Autoimmunity
Abstract
FcɣRIIB is an inhibitory receptor expressed throughout B cell development. Diminished expression or function is associated with lupus in mice and humans, in particular through an effect on autoantibody production and plasma cell differentiation. Here, we analysed the effect of B cell-intrinsic FcɣRIIB expression on B cell activation and plasma cell differentiation. Loss of FcɣRIIB on B cells (Fcgr2b cKO mice) led to a spontaneous increase in autoantibody titers. This increase was most striking for IgG3, suggestive of increased extrafollicular responses. Marginal zone (MZ) B cells had the highest expression of FcɣRIIB in both mouse and human. This high expression of FcɣRIIB was linked to increased MZ B cell activation, Erk phosphorylation, and calcium fluxin the absence of FcɣRIIB triggering. Marked increases in IgG3+ plasma cells and B cells were observed during extrafollicular plasma cell responses in Fcgr2b cKO mice. The increased IgG3 response following immunization of Fcgr2b cKO mice was lost in MZ-deficient Notch2/Fcgr2b cKO mice. Importantly, SLE patients exhibited decreased expression of FcɣRIIB, most strongly in MZ B cells. Thus, we present a model where high FcɣRIIB expression in MZ B cells prevents their hyperactivation and ensuing autoimmunity.
Authors
Ashley N. Barlev, Susan Malkiel, Izumi Kurata-Sato, Annemarie L. Dorjée, Jolien Suurmond, Betty Diamond
Abstract
Plasmacytoid dendritic cell (pDC) is a professional type I interferon producer, which plays critical roles in the pathogenesis of autoimmune diseases. However, both genetic regulation of pDC function and their relationships with autoimmunity are largely undetermined. Here, we investigated the causality of NCF1 missense variant, which is one of the most significant associated risk variants for lupus, and found that the substitution from arginine (R) to histidine (H) at position 90 in NCF1 protein (NCF1 p.R90H) led to excessive activation of pDCs. Mechanism study demonstrated that p.R90H reduced the affinity of NCF1 to phospholipid, thereby impaired endosomal localization of NCF1. As NCF1 is a subunit of NOX2 complex, this impairment led to acidified endosomal pH and facilitated downstream TLR signaling. Consistently, the homozygous knock-in mice manifested aggravated lupus progression in a pDC dependent lupus model. More importantly, pharmaceutical intervention revealed that hydroxychloroquine (HCQ) could antagonize the detrimental function of NCF1 p.R90H in lupus model and systemic lupus erythematosus (SLE) samples, supporting that NCF1 p.R90H could be identified as a genetic biomarker for HCQ application. Therefore, our study provides insights into the genetic control of pDC function and paradigm for applying genetic variants to improve targeted therapy for autoimmune diseases.
Authors
Yao Meng, Jianyang Ma, Chao Yao, Zhizhong Ye, Huihua Ding, Can Liu, Jun Li, Guanhua Li, Yuke He, Jia Li, Zhihua Yin, Li Wu, Haibo Zhou, Nan Shen
Abstract
In Guillain-Barré syndrome (GBS), both axonal and demyelinating variants can be mediated by complement-fixing anti-GM1 ganglioside autoantibodies that target peripheral nerve axonal and Schwann cell (SC) membranes, respectively. Critically, the extent of axon degeneration in both variants dictates long-term outcome. The differing pathomechanisms underlying direct axonal injury and the secondary “bystander” axonal degeneration following SC injury are unresolved. To investigate this, we generated glycosyltransferase-disrupted transgenic mice that express GM1 ganglioside either exclusively in neurons (GalNAcT-/--Tg(neuronal)) or glia (GalNAcT-/--Tg(glial)), thereby allowing anti-GM1 antibodies to solely target GM1 in either axonal or SC membranes, respectively. Myelinated axon integrity in distal motor nerves was studied in transgenic mice exposed to anti-GM1 antibody and complement in ex vivo and in vivo injury paradigms. Axonal targeting induced catastrophic acute axonal disruption as expected. When mice with GM1 in SC membranes were targeted, acute disruption of perisynaptic glia, and SC membranes at nodes of Ranvier (NoR) occurred. Following glial injury, axon disruption at nodes also developed sub-acutely, progressing to secondary axon degeneration. These models differentiate the distinctly different axonopathic pathways under in axonal and glial membrane targeting conditions, and provide insights into primary and secondary axon injury, currently a major unsolved area in GBS research.
Authors
Rhona McGonigal, Clare I. Campbell, Jennifer A. Barrie, Denggao Yao, Madeleine E. Cunningham, Colin L. Crawford, Simon Rinaldi, Edward G. Rowan, Hugh J. Willison
Abstract
BACKGROUND. In human lupus nephritis (LN), tubulointerstitial inflammation (TII) on biopsy predicts progression to end-stage renal disease (ESRD). However, only about half of patients with moderate/severe TII develop ESRD. We hypothesized that this heterogeneity in outcome reflects different underlying inflammatory states. Therefore, we interrogated renal biopsies from LN longitudinal and cross-sectional cohorts. METHODS. Data was acquired using conventional and highly multiplexed confocal microscopy. To accurately segment cells across whole biopsies, and to understand their spatial relationships, we developed computational pipelines by training and implementing several deep learning models and other computer vision techniques. RESULTS. High B cell densities were associated with protection from ESRD. In contrast, CD8, γδ and other CD4-CD8- T cells, were associated with both acute renal failure and progression to ESRD. B cells were often organized into large periglomerular neighborhoods with T follicular helper cells while CD4- T cells formed small neighborhoods in the tubulointerstitium whose frequency predicted progression to ESRD. CONCLUSIONS. These data reveal that specific in situ inflammatory states are associated with refractory and progressive renal disease. FUNDING. These studies were funded by the NIH Autoimmunity Centers of Excellence (AI082724), Department of Defense (LRI180083) and Alliance for Lupus Research, NIH S10-OD025081, S10-RR021039, and P30-CA14599 awards.
Authors
Rebecca Abraham, Madeleine S. Durkee, Junting Ai, Margaret Veselits, Gabriel Casella, Yuta Asano, Anthony Chang, Kichul Ko, Charles Oshinsky, Emily Peninger, Maryellen L. Giger, Marcus R. Clark
Abstract
The major therapeutic goal for immune thrombocytopenia (ITP) is to restore normal platelet counts using drugs to promote platelet production or by interfering with mechanisms responsible for platelet destruction. 80% of patients possess anti-integrin αIIbβ3 (GPIIbIIIa) IgG autoantibodies causing platelet opsonization and phagocytosis. The spleen is considered the primary site of autoantibody production by autoreactive B cells and platelet destruction. The immediate failure in ~50% of patients to recover a normal platelet count after anti-CD20 Rituximab-mediated B cell depletion and splenectomy suggest that autoreactive, rituximab-resistant, IgG-secreting B cells (IgG-SC) reside in other anatomical compartments. We analyzed >3,300 single IgG-SC from spleen, bone marrow and/or blood of 27 patients with ITP revealing high inter-individual variability in affinity for GPIIbIIIa with variations over 3 logs. IgG-SC dissemination and range of affinities were however similar per patient. Longitudinal analysis of autoreactive IgG-SC upon treatment with anti-CD38 mAb daratumumab demonstrated variable outcomes, from complete remission to failure with persistence of high-affinity anti-GPIIbIIIa IgG-SC in the bone marrow. This study demonstrates the existence and dissemination of high-affinity autoreactive plasma cells in multiple anatomical compartments of patients with ITP that may cause the failure of current therapies.
Authors
Pablo Canales-Herrerias, Etienne Crickx, Matteo Broketa, Aurélien Sokal, Guilhem Chenon, Imane Azzaoui, Alexis Vandenberghe, Angga Perima, Bruno Iannascoli, Odile Richard-Le Goff, Carlos Castrillon, Guillaume Mottet, Delphine Sterlin, Ailsa Robbins, Marc Michel, Patrick England, Gael A. Millot, Klaus Eyer, Jean Baudry, Matthieu Mahevas, Pierre Bruhns
Abstract
The trace element iron affects immune responses and vaccination, but knowledge of its role in autoimmune diseases is limited. Expansion of pathogenic T cells, especially T follicular helper (Tfh) cells, has great significance to systemic lupus erythematosus (SLE) pathogenesis. Here, we show an important role of iron in regulation of pathogenic T cell differentiation in SLE. We found that iron overload promoted Tfh cell expansion, proinflammatory cytokine secretion, and autoantibody production in lupus-prone mice. Mice treated with a high-iron diet exhibited an increased proportion of Tfh cell and antigen-specific GC response. Iron supplementation contributed to Tfh cell differentiation. In contrast, iron chelation inhibited Tfh cell differentiation. We demonstrated that the miR-21/BDH2 axis drove iron accumulation during Tfh cell differentiation and further promoted Fe2+-dependent TET enzyme activity and BCL6 gene demethylation. Thus, maintaining iron homeostasis might be critical for eliminating pathogenic Th cells and might help improve the management of patients with SLE.
Authors
Xiaofei Gao, Yang Song, Jiali Wu, Shuang Lu, Xiaoli Min, Limin Liu, Longyuan Hu, Meiling Zheng, Pei Du, Yaqin Yu, Hai Long, Haijing Wu, Sujie Jia, Di Yu, Qianjin Lu, Ming Zhao
Abstract
Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation with aberrant epigenetic alterations, eventually leading to joint destruction. However, the epigenetic regulatory mechanisms underlying RA pathogenesis remain largely unknown. Here we showed that Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) is a central epigenetic regulator that suppressively orchestrates multiple pathogeneses in RA. UHRF1 expression was remarkably up-regulated in synovial fibroblasts (SF) from arthritis model mice and RA patients. Mice with SF-specific Uhrf1 conditional knockout showed more severe arthritic phenotypes than littermate control. Uhrf1-deficient SF also exhibited enhanced apoptosis resistance and up-regulated expression of several cytokines including Ccl20. In RA patients, DAS28, CRP, and Th17 accumulation as well as apoptosis resistance were negatively correlated with UHRF1 expression in synovium. Finally, Ryuvidine administration that stabilizes UHRF1 ameliorated arthritis pathogeneses in a mouse model of RA. This study demonstrated that UHRF1 expressed in RA SF can contribute to negative feedback mechanisms that suppress multiple pathogenic events in arthritis, suggesting that targeting UHRF1 could be one of the therapeutic strategies for RA.
Authors
Noritaka Saeki, Kazuki Inoue, Maky Ideta-Otsuka, Kunihiko Watamori, Shinichi Mizuki, Katsuto Takenaka, Katsuhide Igarashi, Hiromasa Miura, Shu Takeda, Yuuki Imai
Abstract
CD13, an ectoenzyme on myeloid and stromal cells, also circulates as a shed, soluble protein (sCD13) with powerful chemoattractant, angiogenic and arthritogenic properties, which require engagement of a G protein-coupled receptor (GPCR). Here we identify the GPCR that mediates sCD13 arthritogenic actions as the bradykinin receptor B1 (B1R). Immunofluorescence and immunoblotting verified high expression of B1R in rheumatoid arthritis (RA) synovial tissue and synovial cell (FLS) lines, and demonstrated binding of sCD13 to B1R. Chemotaxis, and phosphorylation of Erk1/2, induced by sCD13, were inhibited by B1R antagonists. In ex vivo RA synovial tissue organ cultures, a B1R antagonist reduced secretion of inflammatory cytokines. Several mouse arthritis models, including serum-transfer, antigen-induced, and local innate immune stimulation arthritis models, were attenuated in Cd13-/- and B1R-/- mice and were alleviated by B1R antagonism. These results establish a CD13/B1R axis in the pathogenesis of inflammatory arthritis and identify B1R as a compelling novel therapeutic target in RA and potentially other inflammatory diseases.
Authors
Pei-Suen Tsou, Chenyang Lu, Mikel Gurrea-Rubio, Sei Muraoka, Phillip L. Campbell, Qi Wu, Ellen N. Model, Matthew E. Lind, Sirapa Vichaikul, Megan N. Mattichak, William D. Brodie, Jonatan L. Hervoso, Sarah Ory, Camila I. Amarista, Rida Pervez, Lucas Junginger, Mustafa Ali, Gal Hodish, Morgan M. O'Mara, Jeffrey H. Ruth, Aaron M. Robida, Andrew J. Alt, Chengxin Zhang, Andrew G. Urquhart, Jeffrey N. Lawton, Kevin C. Chung, Tristan Maerz, Thomas L. Saunders, Vincent E. Groppi, David A. Fox, Mohammad A. Amin
Abstract
Dysregulation of Toll-like receptor (TLR) signaling contributes to the pathogenesis of autoimmune diseases. Here, we provide genetic evidence that tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, negatively regulates TLR2 signaling. We show that mice lacking tankyrase in myeloid cells developed severe systemic inflammation with high serum inflammatory cytokine levels. We provide mechanistic evidence that tankyrase deficiency resulted in tyrosine phosphorylation and activation of TLR2 and show that phosphorylation of tyrosine 647 within the TIR domain by SRC and SYK kinases was critical for TLR2 stabilization and signaling. Last, we show that the elevated cytokine production and inflammation observed in mice lacking tankyrase in myeloid cells were dependent on the adaptor protein 3BP2, which is required for SRC and SYK activation. These data demonstrate that tankyrase provides a checkpoint on the TLR-mediated innate immune response.
Authors
Yoshinori Matsumoto, Ioannis D. Dimitriou, Jose La Rose, Melissa Lim, Susan Camilleri, Napoleon Law, Hibret A. Adissu, Jiefei Tong, Michael F. Moran, Andrzej Chruscinski, Fang He, Yosuke Asano, Takayuki Katsuyama, Ken-ei Sada, Jun Wada, Robert Rottapel
Abstract
A disequilibrium between immunosuppressive regulatory T cells (Tregs) and inflammatory interleukin (IL)-17-producing Th17 cells is a hallmark of autoimmune diseases, including multiple sclerosis (MS). However, the molecular mechanisms underlying Treg and Th17 imbalance in central nervous system (CNS) autoimmunity remain largely unclear. Identifying factors which drive this imbalance is of high clinical interest. Here, we report a major disease-promoting role for microRNA-92a (miR-92a) in CNS autoimmunity. MiR-92a was elevated in experimental autoimmune encephalomyelitis (EAE), and its loss attenuated EAE. Mechanistically, miR-92a mediated EAE susceptibility in a T cell-intrinsic manner by restricting Treg induction and suppressive capacity, while supporting Th17 responses, by directly repressing the transcription factor, Foxo1. Although miR-92a did not directly alter Th1 differentiation, it appeared to indirectly promote Th1 cells by inhibiting Treg responses. Correspondingly, miR-92a inhibitor therapy ameliorated EAE by concomitantly boosting Treg cell responses and dampening inflammatory T cell responses. Analogous to mice, miR-92a was elevated in MS patient CD4+ T cells, and miR-92a silencing in patient T cells promoted Treg development whereas it limited Th17 differentiation. Together, our results demonstrate that miR-92a drives CNS autoimmunity by sustaining the Treg/Th17 imbalance and implicate miR-92a as a potential therapeutic target for MS.
Authors
Mai Fujiwara, Radhika Raheja, Lucien P. Garo, Amrendra K. Ajay, Ryoko Kadowaki-Saga, Sukrut H. Karandikar, Galina Gabriely, Rajesh Krishnan, Vanessa Beynon, Anu Paul, Amee Patel, Shrishti Saxena, Dan Hu, Brian C. Healy, Tanuja Chitnis, Roopali Gandhi, Howard L. Weiner, Gopal Murugaiyan
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Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)