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1. Exposure of Keratinocytes to Candida Albicans in the Context of Atopic Milieu Induces Changes in the Surface Glycosylation Pattern of Small Extracellular Vesicles to Enhance Their Propensity to Interact With Inhibitory Siglec Receptors.

Front Immunol

2022 Jun 9

Kobiela A, Frackowiak JE, Biernacka A

2. Meta-Analysis of Human Antibodies Against Plasmodium falciparum Variable Surface and Merozoite Stage Antigens.

Front Immunol

2022 Jun 9

Takashima E, Kanoi BN, Nagaoka H

Concerted efforts to fight malaria have caused significant reductions in global malaria cases and mortality. Sustaining this will be critical to avoid rebound and outbreaks of seasonal malaria. Identifying predictive attributes that define clinical malaria will be key to guide development of second-generation tools to fight malaria. Broadly reactive antibodies against variable surface antigens that are expressed on the surface of infected erythrocytes and merozoites stage antigens are targets of naturally acquired immunity and prime candidates for anti-malaria therapeutics and vaccines. However, predicting the relationship between the antigen-specific antibodies and protection from clinical malaria remains unresolved. Here, we used new datasets and multiple approaches combined with re-analysis of our previous data to assess the multi-dimensional and complex relationship between antibody responses and clinical malaria outcomes. We observed 22 antigens (17 PfEMP1 domains, 3 RIFIN family members, merozoite surface protein 3 (PF3D7_1035400), and merozoites-associated armadillo repeats protein (PF3D7_1035900) that were selected across three different clinical malaria definitions (1,000/2,500/5,000 parasites/µl plus fever). In addition, Principal Components Analysis (PCA) indicated that the first three components (Dim1, Dim2 and Dim3 with eigenvalues of 306, 48, and 29, respectively) accounted for 66.1% of the total variations seen. Specifically, the Dim1, Dim2 and Dim3 explained 52.8%, 8.2% and 5% of variability, respectively. We further observed a significant relationship between the first component scores and age with antibodies to PfEMP1 domains being the key contributing variables. This is consistent with a recent proposal suggesting that there is an ordered acquisition of antibodies targeting PfEMP1 proteins. Thus, although limited, and further work on the significance of the selected antigens will be required, these approaches may provide insights for identification of drivers of naturally acquired protective immunity as well as guide development of additional tools for malaria elimination and eradication.

3. Editorial: Perforins and Cholesterol-Dependent Cytolysins in Immunity and Pathogenesis.

Front Immunol

2022 Jun 9

Munson GP, Gilbert RJC, Pradel G.

4. Identification of a Novel Densovirus in Aphid, and Uncovering the Possible Antiviral Process During Its Infection.

Front Immunol

2022 Jun 9

Li T, Li H, Wu Y

5. Immunogenicity, Effectiveness, and Safety of Inactivated Virus (CoronaVac) Vaccine in a Two-Dose Primary Protocol and BNT162b2 Heterologous Booster in Brazil (Immunita-001): A One Year Period Follow Up Phase 4 Study.

Front Immunol

2022 Jun 9

Grenfell RFQ, Almeida NBF, Filgueiras PS

6. Potentiality of Exosomal Proteins as Novel Cancer Biomarkers for Liquid Biopsy.

Front Immunol

2022 Jun 9

Hu C, Jiang W, Lv M

7. Cardiovascular Disease in Primary Sjögren's Syndrome: Raising Clinicians' Awareness.

Front Immunol

2022 Jun 9

Casian M, Jurcut C, Dima A

8. Integrins in the Immunity of Insects: A Review.

Front Immunol

2022 Jun 9

Kausar S, Abbas MN, Gul I

9. Xenotransplantation: A New Era.

Front Immunol

2022 Jun 9

Carrier AN, Verma A, Mohiuddin M

10. Fc-Mediated Functions of Porcine IgG Subclasses.

Front Immunol

2022 Jun 9

Paudyal B, Mwangi W, Rijal P

11. Hepatic Tumor Stiffness Measured by Shear Wave Elastography Is Prognostic for HCC Progression Following Treatment With Anti-PD-1 Antibodies Plus Lenvatinib: A Retrospective Analysis of Two Independent Cohorts.

Front Immunol

2022 Jun 9

Yuan G, Xie F, Song Y

BACKGROUND: The clinical significance of liver stiffness (LS) measured by shear wave elastography (SWE) in programmed cell death protein-1 (PD-1) inhibitors treated advanced hepatocellular carcinoma (HCC) patients remains unknown. This study aimed to explore the prognostic value of baseline LS by SWE prior to PD-1 inhibitor treatment in combination with lenvatinib. METHODS: We retrospectively evaluated patients (n=133) with HCC who received anti-PD-1 antibodies plus lenvatinib at two high-volume medical centres, between January 2020 and June 2021. Univariate and multivariate logistic regression analysis were used to develop a novel nomogram. RNA sequencing and immunohistochemical staining were used to assess the heterogeneity of biological and immune characteristics associated with tumor stiffness. RESULTS: The objective response rate (ORR) and disease control rate (DCR) of the whole population were 23.4% and 72.2%, respectively. A LS value of the baseline tumorous foci of 19.53 kPa had the maximum sum of sensitivity and specificity, making it the optimal cut-off value for predicting PD-1 inhibitor efficacy. The nomogram comprised baseline tumor LS and albumin-bilirubin grade (ALBI), which provided favorable calibration and discrimination in the training dataset with an AUC of 0.840 (95%CI: 0.750-0.931) and a C-index of 0.828. Further, it showed acceptable discrimination in the validation cohort, with an AUC of 0.827 (95%CI: 0.673-0.980) and C-index of 0.803. The differentially expressed genes enriched in high stiffness tumors were predominantly associated with metabolic pathways, while those enriched in low stiffness tumors were related to DNA damage repair. Furthermore, patients with high stiffness tumors had a relatively lower infiltration of immune cells and histone deacetylase pathway inhibitors were identified as candidate drugs to promote the efficacy of immunotherapy. CONCLUSIONS: Baseline LS value of tumorous foci by SWE-that is, before administration of a PD-1 inhibitor in combination with lenvatinib-is a convenient predictor of PD-1 inhibitor efficacy in patients with advanced HCC, which has potential to be used for pretreatment stratification to optimize treatment of advanced HCC.

12. FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development.

Front Immunol

2022 Jun 9

Luu TT, Søndergaard JN, Peña-Pérez L

13. The Past, Present, and Future of Non-Viral CAR T Cells.

Front Immunol

2022 Jun 9

Moretti A, Ponzo M, Nicolette CA

14. Harnessing the B Cell Response in Kidney Transplantation - Current State and Future Directions.

Front Immunol

2022 Jun 9

Anwar IJ, DeLaura IF, Gao Q

15. ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain.

Front Immunol

2022 Jun 9

Zhang T, Lin C, Wu S

16. Endogenous Retroviruses (ERVs): Does RLR (RIG-I-Like Receptors)-MAVS Pathway Directly Control Senescence and Aging as a Consequence of ERV De-Repression?

Front Immunol

2022 Jun 9

Di Giorgio E, Xodo LE.

17. Comparing Mouse and Human Tissue-Resident γδ T Cells.

Front Immunol

2022 Jun 8

Qu G, Wang S, Zhou Z

18. Identification of the Immune Subtype of Hepatocellular Carcinoma for the Prediction of Disease-Free Survival Time and Prevention of Recurrence by Integrated Analysis of Bulk- and Single-Cell RNA Sequencing Data.

Front Immunol

2022 Jun 6

Fu J, Lei X.

19. CaMK4 Promotes Acute Lung Injury Through NLRP3 Inflammasome Activation in Type II Alveolar Epithelial Cell.

Front Immunol

2022 Jun 6

Zhang T, Li M, Zhao S

20. Innate Immune Responses and P. falciparum CS Repeat-Specific Neutralizing Antibodies Following Vaccination by Skin Scarification.

Front Immunol

2022 Jun 6

Mitchell RA, Altszuler R, Gonzalez S

21. The Internal Conduit System of the Swine Inverted Lymph Node.

Front Immunol

2022 Jun 6

Dubreil L, Ledevin M, Hervet C

22. Dynamics of Type I and Type II Interferon Signature Determines Responsiveness to Anti-TNF Therapy in Rheumatoid Arthritis.

Front Immunol

2022 Jun 6

Iwasaki T, Watanabe R, Ito H

The factors influencing long-term responses to a tumor necrosis factor inhibitor (TNFi) in rheumatoid arthritis (RA) patients currently remain unknown. Therefore, we herein conducted a multi-omics analysis of TNFi responses in a Japanese RA cohort. Blood samples were collected from 27 biological disease-modifying antirheumatic drug (DMARD)-naive RA patients at the initiation of and after three months of treatment with TNFi. Treatment responses were evaluated at one year. Differences in gene expression levels in peripheral blood mononuclear cells (PBMCs), plasma protein levels, drug concentrations, and the presence/absence of anti-drug antibodies were investigated, and a cell phenotypic analysis of PBMCs was performed using flow cytometry. After one year of treatment, thirteen patients achieved clinical remission (responders), while the others did not or switched to other biologics (non-responders). Differentially expressed genes related to treatment responses were enriched for the interferon (IFN) pathway. The expression of type I IFN signaling-related genes was higher in non-responders than in responders before and after treatment (P = 0.03, 0.005, respectively). The expression of type II IFN signaling-related genes did not significantly differ before treatment; however, it increased in non-responders and decreased in responders, with a significant difference being observed after three months of treatment (P = 1.2×10-3). The total number of lymphocytes and C-X-C Motif Chemokine Ligand 10 (CXCL10) protein levels were associated with the type I IFN signature (P = 6.7×10-7, 6.4×10-3, respectively). Hepatocyte growth factor (HGF) protein levels before treatment predicted fold increases in type II IFN (P = 0.03). These IFN signature-related indices (the number of lymphocytes, CXCL10, and HGF) significantly differed between responders and non-responders (P = 0.01, 0.01, and 0.04, respectively). A single-cell analysis revealed that the type I IFN signature was more highly enriched in monocytes than in other cell types. A deconvolution analysis of bulk-RNA sequence data identified CD4+ and CD8+ T cells as the main sources of the type II IFN signature in non-responders. Collectively, the present results demonstrated that the dynamics of the type I and II IFN pathways affected long-term responses to TNFi, providing information on its biological background and potential for clinical applications.

23. Differentially Expressed miRNAs in Ulcerative Colitis and Crohn's Disease.

Front Immunol

2022 Jun 6

Yarani R, Shojaeian A, Palasca O

24. Signaling Crosstalks Drive Generation and Regeneration of the Thymus.

Front Immunol

2022 Jun 6

Rosichini M, Catanoso M, Screpanti I

25. Bioinformatics-Led Discovery of Osteoarthritis Biomarkers and Inflammatory Infiltrates.

Front Immunol

2022 Jun 6

Hu X, Ni S, Zhao K

26. Transcriptional Pattern Analysis of Virus-Specific CD8+ T Cells in Hepatitis C Infection: Increased Expression of TOX and Eomesodermin During and After Persistent Antigen Recognition.

Front Immunol

2022 Jun 6

Wildner NH, Walker A, Brauneck F

Thymocyte selection-associated high mobility group box (TOX) has been described to be a key regulator in the formation of CD8+ T cell exhaustion. Hepatitis C virus (HCV) infection with different lengths of antigen exposure in acute, chronic, and after resolution of HCV infection is the ideal immunological model to study the expression of TOX in HCV-specific CD8+ T cells with different exposure to antigen. HCV-specific CD8+ T cells from 35 HLA-A*01:01, HLA-A*02:01, and HLA-A*24:02 positive patients were analyzed with a 16-color FACS-panel evaluating the surface expression of lineage markers (CD3, CD8), ectoenzymes (CD39, CD73), markers of differentiation (CD45RO, CCR7, CD127), and markers of exhaustion and activation (TIGIT, PD-1, KLRG1, CD226) and transcription factors (TOX, Eomesodermin, T-bet). Here, we defined on-target T cells as T cells against epitopes without escape mutations and off-target T cells as those against a "historical" antigen mutated in the autologous sequence. TOX+HCV-specific CD8+ T cells from patients with chronic HCV and on-target T cells displayed co-expression of Eomesodermin and were associated with the formation of terminally exhausted CD127-PD1hi, CD39hi, CD73low CD8+ T cells. In contrast, TOX+HCV-specific CD8+ T cells in patients with off-target T cells represented a progenitor memory Tex phenotype characterized by CD127hi expression and a CD39low and CD73hi phenotype. TOX+HCV-specified CD8+ T cells in patients with a sustained virologic response were characterized by a memory phenotype (CD127+, CD73hi) and co-expression of immune checkpoints and Eomesodermin, indicating a key structure in priming of HCV-specific CD8+ T cells in the chronic stage, which persisted as a residual after therapy. Overall, the occurrence of TOX+HCV-specific CD8+ T cells was revealed at each disease stage, which impacted the development of progenitor Tex, intermediate Tex, and terminally exhausted T cell through an individual molecular footprint. In sum, TOX is induced early during acute infection but is modulated by changes in viral sequence and antigen recognition. In the case of antigen persistence, the interaction with Eomesodermin leads to the formation of terminally exhausted virus-specific CD8+ T cells, and there was a direct correlation of the co-expression of TOX and Eomes and terminally exhausted phenotype of virus-specific CD8+ T cells.

27. Added Value of Reanalysis of Whole Exome- and Whole Genome Sequencing Data From Patients Suspected of Primary Immune Deficiency Using an Extended Gene Panel and Structural Variation Calling.

Front Immunol

2022 Jun 30

Mørup SB, Nazaryan-Petersen L, Gabrielaite M

BACKGROUND: Knowledge of the genetic variation underlying Primary Immune Deficiency (PID) is increasing. Reanalysis of genome-wide sequencing data from undiagnosed patients with suspected PID may improve the diagnostic rate. METHODS: We included patients monitored at the Department of Infectious Diseases or the Child and Adolescent Department, Rigshospitalet, Denmark, for a suspected PID, who had been analysed previously using a targeted PID gene panel (457 PID-related genes) on whole exome- (WES) or whole genome sequencing (WGS) data. A literature review was performed to extend the PID gene panel used for reanalysis of single nucleotide variation (SNV) and small indels. Structural variant (SV) calling was added on WGS data. RESULTS: Genetic data from 94 patients (86 adults) including 36 WES and 58 WGS was reanalysed a median of 23 months after the initial analysis. The extended gene panel included 208 additional PID-related genes. Genetic reanalysis led to a small increase in the proportion of patients with new suspicious PID related variants of uncertain significance (VUS). The proportion of patients with a causal genetic diagnosis was constant. In total, five patients (5%, including three WES and two WGS) had a new suspicious PID VUS identified due to reanalysis. Among these, two patients had a variant added due to the expansion of the PID gene panel, and three patients had a variant reclassified to a VUS in a gene included in the initial PID gene panel. The total proportion of patients with PID related VUS, likely pathogenic, and pathogenic variants increased from 43 (46%) to 47 (50%), as one patient had a VUS detected in both initial- and reanalysis. In addition, we detected new suspicious SNVs and SVs of uncertain significance in PID candidate genes with unknown inheritance and/or as heterozygous variants in genes with autosomal recessive inheritance in 8 patients. CONCLUSION: These data indicate a possible diagnostic gain of reassessing WES/WGS data from patients with suspected PID. Reasons for the possible gain included improved knowledge of genotype-phenotype correlation, expanding the gene panel, and adding SV analyses. Future studies of genotype-phenotype correlations may provide additional knowledge on the impact of the new suspicious VUSs.

28. Metabolic Profiling at COVID-19 Onset Shows Disease Severity and Sex-Specific Dysregulation.

Front Immunol

2022 Jun 30

Ceballos FC, Virseda-Berdices A, Resino S

BACKGROUND: metabolic changes through SARS-CoV-2 infection has been reported but not fully comprehended. This metabolic dysregulation affects multiple organs during COVID-19 and its early detection can be used as a prognosis marker of severity. Therefore, we aimed to characterize metabolic and cytokine profile at COVID-19 onset and its relationship with disease severity to identify metabolic profiles predicting disease progression. MATERIAL AND METHODS: we performed a retrospective cross-sectional study in 123 COVID-19 patients which were stratified as asymptomatic/mild, moderate and severe according to the highest COVID-19 severity status, and a group of healthy controls. We performed an untargeted plasma metabolic profiling (gas chromatography and capillary electrophoresis-mass spectrometry (GC and CE-MS)) and cytokine evaluation. RESULTS: After data filtering and identification we observed 105 metabolites dysregulated (66 GC-MS and 40 CE-MS) which shown different expression patterns for each COVID-19 severity status. These metabolites belonged to different metabolic pathways including amino acid, energy, and nitrogen metabolism among others. Severity-specific metabolic dysregulation was observed, as an increased transformation of L-tryptophan into L-kynurenine. Thus, metabolic profiling at hospital admission differentiate between severe and moderate patients in the later phase of worse evolution. Several plasma pro-inflammatory biomarkers showed significant correlation with deregulated metabolites, specially with L-kynurenine and L-tryptophan. Finally, we describe a strong sex-related dysregulation of metabolites, cytokines and chemokines between severe and moderate patients. In conclusion, metabolic profiling of COVID-19 patients at disease onset is a powerful tool to unravel the SARS-CoV-2 molecular pathogenesis. CONCLUSIONS: This technique makes it possible to identify metabolic phenoconversion that predicts disease progression and explains the pronounced pathogenesis differences between sexes.

29. Human IL-17 and TNF-α Additively or Synergistically Regulate the Expression of Proinflammatory Genes, Coagulation-Related Genes, and Tight Junction Genes in Porcine Aortic Endothelial Cells.

Front Immunol

2022 Jun 30

Li W, Chen P, Zhao Y

Immune rejection is the major limitation for porcine xenograft survival in primate recipients. Proinflammatory cytokines play important roles in immune rejection and have been found to mediate the pathological effects in various clinical and experimental transplantation trials. IL-17 and TNF-α play critical pathological roles in immune disorders, such as psoriasis and rheumatoid arthritis. However, the pathological roles of human IL-17 (hIL-17) and human TNF-α (hTNF-α) in xenotransplantation remain unclear. Here we found that hIL-17 and hTNF-α additively or synergistically regulate the expression of 697 genes in porcine aortic endothelial cells (PAECs). Overall, 415 genes were found to be synergistically regulated, while 282 genes were found to be additively regulated. Among these, 315 genes were upregulated and 382 genes were downregulated in PAECs. Furthermore, we found that hIL-17 and hTNF-α additively or synergistically induced the expression of various proinflammatory cytokines and chemokines (e.g., IL1α, IL6, and CXCL8) and decreased the expression of certain anti-inflammatory genes (e.g., IL10). Moreover, hIL-17 plus hTNF-α increased the expression of IL1R1 and IL6ST, receptors for IL1 and IL6, respectively, and decreased anti-inflammatory gene receptor expression (IL10R). hIL-17 and hTNF-α synergistically or additively induced CXCL8 and CCL2 expression and consequently promoted primary human neutrophil and human leukemia monocytic cell migration, respectively. In addition, hIL-17 and hTNF-α induced pro-coagulation gene (SERPINB2 and F3) expression and decreased anti-coagulation gene (TFPI, THBS1, and THBD) expression. Additionally, hIL-17 and hTNF-α synergistically decreased occludin expression and consequently promoted human antibody-mediated complement-dependent cytotoxicity. Interestingly, hTNF-α increased swine leukocyte antigen (SLA) class I expression; however, hIL-17 decreased TNF-α-mediated SLA-I upregulation. We concluded that hIL-17 and hTNF-α likely promote the inflammatory response, coagulation cascade, and xenoantibody-mediated cell injury. Thus, blockade of hIL-17 and hTNF-α together might be beneficial for xenograft survival in recipients.

30. Long-Term Prognostic Factors in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A 15-Year Multicenter Retrospective Study.

Front Immunol

2022 Jun 30

Liao QQ, Ren YF, Zhu KW

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a multisystem autoimmune disease with small-vessel involvement. In AAV, microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are major clinicopathologic variants. In addition, myeloperoxidase (MPO) and proteinase 3 (PR3) are major target antigens. The objective of the study was to explore the predictive factors for long-term survival in AAV patients. MATERIALS AND METHODS: A multicenter retrospective study was carried out on 407 patients between 2005 and 2020. Clinical parameters were obtained from laboratory tests including the ANCA types, antinuclear antibody (ANA), extractable nuclear antigen (ENA), anti-streptolysin O (ASO), glomerular filtration rate (GFR), and the laboratory examinations for the blood routine, liver function, renal function, and immunity, etc. The data for clinical parameters were collected from electronic medical records (EMRs), and the data for patient survival were acquired through regular follow-up. The association of clinical parameters with overall survival (OS) along with 3-year and 5-year survival rates was analyzed, and the nomogram as a predictive model was established according to the analysis results. RESULTS: In the present study, 336 (82.6%) patients and 46 (11.3%) patients were diagnosed with MPA and GPA, respectively. The mean and median OS for all the patients were 2,285 and 2,290 days, respectively. The 1-year, 3-year, 5-year, and 10-year cumulative survival rates for all the patients were 84.2%, 76.3%, 57.2%, and 32.4%, respectively. Univariate and multivariate survival analyses indicated that the independent prognostic factors included age, pathological categories (MPA, GPA, and other types), serum ANCA types (negative or positive for MPO and/or PR3), ANA, ASO, GFR, lymphocyte, neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP), and these clinical parameters except for ASO were used to construct a nomogram. The nomogram for 3-year and 5-year survival rates had a C-index of 0.721 (95% CI 0.676-0.766). The calibration curves showed that the predicted values of the nomogram for 3-year and 5-year survival rates were generally consistent with practical observed values, and decision curve analysis (DCA) further demonstrated the practicability and accuracy of the predictive model. CONCLUSION: Laboratory tests at diagnosis have great significance in the prediction of long-term survival in AAV patients.

31. Shaping Polarization Of Tumor-Associated Macrophages In Cancer Immunotherapy.

Front Immunol

2022 Jun 30

Gao J, Liang Y, Wang L.

32. TNFR2 Costimulation Differentially Impacts Regulatory and Conventional CD4(+) T-Cell Metabolism.

Front Immunol

2022 Jun 30

Mensink M, Tran TNM, Zaal EA

33. Combining Clinical Parameters and Acute Tubular Injury Grading Is Superior in Predicting the Prognosis of Deceased-Donor Kidney Transplantation: A 7-Year Observational Study.

Front Immunol

2022 Jun 30

Wang J, Liu J, Wu W

BACKGROUND: We developed a pragmatic dichotomous grading criterion to stratify the acute tubular injury (ATI) of deceased-donor kidneys. We intended to verify the predictive value of this criterion for the prognosis of deceased-donor kidney transplantation. METHODS: The allografts with ATI were classified into severe and mild groups. Severe ATI was defined as the presence of extreme and diffuse flattening of the tubular epithelial cells, or denudement of the tubular basement membrane. The clinical delayed graft function (DGF) risk index was calculated based on a regression model for posttransplant DGF using 17 clinical parameters related to donor-recipient characteristics. RESULTS: A total of 140 recipients were enrolled: 18 severe and 122 mild ATI. Compared with the mild ATI group, the severe ATI group had more donors after cardiac death, higher median donor terminal serum creatinine level (dScr), and longer median cold ischemia time. Severe ATI had a higher DGF rate (55.6% vs 14.6%, p < 0.001), longer DGF recovery time (49.6 vs 26.3 days, p < 0.001), and a lower estimated glomerular filtration rate (eGFR) at 1 month (23.5 vs 54.0 ml/min/1.73 m2, p < 0.001), 3 months (40.4 vs 59.0, p = 0.001), and 6 months after transplant (46.8 vs 60.3, p = 0.033). However, there was no significant difference in eGFR at 1 year or beyond, graft, and patient survival. The predictive value of combined dScr with ATI severity for DGF rate and DGF recovery time was superior to that of dScr alone. The predictive value of the combined DGF risk index with ATI severity for DGF was also better than that of the DGF risk index alone; however, the association of the DGF risk index with DGF recovery time was not identified. Chronic lesions including glomerulosclerosis, interstitial fibrosis, arterial intimal fibrosis, and arteriolar hyalinosis were associated with declined posttransplant 1-year eGFR. CONCLUSION: Based on our pragmatic dichotomous grading criterion for ATI in a preimplantation biopsy, donor kidneys with severe ATI increased DGF risk, prolonged DGF recovery, and decreased short-term graft function but demonstrated favorable long-term graft function. Our grading method can offer additive valuable information for assessing donor kidneys with acute kidney injury and may act as an effective supplementary index of the Banff criteria.

34. Immunogenicity of SARS-CoV-2 Trimeric Spike Protein Associated to Poly(I:C) Plus Alum.

Front Immunol

2022 Jun 30

Dos-Santos JS, Firmino-Cruz L, da Fonseca-Martins AM

The SARS-CoV-2 pandemic has had a social and economic impact worldwide, and vaccination is an efficient strategy for diminishing those damages. New adjuvant formulations are required for the high vaccine demands, especially adjuvant formulations that induce a Th1 phenotype. Herein we assess a vaccination strategy using a combination of Alum and polyinosinic:polycytidylic acid [Poly(I:C)] adjuvants plus the SARS-CoV-2 spike protein in a prefusion trimeric conformation by an intradermal (ID) route. We found high levels of IgG anti-spike antibodies in the serum by enzyme linked immunosorbent assay (ELISA) and high neutralizing titers against SARS-CoV-2 in vitro by neutralization assay, after two or three immunizations. By evaluating the production of IgG subtypes, as expected, we found that formulations containing Poly(I:C) induced IgG2a whereas Alum did not. The combination of these two adjuvants induced high levels of both IgG1 and IgG2a. In addition, cellular immune responses of CD4+ and CD8+ T cells producing interferon-gamma were equivalent, demonstrating that the Alum + Poly(I:C) combination supported a Th1 profile. Based on the high neutralizing titers, we evaluated B cells in the germinal centers, which are specific for receptor-binding domain (RBD) and spike, and observed that more positive B cells were induced upon the Alum + Poly(I:C) combination. Moreover, these B cells produced antibodies against both RBD and non-RBD sites. We also studied the impact of this vaccination preparation [spike protein with Alum + Poly(I:C)] in the lungs of mice challenged with inactivated SARS-CoV-2 virus. We found a production of IgG, but not IgA, and a reduction in neutrophil recruitment in the bronchoalveolar lavage fluid (BALF) of mice, suggesting that our immunization scheme reduced lung inflammation. Altogether, our data suggest that Alum and Poly(I:C) together is a possible adjuvant combination for vaccines against SARS-CoV-2 by the intradermal route.

35. Epigenetic Aspects and Prospects in Autoimmune Hepatitis.

Front Immunol

2022 Jun 30

Czaja AJ.

36. Role of Fc Core Fucosylation in the Effector Function of IgG1 Antibodies.

Front Immunol

2022 Jun 30

Golay J, Andrea AE, Cattaneo I.

37. Altered Balance of Pro-Inflammatory Immune Cells to T Regulatory Cells Differentiates Symptomatic From Asymptomatic Individuals With Anti-Nuclear Antibodies.

Front Immunol

2022 Jun 30

Gupta R, Vanlieshout E, Manion K

38. Elucidation of the Application of Blood Test Biomarkers to Predict Immune-Related Adverse Events in Atezolizumab-Treated NSCLC Patients Using Machine Learning Methods.

Front Immunol

2022 Jun 30

Zhou JG, Wong AH, Wang H

39. IL-1α and IL-36 Family Cytokines Can Undergo Processing and Activation by Diverse Allergen-Associated Proteases.

Front Immunol

2022 Jun 30

Frezza V, Najda Z, Davidovich P

40. Key Factors for Thymic Function and Development.

Front Immunol

2022 Jun 30

Shichkin VP, Antica M.

41. Rituximab Therapy for Mucous Membrane Pemphigoid: A Retrospective Monocentric Study With Long-Term Follow-Up in 109 Patients.

Front Immunol

2022 Jun 30

Bohelay G, Alexandre M, Le Roux-Villet C

Mucous membrane pemphigoid (MMP) is a heterogeneous group of rare, chronic, subepithelial autoimmune blistering diseases (AIBDs) with predominant involvement of mucous membranes that can be sight-threatening and life-threatening. Rituximab (RTX) has demonstrated its efficacy in severe MMP refractory to conventional immunosuppressants in small series that differed in RTX scheme, concomitant therapies, and outcome definitions. In a meta-analysis involving 112 patients with MMP treated with RTX, complete remission (CR) was reported in 70.5% of cases. Herein, we report the largest retrospective monocentric study on RTX efficacy in a series of 109 severe and/or refractory patients with MMP treated with RTX with a median follow-up period of 51.4 months. RTX was administered in association with immunomodulatory drugs (dapsone, salazopyrine) without any other systemic immunosuppressant in 104 patients. The RTX schedule comprised two injections (1 g, 2 weeks apart), repeated every 6 months until CR or failure, with a unique consolidation injection (1 g) after CR. The median survival times to disease control and to CR were 7.1 months and 12.2 months, respectively. The median number of RTX cycles required to achieve CR in 85.3% of patients was two. The larynx was the lesional site that took the longest time to achieve disease control. One year after RTX weaning, CR off RTX was obtained in 68.7% of cases. CR off RTX with only minimum doses of immunomodulatory drugs was achieved in 22.0% of patients. Further, 10.1% of patients were partial responders and 4.6% were non-responders to RTX. Relapse occurred in 38.7% of cases, of whom 91.7% had achieved CR again at the last follow-up. In MMP, CR was achieved in a longer time and after more rituximab cycles than in pemphigus, especially for patients with MMP with anti-type VII collagen reactivity. RTX with concomitant immunomodulatory drugs was not responsible for an unusual proportion of adverse events. This large study confirms that RTX is an effective therapy in patients with severe and/or refractory MMP, corroborating previous findings regarding the effects of RTX on AIBDs such as pemphigus.

42. Immunolipidomics Reveals a Globoside Network During the Resolution of Pro-Inflammatory Response in Human Macrophages.

Front Immunol

2022 Jun 30

Muralidharan S, Torta F, Lin MK

43. Key Signature Genes of Early Terminal Granulocytic Differentiation Distinguish Sepsis From Systemic Inflammatory Response Syndrome on Intensive Care Unit Admission.

Front Immunol

2022 Jun 30

Velásquez SY, Coulibaly A, Sticht C

44. Corrigendum: Brief Research Report: Virus-Specific Humoral Immunity at Admission Predicts the Development of Respiratory Failure in Unvaccinated SARS-CoV-2 Patients.

Front Immunol

2022 Jun 30

Tajuelo A, Carretero O, García-Ríos E

45. Editorial: Immunological Tolerance in Transplantation: More Than Deletion.

Front Immunol

2022 Jun 30

Pilat N, Wekerle T, Geissler EK

46. Acinetobacter baumannii Outer Membrane Protein A Induces Pulmonary Epithelial Barrier Dysfunction and Bacterial Translocation Through The TLR2/IQGAP1 Axis.

Front Immunol

2022 Jun 30

Zhang W, Zhou H, Jiang Y

47. T(REG)king From Gut to Brain: The Control of Regulatory T Cells Along the Gut-Brain Axis.

Front Immunol

2022 Jun 30

Choi J, Kim BR, Akuzum B

48. Neutralizing Potency of Prototype and Omicron RBD mRNA Vaccines Against Omicron Variant.

Front Immunol

2022 Jun 30

Zang J, Yin Y, Xu S

49. Mapping the Tumor Microenvironment in TNBC and Deep Exploration for M1 Macrophages-Associated Prognostic Genes.

Front Immunol

2022 Jun 30

Xu B, Sun H, Song X

50. Alt a 1 Promotes Allergic Asthma In Vivo Through TLR4-Alveolar Macrophages.

Front Immunol

2022 Jun 30

Hernandez-Ramirez G, Pazos-Castro D, Gonzalez-Klein Z

51. Exploration of Novel Immunological Terms in Lung Cancer With Large Populations: Implications for Immunotherapy.

Front Immunol

2022 Jun 30

Yao Y, Wang J, Yang F

BACKGROUND: Ideal biomarkers to predict the response to immunotherapy in lung cancer are still lacking. Therefore, there is a need to explore effective biomarkers in large populations. OBJECTIVE: The objective of this study is to explore novel immunological classifications that are associated with immunotherapy response through the ssGSEA algorithm. METHODS: Six independent lung cancer cohorts were collected for analysis including The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and the EMBL-EBI database. The ssGSEA algorithm was performed to extract immune terms. Then, TCGA samples were involved as a training group and other cohorts were used as a validation group. After LASSO and Cox regression, prognostic associated immune terms were extracted and an immune-related risk score (IRS) signature was constructed. Furthermore, the association between IRS signature and clinical data, genome features, stemness indices analysis, tumor immune microenvironment, immunotherapy efficiency, and targeted therapy response was also investigated. RESULTS: A total of 1,997 samples were enrolled in this study including six large lung cancer cohorts. Fifty-four immune terms were calculated through the ssGSEA algorithm in combined cohorts. Then, a nine-immune-term risk score model named IRS signature was established to predict the prognosis in combined cohorts. We classified patients into high-risk and low-risk subgroups according to the cutoff point. Subsequently, analysis of clinical data and genome features indicated that the patients in the high-IRS group tend to have advanced clinical features (clinical stage and T classification), as well as a higher level of copy number variation burden, higher tumor burden mutation, and higher tumor stemness indices. Immune landscape analysis demonstrated that high-IRS groups exhibited lower immune cell infiltration and immune-suppressive state. More importantly, the predicted result of the Tumor Immune Dysfunction and Exclusion analysis showed that high-IRS groups might be more insensitive to immunotherapy. Meanwhile, we have also identified that high-IRS groups were associated with better efficiency of several targeted drugs. CONCLUSION: To summarize, we identified a novel IRS model based on nine immune terms, which was quantified by the ssGSEA algorithm. This model had good efficacy in predicting overall survival and immunotherapy response in non-small cell lung cancer patients, which might be an underlying biomarker.

52. Determining the Optimal (Neo)Adjuvant Regimen for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Regarding Survival Outcome: A Network Meta-Analysis.

Front Immunol

2022 Jun 30

Cai YW, Shao ZM, Yu KD.

BACKGROUND: The optimal (neo)adjuvant regimen for human epidermal growth factor receptor-2 (HER2)-positive breast cancer regarding survival outcomes remains unclear. METHODS: We searched Web of Science, PubMed, and the Cochrane Central Register of Controlled Trials systematically to find out randomized controlled studies, up to January 2022, that compared different anti-HER2 regimens in the (neo)adjuvant setting. The primary endpoint was disease-free survival (DFS). We used a Bayesian statistical model to combine direct and indirect comparisons and used odds ratios (ORs) to pool effect sizes and performed the surface under the cumulative ranking area (SUCRA) curves to estimate the ranking probabilities of various regimens. For survival outcomes, we performed two parallel analyses, one based on data from both neoadjuvant and adjuvant studies and the other specific to adjuvant studies. All statistics were two-sided. RESULTS: Fifteen studies were finally enrolled. Regarding DFS, the overall analysis indicated that the top two regimens for HER2-positive breast cancer were chemotherapy plus trastuzumab with lapatinib, and chemotherapy plus trastuzumab with pertuzumab (SUCAR of 81% and 79%, respectively), with the OR of 0.99 [95% confidence interval (CI), 0.59 to 1.54]; the parallel analysis specific to adjuvant trials indicated that the top two regimens were chemotherapy plus trastuzumab with sequential neratinib, and chemotherapy plus trastuzumab with pertuzumab (SUCRA of 80% and 76%, respectively), with the OR of 1.04 (95% CI, 0.63 to 1.73). The dual-target therapy that combines trastuzumab and pertuzumab showed the highest risk of inducing cardiac events, with an SUCRA of 92%. CONCLUSIONS: Chemotherapy plus trastuzumab and pertuzumab might be the optimal regimen for HER2-positive breast cancer in improving the survival rate. However, the cardiotoxicity of this dual-target therapy should be taken care of.

53. Obesity-Mediated Immune Modulation: One Step Forward, (Th)2 Steps Back.

Front Immunol

2022 Jun 30

Schmidt V, Hogan AE, Fallon PG

54. RNA-Seq and 16S rRNA Analysis Revealed the Effect of Deltamethrin on Channel Catfish in the Early Stage of Acute Exposure.

Front Immunol

2022 Jun 3

Yang Y, Zhu X, Huang Y

Deltamethrin (Del) is a widely used pyrethroid insecticide and a dangerous material that has brought serious problems to the healthy breeding of aquatic animals. However, the toxicological mechanisms of Del on channel catfish remain unclear. In the present study, we exposed channel catfish to 0, 0.5, and 5 μg/L Del for 6 h, and analyzed the changes in histopathology, trunk kidney transcriptome, and intestinal microbiota composition. The pathological analyses showed that a high concentration of Del damaged the intestine and trunk kidney of channel catfish in the early stage. The transcriptome analysis detected 32 and 1837 differentially expressed genes (DEGs) in channel catfish trunk kidneys after exposure to 0.5 and 5 μg/L Del, respectively. Moreover, the KEGG pathway and GO enrichment analyses showed that the apoptosis signaling pathway was significantly enriched, and apoptosis-related DEGs, including cathepsin L, p53, Bax, and caspase-3, were also detected. These results suggested that apoptosis occurs in the trunk kidney of channel catfish in the early stage of acute exposure to Del. We also detected some DEGs and signaling pathways related to immunity and drug metabolism, indicating that early exposure to Del can lead to immunotoxicity and metabolic disorder of channel catfish, which increases the risk of pathogenic infections and energy metabolism disorders. Additionally, 16S rRNA gene sequencing showed that the composition of the intestinal microbiome significantly changed in channel catfish treated with Del. At the phylum level, the abundance of Firmicutes, Fusobacteria, and Actinobacteria significantly decreased in the early stage of Del exposure. At the genus level, the abundance of Romboutsia, Lactobacillus, and Cetobacterium decreased after Del exposure. Overall, early exposure to Del can lead to tissue damage, metabolic disorder, immunotoxicity, and apoptosis in channel catfish, and affect the composition of its intestinal microbiota. Herein, we clarified the toxic effects of Del on channel catfish in the early stage of exposure and explored why fish under Del stress are more vulnerable to microbial infections and slow growth.

55. Timeline Kinetics of Systemic and Airway Immune Mediator Storm for Comprehensive Analysis of Disease Outcome in Critically Ill COVID-19 Patients.

Front Immunol

2022 Jun 3

Gonçalves JJ, da Mata CPSM, Lourenço AA

56. Granulocyte-Macrophage Colony-Stimulating Factor Modulates Myeloid-Derived Suppressor Cells and Treg Activity in Decompensated Cirrhotic Patients With Sepsis.

Front Immunol

2022 Jun 3

Sehgal R, Maiwall R, Rajan V

BACKGROUND: Decompensated cirrhosis patients are more prone to bacterial infections. Myeloid-derived suppressor cells (MDSCs) expand in sepsis patients and disrupt immune cell functions. Granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy helps in restoring immune cell functions and resolving infections. Its role in MDSC modulation in cirrhosis with sepsis is not well understood. METHODS: A total of 164 decompensated cirrhotic-62 without (w/o), 72 with sepsis, and 30 with sepsis treated with GM-CSF-and 15 healthy were studied. High-dimensional flow cytometry was performed to analyze MDSCs, monocytes, neutrophils, CD4 T cells, and Tregs at admission and on days 3 and day 7. Ex vivo co-cultured MDSCs with T cells were assessed for proliferation and apoptosis of T cells and differentiation to Tregs. Plasma factors and mRNA levels were analyzed by cytokine-bead assay and qRT-PCR. RESULTS: Frequencies of MDSCs and Tregs were significantly increased (p = 0.011 and p = 0.02) with decreased CD4 T cells (p = 0.01) in sepsis than w/o sepsis and healthy controls (HCs) (p = 0.000, p = 0.07, and p = 0.01) at day 0 and day 7. In sepsis patients, MDSCs had increased IL-10, Arg1, and iNOS mRNA levels (p = 0.016, p = 0.043, and p = 0.045). Ex vivo co-cultured MDSCs with T cells drove T-cell apoptosis (p = 0.03, p = 0.03) with decreased T-cell proliferation and enhanced FOXP3+ expression (p = 0.044 and p = 0.043) in sepsis compared to w/o sepsis at day 0. Moreover, blocking the MDSCs with inhibitors suppressed FOXP3 expression. GM-CSF treatment in sepsis patients significantly decreased MDSCs and FOXP3+ Tregs but increased CD4 T-cell functionality and improved survival. CONCLUSION: MDSCs have an immunosuppressive function by expanding FOXP3+ Tregs and inhibiting CD4+ T-cell proliferation in sepsis. GM-CSF treatment suppressed MDSCs, improved T-cell functionality, and reduced Tregs in circulation.

57. High Salt Induces a Delayed Activation of Human Neutrophils.

Front Immunol

2022 Jun 3

Mazzitelli I, Bleichmar L, Melucci C

58. Quantifying Reductions in Plasmodium falciparum Infectivity to Mosquitos: A Sample Size Calculator to Inform Clinical Trials on Transmission-Reducing Interventions.

Front Immunol

2022 Jun 3

Ramjith J, Alkema M, Bradley J

59. Large-Scale Transcriptome Data Analysis Identifies KIF2C as a Potential Therapeutic Target Associated With Immune Infiltration in Prostate Cancer.

Front Immunol

2022 Jun 3

Zhang P, Gao H, Ye C

60. Role of ILC2s in Solid Tumors: Facilitate or Inhibit?

Front Immunol

2022 Jun 3

Wu L, Zhao W, Tang S

61. ASCL2 Affects the Efficacy of Immunotherapy in Colon Adenocarcinoma Based on Single-Cell RNA Sequencing Analysis.

Front Immunol

2022 Jun 3

Wu L, Sun S, Qu F

62. Estrogen May Enhance Toll-Like Receptor 4-Induced Inflammatory Pathways in People With HIV: Implications for Transgender Women on Hormone Therapy.

Front Immunol

2022 Jun 3

Kettelhut A, Bowman E, Gabriel J

BACKGROUND: Transgender women (TW) are at increased risk for both human immunodeficiency virus (HIV) and cardiovascular disease (CVD). Antiretroviral therapy-treated HIV has been associated with a two-fold increased risk of CVD, potentially due to dysregulated Toll-like receptor (TLR)-induced immune activation. Use of estrogens in feminizing hormone therapy (FHT) may enhance inflammatory responses and the risk of cardiovascular mortality in TW. Despite this, the immunomodulatory effects of estrogen use in TW with HIV have been inadequately explored. METHODS: As an in vitro model for FHT, cryopreserved PBMCs (cryoPBMCs) from HIV negative (HIV-), HIV+ ART-suppressed (HIV+SP), and HIV+ ART-unsuppressed (HIV+USP) cisgender men were cultured overnight in the presence of 17-β estradiol or 17-α ethinylestradiol with and without the TLR4 agonist LPS or the TLR8 agonist ssPolyU. Monocyte activation (CD69, HLA-DR, CD38) was assessed by flow cytometry. Cytokine levels (IL-6, TNF-α, IL-1β, and IL-10) were measured in cell culture supernatants by Legendplex. Levels of phosphorylated TLR signaling molecules (JNK, MAPK p38) were assessed by Phosflow. Plasma levels of immune activation biomarkers (LPS-binding protein, monocyte activation markers sCD14 and sCD163, and inflammatory molecules IL-6 and TNF-α receptor I) were measured by ELISA. RESULTS: PBMCs from people with HIV (PWH) produced greater levels of inflammatory cytokines following exposure to LPS or ssPolyU compared to levels from cells of HIV- individuals. While estrogen exposure alone induced mild changes in immune activation, LPS-induced TLR4 activation was elevated with estrogen in cisgender men (CM) with HIV, increasing monocyte activation and inflammatory cytokine production (IL-6, TNF-α). Interestingly, testosterone inhibited LPS-induced cytokine production in CM regardless of HIV status. Plasma markers of immune activation and microbial translocation (e.g., sCD14, sCD163, LPS-binding protein) were generally higher in PWH compared to HIV- CM, and these markers were positively associated with in vitro responsiveness to estrogen and LPS in CM with HIV. CONCLUSIONS: Our in vitro data suggest that estrogen exposure may enhance innate immune activation in PWH. Further examination is needed to fully understand the complex interactions of FHT, HIV, and CVD in TW, and determine optimal FHT regimens or supplementary treatments aimed at reducing excess immune activation.

63. TIGIT as a Promising Therapeutic Target in Autoimmune Diseases.

Front Immunol

2022 Jun 3

Yue C, Gao S, Li S

64. Vaccine Protection Through Placenta and Breastfeeding: The Unmet Topic in COVID-19 Pandemic.

Front Immunol

2022 Jun 3

Laguila Altoé A, Marques Mambriz AP, Cardozo DM

65. Autoantigen Discovery in the Hair Loss Disorder, Alopecia Areata: Implication of Post-Translational Modifications.

Front Immunol

2022 Jun 3

Jadeja SD, Tobin DJ.

Alopecia areata (AA) is a chronic, multifactorial, polygenic, and heterogeneous disorder affecting growing hair follicles in susceptible individuals, which results in a non-scarring and reversible hair loss with a highly unpredictable course. Despite very considerable research effort, the nature of the precipitating factor(s) responsible for initiating AA in any given hair follicle remains unclear, due largely to significant gaps in our knowledge of the precise sequence of the etiopathogenic events in this dermatosis. However, disease-related changes in the immune-competence of the lower growing hair follicle, together with an active immune response (humoral and cellular) to hair follicle-associated antigens, are key associated phenomena. Confirmation of the hair follicle antigen(s) implicated in AA disease onset has remained stubbornly elusive. While it may be considered somewhat philosophical by some, it is also unclear whether immune-mediated hair loss in AA results from a) an ectopic (i.e., in an abnormal location) immune response to native (unmodified) self-antigens expressed by the healthy hair follicle, b) a normal immune response against modified self-antigens (or neoantigens), or c) a normal immune response against self-antigens (modified/non-modified) that were not previously visible to the immune system (because they were conformationally-hidden or sequestered) but become exposed and presentable in an MHC-I/-II molecule-restricted manner. While some candidate hair follicle antigen target(s) in AA are beginning to emerge, with a potential role for trichohyalin, it is not yet clear whether this represents the initial and immunodominant antigenic focus in AA or is simply one of an expanding repertoire of exposed hair follicle tissue damage-associated antigens that are secondary to the disease. Confirmation of autoantigen identity is essential for our understanding of AA etiopathogenesis, and consequently for developing a more informed therapeutic strategy. Major strides have been made in autoantigen discovery in other autoimmune conditions. In particular, some of these conditions may provide insights into how post-translational modifications (e.g., citrullination, deamidation, etc.) of hair follicle-restricted proteins may increase their antigenicity and so help drive the anti-hair follicle immune attack in AA.

66. Adiponectin Ameliorates GMH-Induced Brain Injury by Regulating Microglia M1/M2 Polarization Via AdipoR1/APPL1/AMPK/PPARγ Signaling Pathway in Neonatal Rats.

Front Immunol

2022 Jun 3

Xu N, Li X, Weng J

67. Coevolved Canonical Loops Conformations of Single-Domain Antibodies: A Tale of Three Pockets Playing Musical Chairs.

Front Immunol

2022 Jun 3

Gaudreault F, Corbeil CR, Purisima EO

Single-domain antibodies (sdAbs) are a promising class of biotherapeutics with unique structural traits within their paratope region. The distribution of canonical conformations explored by their complementarity determining region (CDR) loops differs to some extent from conventional two-chain Fv fragments of monoclonal antibodies (mAbs). In this study, we explored in detail the canonical structures of sdAb CDR-H1 and CDR-H2 loops and compared those with mAbs from the IGHV3 and IGHV1 gene families. We surveyed the antibody structures catalogued in SAbDab and clustered the CDR canonical loops in Cartesian space. While most of the sdAb clusters were sub-populations of previously defined canonical Fv conformations of CDR-H1 and CDR-H2, our stricter clustering approach defined narrower clusters in sequence-space. Meticulous visual inspection of sub-populations allowed a clearer understanding of sequence-structure relationships. The packing densities within structural pockets contacted by CDR-H1 and CDR-H2 canonical conformations were analyzed on the premise that these pockets cannot be left vacant as they would leave exposed supportive hydrophobic residues. The fine resolution of the canonical clusters defined here revealed unique signatures within these pockets, including distinct structural complementarities between CDR-H1 and CDR-H2 canonical clusters, which could not be perceived with the previous coarser clusters. We highlight examples where a single residue change in CDR-H1 sequence is sufficient to induce a dramatic population shift in CDR-H2 conformation. This suggests that preferences in combining CDR-H1 and CDR-H2 emerged naturally during antibody evolution, leading to preferred sets of conserved amino acids at key positions in the framework as well as within the CDR loops. We outline a game of musical chairs that is necessary to maintain the integrity of the antibody structures that arose during evolution. Our study also provides refined CDR-H1 and CDR-H2 structural templates for sdAb homology modeling that could be leveraged for improved antibody design.

68. A BALB/c IGHV Reference Set, Defined by Haplotype Analysis of Long-Read VDJ-C Sequences From F1 (BALB/c x C57BL/6) Mice.

Front Immunol

2022 Jun 3

Jackson KJL, Kos JT, Lees W

69. Ferroptosis and Autoimmune Diseases.

Front Immunol

2022 Jun 3

Lai B, Wu CH, Wu CY

70. CT-M8 Mice: A New Mouse Model Demonstrates That Basophils Have a Nonredundant Role in Lupus-Like Disease Development.

Front Immunol

2022 Jun 29

Tchen J, Simon Q, Chapart L

71. Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic Stress.

Front Immunol

2022 Jun 29

Wu H, Bao H, Liu C

Damage-associated molecular patterns (DAMPs) are the primary promoter of progressive neuroinflammation and are associated with chronic stress-related emotional disorders. The present study investigated the role and mechanism of extracellular nucleosomes and histones, the newly defined DAMPs, in mice with chronic stress. C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) and corticosterone drinking, respectively, for 4 weeks. Negative emotional behaviors were comprehensively investigated. Microglial morphology, oxidative stress, and inflammation, as well as C-type lectin receptor 2D (Clec2d) and Toll-like receptor 9 (TLR9) expression in medial prefrontal cortex (mPFC) were assessed with flow cytometer and cell sorting. Specifically, microglial pro-inflammatory activation and inflammation were further investigated with stereotactic injection of recombinant nucleosomes and histones in mPFC and further evaluated with AAV-Clec2d knocking-down, DNase I, and activated protein C (APC) pretreatment. Moreover, the rescue effect by AAV-Clec2d knocking-down was observed in mice with chronic stress. Mice with chronic stress were presented as obviously depressive- and anxiety-like behaviors and accompanied with significant microglial oxidative stress and inflammation, indicating by reactive oxygen species (ROS) production, primed nuclear factor-κB (NF-κB) signaling pathway, activated NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome, and upregulated Clec2d and TLR9 in mPFC, together with histones dictation in cerebrospinal fluid and extracellular trap formation. Stereotactic injection of nucleosomes was contributed to promote microglial inflammation rather than histones in mPFC, indicating that the pro-inflammatory role was derived from extracellular histones-bound DNA but not freely histones. AAV-Clec2d knocking-down, DNase I, and APC were all effective to inhibit nucleosome-induced microglial oxidative stress and inflammation. Moreover, AAV-Clec2d knocking-down in mice with chronic stress exhibited reduced microglial inflammation and improved negative emotional behaviors. Our findings reveal a novel mechanism of DAMP-associated inflammation that extracellular nucleosomes accelerate microglial inflammation via Clec2d and TLR9, and then contribute to chronic stress-induced emotional disorders.

72. Heterogeneity of Group 2 Innate Lymphoid Cells Defines Their Pleiotropic Roles in Cancer, Obesity, and Cardiovascular Diseases.

Front Immunol

2022 Jun 29

Ikutani M, Nakae S.

73. Activation of the AIM2 Receptor in Circulating Cells of Post-COVID-19 Patients With Signs of Lung Fibrosis Is Associated With the Release of IL-1α, IFN-α and TGF-β.

Front Immunol

2022 Jun 29

Colarusso C, Terlizzi M, Maglio A

74. Immune System Modulation by the Adjuvants Poly (I:C) and Montanide ISA 720.

Front Immunol

2022 Jun 29

Marques RF, de Melo FM, Novais JT

75. Single-Cell RNA Sequencing of Peripheral Blood Mononuclear Cells From Acute Myocardial Infarction.

Front Immunol

2022 Jun 29

Qian J, Gao Y, Lai Y

BACKGROUND: Acute myocardial infarction (AMI) can occur in patients with atherosclerotic disease, with or without plaque rupture. Previous studies have indicated a set of immune responses to plaque rupture. However, the specific circulating immune cell subsets that mediate inflammatory plaque rupture remain elusive. METHODS: Ten AMI patients were enrolled in our study (five with and five without plaque rupture; plaque characteristics were identified by optical coherence tomography). By single-cell RNA sequencing, we analyzed the transcriptomic profile of peripheral blood mononuclear cells. RESULTS: We identified 27 cell clusters among 82,550 cells, including monocytes, T cells, NK cells, B cells, megakaryocytes, and CD34+ cells. Classical and non-classical monocytes constitute the major inflammatory cell types, and pro-inflammatory genes such as CCL5, TLR7, and CX3CR1 were significantly upregulated in patients with plaque rupture, while the neutrophil activation and degranulation genes FPR2, MMP9, and CLEC4D were significantly expressed in the intermediate monocytes derived from patients without plaque rupture. We also found that CD4+ effector T cells may contribute to plaque rupture by producing a range of cytokines and inflammatory-related chemokines, while CD8+ effector T cells express more effector molecules in patients without plaque rupture, such as GZMB, GNLY, and PRF1, which may contribute to the progress of plaque erosion. Additionally, NK and B cells played a significant role in activating inflammatory cells and promoting chemokine production in the plaque rupture. Cell-cell communication elaborated characteristics in signaling pathways dominated by inflammatory activation of classical monocytes in patients with plaque rupture. CONCLUSIONS: Our studies demonstrate that the circulating immune cells of patients with plaque rupture exhibit highly pro-inflammatory characteristics, while plaque erosion is mainly associated with intermediate monocyte amplification, neutrophil activation, and degranulation. These findings may provide novel targets for the precise treatment of patients with AMI.

76. Extracellular CIRP Promotes GPX4-Mediated Ferroptosis in Sepsis.

Front Immunol

2022 Jun 29

Shimizu J, Murao A, Nofi C

77. Allele and Haplotype Frequencies of HLA-A, -B, -C, and -DRB1 Genes in 3,750 Cord Blood Units From a Kinh Vietnamese Population.

Front Immunol

2022 Jun 29

Que TN, Khanh NB, Khanh BQ

The frequencies and diversities of human leukocyte antigen (HLA) alleles and haplotypes are representative of ethnicities. Matching HLA alleles is essential for many clinical applications, including blood transfusion, stem cell transplantation, and tissue/organ transplantation. To date, the information about the frequencies and distributions of HLA alleles and haplotypes among the Kinh Vietnamese population is limited because of the small sample size. In this study, more than 3,750 cord blood units from individuals belonging to the Kinh Vietnamese population were genotyped using PCR sequence-specific oligonucleotide (PCR-SSO) for HLA testing. The results of the study demonstrated that the most frequently occurring HLA-A, -B, -C, and -DRB1 alleles were A*11:01 (25%), A*24:02 (12.3%), A*02:01 (11.2); A*03:03 (8.95%), A*02:03 (7.81%), A*29:01 (7.03%); B*15:02 (15.1%), B*46:01 (10.7%), B*58:01 (7.65%), B*38:02 (7.29%); C*08:01 (17.2), C*07:02 (16.2%), C*01:02 (15.2), C*03:02 (8.3%), C*15:05 (6.13); DRB1*12:02 (31.0%), DRB1*09:01 (10.47%), DRB1*15:02 (7.54%); DRB1*07:01 (6.68%), DRB1*10:01 (6.63%), respectively, with the highest allele diversity level observed in locus B (93 alleles). The most frequent haplotypes of two-locus combinations of HLA-A-B, HLA-A-C, HLA-A-DRB1, HLA-B-C, HLA-B-DRB1, and HLA-C-DRB1 haplotypes were A*11:01-B*15:02 (7.63%), A*11:01-C*08:01 (7.98%), A*11:01-DRB1*12:02 (10.56%), B*15:02-C*08:01 (14.0%), B*15:02-DRB1*12:02 (10.47%), and C*08:01-DRB1*12:02 (11.38%), respectively. In addition, the most frequent haplotypes of three- and four-locus sets of HLA-A-B-C, HLA-A-B-DRB1, HLA-A-C-DRB1, HLA-B-C-DRB1, and HLA-A-B-C-DRB1 were A*11:01-B*15:02-C*08:01 (7.57%), A*11:01-B*15:02-DRB1*12:02 (5.39%), A*11:01-C*08:01-DRB1*12:02 (5.54%), B*15:02-C*08:01-DRB1*12:02 (10.21%), and A*11:01-B*15:02-C*08:01-DRB1*12:02 (5.45%), respectively. This study provides critical information on the frequencies and distributions of HLA alleles and haplotypes in the Kinh Vietnamese population, accounting for more than 85% of Vietnamese citizens. It paves the way to establish an umbilical cord blood bank for cord blood transplantation programs in Vietnam.

78. The Association Between Psoriasis and Risk of Cardiovascular Disease: A Mendelian Randomization Analysis.

Front Immunol

2022 Jun 29

Gao N, Kong M, Li X

79. Octanoate Alleviates Dietary Soybean Oil-Induced Intestinal Physical Barrier Damage, Oxidative Stress, Inflammatory Response and Microbial Dysbiosis in Large Yellow Croaker (Larimichthys Crocea).

Front Immunol

2022 Jun 29

Zhang Z, Tang Y, Fang W

80. Diabetes Mellitus Promotes the Development of Atherosclerosis: The Role of NLRP3.

Front Immunol

2022 Jun 29

Ye J, Li L, Wang M

81. CXCR6(+) and NKG2C(+) Natural Killer Cells Are Distinct With Unique Phenotypic and Functional Attributes Following Bone Marrow Transplantation.

Front Immunol

2022 Jun 29

Aviles-Padilla K, Angelo LS, Fan D

82. Endocrine Autoimmunity in Pregnancy.

Front Immunol

2022 Jun 29

Świątkowska-Stodulska R, Berlińska A, Stefańska K

Human gestation leads to a number of physiological alterations which peak at the development of placentta known for, among many other functions, being a transient but highly potent endocrine organ. Hormonal activity of placenta is marked by its ability to continuously produce and secrete high levels of progesterone. Progesterone guards the well-being of the fetoplacental unit throughout the gestation and one of the proposed mechanisms of this principle involves the development of local and systemic immune tolerance mainly due to impediment of CD4+ lymphocyte activation. However, though these alterations are present and well-established, autoimmunity is not entirely rare and a wide spectrum of diseases can continue, or develop de novo, throughout the gestation or even after the delivery. Up-to-date data supports the existence of a relationship between the clinical course of chosen autoimmune diseases and levels of circulating sex steroids. The most common autoimmune endocrinopathies in pregnant women are Hashimoto's disease, Graves' disease, and, more rarely, primary adrenal insufficiency in the form of Addison's disease. Gestation can influence the clinical course of these endocrinopathies in patients who were diagnosed before conception. Multiple particles, like TSH-receptor stimulating antibodies, thyroid hormones, glucocorticoids, and anti-thyroid medications, can cross the placental barrier and evoke biological action in fetal tissues. Thyroid pathology in the form of postpartum thyroiditis is particularly prevalent in patients with positive anti-thyroperoxidase and anti-thyroglobulin antibodies. Certain populations are more at risk of developing numerous gestational complications and require regular follow-up. In our paper, we would like to address physiological, physiopathological, and clinical aspects of endocrine autoimmunity throughout human gestation, as well as special circumstances to consider in pregnant women.

83. Nutrient Condition in the Microenvironment Determines Essential Metabolisms of CD8(+) T Cells for Enhanced IFNγ Production by Metformin.

Front Immunol

2022 Jun 29

Chao R, Nishida M, Yamashita N

84. Immunological Changes of Basophil Hyperreactivity to Sweat in Patients With Well-Controlled Atopic Dermatitis.

Front Immunol

2022 Jun 29

Numata T, Takahagi S, Ishii K

85. Phosphorus Nutrition in Songpu Mirror Carp (Cyprinus carpio Songpu) During Chronic Carbonate Alkalinity Stress: Effects on Growth, Intestinal Immunity, Physical Barrier Function, and Intestinal Microflora.

Front Immunol

2022 Jun 29

Fan Z, Wu D, Li J

Carbonate alkalinity is a major environmental stress factor affecting aquatic feed configuration, which easily causes oxidative stress and hypoimmunity for fish. Hence, the purpose of the study is to assess the potential effect of phosphorus on growth, intestinal oxidation resistance, physical barrier function, and microflora for Songpu mirror carp (Cyprinus carpio Songpu) (initial average weight of 2.95 ± 0.21 g) reared at the high-concentration carbonate alkalinity environment. A two-factor, three-level (2 × 3) design was applied, in which diets with three different phosphorus levels (3.6, 7.0, and 10.5 g/kg dry matter) were randomly assigned to 0 and 15 mmol/L carbonate alkalinity groups with three replicate aquariums. After the 8-week trial, we found that weight gain rate (WGR), specific growth rate (SGR), protein efficiency ratio (PER), and lipase and amylase activities in the intestine significantly (p < 0.05) declined with increasing carbonate alkalinity. Carbonate alkalinity of 15 mmol/L significantly reduced glutathione peroxidase (GSHPx) activities in the intestine (p < 0.05). The relative expressions of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), glutathione peroxidase 1a (GPX1a), Clautin3, Clautin11, and tumor necrosis factor β (TNF-β) in the intestine were markedly downregulated by increasing carbonate alkalinity levels (p < 0.05), whilst the relative expressions of interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) in the intestine were markedly upregulated (p < 0.05). At the 15 mmol/L carbonate alkalinity treatment, Songpu mirror carp suffer from hypoimmunity status with failed digestion, antioxidant, inflammation, and immune response, thereby inducing impaired growth. Additionally, significant increments in the abundance of Proteobacteria and a significant decrease in the abundance of Fusobacteria and the Firmicutes/Bacteroidetes ratio were caused due to excessively high carbonate alkalinity (15 mmol/L) and excessively low dietary phosphorus supply (3.6 g/kg). Collectively, 7.0 g/kg dietary phosphorus supplementation was effective in promoting intestinal antioxidant enzyme activities and the corresponding gene expression via the Keap1-Nrf2 signaling pathway and in enhancing intestinal immunity by upregulating anti-inflammatory and downregulating pro-inflammatory genes. Appropriate dietary phosphorus supply could promote the formation of beneficial microflora in freshwater, and it has the potential ability to transfer the adverse effect of carbonate alkalinity stress to the structural composition of intestinal microflora. Hence, consideration should be given to suitable phosphorus supply for fish under the chronic carbonate alkalinity stress.

86. IL-17RA receptor signaling contributes to lung inflammation and parasite burden during Toxocara canis infection in mice.

Front Immunol

2022 Jun 29

Leal-Silva T, Lopes CA, Vieira-Santos F

87. Efficient T Cell Migration and Activation Require L-Plastin.

Front Immunol

2022 Jun 29

Joshi H, Morley SC.

88. Exposing and Overcoming Limitations of Clinical Laboratory Tests in COVID-19 by Adding Immunological Parameters; A Retrospective Cohort Analysis and Pilot Study.

Front Immunol

2022 Jun 29

Sánchez-Montalvá A, Álvarez-Sierra D, Martínez-Gallo M

Author information: (1)Infectious Disease Department, Hospital Universitari Vall Hebron, Barcelona, Spain. (2)International Health Program Institut Català de la Salut, Vall Hebron Research Institute (VHIR), Barcelona, Spain. (3)Department of Medicine, Universitat Autònoma Barcelona, Barcelona, Spain. (4)Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Barcelona, Spain. (5)Translational Immunology Research Group, Vall Hebron Research Institute (VHIR), Barcelona, Spain. (6)Immunology Department, Hospital Universitari Vall Hebron, Barcelona, Spain. (7)Department of Cell Biology, Physiology, and Immunology, Universitat Autònoma Barcelona, Barcelona, Spain. (8)Intensive Medicine Department, Hospital Universitari Vall Hebron, Barcelona, Spain. (9)Organ Dysfunction and Resuscitation Research Group, Vall Hebron Research Institute (VHIR), Barcelona, Spain. (10)Epidemiology and Public Health Department, Hospital Universitari Vall Hebron, Barcelona, Spain. (11)Epidemiology and Public Health Research Group, Vall Hebron Research Institute (VHIR), Barcelona, Spain. (12)Department of Pediatrics, Obstetrics and Gynecology, Epidemiology and Public Health, Universitat Autònoma Barcelona, Barcelona, Spain. (13)Microbiology Department, Hospital Universitari Vall Hebron, Barcelona, Spain. (14)Microbiology Research Group, Vall Hebron Research Institute (VHIR), Barcelona, Spain. (15)Department of Genetics and Microbiology, Autonomous University of Barcelona, Barcelona, Spain. (16)Internal Medicine Department, Hospital Universitari Vall Hebron, Barcelona, Spain. (17)Systemic Disease Research Group, Valle Hebron Research Institute (VHIR), Barcelona, Spain. (18)Liver Disease Research Group, Valle Hebron Research Institute (VHIR), Barcelona, Spain. (19)CIBERehd - Instituto de Salud Carlos III, Barcelona, Spain. (20)Clinical Biochemistry Department, Hospital Universitari Vall d'Hebron and Clinical Biochemistry Research Group, Valle Hebron Research Institute (VHIR), Barcelona, Spain. (21)Bioinformatics and Statistics Group, University of Barcelona, Barcelona, Spain. (22)Immunology Division, Bellvitge University Hospital, Hospitalet de Llobregat, Barcelona, Spain. (23)Immunology Group, Germans Trias i Pujol Health Sciences Research Institute (IGTP), Badalona (Barcelona), Spain. (24)Immunology Department, Hospital Universitari Germans Trias Pujol, Badalona (Barcelona), Spain. (25)Statistics and Bioinformatics Unit, Vall Hebron Research Institute (VHIR), Barcelona, Spain.

89. Altered Circulating Immune Cell Distribution in Traumatic Spinal Cord Injury Patients in Relation to Clinical Parameters.

Front Immunol

2022 Jun 28

Fraussen J, Beckers L, van Laake-Geelen CCM

90. Plasmablast Expansion Following the Tetravalent, Live-Attenuated Dengue Vaccine Butantan-DV in DENV-Naïve and DENV-Exposed Individuals in a Brazilian Cohort.

Front Immunol

2022 Jun 28

Silveira CGT, Magnani DM, Costa PR

91. Targeting Aberrantly Elevated Sialyl Lewis A as a Potential Therapy for Impaired Endometrial Selection Ability in Unexplained Recurrent Miscarriage.

Front Immunol

2022 Jun 28

Ma Z, Yang H, Kessler M

BACKGROUND: Carbohydrate Lewis antigens including sialyl Lewis A (sLeA), sialyl Lewis X (sLeX), Lewis X (LeX), and Lewis Y (LeY) are the commonest cell surface glycoconjugates that play pivotal roles in multiple biological processes, including cell adhesion and cell communication events during embryogenesis. SLeX, LeY, and associated glycosyltransferases ST3GAL3 and FUT4 have been reported to be involved in human embryo implantation. While the expression pattern of Lewis antigens in the decidua of unexplained recurrent miscarriage (uRM) patients remains unclear. METHODS: Paraffin-embedded placental tissue slides collected from patients experiencing early miscarriages (6-12 weeks) were analyzed using immunohistochemical (IHC) and immunofluorescent (IF) staining. An in vitro assay was developed using endometrial cell line RL95-2 and trophoblast cell line HTR-8/SVneo. Modulatory effect of potential glycosyltransferase on Lewis antigens expression was investigated by target-specific small interfering RNA (siRNA) knockdown in RL95-2 cells. HTR-8/SVneo cells spheroids adhesion assay was applied to investigate the intrinsic role of Lewis antigens in the abnormal implantation process of uRM. The expression of Lewis antigens in RL95-2 cells in response to the treatment with pro-implantation cytokine IL-1β was further measured by flow cytometry and immunocytochemical (ICC) staining. RESULTS: IHC staining revealed that Lewis antigens are mainly expressed in the luminal and glandular epithelium, IF staining further indicated the cellular localization at the apical membrane of the epithelial cells. FUTs, ST3GALs, and NEU1 located in both stromal and epithelial cells. We have found that the expression of sLeA, LeX, FUT3/4, and ST3GAL3/4 are significantly upregulated in the RM group, while FUT1 is downregulated. SLeX, LeY, ST3GAL6, and NEU1 showed no significant differences between groups. FUT3 knockdown in RL95-2 cells significantly decreased the expression of sLeA and the spheroids adhesion to endometrial monolayer. Anti-sLeA antibody can remarkably suppress both the basal and IL-1β induced adhesion of HTR-8/SVneo spheroids to RL95-2 cells monolayer. While further flow cytometry and ICC detection indicated that the treatment of RL95-2 cells with IL-1β significantly increases the surface expression of LeX, but not sLeA. CONCLUSIONS: SLeA, LeX, and pertinent glycosyltransferase genes FUT1/3/4 and ST3GAL3/4 are notably dysregulated in the decidua of uRM patients. FUT3 accounts for the synthesis of sLeA in RL95-2 cells and affects the endometrial receptivity. Targeting aberrantly elevated sLeA may be a potential therapy for the inappropriate implantation in uRM.

92. The Crosstalk Between Liver Sinusoidal Endothelial Cells and Hepatic Microenvironment in NASH Related Liver Fibrosis.

Front Immunol

2022 Jun 28

Du W, Wang L.

93. Host and Microbiome Interplay Shapes the Vaginal Microenvironment.

Front Immunol

2022 Jun 28

Kwon MS, Lee HK.

94. Innate and Adaptive Lymphocytes in Non-Tuberculous Mycobacteria Lung Disease: A Review.

Front Immunol

2022 Jun 28

Gramegna A, Lombardi A, Lorè NI

95. Response: Commentary: Single-Cell Sequencing Analysis and Weighted CoExpression Network Analysis Based on Public Databases Identified That TNC Is a Novel Biomarker for Keloid.

Front Immunol

2022 Jun 28

Xie J, Cao Y, Chen L

96. Probiotics Surface-Delivering Fiber2 Protein of Fowl Adenovirus 4 Stimulate Protective Immunity Against Hepatitis-Hydropericardium Syndrome in Chickens.

Front Immunol

2022 Jun 28

Jia Z, Pan X, Zhi W

BACKGROUND AND OBJECTIVES: Hepatitis-hydropericardium syndrome (HHS) caused by Fowl adenoviruses serotype 4 (FAdV-4) leads to severe economic losses to the poultry industry. Although various vaccines are available, vaccines that effectively stimulate intestinal mucosal immunity are still deficient. In the present study, novel probiotics that surface-deliver Fiber2 protein, the major virulence determiner and efficient immunogen for FAdV-4, were explored to prevent this fecal-oral-transmitted virus, and the induced protective immunity was evaluated after oral immunization. METHODS: The probiotic Enterococcus faecalis strain MDXEF-1 and Lactococcus lactis NZ9000 were used as host strains to deliver surface-anchoring Fiber2 protein of FAdV-4. Then the constructed live recombinant bacteria were orally vaccinated thrice with chickens at intervals of 2 weeks. Following each immunization, immunoglobulin G (IgG) in sera, secretory immunoglobulin A (sIgA) in jejunum lavage, immune-related cytokines, and T-cell proliferation were detected. Following challenge with the highly virulent FAdV-4, the protective effects of the probiotics surface-delivering Fiber2 protein were evaluated by verifying inflammatory factors, viral load, liver function, and survival rate. RESULTS: The results demonstrated that probiotics surface-delivering Fiber2 protein stimulated humoral and intestinal mucosal immune responses in chickens, shown by high levels of sIgA and IgG antibodies, substantial rise in mRNA levels of cytokines, increased proliferative ability of T cells in peripheral blood, improved liver function, and reduced viral load in liver. Accordingly, adequate protection against homologous challenges and a significant increase in the overall survival rate were observed. Notably, chickens orally immunized with E. faecalis/DCpep-Fiber2-CWA were completely protected from the FAdV-4 challenge, which is better than L. lactis/DCpep-Fiber2-CWA. CONCLUSION: The recombinant probiotics surface-expressing Fiber2 protein could evoke remarkable humoral and cellular immune responses, relieve injury, and functionally damage target organs. The current study indicates a promising method used for preventing FAdV-4 infection in chickens.

97. Spatiotemporal Patterns of Substance P-Bound MRGPRX2 Reveal a Novel Connection Between Macropinosome Resolution and Secretory Granule Regeneration in Mast Cells.

Front Immunol

2022 Jun 28

Lazki-Hagenbach P, Kleeblatt E, Ali H

98. Recombinant Full-Length Hepatitis C Virus E1E2 Dimer Elicits Pangenotypic Neutralizing Antibodies.

Front Immunol

2022 Jun 28

Lin T, Chi X, Liu X

99. Surface Display of Peptides Corresponding to the Heptad Repeat 2 Domain of the Feline Enteric Coronavirus Spike Protein on Bacillus subtilis Spores Elicits Protective Immune Responses Against Homologous Infection in a Feline Aminopeptidase-N-Transduced Mouse Model.

Front Immunol

2022 Jun 28

Chen C, Li YL, Lv FL

100. Immunovirotherapy Based on Recombinant Vesicular Stomatitis Virus: Where Are We?

Front Immunol

2022 Jun 28

Zhang Y, Nagalo BM.

Front Immunol

2022 Jun 28

Zhang X, Min S, Yang Y

102. Regulatory Roles of Phospholipase A(2) Enzymes and Bioactive Lipids in Mast Cell Biology.

Front Immunol

2022 Jun 27

Taketomi Y, Murakami M.

103. N-Glycosylation and Inflammation; the Not-So-Sweet Relation.

Front Immunol

2022 Jun 27

Radovani B, Gudelj I.

104. The Robustness of Cellular Immunity Determines the Fate of SARS-CoV-2 Infection.

Front Immunol

2022 Jun 27

Moga E, Lynton-Pons E, Domingo P.

Two years after the appearance of the SARS-CoV-2 virus, the causal agent of the current global pandemic, it is time to analyze the evolution of the immune protection that infection and vaccination provide. Cellular immunity plays an important role in limiting disease severity and the resolution of infection. The early appearance, breadth and magnitude of SARS-CoV-2 specific T cell response has been correlated with disease severity and it has been thought that T cell responses may be sufficient to clear infection with minimal disease in COVID-19 patients with X-linked or autosomal recessive agammaglobulinemia. However, our knowledge of the phenotypic and functional diversity of CD8+ cytotoxic lymphocytes, CD4+ T helper cells, mucosal-associated invariant T (MAIT) cells and CD4+ T follicular helper (Tfh), which play a critical role in infection control as well as long-term protection, is still evolving. It has been described how CD8+ cytotoxic lymphocytes interrupt viral replication by secreting antiviral cytokines (IFN-γ and TNF-α) and directly killing infected cells, negatively correlating with stages of disease progression. In addition, CD4+ T helper cells have been reported to be key pieces, leading, coordinating and ultimately regulating antiviral immunity. For instance, in some more severe COVID-19 cases a dysregulated CD4+ T cell signature may contribute to the greater production of pro-inflammatory cytokines responsible for pathogenic inflammation. Here we discuss how cellular immunity is the axis around which the rest of the immune system components revolve, since it orchestrates and leads antiviral response by regulating the inflammatory cascade and, as a consequence, the innate immune system, as well as promoting a correct humoral response through CD4+ Tfh cells. This review also analyses the critical role of cellular immunity in modulating the development of high-affinity neutralizing antibodies and germinal center B cell differentiation in memory and long-lived antibody secreting cells. Finally, since there is currently a high percentage of vaccinated population and, in some cases, vaccine booster doses are even being administered in certain countries, we have also summarized newer approaches to long-lasting protective immunity and the cross-protection of cellular immune response against SARS-CoV-2.

105. Revealing the Key MSCs Niches and Pathogenic Genes in Influencing CEP Homeostasis: A Conjoint Analysis of Single-Cell and WGCNA.

Front Immunol

2022 Jun 27

Li W, Zhang S, Zhao Y

Degenerative disc disease (DDD), a major contributor to discogenic pain, which is mainly resulted from the dysfunction of nucleus pulposus (NP), annulus fibrosis (AF) and cartilage endplate (CEP) cells. Genetic and cellular components alterations in CEP may influence disc homeostasis, while few single-cell RNA sequencing (scRNA-seq) report in CEP makes it a challenge to evaluate cellular heterogeneity in CEP. Here, this study conducted a first conjoint analysis of weighted gene co-expression network analysis (WGCNA) and scRNA-seq in CEP, systematically analyzed the interested module, immune infiltration situation, and cell niches in CEP. WGCNA and protein-protein interaction (PPI) network determined a group of gene signatures responsible for degenerative CEP, including BRD4, RAF1, ANGPT1, CHD7 and NOP56; differentially immune analysis elucidated that CD4+ T cells, NK cells and dendritic cells were highly activated in degenerative CEP; then single-cell resolution transcriptomic landscape further identified several mesenchymal stem cells and other cellular components focused on human CEP, which illuminated niche atlas of different cell subpopulations: 8 populations were identified by distinct molecular signatures. Among which, NP progenitor/mesenchymal stem cells (NPMSC), also served as multipotent stem cells in CEP, exhibited regenerative and therapeutic potentials in promoting bone repair and maintaining bone homeostasis through SPP1, NRP1-related cascade reactions; regulatory and effector mesenchymal chondrocytes could be further classified into 2 different subtypes, and each subtype behaved potential opposite effects in maintaining cartilage homeostasis; next, the potential functional differences of each mesenchymal stem cell populations and the possible interactions with different cell types analysis revealed that JAG1, SPP1, MIF and PDGF etc. generated by different cells could regulate the CEP homeostasis by bone formation or angiogenesis, which could be served as novel therapeutic targets for degenerative CEP. In brief, this study mainly revealed the mesenchymal stem cells populations complexity and phenotypic characteristics in CEP. In brief, this study filled the gap in the knowledge of CEP components, further enhanced researchers' understanding of CEP and their cell niches constitution.

106. Improvement Effect of Bifidobacterium animalis subsp. lactis MH-02 in Patients Receiving Resection of Colorectal Polyps: A Randomized, Double-Blind, Placebo-Controlled Trial.

Front Immunol

2022 Jun 27

Liu H, Zhang K, Liu P

107. Lnc90386 Sponges miR-33-5p to Mediate Mycoplasma gallisepticum-Induced Inflammation and Apoptosis in Chickens via the JNK Pathway.

Front Immunol

2022 Jun 27

Sun Y, Wang Y, Zou M

108. Penpulimab, an Fc-Engineered IgG1 Anti-PD-1 Antibody, With Improved Efficacy and Low Incidence of Immune-Related Adverse Events.

Front Immunol

2022 Jun 27

Huang Z, Pang X, Zhong T

BACKGROUND: IgG4 anbibodies are deficient in stability and may contribute to tumor-associated escape from immune surveillance. We developed an IgG1 backbone anti-programmed cell death protein-1 (PD-1) antibody, penpulimab, which is designed to remove crystallizable fragment (Fc) gamma receptor (FcγR) binding that mediates antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and proinflammatory cytokine release. METHODS: Aggregation of different anti-PD-1 antibodies was tested by size exclusion chromatography, and melting temperature midpoint (Tm) and aggregation temperature onset (Tagg) were also determined. The affinity constants of penpulimab for PD-1 and human FcγRs were measured by surface plasmon resonance and biolayer interferometry. ADCC and ADCP were determined in cellular assays and antibody-dependent cytokine release (ADCR) from human macrophages was detected by ELISA. Binding kinetics of penpulimab to human PD-1 was determined by Biacore, and epitope/paratope mapping of PD-1/penpulimab was investigated using x-ray crystallography. Additionally, patients from six ongoing trials were included for analysis of immune-related adverse events (irAEs). RESULTS: Penpulimab demonstrated better stability and a lower level of host-cell protein residue compared with IgG4 backbone anti-PD-1 antibodies. As expected, penpulimab exhibited no apparent binding to FcγRIa, FcγRIIa_H131, FcγRIIIa_V158 and FcγRIIIa_F158, elicited no apparent ADCC and ADCP activities, and induced no remarkable IL-6 and IL-8 release by activated macrophages in vitro. Penpulimab was shown in the co-crystal study to bind to human PD-1 N-glycosylation site at N58 and had a slower off-rate from PD-1 versus nivolumab or pembrolizumab. Four hundred sixty-five patients were analyzed for irAEs. Fifteen (3.2%) patients had grade 3 or above irAEs. No death from irAEs was reported. CONCLUSIONS: IgG1 backbone anti-PD1 antibody penpulimab has a good stability and reduced host cell protein residue, as well as potent binding to the antigen. Fc engineering has eliminated Fc-mediated effector functions of penpulimab including ADCC, ADCP and reduced ADCR, which may contribute to its more favorable safety profile. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier: AK105-101: NCT03352531, AK105-201: NCT03722147, AK105-301: NCT03866980, AK105-202:NCT03866967, AK105-203: NCT04172571, AK105-204: NCT04172506.

109. Immune- and Stemness-Related Genes Revealed by Comprehensive Analysis and Validation for Cancer Immunity and Prognosis and Its Nomogram in Lung Adenocarcinoma.

Front Immunol

2022 Jun 27

Chen M, Wang X, Wang W

OBJECTIVE: Lung adenocarcinoma (LUAD) is a familiar lung cancer with a very poor prognosis. This study investigated the immune- and stemness-related genes to develop model related with cancer immunity and prognosis in LUAD. METHOD: The Cancer Genome Atlas (TCGA) was utilized for obtaining original transcriptome data and clinical information. Differential expression, prognostic value, and correlation with clinic parameter of mRNA stemness index (mRNAsi) were conducted in LUAD. Significant mRNAsi-related module and hub genes were screened using weighted gene coexpression network analysis (WGCNA). Meanwhile, immune-related differential genes (IRGs) were screened in LUAD. Stem cell index and immune-related differential genes (SC-IRGs) were screened and further developed to construct prognosis-related model and nomogram. Comprehensive analysis of hub genes and subgroups, involving enrichment in the subgroup [gene set enrichment analysis (GSEA)], gene mutation, genetic correlation, gene expression, immune, tumor mutation burden (TMB), and drug sensitivity, used bioinformatics and reverse transcription polymerase chain reaction (RT-PCR) for verification. RESULTS: Through difference analysis, mRNAsi of LUAD group was markedly higher than that of normal group. Clinical parameters (age, gender, and T staging) were ascertained to be highly relevant to mRNAsi. MEturquoise and MEblue were found to be the most significant modules (including positive and negative correlations) related to mRNAsi via WGCNA. The functions and pathways of the two mRNAsi-related modules were mainly enriched in tumorigenesis, development, and metastasis. Combining stem cell index-related differential genes and immune-related differential genes, 30 prognosis-related SC-IRGs were screened via Cox regression analysis. Then, 16 prognosis-related SC-IRGs were screened to construct a LASSO regression model at last. In addition, the model was successfully validated by using TCGA-LUAD and GSE68465, whereas c-index and the calibration curves were utilized to demonstrate the clinical value of our nomogram. Following the validation of the model, GSEA, immune cell correlation, TMB, clinical relevance, etc., have found significant difference in high- and low-risk groups, and 16-gene expression of the SC-IRG model also was tested by RT-PCR. ADRB2, ANGPTL4, BDNF, CBLC, CX3CR1, and IL3RA were found markedly different expression between the tumor and normal group. CONCLUSION: The SC-IRG model and the prognostic nomogram could accurately predict LUAD survival. Our study used mRNAsi combined with immunity that may lay a foundation for the future research studies in LUAD.

110. Editorial: Advances in Heart Transplantation.

Front Immunol

2022 Jun 27

Moll G, Dai Z, Câmara NOS.

111. Markers of Immune Cell Exhaustion as Predictor of Survival in Surgically-Treated Early-Stage NSCLC.

Front Immunol

2022 Jun 27

Sellmer L, Kovács J, Walter J

112. Checkpoint Inhibitors Modulate Plasticity of Innate Lymphoid Cells in Peripheral Blood of Patients With Hepatocellular Carcinoma.

Front Immunol

2022 Jun 27

Heinrich B, Ruf B, Subramanyam V

113. Current Advances in PD-1/PD-L1 Blockade in Recurrent Epithelial Ovarian Cancer.

Front Immunol

2022 Jun 27

Zhang Y, Cui Q, Xu M

114. IFNAR1 Deficiency Impairs Immunostimulatory Properties of Neutrophils in Tumor-Draining Lymph Nodes.

Front Immunol

2022 Jun 27

Hussain T, Domnich M, Bordbari S

Tumor-draining lymph nodes (TDLNs) are the first organs where the metastatic spread of different types of cancer, including head and neck cancer (HNC), occurs and have therefore high prognostic relevance. Moreover, first anti-cancer immune responses have been shown to be initiated in such LNs via tumor-educated myeloid cells. Among myeloid cells present in TDLNs, neutrophils represent a valuable population and considerably participate in the activation of effector lymphocytes there. Tumor-supportive or tumor-inhibiting activity of neutrophils strongly depends on the surrounding microenvironment. Thus, type I interferon (IFN) availability has been shown to prime anti-tumor activity of these cells. In accordance, mice deficient in type I IFNs show elevated tumor growth and metastatic spread, accompanied by the pro-tumoral neutrophil bias. To reveal the mechanism responsible for this phenomenon, we have studied here the influence of defective type I IFN signaling on the immunoregulatory activity of neutrophils in TDLNs. Live imaging of such LNs was performed using two-photon microscopy in a transplantable murine HNC model. CatchupIVM-red and Ifnar1-/- (type I IFN receptor- deficient) CatchupIVM-red mice were used to visualize neutrophils and to assess their interaction with T-cells in vivo. We have evaluated spatiotemporal patterns of neutrophil/T-cell interactions in LNs in the context of type I interferon receptor (IFNAR1) availability in tumor-free and tumor-bearing animals. Moreover, phenotypic and functional analyses were performed to further characterize the mechanisms regulating neutrophil immunoregulatory capacity. We demonstrated that inactive IFNAR1 leads to elevated accumulation of neutrophils in TDLNs. However, these neutrophils show significantly impaired capacity to interact with and to stimulate T-cells. As a result, a significant reduction of contacts between neutrophils and T lymphocytes is observed, with further impairment of T-cell proliferation and activation. This possibly contributes to the enhanced tumor growth in Ifnar1-/- mice. In agreement with this, IFNAR1-independent activation of downstream IFN signaling using IFN-λ improved the immunostimulatory capacity of neutrophils in TDLNs and contributed to the suppression of tumor growth. Our results suggest that functional type I IFN signaling is essential for neutrophil immunostimulatory capacity and that stimulation of this signaling may provide a therapeutic opportunity in head and neck cancer patients.

115. Gut Microbiota, Leaky Gut, and Autoimmune Diseases.

Front Immunol

2022 Jun 27

Christovich A, Luo XM.

116. Th2 to Th1 Transition Is Required for Induction of Skin Lesions in an Inducible and Recurrent Murine Model of Cutaneous Lupus-Like Inflammation.

Front Immunol

2022 Jun 27

Haddadi NS, Mande P, Brodeur TY

117. Beneficial Immune Regulation by Biological Response Modifier Glucans in COVID-19 and Their Envisaged Potentials in the Management of Sepsis.

Front Immunol

2022 Jun 27

Preethy S, Raghavan K, Dedeepiya VD

118. Development of Immunotherapy Strategies Targeting Tumor Microenvironment Is Fiercely Ongoing.

Front Immunol

2022 Jun 27

Bai R, Cui J.

119. Immune Responses Against SARS-CoV-2 WT and Delta Variant in Elderly BNT162b2 Vaccinees.

Front Immunol

2022 Jun 27

Jäger M, Sonnleitner ST, Dichtl S

120. Anti-MDA5 Antibody Linking COVID-19, Type I Interferon, and Autoimmunity: A Case Report and Systematic Literature Review.

Front Immunol

2022 Jun 27

Tonutti A, Motta F, Ceribelli A

121. Dynamic Metabolic Changes During Prolonged Ex Situ Heart Perfusion Are Associated With Myocardial Functional Decline.

Front Immunol

2022 Jun 24

Olkowicz M, Ribeiro RVP, Yu F

Ex situ heart perfusion (ESHP) was developed to preserve and evaluate donated hearts in a perfused beating state. However, myocardial function declines during ESHP, which limits the duration of perfusion and the potential to expand the donor pool. In this research, we combine a novel, minimally-invasive sampling approach with comparative global metabolite profiling to evaluate changes in the metabolomic patterns associated with declines in myocardial function during ESHP. Biocompatible solid-phase microextraction (SPME) microprobes serving as chemical biopsy were used to sample heart tissue and perfusate in a translational porcine ESHP model and a small cohort of clinical cases. In addition, six core-needle biopsies of the left ventricular wall were collected to compare the performance of our SPME sampling method against that of traditional tissue-collection. Our state-of-the-art metabolomics platform allowed us to identify a large number of significantly altered metabolites and lipid species that presented comparable profile of alterations to conventional biopsies. However, significant discrepancies in the pool of identified analytes using two sampling methods (SPME vs. biopsy) were also identified concerning mainly compounds susceptible to dynamic biotransformation and most likely being a result of low-invasive nature of SPME. Overall, our results revealed striking metabolic alterations during prolonged 8h-ESHP associated with uncontrolled inflammation not counterbalanced by resolution, endothelial injury, accelerated mitochondrial oxidative stress, the disruption of mitochondrial bioenergetics, and the accumulation of harmful lipid species. In conclusion, the combination of perfusion parameters and metabolomics can uncover various mechanisms of organ injury and recovery, which can help differentiate between donor hearts that are transplantable from those that should be discarded.

122. The Immune Subtype Contributes to Distinct Overall Survival for Ovarian Cancer Patients With Platinum-Based Adjuvant Therapy.

Front Immunol

2022 Jun 24

Li Y, Wang H, Chen M

OBJECTIVE: Nowadays, platinum-based therapy has been widely used as the first-line therapy of ovarian cancer. However, the effect of the tumor microenvironment on platinum-based therapy remains unclear. In this study, we aim to investigate the relationship between immune microenvironment subtypes and the prognosis of platinum-based therapy in ovarian cancer. METHODS: We integrated 565 ovarian cancer samples from two datasets and obtained the immune subtypes (ISs) by consistent clustering of 1190 immune-related gene expressions. The proportional hazards regression model was used to assess the relationship between ISs and the prognosis of platinum-based adjuvant therapy including progression-free survival (PFS) and overall survival (OS). The prognostic contribution of ISs was validated in three additional cohorts. Non-parametric tests were used to assess genomic characteristics, the proportion of immune cells, and immune-related signature differences among ISs. RESULTS: We identified and validated five ISs associated with different clinical outcomes of the platinum-based adjuvant therapy in ovarian cancer patients. These differences were only found in OS rather than PFS. An immune subtype had the worst OS. Those patients mainly derived from the mesenchymal subtype had the lowest tumor purity with a high leukocyte fraction as well as stromal fraction and had the highest TGF-β response signaling. By contrast, an immune subtype characterized by immunoreactive status with the highest CD8+T cell infiltration and elevated IFN-γ response signaling had the best prognosis. Other subtypes with more diverse immunologic features such as lowest macrophage regulation signaling showed intermediate prognoses. Notably, the contribution of ISs to OS was independent of the clinical response to platinum-based drugs. CONCLUSION: Our analysis revealed the association between different immune characteristics and platinum-based adjuvant therapy, indicating the combination of ISs and chemotherapy could optimize the treatment strategy of OC patients.

123. Monocytic-Myeloid Derived Suppressor Cells Suppress T-Cell Responses in Recovered SARS CoV2-Infected Individuals.

Front Immunol

2022 Jun 24

Beliakova-Bethell N, Maruthai K, Xu R

Coronavirus disease 2019 (COVID-19) caused by SARS Coronavirus 2 (CoV2) is associated with massive immune activation and hyperinflammatory response. Acute and severe CoV2 infection is characterized by the expansion of myeloid derived suppressor cells (MDSC) because of cytokine storm, these MDSC suppress T cell functions. However, the presence of MDSC and its effect on CoV2 antigen specific T cell responses in individuals long after first detection of CoV2 and recovery from infection has not been studied. We and others have previously shown that CD11b+CD33+CD14+HLA-DR-/lo monocytic MDSC (M-MDSC) are present in individuals with clinical recovery from viral infection. In this study, we compared the frequency, functional and transcriptional signatures of M-MDSC isolated from CoV2 infected individuals after 5-months of the first detection of the virus (CoV2+) and who were not infected with CoV2 (CoV2-). Compared to CoV2- individuals, M-MDSC were present in CoV2+ individuals at a higher frequency, the level of M-MDSC correlated with the quantity of IL-6 in the plasma. Compared to CoV2-, increased frequency of PD1+, CD57+ and CX3CR1+ T effector memory (TEM) cell subsets was also present in CoV2+ individuals, but these did not correlate with M-MDSC levels. Furthermore, depleting M-MDSC from peripheral blood mononuclear cells (PBMC) increased T cell cytokine production when cultured with the peptide pools of immune dominant spike glycoprotein (S), membrane (M), and nucleocapsid (N) antigens of CoV2. M-MDSC suppressed CoV2 S- antigen-specific T cell in ROS, Arginase, and TGFβ dependent manner. Our gene expression, RNA-seq and pathway analysis studies further confirm that M-MDSC isolated from CoV2+ individuals are enriched in pathways that regulate both innate and adaptive immune responses, but the genes regulating these functions (HLA-DQA1, HLA-DQB1, HLA-B, NLRP3, IL1β, CXCL2, CXCL1) remained downregulated in M-MDSC isolated from CoV2+ individuals. These results demonstrate that M-MDSC suppresses recall responses to CoV2 antigens long after recovery from infection. Our findings suggest M-MDSC as novel regulators of CoV2 specific T cell responses, and should be considered as target to augment responses to vaccine.

124. Case Report: A Pediatric Case of Familial Mediterranean Fever Concurrent With Autoimmune Hepatitis.

Front Immunol

2022 Jun 24

Aoki M, Izawa K, Tanaka T

125. Galectin-3 Decreases 4-1BBL Bioactivity by Crosslinking Soluble and Membrane Expressed 4-1BB.

Front Immunol

2022 Jun 24

Nielsen MA, Juul-Madsen K, Stegmayr J

126. Emergence of the CD226 Axis in Cancer Immunotherapy.

Front Immunol

2022 Jun 24

Conner M, Hance KW, Yadavilli S

127. Identification and Verification of Necroptosis-Related Gene Signature With Prognosis and Tumor Immune Microenvironment in Ovarian Cancer.

Front Immunol

2022 Jun 24

Wang Z, Chen G, Dai F

Ovarian cancer is the most lethal heterogeneous disease among gynecological tumors with a poor prognosis. Necroptosis, the most studied way of death in recent years, is different from apoptosis and pyroptosis. It is a kind of regulated programmed cell death and has been shown to be closely related to a variety of tumors. However, the expression and prognosis of necroptosis-related genes in ovarian cancer are still unclear. Our study therefore firstly identified the expression profiles of necroptosis-related genes in normal and ovarian cancer tissues. Next, based on differentially expressed necroptosis-related genes, we clustered ovarian cancer patients into two subtypes and performed survival analysis. Subsequently, we constructed a risk model consisting of 5 genes by LASSO regression analysis based on the differentially expressed genes in the two subtypes, and confirmed the strong prognostic ability of the model and its potential as an independent risk factor via survival analysis and independent risk factor analysis. Based on this risk model, patients were divided into high and low risk groups. By exploring differentially expressed genes, enrichment functions and tumor immune microenvironment in patients in high and low risk groups, the results showed that patients in the low risk group were significantly enriched in immune signaling pathways. Besides, immune cells content, immune function activity was significantly better than the high-risk group. Eventually, we also investigated the sensitivity of patients with different risk groups to ICB immunotherapy and chemotherapy drugs. In conclusion, the risk model could effectively predict the survival and prognosis of patients, and explore the tumor microenvironment status of ovarian cancer patients to a certain extent, and provide promising and novel molecular markers for clinical diagnosis, individualized treatment and immunotherapy of patients.

128. Gut Microbiota: A Novel Therapeutic Target for Parkinson's Disease.

Front Immunol

2022 Jun 24

Zhu M, Liu X, Ye Y

129. Immune Dysfunction Mediated by the ceRNA Regulatory Network in Human Placenta Tissue of Intrahepatic Cholestasis Pregnancy.

Front Immunol

2022 Jun 24

Wang Y, Tang Y, Yang X

130. Decoding the Immune Microenvironment of Clear Cell Renal Cell Carcinoma by Single-Cell Profiling to Aid Immunotherapy.

Front Immunol

2022 Jun 24

Liu J, Xu J, Zhang T

131. Nucleic Acid Sensing by Toll-Like Receptors in the Endosomal Compartment.

Front Immunol

2022 Jun 23

Miyake K, Shibata T, Fukui R

132. Relationship Between Anemia and Systemic Inflammation in People Living With HIV and Tuberculosis: A Sub-Analysis of the CADIRIS Clinical Trial.

Front Immunol

2022 Jun 23

Araújo-Pereira M, Barreto-Duarte B, Arriaga MB

133. Risks of SARS-CoV-2 Infection and Immune Response to COVID-19 Vaccines in Patients With Inflammatory Bowel Disease: Current Evidence.

Front Immunol

2022 Jun 23

Esposito S, Caminiti C, Giordano R

Inflammatory bowel diseases (IBD), including Crohn's disease, ulcerative colitis, and unclassified inflammatory bowel disease, are a group of chronic, immune mediated conditions that are presumed to occur in genetically susceptible individuals because of a dysregulated intestinal immune response to environmental factors. IBD patients can be considered subjects with an aberrant immune response that makes them at increased risk of infections, particularly those due to opportunistic pathogens. In many cases this risk is significantly increased by the therapy they receive. Aim of this narrative review is to describe the impact of SARS-CoV-2 infection and the immunogenicity of COVID-19 vaccines in patients with IBD. Available data indicate that patients with IBD do not have an increased susceptibility to infection with SARS-CoV-2 and that, if infected, in the majority of the cases they must not modify the therapy in place because this does not negatively affect the COVID-19 course. Only corticosteroids should be reduced or suspended due to the risk of causing severe forms. Furthermore, COVID-19 seems to modify the course of IBD mainly due to the impact on intestinal disease of the psychological factors deriving from the measures implemented to deal with the pandemic. The data relating to the immune response induced by SARS-CoV-2 or by COVID-19 vaccines can be considered much less definitive. It seems certain that the immune response to disease and vaccines is not substantially different from that seen in healthy subjects, with the exception of patients treated with anti-tumor necrosis factor alone or in combination with other immunosuppressants who showed a reduced immune response. How much, however, this problem reduces induced protection is not known. Moreover, the impact of SARS-CoV-2 variants on IBD course and immune response to SARS-CoV-2 infection and COVID-19 vaccines has not been studied and deserves attention. Further studies capable of facing and solving unanswered questions are needed in order to adequately protect IBD patients from the risks associated with SARS-CoV-2 infection.

134. Baicalin Induces a Potent Innate Immune Response to Inhibit Respiratory Syncytial Virus Replication via Regulating Viral Non-Structural 1 and Matrix RNA.

Front Immunol

2022 Jun 23

Qin S, Huang X, Qu S.

135. Individuals With Weaker Antibody Responses After Booster Immunization Are Prone to Omicron Breakthrough Infections.

Front Immunol

2022 Jun 23

Möhlendick B, Čiučiulkaitė I, Elsner C

136. Comparison of Haploidentical Hematopoietic Stem Cell Transplant With or Without Unrelated Cord Blood Infusion in Severe Aplastic Anemia: Outcomes of a Multicenter Study.

Front Immunol

2022 Jun 23

Lei M, Zhang Y, Jiao W

137. External Assessment of the Anti-N-Methyl-D-Aspartate Receptor Encephalitis One-Year Functional Status Score in Chinese Pediatric Patients.

Front Immunol

2022 Jun 23

Luo H, Li Y, Zheng Y

138. Identification of Highly Cross-Reactive Mimotopes for a Public T Cell Response in Murine Melanoma.

Front Immunol

2022 Jun 23

Grace BE, Backlund CM, Morgan DM

139. Heterologous Expression and Evaluation of Novel Plasmodium falciparum Transmission Blocking Vaccine Candidates.

Front Immunol

2022 Jun 23

de Jong RM, Singh SK, Teelen K

Malaria transmission blocking vaccines (TBV) aim to induce antibodies that can interrupt Plasmodium falciparum development in the mosquito midgut and thereby prevent onward malaria transmission. A limited number of TBV candidates have been identified and only three (Pfs25, Pfs230 and Pfs48/45) have entered clinical testing. While one of these candidates may emerge as a highly potent TBV candidate, it is premature to determine if they will generate sufficiently potent and sustained responses. It is therefore important to explore novel candidate antigens. We recently analyzed sera from naturally exposed individuals and found that the presence and/or intensity of antibodies against 12 novel putative surface expressed gametocyte antigens was associated with transmission reducing activity. In this study, protein fragments of these novel TBV candidates were designed and heterologously expressed in Drosophila melanogaster S2 cells and Lactococcus lactis. Eleven protein fragments, covering seven TBV candidates, were successfully produced. All tested antigens were recognized by antibodies from individuals living in malaria-endemic areas, indicating that native epitopes are present. All antigens induced antigen-specific antibody responses in mice. Two antigens induced antibodies that recognized a native protein in gametocyte extract, and antibodies elicited by four antigens recognized whole gametocytes. In particular, we found that antigen Pf3D7_0305300, a putative transporter, is abundantly expressed on the surface of gametocytes. However, none of the seven novel TBV candidates expressed here induced an antibody response that reduced parasite development in the mosquito midgut as assessed in the standard membrane feeding assay. Altogether, the antigen fragments used in this study did not prove to be promising transmission blocking vaccine constructs, but led to the identification of two gametocyte surface proteins that may provide new leads for studying gametocyte biology.

140. Pathogenetic Aspects of Systemic Sclerosis: A View Through the Prism of B Cells.

Front Immunol

2022 Jun 23

Melissaropoulos K, Iliopoulos G, Sakkas LI

141. Research Progress on the Mechanism of Itaconate Regulating Macrophage Immunometabolism.

Front Immunol

2022 Jun 23

Shi J, Cai C.

142. Identification of a Disease-Associated Network of Intestinal Immune Cells in Treatment-Naive Inflammatory Bowel Disease.

Front Immunol

2022 Jun 23

van Unen V, Ouboter LF, Li N

143. Exosomally Targeting microRNA23a Ameliorates Microvascular Endothelial Barrier Dysfunction Following Rickettsial Infection.

Front Immunol

2022 Jun 23

Zhou C, Bei J, Qiu Y

144. The Complement System and ANCA Associated Vasculitis in the Era of Anti-Complement Drugs.

Front Immunol

2022 Jun 23

Kimoto Y, Horiuchi T.

145. Gut Microbiota-Derived Indole-3-Carboxylate Influences Mucosal Integrity and Immunity Through the Activation of the Aryl Hydrocarbon Receptors and Nutrient Transporters in Broiler Chickens Challenged With Eimeria maxima.

Front Immunol

2022 Jun 23

Park I, Nam H, Goo D

Two studies were conducted to evaluate the effects of indole-3-carboxylate (ICOOH) as a postbiotic on maintaining intestinal homeostasis against avian coccidiosis. In the first study, an in vitro culture system was used to investigate the effects of ICOOH on the proinflammatory cytokine response of chicken macrophage cells (CMCs), gut integrity of chicken intestinal epithelial cells (IECs), differentiation of quail muscle cells (QMCs), and primary chicken embryonic muscle cells (PMCs) and anti-parasitic effect against Eimeria maxima. Cells to be tested were seeded in the 24-well plates and treated with ICOOH at concentrations of 0.1, 1.0, and 10.0 µg. CMCs were first stimulated by lipopolysaccharide (LPS) to induce an innate immune response, and QMCs and PMCs were treated with 0.5% and 2% fetal bovine serum, respectively, before they were treated with ICOOH. After 18 h of incubation, cells were harvested, and RT-PCR was performed to measure gene expression of proinflammatory cytokines of CMCs, tight junction (TJ) proteins of IECs, and muscle cell growth markers of QMCs and PMCs. In the second study, in vivo trials were carried out to study the effect of dietary ICOOH on disease parameters in broiler chickens infected with E. maxima. One hundred twenty male broiler chickens (0-day-old) were allocated into the following four treatment groups: 1) basal diet without infection (CON), 2) basal diet with E. maxima (NC), 3) ICOOH at 10.0 mg/kg feed with E. maxima (HI), and 4) ICOOH at 1.0 mg/kg feed with E. maxima (LO). Body weights (BWs) were measured on 0, 7, 14, 20, and 22 days. All groups except the CON chickens were orally infected with E. maxima on day 14. Jejunal samples were collected for lesion score and the transcriptomic analysis of cytokines and TJ proteins. In vitro, ICOOH increased the expression of TJ proteins in IECs and decreased IL-1β and IL-8 transcripts in the LPS-stimulated CMCs. In vivo, chickens on the HI diet showed reduced jejunal IL-1β, IFN-γ, and IL-10 expression and increased expression of genes activated by aryl hydrocarbon receptors and nutrient transporters in E. maxima-infected chickens. In conclusion, these results demonstrate the beneficial effects of dietary ICOOH on intestinal immune responses and barrier integrity in broiler chickens challenged with E. maxima. Furthermore, the present finding supports the notion to use microbial metabolites as novel feed additives to enhance resilience in animal agriculture.

146. Proteomic Signatures of Monocytes in Hereditary Recurrent Fevers.

Front Immunol

2022 Jun 23

Penco F, Petretto A, Lavarello C

147. Effect of Exercise Training on Body Composition and Inflammatory Cytokine Levels in Overweight and Obese Individuals: A Systematic Review and Network Meta-Analysis.

Front Immunol

2022 Jun 23

Wang S, Zhou H, Zhao C

OBJECTIVE: This study aimed to compare and rank the effectiveness of aerobic exercise (AE), resistance training (RT), combined aerobic and resistance training (CT), and high-intensity interval training (HIIT) on body composition and inflammatory cytokine levels in overweight and obese individuals by using network meta-analysis (NMA). METHODS: We searched the PubMed, Cochrane, Embase, Web of Science, and EBSCO databases to identify randomized controlled trials investigating the effects of exercise training on inflammatory cytokines in overweight and obese patients. The retrieval period was from inception to November 2021. Two reviewers independently screened the retrieved articles, extracted the pertinent data, and assessed the risk of bias of the included studies; then, they used Stata 16.0 and Review Manager 5.3 to perform an NMA. RESULTS: A total of 38 studies involving 1317 patients were included in this study. The results of the NMA indicated that AE had the greatest effect on weight loss (SUCRA=78.3; SMD=-0.51, 95% CI: -0.70, -0.33); CT had the greatest effect on reducing body mass index (SUCRA=70.7; SMD=-0.46, 95% CI: -0.81, -0.10), waist circumference (SUCRA=93.4; SMD=-1.86, 95% CI: -2.80, -0.93), percentage body fat (SUCRA=79.6; SMD=-1.38, 95% CI: -2.29, -0.48), interleukin-6 level (SUCRA=86.4; SMD=-1.98, 95% CI: -3.87, -0.09), and tumor necrosis factor-α level (SUCRA=79.4; SMD=-2.08, 95% CI: -3.75, -0.42); AE (SMD=0.51, 95% CI: -1.68, 2.69), RT (SMD=0.15, 95% CI: -3.01, 3.32), CT (SMD=1.78, 95% CI: -1.35, 4.92), and HIIT (SMD=2.29, 95% CI: -1.27, 5.86) did not significantly increase the adiponectin level. CONCLUSION: The current results suggest that CT is the best exercise modality for improving body composition and inflammatory status in overweight and obese individuals. More rigorous randomized control trials are needed for further validation. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD42022303165.

148. DDOST Correlated with Malignancies and Immune Microenvironment in Gliomas.

Front Immunol

2022 Jun 23

Chang X, Pan J, Zhao R

Among the most common types of brain tumor, gliomas are the most aggressive and have the poorest prognosis. Dolichyl-diphosphooligosaccharide protein glycosyltransferase non-catalytic subunit (DDOST) encodes a component of the oligosaccharide transferase complex and is related to the N-glycosylation of proteins. The role of DDOST in gliomas, however, is not yet known. First, we performed a pan cancer analysis of DDOST in the TCGA cohort. The expression of DDOST was compared between glioma and normal brain tissues in the GEO and Chinese Glioma Genome Atlas (CGGA) databases. In order to explore the role of DDOST in glioma, we analyze the impact of DDOST on the prognosis of glioma patients, with the CGGA 325 dataset as a test set and the CGGA 693 dataset as a validation set. Immunohistochemistry was performed on tissue microarrays to examine whether DDOST has an impact on glioma patient survival. Next, using single-cell sequencing analysis, GSEA, immune infiltration analysis, and mutation analysis, we explored how DDOST affected the glioma tumor microenvironment. Finally, we evaluated the clinical significance of DDOST for glioma treatment by constructing nomograms and decision curve analysis (DCA) curves. We found that DDOST was overexpressed in patients with high grade, IDH wild type, 1p19q non-codel and MGMT un-methylated, which was associated with poor prognosis. Patients with high levels of DDOST, regardless of their clinical characteristics, had a worse prognosis. Immunohistochemical analysis confirmed the results of the above bioinformatics analysis. Mechanistic analysis revealed that DDOST was closely associated with the glioma microenvironment and negatively related to tumor-infiltrating B cells and CD4+ T cells and positively related to CAFs and tumor-associated macrophages. In conclusion, these findings suggested that DDOST mediated the immunosuppressive microenvironment of gliomas and could be an important biomarker in diagnosing and treating gliomas.

149. Erratum: Preliminary Study on the Imbalance Between Th17 and Regulatory T Cells in Antiphospholipid Syndrome.

Front Immunol

2022 Jun 23

Frontiers Production Office.

150. Elevated Plasma Complement C1q Levels Contribute to a Poor Prognosis After Acute Primary Intracerebral Hemorrhage: A Prospective Cohort Study.

Front Immunol

2022 Jun 23

Wang Z, Wu X, Yan T

OBJECTIVE: The complement cascade is activated early following intracerebral hemorrhage (ICH) and causes acute brain injury. We intended to explore the effects of plasma complement component 1q (C1q) levels on hemorrhagic severity and functional outcome in ICH patients. METHODS: In this prospective cohort study, we measured the plasma C1q levels of 101 ICH patients and 101 healthy controls. The Glasgow Coma Scale (GCS) score and hematoma volume were used to assess the ICH severity. Poor prognosis was referred to as a Glasgow Outcome Scale (GOS) score of 1-3 at three months following a stroke. A multivariate logistic regression model was configured to determine the independent relation of plasma C1q levels to severity and poor prognosis. Under receiver operating characteristic (ROC) curve, prognostic capability of plasma C1q levels was evaluated. RESULTS: There was a significant elevation of plasma C1q levels in patients, as compared to controls [median (percentiles 25th-75th), 225.04 mg/l (156.10-280.15 mg/l) versus 88.18 mg/l (70.12-117.69 mg/l); P<0.001]. Plasma C1q levels of patients were independently related to GCS score (t =-3.281, P=0.001) and hematoma volume (t = 2.401, P=0.018), and were highly correlated with the GOS score at 3 months post-stroke (r=-0.658, P<0.001). Plasma C1q levels were obviously higher in poor prognosis patients than in other remainders (median percentiles 25th-75th), 278.40 mg/l (213.81-340.05 mg/l) versus 174.69 mg/l (141.21-239.93 mg/l); P<0.001). Under the ROC curve, plasma C1q levels significantly discriminated the development of poor prognosis (area under ROC curve 0.795; 95% confidence interval, 0.703-0.869; P<0.001). Using maximum Youden method, plasma C1q levels > 270.11 mg/l distinguished patients at risk of poor prognosis at 3 months with 56.52% sensitivity and 94.55% specificity. Meanwhile, the prognostic predictive ability of plasma C1q levels was equivalent to those of GCS score and hematoma volume (both P>0.05). Moreover, plasma C1q levels > 270.11 mg/l independently predicted a poor prognosis at 3 months (odds ratio, 4.821; 95% confidence interval, 1.211-19.200; P=0.026). CONCLUSION: Plasma C1q levels are closely related to the illness severity and poor prognosis of ICH at 3 months. Hence, complement C1q may play an important role in acute brain injury after ICH and plasma C1q may represent a promising prognostic predictor of ICH.

151. Insight of a Metabolic Prognostic Model to Identify Tumor Environment and Drug Vulnerability for Lung Adenocarcinoma.

Front Immunol

2022 Jun 23

Peng SL, Wang R, Zhou YL

Metabolic reprogramming is a novel method for the treatment of malignant tumors. The exploration of metabolism procedures between radiosensitive and radioresistant tumors may provide novel perspectives for lung adenocarcinoma (LUAD) patients after radiation therapy. In our study, metabolic reprogramming and immune response changes were found between radioresistant cell line (A549RR) and its parent cells (A549) using gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Nucleotide/amino acid, lipid, and glucose metabolic process, including Alanine, aspartate and glutamate metabolism, Tryptophan/Tyrosine metabolism, Butanoate metabolism, Purine/Pyrimidine metabolism, were screened out. Then molecular signatures database and The Cancer Genome Atlas Program (TCGA) lung adenocarcinoma datasets were used to identify metabolism-related genes (MRGs) between radiosensitive and radioresistant lung adenocarcinoma (LUAD) cells. A metabolism-based prognostic model, receiver operating characteristic (ROC) curve and nomogram were constructed using Metabolism Score calculated by 14 metabolism-related genes (MRGs). Three independent public datasets, (GSE72094, GSE3141, GSE8894) and one immunotherapy cohort (IMvigor210) were used as external validation cohorts. Expression of 14 hub genes in cells, normal and LUAD specimens were explored by Human Protein Atlas, TIMER2.0 and RT-qPCR. Patients with low-Metabolism Scores were correlated with longer survival times, higher response rates to immune checkpoint inhibitors (ICIs), different immune cell infiltrations and drug vulnerability. Our study demonstrated a comprehensive landscape between radiosensitive and radioresistant LUAD, and provide novel targets for NSCLC, especially those patients received radiation therapy. Moreover, this metabolism-based prognostic model may help to investigate connections between radiosensitivity, immune response, metabolic reprogramming, and patients' prognosis.

152. Characterization of the Intra-tumoral B Cell Immunoglobulin Repertoire Is of Prognostic Value for Esophageal Squamous Cell Carcinoma.

Front Immunol

2022 Jun 22

Wang Z, Cheng Z, Lu S

153. Antibodies to Citrullinated Protein Antigens, Rheumatoid Factor Isotypes and the Shared Epitope and the Near-Term Development of Clinically-Apparent Rheumatoid Arthritis.

Front Immunol

2022 Jun 22

Bergstedt DT, Tarter WJ, Peterson RA

154. Fibrin(ogen) Is Constitutively Expressed by Differentiated Intestinal Epithelial Cells and Mediates Wound Healing.

Front Immunol

2022 Jun 22

Seltana A, Cloutier G, Reyes Nicolas V

Fibrinogen is a large molecule synthesized in the liver and released in the blood. Circulating levels of fibrinogen are upregulated after bleeding or clotting events and support wound healing. In the context of an injury, thrombin activation drives conversion of fibrinogen to fibrin. Fibrin deposition contains tissue damage, stops blood loss, and prevents microbial infection. In most circumstances, fibrin needs to be removed to allow the resolution of inflammation and tissue repair, whereas failure of this may lead to the development of various disorders. However, the contribution of fibrinogen to tissue inflammation and repair is likely to be context-dependent. In this study, the concept that fibrin needs to be removed to allow tissue repair and to reduce inflammation is challenged by our observations that, in the intestine, fibrinogen is constitutively produced by a subset of intestinal epithelial cells and deposited at the basement membrane as fibrin where it serves as a substrate for wound healing under physiological conditions such as epithelial shedding at the tip of the small intestinal villus and surface epithelium of the colon as well as under pathological conditions that require rapid epithelial repair. The functional integrity of the intestine is ensured by the constant renewal of its simple epithelium. Superficial denuding of the epithelial cell layer occurs regularly and is rapidly corrected by a process called restitution that can be influenced by various soluble and insoluble factors. Epithelial cell interaction with the extracellular matrix greatly influences the healing process by acting on cell morphology, adhesion, and migration. The functional contribution of a fibrin(ogen) matrix in the intestine was studied under physiological and pathological contexts. Our results (immunofluorescence, immunoelectron microscopy, and quantitative PCR) show that fibrin(ogen) is a novel component of the basement membrane associated with the differentiated epithelial cell population in both the small intestine and colon. Fibrin(ogen) alone is a weak ligand for epithelial cells and behaves as an anti-adhesive molecule in the presence of type I collagen. Furthermore, the presence of fibrin(ogen) significantly shortens the time required to achieve closure of wounded epithelial cell monolayers and co-cultures in a PI3K-dependent manner. In human specimens with Crohn's disease, we observed a major accumulation of fibrin(ogen) throughout the tissue and at denuded sites. In mice in which fibrin formation was inhibited with dabigatran treatment, dextran sulfate sodium administration provoked a significant increase in the disease activity index and pathological features such as mucosal ulceration and crypt abscess formation. Taken together, these results suggest that fibrin(ogen) contributes to epithelial healing under both normal and pathological conditions.

155. Supplementation of Dietary Crude Lentinan Improves the Intestinal Microbiota and Immune Barrier in Rainbow Trout (Oncorhynchus mykiss) Infected by Infectious Hematopoietic Necrosis Virus.

Front Immunol

2022 Jun 22

Ren G, Xu L, Zhao J

156. Persistent Antiphospholipid Antibodies Are Not Associated With Worse Clinical Outcomes in a Prospective Cohort of Hospitalised Patients With SARS-CoV-2 Infection.

Front Immunol

2022 Jun 22

Espinosa G, Zamora-Martínez C, Pérez-Isidro A

157. The Immunological Effect of Oxygen Carriers on Normothermic Ex Vivo Liver Perfusion.

Front Immunol

2022 Jun 22

Jennings H, Carlson KN, Little C

INTRODUCTION: Normothermic ex vivo liver perfusion (NEVLP) is an organ preservation method that allows liver graft functional assessment prior to transplantation. One key component of normothermic perfusion solution is an oxygen carrier to provide oxygen to the liver to sustain metabolic activities. Oxygen carriers such as red blood cells (RBCs) or hemoglobin-based oxygen carriers have an unknown effect on the liver-resident immune cells during NEVLP. In this study, we assessed the effects of different oxygen carriers on the phenotype and function of liver-resident immune cells. METHODS: Adult Lewis rat livers underwent NEVLP using three different oxygen carriers: human packed RBCs (pRBCs), rat pRBCs, or Oxyglobin (a synthetic hemoglobin-based oxygen carrier). Hourly perfusate samples were collected for downstream analysis, and livers were digested to isolate immune cells. The concentration of common cytokines was measured in the perfusate, and the immune cells underwent phenotypic characterization with flow cytometry and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The stimulatory function of the liver-resident immune cells was assessed using mixed lymphocyte reactions. RESULTS: There were no differences in liver function, liver damage, or histology between the three oxygen carriers. qRT-PCR revealed that the gene expression of nuclear factor κ light chain enhancer of activated B cells (NF-kB), Interleukin (IL-1β), C-C motif chemokine ligand 2 (CCL2), C-C motif chemokine ligand 7 (CCL7), and CD14 was significantly upregulated in the human pRBC group compared with that in the naive, whereas the rat pRBC and Oxyglobin groups were not different from that of naive. Flow cytometry demonstrated that the cell surface expression of the immune co-stimulatory protein, CD86, was significantly higher on liver-resident macrophages and plasmacytoid dendritic cells perfused with human pRBC compared to Oxyglobin. Mixed lymphocyte reactions revealed increased allogeneic T-cell proliferation in the human and rat pRBC groups compared to that in the Oxyglobin group. CONCLUSIONS: Liver-resident immune cells are important mediators of rejection after transplantation. In this study, we show that the oxygen carrier used in NEVLP solutions can affect the phenotype of these liver-resident immune cells. The synthetic hemoglobin-based oxygen carrier, Oxyglobin, showed the least amount of liver-resident immune cell activation and the least amount of allogeneic proliferation when compared to human or rat pRBCs. To mitigate liver-resident immune cell activation during NEVLP (and subsequent transplantation), Oxyglobin may be an optimal oxygen carrier.

158. Strain Specific Variations in Acinetobacter baumannii Complement Sensitivity.

Front Immunol

2022 Jun 22

Kamuyu G, Ercoli G, Ramos-Sevillano E

159. Case Report: Successful Immunotherapy Improved the Prognosis of the Unfavorable Subset of Cancer of Unknown Primary.

Front Immunol

2022 Jun 22

Mei J, Wang H, Fan H

160. 3D Genome Organization as an Epigenetic Determinant of Transcription Regulation in T Cells.

Front Immunol

2022 Jun 22

Papadogkonas G, Papamatheakis DA, Spilianakis C.

161. Impaired Kallikrein-Kinin System in COVID-19 Patients' Severity.

Front Immunol

2022 Jun 22

Alfaro E, Díaz-García E, García-Tovar S

162. Pathogenic Leptospires Limit Dendritic Cell Activation Through Avoidance of TLR4 and TRIF Signaling.

Front Immunol

2022 Jun 22

Cagliero J, Vernel-Pauillac F, Murray G

Leptospira interrogans is a bacterial species responsible for leptospirosis, a neglected worldwide zoonosis. Mice and rats are resistant and can become asymptomatic carriers, whereas humans and some other mammals may develop severe forms of leptospirosis. Uncommon among spirochetes, leptospires contain lipopolysaccharide (LPS) in their outer membrane. LPS is highly immunogenic and forms the basis for a large number of serovars. Vaccination with inactivated leptospires elicits a protective immunity, restricted to serovars with related LPS. This protection that lasts in mice, is not long lasting in humans and requires annual boosts. Leptospires are stealth pathogens that evade the complement system and some pattern recognition receptors from the Toll-like (TLR) and Nod-Like families, therefore limiting antibacterial defense. In macrophages, leptospires totally escape recognition by human TLR4, and escape the TRIF arm of the mouse TLR4 pathway. However, very little is known about the recognition and processing of leptospires by dendritic cells (DCs), although they are crucial cells linking innate and adaptive immunity. Here we tested the activation of primary DCs derived from human monocytes (MO-DCs) and mouse bone marrow (BM-DCs) 24h after stimulation with saprophytic or different pathogenic virulent or avirulent L. interrogans. We measured by flow cytometry the expression of DC-SIGN, a lectin involved in T-cell activation, co-stimulation molecules and MHC-II markers, and pro- and anti-inflammatory cytokines by ELISA. We found that exposure to leptospires, live or heat-killed, activated dendritic cells. However, pathogenic L. interrogans, especially from the Icterohaemorraghiae Verdun strain, triggered less marker upregulation and less cytokine production than the saprophytic Leptospira biflexa. In addition, we showed a better activation with avirulent leptospires, when compared to the virulent parental strains in murine BM-DCs. We did not observe this difference in human MO-DCs, suggesting a role for TLR4 in DC stimulation. Accordingly, using BM-DCs from transgenic deficient mice, we showed that virulent Icterohaemorraghiae and Manilae serovars dampened DC activation, at least partly, through the TLR4 and TRIF pathways. This work shows a novel bacterial immune evasion mechanism to limit DC activation and further illustrates the role of the leptospiral LPS as a virulence factor.

163. Editorial: Advances in Using Big Data and Artificial Intelligence to Understand Heterogeneity in Inflammatory Responses.

Front Immunol

2022 Jun 22

Zhou XJ, MacLeod AS, Tsoi LC.

164. Editorial: Immune Aging: Implications for Transplantation.

Front Immunol

2022 Jun 21

Greenland JR, Tullius SG, Schaenman J.

165. Proteomic Analyses Reveal Higher Levels of Neutrophil Activation in Men Than in Women With Systemic Lupus Erythematosus.

Front Immunol

2022 Jun 21

Cai ML, Gui L, Huang H

166. An Emerging Role for Neutrophil Extracellular Traps in IgA Vasculitis: A Mini-Review.

Front Immunol

2022 Jun 21

Chen XQ, Tu L, Tang Q

167. Case Report: Successful Treatment With Monoclonal Antibodies in One APDS Patient With Prolonged SARS-CoV-2 Infection Not Responsive to Previous Lines of Treatment.

Front Immunol

2022 Jun 21

Rivalta B, Amodio D, Giancotta C

168. Effects of Occult Hypoperfusion on Local Circulation and Inflammation - An Analysis in a Standardized Polytrauma Model.

Front Immunol

2022 Jun 21

Halvachizadeh S, Kalbas Y, Teuben MPJ

INTRODUCTION: Occult hypoperfusion (OH) is defined as persistent lactic acidosis despite normalization of vital parameters following trauma. The aim of this study was to analyze the association of occult hypoperfusion with local circulation and inflammation of injured soft tissue in a porcine polytrauma model. METHODS: This experimental study was performed with male landrace pigs who suffered a standardized polytrauma, including a femoral fracture, blunt chest trauma, liver laceration and a mean arterial pressure (MAP) controlled hemorrhagic shock. One hour after induction of trauma, the animals were resuscitated with retrograde femoral nailing, liver packing and volume replacement. Animals were stratified into Group Norm (normalizing lactate levels after resuscitation) and Group occult hypoperfusion (OH) (persistent lactate levels above 2 mmol/l with normalizing vital parameters after resuscitation). Local circulation (oxygen saturation, hemoglobin amount, blood flow) was measured with optical sensors at the subcutaneous soft tissue at the fractured extremity as well as at the stomach and colon. Local inflammatory parameters [interleukin (IL) 6, 8, 10, and heat shock protein (HSP)] were analyzed in the subcutaneous tissue of the fractured extremity. RESULTS: Group Norm (n = 19) and Group OH (n = 5) were comparable in baseline vital and laboratory parameters. The shock severity and total amount of blood loss were comparable among Group Norm and Group OH. Following resuscitation Group OH had significantly lower local relative hemoglobin amount at the injured soft tissue of the fractured extremity when compared with Group Norm (39.4, SD 5.3 vs. 63.9, SD 27.6 A.U., p = 0.031). The local oxygenation was significantly lower in Group OH compared to Group Norm (60.4, SD 4.6 vs. 75.8, SD 12.8, p = 0.049). Local IL-6 in the fatty tissue was significantly higher in Group OH (318.3, SD 326.6 [pg/ml]) when compared with Group Norm (73.9,SD 96.3[pg/ml], p = 0.03). The local circulation at the abdominal organs was comparable in both groups. CONCLUSION: OH is associated with decreased local circulation and increased local inflammation at the injured soft tissue of the extremity in polytrauma. OH might reflect the severity of local soft tissue injuries, and guide treatment strategies.

169. Characterization of Different Subtypes of Immune Cell Infiltration in Glioblastoma to Aid Immunotherapy.

Front Immunol

2022 Jun 21

Feng P, Li Z, Li Y

170. Cellular Mechanisms Underlying B Cell Abnormalities in Patients With Gain-of-Function Mutations in the PIK3CD Gene.

Front Immunol

2022 Jun 21

Wang W, Min Q, Lai N

171. Innate Immune Responses by Respiratory Viruses, Including Rhinovirus, During Asthma Exacerbation.

Front Immunol

2022 Jun 20

Nakagome K, Nagata M.

172. A Bibliometric and Knowledge-Map Analysis of Macrophage Polarization in Atherosclerosis From 2001 to 2021.

Front Immunol

2022 Jun 20

Song L, Zhang J, Ma D

173. Loss of Gut Barrier Integrity In Lupus.

Front Immunol

2022 Jun 20

Ma L, Morel L.

174. Gene Expression Signatures Reveal Common Virus Infection Pathways in Target Tissues of Type 1 Diabetes, Hashimoto's Thyroiditis, and Celiac Disease.

Front Immunol

2022 Jun 20

Yin M, Zhang Y, Liu S

175. Autoimmune Cytopenias in Common Variable Immunodeficiency Are a Diagnostic and Therapeutic Conundrum: An Update.

Front Immunol

2022 Jun 20

Chawla S, Barman P, Tyagi R

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency (PID). CVID is a heterogenous condition and clinical manifestations may vary from increased susceptibility to infections to autoimmune manifestations, granulomatous disease, polyclonal lymphoproliferation, and increased risk of malignancy. Autoimmune manifestations may, at times, be the first and only clinical presentation of CVID, resulting in diagnostic dilemma for the treating physician. Autoimmune cytopenias (autoimmune haemolytic anaemia and/or thrombocytopenia) are the most common autoimmune complications seen in patients with CVID. Laboratory investigations such as antinuclear antibodies, direct Coomb's test and anti-platelet antibodies may not be useful in patients with CVID because of lack of specific antibody response. Moreover, presence of autoimmune cytopenias may pose a significant therapeutic challenge as use of immunosuppressive agents can be contentious in these circumstances. It has been suggested that serum immunoglobulins must be checked in all patients presenting with autoimmune cytopenia such as immune thrombocytopenia or autoimmune haemolytic anaemia. It has been observed that patients with CVID and autoimmune cytopenias have a different clinical and immunological profile as compared to patients with CVID who do not have an autoimmune footprint. Monogenic defects have been identified in 10-50% of all patients with CVID depending upon the population studied. Monogenic defects are more likely to be identified in patients with CVID with autoimmune complications. Common genetic defects that may lead to CVID with an autoimmune phenotype include nuclear factor kappa B subunit 1 (NF-kB1), Lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA), cytotoxic T lymphocyte antigen 4 (CTLA4), Phosphoinositide 3-kinase (PI3K), inducible T-cell costimulatory (ICOS), IKAROS and interferon regulatory factor-2 binding protein 2 (IRF2BP2). In this review, we update on recent advances in pathophysiology and management of CVID with autoimmune cytopenias.

176. Case Report: Successful Treatment of Alopecia Universalis With Tofacitinib and Increased Cytokine Levels: Normal Therapeutic Reaction or Danger Signal?

Front Immunol

2022 Jun 20

Yu L, Yu H, Zhang S

177. Naive T Cells in Graft Versus Host Disease and Graft Versus Leukemia: Innocent or Guilty?

Front Immunol

2022 Jun 20

Dekker L, Sanders E, Lindemans CA

178. The Translational Potential of Microglia and Monocyte-Derived Macrophages in Ischemic Stroke.

Front Immunol

2022 Jun 20

Wicks EE, Ran KR, Kim JE

179. Nuclear Coregulatory Complexes in Tregs as Targets to Promote Anticancer Immune Responses.

Front Immunol

2022 Jun 20

Christensen LM, Hancock WW.

180. First Characterization of Chicken Interleukin-9.

Front Immunol

2022 Jun 20

He S, Chen L, Hao X

181. Immunity and Extracellular Matrix Characteristics of Breast Cancer Subtypes Based on Identification by T Helper Cells Profiling.

Front Immunol

2022 Jun 20

Zhou Y, Tian Q, Gao H

BACKGROUND: The therapeutic effect of immune checkpoint inhibitors on tumors is not only related to CD8+ effector T cells but also sufficiently related to CD4+ helper T (TH) cells. The immune characteristics of breast cancer, including gene characteristics and tumor-infiltrating lymphocytes, have become significant biomarkers for predicting prognosis and immunotherapy response in recent years. METHODS: Breast cancer samples from The Cancer Genome Atlas (TCGA) database and triple-negative breast cancer (TNBC) samples from GSE31519 in the Gene Expression Omnibus (GEO) database were extracted and clustered based on gene sets representing TH cell signatures. CIBERSORT simulations of immune cell components in the tumor microenvironment and gene set enrichment analyses (GSEAs) were performed in the different clusters to verify the classification of the subtypes. The acquisition of differentially expressed genes (DEGs) in the different clusters was further used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The clinical information from different clusters was used for survival analysis. Finally, the surgical tissues of TNBC samples were stained by immunofluorescence staining and Masson's trichrome staining to explore the correlation of TH cell subtypes with extracellular matrix (ECM). RESULTS: The breast cancer samples from the datasets in TCGA database and GEO database were classified into TH-activated and TH-silenced clusters, which was verified by the immune cell components and enriched immune-related pathways. The DEGs of TH-activated and TH-silenced clusters were obtained. In addition to TH cells and other immune-related pathways, ECM-related pathways were found to be enriched by DEGs. Furthermore, the survival data of TCGA samples and GSE31519 samples showed that the 10-year overall survival (p-value < 0.001) and 10-year event-free survival (p-value = 0.162) of the TH-activated cluster were better, respectively. Fluorescent labeling of TH cell subtypes and staining of the collagen area of surgical specimens further illustrated the relationship between TH cell subtypes and ECM in breast cancer, among which high TH1 infiltration was related to low collagen content (p-value < 0.001), while high TH2 and Treg infiltration contained more abundant collagen (p-value < 0.05) in TNBC. With regard to the relationship of TH cell subtypes, TH2 was positively correlated with Treg (p-value < 0.05), while TH1 was negatively correlated with both of them. CONCLUSIONS: The immune and ECM characteristics of breast cancer subtypes based on TH cell characteristics were revealed, and the relationship between different TH cell subsets and ECM and prognosis was explored in this study. The crosstalk between ECM and TH cell subtypes formed a balanced TME influencing the prognosis and treatment response in breast cancer, which suggests that the correlation between TH cells and ECM needs to be further emphasized in future breast cancer studies.

182. Neutrophil Infiltration Characterized by Upregulation of S100A8, S100A9, S100A12 and CXCR2 Is Associated With the Co-Occurrence of Crohn's Disease and Peripheral Artery Disease.

Front Immunol

2022 Jun 20

Yao Z, Zhang B, Niu G

BACKGROUND: Crohn's disease (CD) and peripheral arterial disease (PAD) are closely related. The pathophysiological mechanisms underlying the coexistence of CD and PAD are unknown. The aim of this study was to investigate the key molecules and pathways mediating the co-occurrence of CD and PAD through quantitative bioinformatic analysis of a public RNA sequencing database. METHODS: Datasets of CD (GSE111889) and PAD (GSE120642) were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were analyzed using the 'edgeR' and 'limma' packages of R. Gene Ontology and Kyoto Encyclopedia analyses of common DEGs were performed to explore the functions of DEGs. Protein-protein interaction (PPI) networks were established by the Search Tool for the Retrieval of Interacting Genes (STRING) database and visualized by Cytoscape. Hub genes were selected using the plugin cytoHubba. Hub gene validation was performed in GSE95095 for CD and GSE134431 for PAD. Receiver operating characteristic curves were used to evaluate the predictive values of the hub genes. Gene set enrichment analysis and immune infiltration of the hub genes were performed. RESULTS: A total of 54 common DEGs (2 downregulated and 52 upregulated) were identified. Pathways of neutrophil chemotaxis, neutrophil migration and cytokine and cytokine receptors were enriched in CD and PAD. S100A8, S100A9, S100A12 and CXCR2 were identified as hub genes after validation, with all area under the curve > 0.7 for both CD and PAD. Neutrophil infiltration was associated with upregulation of the hub genes. Pathways of immune processes, including neutrophil activation, neutrophil chemotaxis, neutrophil migration were significantly correlated with high expression of S100A8, S100A9, S100A12 and CXCR2 in both CD and PAD. CONCLUSIONS: This bioinformatic study elucidates S100A8, S100A9, S100A12 and CXCR2 as hub genes for the co-occurrence of Crohn's disease and peripheral artery disease. Inflammation and immune regulation modulated by neutrophil infiltration play a central role in the development of CD and PAD and may be potential targets for diagnosis and treatment.

183. Recent Advancements in Poor Graft Function Following Hematopoietic Stem Cell Transplantation.

Front Immunol

2022 Jun 2

Man Y, Lu Z, Yao X

184. A Phase I Study of Locoregional High-Dose Autologous Natural Killer Cell Therapy With Hepatic Arterial Infusion Chemotherapy in Patients With Locally Advanced Hepatocellular Carcinoma.

Front Immunol

2022 Jun 2

Bae WK, Lee BC, Kim HJ

185. CD5 Controls Gut Immunity by Shaping the Cytokine Profile of Intestinal T Cells.

Front Immunol

2022 Jun 2

Schuster C, Kiaf B, Hatzihristidis T

186. Drosophila Relish Activating lncRNA-CR33942 Transcription Facilitates Antimicrobial Peptide Expression in Imd Innate Immune Response.

Front Immunol

2022 Jun 2

Zhou H, Wu S, Liu L

187. One Stone, Two Birds: N6-Methyladenosine RNA Modification in Leukemia Stem Cells and the Tumor Immune Microenvironment in Acute Myeloid Leukemia.

Front Immunol

2022 Jun 2

Ouyang X, Gong Y.

Acute myeloid leukemia is the most common acute leukemia in adults, with accumulation of abundant blasts and impairment of hematogenic function. Despite great advances in diagnosis and therapy, the overall survival of patients with acute myeloid leukemia remains poor. Leukemia stem cells are the root cause of relapse and chemoresistance in acute myeloid leukemia. The tumor immune microenvironment is another trigger to induce recurrence and drug resistance. Understanding the underlying factors influencing leukemia stem cells and the tumor immune microenvironment is an urgent and unmet need. Intriguingly, N6-methyladenosine, the most widespread internal mRNA modification in eukaryotes, is found to regulate both leukemia stem cells and the tumor immune microenvironment. Methyltransferases and demethylases cooperatively make N6-methyladenosine modification reversible and dynamic. Increasing evidence demonstrates that N6-methyladenosine modification extensively participates in tumorigenesis and progression in various cancers, including acute myeloid leukemia. In this review, we summarize the current progress in studies on the functions of N6-methyladenosine modification in acute myeloid leukemia, especially in leukemia stem cells and the tumor immune microenvironment. We generalize the landscape of N6-methyladenosine modification in self-renewal of leukemia stem cells and immune microenvironment regulation, as well as in the initiation, growth, proliferation, differentiation, and apoptosis of leukemia cells. In addition, we further explore the clinical application of N6-methyladenosine modification in diagnosis, prognostic stratification, and effect evaluation. Considering the roles of N6-methyladenosine modification in leukemia stem cells and the tumor immune microenvironment, we propose targeting N6-methyladenosine regulators as one stone to kill two birds for acute myeloid leukemia treatment.

188. The Effect of Normothermic Machine Perfusion on the Immune Profile of Donor Liver.

Front Immunol

2022 Jun 2

Lee ACH, Edobor A, Lysandrou M

BACKGROUND: Normothermic machine perfusion (NMP) allows viability assessment and potential resuscitation of donor livers prior to transplantation. The immunological effect of NMP on liver allografts is undetermined, with potential implications on allograft function, rejection outcomes and overall survival. In this study we define the changes in immune profile of human livers during NMP. METHODS: Six human livers were placed on a NMP device. Tissue and perfusate samples were obtained during cold storage prior to perfusion and at 1, 3, and 6 hours of perfusion. Flow cytometry, immunohistochemistry, and bead-based immunoassays were used to measure leukocyte composition and cytokines in the perfusate and within the liver tissue. Mean values between baseline and time points were compared by Student's t-test. RESULTS: Within circulating perfusate, significantly increased frequencies of CD4 T cells, B cells and eosinophils were detectable by 1 hour of NMP and continued to increase at 6 hours of perfusion. On the other hand, NK cell frequency significantly decreased by 1 hour of NMP and remained decreased for the duration of perfusion. Within the liver tissue there was significantly increased B cell frequency but decreased neutrophils detectable at 6 hours of NMP. A transient decrease in intermediate monocyte frequency was detectable in liver tissue during the middle of the perfusion run. Overall, no significant differences were detectable in tissue resident T regulatory cells during NMP. Significantly increased levels of pro-inflammatory and anti-inflammatory cytokines were seen following initiation of NMP that continued to rise throughout duration of perfusion. CONCLUSIONS: Time-dependent dynamic changes are seen in individual leukocyte cell-types within both perfusate and tissue compartments of donor livers during NMP. This suggests a potential role of NMP in altering the immunogenicity of donor livers prior to transplant. These data also provide insights for future work to recondition the intrinsic immune profile of donor livers during NMP prior to transplantation.

189. Single Nucleotide Polymorphisms (SNP) and SNP-SNP Interactions of the Surfactant Protein Genes Are Associated With Idiopathic Pulmonary Fibrosis in a Mexican Study Group; Comparison With Hypersensitivity Pneumonitis.

Front Immunol

2022 Jun 2

Abbasi A, Chen C, Gandhi CK

Surfactant proteins (SPs) are important for normal lung function and innate immunity of the lungs and their genes have been identified with significant genetic variability. Changes in quantity or quality of SPs due to genetic mutations or natural genetic variability may alter their functions and contribute to the host susceptibility for particular diseases. Alternatively, SP single nucleotide polymorphisms (SNPs) can serve as markers to identify disease risk or response to therapies, as shown for other genes in a number of other studies. In the current study, we evaluated associations of SFTP SNPs with idiopathic pulmonary fibrosis (IPF) by studying novel computational models where the epistatic effects (dominant, additive, recessive) of SNP-SNP interactions could be evaluated, and then compared the results with a previously published hypersensitivity pneumonitis (HP) study where the same novel models were used. Mexican Hispanic patients (IPF=84 & HP=75) and 194 healthy control individuals were evaluated. The goal was to identify SP SNPs and SNP-SNP interactions that associate with IPF as well as SNPs and interactions that may be unique to each of these interstitial diseases or common between them. We observed: 1) in terms of IPF, i) three single SFTPA1 SNPs to associate with decreased IPF risk, ii) three SFTPA1 haplotypes to associate with increased IPF risk, and iii) a number of three-SNP interactions to associate with IPF susceptibility. 2) Comparison of IPF and HP, i) three SFTPA1 and one SFTPB SNP associated with decreased risk in IPF but increased risk in HP, and one SFTPA1 SNP associated with decreased risk in both IPF and HP, ii) a number of three-SNP interactions with the same or different effect pattern associated with IPF and/or HP susceptibility, iii) one of the three-SNP interactions that involved SNPs of SFTPA1, SFTPA2, and SFTPD, with the same effect pattern, was associated with a disease-specific outcome, a decreased and increased risk in HP and IPF, respectively. This is the first study that compares the SP gene variants in these two phenotypically similar diseases. Our findings indicate that SNPs of all SFTPs may play an important role in the genetic susceptibility to IPF and HP. Importantly, IPF and HP share some SP genetic variants, suggesting common pathophysiological mechanisms and pathways regarding surfactant biogenesis, but also some differences, highlighting the diverse underlying pathogenic mechanisms between an inflammatory-driven fibrosis (HP) and an epithelial-driven fibrosis (IPF). Alternatively, the significant SNPs identified here, along with SNPs of other genes, could serve as markers to distinguish these two devastating diseases.

190. Antimicrobial Resistance in the COVID-19 Landscape: Is There an Opportunity for Anti-Infective Antibodies and Antimicrobial Peptides?

Front Immunol

2022 Jun 2

Pérez de la Lastra JM, Anand U, González-Acosta S

191. Mechanism of COVID-19-Related Proteins in Spinal Tuberculosis: Immune Dysregulation.

Front Immunol

2022 Jun 2

Chen L, Liu C, Liang T

192. Corrigendum: Antigen Presentation Machinery Signature-Derived CALR Mediates Migration, Polarization of Macrophages in Glioma and Predicts Immunotherapy Response.

Front Immunol

2022 Jun 2

Chen R, Zhang H, Wu W

193. Tislelizumab Plus Chemotherapy Sequential Neoadjuvant Therapy for Non-cCR Patients After Neoadjuvant Chemoradiotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma (ETNT): An Exploratory Study.

Front Immunol

2022 Jun 2

He W, Wang C, Wu L

194. The Aging Features of Thyrotoxicosis Mice: Malnutrition, Immunosenescence and Lipotoxicity.

Front Immunol

2022 Jun 2

Feng Q, Xia W, Dai G

195. mRNA Vaccines: The Dawn of a New Era of Cancer Immunotherapy.

Front Immunol

2022 Jun 2

Deng Z, Tian Y, Song J

196. GMZ2 Vaccine-Induced Antibody Responses, Naturally Acquired Immunity and the Incidence of Malaria in Burkinabe Children.

Front Immunol

2022 Jun 2

Dassah S, Adu B, Tiendrebeogo RW

197. OX40 Expression in Eosinophils Aggravates OVA-Induced Eosinophilic Gastroenteritis.

Front Immunol

2022 Jun 2

Xu L, Tian D, Zhou M

198. PET/CT-Based Characterization of 18F-FDG Uptake in Various Tissues Reveals Novel Potential Contributions to Coronary Artery Disease in Psoriatic Arthritis.

Front Immunol

2022 Jun 2

Schwartz DM, Parel P, Li H

BACKGROUND AND OBJECTIVES: Psoriasis is a heterogeneous inflammatory disease that involves the skin, joints, liver, heart, and other organs. Psoriatic arthritis (PsA) is associated with cardiovascular disease (CVD), but the relative contributions of inflammatory and metabolic dysregulation to CVD are incompletely understood. We set out to discover novel potential contributors to CVD in PsA patients by comprehensively phenotyping a cohort of PsA patients using these advanced technologies. METHODS: In this cross-sectional analysis of a cohort study, we investigated associations of systemic inflammation and metabolic dysregulation with Coronary CT angiography (CCTA)-proven coronary artery disease (CAD) in 39 subjects with PsA. We measured traditional CVD risk factors [blood pressure, Body Mass Index (BMI), diabetes, age, sex, smoking], serum markers of systemic inflammation (hsCRP, GlycA) and metabolic dysfunction (cholesterol efflux capacity), and inflammatory cytokines (IL-1β, IL-6, IL-12/IL-23, IL-17A, TNF-α, IFN-γ). We also incorporated radiographic measures of metabolic dysfunction (visceral and subcutaneous adipose volume) and tissue-specific inflammation (positron emission tomography-computed tomography, PET-CT). To quantify relative contributions of FDG (fluorodeoxyglucose) uptake and adiposity to coronary plaque, we performed multiple linear regression, controlling for Framingham risk score (FRS) and FRS + visceral adiposity. RESULTS: Compared with non-psoriatic volunteers, subjects with PsA had elevated markers of metabolic and inflammatory disease, which was more pronounced in subjects with moderate-to-severe skin disease. This included visceral (p = 0.005) and subcutaneous (p = 0.004) adiposity, BMI (p = 0.001), hemoglobin A1C (p = 0.037), high sensitivity C-reactive protein (p = 0.005), IL-6 (p = 0.003), IFN-γ (p = 0.006), and liver FDG uptake (p = 0.03). In subjects with PsA, visceral adiposity correlated significantly with subclinical CAD (standardized β = 0.681, p = 0.002), as did FDG uptake in bone marrow (standardized β = 0.488, p = 0.008), liver (standardized β = 0.619, p < 0.001), spleen (standardized β = 0.523, p = 0.004), and subcutaneous adipose (standardized β = 0.524, p = 0.003). INTERPRETATION: Together, these findings reveal inflammatory and metabolic potential contributors to subclinical CAD in PsA, including adipose inflammation, and suggesting novel targets for CVD prevention and treatment in PsA.

199. High Mobility Group Proteins in Sepsis.

Front Immunol

2022 Jun 2

Liang G, He Z.

200. Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp (Cyprinus carpio).

Front Immunol

2022 Jun 2

Wu D, Fan Z, Li J

To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp (Cyprinus carpio), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3, claudin-7, ZO-1, and MLCK were significantly up-regulated in the LP+0.4% AKG group, and the relative expression levels of the pro-inflammatory factors IL-1β and IL-6α were significantly lower with the addition of 0.4%, 0.8%, and 1.2% AKG. Moreover, the abundance of Proteobacteria in the LP+0.4% AKG group was lower than that in the LP group, and the abundance of Firmicutes and Fusobacteria was higher at the phylum level. The abundance of Citrobacter in the LP+0.4% AKG group was decreased compared to the LP group, while the abundance of Aeromonas was increased at the genus level. In short, the effects of AKG on the intestinal health of the common carp were systematically and comprehensively evaluated from the perspectives of intestinal physical barrier, chemical barrier, biological barrier, and immune barrier. We found that an LP diet supplemented with 0.4% AKG was beneficial to the growth performance and intestinal health of common carp.

201. mRNA or ChAd0x1 COVID-19 Vaccination of Adolescents Induces Robust Antibody and Cellular Responses With Continued Recognition of Omicron Following mRNA-1273.

Front Immunol

2022 Jun 2

Dowell AC, Powell AA, Davis C

Children and adolescents generally experience mild COVID-19. However, those with underlying physical health conditions are at a significantly increased risk of severe disease. Here, we present a comprehensive analysis of antibody and cellular responses in adolescents with severe neuro-disabilities who received COVID-19 vaccination with either ChAdOx1 (n=6) or an mRNA vaccine (mRNA-1273, n=8, BNT162b2, n=1). Strong immune responses were observed after vaccination and antibody levels and neutralisation titres were both higher after two doses. Both measures were also higher after mRNA vaccination and were further enhanced by prior natural infection where one vaccine dose was sufficient to generate peak antibody response. Robust T-cell responses were generated after dual vaccination and were also higher following mRNA vaccination. Early T-cells were characterised by a dominant effector-memory CD4+ T-cell population with a type-1 cytokine signature with additional production of IL-10. Antibody levels were well-maintained for at least 3 months after vaccination and 3 of 4 donors showed measurable neutralisation titres against the Omicron variant. T-cell responses also remained robust, with generation of a central/stem cell memory pool and showed strong reactivity against Omicron spike. These data demonstrate that COVID-19 vaccines display strong immunogenicity in adolescents and that dual vaccination, or single vaccination following prior infection, generate higher immune responses than seen after natural infection and develop activity against Omicron. Initial evidence suggests that mRNA vaccination elicits stronger immune responses than adenoviral delivery, although the latter is also higher than seen in adult populations. COVID-19 vaccines are therefore highly immunogenic in high-risk adolescents and dual vaccination might be able to provide relative protection against the Omicron variant that is currently globally dominant.

202. Comprehensive Analysis of Senescence Characteristics Defines a Novel Prognostic Signature to Guide Personalized Treatment for Clear Cell Renal Cell Carcinoma.

Front Immunol

2022 Jun 2

Zhou P, Liu Z, Hu H

203. C1QTNF3 is Upregulated During Subcutaneous Adipose Tissue Remodeling and Stimulates Macrophage Chemotaxis and M1-Like Polarization.

Front Immunol

2022 Jun 2

Micallef P, Vujičić M, Wu Y

204. UVB-Induced Skin Autoinflammation Due to Nlrp1b Mutation and Its Inhibition by Anti-IL-1β Antibody.

Front Immunol

2022 Jun 17

Murase Y, Takeichi T, Koseki J

205. Identification of New Antibodies Targeting Malignant Plasma Cells for Immunotherapy by Next-Generation Sequencing-Assisted Phage Display.

Front Immunol

2022 Jun 17

Krohn S, Boje AS, Gehlert CL

206. Comprehensive Evaluation of the m(6)A Regulator Prognostic Risk Score in the Prediction of Immunotherapy Response in Clear Cell Renal Cell Carcinoma.

Front Immunol

2022 Jun 17

Yu M, Liu X, Xu H

207. Editorial: Versatile Roles for B Cells in Tumor Immunity.

Front Immunol

2022 Jun 17

Brossart P.

208. Hypercholesterolemia Correlates With Glomerular Phospholipase A2 Receptor Deposit and Serum Anti-Phospholipase A2 Receptor Antibody and Predicts Proteinuria Outcome in Idiopathic Membranous Nephropathy.

Front Immunol

2022 Jun 17

Dong L, Li YQ, Guo SM

BACKGROUND: The anti-phospholipase A2 receptor (PLA2R) antibody is a non-invasive diagnostic tool and prognosis predictor of idiopathic membranous nephropathy (IMN). Baseline hypercholesterolemia independently predicts proteinuria outcomes in IMN patients. Thus, we investigated whether hyperlipidemia is correlated with anti-PLA2R and pathological indicators. METHODS: A total of 495 IMN patients identified by kidney biopsy in Wuhan Tongji Hospital, China, from January 2016 through December 2020 were enrolled in this study. Data on clinical features, pathology findings, and outcomes were collected. RESULTS: Total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were positively related to proteinuria, indicating damage to the renal glomerulus [Spearman's rank correlation coefficient = 0.432, 0.462, 0.315, and 0.289, respectively, P < 0.001 for all]. In univariate logistic regression, low HDL-C [odds ratio (OR): 0.856; 95% CI: 0.778-0.939; P = 0.001] and high TG [OR: 1.025; 95% CI: 1.006-1.044; P = 0.011] were correlated with tubular atrophy, suggesting lesions on tubules. Increased TC [adjusted OR: 1.285; 95% CI: 1.119-1.475; P < 0.001], non-HDL-C [adjusted OR: 1.284; 95% CI: 1.113-1.482; P = 0.001], and LDL-C [adjusted OR: 1.178; 95% CI: 1.009-1.376; P = 0.039] independently predicted glomerular PLA2R deposit; similar results were observed for lipids in predicting the seropositivity of anti-PLA2R antibodies. After treatment, increased HDL-C [adjusted hazard ratio (HR): 1.764; 95% CI: 1.241-2.507; P = 0.002] and decreased non-HDL-C [adjusted HR: 0.884; 95% CI: 0.795-0.983; P = 0.022] independently predicted proteinuria remission. CONCLUSION: Hypercholesterolemia is a potentially useful biomarker for disease severity, serum anti-PLA2R antibody, glomerular PLA2R deposit, and proteinuria outcome of IMN.

209. Mystifying Molecular Structure, Expression and Repertoire Diversity of IgM Heavy Chain Genes (Ighμ) in Clarias Catfish and Hybrids: Two Novel Transcripts in Vertebrates.

Front Immunol

2022 Jun 17

Bunnoy A, Na-Nakorn U, Srisapoome P.

210. Review: Sustainable Clinical Development of CAR-T Cells - Switching From Viral Transduction Towards CRISPR-Cas Gene Editing.

Front Immunol

2022 Jun 17

Wagner DL, Koehl U, Chmielewski M

211. FOXO3a Alleviates the Inflammation and Oxidative Stress via Regulating TGF-β and HO-1 in Ankylosing Spondylitis.

Front Immunol

2022 Jun 17

Xu S, Zhang X, Ma Y

212. Innate Lymphoid Cells - Neglected Players in Multiple Sclerosis.

Front Immunol

2022 Jun 17

Sadeghi Hassanabadi N, Broux B, Marinović S

213. Human Testicular Germ Cells, a Reservoir for Zika Virus, Lack Antiviral Response Upon Zika or Poly(I:C) Exposure.

Front Immunol

2022 Jun 17

Kuassivi ON, Abiven H, Satie AP

214. Dual Role of Indoles Derived From Intestinal Microbiota on Human Health.

Front Immunol

2022 Jun 17

Ye X, Li H, Anjum K

215. Is Estrogen a Missing Culprit in Thyroid Eye Disease? Sex Steroid Hormone Homeostasis Is Key to Other Fibrogenic Autoimmune Diseases - Why Not This One?

Front Immunol

2022 Jun 17

FitzPatrick AM.

216. Validation of a Harmonized Enzyme-Linked-Lectin-Assay (ELLA-NI) Based Neuraminidase Inhibition Assay Standard Operating Procedure (SOP) for Quantification of N1 Influenza Antibodies and the Use of a Calibrator to Improve the Reproducibility of the ELLA-NI With Reverse Genetics Viral and Recombinant Neuraminidase Antigens: A FLUCOP Collaborative Study.

Front Immunol

2022 Jun 17

Bernard MC, Waldock J, Commandeur S

217. Beta-Hydroxybutyrate: A Dual Function Molecular and Immunological Barrier Function Regulator.

Front Immunol

2022 Jun 16

Qi J, Gan L, Fang J

218. Subsets of Tissue CD4 T Cells Display Different Susceptibilities to HIV Infection and Death: Analysis by CyTOF and Single Cell RNA-seq.

Front Immunol

2022 Jun 16

Luo X, Frouard J, Zhang G

219. The H(2)S Donor Sodium Thiosulfate (Na(2)S(2)O(3)) Does Not Improve Inflammation and Organ Damage After Hemorrhagic Shock in Cardiovascular Healthy Swine.

Front Immunol

2022 Jun 16

Messerer DAC, Gaessler H, Hoffmann A

We previously demonstrated marked lung-protective properties of the H2S donor sodium thiosulfate (Na2S2O3, STS) in a blinded, randomized, controlled, long-term, resuscitated porcine model of swine with coronary artery disease, i.e., with decreased expression of the H2S-producing enzyme cystathionine-γ-lyase (CSE). We confirmed these beneficial effects of STS by attenuation of lung, liver and kidney injury in mice with genetic CSE deletion (CSE-ko) undergoing trauma-and-hemorrhage and subsequent intensive care-based resuscitation. However, we had previously also shown that any possible efficacy of a therapeutic intervention in shock states depends both on the severity of shock as well as on the presence or absence of chronic underlying co-morbidity. Therefore, this prospective, randomized, controlled, blinded experimental study investigated the effects of the STS in cardiovascular healthy swine. After anesthesia and surgical instrumentation, 17 adult Bretoncelles-Meishan-Willebrand pigs were subjected to 3 hours of hemorrhage by removal of 30% of the blood volume and titration of the mean arterial pressure (MAP) ≈ 40 ± 5 mmHg. Afterwards, the animals received standardized resuscitation including re-transfusion of shed blood, fluids, and, if needed, continuous i.v. noradrenaline to maintain MAP at pre-shock values. Animals were randomly allocated to either receive Na2S2O3 or vehicle control starting 2 hours after initiation of shock until 24 hours of resuscitation. The administration of Na2S2O3 did not alter survival during the observation period of 68 hours after the initiation of shock. No differences in cardio-circulatory functions were noted despite a significantly higher cardiac output, which coincided with significantly more pronounced lactic acidosis at 24 hours of resuscitation in the Na2S2O3 group. Parameters of liver, lung, and kidney function and injury were similar in both groups. However, urine output was significantly higher in the Na2S2O3 group at 24 hours of treatment. Taken together, this study reports no beneficial effect of Na2S2O3 in a clinically relevant model of hemorrhagic shock-and-resuscitation in animals without underlying chronic cardiovascular co-morbidity.

220. Editorial: Innate Anti-Tumor Immune Responses in Solid and Hematological Malignancies: From Basic Research to Clinical Applications.

Front Immunol

2022 Jun 16

Chretien AS, Dulphy N, Marcenaro E.

221. Case Report: Primary Cardiac T-Cell Lymphoma With Complete Atrio-Ventricular Block Diagnosed by Endomyocardial Biopsy.

Front Immunol

2022 Jun 16

Chen P, Hao Y, Qiu X

222. Tumor-Specific CD4(+) T Cells Restrain Established Metastatic Melanoma by Developing Into Cytotoxic CD4(-) T Cells.

Front Immunol

2022 Jun 16

Liu Q, Wang L, Lin H

223. Neuro-Immune Regulation in Inflammation and Airway Remodeling of Allergic Asthma.

Front Immunol

2022 Jun 16

Zhang N, Xu J, Jiang C

224. Pathogenesis of SARS-CoV-2 and Mycobacterium tuberculosis Coinfection.

Front Immunol

2022 Jun 16

Shah T, Shah Z, Yasmeen N

225. Contribution of Dysregulated B-Cells and IgE Antibody Responses to Multiple Sclerosis.

Front Immunol

2022 Jun 16

Seals MR, Moran MM, Leavenworth JD

226. ILC2s and Adipose Tissue Homeostasis: Progress to Date and the Road Ahead.

Front Immunol

2022 Jun 16

Misawa T, Wagner M, Koyasu S.

227. Ultrasound Neuromodulation of the Spleen Has Time-Dependent Anti-Inflammatory Effect in a Pneumonia Model.

Front Immunol

2022 Jun 16

Ahmed U, Graf JF, Daytz A

228. CF Patients' Airway Epithelium and Sex Contribute to Biosynthesis Defects of Pro-Resolving Lipids.

Front Immunol

2022 Jun 16

Shum M, London CM, Briottet M

229. Neutrophil Extracellular Traps in Candida albicans Infection.

Front Immunol

2022 Jun 16

He Y, Liu J, Chen Y

230. Process Development for Adoptive Cell Therapy in Academia: A Pipeline for Clinical-Scale Manufacturing of Multiple TCR-T Cell Products.

Front Immunol

2022 Jun 16

Silva DN, Chrobok M, Rovesti G

231. Dynamic Changes in Uterine NK Cell Subset Frequency and Function Over the Menstrual Cycle and Pregnancy.

Front Immunol

2022 Jun 16

Whettlock EM, Woon EV, Cuff AO

232. Gut Mycobiome in Patients With Chronic Kidney Disease Was Altered and Associated With Immunological Profiles.

Front Immunol

2022 Jun 16

Hu J, Wei S, Gu Y

233. Development and Optimization of Bifunctional Fusion Proteins to Locally Modulate Complement Activation in Diseased Tissue.

Front Immunol

2022 Jun 16

Fahnoe KC, Liu F, Morgan JG

Sustained complement activation is an underlying pathologic driver in many inflammatory and autoimmune diseases. Currently approved anti-complement therapies are directed at the systemic blockade of complement. Consequently, these therapies provide widespread inhibition of complement pathway activity, beyond the site of ongoing activation and the intended pharmacodynamic (PD) effects. Given the essential role for complement in both innate and adaptive immunity, there is a need for therapies that inhibit complement in diseased tissue while limiting systemic blockade. One potential approach focuses on the development of novel fusion proteins that enable tissue-targeted delivery of complement negative regulatory proteins. These therapies are expected to provide increased potency and prolonged tissue PD, decreased dosing frequency, and the potential for improved safety profiles. We created a library of bifunctional fusion proteins that direct a fragment of the complement negative regulator, complement receptor type 1 (CR1) to sites of tissue injury. Tissue targeting is accomplished through the binding of the fusion protein to complement C3 fragments that contain a surface-exposed C3d domain and which are covalently deposited on tissues where complement is being activated. To that end, we generated a fusion protein that contains an anti-C3d monoclonal antibody recombinantly linked to the first 10 consensus repeats of CR1 (CR11-10) with the intention of delivering high local concentrations of this complement negative regulatory domain to tissue-bound complement C3 fragments iC3b, C3dg and C3d. Biochemical and in vitro characterization identified several fusion proteins that inhibit complement while maintaining the C3d domain binding properties of the parent monoclonal antibody. Preclinical in vivo studies further demonstrate that anti-C3d fusion proteins effectively distribute to injured tissue and reduce C3 fragment deposition for periods beyond 14 days. The in vitro and in vivo profiles support the further evaluation of C3d mAb-CR11-10 as a novel approach to restore proper complement activation in diseased tissue in the absence of continuous systemic complement blockade.

234. Virus-Like Particles Are Efficient Tools for Boosting mRNA-Induced Antibodies.

Front Immunol

2022 Jun 16

Vogt AS, Jörg L, Martina B

235. Glucocorticoids Bind to SARS-CoV-2 S1 at Multiple Sites Causing Cooperative Inhibition of SARS-CoV-2 S1 Interaction With ACE2.

Front Immunol

2022 Jun 15

Sarker H, Panigrahi R, Hardy E

236. Dietary Mannan Oligosaccharides Enhance the Non-Specific Immunity, Intestinal Health, and Resistance Capacity of Juvenile Blunt Snout Bream (Megalobrama amblycephala) Against Aeromonas hydrophila.

Front Immunol

2022 Jun 15

Ding Z, Wang X, Liu Y

Mannan oligosaccharides (MOS) have been studied and applied as a feed additive, whereas their regulation on the growth performance and immunity of aquatic animals lacks consensus. Furthermore, their immunoprotective effects on the freshwater fish Megalobrama amblycephala have not been sufficiently studied. Thus, we investigated the effects of dietary MOS of 0, 200, and 400 mg/kg on the growth performance, non-specific immunity, intestinal health, and resistance to Aeromonas hydrophila infection in juvenile M. amblycephala. The results showed that the weight gain rate of juvenile M. amblycephala was not significantly different after 8 weeks of feeding, whereas the feed conversion ratio decreased in the MOS group of 400 mg/kg. Moreover, dietary MOS increased the survival rate of juvenile M. amblycephala upon infection, which may be attributed to enhanced host immunity. For instance, dietary MOS increase host bactericidal and antioxidative abilities by regulating the activities of hepatic antimicrobial and antioxidant enzymes. In addition, MOS supplementation increased the number of intestinal goblet cells, and the intestine was protected from necrosis of the intestinal folds and disruption of the microvilli and junctional complexes, thus maintaining the stability of the intestinal epithelial barrier. The expression levels of M. amblycephala immune and tight junction-related genes increased after feeding dietary MOS for 8 weeks. However, the upregulated expression of immune and tight junction-related genes in the MOS supplemental groups was not as notable as that in the control group postinfection. Therefore, MOS supplementation might suppress the damage caused by excessive intestinal inflammation. Furthermore, dietary MOS affected the richness and composition of the gut microbiota, which improved the gut health of juvenile M. amblycephala by increasing the relative abundance of beneficial gut microbiota. Briefly, dietary MOS exhibited significant immune protective effects to juvenile M. amblycephala, which is a functional feed additive and immunostimulant.

237. Vasculitogenic T Cells in Large Vessel Vasculitis.

Front Immunol

2022 Jun 15

Watanabe R, Hashimoto M.

238. IgG Anti-Spike Antibodies and Surrogate Neutralizing Antibody Levels Decline Faster 3 to 10 Months After BNT162b2 Vaccination Than After SARS-CoV-2 Infection in Healthcare Workers.

Front Immunol

2022 Jun 15

Decru B, Van Elslande J, Steels S

239. The Effect of Acupuncture on Modulating Inflammatory Cytokines in Rodent Animal Models of Respiratory Disease: A Systematic Review and Meta-Analysis.

Front Immunol

2022 Jun 15

Lee S, Kim SN.

240. T-Follicular-Like CD8(+) T Cell Responses in Chronic HIV Infection Are Associated With Virus Control and Antibody Isotype Switching to IgG.

Front Immunol

2022 Jun 15

Romero-Martín L, Tarrés-Freixas F, Pedreño-López N

241. Elevated Expression of Growth Differentiation Factor-15 Is Associated With Acute Exacerbation of Idiopathic Pulmonary Fibrosis.

Front Immunol

2022 Jun 15

Cao M, Gu L, Guo L

242. Humanized Anti-RGMa Antibody Treatment Promotes Repair of Blood-Spinal Cord Barrier Under Autoimmune Encephalomyelitis in Mice.

Front Immunol

2022 Jun 15

Hirata T, Itokazu T, Sasaki A

243. TREM-1 Modulation Strategies for Sepsis.

Front Immunol

2022 Jun 15

Siskind S, Brenner M, Wang P.

244. MIR4435-2HG Is a Potential Pan-Cancer Biomarker for Diagnosis and Prognosis.

Front Immunol

2022 Jun 15

Zhong C, Xie Z, Zeng LH

245. Risk of Ankylosing Spondylitis in Patients With Endometriosis: A Population-Based Retrospective Cohort Study.

Front Immunol

2022 Jun 15

Yin Z, Low HY, Chen BS

246. Transcriptome Analysis and Single-Cell Sequencing Analysis Constructed the Ubiquitination-Related Signature in Glioma and Identified USP4 as a Novel Biomarker.

Front Immunol

2022 Jun 14

Tang Q, Chen Z, Xie J

247. Intestinal Microbiota - An Unmissable Bridge to Severe Acute Pancreatitis-Associated Acute Lung Injury.

Front Immunol

2022 Jun 14

Wang Z, Li F, Liu J

248. Different Immunoregulation Roles of Activin A Compared With TGF-β.

Front Immunol

2022 Jun 14

Li F, Long Y, Yu X

249. microRNA Expression and Its Association With Disability and Brain Atrophy in Multiple Sclerosis Patients Treated With Glatiramer Acetate.

Front Immunol

2022 Jun 14

Dominguez-Mozo MI, Casanova I, De Torres L

250. Cytokine TGFβ Gene Polymorphism in Asthma: TGF-Related SNP Analysis Enhances the Prediction of Disease Diagnosis (A Case-Control Study With Multivariable Data-Mining Model Development).

Front Immunol

2022 Jun 14

Panek M, Stawiski K, Kaszkowiak M

INTRODUCTION: TGF-β and its receptors play a crucial role in asthma pathogenesis and bronchial remodeling in the course of the disease. TGF-β1, TGF-β2, and TGF-β3 isoforms are responsible for chronic inflammation, bronchial hyperreactivity, myofibroblast activation, fibrosis, bronchial remodeling, and change the expression of approximately 1000 genes in asthma. TGF-β SNPs are associated with the elevated plasma level of TGF-β1, an increased level of total IgE, and an increased risk of remodeling of bronchi. METHODS: The analysis of selected TGF-β1, TGF-β2, TGF-β3-related single-nucleotide polymorphisms (SNP) was conducted on 652 DNA samples with an application of the MassARRAY® using the mass spectrometry (MALDI-TOF MS). Dataset was randomly split into training (80%) and validation sets (20%). For both asthma diagnosis and severity prediction, the C5.0 modelling with hyperparameter optimization was conducted on: clinical and SNP data (Clinical+TGF), only clinical (OnlyClinical) and minimum redundancy feature selection set (MRMR). Area under ROC (AUCROC) curves were compared using DeLong's test. RESULTS: Minor allele carriers (MACs) in SNP rs2009112 [OR=1.85 (95%CI:1.11-3.1), p=0.016], rs2796821 [OR=1.72 (95%CI:1.1-2.69), p=0.017] and rs2796822 [OR=1.71 (95%CI:1.07-2.71), p=0.022] demonstrated an increased odds of severe asthma. Clinical+TGF model presented better diagnostic potential than OnlyClinical model in both training (p=0.0009) and validation (AUCROC=0.87 vs. 0.80,p=0.0052). At the same time, the MRMR model was not worse than the Clinical+TGF model (p=0.3607 on the training set, p=0.1590 on the validation set), while it was better in comparison with the Only Clinical model (p=0.0010 on the training set, p=0.0235 on validation set, AUCROC=0.85 vs. 0.87). On validation set Clinical+TGF model allowed for asthma diagnosis prediction with 88.4% sensitivity and 73.8% specificity. DISCUSSION: Derived predictive models suggest the analysis of selected SNPs in TGF-β genes in combination with clinical factors could predict asthma diagnosis with high sensitivity and specificity, however, the benefit of SNP analysis in severity prediction was not shown.

251. The Regulation and Modification of GSDMD Signaling in Diseases.

Front Immunol

2022 Jun 14

Li Z, Ji S, Jiang ML

252. Comprehensive Urinomic Identification of Protein Alternatives to Creatinine Normalization for Diagnostic Assessment of Lupus Nephritis.

Front Immunol

2022 Jun 14

Soomro S, Stanley S, Lei R

253. Immunotherapy for Pediatric Acute Lymphoblastic Leukemia: Recent Advances and Future Perspectives.

Front Immunol

2022 Jun 13

Lv M, Liu Y, Liu W

254. Biological Characteristics of HLA-G and Its Role in Solid Organ Transplantation.

Front Immunol

2022 Jun 13

Liu S, Bos NA, Verschuuren EAM

255. Rituximab, Omalizumab, and Dupilumab Treatment Outcomes in Bullous Pemphigoid: A Systematic Review.

Front Immunol

2022 Jun 13

Cao P, Xu W, Zhang L.

256. Non-Communicable Neurological Disorders and Neuroinflammation.

Front Immunol

2022 Jun 13

Ballerini C, Njamnshi AK, Juliano SL

257. Corrigendum: Recent Progress in Recombinant Influenza Vaccine Development Toward Heterosubtypic Immune Response.

Front Immunol

2022 Jun 13

Carascal MB, Pavon RDN, Rivera WL.

258. Intrahepatic Cholestasis of Pregnancy Increases Inflammatory Susceptibility in Neonatal Offspring by Modulating Gut Microbiota.

Front Immunol

2022 Jun 13

Lin QX, Huang WW, Shen W

Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that is characterized by increased bile acid levels in maternal serum. Studies have shown that cholestatic pregnancy can result in long-term metabolic disturbances in the offspring. However, how ICP shapes the offspring's immunity and predisposition to inflammatory disorders at an early stage is unknown. In this study, we investigated the effect of maternal cholestasis on neonatal offspring metabolism and immune function. We compared 71 neonates with ICP mothers and 63 neonates with healthy mothers and found that the incidence of jaundice and infection was significantly higher in ICP offspring. Maternal serum total bile acid level was associated with blood cell counts in full-term ICP offspring. In animal experiments, a compensatory activation of hepatic and ileal farnesoid X receptor (FXR) and altered gut microbiota in the first week were found in ICP offspring. We also investigated lipopolysaccharide (LPS)-induced inflammatory responses in neonatal rats and found that ICP offspring were more susceptible to inflammation. To understand the correlation between congenital abnormal FXR activation and tissue immunity dysregulation, we assessed the effects of the FXR agonist GW4064 and FXR antagonist E/Z-GS in ICP offspring after LPS exposure. The expression of several pro-inflammatory cytokines significantly decreased after treatment with E/Z-GS but increased after treatment with GW4064. Treatment with the probiotic Lactobacillus rhamnosus LRX01 that inhibits FXR expression in the ileum reduced susceptibility to LPS exposure in ICP offspring. The current study indicated that cholestatic pregnancy may increase the susceptibility of the offspring to inflammation by altering bile acid metabolism and gut microbiota at an early stage. We suggest that supplementation with Lactobacillus rhamnosus LRX01, which inhibits FXR expression in the ileum, may improve intestinal immunity in ICP offspring.

259. Differentiation of T Helper 17 Cells May Mediate the Abnormal Humoral Immunity in IgA Nephropathy and Inflammatory Bowel Disease Based on Shared Genetic Effects.

Front Immunol

2022 Jun 13

Qing J, Li C, Hu X

BACKGROUND: IgA nephropathy (IgAN) is the most frequent glomerulonephritis in inflammatory bowel disease (IBD). However, the inter-relational mechanisms between them are still unclear. This study aimed to explore the shared gene effects and potential immune mechanisms in IgAN and IBD. METHODS: The microarray data of IgAN and IBD in the Gene Expression Omnibus (GEO) database were downloaded. The differential expression analysis was used to identify the shared differentially expressed genes (SDEGs). Besides, the shared transcription factors (TFs) and microRNAs (miRNAs) in IgAN and IBD were screened using humanTFDB, HMDD, ENCODE, JASPAR, and ChEA databases. Moreover, weighted gene co-expression network analysis (WGCNA) was used to identify the shared immune-related genes (SIRGs) related to IgAN and IBD, and R software package org.hs.eg.db (Version3.1.0) were used to identify common immune pathways in IgAN and IBD. RESULTS: In this study, 64 SDEGs and 28 SIRGs were identified, and the area under the receiver operating characteristic curve (ROC) of 64 SDEGs was calculated and two genes (MVP, PDXK) with high area under the curve (AUC) in both IgAN and IBD were screened out as potential diagnostic biomarkers. We then screened 3 shared TFs (SRY, MEF2D and SREBF1) and 3 miRNAs (hsa-miR-146, hsa-miR-21 and hsa-miR-320), and further found that the immune pathways of 64SDEGs, 28SIRGs and 3miRNAs were mainly including B cell receptor signaling pathway, FcγR-mediated phagocytosis, IL-17 signaling pathway, toll-like receptor signaling pathway, TNF signaling pathway, TRP channels, T cell receptor signaling pathway, Th17 cell differentiation, and cytokine-cytokine receptor interaction. CONCLUSION: Our work revealed the differentiation of Th17 cells may mediate the abnormal humoral immunity in IgAN and IBD patients and identified novel gene candidates that could be used as biomarkers or potential therapeutic targets.

260. A Whole Exon Screening-Based Score Model Predicts Prognosis and Immune Checkpoint Inhibitor Therapy Effects in Low-Grade Glioma.

Front Immunol

2022 Jun 13

Luo C, Wang S, Shan W

OBJECTIVE: This study aims to identify prognostic factors for low-grade glioma (LGG) via different machine learning methods in the whole genome and to predict patient prognoses based on these factors. We verified the results through in vitro experiments to further screen new potential therapeutic targets. METHOD: A total of 940 glioma patients from The Cancer Genome Atlas (TCGA) and The Chinese Glioma Genome Atlas (CGGA) were included in this study. Two different feature extraction algorithms - LASSO and Random Forest (RF) - were used to jointly screen genes significantly related to the prognosis of patients. The risk signature was constructed based on these screening genes, and the K-M curve and ROC curve evaluated it. Furthermore, we discussed the differences between the high- and low-risk groups distinguished by the signature in detail, including differential gene expression (DEG), single-nucleotide polymorphism (SNP), copy number variation (CNV), immune infiltration, and immune checkpoint. Finally, we identified the function of a novel molecule, METTL7B, which was highly correlated with PD-L1 expression on tumor cell, as verified by in vitro experiments. RESULTS: We constructed an accurate prediction model based on seven genes (AUC at 1, 3, 5 years= 0.91, 0.85, 0.74). Further analysis showed that extracellular matrix remodeling and cytokine and chemokine release were activated in the high-risk group. The proportion of multiple immune cell infiltration was upregulated, especially macrophages, accompanied by the high expression of most immune checkpoints. According to the in vitro experiment, we preliminarily speculate that METTL7B affects the stability of PD-L1 mRNA by participating in the modification of m6A. CONCLUSION: The seven gene signatures we constructed can predict the prognosis of patients and identify the potential benefits of immune checkpoint inhibitors (ICI) therapy for LGG. More importantly, METTL7B, one of the risk genes, is a crucial molecule that regulates PD-L1 and could be used as a new potential therapeutic target.

261. A Murine Point Mutation of Sgpl1 Skin Is Enriched With Vγ6 IL17-Producing Cell and Revealed With Hyperpigmentation After Imiquimod Treatment.

Front Immunol

2022 Jun 13

Yang W, Zhou B, Liu Q

262. Distinct Fates of Chemokine and Surrogate Molecule Gradients: Consequences for CCR7-Guided Dendritic Cell Migration.

Front Immunol

2022 Jun 13

Artinger M, Gerken OJ, Purvanov V

263. Case Report: Tocilizumab Treatment for VEXAS Syndrome With Relapsing Polychondritis: A Single-Center, 1-Year Longitudinal Observational Study In Japan.

Front Immunol

2022 Jun 13

Kunishita Y, Kirino Y, Tsuchida N

264. A TNFR2-Specific TNF Fusion Protein With Improved In Vivo Activity.

Front Immunol

2022 Jun 13

Vargas JG, Wagner J, Shaikh H

Tumor necrosis factor (TNF) receptor-2 (TNFR2) has attracted considerable interest as a target for immunotherapy. Indeed, using oligomeric fusion proteins of single chain-encoded TNFR2-specific TNF mutants (scTNF80), expansion of regulatory T cells and therapeutic activity could be demonstrated in various autoinflammatory diseases, including graft-versus-host disease (GvHD), experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). With the aim to improve the in vivo availability of TNFR2-specific TNF fusion proteins, we used here the neonatal Fc receptor (FcRn)-interacting IgG1 molecule as an oligomerizing building block and generated a new TNFR2 agonist with improved serum retention and superior in vivo activity. METHODS: Single-chain encoded murine TNF80 trimers (sc(mu)TNF80) were fused to the C-terminus of an in mice irrelevant IgG1 molecule carrying the N297A mutation which avoids/minimizes interaction with Fcγ-receptors (FcγRs). The fusion protein obtained (irrIgG1(N297A)-sc(mu)TNF80), termed NewSTAR2 (New selective TNF-based agonist of TNF receptor 2), was analyzed with respect to activity, productivity, serum retention and in vitro and in vivo activity. STAR2 (TNC-sc(mu)TNF80 or selective TNF-based agonist of TNF receptor 2), a well-established highly active nonameric TNFR2-specific variant, served as benchmark. NewSTAR2 was assessed in various in vitro and in vivo systems. RESULTS: STAR2 (TNC-sc(mu)TNF80) and NewSTAR2 (irrIgG1(N297A)-sc(mu)TNF80) revealed comparable in vitro activity. The novel domain architecture of NewSTAR2 significantly improved serum retention compared to STAR2, which correlated with efficient binding to FcRn. A single injection of NewSTAR2 enhanced regulatory T cell (Treg) suppressive activity and increased Treg numbers by > 300% in vivo 5 days after treatment. Treg numbers remained as high as 200% for about 10 days. Furthermore, a single in vivo treatment with NewSTAR2 upregulated the adenosine-regulating ectoenzyme CD39 and other activation markers on Tregs. TNFR2-stimulated Tregs proved to be more suppressive than unstimulated Tregs, reducing conventional T cell (Tcon) proliferation and expression of activation markers in vitro. Finally, singular preemptive NewSTAR2 administration five days before allogeneic hematopoietic cell transplantation (allo-HCT) protected mice from acute GvHD. CONCLUSIONS: NewSTAR2 represents a next generation ligand-based TNFR2 agonist, which is efficiently produced, exhibits improved pharmacokinetic properties and high serum retention with superior in vivo activity exerting powerful protective effects against acute GvHD.

265. Metastasis Related Epithelial-Mesenchymal Transition Signature Predicts Prognosis and Response to Immunotherapy in Gastric Cancer.

Front Immunol

2022 Jun 13

Song J, Wei R, Huo S

266. Differential Contribution of NF-κB Signaling Pathways to CD4(+) Memory T Cell Induced Activation of Endothelial Cells.

Front Immunol

2022 Jun 13

Jeucken KCM, van Rooijen CCN, Kan YY

267. B10 Cells Are Associated With Clinical Prognosis During Adult Symptomatic Acute HBV Infection.

Front Immunol

2022 Jun 13

Liu Y, Du X, Lu J

268. Immunological Characteristics of Alternative Splicing Profiles Related to Prognosis in Bladder Cancer.

Front Immunol

2022 Jun 13

Ye F, Liang Y, Cheng Z

269. To Be or Not to Be: The Case of Endoplasmic Reticulum Aminopeptidase 2.

Front Immunol

2022 Jun 13

Kuśnierczyk P.

270. How RA Associated HLA-DR Molecules Contribute to the Development of Antibodies to Citrullinated Proteins: The Hapten Carrier Model.

Front Immunol

2022 Jun 10

Roudier J, Balandraud N, Auger I.

271. The Emerging Role of Plant-Derived Exosomes-Like Nanoparticles in Immune Regulation and Periodontitis Treatment.

Front Immunol

2022 Jun 10

Zhang Z, Yu Y, Zhu G

272. Aberrant IL-17 Levels in Rodent Models of Autism Spectrum Disorder: A Systematic Review.

Front Immunol

2022 Jun 10

Thawley AJ, Veneziani LP, Rabelo-da-Ponte FD

273. Differential Biodistribution of Adenoviral-Vectored Vaccine Following Intranasal and Endotracheal Deliveries Leads to Different Immune Outcomes.

Front Immunol

2022 Jun 10

Jeyananthan V, Afkhami S, D'Agostino MR

274. Adipose-Derived Mesenchymal Stem Cells Reprogram M1 Macrophage Metabolism via PHD2/HIF-1α Pathway in Colitis Mice.

Front Immunol

2022 Jun 10

Yuan Y, Ni S, Zhuge A

275. Effect of the Combination of Everolimus and Mesenchymal Stromal Cells on Regulatory T Cells Levels and in a Liver Transplant Rejection Model in Rats.

Front Immunol

2022 Jun 10

Vandermeulen M, Erpicum P, Bletard N

276. The Prognostic and Immunotherapeutic Significance of AHSA1 in Pan-Cancer, and Its Relationship With the Proliferation and Metastasis of Hepatocellular Carcinoma.

Front Immunol

2022 Jun 10

Li W, Liu J.

The AHSA1 is a main activator of ATPase of Hsp90. Hsp90 is involved in various metabolic and developmental processes of tumor cells. Although, the role of AHSA1 in tumor cells is still unrecognized. In the current research, the RNA-seq of 33 tumors were downloaded using The Cancer Genome Atlas (TCGA) database for the analysis of AHSA1 expression in tumors. The Kaplan-Meier method was used for the evaluation of the prognostic significance of AHSA1 in patients with pan-cancer. Additionally, the correlation between AHSA1 and immune cell infiltration, immune checkpoint, pyroptosis-related molecules, epithelial cell transformation-related molecules, and autophagy-related molecules were analyzed by co-expression. Furthermore, we examined the effect of AHSA1 knockdown on cell function in Huh7 and HCCLM3 cells of hepatocellular carcinoma (HCC) cell lines. According to the finding of this study, up-regulation of AHSA1 expression was observed in numerous tumor tissues, and its over-expression in liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), and esophageal carcinoma (ESCA) could affect the overall survival and disease-specific survival of the patients. Meanwhile, as per the correlation analysis the expression of AHSA1 was greatly correlated with the expression of various immune cell infiltrates, immune checkpoint inhibitors, tumor mutation load, and microsatellite instability. Moreover, this study focused on analyzing the association of AHSA1 expression with multiple pathological stages in HCC, and confirmed that AHSA1 was an independent prognostic factor of HCC by univariate and multivariate COX regression in TCGA and The International Cancer Genome Consortium (ICGC) cohorts. At the same time, cellular experiments proved that the AHSA1 knockdown could decrease the proliferation activity, cell migration and invasion ability of HCC cells. Therefore, the results of this study indicated that AHSA1 can be used as a potential prognostic biomarker of tumors and it may have a significant role in the proliferation as well as migration of HCC cells.

277. Case Report: Dual Inhibition of HDAC and BTK for Diffuse Large B-Cell Lymphoma After Failure to CD19-Targeted CAR-T Therapy.

Front Immunol

2022 Jun 10

Zhu W, Tao S, Miao W

278. Global Trends in Research of Gouty Arthritis Over Past Decade: A Bibliometric Analysis.

Front Immunol

2022 Jun 10

Deng P, Wang S, Sun X

Gouty arthritis (GA), as a multifactorial disease, is characterised by intense pain, active inflammation symptoms, and swollen joints. It has utterly complex pathogenesis, of which the amount of research publications on GA has increased during the last few decades. A bibliometric analysis was carried out to investigate the trends, frontiers, and hot spots in global scientific output in GA research over the last decade. We retrieved the Science Citation Index Expanded (SCI-Expanded) of the Web of Science Core Collection (WoSCC) for publications and recorded information published from 2012 to 2021. we carried out the bibliometric analysis and visualisation analysis of the overall distribution of annual outputs, leading countries, active institutions, journals, authors, co-cited references, and keywords with the VOSviewer and CiteSpace. The impact and quality of papers were assessed using a global citation score (GCS). We retrieved 2052 articles and reviews in total. The annual number of publications (Np) related to GA research has increased during the latest decade. China published the most papers, and the USA achieved the highest H-index and number of citations (Nc). The League of European Research Universities (LERU) and Clinical Rheumatology (Clin Rheumatol) are the most productive institutions and periodicals. The total GCS of the paper written by Kottgen, A. in 2013 was 479, ranking the first. The most common keywords were "Gout," "hyperuricemia," and "gouty arthritis." This research revealed that though there was a slight fluctuation in publications related to GA, the Np raised on the whole. China was an enormous creator, and the USA was an influential nation in this domain. The top three contributor authors were Dalbeth, N., Singh, JA., and Choi, HK. There were few investigations on the treatment of GA by Chinese medicine monomer, and the "mechanism," "pathway", "nf- kappa-b", "injury", "receptor", and "animal model" were growing research hotspots. Our research illustrated the hotspots of research and development trends in the research field of GA during the last decade. Recognition of the most critical indicators (researchers, countries, institutes, and journals for the release of GA research), hotspots in the research field of GA can be helpful for countries, scholars, and policymakers in this field to understand GA better make decisions.

279. Single-Cell Landscape of Mouse Islet Allograft and Syngeneic Graft.

Front Immunol

2022 Jun 10

Chen P, Yao F, Lu Y

280. Role of the ITAM-Bearing Receptors Expressed by Natural Killer Cells in Cancer.

Front Immunol

2022 Jun 10

Medjouel Khlifi H, Guia S, Vivier E

281. suPAR to Risk-Stratify Patients With Malaria.

Front Immunol

2022 Jun 10

Stefanova V, Crowley VM, Weckman AM

282. Comprehensive Analysis and Reinforcement Learning of Hypoxic Genes Based on Four Machine Learning Algorithms for Estimating the Immune Landscape, Clinical Outcomes, and Therapeutic Implications in Patients With Lung Adenocarcinoma.

Front Immunol

2022 Jun 10

Sun Z, Zeng Y, Yuan T

BACKGROUND: Patients with lung adenocarcinoma (LUAD) exhibit significant heterogeneity in therapeutic responses and overall survival (OS). In recent years, accumulating research has uncovered the critical roles of hypoxia in a variety of solid tumors, but its role in LUAD is not currently fully elucidated. This study aims to discover novel insights into the mechanistic and therapeutic implications of the hypoxia genes in LUAD cancers by exploring the potential association between hypoxia and LUAD. METHODS: Four machine learning approaches were implemented to screen out potential hypoxia-related genes for the prognosis of LUAD based on gene expression profile of LUAD samples obtained from The Cancer Genome Atlas (TCGA), then validated by six cohorts of validation datasets. The risk score derived from the hypoxia-related genes was proven to be an independent factor by using the univariate and multivariate Cox regression analyses and Kaplan-Meier survival analyses. Hypoxia-related mechanisms based on tumor mutational burden (TMB), the immune activity, and therapeutic value were also performed to adequately dig deeper into the clinical value of hypoxia-related genes. Finally, the expression level of hypoxia genes was validated at protein level and clinical samples from LUAD patients at transcript levels. RESULTS: All patients in TCGA and GEO-LUAD group were distinctly stratified into low- and high-risk groups based on the risk score. Survival analyses demonstrated that our risk score could serve as a powerful and independent risk factor for OS, and the nomogram also exhibited high accuracy. LUAD patients in high-risk group presented worse OS, lower TMB, and lower immune activity. We found that the model is highly sensitive to immune features. Moreover, we revealed that the hypoxia-related genes had potential therapeutic value for LUAD patients based on the drug sensitivity and chemotherapeutic response prediction. The protein and gene expression levels of 10 selected hypoxia gene also showed significant difference between LUAD tumors tissues and normal tissues. The validation experiment showed that the gene transcript levels of most of their genes were consistent with the levels of their translated proteins. CONCLUSIONS: Our study might contribute to the optimization of risk stratification for survival and personalized management of LUAD patients by using the hypoxia genes, which will provide a valuable resource that will guide both mechanistic and therapeutic implications of the hypoxia genes in LUAD cancers.

283. The Nuclear Envelope as a Regulator of Immune Cell Function.

Front Immunol

2022 Jun 10

Selezneva A, Gibb AJ, Willis D.

284. Antibody-Mediated LILRB2-Receptor Antagonism Induces Human Myeloid-Derived Suppressor Cells to Kill Mycobacterium tuberculosis.

Front Immunol

2022 Jun 10

Singh VK, Khan A, Xu Y

285. Discovering Immune-Mediated Mechanisms of Gastric Carcinogenesis Through Single-Cell RNA Sequencing.

Front Immunol

2022 Jun 10

Hoft SG, Pherson MD, DiPaolo RJ.

Single-cell RNA sequencing (scRNAseq) technology is still relatively new in the field of gastric cancer immunology but gaining significant traction. This technology now provides unprecedented insights into the intratumoral and intertumoral heterogeneities at the immunological, cellular, and molecular levels. Within the last few years, a volume of publications reported the usefulness of scRNAseq technology in identifying thus far elusive immunological mechanisms that may promote and impede gastric cancer development. These studies analyzed datasets generated from primary human gastric cancer tissues, metastatic ascites fluid from gastric cancer patients, and laboratory-generated data from in vitro and in vivo models of gastric diseases. In this review, we overview the exciting findings from scRNAseq datasets that uncovered the role of critical immune cells, including T cells, B cells, myeloid cells, mast cells, ILC2s, and other inflammatory stromal cells, like fibroblasts and endothelial cells. In addition, we also provide a synopsis of the initial scRNAseq findings on the interesting epithelial cell responses to inflammation. In summary, these new studies have implicated roles for T and B cells and subsets like NKT cells in tumor development and progression. The current studies identified diverse subsets of macrophages and mast cells in the tumor microenvironment, however, additional studies to determine their roles in promoting cancer growth are needed. Some groups specifically focus on the less prevalent ILC2 cell type that may contribute to early cancer development. ScRNAseq analysis also reveals that stromal cells, e.g., fibroblasts and endothelial cells, regulate inflammation and promote metastasis, making them key targets for future investigations. While evaluating the outcomes, we also highlight the gaps in the current findings and provide an assessment of what this technology holds for gastric cancer research in the coming years. With scRNAseq technology expanding rapidly, we stress the need for periodic review of the findings and assess the available scRNAseq analytical tools to guide future work on immunological mechanisms of gastric carcinogenesis. .

286. Advances in Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma.

Front Immunol

2022 Jun 10

Chen Y, Hu H, Yuan X

287. Serum Proteomic Analysis Identifies SAA1, FGA, SAP, and CETP as New Biomarkers for Eosinophilic Granulomatosis With Polyangiitis.

Front Immunol

2022 Jun 10

Xiao J, Lu S, Wang X

288. Current Status and Future Directions of Bacteria-Based Immunotherapy.

Front Immunol

2022 Jun 10

Tang Q, Peng X, Xu B

289. Comprehensive Analysis of m5C Methylation Regulatory Genes and Tumor Microenvironment in Prostate Cancer.

Front Immunol

2022 Jun 10

Yu G, Bao J, Zhan M

BACKGROUND: 5-Methylcytidine (m5C) methylation is an emerging epigenetic modification in recent years, which is associated with the development and progression of various cancers. However, the prognostic value of m5C regulatory genes and the correlation between m5C methylation and the tumor microenvironment (TME) in prostate cancer remain unknown. METHODS: In the current study, the genetic and transcriptional alterations and prognostic value of m5C regulatory genes were investigated in The Cancer Genome Atlas and Gene Expression Omnibus datasets. Then, an m5C prognostic model was established by LASSO Cox regression analysis. Gene set variation analyses (GSVA), gene set enrichment analysis (GSEA), clinical relevance, and TME analyses were conducted to explain the biological functions and quantify the TME scores between high-risk and low-risk subgroups. m5C regulatory gene clusters and m5C immune subtypes were identified using consensus unsupervised clustering analysis. The Cell-type Identification By Estimating Relative Subsets of RNA Transcripts algorithm was used to calculate the contents of immune cells. RESULTS: TET3 was upregulated at transcriptional levels in PCa compared with normal tissues, and a high TET3 expression was associated with poor prognosis. An m5C prognostic model consisting of 3 genes (NSUN2, TET3, and YBX1) was developed and a nomogram was constructed for improving the clinical applicability of the model. Functional analysis revealed the enrichment of pathways and the biological processes associated with RNA regulation and immune function. Significant differences were also found in the expression levels of m5C regulatory genes, TME scores, and immune cell infiltration levels between different risk subgroups. We identified two distinct m5C gene clusters and found their correlation with patient prognosis and immune cell infiltration characteristics. Naive B cells, CD8+ T cells, M1 macrophages and M2 macrophages were obtained and 2 m5C immune subtypes were identified. CTLA4, NSUN6, TET1, and TET3 were differentially expressed between immune subtypes. The expression of CTLA4 was found to be correlated with the degree of immune cell infiltration. CONCLUSIONS: Our comprehensive analysis of m5C regulatory genes in PCa demonstrated their potential roles in the prognosis, clinical features, and TME. These findings may improve our understanding of m5C regulatory genes in the tumor biology of PCa.

290. Next-Generation Anti-Angiogenic Therapies as a Future Prospect for Glioma Immunotherapy; From Bench to Bedside.

Front Immunol

2022 Jun 10

Shamshiripour P, Hajiahmadi F, Lotfi S

291. Neutrophil Extracellular Traps, Sepsis and COVID-19 - A Tripod Stand.

Front Immunol

2022 Jun 10

Ventura-Santana E, Ninan JR, Snyder CM

292. Myeloid-Derived Suppressor Cells: The Expanding World of Helminth Modulation of the Immune System.

Front Immunol

2022 Jun 10

Stevenson MM, Valanparambil RM, Tam M.

Infection with helminths or parasitic worms are highly prevalent worldwide especially in developing regions. Helminths cause chronic infections that are associated with suppression of immune responses to unrelated pathogens, vaccines, and by-stander antigens responsible for dysregulated immune responses as occurs in diseases such as allergies. Helminths use multiple mechanisms to modulate the immune system to evade the highly polarized type 2 immune response required to expel adult worms and for immunity to reinfection. Anthelmintic drugs are efficient in reducing adult worm burdens in helminth-infected individuals, but resistance to these drugs is rapidly increasing and vaccines against these pathogens are not available. Emerging evidence indicate that helminths induce myeloid-derived suppressor cells (MDSC), originally described in tumor-bearing mice and cancer patients. MDSC are a heterogenous population of immature cells that consist of two distinct sub-populations, polymorphonuclear (PMN)-MDSC and monocytic (M)-MDSC based on morphology and phenotype. MDSC suppress the function of T cells and other innate and adaptive immune cells including NK cells and B cells. During cancer or infection with bacteria or viruses, there is marked expansion of MDSC. Furthermore, the frequencies of MDSC correlate inversely with the prognosis and survival of tumor-bearing hosts as well as bacterial and viral burdens, persistence, and outcome in infected hosts. Currently, there is a paucity of data on MDSC and helminth infections. Here, we provide a survey of the evidence accumulated so far that overall support a role for MDSC in modulating immune responses during helminth infections. We review data from studies in various helminths, including those that infect humans. Finally, we summarize the progress to date in understanding the role of MDSC in helminth infections and briefly discuss potential host-directed strategies to target MDSC-mediated suppression of immune responses to helminths in favor of development of immunity to eliminate adult worms and possibly induce protection against reinfection.

293. Global Expansion of Jeffrey's Insights: Jeffrey Modell Foundation's Genetic Sequencing Program for Primary Immunodeficiency.

Front Immunol

2022 Jun 10

Quinn J, Modell V, Johnson B

Genetic disorders that impair the immune system, known as Primary Immunodeficiencies (PI), include over 450 single-gene inborn errors of immunity. Timely and appropriate diagnosis and treatment is vital to quality of life (QOL) and sometimes survival, as patients are susceptible to frequent, persistent, severe, and sometimes life-threatening infections or autoimmunity. Suspected PI patients that do not have a genetic diagnosis often endure a prolonged, onerous, inefficient, and expensive experience, known as a diagnostic odyssey. The resulting diagnostic delay prohibits proper disease management and treatment, causing unnecessary distress and diminished QOL. Next-generation sequencing (NGS) offers relief from the distress of the diagnostic odyssey, but because of cost and barriers to access, it is regularly unobtainable. The Jeffrey Modell Foundation (JMF) introduced "Jeffrey's Insights", a no-charge genetic sequencing pilot program, in January 2019 for patients within the Jeffrey Modell Centers Network (JMCN) with an underlying PI, but no genetic diagnosis. Building on the success of the pilot program, JMF expanded it globally to more than 400 Centers in the JMCN in early 2020. The most current version of Invitae's PI Panel available was used for this program. All participating clinicians were invited to complete a brief questionnaire assessing prior impediments to access and post-sequencing alterations in disease management and treatment. A total of 1,398 patients were tested, with 20.3% receiving a molecular diagnosis and many more receiving helpful diagnostic leads. Results obtained from genetic sequencing led to an alteration of clinical diagnosis, disease management, treatment, and genetic counseling in 39%, 38%, 35%, and 53% of patients, respectively. The global expansion of this program further underscores the crucial need for NGS for PI, along with its efficiency and potential cost savings. The results of this program to date further define rationale for the availability of comprehensive diagnostic NGS for patients with PI when requisitioned by an expert immunologist.

294. CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges.

Front Immunol

2022 Jun 10

Zhang X, Zhu L, Zhang H

295. Epidemiology of Psoriasis and Comorbid Diseases: A Narrative Review.

Front Immunol

2022 Jun 10

Bu J, Ding R, Zhou L

296. Toxoplasma gondii CDPK3 Controls the Intracellular Proliferation of Parasites in Macrophages.

Front Immunol

2022 Jun 10

Wu M, An R, Zhou N

297. Leishmania tarentolae as Potential Live Vaccine Co-Expressing Distinct Salivary Gland Proteins Against Experimental Cutaneous Leishmaniasis in BALB/c Mice Model.

Front Immunol

2022 Jun 10

Lajevardi MS, Gholami E, Taheri T

298. Clinical Significance of Serum Albumin and Implications of FcRn Inhibitor Treatment in IgG-Mediated Autoimmune Disorders.

Front Immunol

2022 Jun 1

Ward ES, Gelinas D, Dreesen E

299. Post Transplantation Bilirubin Nanoparticles Ameliorate Murine Graft Versus Host Disease via a Reduction of Systemic and Local Inflammation.

Front Immunol

2022 Jun 1

Pareek S, Flegle AS, Boagni D

Allogeneic stem cell transplantation is a curative immunotherapy where patients receive myeloablative chemotherapy and/or radiotherapy, followed by donor stem cell transplantation. Graft versus host disease (GVHD) is a major complication caused by dysregulated donor immune system, thus a novel strategy to modulate donor immunity is needed to mitigate GVHD. Tissue damage by conditioning regimen is thought to initiate the inflammatory milieu that recruits various donor immune cells for cross-priming of donor T cells against alloantigen and eventually promote strong Th1 cytokine storm escalating further tissue damage. Bilirubin nanoparticles (BRNP) are water-soluble conjugated of bilirubin and polyethylene glycol (PEG) with potent anti-inflammatory properties through its ability to scavenge reactive oxygen species generated at the site of inflammation. Here, we evaluated whether BRNP treatment post-transplantation can reduce initial inflammation and subsequently prevent GVHD in a major histocompatibility (MHC) mismatched murine GVHD model. After myeloablative irradiation, BALB/c mice received bone marrow and splenocytes isolated from C57BL/6 mice, with or without BRNP (10 mg/kg) daily on days 0 through 4 post-transplantation, and clinical GVHD and survival was monitored for 90 days. First, BRNP treatment significantly improved clinical GVHD score compared to untreated mice (3.4 vs 0.3, p=0.0003), and this translated into better overall survival (HR 0.0638, p=0.0003). Further, BRNPs showed a preferential accumulation in GVHD target organs leading to a reduced systemic and local inflammation evidenced by lower pathologic GVHD severity as well as circulating inflammatory cytokines such as IFN-γ. Lastly, BRNP treatment post-transplantation facilitated the reconstitution of CD4+ iNK T cells and reduced expansion of proinflammatory CD8α+ iNK T cells and neutrophils especially in GVHD organs. Lastly, BRNP treatment decreased ICOS+ or CTLA-4+ T cells but not PD-1+ T cells suggesting a decreased level of T cell activation but maintaining T cell tolerance. In conclusion, we demonstrated that BRNP treatment post-transplantation ameliorates murine GVHD via diminishing the initial tissue damage and subsequent inflammatory responses from immune subsets.

300. Untangling the Knots of Regulatory T Cell Therapy in Solid Organ Transplantation.

Front Immunol

2022 Jun 1

Orozco G, Gupta M, Gedaly R

301. Bacillus subtilis Expressing the Infectious Pancreatic Necrosis Virus VP2 Protein Retains Its Immunostimulatory Properties and Induces a Specific Antibody Response.

Front Immunol

2022 Jun 1

Docando F, Nuñez-Ortiz N, Gonçalves G

302. The Extended N-Terminal Domain Confers Atypical Chemokine Receptor Properties to CXCR3-B.

Front Immunol

2022 Jun 1

D'Uonnolo G, Reynders N, Meyrath M

303. Sandfly Fever Viruses Attenuate the Type I Interferon Response by Targeting the Phosphorylation of JAK-STAT Components.

Front Immunol

2022 Jun 1

Moalem Y, Malis Y, Voloshin K

304. Clinical Variables, Deep Learning and Radiomics Features Help Predict the Prognosis of Adult Anti-N-methyl-D-aspartate Receptor Encephalitis Early: A Two-Center Study in Southwest China.

Front Immunol

2022 Jun 1

Xiang Y, Dong X, Zeng C

OBJECTIVE: To develop a fusion model combining clinical variables, deep learning (DL), and radiomics features to predict the functional outcomes early in patients with adult anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in Southwest China. METHODS: From January 2012, a two-center study of anti-NMDAR encephalitis was initiated to collect clinical and MRI data from acute patients in Southwest China. Two experienced neurologists independently assessed the patients' prognosis at 24 moths based on the modified Rankin Scale (mRS) (good outcome defined as mRS 0-2; bad outcome defined as mRS 3-6). Risk factors influencing the prognosis of patients with acute anti-NMDAR encephalitis were investigated using clinical data. Five DL and radiomics models trained with four single or combined four MRI sequences (T1-weighted imaging, T2-weighted imaging, fluid-attenuated inversion recovery imaging and diffusion weighted imaging) and a clinical model were developed to predict the prognosis of anti-NMDAR encephalitis. A fusion model combing a clinical model and two machine learning-based models was built. The performances of the fusion model, clinical model, DL-based models and radiomics-based models were compared using the area under the receiver operating characteristic curve (AUC) and accuracy and then assessed by paired t-tests (P < 0.05 was considered significant). RESULTS: The fusion model achieved the significantly greatest predictive performance in the internal test dataset with an AUC of 0.963 [95% CI: (0.874-0.999)], and also significantly exhibited an equally good performance in the external validation dataset, with an AUC of 0.927 [95% CI: (0.688-0.975)]. The radiomics_combined model (AUC: 0.889; accuracy: 0.857) provided significantly superior predictive performance than the DL_combined (AUC: 0.845; accuracy: 0.857) and clinical models (AUC: 0.840; accuracy: 0.905), whereas the clinical model showed significantly higher accuracy. Compared with all single-sequence models, the DL_combined model and the radiomics_combined model had significantly greater AUCs and accuracies. CONCLUSIONS: The fusion model combining clinical variables and machine learning-based models may have early predictive value for poor outcomes associated with anti-NMDAR encephalitis.

305. Kidney Normothermic Machine Perfusion Can Be Used as a Preservation Technique and a Model of Reperfusion to Deliver Novel Therapies and Assess Inflammation and Immune Activation.

Front Immunol

2022 Jun 1

Mellati A, Lo Faro L, Dumbill R

Ischaemia-reperfusion injury (IRI) is an inevitable process in transplantation and results in inflammation and immune system activation. Alpha-1 antitrypsin (AAT) has anti-inflammatory properties. Normothermic machine perfusion (NMP) can be used to deliver therapies and may help in assessing the effects of IRI and immunity. This study investigated the effects of AAT on IRI and inflammation in pig kidneys when administered during preservation, followed by normothermic reperfusion (NR) with autologous whole blood, as a surrogate for transplant. Two different models were used to deliver AAT or placebo to paired slaughterhouse pig kidneys: Model 1: 7-h static cold storage (SCS) + 3-h NR (n = 5 pairs), where either AAT (10 mg/ml) or placebo was delivered in the flush following retrieval; Model 2: 4-h SCS + 3-h NMP + 3-h NR (n = 5 pairs), where either AAT or placebo was delivered during NMP. Injury markers and cytokines levels were analysed in the perfusate, and heat shock protein 70 KDa (HSP-70) was analysed in biopsies. AAT delivered to kidneys showed no adverse effects on perfusion parameters. HSP-70 fold changes were significantly lower in the AAT group during NMP (P < 0.01, paired t-test) but not during NR. Interleukin-1 receptor antagonist (IL-1ra) fold changes were significantly higher in the AAT group during NR model 1 (p < 0.05, two-way ANOVA). In contrast to the AAT group, significant upregulation of interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) between t = 90 min and t = 180 min and interleukin-8 (IL-8) between baseline and t = 90 min was observed in the control group in NR model 2 (p < 0.05, Tukey's multiple comparison test). However, overall inflammatory cytokines and injury markers showed similar levels between groups. Delivery of AAT to pig kidneys was safe without any detrimental effects. NMP and NR provided excellent methods for comparison of inflammation and immune activation in the delivery of a novel therapy.

306. Induction Strategies in Lung Transplantation: Alemtuzumab vs. Basiliximab a Single-Center Experience.

Front Immunol

2022 Jun 1

Furukawa M, Chan EG, Ryan JP

BACKGROUND: Induction therapy is used in about 80% of lung transplant centers and is increasing globally. Currently, there are no standards or guidelines for the use of induction therapy. At our institution, we have two induction strategies, basiliximab, and alemtuzumab. The goal of this manuscript is to share our experience and practice since this is an area of controversy. METHODS: We retrospectively reviewed 807 lung transplants performed at our institution between 2011 and 2020. Indications for the use of the basiliximab protocol were as follows: patients over the age of 70 years, history of cancer, hepatitis C virus or human immunodeficiency virus infection history, and cytomegalovirus or Epstein-Barr virus (donor positive/ recipient negative). In the absence of these clinical factors, the alemtuzumab protocol was used. RESULTS: 453 patients underwent alemtuzumab induction and 354 patients underwent basiliximab. There were significant differences in delayed chest closure (24.7% alemtuzumab vs 31.4% basiliximab, p = 0.037), grade 3 primary graft dysfunction observed within 72 hours (19.9% alemtuzumab vs 29.9% basiliximab, p = 0.002), postoperative hepatic dysfunction (8.8% alemtuzumab vs 14.7% basiliximab, p = 0.009), acute cellular rejection in first year (39.1% alemtuzumab vs 53.4% basiliximab, p < 0.001). The overall survival rate of the patients with alemtuzumab induction was significantly higher than those of the patients with basiliximab induction (5 years survival rate: 64.1% alemtuzumab vs 52.3%, basiliximab, p < 0.001). Multivariate Cox regression analysis confirmed lower 5-year survival for basiliximab induction (HR = 1.41, p = 0.02), recipient cytomegalovirus positive (HR = 1.49, p = 0.01), postoperative hepatic dysfunction (HR = 2.20, p < 0.001), and acute kidney injury requiring renal replacement therapy (HR = 2.27, p < 0.001). CONCLUSIONS: In this single center retrospective review, there was a significant difference in survival rates between induction strategies. This outcome may be attributable to differences in recipient characteristics between the groups. However, the Alemtuzumab group experienced less episodes of acute cellular rejection within the first year.

307. Iguratimod Restrains Circulating Follicular Helper T Cell Function by Inhibiting Glucose Metabolism via Hif1α-HK2 Axis in Rheumatoid Arthritis.

Front Immunol

2022 Jun 1

Bai Z, Lu Z, Liu R

308. Retrospective Comparison of Efficacy and Safety of Rabbit Anti-Thymocyte Globulin and Porcine Anti-Lymphocyte Globulin in Patients With Acquired Aplastic Anemia Undergoing Hematopoietic Stem Cell Transplantation From Matched Sibling Donors.

Front Immunol

2022 Jun 1

Zhang Y, Chen X, Li L

309. Modulation of Autoimmune and Autoinflammatory Diseases by Gasdermins.

Front Immunol

2022 Jun 1

Liang F, Qin W, Zeng Y

310. Case Report: Mucous Membrane Pemphigoid With IgG and IgA Anti-Laminin γ1 Antibodies and IgA Anti-Laminin α5 Antibodies.

Front Immunol

2022 Jun 1

Kuang W, Qian H, Zhang Q

311. Egg-Derived Anti-SARS-CoV-2 Immunoglobulin Y (IgY) With Broad Variant Activity as Intranasal Prophylaxis Against COVID-19.

Front Immunol

2022 Jun 1

Frumkin LR, Lucas M, Scribner CL

COVID-19 emergency use authorizations and approvals for vaccines were achieved in record time. However, there remains a need to develop additional safe, effective, easy-to-produce, and inexpensive prevention to reduce the risk of acquiring SARS-CoV-2 infection. This need is due to difficulties in vaccine manufacturing and distribution, vaccine hesitancy, and, critically, the increased prevalence of SARS-CoV-2 variants with greater contagiousness or reduced sensitivity to immunity. Antibodies from eggs of hens (immunoglobulin Y; IgY) that were administered the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein were developed for use as nasal drops to capture the virus on the nasal mucosa. Although initially raised against the 2019 novel coronavirus index strain (2019-nCoV), these anti-SARS-CoV-2 RBD IgY surprisingly had indistinguishable enzyme-linked immunosorbent assay binding against variants of concern that have emerged, including Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529). This is different from sera of immunized or convalescent patients. Culture neutralization titers against available Alpha, Beta, and Delta were also indistinguishable from the index SARS-CoV-2 strain. Efforts to develop these IgY for clinical use demonstrated that the intranasal anti-SARS-CoV-2 RBD IgY preparation showed no binding (cross-reactivity) to a variety of human tissues and had an excellent safety profile in rats following 28-day intranasal delivery of the formulated IgY. A double-blind, randomized, placebo-controlled phase 1 study evaluating single-ascending and multiple doses of anti-SARS-CoV-2 RBD IgY administered intranasally for 14 days in 48 healthy adults also demonstrated an excellent safety and tolerability profile, and no evidence of systemic absorption. As these antiviral IgY have broad selectivity against many variants of concern, are fast to produce, and are a low-cost product, their use as prophylaxis to reduce SARS-CoV-2 viral transmission warrants further evaluation. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov/ct2/show/NCT04567810, identifier NCT04567810.

312. Vaccination Against SARS-CoV-2 in Lung Transplant Recipients: Immunogenicity, Efficacy and Safety.

Front Immunol

2022 Jun 1

Svorcova M, Novysedlak R, Lischke R

313. Genome Wide Identification and Expression Profiling Indicate Expansion of Family I84 Protease Inhibitor via Gene Tandem Duplication and Divergence in Razor Clam Sinonovacula constricta.

Front Immunol

2022 Jun 1

Liu S, Liu Y, Lu J

Family I84 protease inhibitors represent a novel family in the MEROPS peptidase database and are likely unique for molluscan host defense. Two Family I84 members, scSI-1 and scSI-2, were reported from the razor clam Sinonovacula constricta in a previous research. In the present study, 12 additional genes, named scSI-3 to scSI-14, were identified via genome wide sequence analyses. Among them, 10 genes were predicted to have a signal sequence, but one (scSI-7) was not. Besides, one sequence (scSI-14) was likely to encode a prematurely terminated peptide. The predicted mature peptides shared characteristics including 12 conserved cysteine residues, isoelectric points of 4.98 to 6.11, and molecular weights of 7.1 to 9.3 kDa with previously reported family members. Four motifs were characterized in 13 predicted mature peptides (with exception of scSI-14), which shared two to four conserved cysteine residues, are possibly to form two functional domain comprised 6 cysteine residues, respectively. At genomic level, all the 14 razor clam Family I84 genes were organized into 3 exons and 2 introns; 13 of them clustered in 3 regions of 100 kb on 3 separate chromosomes, suggesting tandem duplications of related genes. The promoter region of all the 14 genes was predicted to share some transcription factor binding sites, in particular those responsive to pathological and physiological stimuli, but no shared motifs were identified. Analyses also revealed differences in expression patterns among the genes. One gene in a tandem duplicated gene pairs usually showed a higher expression level than the other whereas non-tandem duplicated genes exhibited a higher degree of correlation in expression level. In addition, 8 of the 14 genes demonstrated higher level of expression in Vibrio tolerant clams than in non-tolerant clams following challenges with Vibrio parahaemolyticus. These results generated important information about the evolution of Family I84 protease inhibitors in S. constricta.

314. Case Report: Immune Checkpoint Blockade Plus Interferon-Γ Add-On Antifungal Therapy in the Treatment of Refractory Covid-Associated Pulmonary Aspergillosis and Cerebral Mucormycosis.

Front Immunol

2022 Jun 1

Serris A, Ouedrani A, Uhel F

315. Nanoscale Colocalization of NK Cell Activating and Inhibitory Receptors Controls Signal Integration.

Front Immunol

2022 Jun 1

Tomaz D, Pereira PM, Guerra N

Newmer生物

Newmer生物