Journal of autoimmunity最新文献

{"title":"Cellular communication network factor 3 contributes to the pathological process of rheumatoid arthritis through promoting cell senescence and osteoclastogenesis in the joint","authors":"Taiki Tokuhiro,&nbsp;Gen Matsumae,&nbsp;Tsutomu Endo,&nbsp;Yuki Ogawa,&nbsp;Takuya Ogawa,&nbsp;Chen Liyile,&nbsp;Yoshio Nishida,&nbsp;Hend Alhasan,&nbsp;Hideyuki Kobayashi,&nbsp;Taku Ebata,&nbsp;Tomohiro Shimizu,&nbsp;Daisuke Takahashi,&nbsp;Tomohiro Onodera,&nbsp;Ken Kadoya,&nbsp;M Alaa Terkawi,&nbsp;Norimasa Iwasaki","doi":"10.1016/j.jaut.2024.103334","DOIUrl":"10.1016/j.jaut.2024.103334","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is a chronic systemic and autoimmune disease that primarily affects joints and causes pain, stiffness and swelling. The affected joints exhibit severe inflammation in the synovium and bone erosion, leading to joint deformity. Aging is an important factor facilitating the development of RA, as it is associated with an increase in the number of senescent cells and the production of the autoantibodies and proinflammatory cytokines in tissues. Given that CCN3 is highly expressed in RA joints and that its level is associated with the severity of the disease, we explored its molecular function in joints and therapeutic potential in RA. An analysis of public scRNA-seq data from the RA synovium revealed that CCN3 is expressed by an inflammatory fibroblast subset. Interestingly, stimulation with CCN3 resulted in the activation of the senescence pathway in synoviocytes and osteoclast differentiation in monocytes in vitro. Consistent with these results, the administration of CCN3 into the knee joint and onto the calvarial bone resulted in increased numbers of senescent synoviocytes in the joint and osteoclasts in the bone, respectively. Furthermore, the therapeutic potential of targeting CCN3 was evaluated in an experimental RA model. Administration of the CCN3 antibody significantly suppressed inflammation and osteoclast numbers in the joints of the RA model mice. Our findings suggest that CCN3 contributes to pathological processes in RA and represents a promising therapeutic target for the treatment of RA.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103334"},"PeriodicalIF":7.9,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucocorticoids versus glucocorticoids plus cyclophosphamide in eosinophilic granulomatosis with polyangiitis with poor-prognosis factors","authors":"Boris Sorin ,&nbsp;Matthias Papo ,&nbsp;Renato A. Sinico ,&nbsp;Vítor Silvestre Teixeira ,&nbsp;Nils Venhoff ,&nbsp;Maria-Letizia Urban ,&nbsp;Michele Iudici ,&nbsp;Juliane Mahrhold ,&nbsp;Francesco Locatelli ,&nbsp;Giulia Cassone ,&nbsp;Franco Schiavon ,&nbsp;Benjamin Seeliger ,&nbsp;Thomas Neumann ,&nbsp;Claudia Feder ,&nbsp;Claus Kroegel ,&nbsp;Matthieu Groh ,&nbsp;Chiara Marvisi ,&nbsp;Maxime Samson ,&nbsp;Thomas Barba ,&nbsp;David Jayne ,&nbsp;Benjamin Terrier","doi":"10.1016/j.jaut.2024.103338","DOIUrl":"10.1016/j.jaut.2024.103338","url":null,"abstract":"<div><h3>Objectives</h3><div>Current guidelines suggest treating poor-prognosis eosinophilic granulomatosis with polyangiitis (EGPA) with a combination of glucocorticoids (GCs) plus cyclophosphamide (CYC). However, there is little data to support the need for the addition of CYC. The objective of this study was to compare GCs plus CYC to GCs alone as induction therapy in poor-prognosis EGPA.</div></div><div><h3>Methods</h3><div>We emulated a target trial using observational data from a European multicenter retrospective database. We included patients with newly diagnosed EGPA with a 1996 Five Factor Score (FFS) of at least 1, treated with GCs or GCs plus CYC between June 1985 and November 2018. Propensity score analysis was used to adjust for potential confounders. Primary outcome was relapse at 12months. Secondary outcomes included major relapse at 12months and GC-dependent asthma and/or ear nose and throat (ENT) manifestations at 24months.</div></div><div><h3>Results</h3><div>A total of 209 patients were included: 47 % were male and the mean age at diagnosis was 52 (±16 years); 26 % were treated with GCs alone and 74 % with GCs plus CYC. After adjustment, the risk of relapse (hazard ratio [HR]: 0.24, 95%CI [0.08–0.67], p = 0.007), major relapse (HR: 0.24, 95%CI [0.07–0.85], p = 0.026) and the proportion of GC-dependent asthma and/or ENT manifestations (odds ratio:0.30, 95%CI [0.14–0.66], p = 0.003) were lower in the GCs plus CYC group compared to the GCs alone group.</div></div><div><h3>Conclusion</h3><div>This target trial emulation study shows that the addition of CYC to GCs reduces the risk of vasculitis relapse and the rate of GC-dependent asthma and/or ENT manifestations in patients with poor-prognosis EGPA.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103338"},"PeriodicalIF":7.9,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trained innate immunity in response to nuclear antigens in systemic lupus erythematosus","authors":"Cansu Yanginlar ,&nbsp;Nils Rother ,&nbsp;Tomas G.J.M. Post ,&nbsp;Maaike Jacobs ,&nbsp;Inge Jonkman ,&nbsp;Montsy Brouns ,&nbsp;Sybren Rinzema ,&nbsp;Joost H.A. Martens ,&nbsp;Michiel Vermeulen ,&nbsp;Leo A.B. Joosten ,&nbsp;Mihai G. Netea ,&nbsp;Luuk B. Hilbrands ,&nbsp;Zaheeb A. Choudhry ,&nbsp;Johan van der Vlag ,&nbsp;Raphaël Duivenvoorden","doi":"10.1016/j.jaut.2024.103335","DOIUrl":"10.1016/j.jaut.2024.103335","url":null,"abstract":"<div><div>Systemic lupus erythematosus (SLE) is an autoimmune disease directed against nuclear antigens, including those derived from apoptotic microparticles (MPs) and neutrophil extracellular traps (NETs). Here we investigated whether nuclear autoantigens can induce trained immunity in SLE patients. Trained immunity is a <em>de facto</em> innate immune memory elicited by an initial stimulus that induces a more vigorous long-term inflammatory response to subsequent stimuli. Isolated monocytes were stimulated with SLE-typical nuclear antigens, neutrophil extracellular traps (NETs), and apoptotic microparticles (MPs) or plasma from SLE patients. After five days of rest, cells were restimulated with Toll-like receptor (TLR) agonists, and cytokine production was measured using ELISA. Functional, transcriptomic and epigenetic changes in monocytes from SLE patients were evaluated by <em>ex vivo</em> stimulations, flow cytometric analysis, RNA sequencing, and chromatin immunoprecipitation (ChIP) sequencing for histone 3 lysine 4 trimethylation. We found that <em>in vitro,</em> both MPs and NETs, as well as plasma from SLE patients, can induce trained immunity. Furthermore, circulating monocytes from SLE patients produce increased levels of pro-inflammatory cytokines after stimulation with TLR ligands, indicating trained immunity. This is accompanied by deregulation in histone 3 lysine 4 trimethylation and increased expression of metabolism and inflammation-related genes. Our findings demonstrate that trained immunity can develop against nuclear antigens and that trained immunity is involved in the immunological dysregulation in SLE patients.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103335"},"PeriodicalIF":7.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of the central tolerance checkpoint for autoreactive proteinase 3+ B cells in human bone marrow","authors":"Alvise Berti ,&nbsp;Michele Tomasi ,&nbsp;Isabella Pesce ,&nbsp;Enrico Lista ,&nbsp;Anna Guella ,&nbsp;Roberto Bortolotti ,&nbsp;Giuseppe Paolazzi ,&nbsp;Sophie Hillion ,&nbsp;Ulrich Specks ,&nbsp;Guido Grandi ,&nbsp;Divi Cornec","doi":"10.1016/j.jaut.2024.103330","DOIUrl":"10.1016/j.jaut.2024.103330","url":null,"abstract":"<div><div>Major target antigens of ANCA-associated vasculitis (AAV) are myeloperoxidase (MPO) and proteinase 3 (PR3). High-affinity MPO- and PR3-ANCA immunoglobulins are produced by antigen-experienced, class-switched autoreactive B cells. To prevent autoreactivity, B cells are subjected to several self-tolerance checkpoints, from the early immature stages in the bone marrow (BM), collectively called “central tolerance”, to late mature stages, collectively called “peripheral tolerance”; the latter was recently elucidated for autoreactive PR3⁺ B cells.</div><div>Here we investigated central tolerance controlling immature PR3⁺B cells in the BM before their migration into the periphery as transitional B cells. We applied an established flow cytometry-based method using labeled recombinant PR3 (rPR3) to identify the PR3⁺B cells to compare the phenotype of PR3⁺B cells in paired samples of BM mononuclear cells (BMMC) and peripheral blood mononuclear cells (PBMC) of non-vasculitis controls (No-AAV), and PBMC of patients with PR3-ANCA-associated vasculitis (PR3-AAV).</div><div>We observed that the proportion of PR3⁺B cells within BMMC was higher (median [IQR]; 1.98 % [1.77–2.75]) than within PBMC of No-AAV (0.9 % [0.63–1.44], p &lt; 0.01 by paired comparison) and similar to their proportion within PBMC of patients with PR3-AAV (1.82 % [1.66–3.21]; p &gt; 0.05). Within CD24⁺⁺CD38⁺⁺ B cells, the subset of B cell migrating from BM to the periphery, BMMC contained a greater proportion of PR3⁺B cells as compared to PBMC in No-AAV (3.35 % [1.99–4.92] versus 1.23 % [0.62–1.55], p &lt; 0.01), showing different surface markers of maturation (i.e. higher proportion of CD27⁻CD10⁺ and lower expression of CD21, IgD, IgM). Importantly, we observed a significant decline of the PR3⁺ fraction from the immature subset (IgD⁻IgM⁺; 2.80 % [1.23–4.02]) to the early transitional subset (IgD⁺IgM⁺; 1.76 % [0.96–2.68], p &lt; 0.01) in BMMC, while no significant reduction was observed between the early transitional of BMMC and the transitional compartment of PBMC in No-AAV (1.26 % [0.62–1.56], p &gt; 0.05).</div><div>In conclusion, to prevent PR3-related autoimmunity, autoreactive PR3⁺B cells pass a stringent selection in the BM, and their removal by central tolerance checkpoint activity occurs mainly between T1-like/immature to T2-like/early transitional B cells of BMMC.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103330"},"PeriodicalIF":7.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory B cells in autoimmune diseases: Insights and therapeutic potential","authors":"Qin-Yi Su ,&nbsp;Zhong-Qing Jiang ,&nbsp;Xuan-Yi Song ,&nbsp;Sheng-Xiao Zhang","doi":"10.1016/j.jaut.2024.103326","DOIUrl":"10.1016/j.jaut.2024.103326","url":null,"abstract":"<div><div>Autoimmune diseases are characterized by the body's immune system attacking its own cells, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). In recent studies, regulatory B cells (Bregs), which play a vital role in maintaining peripheral tolerance and controlling persistent autoimmune diseases (ADs), have shown great potential in treating ADs. This review synthesizes the latest advancements in targeted therapies for ADs, with a particular emphasis on the subgroups, phenotypic markers, and signal pathways associated with Bregs. Following an examination of these elements, the discussion pivots to innovative Breg-based therapeutic approaches for the management of ADs.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103326"},"PeriodicalIF":7.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synovial regulatory T cells expressing ST2 deteriorate joint inflammation through the suppression of immunoregulatory eosinophils","authors":"Koto Hattori ,&nbsp;Shigeru Tanaka ,&nbsp;Daisuke Hashiba ,&nbsp;Jun Tamura ,&nbsp;Keishi Etori ,&nbsp;Takahiro Kageyama ,&nbsp;Takashi Ito ,&nbsp;Kazuyuki Meguro ,&nbsp;Arifumi Iwata ,&nbsp;Akira Suto ,&nbsp;Kotaro Suzuki ,&nbsp;Junichi Nakamura ,&nbsp;Seiji Ohtori ,&nbsp;Steven F. Ziegler ,&nbsp;Hiroshi Nakajima","doi":"10.1016/j.jaut.2024.103333","DOIUrl":"10.1016/j.jaut.2024.103333","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic polyarthritis. It is well-established that helper T cells play crucial roles in the development and deterioration of RA. Recent studies also revealed the significant roles of regulatory T (Treg) cells in this context. Although Treg cells distributed in peripheral tissues exhibit various functions, the characteristics of synovial Treg cells remain unknown. In this study, we demonstrate that synovial Treg cells exacerbate synovial inflammation by reducing the number of immunoregulatory eosinophils through competitive consumption of IL-33. Synovial Treg cells expressed ST2 in a murine arthritis model, and surprisingly, Treg-specific ST2 knockout (ST2^ΔTreg) mice exhibited attenuated arthritis. In ST2^ΔTreg mice, an increase in immunoregulatory synovial eosinophils was observed. Additionally, immunoregulatory eosinophils were found to express ST2, and ST2-expressing Treg cells controlled the abundance of immunoregulatory eosinophils, possibly by consuming IL-33. Our results highlight that a subset of synovial Treg cells possesses the machinery to worsen arthritis by suppressing eosinophils. In the future landscape where Treg cell-based therapies are employed for autoimmune diseases, it is important to comprehend the characteristics of disease-related Treg cells. Understanding these aspects is crucial for ensuring safer treatment modalities that do not inadvertently worsen the diseases.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103333"},"PeriodicalIF":7.9,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of Advanced Combination Treatment in immune-mediated inflammatory disease: A systematic review and meta-analysis of randomized controlled trials","authors":"Virginia Solitano ,&nbsp;Yuhong Yuan ,&nbsp;Siddharth Singh ,&nbsp;Christopher Ma ,&nbsp;Olga Maria Nardone ,&nbsp;Gionata Fiorino ,&nbsp;Maria Laura Acosta Felquer ,&nbsp;Lillian Barra ,&nbsp;Maria-Antonietta D'Agostino ,&nbsp;Janet Pope ,&nbsp;Laurent Peyrin-Biroulet ,&nbsp;Silvio Danese ,&nbsp;Vipul Jairath","doi":"10.1016/j.jaut.2024.103331","DOIUrl":"10.1016/j.jaut.2024.103331","url":null,"abstract":"<div><h3>Objectives</h3><div>Advanced combination treatment (ACT), defined as a combination of at least 2 biologic agents, a biologic agent and an oral small molecule, 2 oral small molecules drug with different mechanisms of action is a proposed strategy to improve outcomes in patients with immune-mediated inflammatory disease (IMID). We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing ACT with monotherapy in patients with select IMIDs.</div></div><div><h3>Methods</h3><div>Through a systematic literature search, we identified 10 RCTs (n = 1154) comparing ACT with single agent therapy (monotherapy). The primary outcome was induction of clinical remission. Secondary outcomes were adverse events, serious adverse events, infections, and serious infections. We performed random-effects meta-analysis and used GRADE to appraise certainty of evidence.</div></div><div><h3>Results</h3><div>Eight out of 10 trials investigated an anti-TNF-α drug (e.g., etanercept, infliximab, golimumab, certolizumab) combined with another biologic (e.g anti-IL-23, anti-integrin, anti-IL-1) or an oral small molecule. There was no significant difference in the likelihood of achieving clinical remission with ACT vs. monotherapy in patients with rheumatoid arthritis (n = 7 RCTs) (RR, 1.75 [95 % CI 0.60–5.13]; moderate heterogeneity (I² = 33 %)] and systemic lupus erythematosus (n = 1) (RR, 1.20 [0.53–2.72]) (GRADE; low certainty evidence). Patients with rheumatoid arthritis in the ACT arm were more likely to experience adverse events (RR, 1.07 [1.01–1.12]) compared to monotherapy. ACT led to higher rates of induction of clinical remission in patients with IBD (n = 2 RCTs) (RR, 1.68 [1.15–2.46]) with minimal heterogeneity (I² = 15 %) (GRADE; low certainty evidence), and no differences in the likelihood of adverse events (RR 0.92 [0.80–1.05]). There were no differences in the risk of infections or serious infections in patients treated with ACT or monotherapy with rheumatological disease or IBD.</div></div><div><h3>Conclusions</h3><div>ACT did not offer clinical benefit in patients with rheumatological IMIDs and resulted in higher rate adverse events in rheumatoid arthritis. ACT may offer clinical benefit without a clear safety signal in patients with IBD, but further trials are warranted. The variability in ACT regimens across studies limits the generalizability of these findings.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103331"},"PeriodicalIF":7.9,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The emerging role of BLyS/APRIL in autoimmune diseases: Biological characteristics, functions, and therapeutic potential","authors":"Shi-Zhi Hu ,&nbsp;Zhan-Yuan Yuan ,&nbsp;Xiao-Xun Zhang ,&nbsp;Xiao-Jing Yu ,&nbsp;Hai-Yan Ni ,&nbsp;Sheng-Jia Sun ,&nbsp;Tao Xu ,&nbsp;He-Qin Zhan","doi":"10.1016/j.jaut.2024.103329","DOIUrl":"10.1016/j.jaut.2024.103329","url":null,"abstract":"<div><div>Autoimmune diseases (AIDs) are common diseases in the world. Some cases are difficult to cure and can only delay the progression of the diseases. The B lymphocyte stimulator (BLyS)/a proliferation-inducing ligand (APRIL) plays an important role in B cell homeostasis, regulation of both innate and adaptive immune responses. After binding to their receptors, BLyS/APRIL primarily affects the survival and development of marginal, transitional, and mature B cells. Of note, elevated BLyS/APRIL is seen in many AIDs, such as systemic lupus erythematosus, rheumatoid arthritis, immunoglobulin A nephropathy, etc. Moreover, there is evidence that blocking these two cytokines can control the number of serum autoantibodies, promote the depletion of B lymphocytes, inhibit the activation of T cells and dendritic lymphocytes, and reduce inflammatory stress. Currently, some clinical studies are underway targeting BLyS/APRIL inhibitors for the treatment of AIDs. However, due to the scattered knowledge on the relationship between BLyS/APRIL and AIDs, it is necessary to sort out the existing data. Therefore, in this review, we describe the basic biological characteristics and functions of BLyS/APRIL in AIDs, summarize the potential clinical applications of related inhibitors, especially monoclonal antibodies and recombinant fusion proteins targeting BLyS/APRIL in AIDs, and also outline promising research directions.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103329"},"PeriodicalIF":7.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142587400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding the landscape of systemic sclerosis-related autoantibodies through RNA immunoprecipitation coupled with massive parallel sequencing","authors":"Janire Perurena-Prieto ,&nbsp;María Teresa Sanz-Martínez ,&nbsp;Laura Viñas-Giménez ,&nbsp;Claudia Codina-Clavaguera ,&nbsp;Laura Triginer ,&nbsp;Fernando Gordillo-González ,&nbsp;Eduardo Andrés-León ,&nbsp;Laura Batlle-Masó ,&nbsp;Javier Martin ,&nbsp;Albert Selva-O’Callaghan ,&nbsp;Ricardo Pujol ,&nbsp;Neil J. McHugh ,&nbsp;Sarah L. Tansley ,&nbsp;Roger Colobran ,&nbsp;Alfredo Guillen-Del-Castillo ,&nbsp;Carmen Pilar Simeón-Aznar","doi":"10.1016/j.jaut.2024.103328","DOIUrl":"10.1016/j.jaut.2024.103328","url":null,"abstract":"<div><h3>Objectives</h3><div>Systemic sclerosis (SSc)-related autoantibodies are widely used diagnostic and prognostic biomarkers. This study aimed to develop a new assay for detecting anti-ribonucleoprotein autoantibodies in SSc based on RNA immunoprecipitation (RNA IP) coupled with massive parallel sequencing.</div></div><div><h3>Methods</h3><div>Serum samples and clinical data were collected from 307 SSc patients. Among these, 57 samples underwent analysis using a new protocol that combines RNA IP with massive parallel sequencing (RIP-Seq). Filtering strategies and statistical outlier detection methods were applied to select RNA molecules that could represent novel ribonucleoprotein autoantigens associated with SSc.</div></div><div><h3>Results</h3><div>Among the 30,966 different RNA molecules identified by RIP-Seq in 57 SSc patients, 197 were ultimately selected. These included all RNA molecules previously identified by RNA IP, which were found to exhibit high counts almost exclusively in samples positive for the autoantibodies associated to the corresponding RNA molecule, indicating high sensitivity and specificity of the RIP-Seq technique. C/D box snoRNAs were the most abundant RNA type identified. The immunoprecipitation patterns of the detected C/D box snoRNAs varied among patients and could be associated with different clinical phenotypes. In addition, other ribonucleoproteins were identified, which could be potential targets for previously undescribed SSc-related autoantibodies. These include H/ACA box snoRNPs, vault complexes, mitochondrial tRNA synthetases, and 7SK snRNP.</div></div><div><h3>Conclusion</h3><div>A novel RIP-Seq assay has been developed to detect autoantibodies targeting ribonucleoprotein complexes in SSc patients. This method successfully identified RNA molecules associated with ribonucleoproteins known to be targeted by SSc-related autoantibodies, validating both the assay and the analysis strategy. Additionally, this approach uncovered RNA molecules associated with ribonucleoproteins that were not previously identified as targets of SSc patients’ sera, suggesting potential new autoantibody candidates in this disease.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103328"},"PeriodicalIF":7.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142578928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a novel PDC-E2 epitope in primary biliary cholangitis: Application for engineered Treg therapy","authors":"Ritika Tewari ,&nbsp;Soo Jung Yang ,&nbsp;Ethan D. McClain ,&nbsp;Alex Hu ,&nbsp;Emma Mortensen ,&nbsp;Aleah DeSchmidt ,&nbsp;Janice Chen ,&nbsp;Aravind Kancharla ,&nbsp;Akhilesh K. Singh ,&nbsp;Eddie A. James ,&nbsp;Blaire E. Burman ,&nbsp;Asma Siddique ,&nbsp;David J. Rawlings ,&nbsp;Chandra Patel ,&nbsp;Karen Cerosaletti ,&nbsp;Jane H. Buckner","doi":"10.1016/j.jaut.2024.103327","DOIUrl":"10.1016/j.jaut.2024.103327","url":null,"abstract":"<div><div>Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease, characterized by progressive destruction of small intrahepatic bile ducts and portal inflammation. Treatment options are limited, with reliance on liver transplantation in advanced cases. The adaptive immune response is implicated in disease pathogenesis by the presence of anti-mitochondrial antibodies targeting the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2) in 90–95 % of patients and T cells infiltrating the portal tracts. Here, we examined T cell responses to peptides derived from PDC-E2, with a focus on CD4 T cell responses restricted to HLA Class II DRB4∗01:01, an allele found in 62 % of PBC patients, to uncover PDC-E2 epitopes that could be used for engineered regulatory T cell (Treg; EngTreg) therapy. Using an activation-induced marker assay and single cell RNA-sequencing, we found clonal expansion of CD4 T cells reactive to PDC-E2 epitopes among both T conventional (Tconv) and Tregs. Those T cell receptor (TCR) repertoires were non-overlapping and private and included TCRs specific for a novel PDC-E2 epitope restricted to DRB4∗01:01. CD4 Tconv cells reactive to the PDC-E2 novel epitope showed phenotypic heterogeneity skewed towards T follicular helper cells. Using a TCR specific for this novel PDC-E2 epitope, we created an EngTreg that suppressed PDC-E2-specific polyclonal CD4 Tconv cells from PBC patients. This study advances knowledge of PDC-E2-specific T cell responses and introduces a novel PDC-E2 epitope recognized by both Tconv and Tregs. Generation of EngTreg specific for this epitope provides therapeutic potential for PBC.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103327"},"PeriodicalIF":7.9,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}