Pub Date : 2025-02-01DOI: 10.1016/j.jaut.2025.103358
Adediwura Arowosegbe, Zhiru Guo, Emma Vanderleeden, Alan G. Derr, Jennifer P. Wang
Numerous studies highlight the essential role of type I interferon (IFN) responses in type 1 diabetes. The absence of type I IFN signaling is associated with a partial reduction of autoimmune diabetes incidence in LEW.1WR1 rats. We sought to delineate type I IFN-independent mechanisms that drive diabetes using type I IFN α/β receptor (IFNAR) knockout rats. Rats were treated with polyinosinic:polycytidylic acid plus Kilham rat virus to induce diabetes. Single-cell RNA-sequencing of islets and cytokine measurements in blood and spleen from prediabetic Ifnar1−/− rats were employed to identify factors driving insulitis in the global absence of IFNAR signaling. Islet immune cells were enriched for Ccl4, Ccl5, and Ifng. In addition, interleukin-1 (IL-1) was increased in spleen, and IFN-γ was increased in serum from prediabetic Ifnar1−/− rats. Based on these findings, rats were treated with a C-C chemokine receptor type 5 inhibitor, an IL-1 receptor antagonist, or a nucleotide-binding oligomerization domain-like receptor family pyrin-domain containing 3 inhibitor, none of which prevented diabetes. The Janus kinase inhibitor ruxolitinib, which blocks both type I and II interferon-driven signaling, completely prevented diabetes, but only when given for a sustained period starting from the time of induction. The tyrosine kinase 2 inhibitor deucravacitinib also prevented diabetes to a significant degree. We conclude that type I and II IFNs act in concert as the main drivers of autoimmune diabetes and that inhibition of downstream signaling events for both is required for disease prevention.
{"title":"Janus kinase inhibition prevents autoimmune diabetes in LEW.1WR1 rats","authors":"Adediwura Arowosegbe, Zhiru Guo, Emma Vanderleeden, Alan G. Derr, Jennifer P. Wang","doi":"10.1016/j.jaut.2025.103358","DOIUrl":"10.1016/j.jaut.2025.103358","url":null,"abstract":"<div><div>Numerous studies highlight the essential role of type I interferon (IFN) responses in type 1 diabetes. The absence of type I IFN signaling is associated with a partial reduction of autoimmune diabetes incidence in LEW.1WR1 rats. We sought to delineate type I IFN-independent mechanisms that drive diabetes using type I IFN α/β receptor (IFNAR) knockout rats. Rats were treated with polyinosinic:polycytidylic acid plus Kilham rat virus to induce diabetes. Single-cell RNA-sequencing of islets and cytokine measurements in blood and spleen from prediabetic <em>Ifnar1</em><sup>−/−</sup> rats were employed to identify factors driving insulitis in the global absence of IFNAR signaling. Islet immune cells were enriched for <em>Ccl4, Ccl5,</em> and <em>Ifng</em>. In addition, interleukin-1 (IL-1) was increased in spleen, and IFN-γ was increased in serum from prediabetic <em>Ifnar1</em><sup>−/−</sup> rats. Based on these findings, rats were treated with a C-C chemokine receptor type 5 inhibitor, an IL-1 receptor antagonist, or a nucleotide-binding oligomerization domain-like receptor family pyrin-domain containing 3 inhibitor, none of which prevented diabetes. The Janus kinase inhibitor ruxolitinib, which blocks both type I and II interferon-driven signaling, completely prevented diabetes, but only when given for a sustained period starting from the time of induction. The tyrosine kinase 2 inhibitor deucravacitinib also prevented diabetes to a significant degree. We conclude that type I and II IFNs act in concert as the main drivers of autoimmune diabetes and that inhibition of downstream signaling events for both is required for disease prevention.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"151 ","pages":"Article 103358"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006102","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 : 2025-02-01DOI: 10.1016/j.jaut.2025.103373
Rui Mao , Tongtong Zhang , Yun Zhong , Xin Meng , Caitan Yi , Fan Wang , Ji Li
Although exposure to hard water is associated with various inflammatory skin conditions, the specific relationship between hard water and psoriasis has not been clearly defined. We analyzed data from 486,414 participants in the UK Biobank cohort to explore the association between domestic hard water exposure and the incidence of psoriasis. Domestic water hardness, measured in calcium carbonate concentration, was obtained in 2005 from local water providers in Wales, Scotland, and England. During a median follow-up period of approximately 14 years, a total of 4801 (1.0 %) participants reported psoriasis, and we observed that for every 50 mg/L increase in water hardness (as CaCO₃), there was a 3 % increase in the risk of psoriasis [Hazard Ratio (HR) = 1.03, 95 % Confidence Interval (CI) 1.01–1.06]. Individuals exposed to very hard water (>180 mg/L) exhibited a 20 % increased risk of psoriasis compared to those exposed to soft water (0–60 mg/L) [HR: 1.20, 95 % CI: 1.07–1.34]. A positive linear relationship was observed between water hardness and the risk of psoriasis. Furthermore, the polygenic risk score indicated a synergistic effect between hard water exposure and genetic risk factors in developing psoriasis. Subgroup analysis suggested that the effect of hard water on psoriasis is more pronounced in individuals with a low polygenic risk score, women, the elderly, non-obese individuals, those of high socioeconomic status or without dyslipidemia. Residential water hardness has been identified as a significant risk factor for psoriasis in adults. Sustained efforts to reduce exposure to hard water may alleviate the psoriasis burden.
{"title":"Associations between domestic hard water exposure and incident psoriasis in adults: Insights from the UK Biobank cohort study","authors":"Rui Mao , Tongtong Zhang , Yun Zhong , Xin Meng , Caitan Yi , Fan Wang , Ji Li","doi":"10.1016/j.jaut.2025.103373","DOIUrl":"10.1016/j.jaut.2025.103373","url":null,"abstract":"<div><div>Although exposure to hard water is associated with various inflammatory skin conditions, the specific relationship between hard water and psoriasis has not been clearly defined. We analyzed data from 486,414 participants in the UK Biobank cohort to explore the association between domestic hard water exposure and the incidence of psoriasis. Domestic water hardness, measured in calcium carbonate concentration, was obtained in 2005 from local water providers in Wales, Scotland, and England. During a median follow-up period of approximately 14 years, a total of 4801 (1.0 %) participants reported psoriasis, and we observed that for every 50 mg/L increase in water hardness (as CaCO₃), there was a 3 % increase in the risk of psoriasis [Hazard Ratio (HR) = 1.03, 95 % Confidence Interval (CI) 1.01–1.06]. Individuals exposed to very hard water (>180 mg/L) exhibited a 20 % increased risk of psoriasis compared to those exposed to soft water (0–60 mg/L) [HR: 1.20, 95 % CI: 1.07–1.34]. A positive linear relationship was observed between water hardness and the risk of psoriasis. Furthermore, the polygenic risk score indicated a synergistic effect between hard water exposure and genetic risk factors in developing psoriasis. Subgroup analysis suggested that the effect of hard water on psoriasis is more pronounced in individuals with a low polygenic risk score, women, the elderly, non-obese individuals, those of high socioeconomic status or without dyslipidemia. Residential water hardness has been identified as a significant risk factor for psoriasis in adults. Sustained efforts to reduce exposure to hard water may alleviate the psoriasis burden.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"151 ","pages":"Article 103373"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143038901","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 : 2025-02-01DOI: 10.1016/j.jaut.2025.103357
Yi Lu, Xiao-Yong Man
Regulatory T cell (Treg) play a pivotal role in immune regulation and maintaining host immune homeostasis. Treg heterogeneity, characterized by diverse gene expression profiles and functional states, is complex in both health and disease. Research reveals that Tregs are not a uniform population but exhibit diversity based on their origin, location, and functional status. This heterogeneity is crucial for understanding Treg roles in various pathological conditions. Dysfunctional Tregs are closely linked to the pathogenesis of autoimmune diseases, although the precise mechanisms remain unclear. The phenotypic and functional heterogeneity of Tregs is particularly significant in diseases such as systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, psoriasis and autoimmune liver diseases. This review explores Treg origins, classifications, and heterogeneity in these conditions, aiming to provide new perspectives and strategies for diagnosis and treatment. Understanding Treg heterogeneity and plasticity promises to reveal novel therapeutic targets and advance precision immunotherapy development.
调节性T细胞（Regulatory T cell, Treg）在免疫调节和维持宿主免疫稳态中起着关键作用。Treg异质性以不同的基因表达谱和功能状态为特征，在健康和疾病中都很复杂。研究表明，treg不是一个统一的种群，而是根据其起源、位置和功能状态表现出多样性。这种异质性对于理解Treg在各种病理条件下的作用至关重要。功能失调的Tregs与自身免疫性疾病的发病机制密切相关，尽管其确切机制尚不清楚。Tregs的表型和功能异质性在系统性红斑狼疮、多发性硬化症、类风湿性关节炎、炎症性肠病、1型糖尿病、牛皮癣和自身免疫性肝病等疾病中尤为显著。本文综述了Treg的起源、分类和异质性，旨在为诊断和治疗提供新的视角和策略。了解Treg的异质性和可塑性有望揭示新的治疗靶点和推进精确免疫治疗的发展。
{"title":"Diversity and function of regulatory T cells in health and autoimmune diseases","authors":"Yi Lu, Xiao-Yong Man","doi":"10.1016/j.jaut.2025.103357","DOIUrl":"10.1016/j.jaut.2025.103357","url":null,"abstract":"<div><div>Regulatory T cell (Treg) play a pivotal role in immune regulation and maintaining host immune homeostasis. Treg heterogeneity, characterized by diverse gene expression profiles and functional states, is complex in both health and disease. Research reveals that Tregs are not a uniform population but exhibit diversity based on their origin, location, and functional status. This heterogeneity is crucial for understanding Treg roles in various pathological conditions. Dysfunctional Tregs are closely linked to the pathogenesis of autoimmune diseases, although the precise mechanisms remain unclear. The phenotypic and functional heterogeneity of Tregs is particularly significant in diseases such as systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, psoriasis and autoimmune liver diseases. This review explores Treg origins, classifications, and heterogeneity in these conditions, aiming to provide new perspectives and strategies for diagnosis and treatment. Understanding Treg heterogeneity and plasticity promises to reveal novel therapeutic targets and advance precision immunotherapy development.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"151 ","pages":"Article 103357"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978548","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 : 2025-02-01DOI: 10.1016/j.jaut.2025.103360
Olivier Espitia , Patrick Bruneval , Eric Liozon , Jacques Pouchot , Hubert de Boysson , Julien Gaudric , Laurent Chiche , Paul Achouh , Jean-Christian Roussel , Sébastien Miranda , Tristan Mirault , Alban Redheuil , Jean-Michel Serfaty , Antoine Bénichou , Christian Agard , Alexis F. Guédon , Patrice Cacoub , François Paraf , Pierre-Jean Fouret , Claire Toquet , David Saadoun
Background
Non-infectious aortitis encompasses various histological patterns, but their specific cardiovascular outcomes remain unclear.
Objective
To evaluate the mortality associated with non-infectious surgical thoracic aortitis.
Methods
This retrospective multicenter study included patients who underwent thoracic aortic surgery and had histological evidence of aortitis. The study analyzed the characteristics of patients with non-infectious aortitis presenting either a granulomatous/giant cell histological pattern or a lymphoplasmacytic pattern. Factors associated with mortality were identified using multivariate analysis.
Results
Among 5666 patients who underwent thoracic aortic surgery, 197 were found to have non-infectious aortitis with either a granulomatous/giant cell histological pattern (n = 138) or a lymphoplasmacytic pattern (n = 59). The overall standardized mortality rate (SMR) for patients with non-infectious surgical thoracic aortitis was 1.61 (95 % CI: 1.05; 2.39), with 31.5 % of patients dying within 10 years of the initial procedure. After a median follow-up of 3.5 years [IQR: 0.5–6.8] post-surgery, 31 % of deaths were due to aortic dissection or rupture. The 10-year cumulative incidence of death was 40.1 % (95 % CI, 17.7–61.8) for patients with a granulomatous/giant cell pattern and 14.4 % (95 % CI, 2.6–35.6) for those with a lymphoplasmacytic pattern. Granulomatous/giant cell histological pattern (HR 4.71 [vs lymphoplasmacytic pattern]; 95 % CI, 1.37–16.2; p = 0.023) and aortic dissection at diagnosis (HR 6.07 [vs aneurysm]; 95 % CI, 2.89–12.7; p < 0.0001) were independently associated with increased mortality.
Conclusion
This multicenter study found that 31.5 % of patients with non-infectious surgical thoracic aortitis are expected to die within 10 years of their initial surgery. The granulomatous/giant cell histological pattern is associated with higher mortality.
{"title":"Histological pattern of non-infectious thoracic aortitis impacts mortality","authors":"Olivier Espitia , Patrick Bruneval , Eric Liozon , Jacques Pouchot , Hubert de Boysson , Julien Gaudric , Laurent Chiche , Paul Achouh , Jean-Christian Roussel , Sébastien Miranda , Tristan Mirault , Alban Redheuil , Jean-Michel Serfaty , Antoine Bénichou , Christian Agard , Alexis F. Guédon , Patrice Cacoub , François Paraf , Pierre-Jean Fouret , Claire Toquet , David Saadoun","doi":"10.1016/j.jaut.2025.103360","DOIUrl":"10.1016/j.jaut.2025.103360","url":null,"abstract":"<div><h3>Background</h3><div>Non-infectious aortitis encompasses various histological patterns, but their specific cardiovascular outcomes remain unclear.</div></div><div><h3>Objective</h3><div>To evaluate the mortality associated with non-infectious surgical thoracic aortitis.</div></div><div><h3>Methods</h3><div>This retrospective multicenter study included patients who underwent thoracic aortic surgery and had histological evidence of aortitis. The study analyzed the characteristics of patients with non-infectious aortitis presenting either a granulomatous/giant cell histological pattern or a lymphoplasmacytic pattern. Factors associated with mortality were identified using multivariate analysis.</div></div><div><h3>Results</h3><div>Among 5666 patients who underwent thoracic aortic surgery, 197 were found to have non-infectious aortitis with either a granulomatous/giant cell histological pattern (n = 138) or a lymphoplasmacytic pattern (n = 59). The overall standardized mortality rate (SMR) for patients with non-infectious surgical thoracic aortitis was 1.61 (95 % CI: 1.05; 2.39), with 31.5 % of patients dying within 10 years of the initial procedure. After a median follow-up of 3.5 years [IQR: 0.5–6.8] post-surgery, 31 % of deaths were due to aortic dissection or rupture. The 10-year cumulative incidence of death was 40.1 % (95 % CI, 17.7–61.8) for patients with a granulomatous/giant cell pattern and 14.4 % (95 % CI, 2.6–35.6) for those with a lymphoplasmacytic pattern. Granulomatous/giant cell histological pattern (HR 4.71 [vs lymphoplasmacytic pattern]; 95 % CI, 1.37–16.2; p = 0.023) and aortic dissection at diagnosis (HR 6.07 [vs aneurysm]; 95 % CI, 2.89–12.7; p < 0.0001) were independently associated with increased mortality.</div></div><div><h3>Conclusion</h3><div>This multicenter study found that 31.5 % of patients with non-infectious surgical thoracic aortitis are expected to die within 10 years of their initial surgery. The granulomatous/giant cell histological pattern is associated with higher mortality.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"151 ","pages":"Article 103360"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006089","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 : 2025-02-01DOI: 10.1016/j.jaut.2025.103375
Benjamin Schrijver , P. Martijn Kolijn , Saad H. Hasib , Josianne C.E.M. ten Berge , Ikhwanuliman Putera , Nicole M.A. Nagtzaam , J. Conny P.A. van Holten Neelen , Anton W. Langerak , Marco W.J. Schreurs , P. Martin van Hagen , Willem A. Dik
Purpose
To explore the autoimmune component of sarcoid uveitis (SU) by analyzing serum anti-retinal antibodies (ARAs), identifying targeted retinal proteins, T- and B-cell receptor repertoires and HLA genotype.
Methods
Material from 45 sarcoidosis patients with no presenting uveitis (SNPU) and 46 with SU was analyzed. Serum ARAs and targeted retinal layers were assessed using indirect immunofluorescence staining. HuScan analysis identified autoantibody-targeted linear epitopes. Validation included a bead-based assay for anti-Piccolo Presynaptic Cytomatrix Protein (PCLO) antibodies and an ELISpot assay for PCLO-reactive T-lymphocytes. T cell receptor beta (TCRB) and B cell receptor heavy (BCRH) repertoire analyses were performed using next-generation sequencing and HLA class II genotypes were determined by sequence-specific primer analysis.
Results
ARAs were more prevalent in SU patients than in SNPU patients (52 vs. 22 %, p = 0.003), with significant more reactivity against the nuclear retinal layer (32 vs. 7 %, p = 0.005). HuScan identified autoantibodies against three retinal proteins, including PCLO. Bead-based analysis showed higher anti-PCLO autoantibody levels in ARA-positive patients (median: 913.3 vs. 544.5, p = 0.035), and PCLO-directed T-lymphocytes were present in ARA-positive SU patients. Two TCRB clusters were identified in four unique ARA positive patients, while absent in ARA negative patients. No HLA allele association with ARA status could be detected.
Conclusion
Our findings reveal an association between serum ARA-positivity and SU, suggesting a link to autoimmune processes. An humoral and cellular response against the retinal protein PCLO was identified, highlighting PCLO as a potential autoimmune target in ARA-positive patients. Additionally, specific TCRB clusters were found to correlate with ARA status.
{"title":"Anti-retinal immune response in sarcoid uveitis: A potential role for PCLO as an antigenic target","authors":"Benjamin Schrijver , P. Martijn Kolijn , Saad H. Hasib , Josianne C.E.M. ten Berge , Ikhwanuliman Putera , Nicole M.A. Nagtzaam , J. Conny P.A. van Holten Neelen , Anton W. Langerak , Marco W.J. Schreurs , P. Martin van Hagen , Willem A. Dik","doi":"10.1016/j.jaut.2025.103375","DOIUrl":"10.1016/j.jaut.2025.103375","url":null,"abstract":"<div><h3>Purpose</h3><div>To explore the autoimmune component of sarcoid uveitis (SU) by analyzing serum anti-retinal antibodies (ARAs), identifying targeted retinal proteins, T- and B-cell receptor repertoires and HLA genotype.</div></div><div><h3>Methods</h3><div>Material from 45 sarcoidosis patients with no presenting uveitis (SNPU) and 46 with SU was analyzed. Serum ARAs and targeted retinal layers were assessed using indirect immunofluorescence staining. HuScan analysis identified autoantibody-targeted linear epitopes. Validation included a bead-based assay for anti-Piccolo Presynaptic Cytomatrix Protein (PCLO) antibodies and an ELISpot assay for PCLO-reactive T-lymphocytes. T cell receptor beta (TCRB) and B cell receptor heavy (BCRH) repertoire analyses were performed using next-generation sequencing and HLA class II genotypes were determined by sequence-specific primer analysis.</div></div><div><h3>Results</h3><div>ARAs were more prevalent in SU patients than in SNPU patients (52 vs. 22 %, p = 0.003), with significant more reactivity against the nuclear retinal layer (32 vs. 7 %, p = 0.005). HuScan identified autoantibodies against three retinal proteins, including PCLO. Bead-based analysis showed higher anti-PCLO autoantibody levels in ARA-positive patients (median: 913.3 vs. 544.5, p = 0.035), and PCLO-directed T-lymphocytes were present in ARA-positive SU patients. Two TCRB clusters were identified in four unique ARA positive patients, while absent in ARA negative patients. No HLA allele association with ARA status could be detected.</div></div><div><h3>Conclusion</h3><div>Our findings reveal an association between serum ARA-positivity and SU, suggesting a link to autoimmune processes. An humoral and cellular response against the retinal protein PCLO was identified, highlighting PCLO as a potential autoimmune target in ARA-positive patients. Additionally, specific TCRB clusters were found to correlate with ARA status.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"151 ","pages":"Article 103375"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074686","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 : 2025-02-01DOI: 10.1016/j.jaut.2025.103370
Natalie V. Scime , Sonia M. Grandi , Mary A. De Vera , Cindy-Lee Dennis , Alexa Boblitz , Hilary K. Brown
Objectives
To determine the association between primary Cesarean delivery and incident autoimmune disease in women.
Methods
We conducted a population-based cohort study of 253,901 females in Ontario, Canada with a first childbirth between 2012 and 2017 and with no pre-existing autoimmune disease. Royston-Parmar models were used to estimate the time-varying association between Cesarean delivery (28.2 % of females) versus vaginal delivery (71.8 % of females; referent) and celiac disease, multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic autoimmune rheumatic disease (SARD), separately, from date of delivery to date of diagnosis or censoring at death, loss of health insurance, or March 31, 2021. To account for potential confounding by indication for Cesarean delivery, models were generated using (i) overlap weighting based on propensity scores for mode of delivery and (ii) with restriction to low-risk pregnancies free of pre-labour Cesarean indications (n = 146,887).
Results
At up to 9 years following childbirth (median = 6.5 years of follow-up), Cesarean delivery was associated with an increased risk of MS, but not celiac disease, RA, or SARD. Overall, cumulative incidence of MS was 0.28 % following Cesarean delivery and 0.21 % following vaginal delivery. After overlap weighting, the adjusted hazard ratio (AHR) curve formed a slight L-shape with the largest magnitude between birth and 3 years (1-year AHR 1.37, 95 % CI 1.04–1.69) and diminishing thereafter (5-year 1.23, 95 % CI 0.91–1.55; 7-year 1.21, 95 % CI 0.84–1.57). Results were similar when restricted to births following low-risk pregnancies.
Conclusions
Findings suggest a possible link between Cesarean delivery and MS development among females that warrants future replication and explanatory studies.
{"title":"Primary Cesarean delivery and future risk of maternal autoimmune disease: A population-based cohort study","authors":"Natalie V. Scime , Sonia M. Grandi , Mary A. De Vera , Cindy-Lee Dennis , Alexa Boblitz , Hilary K. Brown","doi":"10.1016/j.jaut.2025.103370","DOIUrl":"10.1016/j.jaut.2025.103370","url":null,"abstract":"<div><h3>Objectives</h3><div>To determine the association between primary Cesarean delivery and incident autoimmune disease in women.</div></div><div><h3>Methods</h3><div>We conducted a population-based cohort study of 253,901 females in Ontario, Canada with a first childbirth between 2012 and 2017 and with no pre-existing autoimmune disease. Royston-Parmar models were used to estimate the time-varying association between Cesarean delivery (28.2 % of females) versus vaginal delivery (71.8 % of females; referent) and celiac disease, multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic autoimmune rheumatic disease (SARD), separately, from date of delivery to date of diagnosis or censoring at death, loss of health insurance, or March 31, 2021. To account for potential confounding by indication for Cesarean delivery, models were generated using (i) overlap weighting based on propensity scores for mode of delivery and (ii) with restriction to low-risk pregnancies free of pre-labour Cesarean indications (n = 146,887).</div></div><div><h3>Results</h3><div>At up to 9 years following childbirth (median = 6.5 years of follow-up), Cesarean delivery was associated with an increased risk of MS, but not celiac disease, RA, or SARD. Overall, cumulative incidence of MS was 0.28 % following Cesarean delivery and 0.21 % following vaginal delivery. After overlap weighting, the adjusted hazard ratio (AHR) curve formed a slight L-shape with the largest magnitude between birth and 3 years (1-year AHR 1.37, 95 % CI 1.04–1.69) and diminishing thereafter (5-year 1.23, 95 % CI 0.91–1.55; 7-year 1.21, 95 % CI 0.84–1.57). Results were similar when restricted to births following low-risk pregnancies.</div></div><div><h3>Conclusions</h3><div>Findings suggest a possible link between Cesarean delivery and MS development among females that warrants future replication and explanatory studies.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"151 ","pages":"Article 103370"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080091","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 : 2025-01-01DOI: 10.1016/j.jaut.2024.103351
Yue Xin , Ming Yang , Zhidan Zhao , Zhenghao He , Yang Mei , Feng Xiong , Fen Tan , Anqun Chen , Christopher Chang , Helong Dai , Haijing Wu , Qianjin Lu
Psoriasis vulgaris remains a common inflammatory skin disease globally. The imbalance between Th17 and Treg cells plays an integral role in the pathogenesis of psoriasis vulgaris, but the underlying mechanisms remain obscure. The role of AIM2 in Treg cell function in psoriasis is unclear. We found that AIM2 expression is upregulated in peripheral blood and skin lesions from patients with psoriasis vulgaris when compared with healthy controls. In a psoriasis-like mouse model, CD4creAim2fl/fl mice showed aggravated psoriatic symptoms, increased Th17 cell and decreased Treg cell numbers in spleens and dLNs compared to Aim2fl/fl mice. The loss of AIM2 in naïve CD4+ T cells promotes Th17 cell differentiation and decreases Treg cell numbers in vitro. Further, IKZF2 was identified as a downstream regulator of AIM2 through RNAseq analysis. AIM2 deficiency in CD4+ T cells downregulated IKZF2 mRNA expression. Silencing IKZF2 in naïve CD4+ T cells led to a significant increase in the expression of RORc and diminished FOXP3 expression. In summary, AIM2 may regulate the differentiation of Th17 and Treg cell by affecting IKZF2. Our findings might shed light on the pathogenesis of psoriasis and provide potential therapeutic targets for patients with psoriasis.
{"title":"AIM2 deficiency in CD4+ T cells promotes psoriasis-like inflammation by regulating Th17-Treg axis via AIM2-IKZF2 pathway","authors":"Yue Xin , Ming Yang , Zhidan Zhao , Zhenghao He , Yang Mei , Feng Xiong , Fen Tan , Anqun Chen , Christopher Chang , Helong Dai , Haijing Wu , Qianjin Lu","doi":"10.1016/j.jaut.2024.103351","DOIUrl":"10.1016/j.jaut.2024.103351","url":null,"abstract":"<div><div>Psoriasis vulgaris remains a common inflammatory skin disease globally. The imbalance between Th17 and Treg cells plays an integral role in the pathogenesis of psoriasis vulgaris, but the underlying mechanisms remain obscure. The role of AIM2 in Treg cell function in psoriasis is unclear. We found that AIM2 expression is upregulated in peripheral blood and skin lesions from patients with psoriasis vulgaris when compared with healthy controls. In a psoriasis-like mouse model, <em>CD4</em><sup><em>cre</em></sup><em>Aim2</em><sup><em>fl/fl</em></sup> mice showed aggravated psoriatic symptoms, increased Th17 cell and decreased Treg cell numbers in spleens and dLNs compared to <em>Aim2</em><sup><em>fl/fl</em></sup> mice. The loss of AIM2 in naïve CD4<sup>+</sup> T cells promotes Th17 cell differentiation and decreases Treg cell numbers <em>in vitro</em>. Further, IKZF2 was identified as a downstream regulator of AIM2 through RNAseq analysis. AIM2 deficiency in CD4<sup>+</sup> T cells downregulated IKZF2 mRNA expression. Silencing IKZF2 in naïve CD4<sup>+</sup> T cells led to a significant increase in the expression of RORc and diminished FOXP3 expression. In summary, AIM2 may regulate the differentiation of Th17 and Treg cell by affecting IKZF2. Our findings might shed light on the pathogenesis of psoriasis and provide potential therapeutic targets for patients with psoriasis.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"150 ","pages":"Article 103351"},"PeriodicalIF":7.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846777","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}
It has been known that Epstein-Barr virus (EBV) can latently infect immune cells after the initial infection, and epidemiological studies have suggested its association with the onset of immune-mediated diseases (IMDs). However, the specific impact of EBV infection on IMDs pathology remains unclear. We quantified EBV load of B cell subsets (Naïve B cells, Unswitched memory B cells, Switched memory B cells, Double negative B cells, and Plasmablasts) in IMD patients as well as healthy control (HC) using bulk RNA sequencing data of 504 donors. The EBV load was clearly higher in IMD patients compared to HC. Furthermore, the wide range of EBV load in this dataset enabled us to assess the impact of EBV load on gene regulation. We found many examples of expression quantitative trait loci (eQTL) whose effects were associated with EBV load. Expression QTLs that exhibited larger effects with increasing EBV load were significantly overlapped with binding sites of transcription factors derived from the EBV genome. These EBV load-associated eQTLs exhibited high enrichment of systemic lupus erythematosus (SLE) GWAS signals, suggesting the mechanical link of EBV infection and the onset of the disease via gene regulation. These findings provide the first evidence of the influence of EBV infection on gene regulation in human primary cells and its association with the SLE onset and/or progression.
{"title":"Effect of Epstein-Barr Virus infection on gene regulation in immune cells of patients with Immune-Mediated Diseases","authors":"Yuko Akutsu , Mineto Ota , Takahiro Itamiya , Masaaki Mori , Tomohiro Morio , Kazuhiko Yamamoto , Tomohisa Okamura , Keishi Fujio","doi":"10.1016/j.jaut.2024.103355","DOIUrl":"10.1016/j.jaut.2024.103355","url":null,"abstract":"<div><div>It has been known that Epstein-Barr virus (EBV) can latently infect immune cells after the initial infection, and epidemiological studies have suggested its association with the onset of immune-mediated diseases (IMDs). However, the specific impact of EBV infection on IMDs pathology remains unclear. We quantified EBV load of B cell subsets (Naïve B cells, Unswitched memory B cells, Switched memory B cells, Double negative B cells, and Plasmablasts) in IMD patients as well as healthy control (HC) using bulk RNA sequencing data of 504 donors. The EBV load was clearly higher in IMD patients compared to HC. Furthermore, the wide range of EBV load in this dataset enabled us to assess the impact of EBV load on gene regulation. We found many examples of expression quantitative trait loci (eQTL) whose effects were associated with EBV load. Expression QTLs that exhibited larger effects with increasing EBV load were significantly overlapped with binding sites of transcription factors derived from the EBV genome. These EBV load-associated eQTLs exhibited high enrichment of systemic lupus erythematosus (SLE) GWAS signals, suggesting the mechanical link of EBV infection and the onset of the disease via gene regulation. These findings provide the first evidence of the influence of EBV infection on gene regulation in human primary cells and its association with the SLE onset and/or progression.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"150 ","pages":"Article 103355"},"PeriodicalIF":7.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949502","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 : 2025-01-01DOI: 10.1016/j.jaut.2024.103342
Lisa MF. Janssen , Frauke Lemaire , Chiara Longo Sanchez-Calero , François Huaux , Steven Ronsmans , Peter HM. Hoet , Manosij Ghosh
Systemic sclerosis (SSc) is an autoimmune chronic connective tissue disorder with a complex pathogenesis and a strong gene-environment interaction. Despite the low prevalence of SSc, with around 100–250 cases per million, the morbidity and mortality are high and disproportionately affecting women. In this context, we review the influence of the external and internal exposome on the “immunome” in SSc. While several studies have addressed aspects of exposure-induced autoimmunity in general, very few have focused on SSc-specific phenotypes. In epidemiological studies, targeted characterization of the external exposome component in relation to SSc has often been limited to a single exposure. Despite the selective characterization of exposure, such studies play an important role in providing evidence that can be used towards reduction of exposure of modifiable factors, and can lead to proper management and prevention of SSc. Additionally, there is an effort towards integration of external exposome data with health data (health records, medical imaging, diagnostic results, etc.), to significantly improve our understanding of the environmental and occupational causes of SSc. A limited number of studies have identified biological processes related to the vascular homeostasis, fibrotic processes and the immune system. The key findings of the current review show advances in our understanding of the SSc disease phenotype and associated biomarkers in relation to specific pathophysiological features, however most often such studies are not supplemented with external exposome data.
{"title":"External and internal exposome as triggers of biological signalling in systemic sclerosis – A narrative synthesis","authors":"Lisa MF. Janssen , Frauke Lemaire , Chiara Longo Sanchez-Calero , François Huaux , Steven Ronsmans , Peter HM. Hoet , Manosij Ghosh","doi":"10.1016/j.jaut.2024.103342","DOIUrl":"10.1016/j.jaut.2024.103342","url":null,"abstract":"<div><div>Systemic sclerosis (SSc) is an autoimmune chronic connective tissue disorder with a complex pathogenesis and a strong gene-environment interaction. Despite the low prevalence of SSc, with around 100–250 cases per million, the morbidity and mortality are high and disproportionately affecting women. In this context, we review the influence of the external and internal exposome on the “immunome” in SSc. While several studies have addressed aspects of exposure-induced autoimmunity in general, very few have focused on SSc-specific phenotypes. In epidemiological studies, targeted characterization of the external exposome component in relation to SSc has often been limited to a single exposure. Despite the selective characterization of exposure, such studies play an important role in providing evidence that can be used towards reduction of exposure of modifiable factors, and can lead to proper management and prevention of SSc. Additionally, there is an effort towards integration of external exposome data with health data (health records, medical imaging, diagnostic results, etc.), to significantly improve our understanding of the environmental and occupational causes of SSc. A limited number of studies have identified biological processes related to the vascular homeostasis, fibrotic processes and the immune system. The key findings of the current review show advances in our understanding of the SSc disease phenotype and associated biomarkers in relation to specific pathophysiological features, however most often such studies are not supplemented with external exposome data.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"150 ","pages":"Article 103342"},"PeriodicalIF":7.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791803","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 : 2025-01-01DOI: 10.1016/j.jaut.2025.103356
Sarah Sofie Andersen , Terese Frellesen Neumann , Sofie Dannesbo , Anna Axelsson Raja , Ruth Ottilia Birgitta Vøgg , Heather Allison Boyd , Karen Schreiber , Maria Munk Pærregaard , Alex Hørby Christensen , Kasper Karmark Iversen , Henning Bundgaard , Anne-Sophie Sillesen
Introduction
Maternal autoimmune systemic connective tissue diseases (CTDs) and their related antibodies have been associated with adverse fetal outcomes, including complete heart block. In this study, we assessed the association between maternal CTD or vasculitis and neonatal electrocardiographic (ECG) parameters.
Methods
Our study population was drawn from the Copenhagen Baby Heart Study (CBHS), a prospective, population-based cohort study open to all neonates born in the Copenhagen area. All CBHS neonates born to mothers with CTD or vasculitis were matched 1:3 to neonates born to mothers without these diseases on sex, gestational age, age and weight at time of examination, and maternal age at delivery. Maternal CTD and vasculitis diagnoses were validated through medical record review. Our primary analyses compared ECG parameters for exposed and unexposed neonates overall. Where numbers allowed, subanalyses were then conducted by specific CTD diagnoses and autoantibody types.
Results
Among 17,862 CBHS neonates with an available ECG, 40 neonates of mothers with CTDs or vasculitis (50 % males, median age 12 [interquartile range 8–16] days) were matched to unexposed neonates. Overall, no significant differences in heart rate, PR interval, QRS axis, QRS duration, QT/QTc interval, or R- or S-wave amplitudes were found when comparing exposed and unexposed neonates (all p > 0.05). Similarly, separate analyses of the 10 neonates with anti-Ro/SSA-positive mothers and their matched comparators revealed no significant between-group differences. However, neonates born to mothers with antiphospholipid syndrome (n = 15) had a significantly longer QRS duration (median 56 ms vs. 52 ms, p = 0.02) and corrected QT interval (median QTcBaz 430 ms vs. 414 ms, p = 0.01), compared with matched unexposed neonates.
Conclusion
In this population-based study, no significant overall differences in ECG parameters were found between neonates exposed to maternal CTD or vasculitis and unexposed neonates. However, neonates exposed to maternal antiphospholipid syndrome had significantly longer QRS- and QTc intervals than unexposed neonates. The potential clinical implications of these findings are unknown and, combined with the limitations of this study, warrant further investigation in larger cohorts.
母体自身免疫性系统性结缔组织疾病（CTDs）及其相关抗体与胎儿不良结局相关，包括完全性心脏传导阻滞。在这项研究中，我们评估了母体CTD或血管炎与新生儿心电图参数之间的关系。方法：我们的研究人群来自哥本哈根婴儿心脏研究（CBHS），这是一项前瞻性、基于人群的队列研究，对哥本哈根地区出生的所有新生儿开放。所有患有CTD或血管炎的母亲所生的CBHS新生儿在性别、胎龄、检查时的年龄和体重以及分娩时的母亲年龄方面与没有这些疾病的母亲所生的新生儿进行1:3的匹配。产妇CTD和血管炎的诊断是通过医疗记录审查验证。我们的初步分析比较了暴露和未暴露新生儿的心电图参数。在数量允许的情况下，根据特定的CTD诊断和自身抗体类型进行亚分析。结果：在17862名可获得ECG的CBHS新生儿中，40名患有CTDs或血管炎的母亲的新生儿（50%为男性，中位年龄12[四分位数间距8-16]天）与未暴露的新生儿相匹配。总体而言，暴露和未暴露的新生儿在心率、PR间期、QRS轴、QRS持续时间、QT/QTc间期或R波或s波振幅方面无显著差异（均p < 0.05）。同样，对抗ro / ssa阳性母亲的10名新生儿及其匹配比较者的单独分析显示，组间差异不显著。然而，与未暴露的新生儿相比，抗磷脂综合征母亲（n = 15）所生的新生儿QRS持续时间（中位56 ms vs. 52 ms, p = 0.02）和校正QT间期（中位QTcBaz 430 ms vs. 414 ms, p = 0.01）明显更长。结论：在这项基于人群的研究中，暴露于母体CTD或血管炎的新生儿与未暴露于母体CTD或血管炎的新生儿之间的心电图参数没有明显的总体差异。然而，暴露于母体抗磷脂综合征的新生儿的QRS-和QTc间隔明显长于未暴露于母体抗磷脂综合征的新生儿。这些发现的潜在临床意义尚不清楚，并且结合本研究的局限性，需要在更大的队列中进行进一步的调查。
{"title":"Maternal autoimmune systemic connective tissue disease and vasculitis and electrocardiographic findings in the offspring","authors":"Sarah Sofie Andersen , Terese Frellesen Neumann , Sofie Dannesbo , Anna Axelsson Raja , Ruth Ottilia Birgitta Vøgg , Heather Allison Boyd , Karen Schreiber , Maria Munk Pærregaard , Alex Hørby Christensen , Kasper Karmark Iversen , Henning Bundgaard , Anne-Sophie Sillesen","doi":"10.1016/j.jaut.2025.103356","DOIUrl":"10.1016/j.jaut.2025.103356","url":null,"abstract":"<div><h3>Introduction</h3><div>Maternal autoimmune systemic connective tissue diseases (CTDs) and their related antibodies have been associated with adverse fetal outcomes, including complete heart block. In this study, we assessed the association between maternal CTD or vasculitis and neonatal electrocardiographic (ECG) parameters.</div></div><div><h3>Methods</h3><div>Our study population was drawn from the Copenhagen Baby Heart Study (CBHS), a prospective, population-based cohort study open to all neonates born in the Copenhagen area. All CBHS neonates born to mothers with CTD or vasculitis were matched 1:3 to neonates born to mothers without these diseases on sex, gestational age, age and weight at time of examination, and maternal age at delivery. Maternal CTD and vasculitis diagnoses were validated through medical record review. Our primary analyses compared ECG parameters for exposed and unexposed neonates overall. Where numbers allowed, subanalyses were then conducted by specific CTD diagnoses and autoantibody types.</div></div><div><h3>Results</h3><div>Among 17,862 CBHS neonates with an available ECG, 40 neonates of mothers with CTDs or vasculitis (50 % males, median age 12 [interquartile range 8–16] days) were matched to unexposed neonates. Overall, no significant differences in heart rate, PR interval, QRS axis, QRS duration, QT/QTc interval, or R- or S-wave amplitudes were found when comparing exposed and unexposed neonates (all p > 0.05). Similarly, separate analyses of the 10 neonates with anti-Ro/SSA-positive mothers and their matched comparators revealed no significant between-group differences. However, neonates born to mothers with antiphospholipid syndrome (n = 15) had a significantly longer QRS duration (median 56 ms vs. 52 ms, p = 0.02) and corrected QT interval (median QTcBaz 430 ms vs. 414 ms, p = 0.01), compared with matched unexposed neonates.</div></div><div><h3>Conclusion</h3><div>In this population-based study, no significant overall differences in ECG parameters were found between neonates exposed to maternal CTD or vasculitis and unexposed neonates. However, neonates exposed to maternal antiphospholipid syndrome had significantly longer QRS- and QTc intervals than unexposed neonates. The potential clinical implications of these findings are unknown and, combined with the limitations of this study, warrant further investigation in larger cohorts.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"150 ","pages":"Article 103356"},"PeriodicalIF":7.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142965132","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}
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