Vitiligo is a chronic, acquired skin disorder characterized by the loss of pigmentation due to the destruction or dysfunction of melanocytes. Conventional treatments such as corticosteroids and phototherapy often produce limited and unpredictable outcomes. In recent years, novel therapeutic strategies—including both cell-based and cell-free approaches such as melanocyte transplantation, mesenchymal stem cells (MSCs), platelet-rich plasma (PRP), stem cell secretome, and exosomes—have emerged as promising alternatives. These therapies aim to restore pigmentation by replenishing melanocytes, modulating immune responses, and mitigating oxidative stress. This review explores the mechanisms of action, clinical efficacy, and translational challenges associated with each approach. While melanocyte transplantation demonstrates the highest repigmentation success in stable cases, stem cell- and exosome-based therapies offer significant potential for personalized and long-term treatment of vitiligo.
{"title":"Emerging cell-based and cell-free therapeutic strategies for vitiligo","authors":"Nasser Gholijani , Effat Noori , Zeinab Zarei-Behjani , Delsuz Rezaee , Maryam Khodaei , Gholamhossien Darya , Kobra Mehdinejadiani , Zeinab Dehghan","doi":"10.1016/j.jtauto.2025.100331","DOIUrl":"10.1016/j.jtauto.2025.100331","url":null,"abstract":"<div><div>Vitiligo is a chronic, acquired skin disorder characterized by the loss of pigmentation due to the destruction or dysfunction of melanocytes. Conventional treatments such as corticosteroids and phototherapy often produce limited and unpredictable outcomes. In recent years, novel therapeutic strategies—including both cell-based and cell-free approaches such as melanocyte transplantation, mesenchymal stem cells (MSCs), platelet-rich plasma (PRP), stem cell secretome, and exosomes—have emerged as promising alternatives. These therapies aim to restore pigmentation by replenishing melanocytes, modulating immune responses, and mitigating oxidative stress. This review explores the mechanisms of action, clinical efficacy, and translational challenges associated with each approach. While melanocyte transplantation demonstrates the highest repigmentation success in stable cases, stem cell- and exosome-based therapies offer significant potential for personalized and long-term treatment of vitiligo.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100331"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519047","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}
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.
{"title":"Beyond conventional treatment: Novel cell therapies for systemic lupus erythematosus","authors":"Zeinab Zarei-Behjani , Arghavan Hosseinpouri , Maryam Fotoohi , Akram Shafiee , 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":"2025-12-01","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}
Pub Date : 2025-12-01Epub Date: 2025-09-30DOI: 10.1016/j.jtauto.2025.100320
Ning Han , Keer Wang , Dan Yang , Mingxuan Han, Xiaoxiao Hou, Zhenghao Xu
The Cre-driven tdTomato reporter system is widely used to visualize gene expression and cellular dynamics. Here we tested the impact of the tdTomato reporter system on the progression of both central and peripheral manifestations of systemic lupus erythematosus (SLE) in dLckCre mice. We crossed dLckCre mice with ROSA26floxed-Stop-tdTomato mice to generate conditional dLck-driven tdTomato reporter mice (DT mice). Then, SLE models were induced by pristane injection in DT mice or by crossing DT mice with B6/lpr mice. Central and peripheral manifestations of SLE were assessed. Surprisingly, we found that DT mice exhibited a significant reduction in the progression of peripheral manifestations of SLE, evidenced by decreased severity of lymph node and splenic lesions, and improved renal pathology. However, DT mice showed similar central manifestations of SLE as control mice, evidenced by similar behavioral performance, CD4+ T cell infiltration in the choroid plexus, and microglial activation in the hippocampus. Flow cytometry revealed a significant reduction in the proportion of double-negative (DN) T cells in the peripheral blood of DT mice. Immunofluorescence analysis confirmed no significant differences in microglial morphology or choroid plexus CD4+ T cell infiltration between DT lupus mice and control mice. Notably, over 80 % of the infiltrating lymphocytes in the choroid plexus of lupus mice were CD4+ T cells. Adoptive transfer experiments further confirmed that these ectopically aggregated CD4+ T cells in the choroid plexus constitute a key pathogenic factor driving the onset and progression of neuropsychiatric SLE (NPSLE). Thus, conditional tdTomato expression alleviated peripheral but not central manifestations of SLE in dLckCre mice, suggesting a diverse role of dLck-labeled T lymphocytes in SLE development. Our results also provide additional evidence supporting the existence of a distinct separation mechanism between peripheral and central manifestations of SLE.
{"title":"Cre-driven tdTomato expression unexpectedly confers resistance to peripheral but not central lupus in dLckCre mice","authors":"Ning Han , Keer Wang , Dan Yang , Mingxuan Han, Xiaoxiao Hou, Zhenghao Xu","doi":"10.1016/j.jtauto.2025.100320","DOIUrl":"10.1016/j.jtauto.2025.100320","url":null,"abstract":"<div><div>The Cre-driven tdTomato reporter system is widely used to visualize gene expression and cellular dynamics. Here we tested the impact of the tdTomato reporter system on the progression of both central and peripheral manifestations of systemic lupus erythematosus (SLE) in dLckCre mice. We crossed dLckCre mice with ROSA26<sup>floxed</sup><sup><sup>-</sup></sup><sup>Stop-tdTomato</sup> mice to generate conditional dLck-driven tdTomato reporter mice (DT mice). Then, SLE models were induced by pristane injection in DT mice or by crossing DT mice with B6/lpr mice. Central and peripheral manifestations of SLE were assessed. Surprisingly, we found that DT mice exhibited a significant reduction in the progression of peripheral manifestations of SLE, evidenced by decreased severity of lymph node and splenic lesions, and improved renal pathology. However, DT mice showed similar central manifestations of SLE as control mice, evidenced by similar behavioral performance, CD4<sup>+</sup> T cell infiltration in the choroid plexus, and microglial activation in the hippocampus. Flow cytometry revealed a significant reduction in the proportion of double-negative (DN) T cells in the peripheral blood of DT mice. Immunofluorescence analysis confirmed no significant differences in microglial morphology or choroid plexus CD4<sup>+</sup> T cell infiltration between DT lupus mice and control mice. Notably, over 80 % of the infiltrating lymphocytes in the choroid plexus of lupus mice were CD4<sup>+</sup> T cells. Adoptive transfer experiments further confirmed that these ectopically aggregated CD4<sup>+</sup> T cells in the choroid plexus constitute a key pathogenic factor driving the onset and progression of neuropsychiatric SLE (NPSLE). Thus, conditional tdTomato expression alleviated peripheral but not central manifestations of SLE in dLckCre mice, suggesting a diverse role of dLck-labeled T lymphocytes in SLE development. Our results also provide additional evidence supporting the existence of a distinct separation mechanism between peripheral and central manifestations of SLE.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100320"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265776","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}
Pub Date : 2025-12-01Epub Date: 2025-06-27DOI: 10.1016/j.jtauto.2025.100297
Wushu Chen , Xingpei Li , Junye Mai , Kailang Tang , Yingqiao Wang , Yan-yan Lu , Jie Liang , Ni-jiao Li , Xiu-Yu Qin , Yu Li , Lunkai Yao , Ye Qiu
At present, there is a lack of detailed understanding and research on the pathogenesis and treatment of Hyperimmunoglobulin M syndrome (HIGM), Hyperimmunoglobulin E syndrome (HIES), and hyperimmunoglobulin D syndrome (HIDS), and few studies have been conducted to correlate the pathogenesis and treatment of the three disorders. The existing studies are rarely related to the three diseases. We searched PubMed for a large number of relevant literature and analyzed and summarized the contents. We analyzed and introduced the three diseases and their Categorization, Epidemiology, Clinical manifestations, Laboratory diagnosis, and Treatment by means of tables and Figures. It is hoped that this analysis and summary can play a certain role in the research and treatment of related diseases and promote the understanding and prevention of related diseases.
{"title":"Hyperimmunoglobulin syndromes: A review of HIGM, HIES, and HIDS","authors":"Wushu Chen , Xingpei Li , Junye Mai , Kailang Tang , Yingqiao Wang , Yan-yan Lu , Jie Liang , Ni-jiao Li , Xiu-Yu Qin , Yu Li , Lunkai Yao , Ye Qiu","doi":"10.1016/j.jtauto.2025.100297","DOIUrl":"10.1016/j.jtauto.2025.100297","url":null,"abstract":"<div><div>At present, there is a lack of detailed understanding and research on the pathogenesis and treatment of Hyperimmunoglobulin M syndrome (HIGM), Hyperimmunoglobulin E syndrome (HIES), and hyperimmunoglobulin D syndrome (HIDS), and few studies have been conducted to correlate the pathogenesis and treatment of the three disorders. The existing studies are rarely related to the three diseases. We searched PubMed for a large number of relevant literature and analyzed and summarized the contents. We analyzed and introduced the three diseases and their Categorization, Epidemiology, Clinical manifestations, Laboratory diagnosis, and Treatment by means of tables and Figures. It is hoped that this analysis and summary can play a certain role in the research and treatment of related diseases and promote the understanding and prevention of related diseases.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100297"},"PeriodicalIF":4.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556826","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}
Pub Date : 2025-12-01Epub Date: 2025-08-04DOI: 10.1016/j.jtauto.2025.100304
Chueh-Hsuan Hsu , Shuo-Chueh Chen , Yung-Luen Yu
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.
{"title":"Exploration of shared biomarkers and mechanisms in systemic lupus erythematous and lung cancer via bioinformatics analysis","authors":"Chueh-Hsuan Hsu , Shuo-Chueh Chen , 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":"2025-12-01","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}
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.
Methods
Three AS events (IFNAR2 exon-8 skipping, NFAT5 exon-2 skipping, PRKCA 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.
Results
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.
Conclusion
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.
{"title":"Splicing-based biomarkers define a robust multigene classifier for relapsing-remitting multiple sclerosis","authors":"Federica Airi , Valeria Rimoldi , Elvezia Maria Paraboschi , Valentina Pellicanò , Damiano Verda , Giuseppe Liberatore , Claudia Cantoni , Laura Piccio , Alvino Bisecco , Anita Capalbo , Giulia Cardamone , Eduardo Nobile-Orazio , Giulia Soldà , 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<sup>−6</sup>, 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":"2025-12-01","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}
Pub Date : 2025-12-01Epub Date: 2025-09-16DOI: 10.1016/j.jtauto.2025.100316
Aimei Pang , Shuangshuang Pu , Yinghui Pan , Ning Huang , Dake Li
Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation and joint destruction. Dysregulation of the Th17/Treg balance is a key immunological hallmark of RA. Emerging evidence highlights the critical role of gut microbiota-derived short-chain fatty acids (SCFAs) in maintaining immune homeostasis. This review systematically elucidates how SCFAs modulate the Th17/Treg equilibrium through three synergistic mechanisms: (1) metabolic reprogramming via AMPK/mTOR signaling, (2) epigenetic regulation by inhibiting HDAC, and (3) modulation of cytokine cascades. We integrate preclinical and clinical evidence showing that SCFAs reduce synovial inflammation by suppressing NLRP3 inflammasome activation, resulting in a 70 % decrease in IL-1β levels, while enhancing Treg suppressive function with a threefold increase in IL-10. Notably, butyrate exhibits circadian fluctuations that negatively correlate with morning stiffness severity (r = −0.82, p < 0.01), suggesting novel chronotherapeutic opportunities. Therapeutically, we evaluate promising microbiota-targeted strategies including high-fiber diets (which increase butyrate levels by 240 % and reduce Disease Activity Score 28 (DAS28) by 1.8 points), engineered nanoparticle delivery systems (achieving 89 % colonic retention), probiotic interventions (Bifidobacterium-mediated reduction of CCR9-positive Th17 cells), and precision combination therapies (showing a 40 % greater efficacy than monotherapy). Our work establishes a comprehensive translational roadmap, spanning molecular insights to clinical applications. We propose microbiome-guided personalized medicine as a paradigm shift in RA management, supported by the first systematic integration of multi-omics methods-metabolomics, single-cell sequencing, and spatial transcriptomics-to decode the gut-joint axis and identify actionable therapeutic targets for this refractory autoimmune condition.
类风湿性关节炎（RA）是一种以滑膜炎症和关节破坏为特征的慢性自身免疫性疾病。Th17/Treg平衡失调是RA的关键免疫学标志。新出现的证据强调了肠道微生物来源的短链脂肪酸（SCFAs）在维持免疫稳态中的关键作用。本综述系统阐述了SCFAs如何通过三种协同机制调节Th17/Treg平衡：(1)通过AMPK/mTOR信号通路进行代谢重编程，(2)通过抑制HDAC进行表观遗传调控，以及(3)调节细胞因子级联反应。我们综合临床前和临床证据表明，SCFAs通过抑制NLRP3炎性体激活来减少滑膜炎症，导致IL-1β水平降低70%，同时通过将IL-10增加三倍来增强Treg抑制功能。值得注意的是，丁酸盐表现出昼夜节律波动与晨僵严重程度负相关（r = - 0.82, p < 0.01），这表明有新的时间治疗机会。在治疗方面，我们评估了有希望的针对微生物群的策略，包括高纤维饮食（将丁酸盐水平提高240%，将疾病活动评分28 （DAS28）降低1.8分），工程纳米颗粒递送系统（实现89%的结肠保留），益生菌干预（双歧杆菌介导的ccr9阳性Th17细胞减少），以及精确的联合治疗（显示比单一治疗效率高40%）。我们的工作建立了一个全面的转化路线图，跨越分子的见解到临床应用。我们提出以微生物组为指导的个体化医学作为RA管理的范式转变，在多组学方法（代谢组学、单细胞测序和空间转录组学）的首次系统整合的支持下，解码肠道关节轴并确定这种难治性自身免疫性疾病的可行治疗靶点。
{"title":"Short-chain fatty acids from gut microbiota restore Th17/Treg balance in rheumatoid arthritis: Mechanisms and therapeutic potential","authors":"Aimei Pang , Shuangshuang Pu , Yinghui Pan , Ning Huang , Dake Li","doi":"10.1016/j.jtauto.2025.100316","DOIUrl":"10.1016/j.jtauto.2025.100316","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation and joint destruction. Dysregulation of the Th17/Treg balance is a key immunological hallmark of RA. Emerging evidence highlights the critical role of gut microbiota-derived short-chain fatty acids (SCFAs) in maintaining immune homeostasis. This review systematically elucidates how SCFAs modulate the Th17/Treg equilibrium through three synergistic mechanisms: (1) metabolic reprogramming via AMPK/mTOR signaling, (2) epigenetic regulation by inhibiting HDAC, and (3) modulation of cytokine cascades. We integrate preclinical and clinical evidence showing that SCFAs reduce synovial inflammation by suppressing NLRP3 inflammasome activation, resulting in a 70 % decrease in IL-1β levels, while enhancing Treg suppressive function with a threefold increase in IL-10. Notably, butyrate exhibits circadian fluctuations that negatively correlate with morning stiffness severity (r = −0.82, p < 0.01), suggesting novel chronotherapeutic opportunities. Therapeutically, we evaluate promising microbiota-targeted strategies including high-fiber diets (which increase butyrate levels by 240 % and reduce Disease Activity Score 28 (DAS28) by 1.8 points), engineered nanoparticle delivery systems (achieving 89 % colonic retention), probiotic interventions (Bifidobacterium-mediated reduction of CCR9-positive Th17 cells), and precision combination therapies (showing a 40 % greater efficacy than monotherapy). Our work establishes a comprehensive translational roadmap, spanning molecular insights to clinical applications. We propose microbiome-guided personalized medicine as a paradigm shift in RA management, supported by the first systematic integration of multi-omics methods-metabolomics, single-cell sequencing, and spatial transcriptomics-to decode the gut-joint axis and identify actionable therapeutic targets for this refractory autoimmune condition.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"11 ","pages":"Article 100316"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095272","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}
Pub Date : 2025-12-01Epub Date: 2025-08-19DOI: 10.1016/j.jtauto.2025.100309
Fatemeh Farhid , Hadi Rezaeeyan , Reza Habibi , Ehsan Kamali Yazdi , Michael R. Hamblin , Jalal Naghinezhad
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.
{"title":"When the victim becomes the villain: Platelets as drivers of immune dysregulation in ITP","authors":"Fatemeh Farhid , Hadi Rezaeeyan , Reza Habibi , Ehsan Kamali Yazdi , Michael R. Hamblin , 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<sup>+</sup> T helper (Th) and CD8<sup>+</sup> 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":"2025-12-01","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}
Pub Date : 2025-12-01Epub Date: 2025-08-08DOI: 10.1016/j.jtauto.2025.100307
Sonia Spinelli , Andrea Garbarino , Francesca Lugani , Edoardo La Porta , Noemi Rumeo , Giorgio Piaggio , Alberto Magnasco , Antonella Trivelli , Maria Ludovica Degl’Innocenti , Gino Tripodi , Simona Granata , Francesca Leone , Elena Zocchi , Lorenzo Gallon , Gian Marco Ghiggeri , Enrico Verrina , Gianluigi Zaza , Giovanni Candiano , Maurizio Bruschi
Background
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.
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.
Methods
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 + vs 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.
Results
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.
Conclusions
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.
{"title":"Afucosylated IgG in idiopathic nephrotic syndrome patients with anti-nephrin autoantibodies correlate with disease activity","authors":"Sonia Spinelli , Andrea Garbarino , Francesca Lugani , Edoardo La Porta , Noemi Rumeo , Giorgio Piaggio , Alberto Magnasco , Antonella Trivelli , Maria Ludovica Degl’Innocenti , Gino Tripodi , Simona Granata , Francesca Leone , Elena Zocchi , Lorenzo Gallon , Gian Marco Ghiggeri , Enrico Verrina , Gianluigi Zaza , Giovanni Candiano , 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":"2025-12-01","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}
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