms and health-promoting properties. Some basic studies attest to probiotic capabilities and show that Lacticaseibacillus rhamnosus could protect intestinal mucosa from injury in animals infected with Salmonella Typhimurium. However, the mechanisms underlying its protective effects in chicks are still not fully understood. Here, we used the chick infection model combined with histological, immunological, and molecular approaches to address this question. The results indicated that L. rhamnosus significantly reduced the diarrhea rate and increased the daily weight gain and survival rate of chicks infected with S. Typhimurium. Furthermore, we found that L. rhamnosus markedly improved the immunity of gut mucosa by reducing apoptotic cells, hence effectively inhibiting intestinal inflammation. Notably, pre-treatment chicks with L. rhamnosus balanced the expression of interleukin-1β and interleukin-18, moderated endotoxin and D-lactic acid levels, and expanded tight junction protein levels (Zonula occluden-1 and Claudin-1), enhanced the function of the intestinal mucosal epithelial cells. Additionally, investigations using full-length 16S rRNA sequencing also demonstrated that L. rhamnosus greatly weakened the adhesion of Salmonella, the mainly manifestation is the improvement of the diversity of intestinal microbiota in infected chicks. Collectively, these results showed the application of L. rhamnosus against Salmonella fatal infection by enhancing barrier integrity and the stability of the gut microbiota and reducing inflammation in new hatch chicks, offering new antibiotic alternatives for farming animals.

344. Reconstitution of the immune system and clinical correlates after stem cell transplantation for systemic sclerosis.

Front Immunol

2022 Aug 11

Kawashima-Vasconcelos MY, Santana-Gonçalves M, Zanin-Silva DC

345. The Fra-1: Novel role in regulating extensive immune cell states and affecting inflammatory diseases.

Front Immunol

2022 Aug 11

He YY, Zhou HF, Chen L

346. Prenatal antibiotics exposure does not influence experimental allergic asthma in mice.

Front Immunol

2022 Aug 10

Lingel I, Wilburn AN, Hargis J

347. Investigating mammary glands of lactating goats for the presence of tertiary lymphoid organs.

Front Immunol

2022 Aug 10

Tsugami Y, Nakayama S, Suzuki N

348. The role of the complement system in Multiple Sclerosis: A review.

Front Immunol

2022 Aug 10

Saez-Calveras N, Stuve O.

349. Ablation of NLRP3 inflammasome rewires MDSC function and promotes tumor regression.

Front Immunol

2022 Aug 10

Papafragkos I, Grigoriou M, Boon L

350. Insulin B-chain hybrid peptides are agonists for T cells reactive to insulin B:9-23 in autoimmune diabetes.

Front Immunol

2022 Aug 10

Wenzlau JM, DiLisio JE, Barbour G

351. IFN-γ, should not be ignored in SLE.

Front Immunol

2022 Aug 10

Liu W, Zhang S, Wang J.

352. Antiphospholipid antibodies are persistently positive at high titers. Additive value of platelet-bound C4d.

Front Immunol

2022 Aug 10

Sciascia S, Bloch R, O'Malley T

353. Hallmark-guided subtypes of hepatocellular carcinoma for the identification of immune-related gene classifiers in the prediction of prognosis, treatment efficacy, and drug candidates.

Front Immunol

2022 Aug 10

Guo C, Tang Y, Yang Z

354. Mast cells and tryptase are linked to itch and disease severity in mycosis fungoides: Results of a pilot study.

Front Immunol

2022 Aug 10

Terhorst-Molawi D, Lohse K, Ginter K

355. CD4(+) T cell activation and inflammation in NASH-related fibrosis.

Front Immunol

2022 Aug 10

Zhou Y, Zhang H, Yao Y

356. Clinical features, prognostic factors, and survival of patients with antisynthetase syndrome and interstitial lung disease.

Front Immunol

2022 Aug 10

Zhao N, Jiang W, Wu H

357. Penta-o-galloyl-beta-d-Glucose (PGG) inhibits inflammation in human rheumatoid arthritis synovial fibroblasts and rat adjuvant-induced arthritis model.

Front Immunol

2022 Aug 10

Umar S, Singh AK, Chourasia M

O-GlcNAcylation is a reversible post-translational modification that regulates numerous cellular processes, including embryonic development as well as immune responses. However, its role in inflammation remains ambiguous. This study was designed to examine the role of O-GlcNAcylation in rheumatoid arthritis (RA) and its regulation using human RA patient-derived synovial fibroblasts (RASFs). The efficacy of penta-O-galloyl-beta-D-glucose (PGG), a potent anti-inflammatory molecule, in regulating inflammatory processes in human RASFs was also evaluated. Human synovial tissues and RASFs exhibited higher expression of O-GlcNAcylation compared to their non-diseased counterparts. Pretreatment of RASFs with Thiamet G, an inhibitor of O-GlcNAcase, markedly increased the O-GlcNAc-modified proteins and concomitantly inhibited the IL-1β-induced IL-6 and IL-8 production in human RASFs in vitro. Pretreatment of human RASFs with PGG (0.5-10 µM) abrogated IL-1β-induced IL-6 and IL-8 production in a dose-dependent manner. Immunoprecipitation analysis showed that PGG inhibited O-GlcNAcylation of TAB1 to reduce its association with TGF β-activated kinase 1 (TAK1) and its autophosphorylation, an essential signaling step in IL-1β-induced signaling pathways. Molecular docking in silico studies shows that PGG occupies the C174 position, an ATP-binding site in the kinase domain to inhibit TAK1 kinase activity. Oral administration of PGG (25 mg/kg/day) for 10 days from disease onset significantly ameliorated rat adjuvant-induced (AIA) in rats. PGG treatment reduced the phosphorylation of TAK1 in the treated joints compared to AIA joints, which correlated with the reduced disease severity and suppressed levels of serum IL-1β, GM-CSF, TNF-α, and RANKL. These findings suggest O-GlcNAcylation as a potential therapeutic target and provide the rationale for testing PGG or structurally similar molecule for their therapeutic efficacy.

358. Deciphering colorectal cancer immune microenvironment transcriptional landscape on single cell resolution - A role for immunotherapy.

Front Immunol

2022 Aug 10

Tieng FYF, Lee LH, Ab Mutalib NS.

359. The immune phenotypes and different immune escape mechanisms in colorectal cancer.

Front Immunol

2022 Aug 10

Mao Y, Xu Y, Chang J

360. Regulatory CAR-T cells in autoimmune diseases: Progress and current challenges.

Front Immunol

2022 Aug 10

Riet T, Chmielewski M.