PI3Kγ inhibition combined with DNA vaccination unleashes a B-cell-dependent antitumor immunity that hampers pancreatic cancer.

Phosphoinositide-3-kinase γ (PI3Kγ) plays a critical role in pancreatic ductal adenocarcinoma (PDA) by driving the recruitment of myeloid-derived suppressor cells (MDSC) into tumor tissues, leading to tumor growth and metastasis. MDSC also impair the efficacy of immunotherapy. In this study we verify the hypothesis that MDSC targeting, via PI3Kγ inhibition, synergizes with α-enolase (ENO1) DNA vaccination in counteracting tumor growth.Mice that received ENO1 vaccination followed by PI3Kγ inhibition had significantly smaller tumors compared to those treated with ENO1 alone or the control group, and correlated with i) increased circulating anti-ENO1 specific IgG and IFNγ secretion by T cells, ii) increased tumor infiltration of CD8+ T cells and M1-like macrophages, as well as up-modulation of T cell activation and M1-like related transcripts, iii) decreased infiltration of Treg FoxP3+ T cells, endothelial cells and pericytes, and down-modulation of the stromal compartment and T cell exhaustion gene transcription, iv) reduction of mature and neo-formed vessels, v) increased follicular helper T cell activation and vi) increased "antigen spreading", as many other tumor-associated antigens were recognized by IgG2c "cytotoxic" antibodies. PDA mouse models genetically devoid of PI3Kγ showed an increased survival and a pattern of transcripts in the tumor area similar to that of pharmacologically-inhibited PI3Kγ-proficient mice. Notably, tumor reduction was abrogated in ENO1 + PI3Kγ inhibition-treated mice in which B cells were depleted.These data highlight a novel role of PI3Kγ in B cell-dependent immunity, suggesting that PI3Kγ depletion strengthens the anti-tumor response elicited by the ENO1 DNA vaccine.

IgG sialylation occurs in B cells pre antibody secretion.

Sialic acids as terminal sugar residues on cell surface or secreted proteins have many functional roles. In particular, the presence or absence of α2,6-linked sialic acid residues at the immunoglobulin G (IgG) Fc fragment can switch IgG effector functions from pro- to anti-inflammatory activity. IgG glycosylation is considered to take place inside the plasma blast/plasma cell while the molecule travels through the endoplasmic reticulum and Golgi apparatus before being secreted. However, more recent studies have suggested that IgG sialylation may occur predominantly post-antibody secretion. To what extent this extracellular IgG sialylation process contributes to overall IgG sialylation remains unclear, however. By generating bone marrow chimeric mice with a B cell-specific deletion of ST6Gal1, the key enzyme required for IgG sialylation, we now show that sialylation of the IgG Fc fragment exclusively occurs within B cells pre-IgG secretion. We further demonstrate that B cells expressing ST6Gal1 have a developmental advantage over B cells lacking ST6Gal1 expression and thus dominate the plasma cell pool and the resulting serum IgG population in mouse models in which both ST6Gal1-sufficient and -deficient B cells are present.

Peripheral apoptosis and limited clonal deletion during physiologic murine B lymphocyte development.

Self-reactive and polyreactive B cells generated during B cell development are silenced by either apoptosis, clonal deletion, receptor editing or anergy to avoid autoimmunity. The specific contribution of apoptosis to normal B cell development and self-tolerance is incompletely understood. Here, we quantify self-reactivity, polyreactivity and apoptosis during physiologic B lymphocyte development. Self-reactivity and polyreactivity are most abundant in early immature B cells and diminish significantly during maturation within the bone marrow. Minimal apoptosis still occurs at this site, however B cell receptors cloned from apoptotic B cells show comparable self-reactivity to that of viable cells. Apoptosis increases dramatically only following immature B cells leaving the bone marrow sinusoids, but above 90% of cloned apoptotic transitional B cells are not self-reactive/polyreactive. Our data suggests that an apoptosis-independent mechanism, such as receptor editing, removes most self-reactive B cells in the bone marrow. Mechanistically, lack of survival signaling rather than clonal deletion appears to be the underpinning cause of apoptosis in most transitional B cells in the periphery.

Differential expression of lymphocyte subpopulations in the peripheral blood of patients with COVID-19: Implications for disease severity and prognosis.

OBJECTIVE: To investigate the expression patterns and clinical significance of specific lymphocyte subsets in the peripheral blood of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: Between December 2022 and February 2023, a cohort of 165 patients from the First Affiliated Hospital of Guangzhou University of Chinese Medicine were analyzed. The participants represented various stages of coronavirus infection severity: mild, moderate, severe, and critical. Additionally, 40 healthy individuals constituted the control group. The FC 500MPL flow cytometer and associated reagents for flow cytometry. RESULTS: Compared with the healthy control group, activated B lymphocytes witnessed a pronounced increase (p < .05). A significant decrease was observed in the levels of Breg, Cytotoxic T cells or Suppressor T-cell (Tc/s), late-activated T, late-activated Th, and late-activated Tc/s lymphocytes (p < .05). Th, initial Th, initial Tc/s, total Treg, natural Treg, induced Treg, early activated T, and early activated Th lymphocyte levels showed no significant difference (p > .05). As the disease progressed, there was an uptick in midterm activated T lymphocytes (p < .05), while Breg, T, Tc/s, senescent Tc/s, and total senescent T levels dwindled (p < .05). Noteworthy patterns emerged across different groups for B1, T-lymphocytes, Tc/s, B2, CD8+ Treg cells, and other subsets, highlighting variance in immune responses relative to disease severity. When juxtaposed, no significant difference was found in the expression levels of lymphocyte subsets between patients who died and those deemed critically ill (p > .05). CONCLUSION: Subsets of Treg and B-cells could act as yardsticks for the trajectory of SARS-CoV-2 infection and might have potential in forecasting patient trajectories. A comprehensive evaluation of lymphocyte subsets, especially in real-time, holds the key to discerning the clinical severity in those with COVID-19. This becomes instrumental in monitoring treatment outcomes, tracking disease evolution, and formulating prognostications. Moreover, the results provide a deeper understanding of the cellular immune defense mechanisms against the novel coronavirus infection.

NUDCD3 deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome.

Inborn errors of T cell development present a pediatric emergency in which timely curative therapy is informed by molecular diagnosis. In 11 affected patients across four consanguineous kindreds, we detected homozygosity for a single deleterious missense variant in the gene NudC domain-containing 3 (NUDCD3). Two infants had severe combined immunodeficiency with the complete absence of T and B cells (T -B- SCID), whereas nine showed classical features of Omenn syndrome (OS). Restricted antigen receptor gene usage by residual T lymphocytes suggested impaired V(D)J recombination. Patient cells showed reduced expression of NUDCD3 protein and diminished ability to support RAG-mediated recombination in vitro, which was associated with pathologic sequestration of RAG1 in the nucleoli. Although impaired V(D)J recombination in a mouse model bearing the homologous variant led to milder immunologic abnormalities, NUDCD3 is absolutely required for healthy T and B cell development in humans.

Landscape of gut mucosal immune cells showed gap of follicular or memory B cells into plasma cells in immunological non-responders.

BACKGROUND: The gut is an important site for human immunodeficiency virus (HIV) infection and immune responses. The role of gut mucosal immune cells in immune restoration in patients infected with HIV undergoing antiretroviral therapy remains unclear. METHODS: Ileocytes, including 54 475 immune cells, were obtained from colonoscopic biopsies of five HIV-negative controls, nine immunological responders (IRs), and three immunological non-responders (INRs) and were analyzed using single-cell RNA sequencing. Immunohistochemical assays were performed for validation. The 16S rRNA gene was amplified using PCR in faecal samples to analyze faecal microbiota. Flow cytometry was used to analyze CD4+ T-cell counts and the activation of T cells. RESULTS: This study presents a global transcriptomic profile of the gut mucosal immune cells in patients infected with HIV. Compared with the IRs, the INRs exhibited a lower proportion of gut plasma cells, especially the IGKC+IgA+ plasma cell subpopulation. IGKC+IgA+ plasma cells were negatively associated with enriched f. Prevotellaceae the INRs and negatively correlated with the overactivation of T cells, but they were positively correlated with CD4+ T-cell counts. The INRs exhibited a higher proportion of B cells than the IRs. Follicular and memory B cells were significantly higher in the INRs. Reduced potential was observed in the differentiation of follicular or memory B cells into gut plasma cells in INRs. In addition, the receptor-ligand pairs CD74_MIF and CD74_COPA of memory B/ follicular helper T cells were significantly reduced in the INRs, which may hinder the differentiation of memory and follicular B cells into plasma cells. CONCLUSIONS: Our study shows that plasma cells are dysregulated in INRs and provides an extensive resource for deciphering the immune pathogenesis of HIV in INRs. KEY POINTS: An investigation was carried out at the single-cell-level to analyze gut mucosal immune cells alterations in PLWH after ART. B cells were significantly increased and plasma cells were significantly decreased in the INRs compared to the IRs and NCs. There are gaps in the transition from gut follicular or memory B cellsinto plasma cells in INRs.

Transcriptomic Profiling of Peripheral B Cells in Antibody Positive Sjogren's Patients Reveals Interferon Signature.

BACKGROUND: Sjögren's disease (SjD) is a common systemic autoimmune disease that affects mainly women. Key pathologic features include the infiltration of exocrine glands by lymphocytes and the activation of B lymphocytes with the production of autoantibodies. We aimed to analyze the transcriptome of circulating B cells from patients with SJD and healthy controls to decipher the B-cell-specific contribution to SJD. METHODS: RNA from peripheral blood B cells of five untreated female patients with SjD and positive ANA, positive anti-SSA (both Ro-52 and Ro-60), positive anti-SSB and positive rheumatoid-factor, and five healthy controls was subjected to whole-transcriptome sequencing. A false discovery rate of < 0.1 was applied to define differentially expressed genes (DEG). RESULTS: RNA-sequencing identified 56 up and 23 down DEG. Hierarchal clustering showed a clear separation between the two groups. Ingenuity pathway analysis revealed that these genes may play a role in interferon signaling, chronic mycobacterial infection, and transformation to myeloproliferative disorders. CONCLUSIONS: We found upregulated expression of type-I and type-II interferon (IFN)-induced genes, as well as genes that may contribute to other concomitant conditions, including infections and a higher risk of myeloproliferative disorders. This adds insight into the autoimmune process and suggests potential targets for future functional and prognostic studies.

Clinical and Immunological Impact of Ocrelizumab Extended Interval Dosing in Multiple Sclerosis: A Single-Center, Real-World Experience.

Ocrelizumab (OCR), an anti-CD20 monoclonal antibody, is approved for treating relapsing remitting (RR) and primary progressive (PP) multiple sclerosis (MS). The standard interval dosing (SID) regimen requires intravenous infusions every six months. Experience of extended dosing due to COVID-19 pandemic-related issues suggests that this strategy may provide comparable efficacy while reducing treatment burden and healthcare costs. This study aimed to evaluate clinical effectiveness, changes in B- and T-cell count, and immunoglobulin dynamics associated with extended interval dosing (EID) of ocrelizumab in a real-world setting. We retrospectively included RRMS or PPMS patients treated with OCR that had already received two OCR cycles and with at least 6 months of follow up after the last infusion. EID was defined as a ≥4 weeks delay compared to SID. Clinical outcomes were occurrence of relapses, MRI activity, 6-months confirmed disability progression (CDP) and their combination (No Evidence of Disease Activity, NEDA-3). We also evaluated changes in CD19+ B cell count, CD4+ and CD8+ T cell count, immunoglobulin titers, and occurrence of hypogammaglobulinemia (hypo-Ig). Frequency tests, multivariate regression models, and survival analysis were applied as appropriate. We analyzed data on 93 subjects (75.3% RRMS) for a total of 389 infusions (272 SID, 117 EID). Clinical and MRI activity, CDP, and NEDA 3 did not significantly differ between EID and SID. EID was associated with lower rates of B-cell depletion. T-cell dynamics and incidence of hypo-Ig were comparable following EID and SID. Hypo-IgG at index infusion was associated with further occurrence of hypo-IgG; male sex and hypo-IgM at index infusion were independently associated with hypo-IgM. In conclusion, OCR EID does not impact MS clinical and radiological outcomes, although it interferes with B-cell dynamics. These findings provide support for a tailored schedule of OCR in MS.

Everlasting first impressions in B cells.

Initial imprinting by type 1 interferons shapes memory B cell generation in chronic viral infection.

Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis.

Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF-expressing) and anti-inflammatory (IL-10-expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a "fourth signal" that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.

Signatures of CD4+ T and B cells are associated with distinct stages of chronic chagasic cardiomyopathy.

Introduction: Chagas disease is a neglected parasitic disease caused by Trypanosoma cruzi. While most patients are asymptomatic, around 30% develop Chronic Chagasic Cardiomyopathy (CCC). Methods: Here, we employed high-dimensional flow cytometry to analyze CD4+ T and B cell compartments in patients during the chronic phase of Chagas disease, presenting the asymptomatic and mild or moderate/severe cardiac clinical forms. Results: Effector CD27-CD4+ T cells were expanded in both CCC groups, and only mild CCC patients showed higher frequencies of effector memory and T follicular helper (Tfh) cells than healthy donors (CTL) and asymptomatic patients. Unsupervised analysis confirmed these findings and further revealed the expansion of a specific subpopulation composed of Tfh, transitional, and central memory CD4+ T cells bearing a phenotype associated with strong activation, differentiation, and exhaustion in patients with mild but not moderate/severe CCC. In contrast, patients with mild and moderate/severe CCC had lower frequencies of CD4+ T cells expressing lower levels of activation markers, suggesting resting status, than CTL. Regarding the B cell compartment, no alterations were found in naïve CD21-, memory cells expressing IgM or IgD, marginal zone, and plasma cells in patients with Chagas disease. However, expansion of class-switched activated and atypical memory B cells was observed in all clinical forms, and more substantially in mild CCC patients. Discussion: Taken together, our results showed that T. cruzi infection triggers changes in CD4+ T and B cell compartments that are more pronounced in the mild CCC clinical form, suggesting an orchestrated cellular communication during Chagas disease. Conclusion: Overall, these findings reinforce the heterogeneity and complexity of the immune response in patients with chronic Chagas disease and may provide new insights into disease pathology and potential markers to guide clinical decisions.

Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA+ B cells.

BACKGROUND: Dysregulation of immune surveillance is tightly linked to the development of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC); however, its underlying mechanisms remain unclear. Herein, we aimed to determine the role of interleukin-21 receptor (IL-21R) in MASH-driven HCC. METHODS: The clinical significance of IL-21R was assessed in human HCC specimens using immunohistochemistry staining. Furthermore, the expression of IL-21R in mice was assessed in the STAM model. Thereafter, two different MASH-driven HCC mouse models were applied between IL-21R-deficient mice and wild type controls to explore the role of IL-21R in MASH-driven HCC. To further elucidate the potential mechanisms by which IL-21R affected MASH-driven HCC, whole transcriptome sequencing, flow cytometry and adoptive lymphocyte transfer were performed. Finally, flow cytometry, enzyme-linked immunosorbent assay, immunofluorescent staining, chromatin immunoprecipitation assay and western blotting were conducted to explore the mechanism by which IL-21R induced IgA+ B cells. RESULTS: HCC patients with high IL-21R expression exhibited poor relapse-free survival, advanced TNM stage and severe steatosis. Additionally, IL-21R was demonstrated to be upregulated in mouse liver tumors. Particularly, ablation of IL-21R impeded MASH-driven hepatocarcinogenesis with dramatically reduction of lipid accumulation. Moreover, cytotoxic CD8+ T lymphocyte activation was enhanced in the absence of IL-21R due to the reduction of immunosuppressive IgA+ B cells. Mechanistically, the IL-21R-STAT1-c-Jun/c-Fos regulatory axis was activated in MASH-driven HCC and thus promoted the transcription of Igha, resulting in the induction of IgA+ B cells. CONCLUSIONS: IL-21R plays a cancer-promoting role by inducing IgA+ B cells in MASH-driven hepatocarcinogenesis. Targeting IL-21R signaling represents a potential therapeutic strategy for cancer therapy.

Causal relationship between immune cells and atrial fibrillation: A Mendelian randomization study.

Atrial fibrillation (AF) is a prevalent cardiac arrhythmia, with recent research indicating a correlation between immune system characteristics and the development of AF. However, it remains uncertain whether the immunological response is the primary underlying component or a secondary consequence of AF. Initially, we investigated the effect of immune cells on AF by performing forward Mendelian randomization (MR) analyses with immune cells as the exposure variable and their associated genetic variants as instrumental variables. Subsequently, we performed reverse MR analyses with AF as the exposure variable and immune cells as the outcome variable to exclude the interference of reverse causality, to distinguish between primary and secondary effects, and to further elucidate the causal relationship between the immune system and AF. We discovered that membrane proteins on specific immune cells, such as CD25 on memory B cells-which functions as a part of the interleukin-2 receptor-may be risk factors for AF development, with odds ratios of 1.0233 (95% confidence interval: 1.0012-1.0458, P = .0383). In addition, certain immune cell counts, such as the CD4 regulatory T cell Absolute Count, play a protective factor in the development of AF (odds ratio: 0.9513, 95% confidence interval: 0.9165-0.9874; P = .0086). More detailed results are elaborated in the main text. Our MR study has yielded evidence that substantiates a genetically inferred causal association between the immune system and AF. Identifying the risk factors associated with AF is vital to facilitate the development of innovative pharmaceutical treatments.

BAP31 Plays an Essential Role in Mouse B Cell Development via Regulation of BCR Signaling.

B cell receptor-associated protein 31 (BAP31) is a transmembrane protein that is widely expressed and primarily located in the endoplasmic reticulum (ER). B cells play a crucial role in the immune system, and BAP31 significantly contributes to the functions of various immune cells. However, the specific role of BAP31 in B lymphocytes development remains unknown. In this study, we utilized a mouse model with BAP31 deleted from B cells to investigate its effects. Our findings reveal a block in early B cell development in the bone marrow and a significant decrease in the number of B cells in peripheral lymphoid organs taken from BAP31 B cell conditional knockout (BAP31-BCKO) mice. B cell receptor (BCR) signaling is crucial for the normal development and differentiation of B lymphocytes. BAP31, an endoplasmic reticulum membrane protein, directly regulates the BCR signaling pathway and was shown to be significantly positively correlated with B cell activation and proliferation. These findings establish BAP31 as a crucial regulator of early B cell development.

Association of HLA B- and T-cell molecular mismatches with HLA antibodies, rejection, and graft survival in pediatric kidney transplantation.

BACKGROUND: Optimizing graft survival and diminishing human leukocyte antigen (HLA) sensitization are essential for pediatric kidney transplant recipients. More precise HLA matching predicting epitope mismatches could reduce alloreactivity. We investigated the association of predicted HLA B- and T-cell molecular mismatches with the formation of de novo donor-specific antibodies, HLA antibodies, rejection, and graft survival. METHODS: Forty-nine pediatric kidney transplant recipients transplanted from 2009 to 2020 were retrospectively studied. Donors and recipients were high-resolution HLA typed, and recipients were screened for HLA antibodies posttransplant. HLA-EMMA (HLA Epitope MisMatch Algorithm) and PIRCHE-II (Predicted Indirectly ReCognizable HLA Epitopes) predicted the molecular mismatches. The association of molecular mismatches and the end-points was explored with logistic regression. RESULTS: Five recipients (11%) developed de novo donor-specific antibodies. All five had de novo donor-specific antibodies against HLA class II, with four having HLA-DQ antibodies. We found no associations between PIRCHE-II or HLA-EMMA with de novo donor-specific antibodies, HLA sensitization, graft loss, or rejection. However, we did see a tendency towards an increased odds ratio in PIRCHE-II predicting de novo donor-specific antibodies formation, with an odds ratio of 1.12 (95% CI: 0.99; 1.28) on HLA class II. CONCLUSION: While the study revealed no significant associations between the number of molecular mismatches and outcomes, a notable trend was observed - indicating a reduced risk of dnDSA formation with improved molecular match. It is important to acknowledge, however, that the modest population size and limited observed outcomes preclude us from making definitive conclusions.

Severe enterovirus infections in patients with immune-mediated inflammatory diseases receiving anti-CD20 monoclonal antibodies.

OBJECTIVE: Patients with X linked agammaglobulinemia are susceptible to enterovirus (EV) infections. Similarly, severe EV infections have been described in patients with impaired B-cell response following treatment with anti-CD20 monoclonal antibodies (mAbs), mostly in those treated for haematological malignancies. We aimed to describe severe EV infections in patients receiving anti-CD20 mAbs for immune-mediated inflammatory diseases (IMIDs). METHODS: Patients were included following a screening of data collected through the routine surveillance of EV infections coordinated by the National Reference Center and a review of the literature. Additionally, neutralising antibodies were assessed in a patient with chronic EV-A71 meningoencephalitis. RESULTS: Nine original and 17 previously published cases were retrieved. Meningoencephalitis (n=21/26, 81%) associated with EV-positive cerebrospinal fluid (n=20/22, 91%) was the most common manifestation. The mortality rate was high (27%). EV was the only causal agents in all reported cases. Patients received multiple anti-CD20 mAbs infusions (median 8 (5-10)), resulting in complete B-cell depletion and moderate hypogammaglobulinemia (median 4.9 g/L (4.3-6.7)), and had limited concomitant immunosuppressive treatments. Finally, in a patient with EV-A71 meningoencephalitis, a lack of B-cell response to EV was shown. CONCLUSION: EV infection should be evoked in patients with IMIDs presenting with atypical organ involvement, especially meningoencephalitis. Anti-CD20 mAbs may lead to impaired B-cell response against EV, although an underlying primary immunodeficiency should systematically be discussed.

Variable Syndromic Immunodeficiency in Patients with Biallelic PRIM1 Mutations.

Mutations in genes of the DNA polymerase complex have been linked to impaired immunological function next to distinct syndromic features. Biallelic mutations in PRIM1 are associated with a primordial dwarfism syndrome with variable hypogammaglobulinemia. The disease is mostly lethal in infancy due to pulmonary infections as well as hepatic cirrhosis. We studied 3 novel patients with PRIM1-deficiency with a focus on immunological consequences. All three shared dysmorphic features including a prominent forehead, triangular face and bilateral cryptorchidism. P1 carried the novel homozygous PRIM1 splice variant c.103+2T>G, allowing residual protein expression and associated with a mild clinical phenotype. P2 and P3 carried the known homozygous variant c.638+36C>G and died in infancy. Paradoxically, B cell lymphopenia was most pronounced in P1. No other significant lymphocyte abnormalities were detected. Interestingly, all 3 patients showed variable, but intermittently excessive Type I interferon signatures. In summary, the B-cell deficiency in PRIM1-deficiency is markedly variable and the severity of syndromic manifestations is not predictive of the immunological phenotype. We highlight a potential contribution of pathological type I interferon activation to disease pathogenesis which warrants further investigations.

SUMO-specific protease 1 regulates germinal center B cell response through deSUMOylation of PAX5.

Humoral immunity depends on the germinal center (GC) reaction where B cells are tightly controlled for class-switch recombination and somatic hypermutation and finally generated into plasma and memory B cells. However, how protein SUMOylation regulates the process of the GC reaction remains largely unknown. Here, we show that the expression of SUMO-specific protease 1 (SENP1) is up-regulated in GC B cells. Selective ablation of SENP1 in GC B cells results in impaired GC dark and light zone organization and reduced IgG1-switched GC B cells, leading to diminished production of class-switched antibodies with high-affinity in response to a TD antigen challenge. Mechanistically, SENP1 directly binds to Paired box protein 5 (PAX5) to mediate PAX5 deSUMOylation, sustaining PAX5 protein stability to promote the transcription of activation-induced cytidine deaminase. In summary, our study uncovers SUMOylation as an important posttranslational mechanism regulating GC B cell response.

Potent human monoclonal antibodies targeting Epstein-Barr virus gp42 reveal vulnerable sites for virus infection.

Epstein-Barr virus (EBV) is linked to various malignancies and autoimmune diseases, posing a significant global health challenge due to the lack of specific treatments or vaccines. Despite its crucial role in EBV infection in B cells, the mechanisms of the glycoprotein gp42 remain elusive. In this study, we construct an antibody phage library from 100 EBV-positive individuals, leading to the identification of two human monoclonal antibodies, 2B7 and 2C1. These antibodies effectively neutralize EBV infection in vitro and in vivo while preserving gp42's interaction with the human leukocyte antigen class II (HLA-II) receptor. Structural analysis unveils their distinct binding epitopes on gp42, different from the HLA-II binding site. Furthermore, both 2B7 and 2C1 demonstrate potent neutralization of EBV infection in HLA-II-positive epithelial cells, expanding our understanding of gp42's role. Overall, this study introduces two human anti-gp42 antibodies with potential implications for developing EBV vaccines targeting gp42 epitopes, addressing a critical gap in EBV research.