Pub Date : 2025-09-01Epub Date: 2025-08-07DOI: 10.1016/j.jaut.2025.103471
Kastriot Kastrati, Svitlana Pochepnia, Oana C Kulterer, Thomas S Nakuz, Daniel Mrak, Irina Gessl, Elisabeth Simader, Florian Prayer, Helmut Prosch, Lukas Nics, Stefan Schmitl, Daniel Aletaha, Helga Lechner-Radner, Marcus Hacker, Peter Mandl
Background: Interstitial lung disease (ILD) is associated with morbidity and mortality in idiopathic inflammatory myopathies (IIM). Predicting ILD progression remains a significant challenge, as conventional diagnostic tools such as pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) have limited prognostic accuracy. This study evaluated whether 68Ga-labelled inhibitor of Fibroblast-Activation-Protein (FAPI) based PET/CT at baseline predicts ILD evolution over two years.
Material and methods: In this prospective observational study, n = 19 individuals with IIM (n = 14 with ILD) underwent [68Ga] Ga-FAPI PET/CT at baseline. ILD progression was defined by three criteria: (1) FVC decline ≥10 % or FVC 5-9 % plus DLCO decline ≥15 %, (2) INBUILD criteria, and (3) a composite endpoint including INBUILD plus therapy escalation, hospitalization, or mortality. Pulmonary tracer uptake was quantified by calculating the maximum and mean target-to-background ratios across the whole lung (wlTBRmax and wlTBRmean, respectively), derived from standardized uptake values corrected for blood pool activity, and their predictive value was analysed.
Results: Over two years, n = 4 (28.6 %) patients met PFT-based progression criteria, while n = 6 (42.9 %) fulfilled INBUILD criteria, and n = 8 (57.1 %) reached the composite endpoint. Baseline wlTBRmax was significantly higher in INBUILD progressors compared to non-progressors (2.68 ± 1.06 vs. 1.59 ± 0.80, p = 0.04), as was wlTBRmean (0.58 ± 0.22 vs. 0.34 ± 0.10, p = 0.04). Similarly, patients meeting the composite endpoint had higher wlTBRmax (2.63 ± 1.04 vs. 1.30 ± 0.31; p < 0.01) and wlTBRmean (0.55 ± 0.20 vs. 0.31 ± 0.09; p = 0.01). Logistic regression analysis showed that incorporating pulmonary wlTBRmax and wlTBRmean enhanced the predictive accuracy over PFT and HRCT alone.
Conclusion: FAPI PET/CT may serve as a non-invasive biomarker for early prediction of ILD progression in IIM, supporting personalized disease management. However, given the small, single-centre cohort, these findings should be considered as preliminary and require validation in larger, multi-centre studies.
背景：间质性肺疾病（ILD）与特发性炎性肌病（IIM）的发病率和死亡率相关。预测ILD进展仍然是一个重大挑战，因为传统的诊断工具，如肺功能测试（pft）和高分辨率计算机断层扫描（HRCT）的预后准确性有限。本研究评估了68ga标记的纤维母细胞激活蛋白（FAPI）抑制剂在PET/CT基线时是否能预测2年内ILD的演变。材料和方法：在这项前瞻性观察性研究中，n = 19例IIM患者（n = 14例ILD患者）在基线时接受了[68Ga] Ga-FAPI PET/CT检查。ILD进展由三个标准定义：(1)FVC下降≥10%或FVC 5- 9%加DLCO下降≥15%，(2)INBUILD标准，(3)包括INBUILD加治疗升级、住院或死亡率的复合终点。通过计算整个肺的最大和平均目标-背景比（分别为wlTBRmax和wlTBRmean）来量化肺示踪剂的摄取，这些摄取来自校正了血池活性的标准化摄取值，并分析了它们的预测值。结果：两年内，n = 4（28.6%）例患者满足PFT-based进展标准，n = 6（42.9%）例患者满足INBUILD标准，n = 8（57.1%）例患者达到复合终点。INBUILD进展者的基线wlTBRmax显著高于非进展者（2.68±1.06 vs 1.59±0.80,p = 0.04）， wlTBRmean（0.58±0.22 vs 0.34±0.10,p = 0.04）。同样，达到复合终点的患者wlTBRmax更高(2.63±1.04 vs 1.30±0.31；P均值（0.55±0.20∶0.31±0.09）；p = 0.01)。Logistic回归分析显示，合并肺wlTBRmax和wlTBRmean比单独PFT和HRCT的预测准确性更高。结论：FAPI PET/CT可作为一种无创生物标志物，早期预测IIM中ILD的进展，支持个性化疾病管理。然而，考虑到小的单中心队列，这些发现应该被认为是初步的，需要在更大的多中心研究中进行验证。
{"title":"FAPI PET/CT for tracking disease trajectory in myositis-related interstitial lung disease.","authors":"Kastriot Kastrati, Svitlana Pochepnia, Oana C Kulterer, Thomas S Nakuz, Daniel Mrak, Irina Gessl, Elisabeth Simader, Florian Prayer, Helmut Prosch, Lukas Nics, Stefan Schmitl, Daniel Aletaha, Helga Lechner-Radner, Marcus Hacker, Peter Mandl","doi":"10.1016/j.jaut.2025.103471","DOIUrl":"10.1016/j.jaut.2025.103471","url":null,"abstract":"<p><strong>Background: </strong>Interstitial lung disease (ILD) is associated with morbidity and mortality in idiopathic inflammatory myopathies (IIM). Predicting ILD progression remains a significant challenge, as conventional diagnostic tools such as pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) have limited prognostic accuracy. This study evaluated whether <sup>68</sup>Ga-labelled inhibitor of Fibroblast-Activation-Protein (FAPI) based PET/CT at baseline predicts ILD evolution over two years.</p><p><strong>Material and methods: </strong>In this prospective observational study, n = 19 individuals with IIM (n = 14 with ILD) underwent [<sup>68</sup>Ga] Ga-FAPI PET/CT at baseline. ILD progression was defined by three criteria: (1) FVC decline ≥10 % or FVC 5-9 % plus DLCO decline ≥15 %, (2) INBUILD criteria, and (3) a composite endpoint including INBUILD plus therapy escalation, hospitalization, or mortality. Pulmonary tracer uptake was quantified by calculating the maximum and mean target-to-background ratios across the whole lung (wlTBR<sub>max</sub> and wlTBR<sub>mean</sub>, respectively), derived from standardized uptake values corrected for blood pool activity, and their predictive value was analysed.</p><p><strong>Results: </strong>Over two years, n = 4 (28.6 %) patients met PFT-based progression criteria, while n = 6 (42.9 %) fulfilled INBUILD criteria, and n = 8 (57.1 %) reached the composite endpoint. Baseline wlTBR<sub>max</sub> was significantly higher in INBUILD progressors compared to non-progressors (2.68 ± 1.06 vs. 1.59 ± 0.80, p = 0.04), as was wlTBR<sub>mean</sub> (0.58 ± 0.22 vs. 0.34 ± 0.10, p = 0.04). Similarly, patients meeting the composite endpoint had higher wlTBR<sub>max</sub> (2.63 ± 1.04 vs. 1.30 ± 0.31; p < 0.01) and wlTBR<sub>mean</sub> (0.55 ± 0.20 vs. 0.31 ± 0.09; p = 0.01). Logistic regression analysis showed that incorporating pulmonary wlTBR<sub>max</sub> and wlTBR<sub>mean</sub> enhanced the predictive accuracy over PFT and HRCT alone.</p><p><strong>Conclusion: </strong>FAPI PET/CT may serve as a non-invasive biomarker for early prediction of ILD progression in IIM, supporting personalized disease management. However, given the small, single-centre cohort, these findings should be considered as preliminary and require validation in larger, multi-centre studies.</p>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"156 ","pages":"103471"},"PeriodicalIF":7.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804190","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 : 2025-09-01Epub Date: 2025-08-08DOI: 10.1016/j.jaut.2025.103473
Roopa Hebbandi Nanjundappa, Harish Babu Kolla, Alexander Edgar, Patrick S Leung, Deepak S Chauhan, William M Ridgway, M Eric Gershwin, Channakeshava Sokke Umeshappa
Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterized by intrahepatic bile duct destruction, progressive cholestasis, and fibrosis, accompanied by elevated anti-mitochondrial antibodies (AMAs) and IgM. While multiple mouse models have been developed to study PBC pathogenesis, no single model fully recapitulates all aspects of human disease. Among these, the NOD.c3c4 mouse model, generated by incorporating B10 and B6 insulin-dependent diabetes (Idd) loci into NOD mice, uniquely develops PBC-like features without progressing to type-1 diabetes. NOD.c3c4 exhibit PDC-E2-reactive AMAs, elevated autoantibodies, biliary leukocyte infiltration, and progressive liver dysfunction. However, key pathogenic mechanisms, particularly the role of fibrosis, remain poorly understood. Here, we provide a comprehensive characterization of PBC development and progression in NOD.c3c4 mice, focusing on adaptive and innate immune contributions to disease pathology. Our study confirms that both T and B cells are central drivers, as their depletion significantly mitigates PBC pathology. Additionally, our findings highlight a previously underappreciated role of innate immunity in disease progression. Notably, NOD.c3c4 mice develop fibrosis, which advances with age, making them a valuable model for studying fibrotic events in PBC. Given their resemblance to human disease, NOD.c3c4 mice represent a powerful platform for investigating PBC pathogenesis and evaluating new immunotherapeutics.
{"title":"Immunological and fibrotic profiling in the NOD.c3c4 murine model of autoimmune cholangitis.","authors":"Roopa Hebbandi Nanjundappa, Harish Babu Kolla, Alexander Edgar, Patrick S Leung, Deepak S Chauhan, William M Ridgway, M Eric Gershwin, Channakeshava Sokke Umeshappa","doi":"10.1016/j.jaut.2025.103473","DOIUrl":"10.1016/j.jaut.2025.103473","url":null,"abstract":"<p><p>Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterized by intrahepatic bile duct destruction, progressive cholestasis, and fibrosis, accompanied by elevated anti-mitochondrial antibodies (AMAs) and IgM. While multiple mouse models have been developed to study PBC pathogenesis, no single model fully recapitulates all aspects of human disease. Among these, the NOD.c3c4 mouse model, generated by incorporating B10 and B6 insulin-dependent diabetes (Idd) loci into NOD mice, uniquely develops PBC-like features without progressing to type-1 diabetes. NOD.c3c4 exhibit PDC-E2-reactive AMAs, elevated autoantibodies, biliary leukocyte infiltration, and progressive liver dysfunction. However, key pathogenic mechanisms, particularly the role of fibrosis, remain poorly understood. Here, we provide a comprehensive characterization of PBC development and progression in NOD.c3c4 mice, focusing on adaptive and innate immune contributions to disease pathology. Our study confirms that both T and B cells are central drivers, as their depletion significantly mitigates PBC pathology. Additionally, our findings highlight a previously underappreciated role of innate immunity in disease progression. Notably, NOD.c3c4 mice develop fibrosis, which advances with age, making them a valuable model for studying fibrotic events in PBC. Given their resemblance to human disease, NOD.c3c4 mice represent a powerful platform for investigating PBC pathogenesis and evaluating new immunotherapeutics.</p>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"156 ","pages":"103473"},"PeriodicalIF":7.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812074","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 : 2025-08-13DOI: 10.1016/j.jaut.2025.103472
Mengyu Zhu , Xiaolong Li , Kai Zhao , Zhiyan Huang , Ting Zhao
Introduction
Metabolic dysregulation in immune cells is increasingly recognized as a contributing factor in autoimmune diseases. B lymphocytes, which play key roles in immune tolerance and autoantibody production, show altered glucose metabolism. This review examines the role of glucose metabolism in B cell function and its potential impact on autoimmune pathogenesis.
Methods
We reviewed evidence from animal and cell-based studies, together with available clinical findings, on glucose metabolic shifts in various B cell subsets—including naïve, activated, germinal center, plasma, and memory B cells—across major autoimmune diseases. Particular attention was given to glycolysis, oxidative phosphorylation (OXPHOS), and mTOR signaling pathways.
Results
Evidence of altered B cell metabolism, especially increased glycolysis, is most extensively documented in systemic lupus erythematosus (SLE), with growing insights emerging in rheumatoid arthritis (RA), Sjögren's syndrome (SS), and type 1 diabetes (T1D). These metabolic changes are associated with B cell activation, autoantibody production, and broader immune modulation. While many findings are based on comparisons with healthy donors, the understanding of disease-specific metabolic patterns is progressively improving.
Conclusion
Altered glucose metabolism appears to be a common, though variable, feature of B cells in autoimmune diseases. Current data suggest distinct metabolic profiles in SLE, RA, SS, and T1D. Although much of the existing evidence is derived from in vitro and animal studies, ongoing research continues to refine our understanding. Further cross-disease comparative investigations—especially in RA, SS, and T1D—will be instrumental in delineating the unique metabolic adaptations underlying each condition.
{"title":"Altered glucose metabolism in B cells: Implications for the pathogenesis and treatment of autoimmune diseases","authors":"Mengyu Zhu , Xiaolong Li , Kai Zhao , Zhiyan Huang , Ting Zhao","doi":"10.1016/j.jaut.2025.103472","DOIUrl":"10.1016/j.jaut.2025.103472","url":null,"abstract":"<div><h3>Introduction</h3><div>Metabolic dysregulation in immune cells is increasingly recognized as a contributing factor in autoimmune diseases. B lymphocytes, which play key roles in immune tolerance and autoantibody production, show altered glucose metabolism. This review examines the role of glucose metabolism in B cell function and its potential impact on autoimmune pathogenesis.</div></div><div><h3>Methods</h3><div>We reviewed evidence from animal and cell-based studies, together with available clinical findings, on glucose metabolic shifts in various B cell subsets—including naïve, activated, germinal center, plasma, and memory B cells—across major autoimmune diseases. Particular attention was given to glycolysis, oxidative phosphorylation (OXPHOS), and mTOR signaling pathways.</div></div><div><h3>Results</h3><div>Evidence of altered B cell metabolism, especially increased glycolysis, is most extensively documented in systemic lupus erythematosus (SLE), with growing insights emerging in rheumatoid arthritis (RA), Sjögren's syndrome (SS), and type 1 diabetes (T1D). These metabolic changes are associated with B cell activation, autoantibody production, and broader immune modulation. While many findings are based on comparisons with healthy donors, the understanding of disease-specific metabolic patterns is progressively improving.</div></div><div><h3>Conclusion</h3><div>Altered glucose metabolism appears to be a common, though variable, feature of B cells in autoimmune diseases. Current data suggest distinct metabolic profiles in SLE, RA, SS, and T1D. Although much of the existing evidence is derived from in vitro and animal studies, ongoing research continues to refine our understanding. Further cross-disease comparative investigations—especially in RA, SS, and T1D—will be instrumental in delineating the unique metabolic adaptations underlying each condition.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"156 ","pages":"Article 103472"},"PeriodicalIF":7.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144831100","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 : 2025-08-01DOI: 10.1016/j.jaut.2025.103452
Sho Sendo , Allison J. Vela , Myungja Ro , Deepan Thiruppathy , Elizabeth L. Wilkinson , Zixuan Zhao , Wan-Chen Hsieh , Shen Yang , Roxana Coras , Anne-Sophie Bergot , Monica Guma , Anders Nguyen , David A. McBride , Suzanne Devkota , Ranjeny Thomas , Nisarg J. Shah , Mattias N.D. Svensson , Karsten Zengler , Stephanie M. Stanford , Nunzio Bottini
Gut dysbiosis is observed in patients with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), however, how it promotes disease in interaction with other environmental and genetic risk factors remains unclear. Here we assessed interactions between gut dysbiosis and RA/JIA-associated loss of function haplotypes of the RA/JIA-associated PTPN2 gene by inducing mannan-induced arthritis in germ-free PTPN2+/+ and PTPN2 haploinsufficient (PTPN2+/−) SKG mice reconstituted with fecal microbiota from six patients with seropositive RA. Mannan-induced arthritis and lymph node T cell immunophenotypes were identical in germ free PTPN2+/+ vs PTPN2+/− SKG mice. While no difference in arthritis severity was seen among PTPN2+/+ mice recipient of RA gut microbiota, two microbiomes (RA#02 and RA#86) enhanced arthritis in PTPN2+/− mice. The microbiome of RA patient microbiota recipient mice exclusively clustered by patient of origin and the RA#86 microbiome was found to carry a significant expansion of Prevotella genera, which is associated with RA dysbiosis. RA#86 microbiota-recipient PTPN2+/− mice selectively displayed increased joint GM-CSF expression and an expansion of CD4+RORγt+FoxP3− T cells in the joints, without evidence of increased intestinal inflammation, gut barrier leakage or expansion of P. copri in post-mannan fecal samples. Monocolonization with P. copri caused enhanced arthritis and CD4+RORγt+FoxP3− T cells expansion in PTPN2+/− vs PTPN2+/+ mice. Our data support current views about P. copri promotion of autoimmune arthritis and suggest that its pathogenicity can be amplified via interaction with a dysbiotic context and risk factors that enhance gut mucosa immune responses.
在类风湿关节炎（RA）和幼年特发性关节炎（JIA）患者中观察到肠道生态失调，然而，它如何与其他环境和遗传风险因素相互作用促进疾病仍不清楚。在这里，我们通过诱导甘露聚糖诱导的无细菌PTPN2+/+和PTPN2单倍不足（PTPN2+/−）SKG小鼠的关节炎，评估肠道生态失调与RA/ jia相关PTPN2基因单倍型功能丧失之间的相互作用。甘露聚糖诱导的关节炎和淋巴结T细胞免疫表型在无菌PTPN2+/+和PTPN2+/ - SKG小鼠中是相同的。虽然在接受RA肠道微生物群的PTPN2+/+小鼠中，关节炎严重程度没有差异，但两种微生物组（RA#02和RA#86）增强了PTPN2+/ -小鼠的关节炎。RA患者微生物群受体小鼠的微生物组完全按患者来源聚集，发现RA#86微生物组携带显著扩增的普雷沃氏菌属，这与RA生态失调有关。RA#86微生物群受体PTPN2+/−小鼠选择性地表现出关节gmcsf表达增加和关节中CD4+ rr γ T +FoxP3−T细胞的扩增，而在甘露糖后粪便样本中没有增加肠道炎症、肠道屏障渗漏或copri扩增的证据。单定殖copri可增强PTPN2+/−与PTPN2+/+小鼠的关节炎和CD4+ r γ T +FoxP3−T细胞扩增。我们的数据支持目前关于copri促进自身免疫性关节炎的观点，并表明其致病性可以通过与益生菌环境和增强肠道黏膜免疫反应的危险因素相互作用而放大。
{"title":"Interaction between haploinsufficiency of PTPN2 and patient microbiome promotes autoimmune arthritis in mice","authors":"Sho Sendo , Allison J. Vela , Myungja Ro , Deepan Thiruppathy , Elizabeth L. Wilkinson , Zixuan Zhao , Wan-Chen Hsieh , Shen Yang , Roxana Coras , Anne-Sophie Bergot , Monica Guma , Anders Nguyen , David A. McBride , Suzanne Devkota , Ranjeny Thomas , Nisarg J. Shah , Mattias N.D. Svensson , Karsten Zengler , Stephanie M. Stanford , Nunzio Bottini","doi":"10.1016/j.jaut.2025.103452","DOIUrl":"10.1016/j.jaut.2025.103452","url":null,"abstract":"<div><div>Gut dysbiosis is observed in patients with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), however, how it promotes disease in interaction with other environmental and genetic risk factors remains unclear. Here we assessed interactions between gut dysbiosis and RA/JIA-associated loss of function haplotypes of the RA/JIA-associated PTPN2 gene by inducing mannan-induced arthritis in germ-free PTPN2<sup>+/+</sup> and PTPN2 haploinsufficient (PTPN2<sup>+/−</sup>) SKG mice reconstituted with fecal microbiota from six patients with seropositive RA. Mannan-induced arthritis and lymph node T cell immunophenotypes were identical in germ free PTPN2<sup>+/+</sup> vs PTPN2<sup>+/−</sup> SKG mice. While no difference in arthritis severity was seen among PTPN2<sup>+/+</sup> mice recipient of RA gut microbiota, two microbiomes (RA#02 and RA#86) enhanced arthritis in PTPN2<sup>+/−</sup> mice. The microbiome of RA patient microbiota recipient mice exclusively clustered by patient of origin and the RA#86 microbiome was found to carry a significant expansion of <em>Prevotella</em> genera, which is associated with RA dysbiosis. RA#86 microbiota-recipient PTPN2<sup>+/−</sup> mice selectively displayed increased joint GM-CSF expression and an expansion of CD4<sup>+</sup>RORγt<sup>+</sup>FoxP3<sup>−</sup> T cells in the joints, without evidence of increased intestinal inflammation, gut barrier leakage or expansion of <em>P. copri</em> in post-mannan fecal samples. Monocolonization with <em>P. copri</em> caused enhanced arthritis and CD4<sup>+</sup>RORγt<sup>+</sup>FoxP3<sup>−</sup> T cells expansion in PTPN2<sup>+/−</sup> vs PTPN2<sup>+/+</sup> mice. Our data support current views about <em>P. copri</em> promotion of autoimmune arthritis and suggest that its pathogenicity can be amplified via interaction with a dysbiotic context and risk factors that enhance gut mucosa immune responses.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"156 ","pages":"Article 103452"},"PeriodicalIF":7.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749479","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 : 2025-07-31DOI: 10.1016/j.jaut.2025.103468
Raffael Ott , Tarini Singh , Katharina Schütte-Borkovec , Marlon Scholz , Kristina Casteels , Gita Gemulla , Olga Kordonouri , Helena Elding Larsson , Agnieszka Szypowska , John A. Todd , Anette-G. Ziegler , Ezio Bonifacio
Background
Viral infections, including COVID-19, are associated with an increased risk for type 1 diabetes (T1D), but potential underlying mechanisms remain unexplored. We evaluated whether COVID-19 or influenza A infection is characterized by differential DNA methylation at immune and T1D susceptibility genes in young children at risk for T1D.
Methods
Epigenome-wide association analysis using the Illumina MethylationEPIC microarray was performed in blood taken at age 1.5 years (IQR, 1.49–1.52 y) from 740 prospectively followed children with increased risk of T1D. SARS-CoV-2 and influenza A H1N1 antibodies were monitored at 2–4-month intervals from age 6 months to identify infection.
Results
COVID-19 and influenza infection occurred prior to the DNA methylation sample in 81 and 74 children, respectively. Of these, infection occurred within 3 months of the DNA methylation sample (recent infection) in 43 and 22 children. Compared to children without COVID-19 or influenza A infection, children with recent COVID-19 infection showed differential methylation at key immune- and antiviral genes, including ADAR, IFI44L, MX1 and OASL. In addition to ADAR, six further T1D susceptibility genes, including the SARS-CoV-2 cell entry receptor neuropilin-1, had differential methylation at nearby CpGs in children infected by SARS-CoV-2. A quantitatively less differential methylation was also observed in children with an earlier COVID-19 infection at some of these CpG sites. Infections with influenza showed no associations.
Conclusion
Children with SARS-CoV-2 infection showed sustained DNA methylation changes at genes critical for antiviral response and T1D susceptibility, potentially contributing to immune dysregulation and promotion of the autoimmune process underlying T1D.
{"title":"Epigenetic differences at immune and type 1 diabetes susceptibility genes in blood from young children after COVID-19 infection","authors":"Raffael Ott , Tarini Singh , Katharina Schütte-Borkovec , Marlon Scholz , Kristina Casteels , Gita Gemulla , Olga Kordonouri , Helena Elding Larsson , Agnieszka Szypowska , John A. Todd , Anette-G. Ziegler , Ezio Bonifacio","doi":"10.1016/j.jaut.2025.103468","DOIUrl":"10.1016/j.jaut.2025.103468","url":null,"abstract":"<div><h3>Background</h3><div>Viral infections, including COVID-19, are associated with an increased risk for type 1 diabetes (T1D), but potential underlying mechanisms remain unexplored. We evaluated whether COVID-19 or influenza A infection is characterized by differential DNA methylation at immune and T1D susceptibility genes in young children at risk for T1D.</div></div><div><h3>Methods</h3><div>Epigenome-wide association analysis using the Illumina MethylationEPIC microarray was performed in blood taken at age 1.5 years (IQR, 1.49–1.52 y) from 740 prospectively followed children with increased risk of T1D. SARS-CoV-2 and influenza A H1N1 antibodies were monitored at 2–4-month intervals from age 6 months to identify infection.</div></div><div><h3>Results</h3><div>COVID-19 and influenza infection occurred prior to the DNA methylation sample in 81 and 74 children, respectively. Of these, infection occurred within 3 months of the DNA methylation sample (recent infection) in 43 and 22 children. Compared to children without COVID-19 or influenza A infection, children with recent COVID-19 infection showed differential methylation at key immune- and antiviral genes, including <em>ADAR</em>, <em>IFI44L</em>, <em>MX1</em> and <em>OASL</em>. In addition to <em>ADAR</em>, six further T1D susceptibility genes, including the SARS-CoV-2 cell entry receptor neuropilin-1, had differential methylation at nearby CpGs in children infected by SARS-CoV-2. A quantitatively less differential methylation was also observed in children with an earlier COVID-19 infection at some of these CpG sites. Infections with influenza showed no associations.</div></div><div><h3>Conclusion</h3><div>Children with SARS-CoV-2 infection showed sustained DNA methylation changes at genes critical for antiviral response and T1D susceptibility, potentially contributing to immune dysregulation and promotion of the autoimmune process underlying T1D.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"156 ","pages":"Article 103468"},"PeriodicalIF":7.0,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737988","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 : 2025-07-30DOI: 10.1016/j.jaut.2025.103467
Sheta Biswas , Eileen M. Kasperek , Chengsong Zhu , Jeffrey C. Miecznikowski , Jason Osinski , Rose-Anne Romano , Jill M. Kramer
Primary Sjogren's disease (pSD) is a systemic autoimmune disease. Currently, the causes of pSD remain unknown, and no curative therapies are available. Our prior studies showed Tlr7 activation was an important driver of pSD in females. Since Tlr7 is regulated by Tlr9, we hypothesized that ablation of Tlr9 would exacerbate disease in a Tlr7-dependent manner. Towards this end, we generated pSD mice that lacked systemic expression of either Tlr9 (NOD.B10Tlr9-/-) or both Tlr7 and Tlr9 (NOD.B10Tlr−DKO). We harvested tissues for histologic analysis and assessed disease-relevant immune cell populations in secondary lymphoid organs. We examined total and autoreactive antibody levels in sera. Enhanced nephritis was observed in Tlr9-deficient females, while dacryoadenitis was increased in males that lacked Tlr9, and these manifestations were dependent on Tlr7. Moreover, the percentages of splenic Tlr7+ B cells, germinal center and age-associated B cells, CD4+ and CD8+ activated/memory T cells, and Tfh cells were increased in NOD.B10Tlr9-/- females as compared to sex-matched NOD.B10 mice, and this expansion was abrogated in NOD.B10Tlr−DKO females. Finally, total IgM levels were elevated in sera from NOD.B10Tlr9-/- females as compared to the parental strain and autoreactive IgM and IgG were also enriched in NOD.B10Tlr9-/- females. NOD.B10Tlr−DKO females and males showed dramatically reduced IgM and IgG titers as compared to the NOD.B10 strain and anti-nuclear autoantibodies were diminished in this strain. Overall, our study revealed that ablation of Tlr9 drives pSD in females but has negligible effects on disease in males. Moreover, Tlr9 regulates Tlr7-dependent pSD manifestations in a sex-biased manner.
{"title":"Tlr9 expression protects against Tlr7-dependent exocrine gland and systemic disease manifestations in primary Sjögren's disease in a sex-biased manner","authors":"Sheta Biswas , Eileen M. Kasperek , Chengsong Zhu , Jeffrey C. Miecznikowski , Jason Osinski , Rose-Anne Romano , Jill M. Kramer","doi":"10.1016/j.jaut.2025.103467","DOIUrl":"10.1016/j.jaut.2025.103467","url":null,"abstract":"<div><div>Primary Sjogren's disease (pSD) is a systemic autoimmune disease. Currently, the causes of pSD remain unknown, and no curative therapies are available. Our prior studies showed Tlr7 activation was an important driver of pSD in females. Since Tlr7 is regulated by Tlr9, we hypothesized that ablation of Tlr9 would exacerbate disease in a Tlr7-dependent manner. Towards this end, we generated pSD mice that lacked systemic expression of either Tlr9 (NOD.B10<sup><em>Tlr9-/-</em></sup>) or both Tlr7 and Tlr9 (NOD.B10<sup>Tlr−DKO</sup>). We harvested tissues for histologic analysis and assessed disease-relevant immune cell populations in secondary lymphoid organs. We examined total and autoreactive antibody levels in sera. Enhanced nephritis was observed in <em>Tlr9</em>-deficient females, while dacryoadenitis was increased in males that lacked <em>Tlr9</em>, and these manifestations were dependent on Tlr7. Moreover, the percentages of splenic Tlr7+ B cells, germinal center and age-associated B cells, CD4<sup>+</sup> and CD8<sup>+</sup> activated/memory T cells, and Tfh cells were increased in NOD.B10<sup><em>Tlr9-/-</em></sup> females as compared to sex-matched NOD.B10 mice, and this expansion was abrogated in NOD.B10<sup>Tlr−DKO</sup> females. Finally, total IgM levels were elevated in sera from NOD.B10<sup><em>Tlr9-/-</em></sup> females as compared to the parental strain and autoreactive IgM and IgG were also enriched in NOD.B10<sup><em>Tlr9-/-</em></sup> females. NOD.B10<sup>Tlr−DKO</sup> females and males showed dramatically reduced IgM and IgG titers as compared to the NOD.B10 strain and anti-nuclear autoantibodies were diminished in this strain. Overall, our study revealed that ablation of Tlr9 drives pSD in females but has negligible effects on disease in males. Moreover, Tlr9 regulates Tlr7-dependent pSD manifestations in a sex-biased manner.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"156 ","pages":"Article 103467"},"PeriodicalIF":7.0,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723061","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 : 2025-07-23DOI: 10.1016/j.jaut.2025.103457
Mikkel Malham , Christoffer Sejling , Megan Davies , Vibeke Wewer , Samir Bhatt , Matthew P. Fox , Naja H. Rod
Background
The etiology of pediatric-onset immune-mediated inflammatory disease (pIMID) is poorly understood, particularly the interplay of early-life adversities. We explored how interrelated early-life adversities affect the pIMID risk in a life-course birth cohort.
Methods
We included all children born in Denmark between 1981 and 2015. Adversities encountered during the first 1000 days of life were obtained from the Danish registries and categorized into three dimensions: biological, material, and familial. The outcome was developing pIMID (autoimmune liver disease, inflammatory bowel disease, juvenile idiopathic arthritis, vasculitis, and systemic lupus erythematosus) between ages 2 and 18. Cox proportional hazards and additive hazard model assessed the effect of the cumulative adversity load on developing pIMID. A machine learning model identified exposure patterns associated with increased absolute risk estimates.
Results
Of 2,123,827 children, 9070 developed pIMID. The cumulative burden of biological adversities was associated with higher risks of developing pIMID; aHR of two adversities was 1.23 (95 %CI: 1.07 to 1.41), aHR of ≥4 adversities was 1.8 (95 %CI: 1.4 to 2.2). Conversely, >2 familial adversities were associated with a reduced risk (0.66 [95 %CI: 0.41 to 1.1]). No associations were found in the material dimension. The machine learning model identified a pattern of adversities associated with a five-fold higher pIMID risk in a population subgroup.
Conclusion
Early-life biological adversities are important risk factors for developing pIMID. The lower risk observed in the familial dimension was unexpected but may reflect delayed diagnosis in socially vulnerable families. This potential inequality in healthcare needs further exploration.
{"title":"How early-life adversity affects the risk of pediatric-onset immune-mediated inflammatory disease","authors":"Mikkel Malham , Christoffer Sejling , Megan Davies , Vibeke Wewer , Samir Bhatt , Matthew P. Fox , Naja H. Rod","doi":"10.1016/j.jaut.2025.103457","DOIUrl":"10.1016/j.jaut.2025.103457","url":null,"abstract":"<div><h3>Background</h3><div>The etiology of pediatric-onset immune-mediated inflammatory disease (pIMID) is poorly understood, particularly the interplay of early-life adversities. We explored how interrelated early-life adversities affect the pIMID risk in a life-course birth cohort.</div></div><div><h3>Methods</h3><div>We included all children born in Denmark between 1981 and 2015. Adversities encountered during the first 1000 days of life were obtained from the Danish registries and categorized into three dimensions: biological, material, and familial. The outcome was developing pIMID (autoimmune liver disease, inflammatory bowel disease, juvenile idiopathic arthritis, vasculitis, and systemic lupus erythematosus) between ages 2 and 18. Cox proportional hazards and additive hazard model assessed the effect of the cumulative adversity load on developing pIMID. A machine learning model identified exposure patterns associated with increased absolute risk estimates.</div></div><div><h3>Results</h3><div>Of 2,123,827 children, 9070 developed pIMID. The cumulative burden of biological adversities was associated with higher risks of developing pIMID; aHR of two adversities was 1.23 (95 %CI: 1.07 to 1.41), aHR of ≥4 adversities was 1.8 (95 %CI: 1.4 to 2.2). Conversely, >2 familial adversities were associated with a reduced risk (0.66 [95 %CI: 0.41 to 1.1]). No associations were found in the material dimension. The machine learning model identified a pattern of adversities associated with a five-fold higher pIMID risk in a population subgroup.</div></div><div><h3>Conclusion</h3><div>Early-life biological adversities are important risk factors for developing pIMID. The lower risk observed in the familial dimension was unexpected but may reflect delayed diagnosis in socially vulnerable families. This potential inequality in healthcare needs further exploration.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"156 ","pages":"Article 103457"},"PeriodicalIF":7.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144687318","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 : 2025-07-01DOI: 10.1016/j.jaut.2025.103454
Tian-Tian Da , Meng-Chu Liu , Zhen-Hua Bian , Pan-Yue Luo , Rui-Tao Ye , Kai Yan , Liang Li , Zhe-Xiong Lian , Zhi-Bin Zhao
Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease marked by bile duct inflammation, with immune dysregulation playing a central role in its pathogenesis. Here, we identify a novel subset of inflammation-related natural killer (irNK) cells, characterized by CD49a+CXCR6−, which accumulate in the livers of both PBC mouse models and patients. Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing reveal that irNK cells form a distinct cluster with a unique gene expression profile, clearly distinguishing them from conventional NK (cNK) cells and type 1 innate lymphoid cells (ILC1s). We show that irNK cells arise from cNK cells in response to IL-15 stimulation and acquire liver-resident characteristics, including reduced circulation, confirming their tissue-resident identity. Functionally, irNK cells promote CD4+ T cell proliferation through TNF-α secretion, which we identify as the key mediator of immune dysregulation in the PBC murine model (ARE-Del+/− mice; ARE). These findings highlight the pivotal role of irNK cells in modulating immune responses in PBC and suggest that targeting these cells could offer new therapeutic opportunities for autoimmune liver diseases.
{"title":"A novel subset of inflammation-related liver NK cells modulates immune responses in a murine model of primary biliary cholangitis","authors":"Tian-Tian Da , Meng-Chu Liu , Zhen-Hua Bian , Pan-Yue Luo , Rui-Tao Ye , Kai Yan , Liang Li , Zhe-Xiong Lian , Zhi-Bin Zhao","doi":"10.1016/j.jaut.2025.103454","DOIUrl":"10.1016/j.jaut.2025.103454","url":null,"abstract":"<div><div>Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease marked by bile duct inflammation, with immune dysregulation playing a central role in its pathogenesis. Here, we identify a novel subset of inflammation-related natural killer (irNK) cells, characterized by CD49a<sup>+</sup>CXCR6<sup>−</sup>, which accumulate in the livers of both PBC mouse models and patients. Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing reveal that irNK cells form a distinct cluster with a unique gene expression profile, clearly distinguishing them from conventional NK (cNK) cells and type 1 innate lymphoid cells (ILC1s). We show that irNK cells arise from cNK cells in response to IL-15 stimulation and acquire liver-resident characteristics, including reduced circulation, confirming their tissue-resident identity. Functionally, irNK cells promote CD4<sup>+</sup> T cell proliferation through TNF-α secretion, which we identify as the key mediator of immune dysregulation in the PBC murine model (ARE-Del<sup>+/−</sup> mice; ARE). These findings highlight the pivotal role of irNK cells in modulating immune responses in PBC and suggest that targeting these cells could offer new therapeutic opportunities for autoimmune liver diseases.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"155 ","pages":"Article 103454"},"PeriodicalIF":7.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144523847","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 : 2025-07-01DOI: 10.1016/j.jaut.2025.103456
Hila Novak-Kotzer , Jesusa Capera , Ashwin Jainarayanan , Mirudula Elanchezhian , Salvatore Valvo , Viveka Mayya , Alexandra Zanin-Zhorov , Joanne Macdonald , Peter C. Taylor , Michael L. Dustin
Targeting the JAK/STAT pathway has emerged as a key therapeutic strategy for managing Rheumatoid Arthritis (RA). JAK inhibitors suppress cytokine-mediated signaling, including the critical IL-6/STAT3 axis, thereby effectively targeting different aspects of the pathological process. However, despite their clinical efficacy, a subset of RA patients remains refractory to JAK inhibition, underscoring the need for alternative approaches. Here, we identify a novel JAK-independent mechanism of STAT3 activation, which is triggered by the formation of the immunological synapse (IS) in naive CD4+ T cells. Our data demonstrates that LCK mediates the TCR-dependent phosphorylation of STAT3 at the IS, highlighting this pathway as a previously unrecognized hallmark of early T cell activation. Furthermore, we show that the synaptic LCK/TCR-STAT3 pathway is compromised in RA. This discovery highlights a new therapeutic target for RA beyond JAK inhibitors, offering potential avenues for treating patients resistant to current therapies.
{"title":"STAT3 phosphorylation in the rheumatoid arthritis immunological synapse","authors":"Hila Novak-Kotzer , Jesusa Capera , Ashwin Jainarayanan , Mirudula Elanchezhian , Salvatore Valvo , Viveka Mayya , Alexandra Zanin-Zhorov , Joanne Macdonald , Peter C. Taylor , Michael L. Dustin","doi":"10.1016/j.jaut.2025.103456","DOIUrl":"10.1016/j.jaut.2025.103456","url":null,"abstract":"<div><div>Targeting the JAK/STAT pathway has emerged as a key therapeutic strategy for managing Rheumatoid Arthritis (RA). JAK inhibitors suppress cytokine-mediated signaling, including the critical IL-6/STAT3 axis, thereby effectively targeting different aspects of the pathological process. However, despite their clinical efficacy, a subset of RA patients remains refractory to JAK inhibition, underscoring the need for alternative approaches. Here, we identify a novel JAK-independent mechanism of STAT3 activation, which is triggered by the formation of the immunological synapse (IS) in naive CD4<sup>+</sup> T cells. Our data demonstrates that LCK mediates the TCR-dependent phosphorylation of STAT3 at the IS, highlighting this pathway as a previously unrecognized hallmark of early T cell activation. Furthermore, we show that the synaptic LCK/TCR-STAT3 pathway is compromised in RA. This discovery highlights a new therapeutic target for RA beyond JAK inhibitors, offering potential avenues for treating patients resistant to current therapies.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"155 ","pages":"Article 103456"},"PeriodicalIF":7.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144523846","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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