Factors associated with drug retention of mepolizumab in patients with eosinophilic granulomatosis with polyangiitis: A multicentre REVEAL cohort study.

OBJECTIVES: To determine the current retention rate of mepolizumab (MPZ) and identify factors associated with drug retention in patients with eosinophilic granulomatosis with polyangiitis (EGPA) in the Kansai multicentre cohort (REVEAL cohort). METHODS: Sixty patients diagnosed with EGPA and treated with MPZ between December 2016 and June 2023 were enrolled. The clinical characteristics, including laboratory data, treatments administered, and disease course outcomes were collected retrospectively. The patients were stratified into MPZ continuation (n=53) and discontinuation (n=7) groups, and drug retention was statistically compared using the log-rank test. RESULTS: The median age of patients was 54.5 years, with 55% females, and 33% antineutrophil cytoplasmic antibody-positive at disease onset. MPZ exhibited a retention rate of 78.7% after five years. The reasons for discontinuation included treatment of coexisting diseases, inadequate response, and remission. Patient characteristics at disease onset were comparable between the groups. Patients receiving immunosuppressants (IS) before MPZ introduction demonstrated significantly higher retention rates (P = 0.038). During the final observation, the MPZ continuation group had a lower vasculitis damage index score (P = 0.027). CONCLUSIONS: MPZ exhibited a high 5-year retention rate, particularly in patients requiring IS. This study implies that long-term use of MPZ may mitigate irreversible organ damage.

Avacopan's potential to decrease MPO-ANCA titres concurrent with ameliorated activity in ANCA-associated vasculitis.

Avacopan, an orally administered C5a receptor antagonist, is effective in microscopic polyangiitis via the inhibition of neutrophil priming induced by C5a. However, the exact effect of avacopan on the production of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) is yet to be clearly established. This report presents a microscopic polyangiitis patient without major organ damage where high levels of MPO-ANCA persisted with high-dose steroid therapy and azathioprine, but the addition of avacopan led to a reduction in MPO-ANCA titres. The present case implies that avacopan-mediated inhibition of C5a may lead to a reduction in MPO-ANCA levels, thereby potentially ameliorating the pathophysiology of ANCA-associated vasculitis. Nevertheless, the impact of avacopan on MPO-ANCA production cannot be asserted solely based on this report; therefore, further examination is necessary through subgroup analysis using data from larger-scale studies.

Risk factors for serious infections and infection-related mortality in patients with microscopic polyangiitis: Multicentre REVEAL cohort study.

OBJECTIVE: Infections are a critical concern for patients with microscopic polyangiitis (MPA). This study aimed to identify the risk factors associated with serious infections (SIs) and infection-related mortality in patients with MPA, as well as the effect of glucocorticoid (GC) dose tapering on these outcomes. METHODS: This multicentre, retrospective, and observational study utilised data from a cohort of patients with MPA in Japan [Registry of Vasculitis Patients to Establish REAL World Evidence (REVEAL) cohort]. Patients were categorised based on the occurrence of SIs or infection-related deaths, and various characteristics were compared among the groups. RESULTS: Among 182 patients, 66 (36.2%) experienced 129 SIs and 27 (14.8%) developed infection-related deaths. Advanced age, elevated C-reactive protein (CRP) levels, and higher ratio of the GC dose at 3 months to the initial dose were identified as independent risk factors for SIs. Older age was also associated with infection-related deaths. Furthermore, the cumulative incidence of infection-related deaths was significantly higher in patients with a higher ratio of the GC dose at 24 months to the initial dose. CONCLUSION: Older age, elevated CRP levels, and slower GC dose tapering predispose patients to SIs and infection-related deaths. Strategies, such as rapid GC dose tapering, are anticipated to mitigate the risk of infections.

Anti-aminoacyl tRNA synthetase antibodies showing the discrepancy between enzyme-linked immunosorbent assay and RNA-immunoprecipitation.

Anti-aminoacyl-tRNA synthetase (ARS) antibodies are myositis-specific antibodies associated with anti-synthetase syndrome (ASSD). Some patients are positive for anti-ARS antibodies on enzyme-linked immunosorbent assay (ELISA) but negative on RNA-immunoprecipitation (RNA-IP) (the gold standard method). Whether these patients should be considered truly positive for anti-ARS antibodies remains unclear. Therefore, we investigated the clinical characteristics of these patients and verified the authenticity of their anti-ARS positivity. Patients who were positive for anti-ARS antibodies on ELISA were divided into the non-discrepant (positive on RNA-IP, n = 52) and discrepant (negative on RNA-IP, n = 8) groups. Patient clinical characteristics were compared between the groups. For each positive individual, the authenticity of anti-ARS antibody positivity on ELISA was cross-examined using protein-IP and western blotting. All patients in the discrepant group had lung involvement, including five (63%) with interstitial lung disease. The overall survival time was significantly lower in the discrepant group than in the non-discrepant group (p < 0.05). Validation tests confirmed the presence of anti-ARS antibodies in the sera of the discrepant group but indicated different reactivity from typical anti-ARS antibodies. In conclusion, some anti-ARS antibodies are detected by ELISA but not RNA-IP. Such anti-ARS antibody discrepancies need further elucidation to attain validation of the diagnostic process in ASSD.

TAFRO syndrome is associated with anti-SSA/Ro60 antibodies, in contrast to idiopathic castleman disease.

TAFRO syndrome is an acute systemic inflammatory disease characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, and organomegaly. There have been increasing reports that TAFRO is a disease distinct from idiopathic multicentric Castleman disease and that TAFRO patients may be positive for anti-SSA antibodies. To assess anti-SSA antibody positivity and the clinical characteristics of the two diseases, we retrospectively compared 7 TAFRO and 10 iMCD patients in our hospital. The mean age of onset of TAFRO and iMCD was 48.0 (interquartile range [IQR], 41-53) and 45.0 (IQR, 35-53) years, respectively. The TAFRO and iMCD groups had 6 (86%) and 4 (40%) male patients, respectively, and the following pretreatment laboratory values: platelet count, 3.8 (IQR, 2.2-6.4) and 35.5 (IQR, 22.2-42.8) × 104/µL, respectively; C-reactive protein, 10.2 (IQR, 6.8-21.4) and 9.5 (IQR, 6.2-13.6) mg/dL, respectively; IgG, 1431 (IQR, 1112-1815) and 4725 (IQR, 3755-5121) mg/dL, respectively. RNA immunoprecipitation (5 cases for anti-SSA) or protein array (5 cases for anti-SSA/Ro60) detected anti-SSA antibodies in six (86%) TAFRO patients but not in iMCD patients; it did not detect anti-SSB antibodies in any of the patients. None of the patients were diagnosed with Sjögren syndrome. All iMCD patients treated with tocilizumab (TCZ) responded well. Meanwhile, two of six TAFRO patients treated with TCZ showed inadequate responses; thus, both patients were switched to rituximab, following which they achieved remission. TAFRO and iMCD have different clinical features. TAFRO may be categorized as a severe phenotype of the anti-SSA antibody syndrome.

Pathogenicity of IgG-Fc desialylation and its association with Th17 cells in an animal model of systemic lupus erythematosus.

OBJECTIVES: Decreased sialylation of IgG-Fc glycans has been reported in autoimmune diseases, but its role in systemic lupus erythematosus (SLE) is not fully understood. In this study, we examined the pathogenicity of IgG desialylation and its association with Th17 in SLE using an animal model. METHODS: B6SKG mice, which develop lupus-like systemic autoimmunity due to the ZAP70 mutation, were used to investigate the pathogenicity of IgG desialylation. The proportion of sialylated IgG was compared between B6SKG and wild-type mice with or without ß-glucan treatment-induced Th17 expansion. Anti-interleukin (IL)-23 and anti-IL-17 antibodies were used to examine the role of Th17 cells in IgG glycosylation. Activation-induced cytidine deaminase-specific St6gal1 conditionally knockout (cKO) mice were generated to examine the direct effect of IgG desialylation. RESULTS: The proportions of sialylated IgG were similar between B6SKG and wild-type mice in the steady state. However, IgG desialylation was observed after ß-glucan-induced Th17 expansion, and nephropathy also worsened in B6SKG mice. Anti-IL-23/17 treatment suppressed IgG desialylation and nephropathy. Glomerular atrophy was observed in the cKO mice, suggesting that IgG desialylation is directly involved in disease exacerbation. CONCLUSIONS: IgG desialylation contributes to the progression of nephropathy, which is ameliorated by blocking IL-17A or IL-23 in an SLE mouse model.

Risk prediction model for mortality in microscopic polyangiitis: multicentre REVEAL cohort study.

BACKGROUND: To establish refined risk prediction models for mortality in patients with microscopic polyangiitis (MPA) by using comprehensive clinical characteristics. METHODS: Data from the multicentre Japanese registry of patients with vasculitis (REVEAL cohort) were used in our analysis. In total, 194 patients with newly diagnosed MPA were included, and baseline demographic, clinical, laboratory, and treatment details were collected. Univariate and multivariate analyses were conducted to identify the significant risk factors predictive of mortality. RESULTS: Over a median follow-up of 202.5 (84-352) weeks, 60 (30.9%) of 194 patients died. The causes of death included MPA-related vasculitis (18.3%), infection (50.0%), and others (31.7%). Deceased patients were older (median age 76.2 years) than survivors (72.3 years) (P < 0.0001). The death group had shorter observation periods (median 128.5 [35.3-248] weeks) than the survivor group (229 [112-392] weeks). Compared to survivors, the death group exhibited a higher smoking index, lower serum albumin levels, higher serum C-reactive protein levels, higher Birmingham Vasculitis Activity Score (BVAS), higher Five-Factor Score, and a more severe European Vasculitis Study Group (EUVAS) categorization system. Multivariate analysis revealed that higher BVAS and severe EUVAS independently predicted mortality. Kaplan-Meier survival curves demonstrated lower survival rates for BVAS ≥20 and severe EUVAS, and a risk prediction model (RPM) based on these stratified patients into low, moderate, and high-risk mortality groups. CONCLUSIONS: The developed RPM is promising to predict mortality in patients with MPA and provides clinicians with a valuable tool for risk assessment and informed clinical decision-making.

A case of atypical IgG4-related disease presenting hypereosinophilia, polyneuropathy, and liver dysfunction.

Ig (immunoglobulin) G4-related disease (Ig4-RD) affects several organs, including salivary glands, lacrimal glands, pancreas, biliary ducts, and retroperitoneum. A 72-year-old woman was examined for hypereosinophilia, high levels of IgG4, polyneuropathy, liver dysfunction, enlargement of lymph nodes and lacrimal glands, and beaded dilation of the bile ducts. We diagnosed Ig4-RD based on biopsies of the lymph nodes, liver, and submandibular gland. The symptoms of the patient improved after glucocorticoid treatment. This was a novel and atypical case of Ig4-RD that was difficult to differentiate from other diseases, including eosinophilic granulomatosis with polyangiitis, idiopathic hypereosinophilic syndrome, and polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes syndrome. This case report highlights the importance of biopsies in differentiating Ig4-RD.

Long-Term Prognosis of Antimelanoma Differentiation-Associated Gene 5-Positive Dermatomyositis With Interstitial Lung Disease.

OBJECTIVE: Antimelanoma differentiation-associated gene 5 (anti-MDA5)-positive dermatomyositis with interstitial lung disease (DM-ILD) progresses rapidly and has a poor prognosis. Previously, we reported the efficacy of a combination therapy comprising high-dose glucocorticoids (GCs), calcineurin inhibitors (CNIs), and intravenous cyclophosphamide (IV CYC) in a multicenter clinical trial (UMIN000014344). In the present study, we evaluated the long-term outcomes and effects of induction therapy on the maintenance of remission. METHODS: All participants from our previous trial were followed up for > 5 years. Seventy-three other patients with anti-MDA5-positive DM-ILD from our institute were retrospectively integrated into the previous trial for further analysis. Sixty-eight patients achieved remission and survived for > 6 months. Based on the induction treatment, we classified the patients into 2 groups: (1) group T (n = 56), with triple combination therapy (GCs, CNIs, and IV CYC), and (2) group C (n = 12), with monotherapy/dual therapy. The recurrence-free and drug-withdrawal rates of immunosuppressive agents were compared. RESULTS: The overall survival and recurrence-free survival rates at 5 years were 100% for the participants in the previous trial. The 5-year cumulative withdrawal rates for CNIs and GCs were 70% and 53%, respectively. In a comprehensive analysis, the recurrence-free rates in group T were higher than those in group C (90% vs 56%; P < 0.05). The drug-withdrawal rates of CNIs and GCs at 10 years in group T were also higher than those in group C (79% vs 0% and 43% vs 0%, respectively; P < 0.05). CONCLUSION: Triple combination therapy in the induction phase can reduce the risk of recurrence and facilitate drug withdrawal in anti-MDA5-positive DM-ILD.

Prediction model for respiratory-related mortality in microscopic polyangiitis with interstitial lung disease: multicenter REVEAL cohort study.

OBJECTIVE: This study aimed to establish prediction models for respiratory-related mortality in microscopic polyangiitis (MPA) complicated by interstitial lung disease (ILD) using clinical characteristics. METHODS: We enrolled patients with MPA with ILD between May 2005 and June 2021 in a multicentre cohort of Japanese patients with MPA (REVEAL cohort). We evaluated the demographic, clinical, laboratory, radiological findings, treatments, and the presence of honeycombing 1 cm above the diaphragm using chest high-resolution computed tomography (HRCT) on admission. We explored the risk factors predictive of respiratory-related mortality. RESULTS: Of 115 patients, 26 cases died of respiratory-related diseases during a median follow-up of 3.8 years. Eighteen patients (69%) died due to respiratory infection, three (12%) had diffuse alveolar hemorrhage (DAH), and five (19%) had exacerbation of ILD. In univariate analysis, older age, lower percent forced vital capacity (%FVC), lower percent diffusing capacity of carbon monoxide (%DLco), and the presence of honeycombing in the right lower lobe were identified as risk factors. Additionally, in multivariate analysis adjusted for age and treatment, %FVC, %DLco, and the presence of honeycombing in the right lower lobe were independently associated with respiratory-related mortality. We created prediction models based on the values of %FVC, %DLco, and presence of honeycombing on chest HRCT (MPF model). The 5-year respiratory-related death-free rate was significantly different between patients with MPA with ILD stratified by the number of risk factors based on the MPF model. CONCLUSIONS: Our study indicates that the MPF model may help predict respiratory-related death in patients with MPA with ILD.

Prognosis of patients with systemic sclerosis-related interstitial lung disease on the lung transplant waiting list: a retrospective study.

Advanced systemic sclerosis-associated interstitial lung disease (SSc-ILD) can be treated with lung transplantation. There is limited data on lung transplantation outcomes in patients with SSc-ILD, in non-Western populations.We assessed survival data of patients with SSc-ILD, on the lung transplant (LT) waiting list, and evaluated post-transplant outcomes in patients from an Asian LT center. In this single-center retrospective study, 29 patients with SSc-ILD, registered for deceased LT at Kyoto University Hospital, between 2010 and 2022, were identified. We investigated post-transplant outcomes in recipients who underwent LT for SSc-ILD, between February 2002 and April 2022. Ten patients received deceased-donor LT (34%), two received living-donor LT (7%), seven died waiting for LT (24%), and ten survived on the waiting list (34%). Median duration from registration to deceased-donor LT was 28.9 months and that from registration to living-donor LT or death was 6.5 months. Analysis of 15 recipients showed improved forced vital capacity with a median of 55.1% at baseline, 65.8% at 6 months, and 80.3% at 12 months post-transplant. The 5-year survival rate for post-transplant patients with SSc-ILD was 86.2%. The higher post-transplant survival rate at our institute than previously reported suggests that lung transplantation is acceptable in Asian patients with SSc-ILD.

Comparisons of SLE-DAS and SLEDAI-2K and classification of disease activity based on the SLE-DAS with reference to patient-reported outcomes.

OBJECTIVES: Although the SLE Disease Activity Score (SLE-DAS) and its definitions to classify disease activity have been recently developed to overcome the drawbacks of the SLE Disease Activity Index 2000 (SLEDAI-2K), the performance of the SLE-DAS for patient-reported outcomes (PROs) has not been fully examined. We aimed to compare SLE-DAS with SLEDAI-2K and validate the classifications of disease activity based on SLE-DAS in terms of PROs. METHODS: We assessed generic quality of life (QoL) using the Medical Outcome Survey 36-Item Short-Form Health Survey (SF-36), disease-specific QoL using the lupus patient-reported outcome tool (LupusPRO), burden of symptoms using the SLE Symptom Checklist (SSC), patient global assessment (PtGA) and physician global assessment (PhGA). RESULTS: Of the 335 patients with SLE, the magnitudes of the mean absolute error, root mean square error, Akaike information criterion, and Bayesian information criterion were comparable for most PROs between the SLE-DAS and SLEDAI-2K. In contrast, SLEDAI-2K had a higher predictive value for health-related QoL of LupusPRO and PtGA than SLE-DAS. Low disease activity, Boolean and index-based remission and categories of disease activity (remission, mild and moderate/severe activity) were significantly associated with health-related QoL in LupusPRO, SSC and PhGA, but not SF-36 or PtGA. CONCLUSION: No clear differences were identified in the use of the SLE-DAS over the SLEDAI-2K in assessing PROs in patients with SLE. The classification of disease activity based on the SLE-DAS was validated against several PROs. SLE-DAS and its categories of disease activity effectively explain some of the PROs.

Enteric Toll-like receptor 7 stimulation causes acute exacerbation in lupus-susceptible mice.

Autoimmune diseases are often accompanied by acute exacerbation. However, the mechanism underlying systemic lupus erythematosus (SLE) flares remains unclear. We investigated whether short-term enteric Toll-like receptor 7 (TLR7) stimulation can exacerbate SLE using B6SKG mice, which spontaneously develop SLE due to a mutation in the zeta‒chain‒associated protein kinase 70 (Zap70) gene. Imiquimod (IMQ) or phosphate-buffered saline (PBS) were orally administered on B6WT and B6SKG mice every other day for 2 weeks. SLE exacerbation was assessed via fluorescent immunohistochemical staining of glomeruli for IgG and C3, hematoxylin and eosin staining of kidneys, and enzyme-linked immunosorbent assay for antinuclear antibody (ANA). Flow cytometry was used to evaluate germinal center B cells (GCBs), plasma cells, follicular helper T cells (Tfhs), regulatory T cells (Tregs), effector T cells (Th1s and Th17s), plasmacytoid dendritic cells (pDCs), conventional dendritic cells (cDCs), and macrophages (Mφs) in spleens. Oral administration of IMQ every other day for 2 weeks resulted in exacerbation of splenomegaly, increased IgG and C3 deposition in glomeruli, and increased ANA production in the B6SKG IMQ (SKG-IMQ) group compared to the B6SKG PBS (SKG-PBS) group; the percentages of GCBs, plasma cells, Tfhs, Th1s, pDCs, and Mφs were also increased in the SKG-IMQ group. Splenomegaly, IgG, and C3 deposition in glomeruli, and the percentages of GCBs, plasma cells, Tfhs, and Th1s were enhanced in SKG-IMQ mice compared with B6SKG mice topically treated with IMQ (SKG-ear-IMQ). Oral TLR7 stimulation in a Zap70 genetic mutation background can cause acute exacerbations of SLE. Key Points • The mechanism of SLE flares is not well understood. • We have created a model that causes short-term SLE exacerbations in mice with a genetic background. • IMQ administered orally causes more SLE in mice than transdermally.

Genetic architecture underlying IgG-RF production is distinct from that of IgM-RF.

OBJECTIVE: HLA-DRB1 alleles, particularly the shared epitope (SE) alleles, are strongly associated with RA. Different genetic structures underlie the production of the various autoantibodies in RA. While extensive genetic analyses have been conducted to generate a detailed profile of ACPA, a representative autoantibody in RA, the genetic architecture underlying subfractions of RF other than IgM-RF, namely IgG-RF, known to be associated with rheumatoid vasculitis, is not well understood. METHODS: We enrolled a total of 743 RA subjects whose detailed autoantibody (IgG-RF, IgM-RF, and ACPA) data were available. We evaluated co-presence and correlations of the levels of these autoantibodies. We analysed associations between the presence or levels of the autoantibodies and HLA-DRB1 alleles for the 743 RA patients and 2008 healthy controls. RESULTS: We found both IgG-RF(+) and IgG-RF(-) RA subjects showed comparable associations with SE alleles, which was not observed for the other autoantibodies. Furthermore, there was a clear difference in SE allele associations between IgG-RF(+) and (-) subsets: the association with the IgG-RF(+) subsets was solely driven by HLA-DRB1*04:05, the most frequent SE allele in the Japanese population, while not only HLA-DRB1*04:05 but also HLA-DRB1*04:01, less frequent in the Japanese population but the most frequent SE allele in Europeans, were main drivers of the association in the IgG-RF(-) subset. We confirmed that these associations were irrespective of ACPA presence. CONCLUSION: We found a unique genetic architecture for IgG-RF(-) RA, which showed a strong association with a SE allele not frequent in the Japanese population but the most frequent SE allele in Europeans. The findings could shed light on uncovered RA pathology.

Medium-term impact of the SARS-CoV-2 mRNA vaccine against disease activity in patients with systemic lupus erythematosus.

OBJECTIVES: Numerous case reports have referred to new onset or flare of SLE after SARS-CoV-2 messenger RNA (mRNA) vaccines. Several observational studies showed that the short-term flare rate of SLE after SARS-CoV-2 vaccination is low. However, well-controlled clinical surveys are unavailable and the medium-term impact of the SARS-CoV-2 mRNA vaccines against the flare of SLE is uncertain. Therefore, we aimed to analyse the association between vaccination and medium-term subjective and objective disease activities of SLE and flares using matched pair methods. METHODS: Altogether, 150 patients with SLE from the Kyoto Lupus Cohort were included. Patients who received two doses of the SARS-CoV-2 mRNA vaccines were 1:1 matched with unvaccinated patients based on the first vaccination date. The outcome measures were the SLE Disease Activity Index-2000 (SLEDAI-2K), the Japanese version of the SLE Symptom Checklist Questionnaire (SSC-J) and the Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI flare index at 30, 60 and 90 days after vaccination. RESULTS: SLEDAI-2K levels were not significantly different in vaccinated and unvaccinated patients with SLE at 30, 60 and 90 days after the second vaccination (adjusted estimate (95% CI): 30 days: -0.46 (-1.48 to 0.56), p=0.39; 60 days: 0.38 (-0.64 to 1.40), p=0.47; 90 days: 0.40 (-0.54 to 1.34), p=0.41). Similar results were observed in the SSC-J score (adjusted estimate (95% CI), 30 days: 0.05 (-1.46 to 1.56), p=0.95; 60 days: -0.63 (-2.08 to 0.82), p=0.40; 90 days: 0.27 (-1.04 to 1.58), p=0.69) and flare index (adjusted OR (95% CI), 30 days: 0.81 (0.36 to 1.85), p=0.62; 60 days: 1.13 (0.50 to 2.54), p=0.77; 90 days: 0.85 (0.32 to 2.26), p=0.74). CONCLUSION: SARS-CoV-2 vaccination did not significantly influence the medium-term subjective and objective disease activities or flares of SLE until 90 days after the second vaccination.

NR4A nuclear receptors in T and B lymphocytes: Gatekeepers of immune tolerance.

Random VDJ recombination early in T and B cell development enables the adaptive immune system to recognize a vast array of evolving pathogens via antigen receptors. However, the potential of such randomly generated TCRs and BCRs to recognize and respond to self-antigens requires layers of tolerance mechanisms to mitigate the risk of life-threatening autoimmunity. Since they were originally cloned more than three decades ago, the NR4A family of nuclear hormone receptors have been implicated in many critical aspects of immune tolerance, including negative selection of thymocytes, peripheral T cell tolerance, regulatory T cells (Treg), and most recently in peripheral B cell tolerance. In this review, we discuss important insights from many laboratories as well as our own group into the function and mechanisms by which this small class of primary response genes promotes self-tolerance and immune homeostasis to balance the need for host defense against the inherent risks posed by the adaptive immune system.

Negative feedback by NUR77/Nr4a1 restrains B cell clonal dominance during early T-dependent immune responses.

B cell clones compete for entry into and dominance within germinal centers (GCs), where the highest-affinity B cell receptors (BCRs) are selected. However, diverse and low-affinity B cells can enter and reside in GCs for extended periods. To reconcile these observations, we hypothesize that a negative feedback loop may operate within B cells to preferentially restrain high-affinity clones from monopolizing the early GC niche. Here, we report a role for the nuclear receptor NUR77/Nr4a1 in this process. We show that NUR77 expression scales with antigen stimulation and restrains B cell expansion. Although NUR77 is dispensable for regulating GC size when GCs are elicited in a largely clonal manner, it serves to curb immunodominance under conditions where diverse clonal populations must compete for a constrained niche. We propose that this is important to preserve early clonal diversity in order to limit holes in the post-immune repertoire and to optimize GC selection.