Autoimmunity
Abstract
CD20+ T cells are increasingly recognized as drivers of autoimmune and inflammatory diseases. However, their origin, development, and specific role in autoimmune skin diseases remain poorly understood. In this study, we observed an expansion of CD20+ T cells in the peripheral blood and skin lesions of patients with bullous pemphigoid (BP), which correlated with the levels of pathogenic autoantibodies and disease severity. Compared with CD20– T cells, CD20+ T cells exhibited enhanced metabolic and proinflammatory activities. In particular, antigen-specific BP180-NC16A-reactive T cells were enriched within the CD4+CD20+ subset. In both patients with BP and BP180-immunized mice, CD4+CD20+ T cells exhibited an antigen-specific follicular helper T (Tfh)-like phenotype, facilitating antibody production and B cell differentiation, whereas CD8+CD20+ T cells displayed cytotoxic and proinflammatory features. Mechanistically, we found that expression of the CD20-encoding gene MS4A1 in T cells was regulated by PAX5 in a DNA methylation-dependent manner. Therefore, our study elucidates the regulatory mechanisms governing CD20+ T cells and highlights their important role in the pathogenesis of BP.
Authors
Hui Fang, Shengxian Shen, Kang Li, Tianyu Cao, Bing Wang, Haijun Miao, Ke Xue, Yaxing Bai, Liang Li, Xia Li, Pei Qiao, Jieyu Zhang, Huanhuan Qu, Chen Zhang, Chunying Xiao, Bingyu Pang, Meng Fu, Hongjiang Qiao, Shuai Shao, Erle Dang, Gang Wang
Abstract
Background: Rheumatoid factor (RF) autoantibodies are highly prevalent, yet the molecular determinants of RF development and its progression to rheumatoid arthritis (RA) remain poorly understood. Here, we define the genetic, phenotypic, and molecular architecture of RF and its progression to RA. Methods: 469,036 UK Biobank participants with RF testing and 76 ALTRA cohort individuals were studied. Phenome-wide (PheWAS), genome-wide (GWAS), and proteome-wide association studies compared RF-positive individuals without autoimmune disease to RF-negative controls. Single-cell RNA sequencing enabled pseudobulk differential expression and cytokine signature enrichment analyses. Results: RF seroprevalence was 9.3% and longitudinally stable in 94.5% of individuals. PheWAS identified 48 significant associations, led by chronic viral hepatitis (OR 4.8), hypersensitivity pneumonitis (OR 3.6), bronchiectasis (OR 1.9), and COPD (OR 1.4). GWAS of 24,216 RF-positive individuals revealed 29 independent loci; the strongest signal was in the extended HLA region (OR 1.45, P-value=5.4×10-221). Non-HLA loci converged on B cell homeostasis genes (ETS1, BACH2, PAX5, TNFRSF13B, FCGR2A). RF-positive individuals did not carry elevated RA polygenic risk. Proteomic profiling identified 153 differentially abundant proteins enriched for humoral immunity and interferon-induced chemokines, with 79% showing dose-response relationships across titers. Progression to RA involved a shift toward activating tissue-damaging inflammatory pathways rather than amplification of the RF signature. Single-cell transcriptomics of RF-positive individuals without RA localized dysregulation to memory B cells, with downregulation of inhibitory genes (FCGR2B, BACH2, FOXP1) and upregulation of activation markers. Conclusion: RF production is governed by HLA class II and B cell regulatory loci, associated with mucosal inflammation, and is genetically and molecularly distinct from RA.
Authors
Mehmet Hocaoglu, Amr H. Sawalha
Abstract
Vitiligo is an autoimmune skin disease characterized by depigmentation, mainly due to CD8+ T cell–mediated destruction of melanocytes. Hyperglycemia exacerbates autoimmune responses and is associated with vitiligo; however, the underlying immunometabolic mechanisms are poorly understood. Here, we demonstrated the correlation between hyperglycemia and vitiligo in a case-control study and demonstrated that hyperglycemia aggravated vitiligo based on a mouse model. Targeted metabolomics identified succinate as the potential metabolite mediating hyperglycemia-aggravated vitiligo. Mechanistically, succinate promotes the activation of CD8+ T cells through succinate receptor 1 (SUCNR1) and promotes keratinocytes to secrete CXCL9 and CXCL10 by enhancing the stability and nuclear translocation of hypoxia-inducible factor-1α, facilitating the skin-homing of CD8+ T cells. Thus, hyperglycemia aggravates vitiligo through succinate/SUCNR1 axis–regulated CD8+ T cell hyperactivation. Our study provides insights into the long-observed yet previously unclear mechanism by which hyperglycemia accelerates vitiligo progression and highlights SUCNR1 as a potential therapeutic target.
Authors
Pan Kang, Yuqian Chang, Tingting Wang, Xiuli Yi, Yinghan Wang, Pengran Du, Jiaxi Chen, Baizhang Li, Shuli Li, Zhongjun Shao, Jianru Chen, Chunying Li
Abstract
BACKGROUND. Anti-nephrin autoantibodies have emerged as a putative pathogenic driver in a subset of patients with podocytopathies, including those with post-transplant disease recurrence. METHODS. We measured anti-nephrin autoantibodies in a cohort of 65 patients with podocytopathy associated with steroid-sensitive nephrotic syndrome (n = 39) and steroid-resistant nephrotic syndrome (n = 26), and in 34 patients with post-transplant podocytopathy recurrence. Fourteen patients with membranous nephropathy and 20 healthy volunteers served as controls. ELISA and immunoprecipitation assays were performed to detect anti-nephrin IgG using two different recombinant human nephrin proteins. Immunofluorescence analysis was performed to assess the deposition of IgG and their colocalization with nephrin in renal biopsies. RESULTS. When using murine antigen-based ELISA, the highest positivity was found in healthy volunteers (55%), correlating with levels of circulating natural anti-α-galactose-α-1,3-galactose antibodies. This cross-reactivity was abrogated with recombinant human nephrin expressed in human cells. In this setting, very low prevalence (<5%) of anti-nephrin antibody-positive patients was found in steroid-sensitive and steroid-resistant nephrotic syndrome cohorts and in patients with post-transplant disease recurrence. These frequencies were comparable to healthy volunteers. Using confocal and super-resolution microscopy, only trace amounts of IgM, but no IgG, were found in the glomeruli of analyzed biopsies, which did not colocalize with nephrin. CONCLUSIONS. With the methodology presented here, anti-nephrin reactivity was extremely rare and occurred at comparably low frequencies in healthy controls, native-kidney podocytopathies, and post-transplant disease recurrence. This suggests that these autoantibodies are not inherently disease-specific and may not serve as a broad biomarker across podocytopathies. TRIAL REGISTRATION. ClinicalTrials.gov NCT06334692. FUNDING. Private donation.
Authors
Francesco Pecoraro, Luca Perico, Federica Casiraghi, Paola Rizzo, Matias Trillini, Andrea Angeletti, Manuel Alfredo Podestà, Xhuliana Kajana, Agnese Spennacchio, Marta Todeschini, Marilena Mister, Giuseppe Castellano, Ariela Benigni, Giuseppe Remuzzi
Abstract
Acquired generalized lipodystrophy (AGL) is a rare metabolic disorder frequently associated with autoimmunity. Its etiology is incompletely understood, and the effect of adipose tissue loss on intestinal inflammation in AGL remains unclear. Using mass cytometry and single-cell RNA-seq, we observed an oligoclonal expansion of T cells in the periphery and inflamed intestine in a patient with AGL and Crohn’s disease (AGLCD). To explore if loss of adipose tissue triggers lymphoproliferation, we studied lipodystrophic mice as a model for AGL. Unexpectedly, lipodystrophic mice did not show T cell expansion, were protected from colitis, and displayed a defect in the development of proinflammatory T cells, which could be reversed by allogeneic fat transplantations, indicating that clonal T cell expansion in AGLCD is not primarily caused by lipodystrophy. Instead, gene sequencing revealed a T cell–intrinsic de novo neuroblastoma RAS viral oncogene homolog (NRAS) mutation, implicating somatic mosaicism as a facilitator of clonal T cell expansion and intestinal inflammation in AGLCD.
Authors
Marilena Letizia, Toka Omar, Patrick Weidner, Manuel O. Jakob, Inka Freise, Susanne M. Krug, Britt-Sabina Löscher, Elisa Rosati, Benedikt Obermayer, Reyes Gamez-Belmonte, Julia Hecker, Jörn-Felix Ziegler, Benjamin Weixler, Patrick Asbach, Desiree Kunkel, Michael Stumvoll, Konstanze Miehle, Christoph Becker, Christoph S.N. Klose, Rainer Glauben, Dieter Beule, Anja A. Kühl, Thomas Conrad, Frank Tacke, Stefan Wirtz, Andre Franke, Ashley D. Sanders, Britta Siegmund, Carl Weidinger
Abstract
Interstitial lung disease (ILD) is a major cause of morbidity and mortality in systemic sclerosis (SSc); however, the immunopathologic mechanisms driving lung disease in SSc are unclear. T cells have been implicated as a likely driver of lung injury in SSc. Here, we have evaluated T cells in the blood of patients with SSc-ILD and identified a specific population of cytotoxic CD8 T cells that is expanded in SSc-ILD patients. Cytotoxic effector memory CD8 T cells marked by CD57 expression are preferentially expanded in SSc-ILD patients compared to SSc patients without ILD and controls and show prominent clonal expansion. These CD57+ T effector memory (TEM) cells differ from T effector memory cells re-expressing CD45RA (TEMRA) transcriptomically and functionally, with cytotoxic function that is enhanced by CD155 engagement of the costimulatory receptor CD226. We performed immunostaining of lung tissue samples obtained from independent SSc-ILD patients (biopsy or explant) and confirmed the presence of CD57+ TEM. In parallel, we analyzed publicly available lung scRNA-seq datasets from multiple ILD cohorts and identified endothelial cells as a likely source of CD155 to activate CD57+ cytotoxic T cells. Together, the results implicate a CD57+ cytotoxic CD8 T cell population as a potential mediator of lung injury in SSc-ILD.
Authors
Takanori Sasaki, Ye Cao, John M. Sowerby, Kazuhiko Higashioka, Kathryne E. Marks, Mehreen Elahee, Mari Kamiya, Paul F. Dellaripa, Richard I. Ainsworth, Kimberly E. Taylor, Nunzio Bottini, Paul Wolters, Edy Y. Kim, Francesco Boin, Deepak A. Rao
Abstract
Anaphylaxis is a life-threatening hypersensitivity reaction. Clinical observations suggest heightened susceptibility during viral infections, yet the mechanisms remain poorly defined. Here, we show that both active and passive IgG-mediated anaphylaxis were exacerbated in the setting of acute viral infection. In mice, this enhancement was driven predominantly by FcγRIV, the homolog of human FcγRIIIa. FcγRIV crosslinking induced anaphylactic symptoms selectively in infected animals, with no effect in naive conditions. Among leukocytes, inflammatory monocytes emerged as the principal drivers of this lethal reaction. Viral infection triggered a strong upregulation of FcγRIV on inflammatory monocytes, an effect absent in type I IFN receptor–deficient (Ifnar1-deficient) mice. Extending these findings, we observed increased frequencies of CD16-expressing classical monocytes in patients with acute COVID-19, and murine SARS-CoV-2 infection recapitulated this phenotype. Mechanistically, FcγRIV crosslinking during infection promoted the production of platelet-activating factor, the key mediator of mortality, in a type I IFN–dependent (IFN-I–dependent) manner. Together, these findings indicate that viral infection creates an immune milieu that heightens monocyte sensitivity to Fcγ receptor engagement, positioning these cells as major effectors of IgG-mediated hypersensitivity in the infected host. They further suggest that Fc receptor pathway modulation merits further investigation in contexts with heightened IFN-I responses, such as in systemic lupus erythematosus.
Authors
Abdelrahman Elwy, Hossam Abdelrahman, Julia Specht, Gina M. Ewert, Justa Friebus-Kardash, Swati Dhiman, Julia Falkenstein, Theresa Charlotte Christ, Elisa Wiebeck, Arzoo Shamoon, Nils B. Leimkühler, Thomas Gramberg, Alina Russ, Ulrich Kalinke, Fei Kuang, Kathrin Sutter, Manfred Kopf, Matthias Mack, Wiebke Hansen, Falk Nimmerjahn, Karl S. Lang
Abstract
Authors
Bingyu Yan, Jinwoo Lee, Suhas Srinivasan, Pedro Ambriz, Quanming Shi, Diana R. Dou, Srijana Davuluri, Swarna Nandyala, Adrianne Woods, Gwendolyn Leatherman, Yanding Zhao, Roman E. Reggiardo, Manasi Sawant, Hawa Racine Thiam, Ami A. Shah, David F. Fiorentino, Lorinda S. Chung, Howard Y. Chang
Abstract
Neutrophils and neutrophil extracellular traps (NETs) contribute to early neuromyelitis optica (NMO) histopathology initiated by IgG targeting astrocytic aquaporin-4 water (AQP4) channels. Yet, the mechanisms underlying neutrophil recruitment and their pathogenic roles in disease progression remain unclear. To investigate molecular-cellular events preceding classical complement cascade activation in a mouse NMO model, we continuously infused, via spinal subarachnoid route, a non-complement-activating mouse monoclonal AQP4-IgG. Parenchymal infiltration of netting neutrophils containing C5a ensued with microglial activation and motor impairment, but no blood–brain barrier leakage. Motor impairment and neuronal dysfunction both reversed when AQP4-IgG infusion stopped. Two-photon microscopy and electron-microscopy-based reconstructions revealed physical interaction of infiltrating neutrophils with microglia. Ablation of either peripheral neutrophils or microglia attenuated the motor deficit, highlighting their synergistic pathogenic roles. Of note, mice lacking complement receptor C5aR1 exhibited reduction in neutrophil infiltration, microglial lysosomal activation, neuronal lipid-droplet burden and motor impairment. Pharmacological inhibition of C5aR1 recapitulated this protection. Immunohistochemical analysis of an NMO patient’s spinal cord revealed disease-associated microglia surrounding motor neurons in non-destructive lesions. Our study identifies neutrophil-derived C5a signaling through microglial C5aR1 as a key early driver of reversible motor neuron dysfunction in the precytolytic phase of NMO.
Authors
Fangfang Qi, Vanda A. Lennon, Shunyi Zhao, Yong Guo, Husheng Ding, Caiyun Liu, Whitney M. Bartley, Tingjun Chen, Claudia F. Lucchinetti, Long-Jun Wu
Abstract
RORγt is a key transcription factor regulating both Th17 differentiation and thymocyte development. Although Th17 cells drive autoimmune diseases, inhibiting RORγt to treat autoimmunity also disrupts thymocyte development and can cause lethal thymic lymphoma. We identified a previously unreported RORγt cofactor, CBFβ, and a highly selective RORγt inhibitor, IMU-935, that preferentially disrupt the RORγt-CBFβ interaction in Th17 cells but not thymocytes. This interaction is essential for RORγt function; mice with a RORγt mutant unable to bind CBFβ had impaired Th17 differentiation, were resistant to experimental autoimmune encephalomyelitis (EAE), and had defective thymocyte development. IMU-935 inhibited Th17 differentiation and reduced EAE severity without affecting thymocyte development by selectively targeting the RORγt-CBFβ interaction in Th17 cells but not in thymocytes. This differential effect arose because different concentrations of IMU-935 were required to disrupt the interaction in Th17 cells versus thymocytes, due to varying levels of RUNX1 that compete with RORγt for CBFβ binding. This study reveals an unreported mechanism for RORγt regulation and a selective RORγt inhibitor that prevents Th17-driven autoimmunity without the risk of lethal lymphoma from thymocyte disruption.
Authors
Hongmin Wu, Xiancai Zhong, Ning Ma, Zhiheng He, Guanpeng Wang, Geming Lu, Yate-Ching Yuan, Wencan Zhang, Yun Shi, Nagarajan Vaidehi, Evelyn Peelen, Tanja Wulff, Christian Gege, Hella Kohlhof, Daniel Vitt, Yousang Gwack, Ichiro Taniuchi, Hai-Hui Xue, Zuoming Sun
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ISSN: 0021-9738 (print), 1558-8238 (online)