Pub Date : 2025-06-01Epub Date: 2025-05-06DOI: 10.1016/j.jaut.2025.103433
Qin-Yi Su , Xin-Xin Zheng , Xin-Ting Han , Qian Li , Ya-Ru Gao , Sheng-Xiao Zhang , Xiao-Feng Li
Age-associated B cells (ABCs) are a distinct subset of B cells. This B-cell population expands in the elderly but is also abnormally expanded in patients with autoimmune diseases like systemic lupus erythematosus (SLE). ABC differentiation requires unique signaling stimuli, including BCR stimulation, TLR7 and TLR9 signaling, and the action of cytokines. The role of ABCs in the pathogenesis and treatment strategies of SLE has been a research hotspot in recent years. Possible pathogenic mechanisms include the production of autoantibodies and cytokines, as well as stimulation of spontaneous germinal center. Specifically targeting ABCs is a promising strategy for treating SLE. This article reviews the role of ABCs in SLE. Understanding the origin and differentiation of ABCs and their role in SLE will facilitate the discovery of novel drug targets for the treatment of SLE.
{"title":"The role of age-associated B cells in systemic lupus erythematosus","authors":"Qin-Yi Su , Xin-Xin Zheng , Xin-Ting Han , Qian Li , Ya-Ru Gao , Sheng-Xiao Zhang , Xiao-Feng Li","doi":"10.1016/j.jaut.2025.103433","DOIUrl":"10.1016/j.jaut.2025.103433","url":null,"abstract":"<div><div>Age-associated B cells (ABCs) are a distinct subset of B cells. This B-cell population expands in the elderly but is also abnormally expanded in patients with autoimmune diseases like systemic lupus erythematosus (SLE). ABC differentiation requires unique signaling stimuli, including BCR stimulation, TLR7 and TLR9 signaling, and the action of cytokines. The role of ABCs in the pathogenesis and treatment strategies of SLE has been a research hotspot in recent years. Possible pathogenic mechanisms include the production of autoantibodies and cytokines, as well as stimulation of spontaneous germinal center. Specifically targeting ABCs is a promising strategy for treating SLE. This article reviews the role of ABCs in SLE. Understanding the origin and differentiation of ABCs and their role in SLE will facilitate the discovery of novel drug targets for the treatment of SLE.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103433"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912688","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 : 2025-06-01Epub Date: 2025-04-28DOI: 10.1016/j.jaut.2025.103424
Aditya Arra , Katrin Vogel , Irina Han , Christine Behrendt , Ildiko Rita Dunay , Thomas Häupl , Eugen Feist , Monika C. Brunner-Weinzierl
Innate lymphoid cells (ILCs) play a key role in maintaining immune homeostasis and are linked to inflammation and autoimmunity. This study investigates the role of ILCs in the pathogenesis of rheumatoid arthritis (RA) and their response to two targeted therapies - JAK inhibitors (JAKi), which block critical signaling pathways required for their activation, and TNF inhibitors (TNFi), which target a key inflammatory mediator - offering insights into how these interventions shape ILC-driven inflammation.
ILC distribution correlated with RA activity, as indicated by the DAS28 score, and this imbalance was improved significantly within four weeks of JAKi, underscoring its early therapeutic impact on ILC-mediated inflammation. While levels of ILC3-activating cytokines such as IL-1β and IL-23 declined under JAKi therapy, they remained unchanged with TNFi. Although JAKi and TNFi showed similar treatment efficacy, multivariate regression analysis showed that improvement in DAS28 score was strongly associated with increase in CTLA-4+ILC3 and reduction in both PD1+ILC3 frequency and systemic IL12p40/IL-23 levels only with JAKi. Notably, this two ILC3 subtypes determined the DAS28 score after 50 d of JAKi. In contrast, patients showing limited response to JAKi (ΔDAS28 < 1.2) maintained high systemic IL-18 levels, a cytokine that induces signaling independent of the JAK pathway, suggesting a potential resistance mechanism. These findings highlight that monitoring PD1+ILC3s or IL-12p40/IL-23 may serve as an indicator of JAKi responsiveness, while elevated IL-18 may identify patients benefiting from alternative therapies. These results also emphasize the clinical relevance of targeting innate immunity for more personalized, pathway-focused RA therapies.
{"title":"PD1+ innate lymphoid cells 3 predict JAK-dependent inflammation in rheumatoid arthritis","authors":"Aditya Arra , Katrin Vogel , Irina Han , Christine Behrendt , Ildiko Rita Dunay , Thomas Häupl , Eugen Feist , Monika C. Brunner-Weinzierl","doi":"10.1016/j.jaut.2025.103424","DOIUrl":"10.1016/j.jaut.2025.103424","url":null,"abstract":"<div><div>Innate lymphoid cells (ILCs) play a key role in maintaining immune homeostasis and are linked to inflammation and autoimmunity. This study investigates the role of ILCs in the pathogenesis of rheumatoid arthritis (RA) and their response to two targeted therapies - JAK inhibitors (JAKi), which block critical signaling pathways required for their activation, and TNF inhibitors (TNFi), which target a key inflammatory mediator - offering insights into how these interventions shape ILC-driven inflammation.</div><div>ILC distribution correlated with RA activity, as indicated by the DAS28 score, and this imbalance was improved significantly within four weeks of JAKi, underscoring its early therapeutic impact on ILC-mediated inflammation. While levels of ILC3-activating cytokines such as IL-1β and IL-23 declined under JAKi therapy, they remained unchanged with TNFi. Although JAKi and TNFi showed similar treatment efficacy, multivariate regression analysis showed that improvement in DAS28 score was strongly associated with increase in CTLA-4<sup>+</sup>ILC3 and reduction in both PD1<sup>+</sup>ILC3 frequency and systemic IL12p40/IL-23 levels only with JAKi. Notably, this two ILC3 subtypes determined the DAS28 score after 50 d of JAKi. In contrast, patients showing limited response to JAKi (ΔDAS28 < 1.2) maintained high systemic IL-18 levels, a cytokine that induces signaling independent of the JAK pathway, suggesting a potential resistance mechanism. These findings highlight that monitoring PD1<sup>+</sup>ILC3s or IL-12p40/IL-23 may serve as an indicator of JAKi responsiveness, while elevated IL-18 may identify patients benefiting from alternative therapies. These results also emphasize the clinical relevance of targeting innate immunity for more personalized, pathway-focused RA therapies.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103424"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882046","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 : 2025-06-01Epub Date: 2025-04-29DOI: 10.1016/j.jaut.2025.103425
Alpana Singh, Rishabh Chaudhary
VEXAS (Vacuoles, E1 Enzyme, X-linked, Auto-inflammatory, Somatic) syndrome is a recently identified auto-inflammatory disorder predominantly affecting males over the age of 50. It arises due to somatic mutations in the UBA1 gene, an X-linked gene essential for initiating the ubiquitin-proteasome system, leading to dysregulated protein degradation and immune dysfunction. Clinically, VEXAS presents with a diverse array of inflammatory manifestations, including persistent fever, neutrophilic dermatosis, auricular and nasal chondritis, pulmonary infiltrates, ocular inflammation, and venous thrombosis, along with significant haematological abnormalities such as macrocytic anemia, thrombocytopenia, myeloid and erythroid precursor vacuolization, and bone marrow dysplasia. These systemic complications contribute to high morbidity and mortality. Currently, therapeutic strategies remain largely undefined, with treatment focusing on two primary approaches, which are modulating inflammation through corticosteroids, JAK inhibitors, or IL-6 blockade and targeting the mutant hematopoietic clone or allogeneic hematopoietic stem cell transplantation (AHSCT) therapies. Supportive interventions, including red blood cell and platelet transfusions, erythropoiesis-stimulating agents, thromboprophylaxis, and antimicrobial prophylaxis, are crucial in managing disease-associated complications. This review aims to present a comprehensive analysis of VEXAS syndrome, focusing on its genetic underpinnings, pathophysiology, clinical manifestations, diagnostic criteria, and evolving therapeutic strategies. By integrating current findings from the literature and identifying gaps in ongoing research, this review seeks to equip clinicians and researchers with a comprehensive understanding of VEXAS syndrome. Additionally, it aims to guide future investigations toward refining diagnostic strategies, optimizing therapeutic approaches, and ultimately improving patient care and clinical outcomes.
{"title":"VEXAS syndrome: A newly identified X-Linked hematoinflammatory disorder – A comprehensive overview of its genetic, molecular, inflammatory, and clinical landscape","authors":"Alpana Singh, Rishabh Chaudhary","doi":"10.1016/j.jaut.2025.103425","DOIUrl":"10.1016/j.jaut.2025.103425","url":null,"abstract":"<div><div>VEXAS (Vacuoles, E1 Enzyme, X-linked, Auto-inflammatory, Somatic) syndrome is a recently identified auto-inflammatory disorder predominantly affecting males over the age of 50. It arises due to somatic mutations in the <em>UBA1</em> gene, an X-linked gene essential for initiating the ubiquitin-proteasome system, leading to dysregulated protein degradation and immune dysfunction. Clinically, VEXAS presents with a diverse array of inflammatory manifestations, including persistent fever, neutrophilic dermatosis, auricular and nasal chondritis, pulmonary infiltrates, ocular inflammation, and venous thrombosis, along with significant haematological abnormalities such as macrocytic anemia, thrombocytopenia, myeloid and erythroid precursor vacuolization, and bone marrow dysplasia. These systemic complications contribute to high morbidity and mortality. Currently, therapeutic strategies remain largely undefined, with treatment focusing on two primary approaches, which are modulating inflammation through corticosteroids, JAK inhibitors, or IL-6 blockade and targeting the mutant hematopoietic clone or allogeneic hematopoietic stem cell transplantation (AHSCT) therapies. Supportive interventions, including red blood cell and platelet transfusions, erythropoiesis-stimulating agents, thromboprophylaxis, and antimicrobial prophylaxis, are crucial in managing disease-associated complications. This review aims to present a comprehensive analysis of VEXAS syndrome, focusing on its genetic underpinnings, pathophysiology, clinical manifestations, diagnostic criteria, and evolving therapeutic strategies. By integrating current findings from the literature and identifying gaps in ongoing research, this review seeks to equip clinicians and researchers with a comprehensive understanding of VEXAS syndrome. Additionally, it aims to guide future investigations toward refining diagnostic strategies, optimizing therapeutic approaches, and ultimately improving patient care and clinical outcomes.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103425"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143886662","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 : 2025-06-01Epub Date: 2025-05-28DOI: 10.1016/j.jaut.2025.103441
Mehmet Hocaoǧlu , Amr H. Sawalha
Objective
Polygenic risk scores (PRS) have been constructed to summarize genetic risk but there is limited research on environment-wide analysis of risk factors for systemic lupus erythematosus (SLE). In this study, we performed an environment-wide association study to construct an environmental risk score (ERS) for SLE and compare the risk conferred by ERS and PRS.
Methods
A total of 335 incident SLE cases were identified in the UK Biobank and matched 1:10 with age, sex, and ethnic background 3350 healthy controls. We examined the association between 37 environmental factors and SLE, using a univariate followed by a multivariate analysis. We summed the natural logarithm of the odds ratios (OR) of statistically significant environmental variables in the multivariable model to derive an ERS for SLE. Model discrimination was compared by De-Long′s test. PRS was calculated using the ORs of previously reported SLE genetic risk loci.
Results
The multivariate analysis revealed the association between daily sunlight exposure, depression, sleeplessness, sex hormone binding globulin levels, and air pollution with increased risk of SLE, while moderate physical activity was a protective factor. Increasing quartiles of the newly developed ERS were associated with similar degree of risk for SLE as the PRS. Integrating PRS with environmental factors significantly improved model performance.
Conclusions
We devised an ERS for SLE that summarizes the environmental component of the disease risk. We show that ERS confers a comparable degree of SLE risk as the PRS. Combining genetic and environmental factors could improve risk prediction models in SLE.
{"title":"Integrated analysis of polygenic and environmental risk scores for late-onset systemic lupus erythematosus","authors":"Mehmet Hocaoǧlu , Amr H. Sawalha","doi":"10.1016/j.jaut.2025.103441","DOIUrl":"10.1016/j.jaut.2025.103441","url":null,"abstract":"<div><h3>Objective</h3><div>Polygenic risk scores (PRS) have been constructed to summarize genetic risk but there is limited research on environment-wide analysis of risk factors for systemic lupus erythematosus (SLE). In this study, we performed an environment-wide association study to construct an environmental risk score (ERS) for SLE and compare the risk conferred by ERS and PRS.</div></div><div><h3>Methods</h3><div>A total of 335 incident SLE cases were identified in the UK Biobank and matched 1:10 with age, sex, and ethnic background 3350 healthy controls. We examined the association between 37 environmental factors and SLE, using a univariate followed by a multivariate analysis. We summed the natural logarithm of the odds ratios (OR) of statistically significant environmental variables in the multivariable model to derive an ERS for SLE. Model discrimination was compared by De-Long′s test. PRS was calculated using the ORs of previously reported SLE genetic risk loci.</div></div><div><h3>Results</h3><div>The multivariate analysis revealed the association between daily sunlight exposure, depression, sleeplessness, sex hormone binding globulin levels, and air pollution with increased risk of SLE, while moderate physical activity was a protective factor. Increasing quartiles of the newly developed ERS were associated with similar degree of risk for SLE as the PRS. Integrating PRS with environmental factors significantly improved model performance.</div></div><div><h3>Conclusions</h3><div>We devised an ERS for SLE that summarizes the environmental component of the disease risk. We show that ERS confers a comparable degree of SLE risk as the PRS. Combining genetic and environmental factors could improve risk prediction models in SLE.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103441"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144147273","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 : 2025-06-01Epub Date: 2025-05-06DOI: 10.1016/j.jaut.2025.103436
Pengyun Wang , Muhammed Yuksel , Stella Gabeta , Jonathon Graham , Munther Hussain , Laura Jayne Blackmore , Xiaohong Huang , Dino Hadzic , Marianne Samyn , Tassos Grammatikopoulos , Michael Heneghan , Rodrigo Liberal , Maria Serena Longhi , Giorgina Mieli-Vergani , Diego Vergani , Yun Ma
Background & aims
Juvenile autoimmune liver disease (JAILD) comprises autoimmune hepatitis and autoimmune sclerosing cholangitis. JAILD-predisposing genes include HLA-DR3,DR7, DR13 and haplotype A1-B8-DR3. Mechanisms leading to liver autoimmunity remain elusive, though JAILD patients have aberrated immunoregulation. We investigated the influence of HLA genes on immune cells, focusing on T-cells and frequency and function of T regulatory cells (Tregs) in JAILD patients, their first-degree-relatives (FDRs) and healthy controls (HCs).
Methods
HLA class I and II genotypes were defined by PCR and peripheral blood mononuclear cells were immunophenotyped by FACS in 82 patients, 72 FDRs, 50 HCs. Treg function was tested by inhibition of CD4posCD25neg T-cell proliferation. Links between HLA genes, Treg frequency/function, pro-inflammatory/immunoregulatory cytokines, soluble and membrane-bound programmed cell death-1 (PD-1) were investigated.
Results
Proportion of subjects carrying HLA DR3/DR7/DR13 was 88 %, 92 %, 64 % in patients, FDRs and HCs. Circulating Treg frequency was lower in patients and FDRs than HCs. Inhibitory capacity of Tregs was lower in patients but similar in FDRs compared to HCs. FDRs possessing HLA DR3/DR7/DR13 genes had Treg frequencies lower than those without. PD-1 posCD4pos T-cells were fewer in patients than HCs; PD-1posCD8pos T-cells were fewer in patients and FDRs than HCs. Patient plasma levels of IFN-γ were higher, and ratios of IFN-γ/IL-10 and IFN-γ/IL-2 lower than in HCs. All nine FDRs with autoimmune disorders had HLA DR3/DR7/DR13 genes and lower Treg frequency than those without autoimmune disorders and HCs.
Conclusion
We show a link between HLA disease-predisposing genes and defective immunoregulation not only in JAILD patients, but also in their FDRs, who are prone to autoimmune disorders.
{"title":"HLA alleles predisposing to autoimmunity are linked to impaired immunoregulation in patients with juvenile autoimmune liver disease and in their first-degree relatives","authors":"Pengyun Wang , Muhammed Yuksel , Stella Gabeta , Jonathon Graham , Munther Hussain , Laura Jayne Blackmore , Xiaohong Huang , Dino Hadzic , Marianne Samyn , Tassos Grammatikopoulos , Michael Heneghan , Rodrigo Liberal , Maria Serena Longhi , Giorgina Mieli-Vergani , Diego Vergani , Yun Ma","doi":"10.1016/j.jaut.2025.103436","DOIUrl":"10.1016/j.jaut.2025.103436","url":null,"abstract":"<div><h3>Background & aims</h3><div>Juvenile autoimmune liver disease (JAILD) comprises autoimmune hepatitis and autoimmune sclerosing cholangitis. JAILD-predisposing genes include HLA-DR3,DR7, DR13 and haplotype A1-B8-DR3. Mechanisms leading to liver autoimmunity remain elusive, though JAILD patients have aberrated immunoregulation. We investigated the influence of HLA genes on immune cells, focusing on T-cells and frequency and function of T regulatory cells (Tregs) in JAILD patients, their first-degree-relatives (FDRs) and healthy controls (HCs).</div></div><div><h3>Methods</h3><div>HLA class I and II genotypes were defined by PCR and peripheral blood mononuclear cells were immunophenotyped by FACS in 82 patients, 72 FDRs, 50 HCs. Treg function was tested by inhibition of CD4<sup>pos</sup>CD25<sup>neg</sup> T-cell proliferation. Links between HLA genes, Treg frequency/function, pro-inflammatory/immunoregulatory cytokines, soluble and membrane-bound programmed cell death-1 (PD-1) were investigated.</div></div><div><h3>Results</h3><div>Proportion of subjects carrying HLA DR3/DR7/DR13 was 88 %, 92 %, 64 % in patients, FDRs and HCs. Circulating Treg frequency was lower in patients and FDRs than HCs. Inhibitory capacity of Tregs was lower in patients but similar in FDRs compared to HCs. FDRs possessing HLA DR3/DR7/DR13 genes had Treg frequencies lower than those without. PD-1 <sup>pos</sup>CD4<sup>pos</sup> T-cells were fewer in patients than HCs; PD-1<sup>pos</sup>CD8<sup>pos</sup> T-cells were fewer in patients and FDRs than HCs. Patient plasma levels of IFN-γ were higher, and ratios of IFN-γ/IL-10 and IFN-γ/IL-2 lower than in HCs. All nine FDRs with autoimmune disorders had HLA DR3/DR7/DR13 genes and lower Treg frequency than those without autoimmune disorders and HCs.</div></div><div><h3>Conclusion</h3><div>We show a link between HLA disease-predisposing genes and defective immunoregulation not only in JAILD patients, but also in their FDRs, who are prone to autoimmune disorders.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103436"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912689","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 : 2025-06-01Epub Date: 2025-05-06DOI: 10.1016/j.jaut.2025.103435
Yiran Chen , Longyang Zhu , Chen Zong , Shiyu Wu , Xinxin Zhang , Lingling Huo , Yongpeng Ge , Xiaolan Tian , Fang Chen , Wei Jiang , Sizhao Li , Yu Zuo , Shanshan Li , Linrong He , Chunjia Li , Hanbo Yang , Xinyue Xiao , Lin Liang , Xia Liu , Lu Zhang , Qinglin Peng
Objectives
To investigate mortality, patient-reported outcomes (PROs), and drug-free remission (DFR) in a large well-characterised cohort of idiopathic inflammatory myopathies (IIMs).
Methods
This study retrospectively enrolled 1854 patients with IIMs. Follow-up lasted up to 20 years. Mortality was analysed using the standardised mortality ratio (SMR) and Kaplan-Meier survival analysis. PROs and DFR rates were examined in the survivors at the end of follow-up.
Results
Of 1854 patients, 348 (18.8 %) died during follow-up, with an overall SMR of 6.82 (95 % confidence interval [CI] 6.11–7.54). Subgroup analysis revealed the highest SMRs in dermatomyositis (DM), followed by antisynthetase syndrome (ASS), and immune-mediated necrotising myopathy, while SMRs in patients with polymyositis indicated no significant mortality difference from general population. Patients with anti-MDA5-positive DM exhibited higher SMRs than those with other IIM serotypes. Respiratory failure was the leading cause of death among patients with IIMs. Patients with DM had the lowest survival rates within the initial nine years of disease duration, whereas patients with ASS exhibited significantly reduced survival after nine years. At the end of follow-up, 17.1 % of patients achieved DFR (cumulative 3-, 5-, and 10-year DFR rates of 6.1 %, 14.9 %, and 29.3 %, respectively). Patients with DM presented with better PROs and higher DFR rates than those with other IIM subtypes.
Conclusions
Our data indicated increased mortality in patients with IIM compared with the general population and provided an important foundational understanding of IIMs. These findings emphasise the heterogeneity in the long-term outcomes across IIM subtypes, DM's acute nature, and ASS's progressive course.
{"title":"Long-term outcomes of idiopathic inflammatory myopathies: a large-scale longitudinal cohort study","authors":"Yiran Chen , Longyang Zhu , Chen Zong , Shiyu Wu , Xinxin Zhang , Lingling Huo , Yongpeng Ge , Xiaolan Tian , Fang Chen , Wei Jiang , Sizhao Li , Yu Zuo , Shanshan Li , Linrong He , Chunjia Li , Hanbo Yang , Xinyue Xiao , Lin Liang , Xia Liu , Lu Zhang , Qinglin Peng","doi":"10.1016/j.jaut.2025.103435","DOIUrl":"10.1016/j.jaut.2025.103435","url":null,"abstract":"<div><h3>Objectives</h3><div>To investigate mortality, patient-reported outcomes (PROs), and drug-free remission (DFR) in a large well-characterised cohort of idiopathic inflammatory myopathies (IIMs).</div></div><div><h3>Methods</h3><div>This study retrospectively enrolled 1854 patients with IIMs. Follow-up lasted up to 20 years. Mortality was analysed using the standardised mortality ratio (SMR) and Kaplan-Meier survival analysis. PROs and DFR rates were examined in the survivors at the end of follow-up.</div></div><div><h3>Results</h3><div>Of 1854 patients, 348 (18.8 %) died during follow-up, with an overall SMR of 6.82 (95 % confidence interval [CI] 6.11–7.54). Subgroup analysis revealed the highest SMRs in dermatomyositis (DM), followed by antisynthetase syndrome (ASS), and immune-mediated necrotising myopathy, while SMRs in patients with polymyositis indicated no significant mortality difference from general population. Patients with anti-MDA5-positive DM exhibited higher SMRs than those with other IIM serotypes. Respiratory failure was the leading cause of death among patients with IIMs. Patients with DM had the lowest survival rates within the initial nine years of disease duration, whereas patients with ASS exhibited significantly reduced survival after nine years. At the end of follow-up, 17.1 % of patients achieved DFR (cumulative 3-, 5-, and 10-year DFR rates of 6.1 %, 14.9 %, and 29.3 %, respectively). Patients with DM presented with better PROs and higher DFR rates than those with other IIM subtypes.</div></div><div><h3>Conclusions</h3><div>Our data indicated increased mortality in patients with IIM compared with the general population and provided an important foundational understanding of IIMs. These findings emphasise the heterogeneity in the long-term outcomes across IIM subtypes, DM's acute nature, and ASS's progressive course.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103435"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906442","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 : 2025-06-01Epub Date: 2025-06-02DOI: 10.1016/j.jaut.2025.103442
Qiyun Xia , Zhuwan Lyu , Yudong Zhao , Xiting Pu , Jian Wang , Yuyang Liu , Yujie Zhou , Jun Qian , M.E. Gershwin , Min Lian , Xiong Ma
Background & aims
Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset that plays a significant role in the immunopathology of primary biliary cholangitis (PBC). However, our understanding of the subpopulations involved in hepatic residency have not been elucidated. Herein, our goal was to delineate the phenotypic and functional properties of intrahepatic tissue-resident MAIT cells in PBC.
Methods
Liver tissue and intrahepatic mononuclear cells were collected and analyzed by immunohistochemistry, immunofluorescence and flow cytometry. The transcriptome was determined using in vitro generated tissue-resident MAIT cells. FOXM1's immunoregulatory role was evaluated with inhibitor treatment and regulatory features of BHLHE40 were confirmed by CUT&Tag-seq and luciferase assays.
Results
In PBC, the frequency of intrahepatic MAIT cell decreased, but tissue-resident (CD69+CD103+) MAIT cells significantly expanded and expressed a notably pro-inflammatory phenotype, with substantial elevated expression of CXCR3, CXCR6; IL-17A, IFN-γ and T-bet. FOXM1, a transcriptional factor governing cell proliferation cycle, exhibited notably higher expression in tissue-resident MAIT cells than in non-resident MAIT cells. Inhibition of FOXM1 compromised the in vitro expansion of MAIT cells, and impaired the expression of CXCR3, IL-17A, IFN-γ and GM-SCF by tissue-resident MAIT cells. CUT&Tag-seq and luciferase assay revealed a direct regulation of FOXM1 of BHLHE40 expression.
Conclusion
Our data reveals a pro-inflammatory role of expanded tissue-resident MAIT cells in PBC mediated via higher expression of effector cytokines, chemokine receptors and a related transcriptional factor. FOXM1 critically regulates MAIT cell proliferation and tissue-resident pro-inflammatory function, via interaction with BHLHE40, and establishes a transcriptional axis linking proliferation to effector responses.
{"title":"The phenotypic and functional characteristics of intrahepatic CD69+CD103+ tissue-resident MAIT cells in primary biliary cholangitis","authors":"Qiyun Xia , Zhuwan Lyu , Yudong Zhao , Xiting Pu , Jian Wang , Yuyang Liu , Yujie Zhou , Jun Qian , M.E. Gershwin , Min Lian , Xiong Ma","doi":"10.1016/j.jaut.2025.103442","DOIUrl":"10.1016/j.jaut.2025.103442","url":null,"abstract":"<div><h3>Background & aims</h3><div>Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset that plays a significant role in the immunopathology of primary biliary cholangitis (PBC). However, our understanding of the subpopulations involved in hepatic residency have not been elucidated. Herein, our goal was to delineate the phenotypic and functional properties of intrahepatic tissue-resident MAIT cells in PBC.</div></div><div><h3>Methods</h3><div>Liver tissue and intrahepatic mononuclear cells were collected and analyzed by immunohistochemistry, immunofluorescence and flow cytometry. The transcriptome was determined using in vitro generated tissue-resident MAIT cells. FOXM1's immunoregulatory role was evaluated with inhibitor treatment and regulatory features of BHLHE40 were confirmed by CUT&Tag-seq and luciferase assays.</div></div><div><h3>Results</h3><div>In PBC, the frequency of intrahepatic MAIT cell decreased, but tissue-resident (CD69<sup>+</sup>CD103<sup>+</sup>) MAIT cells significantly expanded and expressed a notably pro-inflammatory phenotype, with substantial elevated expression of CXCR3, CXCR6; IL-17A, IFN-γ and T-bet. FOXM1, a transcriptional factor governing cell proliferation cycle, exhibited notably higher expression in tissue-resident MAIT cells than in non-resident MAIT cells. Inhibition of FOXM1 compromised the in vitro expansion of MAIT cells, and impaired the expression of CXCR3, IL-17A, IFN-γ and GM-SCF by tissue-resident MAIT cells. CUT&Tag-seq and luciferase assay revealed a direct regulation of FOXM1 of BHLHE40 expression.</div></div><div><h3>Conclusion</h3><div>Our data reveals a pro-inflammatory role of expanded tissue-resident MAIT cells in PBC mediated via higher expression of effector cytokines, chemokine receptors and a related transcriptional factor. FOXM1 critically regulates MAIT cell proliferation and tissue-resident pro-inflammatory function, via interaction with BHLHE40, and establishes a transcriptional axis linking proliferation to effector responses.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103442"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144195607","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 : 2025-06-01Epub Date: 2025-05-26DOI: 10.1016/j.jaut.2025.103437
Sahana Jayaraman , Andrew Wilson , Xuwen Alice Zheng , Janelle M. Montagne , Iago Pinal-Fernandez , Andrew L. Mammen , Thomas E. Lloyd , H. Benjamin Larman
Objective
Sporadic inclusion body myositis (IBM) is the most common adult idiopathic inflammatory myopathy. IBM etiology has been elusive, due to both degenerative and autoimmune disease features found on muscle biopsy, and significant disease heterogeneity. Investigating the role of antibodies in the muscle of IBM patients may improve our understanding of disease pathogenesis.
Methods
We used an IBM xenograft mouse model in which muscle biopsy tissue from IBM patients (n = 98) and controls (n = 131; including 54 from other types of myopathy) were implanted into immunodeficient mice (NOD-Rag1null-IL2rγnull). We quantified the amount of human IgG, IgA, and IgM in xenografted mouse sera using MesoScale Diagnostics (MSD) assay. We detected donor-derived antibody reactivities targeting autoantigens and infectious agents using Phage ImmunoPrecipitation Sequencing (PhIP-Seq). Finally, we used FR3 AmplifiKation Sequencing (FR3AK-Seq) to sequence the antibody mRNAs from a separate cohort of 146 patient biopsies (14 IBM, 22 healthy controls, 110 other myositis subtypes).
Results
With the MSD assay we found human IgG, IgA, and IgM in a larger percentage of IBM xenografted mice versus controls. Using PhIP-Seq, we found anti-microbial reactivities secreted from IBM muscle are prevalent amongst a healthy control population but autoantigen reactivities in IBM are more unique at the peptide and protein level. Additionally, NT5C1A (IgG/IgA and IgM) and TIF1γ (IgG/A) autoantibodies are secreted from muscle tissues of 4/18 and 10/18 IBM xenograft donors, respectively.
Conclusion
Our characterization of antibody responses within the muscle of IBM patients reveals that muscle-infiltrating B cells produce both disease-associated autoantibodies and a broad spectrum of antibodies targeting non-self antigens.
{"title":"Characterizing local antibody responses in the muscle of inclusion body myositis patients","authors":"Sahana Jayaraman , Andrew Wilson , Xuwen Alice Zheng , Janelle M. Montagne , Iago Pinal-Fernandez , Andrew L. Mammen , Thomas E. Lloyd , H. Benjamin Larman","doi":"10.1016/j.jaut.2025.103437","DOIUrl":"10.1016/j.jaut.2025.103437","url":null,"abstract":"<div><h3>Objective</h3><div>Sporadic inclusion body myositis (IBM) is the most common adult idiopathic inflammatory myopathy. IBM etiology has been elusive, due to both degenerative and autoimmune disease features found on muscle biopsy, and significant disease heterogeneity. Investigating the role of antibodies in the muscle of IBM patients may improve our understanding of disease pathogenesis.</div></div><div><h3>Methods</h3><div>We used an IBM xenograft mouse model in which muscle biopsy tissue from IBM patients (n = 98) and controls (n = 131; including 54 from other types of myopathy) were implanted into immunodeficient mice (NOD-Rag1<sup>null</sup>-IL2rγ<sup>null</sup>). We quantified the amount of human IgG, IgA, and IgM in xenografted mouse sera using MesoScale Diagnostics (MSD) assay. We detected donor-derived antibody reactivities targeting autoantigens and infectious agents using Phage ImmunoPrecipitation Sequencing (PhIP-Seq). Finally, we used FR3 AmplifiKation Sequencing (FR3AK-Seq) to sequence the antibody mRNAs from a separate cohort of 146 patient biopsies (14 IBM, 22 healthy controls, 110 other myositis subtypes).</div></div><div><h3>Results</h3><div>With the MSD assay we found human IgG, IgA, and IgM in a larger percentage of IBM xenografted mice versus controls. Using PhIP-Seq, we found anti-microbial reactivities secreted from IBM muscle are prevalent amongst a healthy control population but autoantigen reactivities in IBM are more unique at the peptide and protein level. Additionally, NT5C1A (IgG/IgA and IgM) and TIF1γ (IgG/A) autoantibodies are secreted from muscle tissues of 4/18 and 10/18 IBM xenograft donors, respectively.</div></div><div><h3>Conclusion</h3><div>Our characterization of antibody responses within the muscle of IBM patients reveals that muscle-infiltrating B cells produce both disease-associated autoantibodies and a broad spectrum of antibodies targeting non-self antigens.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103437"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134595","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 : 2025-06-01Epub Date: 2025-05-26DOI: 10.1016/j.jaut.2025.103438
Hugo J. van Dooren , Yemil Atisha-Fregoso , Annemarie L. Dorjée , Tom W.J. Huizinga , Meggan Mackay , Cynthia Aranow , René E.M. Toes , Betty Diamond , Jolien Suurmond
Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by an array of autoantibodies, in particular anti-nuclear antibodies (ANA). The disease is also hallmarked by an expansion of plasmablasts (PB) and hypergammaglobulinemia. The mechanisms underlying this hyperactivity and its relation to autoantibody production is not clear. We aimed to characterize B cell hyperactivity in SLE to identify its underlying mechanisms.
Using deep phenotyping with spectral flow cytometry and scRNAseq, we demonstrate that a high frequency of PB relative to memory B cells marks a subgroup of SLE patients, particularly those with higher disease activity and positive for Sm/RNP autoantibodies. We identified the origin of this phenotype in a prominent IFN signature in PB and increased activation in the switched CD27+ memory B cell compartment. PB from this group of SLE patients displayed high levels of CD45RB and somatic hypermutation frequencies similar to memory B cells. Repertoire analysis revealed a highly polyclonal expansion of PB and skewing towards IgG1. B cell hyperactivity correlated with hypergammaglobulinemia, especially increased IgG serum levels.
In summary, we show for the first time a direct relationship between IFN and PB expansion in a subgroup of SLE patients. Increased activation and differentiation of class-switched B cells driven by IFN may directly underlie PB expansion and hypergammaglobulinemia. These results provide insight into the pathways leading to B cell hyperactivity and autoantibody production which may guide the tailoring of B cell- and IFN-targeted therapies.
{"title":"Interferon signatures fuel B cell hyperactivity and plasmablast expansion in systemic lupus erythematosus","authors":"Hugo J. van Dooren , Yemil Atisha-Fregoso , Annemarie L. Dorjée , Tom W.J. Huizinga , Meggan Mackay , Cynthia Aranow , René E.M. Toes , Betty Diamond , Jolien Suurmond","doi":"10.1016/j.jaut.2025.103438","DOIUrl":"10.1016/j.jaut.2025.103438","url":null,"abstract":"<div><div>Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by an array of autoantibodies, in particular anti-nuclear antibodies (ANA). The disease is also hallmarked by an expansion of plasmablasts (PB) and hypergammaglobulinemia. The mechanisms underlying this hyperactivity and its relation to autoantibody production is not clear. We aimed to characterize B cell hyperactivity in SLE to identify its underlying mechanisms.</div><div>Using deep phenotyping with spectral flow cytometry and scRNAseq, we demonstrate that a high frequency of PB relative to memory B cells marks a subgroup of SLE patients, particularly those with higher disease activity and positive for Sm/RNP autoantibodies. We identified the origin of this phenotype in a prominent IFN signature in PB and increased activation in the switched CD27<sup>+</sup> memory B cell compartment. PB from this group of SLE patients displayed high levels of CD45RB and somatic hypermutation frequencies similar to memory B cells. Repertoire analysis revealed a highly polyclonal expansion of PB and skewing towards IgG1. B cell hyperactivity correlated with hypergammaglobulinemia, especially increased IgG serum levels.</div><div>In summary, we show for the first time a direct relationship between IFN and PB expansion in a subgroup of SLE patients. Increased activation and differentiation of class-switched B cells driven by IFN may directly underlie PB expansion and hypergammaglobulinemia. These results provide insight into the pathways leading to B cell hyperactivity and autoantibody production which may guide the tailoring of B cell- and IFN-targeted therapies.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103438"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134596","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 : 2025-06-01Epub Date: 2025-05-22DOI: 10.1016/j.jaut.2025.103439
Antonia Mazzucato-Puchner , Helene Ramspeck , Valentin Ritschl , Tanja Stamm , Valerie Kuczwara , Alexandra Szlatinay , Peter Mandl , Stephan Blüml , Helmuth Haslacher , Ulrike Baranyi , Veronica Falcone , Daniel Aletaha , Klara Rosta
Introduction
The transplacental transfer of maternal antibodies is essential for neonatal immunity but can be affected by maternal health conditions and pregnancy complications. In women with systemic autoimmune rheumatic diseases (SARD) this transfer may be influenced by the autoimmune condition itself and/or the immunosuppressive therapies administered during pregnancy.
Objective
This study aimed to assess the transplacental transfer and efficacy of vaccine-induced antibodies in pregnant women with SARD compared to healthy controls.
Methods
We enrolled pregnant women with and without SARD pregnancy. Venous blood samples were collected during the third trimester, and umbilical cord blood was obtained postpartum. Antibody titers were assessed using Roche SARS-CoV-2 RBD ECLIA for SARS-CoV-2 and DiaSorin kits for varicella-zoster virus and rubella.
Results
25 pregnant women with SARD and 30 healthy controls were analyzed. Of these, 25 women were vaccinated against SARS- CoV-2 during pregnancy. Transplacental antibody transfer was effective in the SARD and in the control groups. Rubella and SARS-CoV-2 antibody levels showed no significant differences in either maternal or cord blood samples. Varicella-zoster virus antibody levels were higher in SARD maternal and cord sera than in controls. In all cases maternal and neonatal antibody titers were highly correlated (p < 0.001).
Conclusions
Our findings suggest effective maternal-to-fetal antibody transfer in women with SARD both for existing antibodies (varicella-zoster virus, rubella) as well as newly generated ones (anti-Covid Igs generated after vaccination during pregnancy), indicating robust passive immunity in their newborns.
{"title":"Passive maternal immunity in children born to women with systemic autoimmune rheumatic disease – A case-control study","authors":"Antonia Mazzucato-Puchner , Helene Ramspeck , Valentin Ritschl , Tanja Stamm , Valerie Kuczwara , Alexandra Szlatinay , Peter Mandl , Stephan Blüml , Helmuth Haslacher , Ulrike Baranyi , Veronica Falcone , Daniel Aletaha , Klara Rosta","doi":"10.1016/j.jaut.2025.103439","DOIUrl":"10.1016/j.jaut.2025.103439","url":null,"abstract":"<div><h3>Introduction</h3><div>The transplacental transfer of maternal antibodies is essential for neonatal immunity but can be affected by maternal health conditions and pregnancy complications. In women with systemic autoimmune rheumatic diseases (SARD) this transfer may be influenced by the autoimmune condition itself and/or the immunosuppressive therapies administered during pregnancy.</div></div><div><h3>Objective</h3><div>This study aimed to assess the transplacental transfer and efficacy of vaccine-induced antibodies in pregnant women with SARD compared to healthy controls.</div></div><div><h3>Methods</h3><div>We enrolled pregnant women with and without SARD pregnancy. Venous blood samples were collected during the third trimester, and umbilical cord blood was obtained postpartum. Antibody titers were assessed using Roche SARS-CoV-2 RBD ECLIA for SARS-CoV-2 and DiaSorin kits for varicella-zoster virus and rubella.</div></div><div><h3>Results</h3><div>25 pregnant women with SARD and 30 healthy controls were analyzed. Of these, 25 women were vaccinated against SARS- CoV-2 during pregnancy. Transplacental antibody transfer was effective in the SARD and in the control groups. Rubella and SARS-CoV-2 antibody levels showed no significant differences in either maternal or cord blood samples. Varicella-zoster virus antibody levels were higher in SARD maternal and cord sera than in controls. In all cases maternal and neonatal antibody titers were highly correlated (p < 0.001).</div></div><div><h3>Conclusions</h3><div>Our findings suggest effective maternal-to-fetal antibody transfer in women with SARD both for existing antibodies (varicella-zoster virus, rubella) as well as newly generated ones (anti-Covid Igs generated after vaccination during pregnancy), indicating robust passive immunity in their newborns.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103439"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144107104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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