Journal of Translational Autoimmunity最新文献_第4页

Cell-specific epigenome-wide DNA methylation in peripheral CD4(+) lymphocytes from patients with primary biliary cholangitis 原发性胆管炎患者外周血CD4（+）淋巴细胞的细胞特异性表观基因组DNA甲基化

IF 3.6 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-09-09 DOI: 10.1016/j.jtauto.2025.100314

Pinelopi Arvaniti , Kalliopi Zachou , Aggeliki Lyberopoulou , Eirini Sevdali , Stella Gabeta , Matthaios Speletas , Yves Renaudineau , George N. Dalekos

Background/aims

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.

Methods

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.

Results

Comparison between PBC patients and HC, revealed 1016 differentially methylated positions (DMPs) on autosomal chromosomes and 1203 DMPs on X chromosome (>98 % hypermethylated), corresponding to 695 and 322 genes, respectively (p < 0.05). Hypermethylation mainly affected pathways of immune cells differentiation and signalling (CAMTA1, PRKARB, LNC01993, TLR9). Methylation analysis between PBC and AIH revealed >5000 DMPs (98 % hypermethylated in PBC) corresponding to >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.

Conclusions

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.

背景/目的原发性胆汁性胆管炎（PBC）是一种慢性胆汁淤积性自身免疫性肝病，由遗传、环境和表观遗传因素复杂的相互作用引发。与健康对照（HC）和自身免疫性肝炎（AIH）患者相比，我们研究了PBC患者外周血CD4（+）淋巴细胞的甲基化谱，以阐明导致PBC发病的基因特异性表观遗传修饰，因为类似数据有限。方法采用ROBOSEP平台分离8例PBC treatment-naïve患者、9例HC患者和10例AIH患者的scd4（+）淋巴细胞。全基因组甲基化分析采用Illumina 850k阵列进行。采用RT-PCR定量检测候选基因的转录表达。结果PBC患者与HC患者在常染色体上发现1016个差异甲基化位点（dmp），在X染色体上发现1203个差异甲基化位点（>； 98%高甲基化），分别对应695个和322个基因（p < 0.05）。高甲基化主要影响免疫细胞分化和信号通路（CAMTA1， PRKARB, LNC01993, TLR9）。PBC和AIH之间的甲基化分析显示，5000个DMPs （PBC中98%高甲基化）对应4000个基因。通路分析获得了“细胞因子”和“白细胞介素”信号（C1GTNF3, SMAD3）的富集。差异甲基化区分析显示PBC患者基因启动子富集，ifn调节基因（IFNGR2, TICAM2）高甲基化。转录水平基因表达显示IFNGR2在PBC患者中过表达。结论PBC患者外周血CD4（+）淋巴细胞大部分基因存在过甲基化。表观遗传修饰主要影响免疫应答途径。大量的X染色体位于dmp，进一步支持性别在PBC发病机制中的作用。

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引用次数: 0

Splicing-based biomarkers define a robust multigene classifier for relapsing-remitting multiple sclerosis 基于剪接的生物标志物为复发缓解型多发性硬化症定义了一个强大的多基因分类器

IF 3.6 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-08-29 DOI: 10.1016/j.jtauto.2025.100312

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

Background

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.

选择性剪接（AS）被认为是多发性硬化症（MS）的关键机制。我们旨在构建并验证一个基于多变量as的分类器（MS- splicing Score, MS- ss），用于区分复发-缓解型MS （RRMS）患者和健康对照。方法根据功能和文献证据选择3个AS事件（IFNAR2外显子8跳变，NFAT5外显子2跳变，PRKCA外显子3 *包涵）。通过荧光竞争RT-PCR对来自两个独立队列（意大利：37个RRMS， 50个对照；美国：29个RRMS， 20个对照）的外周血RNA中的同种异构体进行定量。采用logistic回归模型推导MS-SS，并进行ROC分析。结果MS-SS将两组RRMS患者与对照组区分开来（意大利：p = 0.00083, AUC = 0.71, 95% CI = 0.59 ~ 0.82；美国：p = 0.00074, AUC = 0.77, 95% CI = 0.63 ~ 0.90）。在合并的数据集中，MS的评分仍然显著提高（p = 5.9 × 10−6,AUC = 0.72, 95% CI = 0.64-0.81），基于pca的改进提高了分类精度，AUC = 0.87 （95% CI = 0.81-0.94）。在最佳截止点（约登指数），该评分的灵敏度为80%，特异性为86%。使用逻辑学习机算法的基于规则的监督建模确定了可解释的剪接阈值，并在个体水平上实现了临床分类。我们的研究引入了一种新的、鲁棒的基于as的RRMS分类器，并提出了一种基于转录组的神经免疫学生物标志物开发策略。然而，每个队列中相对较小的样本量可能会限制这些发现的普遍性，因此需要更大规模的验证研究来确认该生物标志物的临床实用性。

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引用次数: 0

Redefining multiple sclerosis therapy through microbial immunomodulation and epigenetic control 通过微生物免疫调节和表观遗传控制重新定义多发性硬化治疗

IF 3.6 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-08-29 DOI: 10.1016/j.jtauto.2025.100313

Shan Xu , Christina James Thomas , Sunilgowda Sunnagatta Nagaraja , Rakesh Kumar , Kamlesh Sawant , Duminduni Hewa Angappulige , Andy Fang Song , Krish Suman , Benjamin Borja , Paul de Figueiredo , Jianxun Song

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.

多发性硬化症（MS）是一种慢性自身免疫性疾病，以免疫驱动的脱髓鞘和中枢神经系统的神经变性为特征。本综述探讨了MS的免疫学、分子和表观遗传学基础，强调T和B细胞的参与，信号通路失调（如TGF-β、Akt、Wnt），以及细胞死亡在疾病进展中的作用。表观遗传机制，如DNA甲基化和组蛋白修饰，进一步调节免疫反应。虽然目前的治疗方法广泛抑制免疫，但新兴的方法，包括工程细菌，基于微生物组的干预和细胞治疗，提供了靶向免疫调节和神经保护。总之，这些策略为下一代MS治疗指明了一条更精确、更有效的道路。

引用次数: 0

Beyond conventional treatment: Novel cell therapies for systemic lupus erythematosus 超越传统治疗：系统性红斑狼疮的新细胞疗法

IF 3.6 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-08-27 DOI: 10.1016/j.jtauto.2025.100308

Zeinab Zarei-Behjani , Arghavan Hosseinpouri , Maryam Fotoohi , Akram Shafiee , Dorna Asadi

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.

系统性红斑狼疮（SLE）是一种自身免疫性疾病，其特点是其异质性，因为它可以影响不同的器官，并表现出不同的临床进展。SLE的识别依赖于在皮肤、关节、肾脏和中枢神经系统中存在明显的临床表现，以及血清学标志物，如针对dsDNA的抗核抗体。目前SLE的治疗方法包括使用抗疟药、糖皮质激素、免疫抑制药物和生物疗法。尽管治疗策略取得了进步，但SLE仍然与不良后果有关。疾病的复杂性和不可预测性，以复发和缓解的发作为特征，加上目前治疗方案的副作用，器官损伤的逐渐积累，以及尽管治疗有所改善，但死亡率仍然存在，强调了迫切需要创造创新，有效和专门针对的治疗方法。基于细胞的疗法虽然仍处于初期阶段，但由于其长期疾病抑制甚至治愈的潜力，已经在SLE治疗领域引起了相当大的兴趣。各种细胞类型已成为SLE管理的有希望的候选者。本综述旨在简要概述最新的基于细胞的新型治疗方法的研究进展，这些研究已进展到治疗SLE的临床前或临床试验阶段。

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引用次数: 0

Regulatory T cell therapy for Sjögren's disease: From pathogenesis to targeted treatment 调节性T细胞治疗Sjögren病：从发病机制到靶向治疗

IF 3.6 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-08-26 DOI: 10.1016/j.jtauto.2025.100311

Zhi Feng Sherman Lim , Alberta Y. Hoi , Fabien B. Vincent , Joshua D. Ooi , Eric F. Morand , Maureen Rischmueller , Yi Tian Ting

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.

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.

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.

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.

Sjögren病（SjD）是一种慢性系统性自身免疫性疾病，其特征是淋巴细胞浸润涎腺和泪腺，导致干眼和口干的标志性症状。除了腺体功能障碍外，许多患者还会出现全身性并发症，包括B细胞过度活跃、器官特异性炎症和非霍奇金淋巴瘤的风险显著增加，这些并发症往往未被充分认识和管理不善。目前的治疗仍然主要是经验性和对症治疗，在改变疾病进展或恢复免疫耐受方面疗效有限。最近的进展揭示了先天免疫和适应性免疫的深刻失调，揭示了临床试验中正在研究的新的治疗靶点，包括I型干扰素信号传导、B细胞激活和共刺激途径。这种失调的核心是T细胞驱动的病理：CD8+ T细胞的细胞毒性、有缺陷的调节性T细胞（Treg）功能和HLA ii类介导的自身抗原向自身反应性CD4+ T细胞的呈递是疾病发生和持续的关键机制。越来越多的证据表明，Ro自身抗原ro60和ro52是SjD发病机制的中心靶点。大约70%的患者存在抗ro抗体，并作为诊断标记和全身累及的指标。Ro抗原及其相应的抗体在发炎的唾液组织中一直被检测到，强调了它们作为抗原特异性治疗的引人注目的靶点的潜力。本文综述了ro特异性T细胞反应在SjD中的免疫致病作用，并概述了基于treg的工程化治疗如何能够实现精确的免疫调节，恢复耐受性，并为患有这种复杂自身免疫性疾病的患者提供持久的疾病控制。

{"title":"Regulatory T cell therapy for Sjögren's disease: From pathogenesis to targeted treatment","authors":"Zhi Feng Sherman Lim , Alberta Y. Hoi , Fabien B. Vincent , Joshua D. Ooi , Eric F. Morand , Maureen Rischmueller , 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<sup>+</sup> T cell cytotoxicity, defective regulatory T cell (Treg) function, and HLA class II–mediated presentation of self-antigens to autoreactive CD4<sup>+</sup> 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}

引用次数: 0

Acylcarnitine enrichment as a characteristic of rheumatoid arthritis fibroblast-like synoviocyte metabolic fingerprint 酰基肉碱富集作为类风湿关节炎成纤维细胞样滑膜细胞代谢指纹的特征

IF 3.6 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-08-19 DOI: 10.1016/j.jtauto.2025.100310

Georgios K. Vasileiadis , Yuan Zhang , Marion Laudette , Tahzeeb Fatima , Anna-Karin Hultgård Ekwall , Reshmi Sureshkumar , Ronald van Vollenhoven , Jon Lampa , Bjorn Gudbjornsson , Espen A. Haavardsholm , Dan Nordström , Gerdur Gröndal , Kim Hørslev-Petersen , Kristina Lend , Merete L. Hetland , Michael Nurmohamed , Mikkel Østergaard , Till Uhlig , Tuulikki Sokka-Isler , Anna Rudin , Cristina Maglio

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

目的在类风湿关节炎（RA）中，成纤维细胞样滑膜细胞（FLS）改变其代谢以支持其活化。我们旨在通过在RA FLS与非炎症FLS （NI）中进行非靶向代谢组学分析与RA相关的全谱代谢改变。方法采用质谱法对来自随机对照NORD-STAR试验的早期RA患者的10个原发RA和7个NI FLS培养提取物和220个血清样本进行靶向注释代谢组学分析。Western blot检测肉毒碱相关蛋白。用海马通量分析仪评估FLS生物能量谱。结果基于138个注释代谢物的代谢组学分析显示RA和NI FLS之间具有明显的代谢指纹图谱。在RA FLS富集的12种代谢物中，有11种是酰基肉碱。NI FLS的促炎刺激也导致酰基肉碱积累。与NI FLS相比，RA FLS的脂肪酸转运蛋白CD36水平较低，但左旋肉碱转运蛋白和左旋肉碱棕榈酰基转移酶1a和2水平相似。海马分析显示，RA和NI FLS脂肪酸氧化无差异；然而，RA FLS表现出线粒体功能障碍和能量损伤。在甲氨蝶呤联合阿巴接受或托珠单抗治疗24周后，早期RA患者的血清酰基肉碱含量下降。结论酰基肉碱积累是RA FLS代谢指纹图谱的特征，可能与线粒体功能障碍有关。在早期RA患者中，抗风湿治疗成功后，血清中酰基肉碱含量降低。这些结果表明RA在关节水平和全身水平上的酰基肉碱代谢失调。

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引用次数: 0

When the victim becomes the villain: Platelets as drivers of immune dysregulation in ITP 当受害者变成恶棍：血小板作为ITP免疫失调的驱动因素

IF 3.6 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-08-19 DOI: 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.

免疫性血小板减少症（ITP）是一种异质性自身免疫性疾病，其特征是免疫介导的血小板破坏和血小板产生受损。虽然自身抗体历来是理解ITP的核心，但目前的证据表明，其发病机制远远超出体液机制，涉及先天和适应性免疫反应的复杂失调。多种免疫途径——包括自身反应性B细胞和T细胞、树突状细胞激活和调节性T细胞缺陷——有助于疾病的发病、进展和慢性。此外，ITP包括广泛的临床和免疫学亚型，包括原发性特发性形式和与自身免疫性疾病、感染和先天性免疫错误相关的继发性ITP。这篇综述为ITP的发病机制提供了一个新的视角，强调血小板在免疫失调中的积极免疫调节作用。ITP中的血小板远非被动靶标，而是通过与免疫细胞，特别是CD4+ T辅助细胞（Th）和CD8+细胞毒性T细胞的串扰，主动塑造免疫反应。这种相互作用主要通过p -选择素- psgl -1轴介导，促进Th1/Th17极化，增强自身抗体的产生，加速血小板破坏。与此同时，血小板衍生微粒（pmp）通过传递促炎细胞因子和自身抗原作为有效的免疫效应器，维持慢性免疫激活。长时间的血小板激活也会产生一种独特的亚群，称为“毛血小板”——耗尽的、颗粒耗尽的细胞，表面表型改变，具有持续的促炎潜力。尽管在凝血方面功能衰竭，这些血小板通过持续的磷脂酰丝氨酸暴露和细胞因子释放保持免疫刺激能力。通过将血小板重新定义为ITP发病机制的积极参与者，本文提出靶向血小板活化、血小板- t细胞相互作用和PMP释放可能代表创新的治疗策略。这种方法可以通过恢复免疫平衡和改善长期预后，提供更精确和个性化的治疗选择，特别是对慢性或难治性疾病患者。

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引用次数: 0

Afucosylated IgG in idiopathic nephrotic syndrome patients with anti-nephrin autoantibodies correlate with disease activity 特发性肾病综合征患者的抗肾素自身抗体与疾病活动性相关

IF 3.6 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-08-08 DOI: 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.

didiopathic nephrotic syndrome （INS）是一种以足细胞损伤和蛋白尿为特征的肾小球疾病。新出现的证据表明，抗肾素自身抗体（Abs）可能有助于部分INS患者的疾病发病机制。检测抗肾素抗体的技术差异和尿液数据的缺乏导致了结果的不确定性。虽然已知在非INS自身免疫性疾病中，IgG聚焦化降低可增强抗体依赖的细胞毒性，但其在INS中调节抗肾素自身抗体功能和疾病严重程度的作用仍未被探索。方法：研究活检证实的局灶节段性肾小球硬化症（FSGS）或微小改变病（MCD）患儿和青年成人不同疾病活动性（蛋白尿+与蛋白尿-）的血清和尿液。采用常规ELISA法和重组人肾素全长胞外结构域免疫沉淀法检测抗肾素自身抗体。白念珠菌凝集素（AAL）和欧paeus凝集素I （UEA-I）凝集素评估IgG自身抗体聚焦。结果11%的FSGS患者和15%的MCD患者血清中检测到抗肾素自身抗体，其中肾范围蛋白尿患者的患病率更高。这些自身抗体在健康对照者以及原发性膜性肾病和V型狼疮肾炎患者中均不存在。自身抗体滴度与疾病活动相关，在缓解期间降低。免疫沉淀证实了ELISA获得的结果。在一部分抗肾素阳性患者中，尿中也检测到自身抗体。循环抗肾素自身抗体显示IgG的触角和核心聚焦显著降低。结论sour的发现证实了抗肾素自身抗体在小部分INS患者中作为活动性疾病的标志物的意义，并且在尿液中显示出它们的存在。ELISA与免疫沉淀结果相关。分子研究表明，IgG聚焦化的改变可能导致免疫介导的足细胞损伤。这些见解为INS的疾病监测和治疗靶点提供了潜在的生物标志物。

{"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":"2025-08-08","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}

引用次数: 0

Targeted regulatory T cell activation by site-specific PEGylated interleukin-2 mitigates autoimmune inflammation 靶向调节性T细胞活化的位点特异性聚乙二醇化白细胞介素-2减轻自身免疫性炎症

IF 3.6 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-08-08 DOI: 10.1016/j.jtauto.2025.100306

Masahiro Ikeda , Shinpei Yamaguchi , Shigeki Takaoka , Yasuko Sakaguchi , Shunki Yasui

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.

伴随着调节性T细胞（Treg）功能障碍的免疫稳态失调是各种自身免疫性和炎症性疾病的标志。虽然低剂量的白介素-2 （IL-2）治疗可以提高Treg水平并缓解疾病症状，但其半衰期短，需要频繁给药。此外，经常观察到与其他免疫细胞激活相关的不良事件。在这项研究中，利用位点特异性PEGylation方法，我们开发了一种新的IL-2变体I129-W80，它表现出il - 2r α -偏倚的结合谱，由PEG片段的空间位阻驱动。它在体外选择性激活Tregs，并能克服内源性诱饵受体可溶性IL-2Rα的抑制，不像fc融合IL-2变体AMG-592。在一项单剂量猴子研究中，I129-W80显示出延长的半衰期，同时持续扩增和激活Tregs。在不诱导c反应蛋白升高的最大剂量下，I129-W80的活性优于AMG-592。I129-W80改善了延迟型超敏反应和异种移植物抗宿主病模型的炎症反应。此外，在吡喹莫德诱导的皮炎模型中，与AMG-592相比，I129-W80在炎症组织中的分布减少。这些发现表明I129-W80相对于fc融合IL-2变体具有不同的特性，可以纠正Treg功能障碍引起的免疫失衡，从而改善各种自身免疫性疾病的症状。

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引用次数: 0

Exploration of shared biomarkers and mechanisms in systemic lupus erythematous and lung cancer via bioinformatics analysis 通过生物信息学分析探讨系统性红斑狼疮和肺癌的共同生物标志物和机制

IF 3.6 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-08-04 DOI: 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.

系统性红斑狼疮（SLE）患者表现出发展为肺癌的高风险，但其潜在的分子机制仍然知之甚少。本研究旨在利用基因表达综合（GEO）公开的转录组数据，确定连接SLE和LC的共同遗传因素。通过综合差异表达基因（DEG）分析和加权基因共表达网络分析（WGCNA），我们确定了5个在SLE和肺癌中持续上调的基因。基因集富集分析（GSEA）显示，这些共享基因在炎症通路中富集，特别是那些涉及干扰素- α、干扰素- γ和一般炎症反应的基因。我们应用最小绝对收缩和选择算子（LASSO）回归来确定潜在的诊断性生物标志物，并确定了两个关键候选物：AIM2和SLC26A8。这些生物标志物表现出稳健的诊断性能，在训练和验证队列中，ROC曲线下面积（AUC）值均超过0.75。使用癌症基因组图谱（TCGA）进行免疫浸润和生存分析进一步支持了它们的临床相关性。值得注意的是，AIM2高表达与女性肺腺癌患者较差的总生存率显著相关（P = 0.03）， SLC26A8表达仅与吸烟史患者的生存结果显著相关（P = 0.01）。这些发现对SLE尤其有意义，因为SLE患者多为女性，吸烟是已知的危险因素。我们的研究增强了对自身免疫驱动癌变的理解，并为管理有肺癌风险的SLE患者的精准医学策略开辟了新的途径。

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引用次数: 0