Journal of autoimmunity最新文献

{"title":"Telitacicept: A novel horizon in targeting autoimmunity and rheumatic diseases","authors":"Liuting Zeng ,&nbsp;Kailin Yang ,&nbsp;Yang Wu ,&nbsp;Ganpeng Yu ,&nbsp;Yexing Yan ,&nbsp;Moujia Hao ,&nbsp;Tian Song ,&nbsp;Yuwei Li ,&nbsp;Junpeng Chen ,&nbsp;Lingyun Sun","doi":"10.1016/j.jaut.2024.103291","DOIUrl":"10.1016/j.jaut.2024.103291","url":null,"abstract":"<div><p>BLyS and APRIL have the capability to bind to B cells within the body, allowing these cells to evade elimination when they should naturally be removed. While BLyS primarily plays a role in B cell development and maturation, APRIL is linked to B cell activation and the secretion of antibodies. Thus, in theory, inhibiting BLyS or APRIL could diminish the population of aberrant B cells that contribute to SLE and reduce disease activity in patients. Telitacicept functions by binding to and neutralizing the activities of both BLyS and APRIL, thus hindering the maturation and survival of plasma cells and fully developed B cells. The design of telitacicept is distinctive; it is not a monoclonal antibody but a TACI-Fc fusion protein generated through recombinant DNA technology. This fusion involves merging gene segments of the TACI protein, which can target BLyS/APRIL simultaneously, with the Fc gene segment of the human IgG protein. The TACI-Fc fusion protein exhibits the combined characteristics of both proteins. Currently utilized for autoimmune disease treatment, telitacicept is undergoing clinical investigations globally to assess its efficacy in managing various autoimmune conditions. This review consolidates information on the mechanistic actions, dosing regimens, pharmacokinetics, efficacy, and safety profile of telitacicept—a dual-targeted biological agent. It integrates findings from prior experiments and pharmacokinetic analyses in the treatment of RA and SLE, striving to offer a comprehensive overview of telitacicept's research advancements.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"148 ","pages":"Article 103291"},"PeriodicalIF":7.9,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141985310","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":"WTAP promotes the progression of ulcerative colitis by silencing the expression of CES2 through m6A modification","authors":"Xiaoran Xie ,&nbsp;Sha Cheng ,&nbsp;Xiong Chen ,&nbsp;Xia Wang","doi":"10.1016/j.jaut.2024.103295","DOIUrl":"10.1016/j.jaut.2024.103295","url":null,"abstract":"<div><h3>Objective</h3><p>This study will explore the function of WTAP, the critical segment of m⁶A methyltransferase complex, in UC and its regulation on immune response.</p></div><div><h3>Methods</h3><p>The expression levels of key proteins were detected in colon tissues which were derived from UC patients and mice. Macrophage polarization and CD4⁺ T cell infiltration were detected by flow cytometry and IF staining. ELISA assay was utilized to analyze the level of the inflammatory cytokines. m⁶A-RIP-PCR, actinomycin D test, and RIP assays were utilized to detect the m⁶A level, stability, and bound proteins of CES2 mRNA. A dual luciferase reporter assay was conducted to confirm the transcriptional interactions between genes. A co-culture system of intestinal epithelium-like organs was constructed to detect the primary mouse intestinal epithelial cells (PMIEC) differentiation. The interaction between proteins was detected via Co-IP assay.</p></div><div><h3>Results</h3><p>The expression of WTAP and CES2 in UC tissues was increased and decreased, respectively. Knockdown of WTAP inhibited the progression of UC in mice by inhibiting M1 macrophage polarization and CD4⁺ T cell infiltration. WTAP combined YTHDF2 to promote the m⁶A modification of CES2 mRNA and inhibited its expression. CES2 co-expressed with EPHX2 and overexpression of CES2 promoted the differentiation of PMIEC. The inhibitory effect of WTAP knockdown on the progress of UC was partially abrogated by CES2 knockdown.</p></div><div><h3>Conclusion</h3><p>WTAP/YTHDF2 silences CES2 by promoting its m⁶A modification and then promotes the progression of UC. WTAP could be a promoting therapy target of UC.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"148 ","pages":"Article 103295"},"PeriodicalIF":7.9,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141978305","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":"Antigen-specific T cells and autoimmunity","authors":"Manuel Rojas ,&nbsp;Yeny Acosta-Ampudia ,&nbsp;Luke S. Heuer ,&nbsp;Weici Zang ,&nbsp;Diana M Monsalve ,&nbsp;Carolina Ramírez-Santana ,&nbsp;Juan-Manuel Anaya ,&nbsp;William M Ridgway ,&nbsp;Aftab A Ansari ,&nbsp;M. Eric Gershwin","doi":"10.1016/j.jaut.2024.103303","DOIUrl":"10.1016/j.jaut.2024.103303","url":null,"abstract":"<div><p>Autoimmune diseases (ADs) showcase the intricate balance between the immune system's protective functions and its potential for self-inflicted damage. These disorders arise from the immune system's erroneous targeting of the body's tissues, resulting in damage and disease. The ability of T cells to distinguish between self and non-self-antigens is pivotal to averting autoimmune reactions. Perturbations in this process contribute to AD development. Autoreactive T cells that elude thymic elimination are activated by mimics of self-antigens or are erroneously activated by self-antigens can trigger autoimmune responses. Various mechanisms, including molecular mimicry and bystander activation, contribute to AD initiation, with specific triggers and processes varying across the different ADs. In addition, the formation of neo-epitopes could also be implicated in the emergence of autoreactivity. The specificity of T cell responses centers on the antigen recognition sequences expressed by T cell receptors (TCRs), which recognize peptide fragments displayed by major histocompatibility complex (MHC) molecules. The assortment of TCR gene combinations yields a diverse array of T cell populations, each with distinct affinities for self and non-self antigens. However, new evidence challenges the traditional notion that clonal expansion solely steers the selection of higher-affinity T cells. Lower-affinity T cells also play a substantial role, prompting the “two-hit” hypothesis. High-affinity T cells incite initial responses, while their lower-affinity counterparts perpetuate autoimmunity. Precision treatments that target antigen-specific T cells hold promise for avoiding widespread immunosuppression. Nevertheless, detection of such antigen-specific T cells remains a challenge, and multiple technologies have been developed with different sensitivities while still harboring several drawbacks. In addition, elements such as human leukocyte antigen (HLA) haplotypes and validation through animal models are pivotal for advancing these strategies. In brief, this review delves into the intricate mechanisms contributing to ADs, accentuating the pivotal role(s) of antigen-specific T cells in steering immune responses and disease progression, as well as the novel strategies for the identification of antigen-specific cells and their possible future use in humans. Grasping the mechanisms behind ADs paves the way for targeted therapeutic interventions, potentially enhancing treatment choices while minimizing the risk of systemic immunosuppression.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"148 ","pages":"Article 103303"},"PeriodicalIF":7.9,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141978306","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":"Inflammatory disease status and response to TNF blockade are associated with mechanisms of endotoxin tolerance","authors":"Felix IL. Clanchy ,&nbsp;Federica Borghese ,&nbsp;Jonas Bystrom ,&nbsp;Attila Balog ,&nbsp;Henry Penn ,&nbsp;Dobrina N. Hull ,&nbsp;Rizgar A. Mageed ,&nbsp;Peter C. Taylor ,&nbsp;Richard O. Williams","doi":"10.1016/j.jaut.2024.103300","DOIUrl":"10.1016/j.jaut.2024.103300","url":null,"abstract":"<div><p>The mechanisms of endotoxin tolerance (ET), which down-regulate inflammation, are well described in response to exogenous toll-like receptor ligands, but few studies have focused on ET-associated mechanisms in inflammatory disease. As blocking TNF can attenuate the development of ET, the effect of anti-TNF on the expression of key ET-associated molecules in inflammatory auto-immune disease was measured; changes in inflammatory gene expression were confirmed using an ET bioassay. The expression of immunomodulatory molecules was measured in a murine model of arthritis treated with anti-TNF and the expression of ET-associated molecules was measured in whole blood in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients, before and after therapy. The expression of ET-associated genes was also measured in RA patient monocytes before and after therapy, in anti-TNF responders and non-responders. <em>Tnfaip3</em>, <em>Ptpn6</em> and <em>Irak3</em> were differentially expressed in affected paws, spleens, lymph nodes and circulating leucocytes in experimental murine arthritis treated with anti-TNF. Prior to therapy, the expression of <em>TNFAIP3</em>, <em>INPP5D</em>, <em>PTPN6, CD38</em> and <em>SIGIRR</em> in whole blood differed between human healthy controls and RA or AS patients. In blood monocytes from RA patients, the expression of <em>TNFAIP3</em> was significantly reduced by anti-TNF therapy in non-responders. Prior to therapy, anti-TNF non-responders had higher expression of <em>TNFAIP3</em> and <em>SLPI</em>, compared to responders. Although the expression of <em>TNFAIP3</em> was significantly higher in RA non-responders prior to treatment, the post-treatment reduction to a level similar to responders did not coincide with a clinical response to therapy.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"148 ","pages":"Article 103300"},"PeriodicalIF":7.9,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0896841124001343/pdfft?md5=25d05f69750e974a5293366990c00329&pid=1-s2.0-S0896841124001343-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906715","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":"Transcriptomic analyses of lung tissues reveal key genes associated with progression of systemic sclerosis-interstitial lung disease (SSc-ILD)","authors":"Yehya Al-Adwi ,&nbsp;Johanna Westra ,&nbsp;Harry van Goor ,&nbsp;Leon C. van Kempen ,&nbsp;Mohammed Osman ,&nbsp;C. Tji Gan ,&nbsp;Wim Timens ,&nbsp;Douwe J. Mulder","doi":"10.1016/j.jaut.2024.103297","DOIUrl":"10.1016/j.jaut.2024.103297","url":null,"abstract":"<div><h3>Objective</h3><p>Systemic sclerosis-interstitial lung disease (SSc-ILD) is the leading cause of death in SSc, affecting around 50 % of the patients. Lung tissue of patients with early-stage SSc-ILD is characterized by a predominant inflammatory response with inconspicuous fibrosis, which may progress to honeycombing fibrosis. Hence, a better understanding of the molecular mechanisms underpinning SSc-ILD pathogenesis is needed to improve treatment options and progression prediction. This transcriptomic study aims to reveal the differential gene expression between control (ctrl) lung tissue and inflammatory, prefibrotic and fibrotic lung tissue to capture progression of early to late phase SSc-ILD.</p></div><div><h3>Methods</h3><p>Twelve explanted lungs from patients with SSc-ILD were used to analyze gene expression from formalin-fixed paraffin-embedded lung tissues with varying stages of ILD (n = 18) and control lung tissue (n = 6). The SSc-ILD tissues were stratified into three ROIs: inflammatory, prefibrotic, and fibrotic using histological assessments to define a longitudinal simulation of early to late phases of SSc-ILD. The nanoString (nS) nCounter Human Fibrosis Panel was used to profile the transcriptome in the regions of interest. Validation of potential targetswas performed with immunohistochemistry in the same tissues that were used for transcriptome analysis.</p></div><div><h3>Results</h3><p>To validate our simulation model, we performed subgroup analysis that showed an incremental increase in pathway scores related to the severity of fibrosis. Ctrl vs SSc-ILD comparison demonstrated 24 differentially expressed genes, two of which had the most pronounced p-values. Cyclin-dependent kinase inhibitor (<em>cdkn2c</em>) was overexpressed (<em>P</em> = 0.00052) in SSc-ILD compared to ctrl, while expression of Pellino E3 ubiquitin-protein ligase 1 (<em>peli1</em>) showed lower expression (<em>P</em> = 0.0012). Additionally, in all four groups, <em>cdkn2c</em> and <em>peli1</em> gene expression showed an incremental increase and decrease, respectively. Immunohistochemistry of <em>cdkn2c</em> showed consistent results with the nS analysis.</p></div><div><h3>Conclusion</h3><p>More <em>cdkn2c</em> and less <em>peli1</em> expression were associated with more advanced stages of SSc-ILD on histologic assessment. We report the potential of the cell cycle inhibitor and senescence marker, <em>cdkn2c</em> (p18) to be associated with fibrosis progression.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"148 ","pages":"Article 103297"},"PeriodicalIF":7.9,"publicationDate":"2024-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0896841124001318/pdfft?md5=aa713571c16709788cf60e7237102da2&pid=1-s2.0-S0896841124001318-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889300","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":"Earlier vs. later time period of COVID-19 infection and emergent autoimmune signs, symptoms, and serologies","authors":"Emily G. Oakes ,&nbsp;Eilish Dillon ,&nbsp;Katherine A. Buhler ,&nbsp;Hongshu Guan ,&nbsp;Misti Paudel ,&nbsp;Kathryne Marks ,&nbsp;Ifeoluwakiisi Adejoorin ,&nbsp;Jeong Yee ,&nbsp;Jack Ellrodt ,&nbsp;Sara Tedeschi ,&nbsp;Jeffrey Sparks ,&nbsp;Siobhan M. Case ,&nbsp;Tiffany Hsu ,&nbsp;Daniel H. Solomon ,&nbsp;A. Helena Jonsson ,&nbsp;Roberta Vezza Alexander ,&nbsp;Deepak A. Rao ,&nbsp;May Y. Choi ,&nbsp;Karen H. Costenbader","doi":"10.1016/j.jaut.2024.103299","DOIUrl":"10.1016/j.jaut.2024.103299","url":null,"abstract":"<div><h3>Objective</h3><p>Autoantibodies and autoimmune diseases after SARS-CoV-2 infection are widely reported. Given evolving variants, milder infections, and increasing population vaccination, we hypothesized that SARS-CoV-2 infection earlier in the pandemic would be associated with more autoimmune connective tissue disease (CTD) symptoms and immunologic abnormalities.</p></div><div><h3>Methods</h3><p>Patients ≥18 years old with COVID-19 3/1/2020-8/15/2022 completed the CTD Screening Questionnaire and were tested for 27 autoimmune serologies, SARS-CoV-2 serologies, cell-bound complement activation products (CB-CAPs), and T and B lymphocyte immunophenotypes by flow cytometry. We assessed relationships between symptoms, serologies, and immunophenotypes in earlier (3/1/2020-1/31/2021) vs. later (2/1/2021-8/15/2022) periods, with different predominating SARS-CoV-2 viruses.</p></div><div><h3>Results</h3><p>57 subjects had earlier and 23 had later pandemic COVID-19. 35 % of earlier vs. 17 % of later pandemic patients had CTD symptoms (p 0.18). More patients were antinuclear antibody (ANA) positive (44 % vs. 13 %, p 0.01) and had lupus anticoagulant (11 % vs. 4 %, p 0.67). After adjustment for age, race, and sex, earlier (vs. later) COVID-19 was associated with increased ANA positivity (OR 4.60, 95%CI 1.17, 18.15). No subjects had positive CB-CAPs. T and B cell immunophenotypes and SARS-CoV-2 serologies did not differ by group. In heatmap analyses, higher autoantibody variety was seen among those with infection in the early pandemic.</p></div><div><h3>Conclusion</h3><p>In this sample, having COVID-19 infection in the earlier (pre-2/1/2021) vs. later pandemic was associated with more CTD symptoms, ANA positivity, and autoantibody reactivities. Earlier SARS-CoV-2 variants circulating in a less vaccinated population with less natural immunity may have been more immunogenic.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"148 ","pages":"Article 103299"},"PeriodicalIF":7.9,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141881937","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":"The binding of extracellular cyclophilin A to ACE2 and CD147 triggers psoriasis-like inflammation","authors":"Wenxian Yang ,&nbsp;Xiaoyuan Bai ,&nbsp;Xiaoxiao Jia ,&nbsp;Huizi Li ,&nbsp;Jie Min ,&nbsp;Heqiao Li ,&nbsp;Haoran Zhang ,&nbsp;Jianjing Zhou ,&nbsp;Yuna Zhao ,&nbsp;Wenjun Liu ,&nbsp;Haiming Xin ,&nbsp;Lei Sun","doi":"10.1016/j.jaut.2024.103293","DOIUrl":"10.1016/j.jaut.2024.103293","url":null,"abstract":"<div><p>Psoriasis is a chronic, proliferative, and inflammatory skin disease closely associated with inflammatory cytokine production. Cyclophilin A (CypA) is an important proinflammatory factor; however, its role in psoriasis remains unclear. The present data indicate that CypA levels are increased in the lesion skin and serum of patients with psoriasis, which is positively correlated with the psoriasis area severity index. Furthermore, extracellular CypA (eCypA) triggered psoriasis-like inflammatory responses in keratinocytes. Moreover, anti-CypA mAb significantly reduced pathological injury, keratinocyte proliferation, cytokine expression in imiquimod-induced mice. Notably, the therapeutic effect of anti-CypA mAb was better than that of the clinically used anti-IL-17A mAb and methotrexate. Mechanistically, eCypA binds to ACE2 and CD147 and is blocked by anti-CypA mAb. eCypA not only induces the dimerization and phosphorylation of ACE2 to trigger the JAK1/STAT3 signaling pathway for cytokine expression but also interacts with CD147 to promote PI3K/AKT/mTOR signaling-mediated keratinocyte proliferation. These findings demonstrate that the binding of eCypA to ACE2 and CD147 cooperatively triggers psoriasis-like inflammation and anti-CypA mAb is a promising candidate for the treatment of psoriasis.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"148 ","pages":"Article 103293"},"PeriodicalIF":7.9,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0896841124001276/pdfft?md5=b3539965ed70a5597ba6eee9d53a3563&pid=1-s2.0-S0896841124001276-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141881988","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":"A framework for exclusion of alternative diagnoses in sarcoidosis.","authors":"Logan J Harper, Carol F Farver, Ruchi Yadav, Daniel A Culver","doi":"10.1016/j.jaut.2024.103288","DOIUrl":"https://doi.org/10.1016/j.jaut.2024.103288","url":null,"abstract":"<p><p>Sarcoidosis is a multisystem granulomatous syndrome that arises from a persistent immune response to a triggering antigen(s). There is no \"gold standard\" test or algorithm for the diagnosis of sarcoidosis, making the diagnosis one of exclusion. The presentation of the disease varies substantially between individuals, in both the number of organs involved, and the manifestations seen in individual organs. These qualities dictate that health care providers diagnosing sarcoidosis must consider a wide range of possible alternative diagnoses, from across a range of presentations and medical specialties (infectious, inflammatory, cardiac, neurologic). Current guideline-based diagnosis of sarcoidosis recommends fulfillment of three criteria: 1) compatible clinical presentation and/or imaging 2) demonstration of granulomatous inflammation by biopsy (when possible) and, 3) exclusion of alternative causes, but do not provide guidance on standardized strategies for exclusion of alternative diagnoses. In this review, we provide a summary of the most common differential diagnoses for sarcoidosis involvement of lung, eye, skin, central nervous system, heart, liver, and kidney. We then propose a framework for testing to exclude alternative diagnoses based on pretest probability of sarcoidosis, defined as high (typical findings with sarcoidosis involvement confirmed in another organ), moderate (typical findings in a single organ), or low (atypical/findings suggesting of an alternative diagnosis). This work highlights the need for informed and careful exclusion of alternative diagnoses in sarcoidosis.</p>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":" ","pages":"103288"},"PeriodicalIF":7.9,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859866","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":"Shared aetiology underlying multiple sclerosis and other immune mediated inflammatory diseases: Swedish familial co-aggregation and large-scale genetic correlation analyses","authors":"Qianwen Liu ,&nbsp;Yuan Jiang ,&nbsp;Thomas Frisell ,&nbsp;Pernilla Stridh ,&nbsp;Klementy Shchetynsky ,&nbsp;Lars Alfredsson ,&nbsp;Ingrid Kockum ,&nbsp;Ali Manouchehrinia ,&nbsp;Xia Jiang","doi":"10.1016/j.jaut.2024.103294","DOIUrl":"10.1016/j.jaut.2024.103294","url":null,"abstract":"<div><h3>Background</h3><p>While multiple sclerosis (MS) affects less than 1 % of the general population, immune mediated inflammatory diseases (IMIDs) collectively influence 5–10 % of the population. Understanding familial co-aggregation of MS and other IMIDs carries important clinical and public health implications that will enable early detection and personalized treatment.</p></div><div><h3>Objective</h3><p>To estimate the familial association between MS and other IMIDs and to quantify their shared genetic basis.</p></div><div><h3>Design</h3><p>Register-based multi-generational nested case-control familial co-aggregation study and genetic correlation study.</p></div><div><h3>Setting</h3><p>Sweden.</p></div><div><h3>Participants</h3><p>24,995 individuals with MS matched with 253,870 controls and 1,283,502 first-degree relatives (mothers, fathers, full siblings, and offspring) for familial co-aggregation analysis; population of European ancestry for genetic correlation analysis.</p></div><div><h3>Measurements</h3><p>Logistic regressions with adjustment for covariates were used to estimate the odds ratios (ORs) of developing MS in individuals with first-degree relatives diagnosed with IMIDs compared to those without such family history. Pairwise genome-wide genetic correlations were estimated with linkage-disequilibrium score regression.</p></div><div><h3>Results</h3><p>We observed an OR for familial co-aggregation of MS of 1.09 (95 % confidence interval (95%CI) = 1.07−1.11) in families with IMIDs history compared to families without. The association remained broadly consistent after stratification by sex concordance of relative pairs and by kinships. 18 IMID subtypes showed a familial association with MS, 7 of which including other acute widespread myelin destruction, encephalitis or myelitis or encephalomyelitis, inflammatory bowel disease, autoimmune thyroid diseases, systemic lupus erythematosus, other inflammatory system diseases, and sarcoidosis withstood multiple correction. Genetic correlations further revealed a shared genetic basis between 7 IMID subtypes with MS.</p></div><div><h3>Conclusion</h3><p>We demonstrated a modest familial co-aggregation of MS with several IMIDs, and such association is likely due to shared genetic factors.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"148 ","pages":"Article 103294"},"PeriodicalIF":7.9,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0896841124001288/pdfft?md5=1f67eefcafd5b7fc808603cea2f02fef&pid=1-s2.0-S0896841124001288-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859867","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":"Epidemiologic and genetic associations between primary biliary cholangitis and extrahepatic rheumatic diseases","authors":"Qiwei Qian ,&nbsp;Yi Wu ,&nbsp;Nana Cui ,&nbsp;Yikang Li ,&nbsp;Yujie Zhou ,&nbsp;You Li ,&nbsp;Min Lian ,&nbsp;Xiao Xiao ,&nbsp;Qi Miao ,&nbsp;Zhengrui You ,&nbsp;Qixia Wang ,&nbsp;Yongyong Shi ,&nbsp;Heather J. Cordell ,&nbsp;Suraj Timilsina ,&nbsp;M. Eric Gershwin ,&nbsp;Zhiqiang Li ,&nbsp;Xiong Ma ,&nbsp;Ruqi Tang","doi":"10.1016/j.jaut.2024.103289","DOIUrl":"10.1016/j.jaut.2024.103289","url":null,"abstract":"<div><p>Patients with primary biliary cholangitis (PBC) commonly experience extrahepatic rheumatic diseases. However, the epidemiologic and genetic associations as well as causal relationship between PBC and these extrahepatic conditions remain undetermined. In this study, we first conducted systematic review and meta-analyses by analyzing 73 studies comprising 334,963 participants across 17 countries and found strong phenotypic associations between PBC and rheumatic diseases. Next, we utilized large-scale genome-wide association study summary data to define the shared genetic architecture between PBC and rheumatic diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Sjögren's syndrome (SS). We observed significant genetic correlations between PBC and each of the four rheumatic diseases. Pleiotropy and heritability enrichment analysis suggested the involvement of humoral immunity and interferon-associated processes for the comorbidity. Of note, we identified four variants shared between PBC and RA (rs80200208), SLE (rs9843053), and SSc (rs27524, rs3873182) using cross-trait meta-analysis. Additionally, several pleotropic loci for PBC and rheumatic diseases were found to share causal variants with gut microbes possessing immunoregulatory functions. Finally, Mendelian randomization revealed consistent evidence for a causal effect of PBC on RA, SLE, SSc, and SS, but no or inconsistent evidence for a causal effect of extrahepatic rheumatic diseases on PBC. Our study reveals a profound genetic overlap and causal relationships between PBC and extrahepatic rheumatic diseases, thus providing insights into shared biological mechanisms and novel therapeutic interventions.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"148 ","pages":"Article 103289"},"PeriodicalIF":7.9,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141766131","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}