Journal of Translational Autoimmunity最新文献

{"title":"Across ancestries, HLA-B∗08:01∼DRB1∗03:01 (DR3) and HLA-DQA∗01:02 (DR2) increase the risk to develop juvenile-onset systemic lupus erythematosus through low complement C4 levels","authors":"Yves Renaudineau ,&nbsp;Amandine Charras ,&nbsp;Valentina Natoli ,&nbsp;Nicolas Congy-Jolivet ,&nbsp;Sam Haldenby ,&nbsp;Xuan Liu ,&nbsp;Yongxiang Fang ,&nbsp;Eve MD. Smith ,&nbsp;Michael W. Beresford ,&nbsp;Christian M. Hedrich","doi":"10.1016/j.jtauto.2025.100268","DOIUrl":"10.1016/j.jtauto.2025.100268","url":null,"abstract":"<div><h3>Objective</h3><div>Systemic lupus erythematosus (SLE) is a systemic autoimmune/inflammatory disease with a strong genetic component. Genetic burden is higher in children when compared to patients with adult-onset SLE, contributing to earlier disease expression and more severe phenotypes. The human leukocyte antigen (HLA) cluster on chromosome 6p21.3 is among the most variable genomic regions, representing a major risk-factor for SLE in adults. Its impact on juvenile-onset (j)SLE remains largely unstudied.</div></div><div><h3>Methods</h3><div>High-resolution sequencing of HLA class I (A, B, C), class II (DRB1, DQA1, DQB1) and class III (complement <em>C2</em>) was undertaken in the multi-ancestral UK JSLE Cohort including participants of Caucasian (n = 151, 48.8 %), Asian (n = 108, 35.0 %) and African/Caribbean (n = 50, 16.2 %) descent. Considering ancestral variation, clinical associations were tested at the level of alleles (2-field resolution), associated HLA protein sequences (antigen binding domains, 4-field resolution), and extended haplotypes (DRh).</div></div><div><h3>Results</h3><div>Although important ancestral recombination was reported for HLA-DR2 and -DR3 haplotypes, risk associated with jSLE was conserved at related alleles (DR2h: DRB1∗15:01, DQA∗01:02, DQB1∗06:02; DR3h: C∗07:02 [Asian], B∗08:01, <em>C2</em> rs9332730 [Asian], DRB1∗03:01). HLA-DR7 haplotypes (DRB1∗07:01, OR = 0.44, 95 % CI:0.27–0.72, p = 0.0004; DQA1∗02:01, OR = 0.34, 95 % CI:0.21–0.56, p = 1.8 × 10⁻⁶) protect Asians from jSLE development. Among 23 clinical variables recorded, the main association was found between low levels of complement C4 in Caucasian carriers of HLA-DR3h. This was not the case in Asians due to recombination with HLA-C∗07:02 and integration of the <em>C2</em> rs9332730 minor allele. Low C4 serum levels associated with HLA-DQA1∗01:02 (DR2h) in Caucasians after excluding HLA-DR3h carriers from the analysis. An association between low white blood cell counts and HLA-A∗03:01P was observed across ancestries.</div></div><div><h3>Conclusion</h3><div>Genetic variation in the <em>HLA</em> cluster associates with organ domain involvement (hematological) and complement levels in jSLE. Lupus-associated <em>HLA</em> haplotypes vary between ancestral groups, underscoring the importance of multi-ancestral approaches to genetic studies in SLE and other autoimmune/inflammatory diseases.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100268"},"PeriodicalIF":4.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mimicry in the pathogenesis of autoimmune rheumatic diseases","authors":"Michaela Fehringer,&nbsp;Thomas Vogl","doi":"10.1016/j.jtauto.2025.100269","DOIUrl":"10.1016/j.jtauto.2025.100269","url":null,"abstract":"<div><div>Autoimmune rheumatic diseases (ARDs) are a heterogeneous group of conditions characterized by excessive and misdirected immune responses against the body's own musculoskeletal tissues. Their exact aetiology remains unclear, with genetic, demographic, behavioural and environmental factors implicated in disease onset. One prominent hypothesis for the initial breach of immune tolerance (leading to autoimmunity) is molecular mimicry, which describes structural or sequence similarities between human and microbial proteins (mimotopes). This similarity can lead to cross-reactive antibodies and T-cell receptors, resulting in an immune response against autoantigens. Both commensal microbes in the human microbiome and pathogens can trigger molecular mimicry, thereby potentially contributing to the onset of ARDs.</div><div>In this review, we focus on the role of molecular mimicry in the onset of rheumatoid arthritis and systemic lupus erythematosus. Moreover, implications of molecular mimicry are also briefly discussed for ankylosing spondylitis, systemic sclerosis and myositis.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100269"},"PeriodicalIF":4.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143060841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large soluble CD18 complexes with exclusive ICAM-1-binding properties are shed during immune cell migration in inflammation","authors":"Alexey Ferapontov ,&nbsp;Anders Mellemkjær ,&nbsp;Helen M. McGettrick ,&nbsp;Thomas Vorup-Jensen ,&nbsp;Tue W. Kragstrup ,&nbsp;Kristian Juul-Madsen","doi":"10.1016/j.jtauto.2025.100266","DOIUrl":"10.1016/j.jtauto.2025.100266","url":null,"abstract":"<div><div>The family of heterodimeric CD11/CD18 integrins facilitate leukocyte adhesion and migration in a wide range of normal physiologic responses, as well as in the pathology of inflammatory diseases. Soluble CD18 (sCD18) is found mainly in complexes with hydrodynamic radii of 5 and 7.2 nm, suggesting a compositional difference. Earlier work reported that the complexes include at least part of the CD11a or CD11b chains containing the intercellular adhesion molecule (ICAM)-1 binding domain, and that sCD18 is capable of quantitatively competing with the cell membrane-bound form for ICAM-1 binding. However, it is not clear if the size differences between the sCD18 complexes reflect any functional variance regarding shedding from the cell membrane or binding to ICAM-1. Here, we show evidence that sCD18 found in serum regulates release of the proinflammatory cytokine monocyte chemoattractant protein-1 (MCP-1/CCL2) from fibroblast-like synovial cells. Further, only large sCD18 complexes are capable of binding to ICAM-1. Migrating neutrophils shed large, but not small, sCD18 complexes. Together, these observations explain results measured from patients with rheumatoid arthritis (RA), where large sCD18 complexes dominated in local inflammatory processes involving neutrophil influx into zones of inflammation. Our data points to a previously unappreciated aspect of sCD18 integrin biology as regulators of inflammation in the context of migrating leukocyte. Surprisingly, this regulation is tied to sCD18 complex size, opening new opportunities for therapeutic intervention in serious inflammatory diseases such as arthritis.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100266"},"PeriodicalIF":4.7,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iron metabolism in rheumatic diseases","authors":"Aliakbar Givian ,&nbsp;Amin Azizan ,&nbsp;Ahmadreza Jamshidi ,&nbsp;Mahdi Mahmoudi ,&nbsp;Elham Farhadi","doi":"10.1016/j.jtauto.2025.100267","DOIUrl":"10.1016/j.jtauto.2025.100267","url":null,"abstract":"<div><div>Iron is a crucial element for living organism in terms of oxygen transport, hematopoiesis, enzymatic activity, mitochondrial respiratory chain function and also immune system function. The human being has evolved a mechanism to regulate body iron. In some rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematous (SLE), systemic sclerosis (SSc), ankylosing spondylitis (AS), and gout, this balanced iron regulation is impaired. Altered iron homeostasis can contribute to disease progression through ROS production, fibrosis, inflammation, abnormal bone homeostasis, NETosis and cell senescence. In this review, we have focused on the iron metabolism in rheumatic disease and its role in disease progression.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100267"},"PeriodicalIF":4.7,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11763848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of UV-induced cutaneous matrix metalloproteinases and mi-RNAs in the pathogenesis of lupus erythematosus","authors":"I. Ivanova,&nbsp;T. Svilenska,&nbsp;T. Maisch,&nbsp;S. Karrer,&nbsp;D. Niebel,&nbsp;M. Berneburg,&nbsp;B. Kurz","doi":"10.1016/j.jtauto.2024.100265","DOIUrl":"10.1016/j.jtauto.2024.100265","url":null,"abstract":"<div><div>Cutaneous (CLE) and systemic lupus erythematosus (SLE) are autoimmune diseases with a multifactorial pathogenesis. Ultraviolet radiation (UVR) is the most important trigger of CLE; however, the degree of photosensitivity varies between the clinical subtypes. The expression of matrix metalloproteinases (MMPs)—important enzymes involved in skin turnover and homeostasis—is modulated by UVR.</div><div>To investigate the causality of the clinically observed effects of UVR, sun-exposed lesional skin samples from patients with different subtypes of lupus erythematosus (LE) were examined by immunohistochemistry for the expression of MMP1 and MMP28 and compared with biopsies from polymorphous light eruption (PLE) and healthy skin (HS). The expression of micro-RNAs (miR-31 and miR-150)—regulators of MMP expression and cellular metabolism—in the samples was determined by in-situ hybridization and correlated with the expression of the glucose transporter 1 (GLUT1) receptor to examine potential metabolic regulation. To assess potential UVR regulation of MMP28, we performed <em>in vitro</em> experiments in healthy keratinocytes and fibroblasts.</div><div>MMP28 expression was differentially affected by UVA1 and UVB irradiation in keratinocytes and fibroblasts. Compared with all other LE subtypes, as well as PLE and HS samples, MMP28 expression in Chilblain LE skin showed a distinct vertical distribution, reaching as far as the upper layers of the dermis. This vertical expression pattern coincided with decreased GLUT1 levels and with increased expression of miR-31 and miR-150 in the epidermis of patients with Chilblain LE. These data provide evidence for a potential metabolic dysregulation that may play a role in the etiology of LE. Furthermore, our results suggest MMP28 as a novel complementary marker in Chilblain LE diagnosis.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100265"},"PeriodicalIF":4.7,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular therapies in rheumatic and musculoskeletal diseases","authors":"Pedro Franco-Fuquen ,&nbsp;Juana Figueroa-Aguirre ,&nbsp;David A. Martínez ,&nbsp;Eider F. Moreno-Cortes ,&nbsp;Juan E. Garcia-Robledo ,&nbsp;Fabio Vargas-Cely ,&nbsp;Daniela A. Castro-Martínez ,&nbsp;Mustafa Almaini ,&nbsp;Januario E. Castro","doi":"10.1016/j.jtauto.2024.100264","DOIUrl":"10.1016/j.jtauto.2024.100264","url":null,"abstract":"<div><div>A substantial proportion of patients diagnosed with rheumatologic and musculoskeletal diseases (RMDs) exhibit resistance to conventional therapies or experience recurrent symptoms. These diseases, which include autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, are marked by the presence of autoreactive B cells that play a critical role in their pathogenesis. The persistence of these autoreactive B cells within lymphatic organs and inflamed tissues impairs the effectiveness of B-cell-depleting monoclonal antibodies like rituximab.</div><div>A promising therapeutic approach involves using T cells genetically engineered to express chimeric antigen receptors (CARs) that target specific antigens. This strategy has demonstrated efficacy in treating B-cell malignancies by achieving long-term depletion of malignant and normal B cells. Preliminary data from patients with RMDs, particularly those with lupus erythematosus and dermatomyositis, suggest that CAR T-cells targeting CD19 can induce rapid and sustained depletion of circulating B cells, leading to complete clinical and serological responses in cases that were previously unresponsive to conventional therapies.</div><div>This review will provide an overview of the current state of preclinical and clinical studies on the use of CAR T-cells and other cellular therapies for RMDs. Additionally, it will explore potential future applications of these innovative treatment modalities for managing patients with refractory and recurrent manifestations of these diseases.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100264"},"PeriodicalIF":4.7,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143174020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-12 family cytokines and autoimmune diseases: A potential therapeutic target?","authors":"Xiaoyu Cui ,&nbsp;Wu Liu ,&nbsp;Hanxue Jiang ,&nbsp;Qihan Zhao ,&nbsp;Yuehong Hu ,&nbsp;Xinyue Tang ,&nbsp;Xianli Liu ,&nbsp;Haoran Dai ,&nbsp;Hongliang Rui ,&nbsp;Baoli Liu","doi":"10.1016/j.jtauto.2024.100263","DOIUrl":"10.1016/j.jtauto.2024.100263","url":null,"abstract":"<div><div>In recent years, the discovery of IL-12 family cytokines, which includes IL-12, IL-23, IL-27, IL-35, and IL-39, whose biological functions directly or indirectly affect various autoimmune diseases. In autoimmune diseases, IL-12 family cytokines are aberrantly expressed to varying degrees. These cytokines utilize shared subunits to influence T-cell activation and differentiation, thereby regulating the balance of T-cell subsets, which profoundly impacts the onset and progression of autoimmune diseases. In such conditions, IL-12 family members are aberrantly expressed to varying degrees. By exploring their immunomodulatory functions, researchers have identified varying therapeutic potentials for each member. This review examines the physiological functions of the major IL-12 family members and their interactions, discusses their roles in several autoimmune diseases, and summarizes the progress of clinical studies involving monoclonal antibodies targeting IL-12 and IL-23 subunits currently available for treatment.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100263"},"PeriodicalIF":4.7,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a standardized monoclonal antibody to the inner lipoyl domain of PDC-E2 as a potential international AMA reference","authors":"Zhuye Qin ,&nbsp;Fangming Cheng ,&nbsp;Mingming Zhang ,&nbsp;Ruonan Qian ,&nbsp;Hong Chen ,&nbsp;Yaqin Zhao ,&nbsp;Youtao Zhang ,&nbsp;Yaping Dai ,&nbsp;Chaochao Tang ,&nbsp;Peng Jiang ,&nbsp;Xiaoli Hua ,&nbsp;Shen Li ,&nbsp;Bing Zheng ,&nbsp;Pin Yu ,&nbsp;Xingjuan Shi ,&nbsp;Suraj Timilsina ,&nbsp;M. Eric Gershwin ,&nbsp;Xiangdong Liu ,&nbsp;Chungen Qian ,&nbsp;Fang Qiu","doi":"10.1016/j.jtauto.2024.100262","DOIUrl":"10.1016/j.jtauto.2024.100262","url":null,"abstract":"<div><div>The detection of antimitochondrial antibodies (AMA) is the specific diagnostic marker for primary biliary cholangitis. Indeed, it is the most specific autoantibody in clinical autoimmunity, with a high titer directed response to the inner lipoyl domain of PDC-E2. The current international reference for AMA detection is based upon sera samples of PBC patients. In rheumatic diseases, i.e. rheumatoid arthritis, great efforts are placed at development of international standards. In this study, we report the development of a monoclonal chimeric IgG1 antibody as a reference for AMA testing. A monoclonal 4G6 antibody was constructed from a murine monoclonal antibody specific for the inner lipoyl domain (ILD) of PDC-E2, by combining the variable region with the constant region of human IgG1. The 4G6 antibody recognizes all AMA epitopes containing the ILD of PDC-E2, including the classical BPO recombinant antigen in all currently available diagnostic methods. The binding affinity of the 4G6 antibody to PDC-E2 and BPO antigen reaches <em>K</em>_D value of 7.22 × 10⁻¹¹ M and 4.55 × 10⁻¹¹ M, which is sufficient to use as a quantitative reference for all AMA tests. The unlimited availability of the 4G6 antibody makes it a promising candidate for use as an AMA reference or assay calibrator for the international community.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"9 ","pages":"Article 100262"},"PeriodicalIF":4.7,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142698963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic value of β1 adrenergic receptor autoantibodies for microvascular obstruction in patients with STEMI with Post-PCI: A prospective cohort study","authors":"Ning Cao ,&nbsp;Wenxi Dang ,&nbsp;Yanguo Xin ,&nbsp;Jiayu Li ,&nbsp;Shaohua Guo ,&nbsp;Qitian Li ,&nbsp;Hui Chen ,&nbsp;Shun Li","doi":"10.1016/j.jtauto.2024.100261","DOIUrl":"10.1016/j.jtauto.2024.100261","url":null,"abstract":"<div><h3>Backgrounds</h3><div>Coronary microvascular obstruction (MVO) frequently occurs in patients with ST-segment elevation myocardial infarction (STEMI) following percutaneous coronary intervention (PCI), leading to poor prognosis. β₁ adrenergic receptor autoantibodies (β₁-AA) are present in various cardiovascular diseases and correlate with cardiac damage and dysfunction. However, whether β₁-AA is associated with the occurrence of MVO in patients with STEMI after PCI remains unclear.</div></div><div><h3>Aims</h3><div>To investigate the prognostic relationship between β₁-AA and the occurrence of MVO in patients with STEMI with post-PCI.</div></div><div><h3>Methods</h3><div>This prospective study included 403 patients with STEMI who underwent primary PCI. The patients were divided into MVO+ and MVO- groups. Serum β₁-AA levels were measured prior to primary PCI. The primary outcome was MVO, assessed through cardiac magnetic resonance imaging at 5–7 days after PCI.</div></div><div><h3>Results</h3><div>A total of 127 MVO+ and 276 MVO– patients were identified. Patients with MVO + exhibited higher β₁-AA optical density (OD) compared to MVO- patients. β₁-AA OD, pNT-proBNP, pCK-MB and pTNI were positively associated with MVO following PCI. Notably, the assocition between β₁-AA levels and MVO risk strengthened with increasing pNT-proBNP levels. The combination of β₁-AA, pNT-proBNP and pTNI yielded the most efficient MVO prediction with an area under the ROC curve of 0.87 (95 % CI: 0.83–0.90).</div></div><div><h3>Conclusions</h3><div>β₁-AA is significantly associated with the occurrence of MVO in STEMI patients following primary PCI. The combination of β₁-AA with pNT-proBNP and pTNI improves predictive accuracy, providing a more robust and effective strategy for assessing MVO risk.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"9 ","pages":"Article 100261"},"PeriodicalIF":4.7,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142661280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissecting the genetic basis and mechanisms underlying the associations between multiple extrahepatic factors and autoimmune liver diseases","authors":"Zheng Zhang ,&nbsp;Jiayi Zhang ,&nbsp;Xinyang Yan ,&nbsp;Jiachen Wang ,&nbsp;Haoxiang Huang ,&nbsp;Menghao Teng ,&nbsp;Qingguang Liu ,&nbsp;Shaoshan Han","doi":"10.1016/j.jtauto.2024.100260","DOIUrl":"10.1016/j.jtauto.2024.100260","url":null,"abstract":"<div><h3>Background</h3><div>Autoimmune liver diseases (AILDs) encompass autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The onset of these diseases is fundamentally influenced by genetic susceptibility. Although various extrahepatic factors are potentially linked to AILDs, the genetic underpinnings and mechanisms of these associations remain unclear.</div></div><div><h3>Methods</h3><div>Utilizing large-scale genome-wide association study (GWAS) data, this study systematically investigated the relationships between extrahepatic autoimmune diseases (EHAIDs), immune cells, and various triggering factors with AILDs. Mendelian randomization (MR) was employed to assess the causal effects of these extrahepatic factors on AILDs, complemented by linkage disequilibrium score (LDSC) regression to uncover shared genetic architecture and causal effects underlying the associations between autoimmune diseases. We employed colocalization, enrichment analysis, and protein-protein interaction (PPI) network to identify the functions of shared loci. Additionally, we proposed that activated immune cells in the circulation may contribute to liver and biliary tract inflammation via migration, mediating the impact of extrahepatic factors on AILDs. This hypothesis was tested using two mediation analysis methods: two-step MR (TSMR) and multivariable MR (MVMR).</div></div><div><h3>Results</h3><div>Causal associations between multiple extrahepatic factors and AILDs were identified. Notably, CD27⁺ B cells were found to be a risk factor for PBC, while PSC progression was associated with CD28⁺ CD8⁺ T cells exhaustion and increased levels of CD28⁻ CD8⁺ T cells. Mediation analyses revealed 64 pathways via TSMR and 15 pathways via MVMR, indicating that the effects of extrahepatic factors on AILDs may be mediated by circulating immune cells. The shared genetic architecture also contributed to these associations. Analysis of shared loci and gene functions identified ATXN2 as being shared between PBC and 9 EHAIDs, while SH2B3 and PSMG1 were shared with 6 and 5 EHAIDs, respectively, in PSC.</div></div><div><h3>Conclusions</h3><div>Our research compared three distinct AILDs, enhancing the understanding of their etiology and providing new evidence on risk factors, diagnostic markers, and potential therapeutic targets.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100260"},"PeriodicalIF":4.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11683281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}