Journal of autoimmunity最新文献_第6页

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

The phenotypic and functional characteristics of intrahepatic CD69+CD103+ tissue-resident MAIT cells in primary biliary cholangitis 原发性胆管炎中肝内CD69+CD103+组织驻留MAIT细胞的表型和功能特征

IF 7.9 1区医学 Q1 IMMUNOLOGY

Journal of autoimmunity

Pub Date : 2025-06-01 DOI: 10.1016/j.jaut.2025.103442

Qiyun Xia , Zhuwan Lyu , Yudong Zhao , Xiting Pu , Jian Wang , Yuyang Liu , Yujie Zhou , Jun Qian , M.E. Gershwin , Min Lian , Xiong Ma

Background & aims

Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset that plays a significant role in the immunopathology of primary biliary cholangitis (PBC). However, our understanding of the subpopulations involved in hepatic residency have not been elucidated. Herein, our goal was to delineate the phenotypic and functional properties of intrahepatic tissue-resident MAIT cells in PBC.

Methods

Liver tissue and intrahepatic mononuclear cells were collected and analyzed by immunohistochemistry, immunofluorescence and flow cytometry. The transcriptome was determined using in vitro generated tissue-resident MAIT cells. FOXM1's immunoregulatory role was evaluated with inhibitor treatment and regulatory features of BHLHE40 were confirmed by CUT&Tag-seq and luciferase assays.

Results

In PBC, the frequency of intrahepatic MAIT cell decreased, but tissue-resident (CD69⁺CD103⁺) MAIT cells significantly expanded and expressed a notably pro-inflammatory phenotype, with substantial elevated expression of CXCR3, CXCR6; IL-17A, IFN-γ and T-bet. FOXM1, a transcriptional factor governing cell proliferation cycle, exhibited notably higher expression in tissue-resident MAIT cells than in non-resident MAIT cells. Inhibition of FOXM1 compromised the in vitro expansion of MAIT cells, and impaired the expression of CXCR3, IL-17A, IFN-γ and GM-SCF by tissue-resident MAIT cells. CUT&Tag-seq and luciferase assay revealed a direct regulation of FOXM1 of BHLHE40 expression.

Conclusion

Our data reveals a pro-inflammatory role of expanded tissue-resident MAIT cells in PBC mediated via higher expression of effector cytokines, chemokine receptors and a related transcriptional factor. FOXM1 critically regulates MAIT cell proliferation and tissue-resident pro-inflammatory function, via interaction with BHLHE40, and establishes a transcriptional axis linking proliferation to effector responses.

背景,粘膜相关不变性T细胞（MAIT）是一种先天样T细胞亚群，在原发性胆道胆管炎（PBC）的免疫病理中起重要作用。然而，我们对参与肝居住的亚群的理解尚未阐明。在这里，我们的目标是描述PBC中肝内组织驻留MAIT细胞的表型和功能特性。方法采集银组织和肝内单个核细胞，采用免疫组织化学、免疫荧光和流式细胞术进行分析。使用体外生成的组织驻留MAIT细胞来确定转录组。通过抑制剂治疗评估FOXM1的免疫调节作用，并通过CUT&；Tag-seq和荧光素酶检测证实BHLHE40的调节特性。结果在PBC中，肝内MAIT细胞频率降低，但组织驻留（CD69+CD103+） MAIT细胞显著扩增，表达明显的促炎表型，CXCR3、CXCR6表达显著升高；IL-17A， IFN-γ和T-bet。FOXM1是一种调控细胞增殖周期的转录因子，在组织驻留的MAIT细胞中的表达明显高于非驻留的MAIT细胞。FOXM1的抑制抑制了MAIT细胞的体外扩增，并损害了组织内MAIT细胞CXCR3、IL-17A、IFN-γ和GM-SCF的表达。CUT&；Tag-seq和荧光素酶检测显示FOXM1直接调控BHLHE40的表达。结论：我们的数据揭示了扩大的组织驻留MAIT细胞在PBC中的促炎作用是通过提高效应细胞因子、趋化因子受体和相关转录因子的表达介导的。FOXM1通过与BHLHE40的相互作用，对MAIT细胞增殖和组织驻留的促炎功能进行关键调控，并建立一个连接增殖和效应反应的转录轴。

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引用次数: 0

Integrated analysis of polygenic and environmental risk scores for late-onset systemic lupus erythematosus 迟发性系统性红斑狼疮多基因与环境风险评分的综合分析

IF 7.9 1区医学 Q1 IMMUNOLOGY

Journal of autoimmunity

Pub Date : 2025-05-28 DOI: 10.1016/j.jaut.2025.103441

Mehmet Hocaoǧlu , Amr H. Sawalha

Objective

Polygenic risk scores (PRS) have been constructed to summarize genetic risk but there is limited research on environment-wide analysis of risk factors for systemic lupus erythematosus (SLE). In this study, we performed an environment-wide association study to construct an environmental risk score (ERS) for SLE and compare the risk conferred by ERS and PRS.

Methods

A total of 335 incident SLE cases were identified in the UK Biobank and matched 1:10 with age, sex, and ethnic background 3350 healthy controls. We examined the association between 37 environmental factors and SLE, using a univariate followed by a multivariate analysis. We summed the natural logarithm of the odds ratios (OR) of statistically significant environmental variables in the multivariable model to derive an ERS for SLE. Model discrimination was compared by De-Long′s test. PRS was calculated using the ORs of previously reported SLE genetic risk loci.

Results

The multivariate analysis revealed the association between daily sunlight exposure, depression, sleeplessness, sex hormone binding globulin levels, and air pollution with increased risk of SLE, while moderate physical activity was a protective factor. Increasing quartiles of the newly developed ERS were associated with similar degree of risk for SLE as the PRS. Integrating PRS with environmental factors significantly improved model performance.

Conclusions

We devised an ERS for SLE that summarizes the environmental component of the disease risk. We show that ERS confers a comparable degree of SLE risk as the PRS. Combining genetic and environmental factors could improve risk prediction models in SLE.

目的建立了多基因风险评分（PRS）来总结系统性红斑狼疮（SLE）的遗传风险，但对系统性红斑狼疮（SLE）危险因素的全环境分析研究有限。在本研究中，我们进行了一项全环境关联研究，构建SLE的环境风险评分（ERS），并比较ERS和PRS所赋予的风险。方法在英国生物银行（UK Biobank）共发现335例SLE病例，并将3350名健康对照者与年龄、性别、种族背景进行1:10匹配。我们研究了37个环境因素与SLE之间的关系，采用单变量分析和多变量分析。我们对多变量模型中具有统计学意义的环境变量的比值比（OR）的自然对数求和，得出SLE的ERS。模型判别比较采用De-Long检验。PRS是使用先前报道的SLE遗传风险位点的ORs来计算的。结果多因素分析显示，每日阳光照射、抑郁、失眠、性激素结合球蛋白水平和空气污染与SLE风险增加有关，而适度的体育锻炼是一个保护因素。新发展的ERS的增加四分位数与PRS的SLE风险程度相似。将PRS与环境因素相结合，显著提高了模型性能。结论：我们设计了系统性红斑狼疮的ERS，总结了疾病风险的环境因素。我们发现ERS与PRS具有相当程度的SLE风险。遗传因素与环境因素的结合可以改善SLE的风险预测模型。

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引用次数: 0

Characterizing local antibody responses in the muscle of inclusion body myositis patients 包涵体肌炎患者肌肉局部抗体反应的表征

IF 7.9 1区医学 Q1 IMMUNOLOGY

Journal of autoimmunity

Pub Date : 2025-05-26 DOI: 10.1016/j.jaut.2025.103437

Sahana Jayaraman , Andrew Wilson , Xuwen Alice Zheng , Janelle M. Montagne , Iago Pinal-Fernandez , Andrew L. Mammen , Thomas E. Lloyd , H. Benjamin Larman

Objective

Sporadic inclusion body myositis (IBM) is the most common adult idiopathic inflammatory myopathy. IBM etiology has been elusive, due to both degenerative and autoimmune disease features found on muscle biopsy, and significant disease heterogeneity. Investigating the role of antibodies in the muscle of IBM patients may improve our understanding of disease pathogenesis.

Methods

We used an IBM xenograft mouse model in which muscle biopsy tissue from IBM patients (n = 98) and controls (n = 131; including 54 from other types of myopathy) were implanted into immunodeficient mice (NOD-Rag1^null-IL2rγ^null). We quantified the amount of human IgG, IgA, and IgM in xenografted mouse sera using MesoScale Diagnostics (MSD) assay. We detected donor-derived antibody reactivities targeting autoantigens and infectious agents using Phage ImmunoPrecipitation Sequencing (PhIP-Seq). Finally, we used FR3 AmplifiKation Sequencing (FR3AK-Seq) to sequence the antibody mRNAs from a separate cohort of 146 patient biopsies (14 IBM, 22 healthy controls, 110 other myositis subtypes).

Results

With the MSD assay we found human IgG, IgA, and IgM in a larger percentage of IBM xenografted mice versus controls. Using PhIP-Seq, we found anti-microbial reactivities secreted from IBM muscle are prevalent amongst a healthy control population but autoantigen reactivities in IBM are more unique at the peptide and protein level. Additionally, NT5C1A (IgG/IgA and IgM) and TIF1γ (IgG/A) autoantibodies are secreted from muscle tissues of 4/18 and 10/18 IBM xenograft donors, respectively.

Conclusion

Our characterization of antibody responses within the muscle of IBM patients reveals that muscle-infiltrating B cells produce both disease-associated autoantibodies and a broad spectrum of antibodies targeting non-self antigens.

目的散发性包涵体肌炎（IBM）是成人最常见的特发性炎性肌病。由于在肌肉活检中发现的退行性和自身免疫性疾病特征以及显著的疾病异质性，IBM病因一直难以捉摸。研究抗体在IBM患者肌肉中的作用可能会提高我们对疾病发病机制的理解。方法采用IBM异种移植小鼠模型，其中IBM患者（n = 98）和对照组（n = 131）的肌肉活检组织；包括来自其他类型肌病的54个)植入免疫缺陷小鼠（nod - rag1null - il2r - γnull）。我们使用MesoScale Diagnostics （MSD）测定法定量了异种移植小鼠血清中人IgG、IgA和IgM的含量。我们使用噬菌体免疫沉淀测序（Phage ImmunoPrecipitation Sequencing, PhIP-Seq）检测了针对自身抗原和感染因子的供体来源抗体的反应性。最后，我们使用FR3扩增测序（FR3AK-Seq）对146例活检患者（14例IBM， 22例健康对照，110例其他肌炎亚型）的抗体mrna进行测序。结果通过MSD检测，我们在IBM异种移植小鼠中发现了比对照组更高比例的人IgG、IgA和IgM。使用PhIP-Seq，我们发现IBM肌肉分泌的抗微生物反应在健康对照人群中普遍存在，但IBM的自身抗原反应在肽和蛋白质水平上更为独特。此外，NT5C1A （IgG/IgA和IgM）和TIF1γ (IgG/A)自身抗体分别从4/18和10/18 IBM异种移植物供者的肌肉组织中分泌。我们对IBM患者肌肉内抗体反应的表征表明，肌肉浸润的B细胞既产生疾病相关的自身抗体，也产生针对非自身抗原的广谱抗体。

{"title":"Characterizing local antibody responses in the muscle of inclusion body myositis patients","authors":"Sahana Jayaraman , Andrew Wilson , Xuwen Alice Zheng , Janelle M. Montagne , Iago Pinal-Fernandez , Andrew L. Mammen , Thomas E. Lloyd , H. Benjamin Larman","doi":"10.1016/j.jaut.2025.103437","DOIUrl":"10.1016/j.jaut.2025.103437","url":null,"abstract":"<div><h3>Objective</h3><div>Sporadic inclusion body myositis (IBM) is the most common adult idiopathic inflammatory myopathy. IBM etiology has been elusive, due to both degenerative and autoimmune disease features found on muscle biopsy, and significant disease heterogeneity. Investigating the role of antibodies in the muscle of IBM patients may improve our understanding of disease pathogenesis.</div></div><div><h3>Methods</h3><div>We used an IBM xenograft mouse model in which muscle biopsy tissue from IBM patients (n = 98) and controls (n = 131; including 54 from other types of myopathy) were implanted into immunodeficient mice (NOD-Rag1<sup>null</sup>-IL2rγ<sup>null</sup>). We quantified the amount of human IgG, IgA, and IgM in xenografted mouse sera using MesoScale Diagnostics (MSD) assay. We detected donor-derived antibody reactivities targeting autoantigens and infectious agents using Phage ImmunoPrecipitation Sequencing (PhIP-Seq). Finally, we used FR3 AmplifiKation Sequencing (FR3AK-Seq) to sequence the antibody mRNAs from a separate cohort of 146 patient biopsies (14 IBM, 22 healthy controls, 110 other myositis subtypes).</div></div><div><h3>Results</h3><div>With the MSD assay we found human IgG, IgA, and IgM in a larger percentage of IBM xenografted mice versus controls. Using PhIP-Seq, we found anti-microbial reactivities secreted from IBM muscle are prevalent amongst a healthy control population but autoantigen reactivities in IBM are more unique at the peptide and protein level. Additionally, NT5C1A (IgG/IgA and IgM) and TIF1γ (IgG/A) autoantibodies are secreted from muscle tissues of 4/18 and 10/18 IBM xenograft donors, respectively.</div></div><div><h3>Conclusion</h3><div>Our characterization of antibody responses within the muscle of IBM patients reveals that muscle-infiltrating B cells produce both disease-associated autoantibodies and a broad spectrum of antibodies targeting non-self antigens.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103437"},"PeriodicalIF":7.9,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Interferon signatures fuel B cell hyperactivity and plasmablast expansion in systemic lupus erythematosus 干扰素信号促进系统性红斑狼疮患者B细胞过度活跃和浆母细胞扩张

IF 7.9 1区医学 Q1 IMMUNOLOGY

Journal of autoimmunity

Pub Date : 2025-05-26 DOI: 10.1016/j.jaut.2025.103438

Hugo J. van Dooren , Yemil Atisha-Fregoso , Annemarie L. Dorjée , Tom W.J. Huizinga , Meggan Mackay , Cynthia Aranow , René E.M. Toes , Betty Diamond , Jolien Suurmond

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by an array of autoantibodies, in particular anti-nuclear antibodies (ANA). The disease is also hallmarked by an expansion of plasmablasts (PB) and hypergammaglobulinemia. The mechanisms underlying this hyperactivity and its relation to autoantibody production is not clear. We aimed to characterize B cell hyperactivity in SLE to identify its underlying mechanisms.

Using deep phenotyping with spectral flow cytometry and scRNAseq, we demonstrate that a high frequency of PB relative to memory B cells marks a subgroup of SLE patients, particularly those with higher disease activity and positive for Sm/RNP autoantibodies. We identified the origin of this phenotype in a prominent IFN signature in PB and increased activation in the switched CD27⁺ memory B cell compartment. PB from this group of SLE patients displayed high levels of CD45RB and somatic hypermutation frequencies similar to memory B cells. Repertoire analysis revealed a highly polyclonal expansion of PB and skewing towards IgG1. B cell hyperactivity correlated with hypergammaglobulinemia, especially increased IgG serum levels.

In summary, we show for the first time a direct relationship between IFN and PB expansion in a subgroup of SLE patients. Increased activation and differentiation of class-switched B cells driven by IFN may directly underlie PB expansion and hypergammaglobulinemia. These results provide insight into the pathways leading to B cell hyperactivity and autoantibody production which may guide the tailoring of B cell- and IFN-targeted therapies.

系统性红斑狼疮（SLE）是一种自身免疫性疾病，其特征是一系列自身抗体，特别是抗核抗体（ANA）。本病还以浆母细胞（PB）扩增和高γ -球蛋白血症为特征。这种过度活跃的机制及其与自身抗体产生的关系尚不清楚。我们的目的是表征SLE中的B细胞过度活跃，以确定其潜在机制。利用流式细胞术和scRNAseq的深度表型分析，我们证明了相对于记忆B细胞的高频率PB标志着SLE患者的一个亚组，特别是那些疾病活动性较高且Sm/RNP自身抗体阳性的患者。我们发现这种表型的起源是在PB中显著的IFN特征和CD27+记忆B细胞区室中激活增加。来自这组SLE患者的PB显示出高水平的CD45RB和体细胞高突变频率，类似于记忆B细胞。曲目分析显示PB高度多克隆扩增，并向IgG1倾斜。B细胞过度活跃与高丙种球蛋白血症相关，尤其是血清IgG水平升高。总之，我们首次在SLE患者亚组中发现IFN与PB扩张之间的直接关系。由IFN驱动的类别转换B细胞的激活和分化增加可能是PB扩张和高γ -球蛋白血症的直接基础。这些结果提供了对导致B细胞过度活跃和自身抗体产生的途径的深入了解，这可能指导B细胞和ifn靶向治疗的定制。

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引用次数: 0

Association between occupational and environmental dust exposure and autoimmune diseases: A systematic review and meta-analysis 职业和环境粉尘暴露与自身免疫性疾病之间的关系：系统回顾和荟萃分析

IF 7.9 1区医学 Q1 IMMUNOLOGY

Journal of autoimmunity

Pub Date : 2025-05-25 DOI: 10.1016/j.jaut.2025.103440

Seunghyun Lee , Ah-Reum Jo , Youjin Kim , Wanhyung Lee , Xiaoxue Ma

Background

Occupational and environmental dust exposure is often overlooked, presenting significant public health concerns. Recent studies suggest it may increase the risk of autoimmune diseases. However, previous research has primarily focused on specific diseases or dust types, leaving the broader relationship unclear. A comprehensive meta-analysis are needed to clarify this connection.

Methods

We systematically searched PubMed and Google Scholar up to October 2023, following PRISMA guidelines. Study quality was assessed using standard tools, and a random-effects model was used to estimate pooled odds ratio (OR) and 95 % confidence interval (CI), with subgroup analyses by dust type and disease category.

Results

From 90 initial records, 19 studies were included. Dust exposure was significantly associated with increased autoimmune disease risk (OR 1.36, 95 % CI 1.13–1.59). Both occupational (OR 1.18, 95 % CI 1.11–1.26) and environmental dust exposure (OR 1.12, 95 % CI 1.04–1.20) were linked to higher risk. Subgroup analysis showed a strong association between silica exposure and connective tissue diseases, particularly granulomatosis with polyangiitis (OR 5.75, 95 % CI 2.79–8.71). Sensitivity analysis confirmed the findings, though publication bias was noted.

Conclusion

Our findings highlight a significant association between dust exposure and autoimmune disease risk, underscoring the need for stricter occupational safety measures and environmental regulations. Targeted interventions, such as improved ventilation systems and personal protective equipment (PPE), should be prioritized. Future research should focus on elucidating underlying mechanisms to inform prevention and treatment strategies.

职业和环境粉尘暴露往往被忽视，引起重大的公共卫生问题。最近的研究表明，它可能会增加自身免疫性疾病的风险。然而，之前的研究主要集中在特定的疾病或灰尘类型上，没有明确更广泛的关系。需要一个全面的荟萃分析来澄清这种联系。方法根据PRISMA指南，系统检索PubMed和谷歌Scholar，截止到2023年10月。使用标准工具评估研究质量，并使用随机效应模型估计合并优势比（OR）和95%置信区间（CI），并按粉尘类型和疾病类别进行亚组分析。结果从90份初始记录中纳入19项研究。粉尘暴露与自身免疫性疾病风险增加显著相关（OR 1.36, 95% CI 1.13-1.59）。职业（OR 1.18, 95% CI 1.11-1.26）和环境粉尘暴露（OR 1.12, 95% CI 1.04-1.20）都与较高的风险相关。亚组分析显示二氧化硅暴露与结缔组织疾病，特别是肉芽肿病合并多血管炎之间有很强的相关性（OR 5.75, 95% CI 2.79-8.71）。敏感性分析证实了这一发现，尽管存在发表偏倚。结论：我们的研究结果强调了粉尘暴露与自身免疫性疾病风险之间的显著关联，强调了更严格的职业安全措施和环境法规的必要性。应优先考虑有针对性的干预措施，如改进通风系统和个人防护装备。未来的研究应侧重于阐明潜在的机制，为预防和治疗策略提供信息。

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引用次数: 0