Pub 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":"2025-05-06","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 : 2025-05-06DOI: 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":"2025-05-06","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 : 2025-05-06DOI: 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":"2025-05-06","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 : 2025-05-06DOI: 10.1016/j.jaut.2025.103434
Takayuki Shibahara , Burcu Temizoz , Shiori Egashira , Koji Hosomi , Jonguk Park , Naz Surucu , Albin Björk , Erdal Sag , Takehiko Doi , Rabia Miray Kisla Ekinci , Sibel Balci , Marjan A. Versnel , Jun Kunisawa , Masahiro Yamamoto , Tomoya Hayashi , Shuichi Ito , Yuji Kamiyama , Kouji Kobiyama , Peter D. Katsikis , Cevayir Coban , Ken J. Ishii
Aberrant activation of the stimulator of interferon genes (STING) pathway is a hallmark of autoinflammatory disorders such as STING-associated vasculopathy with onset in infancy (SAVI), characterized by systemic inflammation affecting blood vessels, skin, and lungs. Despite its clinical significance, the mechanisms linking STING activation to disease pathology remain poorly defined. In this study, we demonstrated that SAVI mice harboring the N153S STING mutation exhibit diverse disease phenotypes, with a subset developing severe colitis and diarrhea alongside exacerbated systemic inflammation. These diarrheal SAVI mice showed pronounced dysbiosis, marked by reduced short-chain fatty acid-producing bacteria and an enrichment of segmented filamentous bacteria. This microbial imbalance was accompanied by elevated levels of both microbial and host-derived cyclic dinucleotides (CDNs), potent activators of the STING pathway. Notably, antibiotic treatment ameliorated inflammation, underscoring the role of dysbiosis in driving STING-mediated autoinflammation. Furthermore, in SAVI patients, elevated systemic microbial and host-derived CDNs were observed. In conditions such as systemic lupus erythematosus (SLE)—a heterogeneous autoimmune disease with potential STING involvement—systemic microbial CDNs were significantly correlated with disease biomarkers, including type I interferon scores and anti-dsDNA antibodies. In contrast, no such correlations were observed in STING-independent conditions like rheumatoid arthritis (RA). Importantly, this study highlights that both microbial and host-derived CDNs are key drivers of STING activation, suggesting that personalized treatment strategies could target cGAS or the microbiome based on a patient's specific CDN profile. These findings position systemic CDNs as valuable biomarkers and therapeutic targets for STING-driven diseases.
{"title":"Microbial dysbiosis fuels STING-driven autoinflammation through cyclic dinucleotides","authors":"Takayuki Shibahara , Burcu Temizoz , Shiori Egashira , Koji Hosomi , Jonguk Park , Naz Surucu , Albin Björk , Erdal Sag , Takehiko Doi , Rabia Miray Kisla Ekinci , Sibel Balci , Marjan A. Versnel , Jun Kunisawa , Masahiro Yamamoto , Tomoya Hayashi , Shuichi Ito , Yuji Kamiyama , Kouji Kobiyama , Peter D. Katsikis , Cevayir Coban , Ken J. Ishii","doi":"10.1016/j.jaut.2025.103434","DOIUrl":"10.1016/j.jaut.2025.103434","url":null,"abstract":"<div><div>Aberrant activation of the stimulator of interferon genes (STING) pathway is a hallmark of autoinflammatory disorders such as STING-associated vasculopathy with onset in infancy (SAVI), characterized by systemic inflammation affecting blood vessels, skin, and lungs. Despite its clinical significance, the mechanisms linking STING activation to disease pathology remain poorly defined. In this study, we demonstrated that SAVI mice harboring the N153S STING mutation exhibit diverse disease phenotypes, with a subset developing severe colitis and diarrhea alongside exacerbated systemic inflammation. These diarrheal SAVI mice showed pronounced dysbiosis, marked by reduced short-chain fatty acid-producing bacteria and an enrichment of segmented filamentous bacteria. This microbial imbalance was accompanied by elevated levels of both microbial and host-derived cyclic dinucleotides (CDNs), potent activators of the STING pathway. Notably, antibiotic treatment ameliorated inflammation, underscoring the role of dysbiosis in driving STING-mediated autoinflammation. Furthermore, in SAVI patients, elevated systemic microbial and host-derived CDNs were observed. In conditions such as systemic lupus erythematosus (SLE)—a heterogeneous autoimmune disease with potential STING involvement—systemic microbial CDNs were significantly correlated with disease biomarkers, including type I interferon scores and anti-dsDNA antibodies. In contrast, no such correlations were observed in STING-independent conditions like rheumatoid arthritis (RA). Importantly, this study highlights that both microbial and host-derived CDNs are key drivers of STING activation, suggesting that personalized treatment strategies could target cGAS or the microbiome based on a patient's specific CDN profile. These findings position systemic CDNs as valuable biomarkers and therapeutic targets for STING-driven diseases.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103434"},"PeriodicalIF":7.9,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906441","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 : 2025-05-02DOI: 10.1016/j.jaut.2025.103419
Maxwell McDermott , Wenyi Li , Yin-Hu Wang , Allen Y. Chen , Rodrigo Lacruz , Bettina Nadorp , Stefan Feske
Sjogren's Disease (SjD) is an autoimmune disorder characterized by salivary and lacrimal gland dysfunction and immune cell infiltration leading to gland inflammation and destruction. Although SjD is a common disease, its pathogenesis is not fully understood. In this study, we conducted a single-cell transcriptome analysis of peripheral blood mononuclear cells (PBMC) from patients with SjD and symptomatic non-SjD controls to identify cell types and functional changes involved in SjD pathogenesis. All PBMCs populations showed marked differences in gene expression between SjD patients and controls, particularly an increase in interferon (IFN) signaling gene signatures. T and B cells of SjD patients displayed a depletion of ribosomal gene expression and pathways linked to protein translation. SjD patients had increased frequencies of naive B cells, which featured a unique gene expression profile (GEP) distinct from controls and had hallmarks of B cell hyperactivation. Non-negative matrix factorization (NMF) also identified several non-overlapping GEPs in CD4+ and CD8+ T cells with differential usage in SjD patients and controls. Of these, only the Th1 activation GEP was enriched in T cells of SjD patients whereas the other two GEPs were depleted in T cells, emphasizing the important role of Th1 cells in SjD. Our study provides evidence for aberrant and unique gene expression patterns in both B and T lymphocytes of SjD patients that point to their altered activation states and may provide new insights into the pathogenesis of SjD.
{"title":"Machine learning approach to single cell transcriptomic analysis of Sjogren's disease reveals altered activation states of B and T lymphocytes","authors":"Maxwell McDermott , Wenyi Li , Yin-Hu Wang , Allen Y. Chen , Rodrigo Lacruz , Bettina Nadorp , Stefan Feske","doi":"10.1016/j.jaut.2025.103419","DOIUrl":"10.1016/j.jaut.2025.103419","url":null,"abstract":"<div><div>Sjogren's Disease (SjD) is an autoimmune disorder characterized by salivary and lacrimal gland dysfunction and immune cell infiltration leading to gland inflammation and destruction. Although SjD is a common disease, its pathogenesis is not fully understood. In this study, we conducted a single-cell transcriptome analysis of peripheral blood mononuclear cells (PBMC) from patients with SjD and symptomatic non-SjD controls to identify cell types and functional changes involved in SjD pathogenesis. All PBMCs populations showed marked differences in gene expression between SjD patients and controls, particularly an increase in interferon (IFN) signaling gene signatures. T and B cells of SjD patients displayed a depletion of ribosomal gene expression and pathways linked to protein translation. SjD patients had increased frequencies of naive B cells, which featured a unique gene expression profile (GEP) distinct from controls and had hallmarks of B cell hyperactivation. Non-negative matrix factorization (NMF) also identified several non-overlapping GEPs in CD4<sup>+</sup> and CD8<sup>+</sup> T cells with differential usage in SjD patients and controls. Of these, only the Th1 activation GEP was enriched in T cells of SjD patients whereas the other two GEPs were depleted in T cells, emphasizing the important role of Th1 cells in SjD. Our study provides evidence for aberrant and unique gene expression patterns in both B and T lymphocytes of SjD patients that point to their altered activation states and may provide new insights into the pathogenesis of SjD.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103419"},"PeriodicalIF":7.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898606","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 : 2025-04-29DOI: 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":"2025-04-29","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 : 2025-04-28DOI: 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":"2025-04-28","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 : 2025-04-28DOI: 10.1016/j.jaut.2025.103426
Shuanglan Chen , Lijuan Dan , Li Xiang , Qingman He , Dongsen Hu , Yongxiang Gao
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder with an immune pathogenesis that evolves over decades. Preclinical RA (PreRA) represents a dynamic immune phase preceding clinical RA, marked by the loss of autoimmune tolerance, the appearance of tissue-invasive effector T cells, and the production of autoantibodies (such as antibodies against citrullinated proteins and rheumatoid factors). Extensive research has demonstrated that gut microbiota influence mucosal T-cell responses, driving the progression of PreRA through multiple mechanisms, including altered intestinal permeability, gene-environment interactions, bacterial antigenic specificity, molecular mimicry, and metabolite production. Environmental risk factors such as smoking, hormonal changes, and high-sodium (Na) diets, may contribute to RA pathogenesis via the gut microbiome. The next challenge in RA research lies in developing therapeutic strategies to intervene during the asymptomatic autoimmune phase, where dietary adjustments, natural compounds, probiotics, and other approaches could effectively modulate gut flora to prevent or delay RA onset.
{"title":"The role of gut flora-driven Th cell responses in preclinical rheumatoid arthritis","authors":"Shuanglan Chen , Lijuan Dan , Li Xiang , Qingman He , Dongsen Hu , Yongxiang Gao","doi":"10.1016/j.jaut.2025.103426","DOIUrl":"10.1016/j.jaut.2025.103426","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder with an immune pathogenesis that evolves over decades. Preclinical RA (PreRA) represents a dynamic immune phase preceding clinical RA, marked by the loss of autoimmune tolerance, the appearance of tissue-invasive effector T cells, and the production of autoantibodies (such as antibodies against citrullinated proteins and rheumatoid factors). Extensive research has demonstrated that gut microbiota influence mucosal T-cell responses, driving the progression of PreRA through multiple mechanisms, including altered intestinal permeability, gene-environment interactions, bacterial antigenic specificity, molecular mimicry, and metabolite production. Environmental risk factors such as smoking, hormonal changes, and high-sodium (Na) diets, may contribute to RA pathogenesis <em>via</em> the gut microbiome. The next challenge in RA research lies in developing therapeutic strategies to intervene during the asymptomatic autoimmune phase, where dietary adjustments, natural compounds, probiotics, and other approaches could effectively modulate gut flora to prevent or delay RA onset.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103426"},"PeriodicalIF":7.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878519","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 : 2025-04-23DOI: 10.1016/j.jaut.2025.103422
Jiahui Jin , Zhe Wang , Yifan Liu , Jie Chen , Miao Jiang , Lixia Lu , Jingying Xu , Furong Gao , Juan Wang , Jieping Zhang , Guo-Tong Xu , Caixia Jin , Haibin Tian , Jingjun Zhao , Qingjian Ou
Localized scleroderma (LoSc) is an autoimmune disease that features extensive fibrosis of the skin. Due to its severity and limited understanding, no effective treatments have been developed to date. Bone marrow mesenchymal stem cells (BMSCs) derived extracellular vesicles (EVs) have been demonstrated promising therapeutic effects on the LoSc mouse model in our previous study. However, identifying the targets and underlying mechanisms of EVs remains a significant challenge for therapeutic applications. miR-143-3p, a critical and abundant factor in BMSC-EVs identified through miRNA sequencing, mediates antifibrotic effects in a LoSc mouse model and is significantly lacking in the dermis of LoSc patients. This microRNA inhibits myofibroblast formation and collagen synthesis, contributing to the therapeutic effects of BMSC-EVs in the LoSc mouse model. Moreover, miR-143-3p-reinforced BMSC-EVs demonstrated enhanced therapeutic efficacy compared to normal BMSC-EVs, reducing dermal thickening, collagen deposition, fibroblast differentiation into myofibroblasts, and promoting skin tissue remodeling. IGF1R, highly expressed in the skin of LoSc, was identified as a potential target of miR-143-3p and was inhibited by miR-143-3p-reinforced EVs, thereby modulating the IGF1/IGF1R-AKT/MAPK pathway. In conclusion, miR-143-3p-enriched EVs could be a more efficient candidate for treating dermal fibrosis in LoSc.
{"title":"miR-143-3p boosts extracellular vesicles to improve the dermal fibrosis of localized scleroderma","authors":"Jiahui Jin , Zhe Wang , Yifan Liu , Jie Chen , Miao Jiang , Lixia Lu , Jingying Xu , Furong Gao , Juan Wang , Jieping Zhang , Guo-Tong Xu , Caixia Jin , Haibin Tian , Jingjun Zhao , Qingjian Ou","doi":"10.1016/j.jaut.2025.103422","DOIUrl":"10.1016/j.jaut.2025.103422","url":null,"abstract":"<div><div>Localized scleroderma (LoSc) is an autoimmune disease that features extensive fibrosis of the skin. Due to its severity and limited understanding, no effective treatments have been developed to date. Bone marrow mesenchymal stem cells (BMSCs) derived extracellular vesicles (EVs) have been demonstrated promising therapeutic effects on the LoSc mouse model in our previous study. However, identifying the targets and underlying mechanisms of EVs remains a significant challenge for therapeutic applications. miR-143-3p, a critical and abundant factor in BMSC-EVs identified through miRNA sequencing, mediates antifibrotic effects in a LoSc mouse model and is significantly lacking in the dermis of LoSc patients. This microRNA inhibits myofibroblast formation and collagen synthesis, contributing to the therapeutic effects of BMSC-EVs in the LoSc mouse model. Moreover, miR-143-3p-reinforced BMSC-EVs demonstrated enhanced therapeutic efficacy compared to normal BMSC-EVs, reducing dermal thickening, collagen deposition, fibroblast differentiation into myofibroblasts, and promoting skin tissue remodeling. IGF1R, highly expressed in the skin of LoSc, was identified as a potential target of miR-143-3p and was inhibited by miR-143-3p-reinforced EVs, thereby modulating the IGF1/IGF1R-AKT/MAPK pathway. In conclusion, miR-143-3p-enriched EVs could be a more efficient candidate for treating dermal fibrosis in LoSc.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103422"},"PeriodicalIF":7.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860272","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 : 2025-04-22DOI: 10.1016/j.jaut.2025.103423
Yalong Qi , Hewei Ge , Xiaoying Sun , Yuhan Wei , Jingtong Zhai , Haili Qian , Hongnan Mo , Fei Ma
Background
Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for cancer. However, frequent and sometimes life-threatening immune-related adverse events (irAEs) are associated with ICI treatment. Therefore, it is imperative to establish a model for predicting the risk of irAEs to identify high-risk groups, enable more accurate clinical risk‒benefit analysis for ICI treatment and decrease the incidence of irAEs. However, no ideal model for predicting irAEs has been applied in clinical practice. The aim of this study was to analyze the systemic immune characteristics of patients with irAEs and establish a model for predicting the risk of irAEs.
Methods
We conducted a study to monitor irAEs in patients with advanced breast cancer undergoing immunotherapy during and following the treatment course. Peripheral blood mononuclear cells (PBMCs) were collected before and after two cycles of therapy. Mass cytometry time-of-flight (CyTOF) was employed to identify baseline and posttreatment immune cell subpopulations, and the relationships between the proportions of cells in these subpopulations and the occurrence of irAEs were explored. Additionally, we conducted subgroup analyses stratified by the anatomic location and time of onset of irAEs. Furthermore, we developed a logistic regression model to predict the risk of irAEs and validated this model using two independent validation cohorts from the Gene Expression Omnibus (GEO) database (accession numbers GSE189125 and GSE186143).
Results
By analyzing 106 blood samples and samples from two independent validation cohorts (n = 16 and 60 patients), we found that high proportions of CXCR3+CCR6+CD4+ T cells and CD38+CD86+CXCR3+CCR6+CD8+ T cells and a low proportion of CXCR3lowCD56dim natural killer (NK) cells at baseline were significantly correlated with the incidence of irAEs (P = 0.0029, P < 0.001, and P = 0.0017, respectively). In the subgroup analysis, we observed consistent results in patients with immune-related pneumonitis (ir-pneumonitis) and immune-related thyroiditis (ir-thyroiditis). In the early irAE group, the baseline proportion of CXCR3+CCR6+CD4+ T cells was greater than that in the late irAE group (P = 0.011). An analysis of PBMCs before and after ICI treatment revealed thatthe dynamic changes in the proportions of naïve CD4+ T cells and CXCR3lowCD56dim NK cells were closely related to irAE occurrence. Finally, we ultimately developed a model for predicting the risk of irAEs, which yielded an area under the receiver operating characteristic curve (AUROC) of 0.79 in the training cohort and an AUROC of 0.75 in the single-cell validation cohort (GSE189125).
Concl
免疫检查点抑制剂（ICIs）是最有希望的癌症治疗方案之一。然而，与ICI治疗相关的频繁且有时危及生命的免疫相关不良事件（irAEs）。因此，建立irAEs的风险预测模型，识别高危人群，更准确地进行ICI治疗的临床风险-收益分析，降低irAEs的发生率势在必行。然而，目前尚无理想的irae预测模型应用于临床实践。本研究的目的是分析irAEs患者的全身免疫特征，建立预测irAEs风险的模型。方法对接受免疫治疗的晚期乳腺癌患者在治疗过程中和治疗后的irae进行监测。治疗前后采集外周血单个核细胞（PBMCs）。采用细胞计数飞行时间（CyTOF）鉴定基线和治疗后免疫细胞亚群，并探讨这些亚群中细胞比例与irae发生之间的关系。此外，我们根据irae的解剖位置和发病时间进行了亚组分析。此外，我们建立了一个逻辑回归模型来预测irae的风险，并使用来自基因表达综合数据库（GEO）的两个独立验证队列（登录号为GSE189125和GSE186143）对该模型进行了验证。结果通过分析106份血液样本和来自两个独立验证队列（n = 16和60例患者）的样本，我们发现在基线时CXCR3+CCR6+CD4+ T细胞和CD38+CD86+CXCR3+CCR6+CD8+ T细胞的高比例和CXCR3lowCD56dim自然杀伤（NK）细胞的低比例与irAEs的发生率显著相关(P = 0.0029, P <；0.001, P = 0.0017)。在亚组分析中，我们观察到免疫相关性肺炎（ir-pneumonitis）和免疫相关性甲状腺炎（ir-thyroiditis）患者的结果一致。在irAE早期组，CXCR3+CCR6+CD4+ T细胞的基线比例大于irAE晚期组（P = 0.011）。通过对ICI治疗前后PBMCs的分析发现，naïve CD4+ T细胞和CXCR3lowCD56dim NK细胞比例的动态变化与irAE的发生密切相关。最后，我们最终建立了一个预测irae风险的模型，训练队列的受试者工作特征曲线下面积（AUROC）为0.79，单细胞验证队列（GSE189125）的AUROC为0.75。结论这些发现表明，不同的免疫细胞群体与不同的irae相关，这些细胞的特征可能用作预测特定毒性风险的生物标志物。这将有助管理辐照事件，并可能减少辐照事件的发生。
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