Pub Date : 2024-11-05DOI: 10.1016/j.jaut.2024.103329
Shi-Zhi Hu , Zhan-Yuan Yuan , Xiao-Xun Zhang , Xiao-Jing Yu , Hai-Yan Ni , Sheng-Jia Sun , Tao Xu , He-Qin Zhan
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.
自身免疫性疾病（AID）是世界上常见的疾病。有些病例很难治愈，只能延缓疾病的发展。B 淋巴细胞刺激素（BLyS）/增殖诱导配体（APRIL）在 B 细胞平衡、调节先天性和适应性免疫反应中发挥着重要作用。与受体结合后，BLyS/APRIL 主要影响边缘、过渡和成熟 B 细胞的存活和发育。值得注意的是，BLyS/APRIL 的升高可见于许多 AID，如系统性红斑狼疮、类风湿性关节炎、免疫球蛋白 A 肾病等。此外，有证据表明，阻断这两种细胞因子可以控制血清自身抗体的数量，促进 B 淋巴细胞的消耗，抑制 T 细胞和树突状淋巴细胞的活化，减轻炎症应激反应。目前，一些针对 BLyS/APRIL 抑制剂治疗艾滋病的临床研究正在进行中。然而，由于对 BLyS/APRIL 与艾滋病之间关系的了解比较零散，因此有必要对现有数据进行梳理。因此，在这篇综述中，我们描述了BLyS/APRIL在AIDs中的基本生物学特性和功能，总结了相关抑制剂，尤其是靶向BLyS/APRIL的单克隆抗体和重组融合蛋白在AIDs中的潜在临床应用，并概述了有前景的研究方向。
{"title":"The emerging role of BLyS/APRIL in autoimmune diseases: Biological characteristics, functions, and therapeutic potential","authors":"Shi-Zhi Hu , Zhan-Yuan Yuan , Xiao-Xun Zhang , Xiao-Jing Yu , Hai-Yan Ni , Sheng-Jia Sun , Tao Xu , 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}
Pub Date : 2024-11-04DOI: 10.1016/j.jaut.2024.103328
Janire Perurena-Prieto , María Teresa Sanz-Martínez , Laura Viñas-Giménez , Claudia Codina-Clavaguera , Laura Triginer , Fernando Gordillo-González , Eduardo Andrés-León , Laura Batlle-Masó , Javier Martin , Albert Selva-O’Callaghan , Ricardo Pujol , Neil J. McHugh , Sarah L. Tansley , Roger Colobran , Alfredo Guillen-Del-Castillo , Carmen Pilar Simeón-Aznar
Objectives
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.
Methods
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.
Results
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.
Conclusion
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.
{"title":"Expanding the landscape of systemic sclerosis-related autoantibodies through RNA immunoprecipitation coupled with massive parallel sequencing","authors":"Janire Perurena-Prieto , María Teresa Sanz-Martínez , Laura Viñas-Giménez , Claudia Codina-Clavaguera , Laura Triginer , Fernando Gordillo-González , Eduardo Andrés-León , Laura Batlle-Masó , Javier Martin , Albert Selva-O’Callaghan , Ricardo Pujol , Neil J. McHugh , Sarah L. Tansley , Roger Colobran , Alfredo Guillen-Del-Castillo , 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}
Pub Date : 2024-10-30DOI: 10.1016/j.jaut.2024.103327
Ritika Tewari , Soo Jung Yang , Ethan D. McClain , Alex Hu , Emma Mortensen , Aleah DeSchmidt , Janice Chen , Aravind Kancharla , Akhilesh K. Singh , Eddie A. James , Blaire E. Burman , Asma Siddique , David J. Rawlings , Chandra Patel , Karen Cerosaletti , Jane H. Buckner
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.
{"title":"Identification of a novel PDC-E2 epitope in primary biliary cholangitis: Application for engineered Treg therapy","authors":"Ritika Tewari , Soo Jung Yang , Ethan D. McClain , Alex Hu , Emma Mortensen , Aleah DeSchmidt , Janice Chen , Aravind Kancharla , Akhilesh K. Singh , Eddie A. James , Blaire E. Burman , Asma Siddique , David J. Rawlings , Chandra Patel , Karen Cerosaletti , 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}
Pub Date : 2024-10-15DOI: 10.1016/j.jaut.2024.103325
Tobias Kälin , Katia Passarin , Magdalena Filipowic-Sinnreich , David Semela , Tanja Seifert , Federica Sallusto , Diego Vergani , Andreas Cerny , Giorgina Mieli-Vergani , Benedetta Terziroli Beretta-Piccoli , The Swiss Autoimmune Hepatitis Cohort Study, The Swiss Primary Biliary Cholangitis Cohort Study, The Swiss Primary Sclerosing Cholangitis Study
Introduction and aims
mRNA vaccines against Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) infection have been associated with immune-related adverse reactions. We aimed at investigating whether SARS-CoV-2 vaccines may worsen autoimmune reactions in patients with autoimmune liver diseases.
Methods
We centrally tested a large panel of liver- and non-liver-related autoantibodies in patients with primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and in healthcare workers (HW) before and after SARS-CoV-2 mRNA vaccines.
Results
49 PBC, 35 AIH, 9 PSC and 38 HW were included. The proportion of subjects with at least one autoantibody positivization after vaccination was 11 % for HW, 37 % for AIH, 35 % for PBC and 56 % for PSC patients, patients having a significantly higher frequency of positivization as compared to HW. The proportion of seropositive subjects before vaccination who had at least one autoantibody negativization was 25 % for HW, 57 % for AIH, 40 % for PBC and 50 % for PSC, AIH patients having a significantly higher frequency of negativization as compared to HW. In the AIH group, the number of autoantibody negativizations was higher than the number of positivizations. The BNT162b2 vaccine was associated with a higher risk of developing new autoantibodies as compared to the mRNA-1273 vaccine. No new-onset autoimmune disease was observed after one year. One AIH patient had a relapse after vaccination.
Conclusion
mRNA SARS-CoV-2 vaccines do not induce short-term worsening of autoimmunity in patients with autoimmune liver diseases.
{"title":"SARS-CoV-2 mRNA vaccines do not worsen autoimmunity in patients with autoimmune liver diseases","authors":"Tobias Kälin , Katia Passarin , Magdalena Filipowic-Sinnreich , David Semela , Tanja Seifert , Federica Sallusto , Diego Vergani , Andreas Cerny , Giorgina Mieli-Vergani , Benedetta Terziroli Beretta-Piccoli , The Swiss Autoimmune Hepatitis Cohort Study, The Swiss Primary Biliary Cholangitis Cohort Study, The Swiss Primary Sclerosing Cholangitis Study","doi":"10.1016/j.jaut.2024.103325","DOIUrl":"10.1016/j.jaut.2024.103325","url":null,"abstract":"<div><h3>Introduction and aims</h3><div>mRNA vaccines against Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) infection have been associated with immune-related adverse reactions. We aimed at investigating whether SARS-CoV-2 vaccines may worsen autoimmune reactions in patients with autoimmune liver diseases.</div></div><div><h3>Methods</h3><div>We centrally tested a large panel of liver- and non-liver-related autoantibodies in patients with primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and in healthcare workers (HW) before and after SARS-CoV-2 mRNA vaccines.</div></div><div><h3>Results</h3><div>49 PBC, 35 AIH, 9 PSC and 38 HW were included. The proportion of subjects with at least one autoantibody positivization after vaccination was 11 % for HW, 37 % for AIH, 35 % for PBC and 56 % for PSC patients, patients having a significantly higher frequency of positivization as compared to HW. The proportion of seropositive subjects before vaccination who had at least one autoantibody negativization was 25 % for HW, 57 % for AIH, 40 % for PBC and 50 % for PSC, AIH patients having a significantly higher frequency of negativization as compared to HW. In the AIH group, the number of autoantibody negativizations was higher than the number of positivizations. The BNT162b2 vaccine was associated with a higher risk of developing new autoantibodies as compared to the mRNA-1273 vaccine. No new-onset autoimmune disease was observed after one year. One AIH patient had a relapse after vaccination.</div></div><div><h3>Conclusion</h3><div>mRNA SARS-CoV-2 vaccines do not induce short-term worsening of autoimmunity in patients with autoimmune liver diseases.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103325"},"PeriodicalIF":7.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142434314","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}
Pub Date : 2024-10-11DOI: 10.1016/j.jaut.2024.103319
Norifumi Iijima , Masaya Yamaguchi , Tomoya Hayashi , Yuxiang Rui , Yuta Ohira , Yoichi Miyamoto , Masaaki Niino , Tatsusada Okuno , Osamu Suzuki , Masahiro Oka , Ken J. Ishii
Incomplete Freund's adjuvant (IFA) has long been used to trigger autoimmune diseases in animal models, such as experimental autoimmune encephalitis and collagen-induced arthritis. However, the molecular mechanisms that control CD4 T cell effector functions and lead to the development of autoimmune diseases are not well understood. A self-antigen and heat-killed Mycobacterium tuberculosis emulsified in IFA augmented the activation of CD4 T cells, leading to the differentiation of pathogenic CD4 T cells in the draining lymph nodes. In contrast, IFA emulsification did not elicit Foxp3+ regulatory T cell expansion. We found that pathogenic Th1 cells expressed miR-147-3p, which targets multiple genes to affect T cell function. Finally, miR-147-3p expressed in CXCR6+SLAMF6– Th1 cells was required for the onset of neurological symptoms through the control of CXCR3 expression. Our findings demonstrate that miR-147-3p expressed in pathogenic CD4 T cells regulates the migratory potential in peripheral tissues and impacts the development of autoimmune diseases.
长期以来，不完全弗罗因德佐剂（IFA）一直被用于在动物模型中诱发自身免疫性疾病，如实验性自身免疫性脑炎和胶原诱导性关节炎。然而，控制 CD4 T 细胞效应器功能并导致自身免疫性疾病发生的分子机制尚不十分清楚。在 IFA 中乳化的自身抗原和热杀死的结核分枝杆菌可增强 CD4 T 细胞的活化，导致引流淋巴结中致病性 CD4 T 细胞的分化。与此相反，IFA乳化并不会引起Foxp3+调节性T细胞的扩增。我们发现致病性 Th1 细胞表达了 miR-147-3p，它靶向多个基因，影响 T 细胞功能。最后，CXCR6+SLAMF6- Th1 细胞中表达的 miR-147-3p 通过控制 CXCR3 的表达，是神经症状发病的必要条件。我们的研究结果表明，致病性 CD4 T 细胞中表达的 miR-147-3p 可调节外周组织的迁移潜能，并影响自身免疫性疾病的发展。
{"title":"miR-147-3p in pathogenic CD4 T cells controls chemokine receptor expression for the development of experimental autoimmune diseases","authors":"Norifumi Iijima , Masaya Yamaguchi , Tomoya Hayashi , Yuxiang Rui , Yuta Ohira , Yoichi Miyamoto , Masaaki Niino , Tatsusada Okuno , Osamu Suzuki , Masahiro Oka , Ken J. Ishii","doi":"10.1016/j.jaut.2024.103319","DOIUrl":"10.1016/j.jaut.2024.103319","url":null,"abstract":"<div><div>Incomplete Freund's adjuvant (IFA) has long been used to trigger autoimmune diseases in animal models, such as experimental autoimmune encephalitis and collagen-induced arthritis. However, the molecular mechanisms that control CD4 T cell effector functions and lead to the development of autoimmune diseases are not well understood. A self-antigen and heat-killed <em>Mycobacterium tuberculosis</em> emulsified in IFA augmented the activation of CD4 T cells, leading to the differentiation of pathogenic CD4 T cells in the draining lymph nodes. In contrast, IFA emulsification did not elicit Foxp3<sup>+</sup> regulatory T cell expansion. We found that pathogenic Th1 cells expressed miR-147-3p, which targets multiple genes to affect T cell function. Finally, miR-147-3p expressed in CXCR6<sup>+</sup>SLAMF6<sup>–</sup> Th1 cells was required for the onset of neurological symptoms through the control of CXCR3 expression. Our findings demonstrate that miR-147-3p expressed in pathogenic CD4 T cells regulates the migratory potential in peripheral tissues and impacts the development of autoimmune diseases.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103319"},"PeriodicalIF":7.9,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142420624","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}
Pub Date : 2024-10-01DOI: 10.1016/j.jaut.2024.103318
Signe Hässler , Roberta Lorenzon , Marie Binvignat , Claire Ribet , Alexandra Roux , Catherine Johanet , Chloé Amouyal , Serge Amselem , Francis Berenbaum , Olivier Benveniste , Patrice Cacoub , Gilles Grateau , Agnès Hartemann , David Saadoun , Joe-Elie Salem , Jérémie Sellam , Philippe Seksik , Eric Vicaut , Encarnita Mariotti-Ferrandiz , Michelle Rosenzwajg , David Klatzmann
Background
Autoimmune and inflammatory diseases (AIDs) are a heterogeneous group of disorders with diverse etiopathogenic mechanisms. This study explores the potential utility of family history, together with present and past comorbidities, in identifying distinct etiopathogenic subgroups. This approach may facilitate more accurate diagnosis, prognosis and personalized therapy.
Methods
We performed a multiple correspondence analysis on patients' comorbidities, followed by hierarchical principal component clustering of clinical data from 48 healthy volunteers and 327 patients with at least one of 19 selected AIDs included in the TRANSIMMUNOM cross-sectional study.
Results
We identified three distinct clusters characterized by: 1) the absence of comorbidities, 2) polyautoimmunity, and 3) polyinflammation. These clusters were further distinguished by specific comorbidities and biological parameters. Autoantibodies, allergies, and viral infections characterized the polyautoimmunity cluster, while older age, BMI, depression, cancer, hypertension, periodontal disease, and dyslipidemia characterized the polyinflammation cluster. Rheumatoid arthritis patients were distributed across all three clusters. They had higher DAS28 and prevalence of extra-articular manifestations when belonging to the polyinflammation and polyautoimmunity clusters, and also lower ACPA and RF seropositivity and higher pain scores within the polyinflammation cluster. We developed a model allowing to classify AID patients into comorbidity clusters.
Conclusions
In this study, we have uncovered three distinct comorbidity profiles among AID patients. These profiles suggest the presence of distinct etiopathogenic mechanisms underlying these subgroups. Validation, longitudinal stability assessment, and exploration of their impact on therapy efficacy are needed for a comprehensive understanding of their potential role in personalized medicine.
{"title":"Clinical correlates of lifetime and current comorbidity patterns in autoimmune and inflammatory diseases","authors":"Signe Hässler , Roberta Lorenzon , Marie Binvignat , Claire Ribet , Alexandra Roux , Catherine Johanet , Chloé Amouyal , Serge Amselem , Francis Berenbaum , Olivier Benveniste , Patrice Cacoub , Gilles Grateau , Agnès Hartemann , David Saadoun , Joe-Elie Salem , Jérémie Sellam , Philippe Seksik , Eric Vicaut , Encarnita Mariotti-Ferrandiz , Michelle Rosenzwajg , David Klatzmann","doi":"10.1016/j.jaut.2024.103318","DOIUrl":"10.1016/j.jaut.2024.103318","url":null,"abstract":"<div><h3>Background</h3><div>Autoimmune and inflammatory diseases (AIDs) are a heterogeneous group of disorders with diverse etiopathogenic mechanisms. This study explores the potential utility of family history, together with present and past comorbidities, in identifying distinct etiopathogenic subgroups. This approach may facilitate more accurate diagnosis, prognosis and personalized therapy.</div></div><div><h3>Methods</h3><div>We performed a multiple correspondence analysis on patients' comorbidities, followed by hierarchical principal component clustering of clinical data from 48 healthy volunteers and 327 patients with at least one of 19 selected AIDs included in the TRANSIMMUNOM cross-sectional study.</div></div><div><h3>Results</h3><div>We identified three distinct clusters characterized by: 1) the absence of comorbidities, 2) polyautoimmunity, and 3) polyinflammation. These clusters were further distinguished by specific comorbidities and biological parameters. Autoantibodies, allergies, and viral infections characterized the polyautoimmunity cluster, while older age, BMI, depression, cancer, hypertension, periodontal disease, and dyslipidemia characterized the polyinflammation cluster. Rheumatoid arthritis patients were distributed across all three clusters. They had higher DAS28 and prevalence of extra-articular manifestations when belonging to the polyinflammation and polyautoimmunity clusters, and also lower ACPA and RF seropositivity and higher pain scores within the polyinflammation cluster. We developed a model allowing to classify AID patients into comorbidity clusters.</div></div><div><h3>Conclusions</h3><div>In this study, we have uncovered three distinct comorbidity profiles among AID patients. These profiles suggest the presence of distinct etiopathogenic mechanisms underlying these subgroups. Validation, longitudinal stability assessment, and exploration of their impact on therapy efficacy are needed for a comprehensive understanding of their potential role in personalized medicine.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103318"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365372","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}
Pub Date : 2024-09-28DOI: 10.1016/j.jaut.2024.103322
Yan Hua , Panpan Jiang , Chunyang Dai , Ming Li
Autoantibodies are immunoglobulin proteins produced by autoreactive B cells responding to self-antigens. Extracellular vesicles (EVs) are membranous structures released by almost all types of cells and extensively distributed in various biological fluids. Studies have indicated that EVs loaded with self-antigens not only play important roles in antigen presentation and autoantibody production but can also form functional immune complexes with autoantibodies (termed EV autoantibodies). While numerous papers have summarized the production and function of pathogenic autoantibodies in diseases, especially autoimmune diseases, reviews on EV autoantibodies are rare. In this review, we outline the existing knowledge about EVs, autoantibodies, and EV antigens, highlighting the formation of EV autoantibodies and their functions in autoimmune diseases and cancers. In conclusion, EV autoantibodies may be involved in the occurrence of disease(s) and also serve as potential non-invasive markers that could help in the diagnosis and/or prognosis of disease. Additional studies designed to define in more detail the molecular characteristics of EV autoantibodies and their contribution to disease are recommended.
自身抗体是由对自身抗原产生反应的自身反应性 B 细胞产生的免疫球蛋白。细胞外小泡（EVs）是几乎所有类型细胞释放的膜结构，广泛分布于各种生物液体中。研究表明，含有自身抗原的EV不仅在抗原递呈和自身抗体产生中发挥重要作用，还能与自身抗体形成功能性免疫复合物（称为EV自身抗体）。尽管有许多论文总结了致病性自身抗体在疾病（尤其是自身免疫性疾病）中的产生和功能，但有关EV自身抗体的综述却很少见。在这篇综述中，我们概述了有关EV、自身抗体和EV抗原的现有知识，重点介绍了EV自身抗体的形成及其在自身免疫性疾病和癌症中的功能。总之，EV自身抗体可能与疾病的发生有关，同时也是潜在的非侵入性标志物，有助于疾病的诊断和/或预后。我们建议开展更多研究，以更详细地确定EV自身抗体的分子特征及其对疾病的影响。
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Pub Date : 2024-09-28DOI: 10.1016/j.jaut.2024.103320
Sam Neppelenbroek , Nienke J. Blomberg , Arieke S.B. Kampstra , Joost G.K. van der Hem , Tom W.J. Huizinga , René E.M. Toes , Hans U. Scherer
Background
Autoimmune diseases (AIDs) are frequently hallmarked by the presence of autoreactive B cell responses which are involved in disease pathogenesis. However, the dynamics of such responses and their relation to clinical disease activity in humans is poorly understood. Rheumatoid arthritis (RA), a prototypic chronic AID, is hallmarked by B cell responses directed against citrullinated proteins.
Objective
To determine the relation between the activity of the anti-citrullinated protein antibody (ACPA) B cell response and clinical disease activity in ACPA+ patients with RA.
Methods
Expression of B cell activation markers by ACPA+, tetanus toxoid (TT)+ and ACPA− memory B cells (MBCs) from peripheral blood of ACPA+ RA patients receiving different treatments was analyzed by flow cytometry. Results were correlated to clinical disease activity.
Results
Compared to TT+ and ACPA− MBCs, ACPA+ MBCs displayed a highly activated phenotype as evidenced by increased expression of Ki-67, CD86, CD80, CD19 and CD20 and reduced expression of CD32. The activated phenotype of ACPA+ MBCs did not associate with clinical disease activity in a cross-sectional analysis of RA patients treated with various therapeutic agents. Also, in a longitudinal analysis of patients treated with Janus kinase (JAK) inhibitors, ACPA+ MBCs retained their activated phenotype despite effective control of inflammation and clinical disease.
Conclusion
ACPA+ MBCs remain active despite clinical disease control in patients with RA across a range of interventions. This persistent activity indicates the absence of immunological remission and might explain why ACPA+ patients rarely reach sustained drug-free remission and frequently flare upon drug tapering.
背景：自身免疫性疾病（AIDs）通常以自身反应性 B 细胞反应为特征，这种反应参与了疾病的发病机制。然而，人们对这种反应的动态及其与人类临床疾病活动的关系知之甚少。类风湿性关节炎（RA）是一种典型的慢性 AID，其特征是针对瓜氨酸蛋白的 B 细胞反应：目的：确定抗瓜氨酸蛋白抗体（ACPA）B 细胞反应的活性与 ACPA+ RA 患者临床疾病活动性之间的关系：方法：通过流式细胞术分析接受不同治疗的ACPA+ RA患者外周血中ACPA+、破伤风类毒素（TT）+和ACPA-记忆B细胞（MBC）的B细胞活化标志物表达。结果与临床疾病活动性相关：结果：与TT+和ACPA- MBC相比，ACPA+ MBC表现出高度活化的表型，表现为Ki-67、CD86、CD80、CD19和CD20的表达增加，CD32的表达减少。在对接受各种治疗药物的 RA 患者进行的横断面分析中，ACPA+ MBC 的活化表型与临床疾病活动无关。此外，在对接受Janus激酶（JAK）抑制剂治疗的患者进行的纵向分析中，尽管炎症和临床疾病得到了有效控制，但ACPA+ MBC仍保留了其活化表型：结论：尽管RA患者的临床疾病得到了控制，但ACPA+ MBC在一系列干预措施后仍保持活性。这种持续的活性表明缺乏免疫学缓解，这或许可以解释为什么ACPA+患者很少能达到持续的无药缓解，而且在减药后经常复发。
{"title":"Autoreactive B cells remain active despite clinical disease control in rheumatoid arthritis","authors":"Sam Neppelenbroek , Nienke J. Blomberg , Arieke S.B. Kampstra , Joost G.K. van der Hem , Tom W.J. Huizinga , René E.M. Toes , Hans U. Scherer","doi":"10.1016/j.jaut.2024.103320","DOIUrl":"10.1016/j.jaut.2024.103320","url":null,"abstract":"<div><h3>Background</h3><div>Autoimmune diseases (AIDs) are frequently hallmarked by the presence of autoreactive B cell responses which are involved in disease pathogenesis. However, the dynamics of such responses and their relation to clinical disease activity in humans is poorly understood. Rheumatoid arthritis (RA), a prototypic chronic AID, is hallmarked by B cell responses directed against citrullinated proteins.</div></div><div><h3>Objective</h3><div>To determine the relation between the activity of the anti-citrullinated protein antibody (ACPA) B cell response and clinical disease activity in ACPA<sup>+</sup> patients with RA.</div></div><div><h3>Methods</h3><div>Expression of B cell activation markers by ACPA<sup>+</sup>, tetanus toxoid (TT)<sup>+</sup> and ACPA<sup>−</sup> memory B cells (MBCs) from peripheral blood of ACPA<sup>+</sup> RA patients receiving different treatments was analyzed by flow cytometry. Results were correlated to clinical disease activity.</div></div><div><h3>Results</h3><div>Compared to TT<sup>+</sup> and ACPA<sup>−</sup> MBCs, ACPA<sup>+</sup> MBCs displayed a highly activated phenotype as evidenced by increased expression of Ki-67, CD86, CD80, CD19 and CD20 and reduced expression of CD32. The activated phenotype of ACPA<sup>+</sup> MBCs did not associate with clinical disease activity in a cross-sectional analysis of RA patients treated with various therapeutic agents. Also, in a longitudinal analysis of patients treated with Janus kinase (JAK) inhibitors, ACPA<sup>+</sup> MBCs retained their activated phenotype despite effective control of inflammation and clinical disease.</div></div><div><h3>Conclusion</h3><div>ACPA<sup>+</sup> MBCs remain active despite clinical disease control in patients with RA across a range of interventions. This persistent activity indicates the absence of immunological remission and might explain why ACPA<sup>+</sup> patients rarely reach sustained drug-free remission and frequently flare upon drug tapering.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103320"},"PeriodicalIF":7.9,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142347377","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}
Adult-onset immune-mediated inflammatory disease (IMID) increases the risk of several cancers. However, data on pediatric-onset IMID (pIMID) remains scarce. We estimated the long-term cancer risk in pIMID and the association between medical treatment and specific cancers.
Methods
We used the nationwide Danish health registers to identify pIMID patients diagnosed from Jan 1, 1980 to Dec 31, 2018. Patients were matched with ten reference individuals based on age, sex, and residence. The primary exposure was pIMID, including autoimmune hepatitis, primary sclerosing cholangitis, Crohn's disease, ulcerative colitis, juvenile idiopathic arthritis, systemic lupus erythematosus, vasculitis, and connective tissue disease. Secondary exposures were immunomodulators and tumor necrosis factor-α antagonists (anti-TNFα). The primary outcome was cancer. Estimates are presented as hazard ratios adjusted for family income at diagnosis (AHR).
Results
We included 12,664 pIMID patients and 109,274 reference individuals. Median follow-up time was 10.6 (interquartile range: 5.4–17.7) years for patients and 10.2 (interquartile range: 5.2–17.3) years for reference individuals. Patients with pIMID had a twofold higher cancer risk (AHR 2.2 [95 % confidence interval (CI): 1.8–2.6]) compared with reference individuals. Thiopurine treatment was associated with a higher risk of lymphoma (AHR 6.1 [95%CI: 2.2–16.8]) and skin cancer (AHR 6.1 [95%CI: 2.4–15.4]). Anti-TNFα treatment was associated with a higher risk of lymphoma (AHR 4.9 [95%CI: 1.1–22.6]).
Conclusions
We found an increased cancer risk in patients with pIMID followed into adulthood. Additionally, thiopurines and anti-TNFα were associated with increased lymphoma and skin cancer risks. This highlights the importance of individualized immunotherapy and cancer surveillance.
{"title":"The risk of cancer in pediatric-onset immune-mediated inflammatory diseases – A nationwide study","authors":"Andrea Ehrström , Sabine Jansson , Marianne Hørby Jørgensen , Vibeke Wewer , Mikkel Malham","doi":"10.1016/j.jaut.2024.103321","DOIUrl":"10.1016/j.jaut.2024.103321","url":null,"abstract":"<div><h3>Background and objectives</h3><div>Adult-onset immune-mediated inflammatory disease (IMID) increases the risk of several cancers. However, data on pediatric-onset IMID (pIMID) remains scarce. We estimated the long-term cancer risk in pIMID and the association between medical treatment and specific cancers.</div></div><div><h3>Methods</h3><div>We used the nationwide Danish health registers to identify pIMID patients diagnosed from Jan 1, 1980 to Dec 31, 2018. Patients were matched with ten reference individuals based on age, sex, and residence. The primary exposure was pIMID, including autoimmune hepatitis, primary sclerosing cholangitis, Crohn's disease, ulcerative colitis, juvenile idiopathic arthritis, systemic lupus erythematosus, vasculitis, and connective tissue disease. Secondary exposures were immunomodulators and tumor necrosis factor-α antagonists (anti-TNFα). The primary outcome was cancer. Estimates are presented as hazard ratios adjusted for family income at diagnosis (AHR).</div></div><div><h3>Results</h3><div>We included 12,664 pIMID patients and 109,274 reference individuals. Median follow-up time was 10.6 (interquartile range: 5.4–17.7) years for patients and 10.2 (interquartile range: 5.2–17.3) years for reference individuals. Patients with pIMID had a twofold higher cancer risk (AHR 2.2 [95 % confidence interval (CI): 1.8–2.6]) compared with reference individuals. Thiopurine treatment was associated with a higher risk of lymphoma (AHR 6.1 [95%CI: 2.2–16.8]) and skin cancer (AHR 6.1 [95%CI: 2.4–15.4]). Anti-TNFα treatment was associated with a higher risk of lymphoma (AHR 4.9 [95%CI: 1.1–22.6]).</div></div><div><h3>Conclusions</h3><div>We found an increased cancer risk in patients with pIMID followed into adulthood. Additionally, thiopurines and anti-TNFα were associated with increased lymphoma and skin cancer risks. This highlights the importance of individualized immunotherapy and cancer surveillance.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103321"},"PeriodicalIF":7.9,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142322643","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}
Pub Date : 2024-09-19DOI: 10.1016/j.jaut.2024.103317
Miri Blank , Daphna Israeli , Yehuda Shoenfeld
Diverse forms of physical activities contribute to improvement of autoimmune diseases and may prevent disease burst. T regulatory cells (Tregs) maintain tolerance in autoimmune condition. Physical activity is one of the key factors causing enhancement of Tregs number and functions, keeping homeostatic state by its secrotome. Muscles secrete myokines like IL-6, PGC1α (PPARγ coactivator-1 α), myostatin, transforming growth factor β (TGF-β) superfamily), IL-15, brain derived neurotrophic factor (BDNF) and others. The current concept points to the role of exercise in induction of highly functional and stable muscle Treg phenotype. The residing-Tregs require IL6Rα signaling to control muscle function and regeneration. Skeletal muscle Tregs IL-6Rα is a key target for muscle-Tregs cross-talk. Thus, interplay between the Tregs-skeletal muscle, following exercise, contribute to the balance of immune tolerance and autoimmunity. The cargo delivery, in the local environment and periphery, is performed by extracellular vesicles (EVs) secreted by muscle and Tregs, which deliver proteins, lipids and miRNA during persistent exercise protocols. It has been suggested that this ensemble induce protection against autoimmune diseases.
{"title":"Exercise, autoimmune diseases and T-regulatory cells","authors":"Miri Blank , Daphna Israeli , Yehuda Shoenfeld","doi":"10.1016/j.jaut.2024.103317","DOIUrl":"10.1016/j.jaut.2024.103317","url":null,"abstract":"<div><p>Diverse forms of physical activities contribute to improvement of autoimmune diseases and may prevent disease burst. T regulatory cells (Tregs) maintain tolerance in autoimmune condition. Physical activity is one of the key factors causing enhancement of Tregs number and functions, keeping homeostatic state by its secrotome. Muscles secrete myokines like IL-6, PGC1α (PPARγ coactivator-1 α), myostatin, transforming growth factor β (TGF-β) superfamily), IL-15, brain derived neurotrophic factor (BDNF) and others. The current concept points to the role of exercise in induction of highly functional and stable muscle Treg phenotype. The residing-Tregs require IL6Rα signaling to control muscle function and regeneration. Skeletal muscle Tregs IL-6Rα is a key target for muscle-Tregs cross-talk. Thus, interplay between the Tregs-skeletal muscle, following exercise, contribute to the balance of immune tolerance and autoimmunity. The cargo delivery, in the local environment and periphery, is performed by extracellular vesicles (EVs) secreted by muscle and Tregs, which deliver proteins, lipids and miRNA during persistent exercise protocols. It has been suggested that this ensemble induce protection against autoimmune diseases.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103317"},"PeriodicalIF":7.9,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142271670","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}
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