Journal of autoimmunity最新文献_第5页

Epigenetic differences at immune and type 1 diabetes susceptibility genes in blood from young children after COVID-19 infection 幼儿感染COVID-19后血液中免疫和1型糖尿病易感基因的表观遗传差异

IF 7 1区医学 Q1 IMMUNOLOGY

Journal of autoimmunity

Pub Date : 2025-07-31 DOI: 10.1016/j.jaut.2025.103468

Raffael Ott , Tarini Singh , Katharina Schütte-Borkovec , Marlon Scholz , Kristina Casteels , Gita Gemulla , Olga Kordonouri , Helena Elding Larsson , Agnieszka Szypowska , John A. Todd , Anette-G. Ziegler , Ezio Bonifacio

Background

Viral infections, including COVID-19, are associated with an increased risk for type 1 diabetes (T1D), but potential underlying mechanisms remain unexplored. We evaluated whether COVID-19 or influenza A infection is characterized by differential DNA methylation at immune and T1D susceptibility genes in young children at risk for T1D.

Methods

Epigenome-wide association analysis using the Illumina MethylationEPIC microarray was performed in blood taken at age 1.5 years (IQR, 1.49–1.52 y) from 740 prospectively followed children with increased risk of T1D. SARS-CoV-2 and influenza A H1N1 antibodies were monitored at 2–4-month intervals from age 6 months to identify infection.

Results

COVID-19 and influenza infection occurred prior to the DNA methylation sample in 81 and 74 children, respectively. Of these, infection occurred within 3 months of the DNA methylation sample (recent infection) in 43 and 22 children. Compared to children without COVID-19 or influenza A infection, children with recent COVID-19 infection showed differential methylation at key immune- and antiviral genes, including ADAR, IFI44L, MX1 and OASL. In addition to ADAR, six further T1D susceptibility genes, including the SARS-CoV-2 cell entry receptor neuropilin-1, had differential methylation at nearby CpGs in children infected by SARS-CoV-2. A quantitatively less differential methylation was also observed in children with an earlier COVID-19 infection at some of these CpG sites. Infections with influenza showed no associations.

Conclusion

Children with SARS-CoV-2 infection showed sustained DNA methylation changes at genes critical for antiviral response and T1D susceptibility, potentially contributing to immune dysregulation and promotion of the autoimmune process underlying T1D.

包括COVID-19在内的病毒感染与1型糖尿病（T1D）风险增加有关，但潜在的潜在机制尚未探索。我们评估了在有T1D风险的幼儿中，COVID-19或甲型流感感染是否以免疫和T1D易感基因的差异DNA甲基化为特征。方法使用Illumina MethylationEPIC芯片对740名T1D风险增加的儿童在1.5岁（IQR, 1.49-1.52 y）时采集的血液进行全基因组关联分析。从6个月开始每隔2 - 4个月监测一次SARS-CoV-2和甲型H1N1流感抗体，以确定感染情况。结果81例和74例儿童在DNA甲基化前分别发生了covid -19和流感感染。其中，43名和22名儿童感染发生在DNA甲基化样本（近期感染）后3个月内。与未感染COVID-19或未感染甲型流感的儿童相比，近期感染COVID-19的儿童在关键免疫和抗病毒基因（包括ADAR、IFI44L、MX1和OASL）上表现出不同的甲基化。除ADAR外，另外6个T1D易感基因，包括SARS-CoV-2细胞进入受体neuropilin-1，在感染SARS-CoV-2的儿童中，在附近的CpGs上存在差异甲基化。在一些CpG位点上，在早期感染COVID-19的儿童中也观察到较少的定量差异甲基化。与流感感染没有关联。结论SARS-CoV-2感染儿童在抗病毒反应和T1D易感性的关键基因上显示持续的DNA甲基化变化，可能导致T1D的免疫失调和自身免疫过程的促进。

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引用次数: 0

Tlr9 expression protects against Tlr7-dependent exocrine gland and systemic disease manifestations in primary Sjögren's disease in a sex-biased manner Tlr9表达在原发性Sjögren疾病中以性别偏倚的方式保护tlr7依赖性外分泌腺和全身性疾病表现

IF 7 1区医学 Q1 IMMUNOLOGY

Journal of autoimmunity

Pub Date : 2025-07-30 DOI: 10.1016/j.jaut.2025.103467

Sheta Biswas , Eileen M. Kasperek , Chengsong Zhu , Jeffrey C. Miecznikowski , Jason Osinski , Rose-Anne Romano , Jill M. Kramer

Primary Sjogren's disease (pSD) is a systemic autoimmune disease. Currently, the causes of pSD remain unknown, and no curative therapies are available. Our prior studies showed Tlr7 activation was an important driver of pSD in females. Since Tlr7 is regulated by Tlr9, we hypothesized that ablation of Tlr9 would exacerbate disease in a Tlr7-dependent manner. Towards this end, we generated pSD mice that lacked systemic expression of either Tlr9 (NOD.B10^Tlr9-/-) or both Tlr7 and Tlr9 (NOD.B10^Tlr−DKO). We harvested tissues for histologic analysis and assessed disease-relevant immune cell populations in secondary lymphoid organs. We examined total and autoreactive antibody levels in sera. Enhanced nephritis was observed in Tlr9-deficient females, while dacryoadenitis was increased in males that lacked Tlr9, and these manifestations were dependent on Tlr7. Moreover, the percentages of splenic Tlr7+ B cells, germinal center and age-associated B cells, CD4⁺ and CD8⁺ activated/memory T cells, and Tfh cells were increased in NOD.B10^Tlr9-/- females as compared to sex-matched NOD.B10 mice, and this expansion was abrogated in NOD.B10^Tlr−DKO females. Finally, total IgM levels were elevated in sera from NOD.B10^Tlr9-/- females as compared to the parental strain and autoreactive IgM and IgG were also enriched in NOD.B10^Tlr9-/- females. NOD.B10^Tlr−DKO females and males showed dramatically reduced IgM and IgG titers as compared to the NOD.B10 strain and anti-nuclear autoantibodies were diminished in this strain. Overall, our study revealed that ablation of Tlr9 drives pSD in females but has negligible effects on disease in males. Moreover, Tlr9 regulates Tlr7-dependent pSD manifestations in a sex-biased manner.

原发性干燥病（pSD）是一种全身自身免疫性疾病。目前，pSD的病因尚不清楚，也没有有效的治疗方法。我们之前的研究表明，Tlr7激活是女性pSD的重要驱动因素。由于Tlr7受Tlr9调控，我们假设消融Tlr9会以Tlr7依赖的方式加重疾病。为此，我们培养了缺乏Tlr9 （NOD.B10Tlr9-/-）或Tlr7和Tlr9 （NOD.B10Tlr−DKO）的pSD小鼠。我们收集组织进行组织学分析，并评估次级淋巴器官中与疾病相关的免疫细胞群。我们检测了血清中的总抗体和自身反应性抗体水平。Tlr9缺失的女性肾炎加重，而Tlr9缺失的男性泪腺炎加重，这些表现依赖于Tlr7。脾脏Tlr7+ B细胞、生发中心和年龄相关B细胞、CD4+和CD8+活化/记忆T细胞和Tfh细胞的百分比在NOD中增加。B10Tlr9-/-与性别匹配的NOD相比。B10小鼠，在NOD中这种扩增被废除。B10Tlr−DKO女性。最后，NOD患者血清中IgM总水平升高。与亲本株相比，B10Tlr9-/-雌株和自身反应性IgM和IgG也在NOD中富集。B10Tlr9 - / -女性。点头。与NOD相比，B10Tlr−DKO雌性和雄性小鼠的IgM和IgG滴度显著降低。B10株和抗核自身抗体均明显减少。总的来说，我们的研究表明，Tlr9的消融会导致女性pSD，但对男性疾病的影响可以忽略不计。此外，Tlr9以性别偏倚的方式调节依赖tlr7的pSD表现。

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引用次数: 0

How early-life adversity affects the risk of pediatric-onset immune-mediated inflammatory disease 童年逆境如何影响儿童免疫介导炎症性疾病的风险

IF 7.9 1区医学 Q1 IMMUNOLOGY

Journal of autoimmunity

Pub Date : 2025-07-23 DOI: 10.1016/j.jaut.2025.103457

Mikkel Malham , Christoffer Sejling , Megan Davies , Vibeke Wewer , Samir Bhatt , Matthew P. Fox , Naja H. Rod

Background

The etiology of pediatric-onset immune-mediated inflammatory disease (pIMID) is poorly understood, particularly the interplay of early-life adversities. We explored how interrelated early-life adversities affect the pIMID risk in a life-course birth cohort.

Methods

We included all children born in Denmark between 1981 and 2015. Adversities encountered during the first 1000 days of life were obtained from the Danish registries and categorized into three dimensions: biological, material, and familial. The outcome was developing pIMID (autoimmune liver disease, inflammatory bowel disease, juvenile idiopathic arthritis, vasculitis, and systemic lupus erythematosus) between ages 2 and 18. Cox proportional hazards and additive hazard model assessed the effect of the cumulative adversity load on developing pIMID. A machine learning model identified exposure patterns associated with increased absolute risk estimates.

Results

Of 2,123,827 children, 9070 developed pIMID. The cumulative burden of biological adversities was associated with higher risks of developing pIMID; aHR of two adversities was 1.23 (95 %CI: 1.07 to 1.41), aHR of ≥4 adversities was 1.8 (95 %CI: 1.4 to 2.2). Conversely, >2 familial adversities were associated with a reduced risk (0.66 [95 %CI: 0.41 to 1.1]). No associations were found in the material dimension. The machine learning model identified a pattern of adversities associated with a five-fold higher pIMID risk in a population subgroup.

Conclusion

Early-life biological adversities are important risk factors for developing pIMID. The lower risk observed in the familial dimension was unexpected but may reflect delayed diagnosis in socially vulnerable families. This potential inequality in healthcare needs further exploration.

背景：儿童发病的免疫介导炎症性疾病（pIMID）的病因尚不清楚，特别是早期生活逆境的相互作用。我们探讨了生命早期逆境是如何影响一生中出生队列中piid风险的。方法纳入1981年至2015年在丹麦出生的所有儿童。在生命最初1000天内遇到的逆境从丹麦登记处获得，并分为三个方面：生物、物质和家庭。结果是在2至18岁之间发生pIMID（自身免疫性肝病、炎症性肠病、青少年特发性关节炎、血管炎和系统性红斑狼疮）。Cox比例风险模型和加性风险模型评估了累积逆境负荷对pIMID发生的影响。机器学习模型确定了与增加的绝对风险估计相关的暴露模式。结果在2,123,827名儿童中，9070名发生了pIMID。生物逆境的累积负担与发生pIMID的高风险相关；2种逆境的aHR为1.23 (95% CI: 1.07 ~ 1.41)，≥4种逆境的aHR为1.8 （95% CI: 1.4 ~ 2.2）。相反，家族逆境与风险降低相关（0.66 [95% CI: 0.41 - 1.1]）。在物质维度上没有发现关联。机器学习模型确定了一种逆境模式，这种模式与人群亚组中piid风险高出五倍相关。结论生命早期生物逆境是发生piid的重要危险因素。在家庭方面观察到的较低风险出乎意料，但可能反映了社会弱势家庭的延迟诊断。这种潜在的医疗不平等需要进一步探索。

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引用次数: 0

A novel subset of inflammation-related liver NK cells modulates immune responses in a murine model of primary biliary cholangitis 炎症相关的肝脏NK细胞的一个新亚群调节原发性胆道胆管炎小鼠模型的免疫反应

IF 7.9 1区医学 Q1 IMMUNOLOGY

Journal of autoimmunity

Pub Date : 2025-07-01 DOI: 10.1016/j.jaut.2025.103454

Tian-Tian Da , Meng-Chu Liu , Zhen-Hua Bian , Pan-Yue Luo , Rui-Tao Ye , Kai Yan , Liang Li , Zhe-Xiong Lian , Zhi-Bin Zhao

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease marked by bile duct inflammation, with immune dysregulation playing a central role in its pathogenesis. Here, we identify a novel subset of inflammation-related natural killer (irNK) cells, characterized by CD49a⁺CXCR6⁻, which accumulate in the livers of both PBC mouse models and patients. Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing reveal that irNK cells form a distinct cluster with a unique gene expression profile, clearly distinguishing them from conventional NK (cNK) cells and type 1 innate lymphoid cells (ILC1s). We show that irNK cells arise from cNK cells in response to IL-15 stimulation and acquire liver-resident characteristics, including reduced circulation, confirming their tissue-resident identity. Functionally, irNK cells promote CD4⁺ T cell proliferation through TNF-α secretion, which we identify as the key mediator of immune dysregulation in the PBC murine model (ARE-Del^+/− mice; ARE). These findings highlight the pivotal role of irNK cells in modulating immune responses in PBC and suggest that targeting these cells could offer new therapeutic opportunities for autoimmune liver diseases.

原发性胆道胆管炎（PBC）是一种以胆管炎症为特征的慢性自身免疫性肝病，其发病机制以免疫失调为核心。在这里，我们发现了一个新的炎症相关自然杀伤（irNK）细胞亚群，其特征为CD49a+CXCR6−，在PBC小鼠模型和患者的肝脏中积累。单细胞RNA测序（scRNA-seq）和大量RNA测序显示，irNK细胞形成一个独特的簇，具有独特的基因表达谱，明显区别于传统NK细胞（cNK）和1型先天淋巴样细胞（ILC1s）。我们发现，irNK细胞在IL-15刺激下由cNK细胞产生，并获得肝脏驻留特征，包括循环减少，证实了它们的组织驻留身份。在功能上，irNK细胞通过TNF-α分泌促进CD4+ T细胞增殖，我们认为TNF-α是PBC小鼠模型(ARE-Del+/−小鼠；)。这些发现强调了irNK细胞在调节PBC免疫应答中的关键作用，并提示靶向这些细胞可能为自身免疫性肝病提供新的治疗机会。

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引用次数: 0

STAT3 phosphorylation in the rheumatoid arthritis immunological synapse 类风湿关节炎免疫突触中STAT3的磷酸化

IF 7.9 1区医学 Q1 IMMUNOLOGY

Journal of autoimmunity

Pub Date : 2025-07-01 DOI: 10.1016/j.jaut.2025.103456

Hila Novak-Kotzer , Jesusa Capera , Ashwin Jainarayanan , Mirudula Elanchezhian , Salvatore Valvo , Viveka Mayya , Alexandra Zanin-Zhorov , Joanne Macdonald , Peter C. Taylor , Michael L. Dustin

Targeting the JAK/STAT pathway has emerged as a key therapeutic strategy for managing Rheumatoid Arthritis (RA). JAK inhibitors suppress cytokine-mediated signaling, including the critical IL-6/STAT3 axis, thereby effectively targeting different aspects of the pathological process. However, despite their clinical efficacy, a subset of RA patients remains refractory to JAK inhibition, underscoring the need for alternative approaches. Here, we identify a novel JAK-independent mechanism of STAT3 activation, which is triggered by the formation of the immunological synapse (IS) in naive CD4⁺ T cells. Our data demonstrates that LCK mediates the TCR-dependent phosphorylation of STAT3 at the IS, highlighting this pathway as a previously unrecognized hallmark of early T cell activation. Furthermore, we show that the synaptic LCK/TCR-STAT3 pathway is compromised in RA. This discovery highlights a new therapeutic target for RA beyond JAK inhibitors, offering potential avenues for treating patients resistant to current therapies.

靶向JAK/STAT通路已成为治疗类风湿关节炎（RA）的关键治疗策略。JAK抑制剂抑制细胞因子介导的信号传导，包括关键的IL-6/STAT3轴，从而有效地靶向病理过程的不同方面。然而，尽管它们具有临床疗效，但一部分RA患者对JAK抑制仍然难治，这强调了替代方法的必要性。在这里，我们发现了一种新的不依赖于jak的STAT3激活机制，它是由初始CD4+ T细胞中免疫突触（is）的形成触发的。我们的数据表明，LCK介导IS的tcr依赖性STAT3磷酸化，突出了这一途径作为早期T细胞激活的一个以前未被认识的标志。此外，我们发现突触LCK/TCR-STAT3通路在RA中受损。这一发现强调了JAK抑制剂之外的RA新的治疗靶点，为治疗对当前疗法有耐药性的患者提供了潜在的途径。

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引用次数: 0

Stratifying patients by TNFSF13B genotype revealed increased flare and renal flare risk, but a greater benefit from belimumab: a potential biomarker for personalized treatment in systemic lupus erythematosus 根据TNFSF13B基因型对患者进行分层显示，耀斑和肾脏耀斑风险增加，但贝利单抗的获益更大：一种潜在的系统性红斑狼疮个性化治疗的生物标志物

IF 7.9 1区医学 Q1 IMMUNOLOGY

Journal of autoimmunity

Pub Date : 2025-07-01 DOI: 10.1016/j.jaut.2025.103455

Marta Paola Pireddu , Giulia Rizzo , Fabio Congiu , Elisabetta Chessa , Maristella Pitzalis , Elena Ragusa , Alberto Floris , Francesca Deidda , Mattia Congia , Micaela Rita Naitza , Maria Maddalena Angioni , Francesco Cucca , Alberto Cauli , Matteo Piga

Objective

To examine whether SLE patients carrying the TNFSF13B variant (BAFF-var) differ in the risk of overall and renal flares and the benefits from belimumab.

Methods

This retrospective study analyzed data from a monocentric cohort of Sardinian SLE patients between January 2006 and December 2022. We recorded demographic, clinical, serological, and treatment variables. A flare was defined as a new SLE manifestation or worsening of an existing one that required a change in therapy. Renal flares, categorized as nephritic or nephrotic, were recorded. Soluble B-cell activating factor (sBAFF) levels were evaluated in patients naïve to any treatment. We used Kaplan-Meier curves, Cox regression, and Poisson regression to investigate the association between BAFF-var and flares.

Results

Among 233 screened patients, 194 (89.2 % female, 61.3 % BAFF-var carriers) were included. The mean age was 41.1 (±14.8) years, and the mean number of follow-up visits was 17 (±8). sBAFF levels increased according to BAFF-var genotype (p < 0.001). BAFF-var was significantly associated with an increased risk of flares (HR 1.5 per copy variant; 95 %CI 1.2–2.0; p = 0.002), and the frequency of flares (IRR 1.3 per copy variant; 95 %CI 1.1–1.6; p = 0.009). In 38 biopsy-confirmed lupus nephritis patients, the BAFF-var was associated with a higher risk of renal flare (HR 9.3; 95 %CI 1.7–49.5; p = 0.008). In 35 relapsing-remitting patients, belimumab reduced both the risk and frequency of flares, with higher effectiveness in patients carrying the BAFF-var (HR 0.12; 95 %CI 0.02–0.58; p = 0.009).

Conclusions

Pending further validation, BAFF-var may serve as a predictive and prognostic biomarker for personalized treatment in SLE.

目的研究携带TNFSF13B变异（BAFF-var）的SLE患者在总体和肾脏发作的风险以及贝利单抗的获益方面是否存在差异。方法本回顾性研究分析了2006年1月至2022年12月撒丁岛SLE患者的单中心队列数据。我们记录了人口统计学、临床、血清学和治疗变量。耀斑被定义为新的SLE表现或现有表现的恶化，需要改变治疗。记录肾脏耀斑，分类为肾病或肾病。评估可溶性b细胞活化因子（sBAFF）水平naïve患者的任何治疗。我们使用Kaplan-Meier曲线、Cox回归和泊松回归来研究BAFF-var与耀斑之间的关系。结果在233例筛查患者中，包括194例（女性89.2%，BAFF-var携带者61.3%）。平均年龄41.1（±14.8）岁，平均随访次数17（±8）次。根据BAFF-var基因型，saff水平升高(p <；0.001)。BAFF-var与耀斑风险增加显著相关(每个拷贝变异的HR为1.5；95% ci 1.2-2.0；p = 0.002)，以及耀斑发生的频率(每个拷贝变异的IRR为1.3；95% ci 1.1-1.6；p = 0.009)。在38例活检证实的狼疮性肾炎患者中，BAFF-var与肾脏耀斑的高风险相关(HR 9.3；95% ci 1.7-49.5；p = 0.008)。在35例复发缓解型患者中，贝利单抗降低了耀斑发生的风险和频率，对携带BAFF-var的患者更有效(HR 0.12；95% ci 0.02-0.58；p = 0.009)。结论BAFF-var可作为SLE个体化治疗的预测和预后生物标志物，有待进一步验证。

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引用次数: 0

Post-translationally modified proteins bind and activate complement with implications for cellular uptake and autoantibody formation 翻译后修饰的蛋白质结合并激活补体，影响细胞摄取和自身抗体的形成

IF 7.9 1区医学 Q1 IMMUNOLOGY

Journal of autoimmunity

Pub Date : 2025-06-23 DOI: 10.1016/j.jaut.2025.103444

M.D. van den Beukel , L. Zhang , S. van der Meulen , N.V. Borggreven , S. Nugteren , M.C. Brouwer , R.B. Pouw , K.A. Gelderman , A.H. de Ru , G.M.C. Janssen , P.A. van Veelen , R. Knevel , P.W.H.I. Parren , L.A. Trouw

Introduction

Autoimmune diseases, such as rheumatoid arthritis (RA), are characterized by the presence of autoantibodies including those targeting self-proteins modified by post-translational modifications (PTMs). The complement system is known for its role in innate immune defense, but also in clearing debris and induction of antibody responses. We therefore hypothesized that complement could directly bind to PTMs and target PTM-modified proteins for clearance, or stimulate (chronic) inflammation and development of anti-PTM autoimmunity.

Methods

Six PTMs were investigated: nitration (Nt), citrullination (Cit), carbamylation (Ca), acetylation (Ac), malondialdehyde-acetaldehyde adducts (MAA) and advanced glycation end-products (AGE). We used mass spectrometry and plate-bound assays to analyze binding of serum proteins to PTM-modified proteins. The impact of complement activation on cellular uptake was studied in phagocytosis assays. The relationship between complement SNPs, and presence of anti-PTM autoantibodies was analyzed in 587 RA patients.

Results

Mass spectrometry analysis revealed a strong binding of complement to proteins modified with Ca, Ac, MAA and AGE but not to Nt and Cit. These observations were confirmed by plate-bound assays revealing that Ca-, MAA- and AGE-modified proteins activated the classical pathway, without involving antibodies. Ac activated the lectin pathway through ficolin-3. Complement activation on Ca-, Ac-, MAA- and AGE-coupled beads enhanced phagocytosis. SNPs in complement genes, associated with higher complement activity, were strongly associated with the presence of anti-PTM antibodies in RA patients.

Conclusion

Proteins containing the PTMs Ca, Ac, MAA or AGE activate complement. These complement opsonized PTMs increase phagocytosis and may lead to the development of anti-PTM antibodies.

自身免疫性疾病，如类风湿关节炎（RA），以自身抗体的存在为特征，包括那些靶向经翻译后修饰（PTMs）修饰的自身蛋白的抗体。补体系统以其在先天免疫防御中的作用而闻名，但也在清除碎片和诱导抗体反应中发挥作用。因此，我们假设补体可以直接与ptm结合并靶向ptm修饰蛋白清除，或刺激（慢性）炎症和抗ptm自身免疫的发展。方法研究了6种ptm：硝化（Nt）、瓜氨酸化（Cit）、氨甲酰化（Ca）、乙酰化（Ac）、丙二醛-乙醛加合物（MAA）和晚期糖基化终产物（AGE）。我们使用质谱法和板结合法分析血清蛋白与ptm修饰蛋白的结合。在吞噬实验中研究了补体活化对细胞摄取的影响。分析587例RA患者补体snp与抗ptm自身抗体存在的关系。结果质谱分析显示，补体与Ca、Ac、MAA和AGE修饰的蛋白结合较强，但与Nt和Cit结合不强，这些观察结果通过板结合实验证实，Ca、MAA和AGE修饰的蛋白激活了经典途径，而不涉及抗体。Ac通过ficolin-3激活凝集素途径。补体活化对Ca-， Ac-， MAA-和age偶联珠增强吞噬。补体基因中的snp与较高的补体活性相关，与RA患者中抗ptm抗体的存在密切相关。结论含有ptm的Ca、Ac、MAA或AGE蛋白可激活补体。这些补体调理的ptm增加了吞噬作用，并可能导致抗ptm抗体的产生。

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引用次数: 0

Association between autoimmune diseases and glucagon-like peptide-1 receptor agonists: A real-world evidence study 自身免疫性疾病与胰高血糖素样肽-1受体激动剂之间的关系：一项真实世界的证据研究

IF 7.9 1区医学 Q1 IMMUNOLOGY

Journal of autoimmunity

Pub Date : 2025-06-21 DOI: 10.1016/j.jaut.2025.103453

Yun-Jui Lee , Yu-Wei Fang , Mon-Ting Chen , Hung-Hsiang Liou , Tzu-Hao Li , Ming-Hsien Tsai

Introduction

The therapeutic advantages of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in diabetes management have been demonstrated. However, their potential association with autoimmune diseases remains unknown. Using a comprehensive real-world dataset, this study compared GLP-1 RAs against dipeptidyl peptidase-4 inhibitors (DPP-4is) with respect to the incidence of autoimmune diseases.

Methods

This retrospective cohort study, with an active-comparator and new-user design, analyzed data from the TriNetX US Collaborative Network. We identified 4,841,560 patients aged over 18 years with type 2 diabetes from 1 January 2015 to 31 December 2022. Finally, 412,021 and 383,415 patients were included in the GLP-1 RAs and DPP-4is groups, respectively. Propensity score matching was used to balance baseline characteristics, and hazard ratios (HRs) were estimated with Cox regression models over an eight-year follow-up.

Results

After propensity score matching, each group included 290,770 patients. The analysis revealed that patients receiving GLP-1 RAs exhibited significantly higher risks of certain autoimmune conditions, including ulcerative colitis (HR, 1.11; 95 % CI, 1.04–1.19), rheumatoid arthritis (HR, 1.08; 95 % CI, 1.03–1.12), autoimmune thyroiditis (HR, 1.30; 95 % CI, 1.24–1.38), ankylosing spondylitis (HR, 1.30; 95 % CI, 1.13–1.51), and psoriasis (HR, 1.17; 95 % CI, 1.12–1.22), compared to those on DPP-4is. Moreover, sensitivity analyses consistently revealed a significant link between GLP-1 RAs use and autoimmune diseases.

Conclusions

This study suggests that compared with DPP-4is, the use of GLP-1 RAs is linked to increased risks of certain autoimmune diseases. Careful monitoring might be required among patients on GLP-1 RAs.

胰高血糖素样肽-1受体激动剂（GLP-1 RAs）在糖尿病治疗中的优势已被证实。然而，它们与自身免疫性疾病的潜在关联尚不清楚。使用全面的真实世界数据集，本研究比较了GLP-1 RAs与二肽基肽酶-4抑制剂（DPP-4is）在自身免疫性疾病发病率方面的差异。方法采用主动比较者和新用户设计的回顾性队列研究，分析来自TriNetX美国协作网络的数据。从2015年1月1日至2022年12月31日，我们确定了4,841,560名年龄在18岁以上的2型糖尿病患者。最终，GLP-1 RAs组和DPP-4is组分别纳入412,021例和383,415例患者。使用倾向评分匹配来平衡基线特征，并使用Cox回归模型估计八年随访期间的风险比（hr）。结果经倾向评分匹配后，每组纳入290,770例患者。分析显示，接受GLP-1 RAs治疗的患者出现某些自身免疫性疾病的风险显著增加，包括溃疡性结肠炎(HR, 1.11；95% CI, 1.04-1.19)，类风湿关节炎(HR, 1.08；95% CI, 1.03-1.12)，自身免疫性甲状腺炎(HR, 1.30；95% CI, 1.24-1.38)，强直性脊柱炎(HR, 1.30；95% CI, 1.13-1.51)和牛皮癣(HR, 1.17；95% CI, 1.12-1.22)，与DPP-4is组比较。此外，敏感性分析一致显示GLP-1 RAs使用与自身免疫性疾病之间存在显著联系。结论：本研究提示，与dpp -4相比，GLP-1 RAs的使用与某些自身免疫性疾病的风险增加有关。使用GLP-1 RAs的患者可能需要仔细监测。

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引用次数: 0

Autoimmune associated HLAs and T cell autoantigens exhibit common patterns across several autoimmune diseases 自身免疫性相关hla和T细胞自身抗原在几种自身免疫性疾病中表现出共同的模式

IF 7.9 1区医学 Q1 IMMUNOLOGY

Journal of autoimmunity

Pub Date : 2025-06-13 DOI: 10.1016/j.jaut.2025.103443

Astrid Brix Saksager , Freja Dahl Hede , Carolina Barra

Approximately 80 autoimmune diseases have been identified, with only a few proteins targeted by the immune system in each disease. The rest of the human proteome remains unaffected, indicating that the selection of these specific proteins is not random. Most autoimmune diseases show strong genetic associations with HLA alleles, suggesting a critical role for antigen presentation in autoimmunity.

In this study, we analyzed validated T cell epitopes and their associated HLAs from 21 autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and type 1 diabetes mellitus, using experimental data from the IEDB. We compared autoantigens to proteins not implicated in autoimmunity, investigated HLA binding motifs, and contrasted autoimmunogenic T cell epitopes with non-autoimmune T cell epitopes.

Autoantigens, compared to other non-autoimmunogenic proteins, exhibited higher mRNA expression, greater abundance in disease-specific tissues, and were frequently found in exposed subcellular locations such as membranes and extracellular spaces. Disease-associated HLAs showed distinct binding motifs compared to other HLAs, but the autoimmunogenic epitopes themselves did not differ markedly from other T cell epitopes. Autoantigens were enriched on MHC class II presented peptides, and the self-peptides differed from those seen in non-autoimmune contexts.

Our findings suggest that the interplay between specific HLA class II alleles and specific antigen features play a pivotal role in initiating autoimmune responses, while subsequent T cell activation likely follows typical immune mechanisms.

大约80种自身免疫性疾病已经被确定，在每种疾病中只有少数蛋白质被免疫系统靶向。人类蛋白质组的其余部分不受影响，这表明这些特定蛋白质的选择不是随机的。大多数自身免疫性疾病与HLA等位基因有很强的遗传关联，提示抗原呈递在自身免疫中起关键作用。在这项研究中，我们使用IEDB的实验数据，分析了21种自身免疫性疾病（包括多发性硬化症、类风湿性关节炎和1型糖尿病）的验证T细胞表位及其相关hla。我们比较了自身抗原和与自身免疫无关的蛋白，研究了HLA结合基序，并对比了自身免疫原性T细胞表位和非自身免疫T细胞表位。与其他非自身免疫原性蛋白相比，自身抗原表现出更高的mRNA表达，在疾病特异性组织中的丰度更高，并且经常在暴露的亚细胞位置（如膜和细胞外间隙）中发现。与其他hla相比，疾病相关hla显示出不同的结合基序，但自身免疫原性表位本身与其他T细胞表位没有明显差异。自身抗原在MHC II类呈递的肽上富集，而自身肽与在非自身免疫环境中所见的不同。我们的研究结果表明，特异性HLA II类等位基因和特异性抗原特征之间的相互作用在启动自身免疫反应中起着关键作用，而随后的T细胞激活可能遵循典型的免疫机制。

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引用次数: 0

Common Toll-like receptor 7 variants define disease risk and phenotypes in juvenile-onset systemic lupus erythematosus 常见的toll样受体7变异定义了青少年发病系统性红斑狼疮的疾病风险和表型

IF 7.9 1区医学 Q1 IMMUNOLOGY

Journal of autoimmunity

Pub Date : 2025-06-13 DOI: 10.1016/j.jaut.2025.103451

Yves Renaudineau , Francesca Sposito , Valentina Natoli , Amandine Charras , Jenny Hawkes , Joni Roachdown , Mathieu Fusaro , Eve MD. Smith , Michael W. Beresford , Christian M. Hedrich

Toll-like receptor (TLR)7 contributes to type I interferon (IFN) expression in systemic lupus erythematosus (SLE). This study investigated genetic variability of TLR7 in 319 juvenile-onset (j)SLE patients from the UK. New generation sequencing was used to associate “common” TLR7 variants with demographic and clinical features. Three jSLE-associated variants with in silico predicted impact on gene function presented minor allele frequencies ≥5 %: rs2302267/n.-20T > G (TLR7 promoter); rs179008/p.Gln11Leu (missense variant with predicted loss-of-function); and rs3853839/c.∗881C > G (TLR7 3′UTR). The risk to develop jSLE was increased in African/Caribbean girls carrying rs3853839 GC/GG (OR: 1.8; 95 %-CI: 1.2–2.9), while the risk associated with this variant was reduced in European girls (OR: 0.5; 95 %-CI: 0.4–0.7). At inclusion, rs3853839 minor G allele carrier status associated with activity in the mucocutaneous BILAG domain (p = 0.004), “older” age at diagnosis (p = 0.003, Asian), C3 consumption (p = 0.015, boys), and higher anti-dsDNA antibody levels (p = 0.015, African/Caribbean). The negative linkage disequilibrium between rs179008 (T-C/TT) and rs3853839 (CC) associated with increased global disease activity (pBILAG-2004), and activity in the constitutional and musculoskeletal pBILAG domains. Functionally, rs2302267/n.-20T > G, may protect from leukopenia through reduced TLR7 promoter activity, while rs3853839/c.∗881C > G-3′UTR increases TLR7 mRNA stability contributing to increased gene expression. In conclusion, common TLR7 variants may influence jSLE risk and organ involvement in an ancestry-specific manner. Observations argue for genetic risk stratification and future consideration of gene variants affecting TLR7 to guide personalized treatment and care strategies.

toll样受体（TLR）7参与系统性红斑狼疮（SLE）中I型干扰素（IFN）的表达。本研究调查了来自英国的319例青少年SLE患者TLR7的遗传变异性。新一代测序用于将“常见”TLR7变异与人口学和临床特征联系起来。3个对基因功能影响较小的jsl相关变异的等位基因频率均≥5%:rs2302267/n。-20 t比;G （TLR7启动子）；rs179008 / p。Gln11Leu（预测功能缺失的错义变体）；和rs3853839 / c。∗881 c比;G （tlr7 3'utr）。携带rs3853839 GC/GG的非洲/加勒比女孩发生jSLE的风险增加(OR: 1.8；95% -CI: 1.2-2.9)，而与该变异相关的风险在欧洲女孩中降低(OR: 0.5；95% -ci: 0.4-0.7)。在纳入时，rs3853839小G等位基因携带状态与皮肤粘膜BILAG结构域的活性（p = 0.004）、诊断时年龄“较大”（p = 0.003，亚洲人）、C3消耗（p = 0.015，男孩）和较高的抗dsdna抗体水平（p = 0.015，非洲/加勒比人）相关。rs179008 （T-C/TT）和rs3853839 （CC）之间的负连锁不平衡与全球疾病活动性增加（pBILAG-2004）以及体质和肌肉骨骼pBILAG结构域的活性相关。功能,rs2302267 / n。-20 t比;G，可能通过降低TLR7启动子活性来防止白细胞减少，而rs3853839/c。∗881 c比;G-3'UTR增加了TLR7 mRNA的稳定性，从而增加了基因表达。总之，常见的TLR7变异可能以一种特定于祖先的方式影响jSLE的风险和器官受累。观察结果表明，遗传风险分层和未来考虑影响TLR7的基因变异，以指导个性化治疗和护理策略。

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引用次数: 0