Journal of autoimmunity最新文献

{"title":"Lymphoma driver mutations at the root of somatic evolution of nerve-damaging autoantibodies in myelin associated glycoprotein neuropathy","authors":"Shane Kelly ,&nbsp;Mandeep Singh ,&nbsp;Amanda Russell ,&nbsp;Katherine J.L. Jackson ,&nbsp;Timothy J. Peters ,&nbsp;Andrew Carr ,&nbsp;Anthony D. Kelleher ,&nbsp;Matt Field ,&nbsp;Matthew Silsby ,&nbsp;Dan Suan ,&nbsp;Christopher C. Goodnow","doi":"10.1016/j.jaut.2025.103474","DOIUrl":"10.1016/j.jaut.2025.103474","url":null,"abstract":"<div><h3>Background</h3><div>In autoimmune disease it is not understood how self-reactive B cells escape immune tolerance checkpoints to produce pathogenic autoantibodies.</div></div><div><h3>Objective</h3><div>In patients with demyelinating polyneuropathy caused by IgM autoantibodies against myelin associated glycoprotein (MAG) and the sulphated trisaccharide CD57, we aimed to test the hypothesis that B cells making the autoantibody escaped tolerance by acquiring lymphoma driver somatic mutations.</div></div><div><h3>Methods</h3><div>Deep single-cell RNA, DNA, flow cytometric and antibody specificity analysis of blood from three patients with MAG neuropathy.</div></div><div><h3>Results</h3><div>MAG autoantibody-producing B cell clones exhibited extensive intraclonal immunoglobulin V(D)J hypermutation. In many of the sub-clonal branches, the replacement:silent ratio of V-region mutations was not different from that expected for unselected mutations, although in some branches the mutations either increased or eliminated binding to MAG and CD57 autoantigens. Prior to intraclonal V(D)J diversification, each clone had acquired a gain-of-function <em>MYD88</em>^{<em>p.L265P</em>} mutation, and some branches had acquired additional somatic mutations in <em>CXCR4, IGLL5</em> and <em>BTG2</em>. Whilst all MAG-binding clones harboured the <em>MYD88</em>^{<em>p.L265P</em>} mutation, the same mutation was also found in some control, polyclonal B cells. Deep sequencing of different blood cell subsets indicated <em>MYD88</em>^{<em>p.L265P</em>} was confined to B cells.</div></div><div><h3>Conclusion</h3><div>In three MAG neuropathy patients we find evidence that the self-reactive B cells responsible for their disease acquired a classical lymphoma driver somatic mutation early in their clonal expansion.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103474"},"PeriodicalIF":7.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005150","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":"Methotrexate and low-dose prednisone in idiopathic retroperitoneal fibrosis: a randomised clinical trial","authors":"Francesco Peyronel ,&nbsp;Alessandra Palmisano ,&nbsp;Federica Maritati ,&nbsp;Federico Alberici ,&nbsp;Maria L. Urban ,&nbsp;Davide Gianfreda ,&nbsp;Giovanni M. Rossi ,&nbsp;Paride Fenaroli ,&nbsp;Alessandra Bettiol ,&nbsp;Gabriella Moroni ,&nbsp;Augusto Vaglio","doi":"10.1016/j.jaut.2025.103487","DOIUrl":"10.1016/j.jaut.2025.103487","url":null,"abstract":"<div><h3>Objectives</h3><div>To test the efficacy and safety of methotrexate plus low-dose prednisone in patients with idiopathic retroperitoneal fibrosis.</div></div><div><h3>Methods</h3><div>We conducted an open-label, randomised, active-controlled, non-inferiority phase III trial. Sixty (out of 78 screened) adults with newly diagnosed idiopathic retroperitoneal fibrosis and an estimated glomerular filtration rate &gt;30 mL/min/1.73 m² were enrolled at outpatient clinics of two Italian centres (Nephrology units of Parma University Hospital and Milano Policlinico Hospital). Patients were randomly assigned (1:1) to receive low-dose prednisone plus methotrexate (MTX + LowPred) or standard-dose prednisone alone (standPred) for nine months. The primary endpoint was remission at month 9. Remission was defined as absence of symptoms and ureteral obstruction (free of stents or nephrostomies), and normal acute-phase reactants; secondary endpoints included reduction in RPF thickness, relapses and treatment-related toxicity.</div></div><div><h3>Results</h3><div>29 patients received MTX + LowPred and 31 standPred. Twenty-six patients (89.7 %) receiving MTX + LowPred and 25 (80.6 %) receiving standPred achieved and maintained remission until month 9. The difference between remission rates was 9.1 % (95 %CI -9.9 %–27.3 %), meeting the criterion for non-inferiority. Time-to-remission was similar (log-rank test p = 0.549). The two groups showed comparable RPF thickness reduction and relapse rates. The median cumulative prednisone dose was significantly higher in the standPred group (p &lt; 0.001). No significant differences in adverse events were observed.</div></div><div><h3>Conclusions</h3><div>A low-dose prednisone plus methotrexate regimen is non-inferior to standard-dose prednisone in achieving remission in idiopathic retroperitoneal fibrosis, allowing significant reduction in glucocorticoid exposure.</div></div><div><h3>Trial registration</h3><div>ClinicalTrials.gov: NCT01240850.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103487"},"PeriodicalIF":7.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145099521","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":"Genetic susceptibility and validation of angiographic patterns in Takayasu arteritis","authors":"Desiré Casares-Marfil ,&nbsp;K. Bates Gribbons ,&nbsp;Guher Saruhan-Direskeneli ,&nbsp;Sema Kaymaz-Tahra ,&nbsp;Kaitlin A. Quinn ,&nbsp;Fatma Alibaz-Oner ,&nbsp;Peter C. Grayson ,&nbsp;Haner Direskeneli ,&nbsp;Amr H. Sawalha ,&nbsp;Peter A. Merkel","doi":"10.1016/j.jaut.2025.103496","DOIUrl":"10.1016/j.jaut.2025.103496","url":null,"abstract":"<div><h3>Background</h3><div>Prior studies identified subsets of patients with Takayasu arteritis (TAK) based on angiographic patterns of disease in cohorts from India and North America. This study aimed to validate these patterns in a TAK cohort from Turkey and determine the role of genetics in arterial patterns.</div></div><div><h3>Methods</h3><div>421 Turkish patients with TAK underwent angiography of the aorta and branch vessels, with disease involvement characterized in 13 arterial territories. K-means cluster analysis identified angiographically-based subgroups. 282 patients with TAK from Turkey and 115 European-American patients from North America were genotyped. Approximately 6.5 million SNPs were evaluated in a meta-analysis of both cohorts. Logistic regressions identified genetic associations with angiographic clusters (threshold for association: p-value&lt;1x10⁻⁵). Associated variants were functionally annotated.</div></div><div><h3>Results</h3><div>Three clusters were identified in Turkish patients, validating the previously-identified cluster pattern. Genome-wide meta-analyses revealed a locus in the solute carrier family gene <em>SLC24A2</em> in Cluster One as the most significant association (rs2891138, OR = 3.34, p-value = 2.32x10⁻⁷). Several genetic loci were associated with Cluster Two, including in <em>LGALSL</em> (rs883021, OR = 0.43, p-value = 1.00X10⁻⁵), <em>AK4P3</em> (rs1072778, OR = 0.39, p-value = 4.07X10⁻⁶), and <em>TMEM132B</em> (rs4765045, OR = 3.05, p-value = 6.18X10⁻⁶). The most significant locus associated with Cluster Three was in <em>FRMD6</em> (rs55692665, OR = 2.79, p-value = 1.11X10⁻⁷). Genetic effects were consistent between the cohorts. Several loci were associated with levels of mRNA expression in arterial tissues. A Cluster Two-associated variant in <em>APBB2</em> (rs2465578, OR = 0.35, p-value = 6.69x10⁻⁶) showed evidence for chromatin interaction with the <em>NSUN7</em> promoter and increased aortic <em>NSUN7</em> expression.</div></div><div><h3>Conclusions</h3><div>Genetic factors are associated with distinct subsets of TAK defined by angiographic pattern of disease.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103496"},"PeriodicalIF":7.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145481841","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":"Temporal trajectories and DMARD therapy retention of rheumatoid arthritis patients with different autoimmune and inflammatory comorbidity profiles: a retrospective analysis","authors":"Signe Hässler ,&nbsp;Julie Aste ,&nbsp;Francis Berenbaum ,&nbsp;Michelle Rosenzwajg ,&nbsp;Jérémie Sellam ,&nbsp;David Klatzmann ,&nbsp;Milka Maravic","doi":"10.1016/j.jaut.2025.103502","DOIUrl":"10.1016/j.jaut.2025.103502","url":null,"abstract":"<div><h3>Background</h3><div>Patients with immunological diseases exhibit distinct comorbidity patterns, categorized into low comorbidity, polyautoimmunity, and polyinflammation profiles. This retrospective cohort study aimed to validate these profiles in rheumatoid arthritis (RA) patients, examine their longitudinal trajectories, and assess their impact on treatment persistence.</div></div><div><h3>Methods</h3><div>RA patients, and their associated treatments, were identified from the French pharmacy-dispensing database LRx through an algorithm based on targeted therapies. Algorithms to identify 17 comorbidities were designed based on drug indications. Comorbidity clusters were assigned yearly using a multinomial regression model, and state sequence analysis with hierarchical clustering was used to define their temporal trajectories. DMARD retention across comorbidity trajectories was evaluated through Cox regression models.</div></div><div><h3>Results</h3><div>Among 15,189 RA patients (maximum follow-up: 10 years), initial comorbidity profiles included low comorbidity (61.9 %), polyautoimmunity (24.7 %), and polyinflammation (13.4 %). Four trajectory patterns emerged among 5223 patients with at least 8 years of follow-up: stable low comorbidity (50 %), dominant polyautoimmune (31 %), stable polyinflammatory (9 %), and low comorbidity switching to polyinflammation (polyinflammation switchers, 10 %). The prevalence of polyautoimmunity and polyinflammation increased with age by 2.5 % [0.9 %–4.1 %] and 3.8 % [3.6 %–4.7 %] per decade, respectively.</div><div>Patients with stable polyinflammation had the lowest conventional synthetic DMARD 18-month persistence (stable polyinflammation: 15.68 % [10.26 %; 23.96 %]; polyinflammation switchers: 40.34 % [32.72 %; 49.75 %]; HR: 1.79 [1.33–2.42]). Stable low comorbidity patients had the highest biological and targeted synthetic DMARD persistence (polyinflammation switchers: 58.68 % [53.53 %; 64.32 %]; stable low comorbidity [65.66 % [63.20 %; 68.22 %]; aHR: 1.32 [1.09–1.60]).</div></div><div><h3>Conclusions</h3><div>Comorbidity trajectories in RA are associated with DMARD persistence, reflecting distinct subgroups with potential theranostic relevance. These results should be confirmed through a prospective study on DMARD-initiating patients.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103502"},"PeriodicalIF":7.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534342","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":"Immune mediated inflammatory disease: T cell engager versus antibody drug conjugate","authors":"Zhenguo Liang ,&nbsp;Hui Xie ,&nbsp;Mengyun Mao ,&nbsp;Bing Hou ,&nbsp;James Cheng-Chung Wei ,&nbsp;Dongze Wu","doi":"10.1016/j.jaut.2025.103497","DOIUrl":"10.1016/j.jaut.2025.103497","url":null,"abstract":"<div><div>Immune-mediated inflammatory diseases (IMIDs, distinct from IMiDs, immunomodulatory drugs) pose major therapeutic challenges due to complex pathophysiology, limited treatment durability, and associated adverse effects. T cell engagers (TCEs) and antibody-drug conjugates (ADCs) offer innovative approaches that leverage antibody specificity to precisely target pathogenic immune cells. TCEs redirect T cell cytotoxicity to eliminate autoreactive B cells and plasma cells, showing efficacy in diseases such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. In contrast, ADCs deliver immunomodulatory payloads to disease-relevant cells, with agents like ABBV-154 and brentuximab vedotin showing promise in rheumatoid arthritis and systemic sclerosis. However, challenges such as cytokine release syndrome with TCEs and off- and on-target toxicities with ADCs highlight the need for optimal target selection and innovative design. This review provides a comprehensive comparison of the mechanisms, current evidence, and future directions of TCEs and ADCs in IMIDs, highlighting their potential to address unmet needs in disease management.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103497"},"PeriodicalIF":7.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145451974","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":"2025-09-01","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":"Transcriptomics of autoimmune diseases identifies FGFR1 as a target for pancreatic β-cell protection.","authors":"Xiaoyan Yi, Priscila L Zimath, Eugenia Martin-Vazquez, Junior Garcia Oliveira, Sayro Jawurek, Alexandra C Title, Burcak Yesildag, Nizar I Mourad, Antoine Buemi, François Pattou, Julie Kerr-Conte, Sabine Costagliola, Mírian Romitti, Decio L Eizirik","doi":"10.1016/j.jaut.2025.103469","DOIUrl":"10.1016/j.jaut.2025.103469","url":null,"abstract":"<p><p>Autoimmune diseases, such as type 1 diabetes (T1D) and Hashimoto's thyroiditis (HT), are often studied from an immune perspective with less focus on the target tissue responses. Target tissues, however, are key to disease and engage in a harmful crosstalk with the immune system contributing to their own destruction. We presently integrated transcriptomic data from the target tissues of six autoimmune/inflammatory diseases affecting β-cells (T1D and type 2 diabetes), thyroid (HT), brain (multiple sclerosis and Alzheimer's disease) or the joints (rheumatoid arthritis), using both bulk and single-cell/nucleus RNA-sequencing (sc/snRNA-seq) approaches. Common upregulated pathways were associated with innate/adaptive immunity, antigen presentation and interferon (IFN) signaling. The role of IFNs was confirmed by RNA-seq in human insulin-producing EndoC-βH1 cells and stem cell-derived thyroid follicle cells exposed to IFNα or IFNγ. Commonly upregulated inflammatory gene signatures were explored, and fibroblast growth factor receptor (FGFR) inhibitors emerged as a potential strategy to counteract these inflammatory transcriptional signatures. The effects of the FGFR1 inhibitor PD173074 on IFN-induced immune related genes were evaluated in EndoC-βH1 cells, stem cell-derived islets and adult human islets. We validated the FGFR inhibitor PD173074 as a promising drug for preserving expression of β-cell protective genes (PDL1 and HLA-E) while reducing HLA class I expression and β-cell recognition by diabetogenic pre-proinsulin-specific CD8⁺ T-cells. In conclusion, we integrated transcriptomic data from the target tissues of autoimmune and inflammatory/degenerative diseases and departing from these data identified the potential beneficial effects of FGFR inhibitors in T1D.</p>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"156 ","pages":"103469"},"PeriodicalIF":7.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812075","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":"2025-09-01","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":"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":"2025-09-01","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":"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":"2025-09-01","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}