Journal of Translational Autoimmunity最新文献

{"title":"Cell-specific epigenome-wide DNA methylation in peripheral CD4(+) lymphocytes from patients with primary biliary cholangitis","authors":"Pinelopi Arvaniti ,&nbsp;Kalliopi Zachou ,&nbsp;Aggeliki Lyberopoulou ,&nbsp;Eirini Sevdali ,&nbsp;Stella Gabeta ,&nbsp;Matthaios Speletas ,&nbsp;Yves Renaudineau ,&nbsp;George N. Dalekos","doi":"10.1016/j.jtauto.2025.100314","DOIUrl":"10.1016/j.jtauto.2025.100314","url":null,"abstract":"<div><h3>Background/aims</h3><div>Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease, triggered by a complex interplay between genetic, environmental and epigenetic factors. We investigated the methylation profile of peripheral CD4(+) lymphocytes from PBC patients compared to healthy controls (HC) and autoimmune hepatitis (AIH) patients, to elucidate gene specific epigenetic modifications that contribute to PBC pathogenesis, as similar data are limited.</div></div><div><h3>Methods</h3><div>CD4(+) lymphocytes were isolated from 8 PBC treatment-naïve patients, 9 HC and 10 AIH patients at diagnosis by ROBOSEP platform. Whole genome methylation analysis was performed by 850k array of Illumina. Candidate genes’ transcriptional expression was quantified by RT-PCR.</div></div><div><h3>Results</h3><div>Comparison between PBC patients and HC, revealed 1016 differentially methylated positions (DMPs) on autosomal chromosomes and 1203 DMPs on X chromosome (&gt;98 % hypermethylated), corresponding to 695 and 322 genes, respectively (p &lt; 0.05). Hypermethylation mainly affected pathways of immune cells differentiation and signalling (CAMTA1, PRKARB, LNC01993, TLR9)<em>.</em> Methylation analysis between PBC and AIH revealed &gt;5000 DMPs (98 % hypermethylated in PBC) corresponding to &gt;4000 genes. Pathway analysis retrieved an enrichment of “cytokine” and “interleukin” signalling (C1GTNF3, SMAD3). Analysis of differentially methylated regions showed enrichment on gene promoters and hypermethylation of IFN-regulated genes (IFNGR2, TICAM2) in PBC patients. Genes expression at the transcriptional level showed over-expression of IFNGR2 in PBC patients.</div></div><div><h3>Conclusions</h3><div>Hypermethylation characterizes most genes of peripheral CD4(+) lymphocytes in PBC. The epigenetic modifications mainly affect pathways of immunological responses. The significant number of X chromosome located DMPs, further supports the role of sex in PBC pathogenesis.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100314"},"PeriodicalIF":3.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145044686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Splicing-based biomarkers define a robust multigene classifier for relapsing-remitting multiple sclerosis","authors":"Federica Airi ,&nbsp;Valeria Rimoldi ,&nbsp;Elvezia Maria Paraboschi ,&nbsp;Valentina Pellicanò ,&nbsp;Damiano Verda ,&nbsp;Giuseppe Liberatore ,&nbsp;Claudia Cantoni ,&nbsp;Laura Piccio ,&nbsp;Alvino Bisecco ,&nbsp;Anita Capalbo ,&nbsp;Giulia Cardamone ,&nbsp;Eduardo Nobile-Orazio ,&nbsp;Giulia Soldà ,&nbsp;Rosanna Asselta","doi":"10.1016/j.jtauto.2025.100312","DOIUrl":"10.1016/j.jtauto.2025.100312","url":null,"abstract":"<div><h3>Background</h3><div>Alternative splicing (AS) is recognized as a key mechanism in multiple sclerosis (MS). We aimed to construct and validate a multivariate AS-based classifier (MS-Splicing Score, MS-SS) for the discrimination of relapsing-remitting MS (RRMS) patients from healthy controls.</div></div><div><h3>Methods</h3><div>Three AS events (<em>IFNAR2</em> exon-8 skipping, <em>NFAT5</em> exon-2 skipping, <em>PRKCA</em> exon-3∗ inclusion) were selected based on functional and literature evidence. Isoforms were quantified via fluorescent-competitive RT-PCR in peripheral blood RNA from two independent cohorts (Italy: 37 RRMS, 50 controls; USA: 29 RRMS, 20 controls). A logistic regression model was trained to derive the MS-SS, followed by ROC analysis.</div></div><div><h3>Results</h3><div>The MS-SS distinguished RRMS patients from controls in both cohorts (Italy: p = 0.00083, AUC = 0.71, 95 %CI = 0.59–0.82; USA: p = 0.00074, AUC = 0.77, 95 %CI = 0.63–0.90). In the pooled dataset, the score remained significantly elevated in MS (p = 5.9 × 10⁻⁶, AUC = 0.72, 95 %CI = 0.64–0.81), and a PCA-based refinement improved classification accuracy, yielding an AUC = 0.87 (95 %CI = 0.81–0.94). At the optimal cutoff (Youden's index), the score achieved a sensitivity of 80 % and specificity of 86 %. Supervised rule-based modeling using a logic-learning machine algorithm identified interpretable splicing thresholds and enabled clinical classification at the individual level.</div></div><div><h3>Conclusion</h3><div>Our study introduces a novel, robust AS-based classifier for RRMS and proposes a strategy for transcriptome-based biomarker development in neuroimmunology. However, the relatively small sample sizes within each cohort may limit the generalizability of these findings, warranting larger validation studies to confirm the clinical utility of this biomarker.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100312"},"PeriodicalIF":3.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145019063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redefining multiple sclerosis therapy through microbial immunomodulation and epigenetic control","authors":"Shan Xu ,&nbsp;Christina James Thomas ,&nbsp;Sunilgowda Sunnagatta Nagaraja ,&nbsp;Rakesh Kumar ,&nbsp;Kamlesh Sawant ,&nbsp;Duminduni Hewa Angappulige ,&nbsp;Andy Fang Song ,&nbsp;Krish Suman ,&nbsp;Benjamin Borja ,&nbsp;Paul de Figueiredo ,&nbsp;Jianxun Song","doi":"10.1016/j.jtauto.2025.100313","DOIUrl":"10.1016/j.jtauto.2025.100313","url":null,"abstract":"<div><div>Multiple sclerosis (MS) is a chronic autoimmune disorder marked by immune-driven demyelination and neurodegeneration in the central nervous system. This Review explores the immunological, molecular, and epigenetic underpinnings of MS, emphasizing T and B cell involvement, dysregulated signaling pathways (e.g., TGF-β, Akt, Wnt), and the role of cell death in disease progression. Epigenetic mechanisms—such as DNA methylation and histone modifications, further modulate immune responses. While current therapies broadly suppress immunity, emerging approaches, including engineered bacteria, microbiome-based interventions, and cell therapies, offer targeted immune modulation and neuroprotection. Together, these strategies illuminate a path toward next-generation MS treatments with improved precision and efficacy.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100313"},"PeriodicalIF":3.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond conventional treatment: Novel cell therapies for systemic lupus erythematosus","authors":"Zeinab Zarei-Behjani ,&nbsp;Arghavan Hosseinpouri ,&nbsp;Maryam Fotoohi ,&nbsp;Akram Shafiee ,&nbsp;Dorna Asadi","doi":"10.1016/j.jtauto.2025.100308","DOIUrl":"10.1016/j.jtauto.2025.100308","url":null,"abstract":"<div><div>Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by its heterogeneity, as it can affect various organs and exhibit a diverse clinical progression. The identification of SLE relies on the presence of distinct clinical manifestations in the skin, joints, kidneys, and the central nervous system, along with serological markers like antinuclear antibodies such as antibodies targeting dsDNA. The present therapeutic approaches for SLE encompass the use of antimalarial agents, glucocorticoids, immunosuppressive medications, and biological therapies. Despite the advancements in therapeutic strategies, SLE continues to be linked with adverse outcomes. The complicity and unpredictable nature of disease, characterized by episodes of relapses and remissions, coupled with the side effects of current treatment options, the progressive accumulation of organ damage, and persistent mortality rates despite therapeutic improvements, underscores the urgent necessity for the creation of innovative, effective, and specifically targeted therapies. Cell-based therapies, although still in their nascent stages, have attracted considerable interest in the realm of SLE treatment due to their potential for long-term disease suppression or even the possibility of a cure. Various cell types have emerged as promising candidates for SLE management. This review aims to provide a brief overview of the most recent research on novel cell-based therapeutic approaches that have progressed to either pre-clinical or clinical trial phases for the treatment of SLE.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100308"},"PeriodicalIF":3.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144932217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory T cell therapy for Sjögren's disease: From pathogenesis to targeted treatment","authors":"Zhi Feng Sherman Lim ,&nbsp;Alberta Y. Hoi ,&nbsp;Fabien B. Vincent ,&nbsp;Joshua D. Ooi ,&nbsp;Eric F. Morand ,&nbsp;Maureen Rischmueller ,&nbsp;Yi Tian Ting","doi":"10.1016/j.jtauto.2025.100311","DOIUrl":"10.1016/j.jtauto.2025.100311","url":null,"abstract":"<div><div>Sjögren's disease (SjD) is a chronic systemic autoimmune disorder characterised by lymphocytic infiltration of the salivary and lacrimal glands, leading to the hallmark symptoms of dry eyes and dry mouth. Beyond glandular dysfunction, many patients experience systemic complications—including B cell hyperactivity, organ-specific inflammation, and a markedly increased risk of non-Hodgkin lymphoma—that are frequently under-recognised and poorly managed. Current treatments remain largely empirical and symptomatic, with limited efficacy in modifying disease progression or restoring immune tolerance.</div><div>Recent advances have illuminated profound dysregulation in both innate and adaptive immunity, revealing novel therapeutic targets now under investigation in clinical trials, including type I interferon signalling, B cell activation, and co-stimulatory pathways. Central to this dysregulation is T cell–driven pathology: CD8⁺ T cell cytotoxicity, defective regulatory T cell (Treg) function, and HLA class II–mediated presentation of self-antigens to autoreactive CD4⁺ T cells are key mechanisms in disease initiation and persistence.</div><div>A growing body of evidence implicates Ro autoantigens—Ro60 and Ro52—as central targets in SjD pathogenesis. Anti-Ro antibodies are present in approximately 70 % of patients and serve as both diagnostic markers and indicators of systemic involvement. Ro antigens and their corresponding antibodies are consistently detected in inflamed salivary tissues, underscoring their potential as compelling targets for antigen-specific therapy.</div><div>This review examines the immunopathogenic role of Ro-specific T cell responses in SjD and outlines how engineered Treg-based therapies may enable precise immune modulation, restore tolerance, and provide durable disease control for patients with this complex autoimmune condition.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100311"},"PeriodicalIF":3.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144932219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acylcarnitine enrichment as a characteristic of rheumatoid arthritis fibroblast-like synoviocyte metabolic fingerprint","authors":"Georgios K. Vasileiadis ,&nbsp;Yuan Zhang ,&nbsp;Marion Laudette ,&nbsp;Tahzeeb Fatima ,&nbsp;Anna-Karin Hultgård Ekwall ,&nbsp;Reshmi Sureshkumar ,&nbsp;Ronald van Vollenhoven ,&nbsp;Jon Lampa ,&nbsp;Bjorn Gudbjornsson ,&nbsp;Espen A. Haavardsholm ,&nbsp;Dan Nordström ,&nbsp;Gerdur Gröndal ,&nbsp;Kim Hørslev-Petersen ,&nbsp;Kristina Lend ,&nbsp;Merete L. Hetland ,&nbsp;Michael Nurmohamed ,&nbsp;Mikkel Østergaard ,&nbsp;Till Uhlig ,&nbsp;Tuulikki Sokka-Isler ,&nbsp;Anna Rudin ,&nbsp;Cristina Maglio","doi":"10.1016/j.jtauto.2025.100310","DOIUrl":"10.1016/j.jtauto.2025.100310","url":null,"abstract":"<div><h3>Objective</h3><div>In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) alter their metabolism to support their activation. We aimed to analyse the full spectrum of metabolic alterations associated with RA by performing untargeted metabolomics in RA FLS vs. non-inflamed (NI) FLS.</div></div><div><h3>Methods</h3><div>Untargeted annotated metabolomics was performed using mass spectrometry on ten primary RA and seven NI FLS culture extracts and 220 serum samples from participants with early RA from the randomised controlled NORD-STAR trial. Carnitine-related proteins were measured with Western blot. FLS bioenergetic profile was assessed with a Seahorse flux analyser.</div></div><div><h3>Results</h3><div>Metabolomics analysis based on 138 annotated metabolites revealed a distinct metabolic fingerprint between RA and NI FLS. Of the 12 metabolites enriched in RA FLS, 11 were acylcarnitines. Pro-inflammatory stimulation of NI FLS also led to acylcarnitine accumulation. RA FLS exhibited lower levels of CD36, a fatty acid transporter, but similar levels of L-carnitine transporter, and carnitine palmitoyltransferase 1 A and 2 compared to NI FLS. Seahorse analyses showed no difference in fatty acid oxidation between RA and NI FLS; however, RA FLS displayed mitochondrial dysfunction and energetic impairment. Serum acylcarnitine content decreased after 24 weeks of treatment with methotrexate combined with abatacept or tocilizumab in patients with early RA achieving remission.</div></div><div><h3>Conclusion</h3><div>Acylcarnitine accumulation is a characteristic of RA FLS metabolic fingerprint and could be linked to mitochondrial dysfunction. In patients with early RA, acylcarnitine content in serum decreases after successful anti-rheumatic treatment. These results indicate a dysregulation in acylcarnitine metabolism in RA at the joint level and systemically.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100310"},"PeriodicalIF":3.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144878752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"When the victim becomes the villain: Platelets as drivers of immune dysregulation in ITP","authors":"Fatemeh Farhid ,&nbsp;Hadi Rezaeeyan ,&nbsp;Reza Habibi ,&nbsp;Ehsan Kamali Yazdi ,&nbsp;Michael R. Hamblin ,&nbsp;Jalal Naghinezhad","doi":"10.1016/j.jtauto.2025.100309","DOIUrl":"10.1016/j.jtauto.2025.100309","url":null,"abstract":"<div><div>Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder characterized by immune-mediated destruction of platelets and impaired platelet production. Although autoantibodies have historically been central to the understanding of ITP, current evidence demonstrates that its pathogenesis extends well beyond humoral mechanisms to involve complex dysregulation of both innate and adaptive immune responses. Multiple immune pathways—including autoreactive B and T cells, dendritic cell activation, and regulatory T cell deficiency—contribute to disease onset, progression, and chronicity. Moreover, ITP encompasses a broad spectrum of clinical and immunological subtypes, including primary idiopathic forms and secondary ITP associated with autoimmune diseases, infections, and inborn errors of immunity. This review offers a novel perspective on ITP pathogenesis, emphasizing the active immunoregulatory role of platelets as contributors to immune dysregulation. Far from being passive targets, platelets in ITP actively shape immune responses through crosstalk with immune cells, particularly CD4⁺ T helper (Th) and CD8⁺ cytotoxic T cells. This interaction, primarily mediated via the P-selectin–PSGL-1 axis, promotes Th1/Th17 polarization, enhances autoantibody production, and accelerates platelet destruction. In parallel, platelet-derived microparticles (PMPs) act as potent immune effectors by delivering pro-inflammatory cytokines and autoantigens that sustain chronic immune activation. Prolonged platelet activation also gives rise to a distinct subpopulation known as “hairy platelets”—exhausted, granule-depleted cells with altered surface phenotypes and sustained pro-inflammatory potential. Although functionally exhausted in terms of coagulation, these platelets retain immunostimulatory capacity through persistent phosphatidylserine exposure and cytokine release. By reframing platelets as active participants in the pathogenesis of ITP, this review proposes that targeting platelet activation, platelet–T cell interactions, and PMP release may represent innovative therapeutic strategies. Such approaches could offer more precise and personalized treatment options, particularly for patients with chronic or refractory disease, by restoring immune balance and improving long-term outcomes.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100309"},"PeriodicalIF":3.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144886219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Afucosylated IgG in idiopathic nephrotic syndrome patients with anti-nephrin autoantibodies correlate with disease activity","authors":"Sonia Spinelli ,&nbsp;Andrea Garbarino ,&nbsp;Francesca Lugani ,&nbsp;Edoardo La Porta ,&nbsp;Noemi Rumeo ,&nbsp;Giorgio Piaggio ,&nbsp;Alberto Magnasco ,&nbsp;Antonella Trivelli ,&nbsp;Maria Ludovica Degl’Innocenti ,&nbsp;Gino Tripodi ,&nbsp;Simona Granata ,&nbsp;Francesca Leone ,&nbsp;Elena Zocchi ,&nbsp;Lorenzo Gallon ,&nbsp;Gian Marco Ghiggeri ,&nbsp;Enrico Verrina ,&nbsp;Gianluigi Zaza ,&nbsp;Giovanni Candiano ,&nbsp;Maurizio Bruschi","doi":"10.1016/j.jtauto.2025.100307","DOIUrl":"10.1016/j.jtauto.2025.100307","url":null,"abstract":"<div><h3>Background</h3><div>Idiopathic nephrotic syndrome (INS) is a glomerular disorder characterized by podocyte injury and proteinuria. Emerging evidence suggests that anti-nephrin autoantibodies (Abs) may contribute to disease pathogenesis in a subset of INS patients. Variation in techniques for detecting anti-nephrin Abs and lack of urinary data contribute to uncertainties of results.</div><div>While reduced IgG fucosylation is known to enhance antibody-dependent cellular cytotoxicity in non-INS autoimmune diseases, its role in modulating anti-nephrin autoantibody function and disease severity in INS remains unexplored.</div></div><div><h3>Methods</h3><div>We studied serum and urine of pediatric and young adult patients with biopsy-proven focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) with different disease activity (proteinuria + <em>vs</em> proteinuria-). Anti-nephrin autoantibodies were evaluated with either conventional ELISA and immunoprecipitation using recombinant full-length extracellular domain of FLAG tagged human nephrin. Aleuria Aurantia Lectin (AAL) and Ulex Europaeus Agglutinin I (UEA-I) Lectins assessed IgG autoantibody fucosylation.</div></div><div><h3>Results</h3><div>Anti-nephrin autoantibodies were detected in serum of 11 % of FSGS and 15 % of MCD patients, with a higher prevalence among those with nephrotic-range proteinuria. These autoantibodies were absent in healthy controls as well as in patients with primary membranous nephropathy and class V lupus nephritis. Autoantibody titers correlated with disease activity, decreasing during remission. Immunoprecipitation confirmed results obtained with ELISA. In a subset of anti-nephrin positive patients, the autoantibodies were also detected in urine. Circulating anti-nephrin autoantibodies showed significantly reduced antennary and core fucosylation of IgG.</div></div><div><h3>Conclusions</h3><div>Our findings confirmed the significance of anti-nephrin autoantibodies as markers of active disease in a small subset of INS patients and showed their presence in urine. ELISA and Immunoprecipitation results correlated. Molecular studies showed that altered IgG fucosylation may contribute to immune-mediated podocyte injury. These insights provide potential biomarkers for disease monitoring and therapeutic targets in INS.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100307"},"PeriodicalIF":3.6,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted regulatory T cell activation by site-specific PEGylated interleukin-2 mitigates autoimmune inflammation","authors":"Masahiro Ikeda ,&nbsp;Shinpei Yamaguchi ,&nbsp;Shigeki Takaoka ,&nbsp;Yasuko Sakaguchi ,&nbsp;Shunki Yasui","doi":"10.1016/j.jtauto.2025.100306","DOIUrl":"10.1016/j.jtauto.2025.100306","url":null,"abstract":"<div><div>Dysregulation of immune homeostasis accompanied by regulatory T cell (Treg) dysfunction is a hallmark of various autoimmune and inflammatory diseases. While low-dose interleukin-2 (IL-2) treatment can enhance Treg levels and alleviate disease symptoms, its short half-life necessitates frequent dosing. Furthermore, adverse events associated with the activation of other immune cells are often observed. In this study, using a site-specific PEGylation approach, we developed a novel IL-2 variant, I129-W80, which exhibited an IL-2Rα–biased binding profile, driven by the steric hindrance of the PEG moiety. It selectively activated Tregs in vitro and could overcome inhibition by the endogenous decoy receptor, soluble IL-2Rα, unlike the Fc-fusion IL-2 variant AMG-592. In a single-dose monkey study, I129-W80 demonstrated an extended half-life, along with sustained amplification and activation of Tregs. At the maximum dose that did not induce C-reactive protein elevation, I129-W80 showed superior activity compared with AMG-592. I129-W80 improved inflammatory responses in both delayed-type hypersensitivity and xenogeneic graft-versus-host disease models. Additionally, in an imiquimod-induced dermatitis model, I129-W80 exhibited reduced distribution to inflamed tissues compared with AMG-592. These findings demonstrated that I129-W80 possesses distinct properties relative to Fc-fusion IL-2 variant and can correct immune imbalances caused by Treg dysfunction, thereby improving the symptoms of various autoimmune diseases.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100306"},"PeriodicalIF":3.6,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploration of shared biomarkers and mechanisms in systemic lupus erythematous and lung cancer via bioinformatics analysis","authors":"Chueh-Hsuan Hsu ,&nbsp;Shuo-Chueh Chen ,&nbsp;Yung-Luen Yu","doi":"10.1016/j.jtauto.2025.100304","DOIUrl":"10.1016/j.jtauto.2025.100304","url":null,"abstract":"<div><div>Systemic lupus erythematosus (SLE) patients exhibit a heightened risk of developing lung cancer, yet the underlying molecular mechanisms remain poorly understood. This study aimed to identify shared genetic factors linking SLE and LC using publicly available transcriptomic data from the Gene Expression Omnibus (GEO). Through integrated differentially expressed gene (DEG) analysis and weighted gene co-expression network analysis (WGCNA), we identified five genes consistently upregulated in both SLE and lung cancer. Gene set enrichment analysis (GSEA) revealed that these shared genes were enriched in inflammatory pathways, particularly those involving interferon-alpha, interferon-gamma, and general inflammatory responses. We applied least absolute shrinkage and selection operator (LASSO) regression to pinpoint potential diagnostic biomarkers and identified two key candidates: AIM2 and SLC26A8. These biomarkers demonstrated robust diagnostic performance with area under the ROC curve (AUC) values exceeding 0.75 in both training and validation cohorts. Immune infiltration and survival analyses using The Cancer Genome Atlas (TCGA) further supported their clinical relevance. Notably, high AIM2 expression was significantly associated with poorer overall survival in female lung adenocarcinoma patients (P = 0.03), and SLC26A8 expression was significantly linked to survival outcomes only in patients with a history of smoking (P = 0.01). These findings are particularly meaningful in SLE, where most patients are female and smoking is a known risk factor. Our study enhances the understanding of autoimmune-driven carcinogenesis and opens new avenues for precision medicine strategies in managing patients with SLE at risk for lung cancer.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100304"},"PeriodicalIF":3.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144771488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}