Journal of autoimmunity最新文献

{"title":"Targeted protein degradation in autoimmune diseases: from mechanisms to therapeutic breakthroughs","authors":"Yuxin Song,&nbsp;Boyang Zhou,&nbsp;Jiangang Long,&nbsp;Yunhua Peng","doi":"10.1016/j.jaut.2025.103475","DOIUrl":"10.1016/j.jaut.2025.103475","url":null,"abstract":"<div><div>Autoimmune diseases pose significant challenges due to the high risks associated with abnormal immune responses to self-antigens and the limitations of broad-spectrum immunosuppressants. Current therapeutic approaches primarily rely on immunosuppressive drugs, yet their non-specificity and side effects urge researchers to explore novel targets and the advancement of precision medicine. Recent advances in targeted protein degradation (TPD) technologies, including PROTAC, MGD and LYTAC, offer therapeutic potential by precisely eliminating pathogenic proteins. By leveraging cellular degradation machinery such as ubiquitin-proteasome an endolysosomal systems to overcome the undruggable targets, these TPD technologies offer promising therapeutic strategies for precise immune regulation. Preclinical studies demonstrate PROTAC-mediated degradation of IRAK4 reduce inflammatory cytokines. RIPK2 degraders are expected to become a new approach for treating inflammatory diseases. While BTK degraders L18I surpass inhibitors in blocking autoantibodies. There are still challenges to overcome, such as delivery barriers, off-target effects and limited E3 ligase diversity. Emerging solutions such as AI-driven design and modular platforms may improve the specificity and efficacy. This review summarizes the underlying mechanisms, therapeutic breakthroughs, and translational hurdles of TPD technologies, and explores how integrating AI can optimize the technologies. TPD strategies have the potential to revolutionize the treatment of autoimmune diseases by providing more targeted and personalized therapies.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"156 ","pages":"Article 103475"},"PeriodicalIF":7.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144932341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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 ⁶⁸Ga-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 [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 (wlTBR_max and wlTBR_mean, 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_max 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_mean (0.58 ± 0.22 vs. 0.34 ± 0.10, p = 0.04). Similarly, patients meeting the composite endpoint had higher wlTBR_max (2.63 ± 1.04 vs. 1.30 ± 0.31; p < 0.01) and wlTBR_mean (0.55 ± 0.20 vs. 0.31 ± 0.09; p = 0.01). Logistic regression analysis showed that incorporating pulmonary wlTBR_max and wlTBR_mean 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}

{"title":"Corrigendum to “Anti-DNA antibody-targeted D-peptide nanoparticles ameliorate lupus nephritis in MRL/lpr mice” [J. Autoimmun. 145 (2024) 103205]","authors":"Yaqi Wang ,&nbsp;Shuang Wang ,&nbsp;Wei Liu ,&nbsp;Hanjiang Gu ,&nbsp;Mai Luo ,&nbsp;Tong Xiao ,&nbsp;Mingzhu Zhou ,&nbsp;Yutong Ran ,&nbsp;Shengxiang Xiao ,&nbsp;Yumin Xia ,&nbsp;Huixia Wang","doi":"10.1016/j.jaut.2025.103470","DOIUrl":"10.1016/j.jaut.2025.103470","url":null,"abstract":"","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"156 ","pages":"Article 103470"},"PeriodicalIF":7.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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}

{"title":"Altered glucose metabolism in B cells: Implications for the pathogenesis and treatment of autoimmune diseases","authors":"Mengyu Zhu ,&nbsp;Xiaolong Li ,&nbsp;Kai Zhao ,&nbsp;Zhiyan Huang ,&nbsp;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}

{"title":"Interaction between haploinsufficiency of PTPN2 and patient microbiome promotes autoimmune arthritis in mice","authors":"Sho Sendo ,&nbsp;Allison J. Vela ,&nbsp;Myungja Ro ,&nbsp;Deepan Thiruppathy ,&nbsp;Elizabeth L. Wilkinson ,&nbsp;Zixuan Zhao ,&nbsp;Wan-Chen Hsieh ,&nbsp;Shen Yang ,&nbsp;Roxana Coras ,&nbsp;Anne-Sophie Bergot ,&nbsp;Monica Guma ,&nbsp;Anders Nguyen ,&nbsp;David A. McBride ,&nbsp;Suzanne Devkota ,&nbsp;Ranjeny Thomas ,&nbsp;Nisarg J. Shah ,&nbsp;Mattias N.D. Svensson ,&nbsp;Karsten Zengler ,&nbsp;Stephanie M. Stanford ,&nbsp;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^+/+ 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 <em>Prevotella</em> 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 <em>P. copri</em> in post-mannan fecal samples. Monocolonization with <em>P. copri</em> caused enhanced arthritis and CD4⁺RORγt⁺FoxP3⁻ T cells expansion in PTPN2^+/− vs PTPN2^+/+ 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}

{"title":"Epigenetic differences at immune and type 1 diabetes susceptibility genes in blood from young children after COVID-19 infection","authors":"Raffael Ott ,&nbsp;Tarini Singh ,&nbsp;Katharina Schütte-Borkovec ,&nbsp;Marlon Scholz ,&nbsp;Kristina Casteels ,&nbsp;Gita Gemulla ,&nbsp;Olga Kordonouri ,&nbsp;Helena Elding Larsson ,&nbsp;Agnieszka Szypowska ,&nbsp;John A. Todd ,&nbsp;Anette-G. Ziegler ,&nbsp;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}

{"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 ,&nbsp;Eileen M. Kasperek ,&nbsp;Chengsong Zhu ,&nbsp;Jeffrey C. Miecznikowski ,&nbsp;Jason Osinski ,&nbsp;Rose-Anne Romano ,&nbsp;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^{<em>Tlr9-/-</em>}) or both Tlr7 and Tlr9 (NOD.B10^Tlr−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 <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⁺ and CD8⁺ activated/memory T cells, and Tfh cells were increased in NOD.B10^{<em>Tlr9-/-</em>} females as compared to sex-matched NOD.B10 mice, and this expansion was abrogated in NOD.B10^Tlr−DKO females. Finally, total IgM levels were elevated in sera from NOD.B10^{<em>Tlr9-/-</em>} females as compared to the parental strain and autoreactive IgM and IgG were also enriched in NOD.B10^{<em>Tlr9-/-</em>} females. NOD.B10^Tlr−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.</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}

{"title":"How early-life adversity affects the risk of pediatric-onset immune-mediated inflammatory disease","authors":"Mikkel Malham ,&nbsp;Christoffer Sejling ,&nbsp;Megan Davies ,&nbsp;Vibeke Wewer ,&nbsp;Samir Bhatt ,&nbsp;Matthew P. Fox ,&nbsp;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, &gt;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}

{"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 ,&nbsp;Meng-Chu Liu ,&nbsp;Zhen-Hua Bian ,&nbsp;Pan-Yue Luo ,&nbsp;Rui-Tao Ye ,&nbsp;Kai Yan ,&nbsp;Liang Li ,&nbsp;Zhe-Xiong Lian ,&nbsp;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⁺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.</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}