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Autoimmune diseases and cardiovascular risk: Mendelian randomization analysis for the impact of 19 autoimmune diseases on 14 cardiovascular conditions 自身免疫性疾病与心血管风险:孟德尔随机分析 19 种自身免疫性疾病对 14 种心血管疾病的影响
IF 4.7 Q2 IMMUNOLOGY Pub Date : 2024-11-01 DOI: 10.1016/j.jtauto.2024.100259

Backgroud

Autoimmune diseases (AIDs) have been associated with various cardiovascular diseases (CVDs) in observational data. However, the causality of these associations remains uncertain. Therefore, a systematic assessment of the impact of AIDS on cardiovascular risk is required.

Results

We assessed the impact of 19 common AIDs on 14 CVDs using bidirectional Mendelian randomization (MR). Celiac disease (odds ratio [OR] = 2.949, 95 % confidence interval [CI]: 1.111–7.827, P = 0.030) and type 1 diabetes mellitus (T1DM) (OR = 1.044, 95 % CI: 1.021–1.068, P = 1.82e-4) were associated with an increased risk of peripheral arterial disease (PAD). Additionally, celiac disease was linked to an increased risk of arrhythmia (OR = 1.008, 95 % CI: 1.002–1.013, P = 0.004), multiple sclerosis to venous thromboembolism (OR = 1.001, 95 % CI: 1.000–1.001, P = 0.010), and psoriasis to heart failure (OR = 1.048, 95 % CI: 1.021–1.077, P = 0.001). Sensitivity analyses were conducted to enhance the robustness of these findings. Predominantly, immune response and inflammation-related pathways were enriched in the aforementioned associations. Mediation analysis identified human leukocyte antigen-DR positive myeloid dendritic cells as partially mediating the effect of T1DM on PAD, with a mediated proportion of 16.61 % (P = 0.028). Potential therapeutic agents, such as tumor necrosis factor-alpha inhibitors and interferon, may have efficacy in treating AID-related CVDs.

Conclusions

This study presents genetic evidence of certain AIDs impacting specific CVDs and identifies potential mediators and drugs.
背景在观察性数据中,自身免疫性疾病(AIDs)与各种心血管疾病(CVDs)有关。然而,这些关联的因果关系仍不确定。因此,需要对艾滋病对心血管风险的影响进行系统评估。结果我们采用双向孟德尔随机法(MR)评估了19种常见艾滋病对14种心血管疾病的影响。乳糜泻(几率比[OR] = 2.949,95%置信区间[CI]:1.111-7.827,95%置信区间[CI1.111-7.827,P = 0.030)和 1 型糖尿病(T1DM)(OR = 1.044,95 % 置信区间 [CI]:1.021-1.068,P = 1.82e-4)与外周动脉疾病(PAD)风险增加有关。此外,乳糜泻与心律失常风险增加有关(OR = 1.008,95 % CI:1.002-1.013,P = 0.004),多发性硬化与静脉血栓栓塞有关(OR = 1.001,95 % CI:1.000-1.001,P = 0.010),银屑病与心力衰竭有关(OR = 1.048,95 % CI:1.021-1.077,P = 0.001)。为了增强这些研究结果的可靠性,我们进行了敏感性分析。在上述关联中,主要是免疫反应和炎症相关通路。中介分析发现,人类白细胞抗原-DR阳性髓系树突状细胞部分中介了T1DM对PAD的影响,中介比例为16.61%(P = 0.028)。肿瘤坏死因子-α抑制剂和干扰素等潜在治疗药物可能对治疗艾滋病相关心血管疾病有疗效。
{"title":"Autoimmune diseases and cardiovascular risk: Mendelian randomization analysis for the impact of 19 autoimmune diseases on 14 cardiovascular conditions","authors":"","doi":"10.1016/j.jtauto.2024.100259","DOIUrl":"10.1016/j.jtauto.2024.100259","url":null,"abstract":"<div><h3>Backgroud</h3><div>Autoimmune diseases (AIDs) have been associated with various cardiovascular diseases (CVDs) in observational data. However, the causality of these associations remains uncertain. Therefore, a systematic assessment of the impact of AIDS on cardiovascular risk is required.</div></div><div><h3>Results</h3><div>We assessed the impact of 19 common AIDs on 14 CVDs using bidirectional Mendelian randomization (MR). Celiac disease (odds ratio [OR] = 2.949, 95 % confidence interval [CI]: 1.111–7.827, P = 0.030) and type 1 diabetes mellitus (T1DM) (OR = 1.044, 95 % CI: 1.021–1.068, P = 1.82e-4) were associated with an increased risk of peripheral arterial disease (PAD). Additionally, celiac disease was linked to an increased risk of arrhythmia (OR = 1.008, 95 % CI: 1.002–1.013, P = 0.004), multiple sclerosis to venous thromboembolism (OR = 1.001, 95 % CI: 1.000–1.001, P = 0.010), and psoriasis to heart failure (OR = 1.048, 95 % CI: 1.021–1.077, P = 0.001). Sensitivity analyses were conducted to enhance the robustness of these findings. Predominantly, immune response and inflammation-related pathways were enriched in the aforementioned associations. Mediation analysis identified human leukocyte antigen-DR positive myeloid dendritic cells as partially mediating the effect of T1DM on PAD, with a mediated proportion of 16.61 % (P = 0.028). Potential therapeutic agents, such as tumor necrosis factor-alpha inhibitors and interferon, may have efficacy in treating AID-related CVDs.</div></div><div><h3>Conclusions</h3><div>This study presents genetic evidence of certain AIDs impacting specific CVDs and identifies potential mediators and drugs.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142572346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Homeostatic signals, including IL-7 and self-MHC recognition, induce the development of peripheral helper T cells, which are enriched in the joints of rheumatoid arthritis IL-7和自身MHC识别等体内平衡信号诱导外周辅助T细胞的发育,这些细胞在类风湿性关节炎的关节中富集
IF 4.7 Q2 IMMUNOLOGY Pub Date : 2024-10-30 DOI: 10.1016/j.jtauto.2024.100258

Objective

Dysregulated T cell homeostasis has long been implicated in the pathogenesis of rheumatoid arthritis (RA), in the joint of which peripheral helper T (Tph) cells accumulate and form ectopic lymphoid organs. We examined whether homeostatic signals are involved in the development of Tph cells.

Methods

Human peripheral blood mononuclear cells were cultured with IL-7, the critical cytokine for T cell homeostasis. Development of Tph-like cells was assessed by flow cytometry, gene expression, and functional analysis. Chemotaxis of the Tph-like cells to RA synovial fluid (RASF) and the effect of RASF on the development of Tph-like cells was examined.

Results

PD-1highCXCR5- Tph-like cells developed from human peripheral blood CD4 T cells after proliferation in response to IL-7. Signals from self-MHC recognition and CD28 co-stimulation were also involved. The IL-7-induced Tph-like (IL-7-Tph) cells produced CXCL13 and IL-21 and helped B cells produce IgG. Comprehensive gene expression analysis further supported the similarity with Tph cells in RA joint. IL-7-Tph cells exhibited chemotaxis toward synovial fluid from RA patients (RASF), and RASF promoted the development of IL-7-Tph cells, which were also induced from CD4 T cells residing in non-inflamed joints.

Conclusions

Our results demonstrate an antigen-nonspecific developmental pathway of Tph cells triggered by homeostatic signals and promoted by the local environment of RA, which accounts for the accumulation of Tph cells in inflamed joints.
目的长期以来,T细胞稳态失调一直被认为与类风湿性关节炎(RA)的发病机制有关,在类风湿性关节炎的关节中,外周辅助性T细胞(Tph)聚集并形成异位淋巴器官。我们研究了平衡信号是否参与了 Tph 细胞的发育。方法用 IL-7 培养人外周血单核细胞,IL-7 是 T 细胞平衡的关键细胞因子。通过流式细胞术、基因表达和功能分析评估了Tph样细胞的发育情况。研究了Tph样细胞对RA滑液(RASF)的趋化作用以及RASF对Tph样细胞发育的影响。来自自身-MHC 识别和 CD28 协同刺激的信号也参与其中。IL-7诱导的Tph样细胞(IL-7-Tph)能产生CXCL13和IL-21,并帮助B细胞产生IgG。全面的基因表达分析进一步证实了与 RA 关节中 Tph 细胞的相似性。IL-7-Tph细胞对来自RA患者的滑液(RASF)表现出趋化性,RASF促进了IL-7-Tph细胞的发育,而这些细胞也是从非炎症关节中的CD4 T细胞中诱导出来的。
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引用次数: 0
C3 glomerulopathy is highly prevalent in French Polynesia C3 肾小球病在法属波利尼西亚非常普遍
IF 4.7 Q2 IMMUNOLOGY Pub Date : 2024-10-29 DOI: 10.1016/j.jtauto.2024.100254

Objective

To compare the natural history of C3 glomerulopathy (C3G) to acute post-infectious glomerulonephritis (APIGN) in a cohort of patients with a relative homogeneity of environment conditions and genetic background.

Methods

We retrospectively reviewed the characteristics of all patients with biopsy proven C3G or APIGN referred in 2013–2019 to the only renal unit in French Polynesia.

Results

Point prevalence of C3G is ∼23 cases per 100,000 inhabitants. A recurrent variation of CFI (p.Arg406His) was identified at the heterozygous state in 4/8 (50 %) patients with C3G but its pathogenicity remain elusive. Characteristics at presentation and kidney outcomes were roughly similar between C3G (n = 16) and APIGN (n = 20), excepted for the presence of humps on kidney biopsy.

Conclusions

C3G is highly prevalent in French Polynesia suggesting specific genetic or environmental susceptibility factors. Systematic diagnosis workflow should be proposed to all patients with C3 predominant glomerulonephritis.
目的在环境条件和遗传背景相对相同的一组患者中,比较C3肾小球病(C3G)和感染后急性肾小球肾炎(APIGN)的自然病史。结果C3G的发病率为每10万居民中23例。在4/8(50%)例C3G患者中发现了CFI的复发性变异(p.Arg406His),但其致病性仍难以确定。C3G(16 例)和 APIGN(20 例)的发病特征和肾脏结果大致相似,但肾活检时出现驼峰除外。结论C3G在法属波利尼西亚的发病率很高,这表明存在特定的遗传或环境易感因素。对所有C3为主的肾小球肾炎患者都应采用系统诊断工作流程。
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引用次数: 0
Integrated analysis of multi-omics data for the discovery of biomarkers and therapeutic targets for juvenile idiopathic arthritis 综合分析多组学数据,发现幼年特发性关节炎的生物标记物和治疗靶点
IF 4.7 Q2 IMMUNOLOGY Pub Date : 2024-10-26 DOI: 10.1016/j.jtauto.2024.100256

Background

Juvenile idiopathic arthritis (JIA) is a prevalent chronic rheumatic disease affecting children. Current medications merely alleviate symptoms rather than curing the disease. Hence, the identification and development of novel drug targets and biomarkers for JIA are imperative for enhancing treatment efficacy.

Methods

We employed two-sample Mendelian randomization (MR) analysis to investigate the causal effects of plasma proteins on JIA. Additionally, colocalization, bulk RNA-seq, and single-cell RNA-seq analyses were conducted to further investigate and validate the potential of candidate proteins as drug targets.

Results

Through MR analysis, we successfully identified five plasma proteins that are causally linked to JIA. Genetically inferred lower levels of AIF1, TNF, and TNFSF11 were associated with an elevated risk of JIA, while higher levels of AGER and GP1BA proteins were positively correlated with JIA risk. Colocalization analysis further supported our findings on GP1BA (OR = 9.26, 95 % CI: 2.30–37.20) and TNFSF11 (OR = 0.18, 95 % CI: 0.07–0.45). Based on this evidence, we classified these five proteins into two tiers. Finally, we conducted a systematic evaluation of the druggability and current drug development progress for these identified candidate proteins.

Conclusions

This study employed MR analysis to reveal causal relationships between plasma proteins and JIA, identifying five potential candidate proteins as promising drug targets for JIA, particularly focusing on GP1BA and TNFSF11.
背景青少年特发性关节炎(JIA)是一种影响儿童的流行性慢性风湿病。目前的药物只能缓解症状,而不能治愈疾病。因此,鉴定和开发JIA的新型药物靶点和生物标志物对于提高治疗效果势在必行。方法我们采用双样本孟德尔随机化(MR)分析法研究血浆蛋白对JIA的因果效应。结果通过MR分析,我们成功鉴定了5种与JIA有因果关系的血浆蛋白。根据基因推断,较低水平的AIF1、TNF和TNFSF11与JIA风险升高有关,而较高水平的AGER和GP1BA蛋白与JIA风险呈正相关。共定位分析进一步支持了我们对 GP1BA(OR = 9.26,95 % CI:2.30-37.20)和 TNFSF11(OR = 0.18,95 % CI:0.07-0.45)的研究结果。根据这些证据,我们将这五种蛋白质分为两级。结论 本研究采用磁共振分析揭示了血浆蛋白与 JIA 之间的因果关系,确定了五种潜在的候选蛋白作为治疗 JIA 的有希望的药物靶点,尤其关注 GP1BA 和 TNFSF11。
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引用次数: 0
Association of COVID-19 with Thyroid Dysfunction and Autoimmune Thyroid Disease: A Retrospective Cohort Study COVID-19 与甲状腺功能障碍和自身免疫性甲状腺疾病的关系:一项回顾性队列研究
IF 4.7 Q2 IMMUNOLOGY Pub Date : 2024-10-24 DOI: 10.1016/j.jtauto.2024.100255
<div><h3>Background</h3><div>Since the end of the COVID-19 pandemic, the potential roles of thyroid-inflammatory derangements in driving or being associated with the prognosis of COVID-19 remain controversial. We aimed to clarify the association between COVID-19 infection and thyroid dysfunction, and highlight the impacts of subsequent autoimmune thyroid disease (AITD) on the prognosis of COVID-19.</div></div><div><h3>Methods</h3><div>The retrospective, multicenter, cohort study enrolled 2,339 participants with COVID-19 from three hospitals located in the north, middle, and south regions of Shaan Xi Province, China, between December 2022 and July 2023. 464 non-COVID-19 patients within the same period were supplemented, divided into groups with and without AITD. At hospital admission (baseline), 3- and 6-month follow-ups, we presented a dynamic description and correlation analysis of thyroid-inflammatory-autoimmune derangements in patients with AITD.</div></div><div><h3>Results</h3><div>A total of 2,082 COVID-19 patients diagnosed with AITD and 257 cases without AITD were included in the study, and 464 non-COVID-19 patients were supplemented, dividing into 14 AITD and 450 non-AITD cases. We found that COVID-19 infection was closely associated with thyroid dysfunction (<em>χ</em><sup><em>2</em></sup> = 1518.129, <em>p</em> = 0.000). AITD patients with COVID-19 showed a higher prevalence of symptoms and comorbidities and longer hospital stays at baseline than non-AITD patients with COVID-19 (<em>p</em> = 0.000, <em>p</em> = 0.000, and <em>p</em> = 0.000). The baseline free triiodothyronine (FT3), free thyroxine, and radioactive iodine uptake at 24 hours in AITD cases significantly decreased (<em>p</em> = 0.000, <em>p</em> = 0.000, and <em>p</em> = 0.000), while thyroid stimulating hormone, thyroglobulin, reverse triiodothyronine (rT3), and thyroid antibodies varying elevated from the baseline to the follow-up (baseline: <em>p</em> = 0.000, <em>p</em> = 0.000, <em>p</em> = 0.000, <em>p</em> = 0.000, <em>p</em> = 0.000, and <em>p</em> = 0.000; 3-month follow-up: <em>p</em> = 0.000, <em>p</em> = 0.000, <em>p</em> = 0.000, <em>p</em> = 0.000, <em>p</em> = 0.030, and <em>p</em> = 0.000). C-reactive protein, calcitonin, interleukin-6, -8, -10, and tumor necrosis factor-α rose significantly at baseline (<em>p</em> = 0.000, <em>p</em> = 0.000, <em>p</em> = 0.000, <em>p</em> = 0.000, <em>p</em> = 0.000, and <em>p</em> = 0.000) in AITD. Interferon-α and interferon-γ at baseline showed a significant decrease (<em>p</em> = 0.000 and <em>p</em> = 0.000), and remained at low levels after 6 months (<em>p</em> = 0.000 and <em>p</em> = 0.000). FT3 and rT3 were positively and negatively correlated with hospitalization, respectively (<em>r</em> = -0.208, 0.231; <em>p</em> = 0.000, <em>p</em> = 0.000). ROC curves showed that FT3 and rT3 had better robustness in predicting severe COVID-19 prognosis (AUC = 0.801, 0.705). Ordered logistic regression revealed that ORs were
背景自COVID-19大流行结束以来,甲状腺炎症失调在COVID-19预后中的潜在驱动作用或相关作用仍存在争议。我们旨在阐明 COVID-19 感染与甲状腺功能障碍之间的关联,并强调后续自身免疫性甲状腺疾病(AITD)对 COVID-19 预后的影响。同期补充了464名非COVID-19患者,分为AITD组和非AITD组。在入院(基线)、3个月和6个月的随访中,我们对AITD患者的甲状腺炎症-自身免疫失调情况进行了动态描述和相关分析。我们发现,COVID-19感染与甲状腺功能障碍密切相关(χ2 = 1518.129,P = 0.000)。与感染 COVID-19 的非 AITD 患者相比,感染 COVID-19 的 AITD 患者的症状和合并症发生率更高,基线住院时间更长(p = 0.000、p = 0.000 和 p = 0.000)。AITD 病例的基线游离三碘甲状腺原氨酸(FT3)、游离甲状腺素和 24 小时放射性碘摄取量显著下降(p = 0.000、p = 0.000 和 p = 0.000),而促甲状腺激素、甲状腺球蛋白、反向三碘甲状腺原氨酸(rT3)和甲状腺抗体从基线到随访期间均有不同程度的升高(基线:P = 0.000、p = 0.000、p = 0.000、p = 0.000、p = 0.000 和 p = 0.000;3 个月随访:p = 0.000、p = 0.000、p = 0.000、p = 0.000、p = 0.030 和 p = 0.000)。AITD 患者的 C 反应蛋白、降钙素原、白细胞介素-6、-8、-10 和肿瘤坏死因子-α 在基线时显著升高(p = 0.000、p = 0.000、p = 0.000、p = 0.000 和 p = 0.000)。基线时的干扰素-α和干扰素-γ显著下降(p = 0.000 和 p = 0.000),6 个月后仍保持在较低水平(p = 0.000 和 p = 0.000)。FT3 和 rT3 分别与住院治疗呈正相关和负相关(r = -0.208, 0.231; p = 0.000, p = 0.000)。ROC 曲线显示,FT3 和 rT3 在预测严重 COVID-19 预后方面具有更好的稳健性(AUC = 0.801,0.705)。有序逻辑回归显示,AITD[(亚急性甲状腺炎、格雷夫病和桥本氏甲状腺炎与非甲状腺疾病综合征(NTIS)相比)与 COVID-19 风险的 OR 值分别为 0.370、0.048 和 0.021,表明 NTIS 是 COVID-19 严重程度的主要风险因素。结论 COVID-19感染与甲状腺功能障碍密切相关,而随后的AITD可能会加重COVID-19的不良预后。
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引用次数: 0
Airborne culprits: A comprehensive review of PM, silica, and TCDD in autoimmune diseases 空气中的罪魁祸首:全面回顾可吸入颗粒物、二氧化硅和 TCDD 与自身免疫性疾病的关系
IF 4.7 Q2 IMMUNOLOGY Pub Date : 2024-10-10 DOI: 10.1016/j.jtauto.2024.100253
Autoimmune diseases (ADs) are immunological disorders arising from the breakdown of immune tolerance, influenced by various internal and external factors. Persistent exposure to environmental factors, particularly air pollution, is linked to systemic inflammation, oxidative stress, and apoptosis, which contribute to the development of ADs.
This review examines the impact of air pollutants, including particulate matter, silica, and TCDD, by analyzing epidemiological studies, animal models, and in vitro assays. It focuses on how air pollution disrupts the immune system, leading to apoptosis, increased oxidative stress, cytokine production, autoantigen release, autoantibody production, and autoreactivity, which are particularly significant in ADs like rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, and systemic sclerosis. In essence, this approach aims to provide a profound understanding of how exposure to air pollution can initiate or contribute to ADs, offering potential avenues for more targeted preventive and therapeutic strategies.
自身免疫性疾病(ADs)是受各种内部和外部因素影响,因免疫耐受破坏而引起的免疫紊乱。本综述通过分析流行病学研究、动物模型和体外试验,探讨了空气污染物(包括颗粒物、二氧化硅和 TCDD)的影响。研究重点是空气污染如何扰乱免疫系统,导致细胞凋亡、氧化应激增加、细胞因子产生、自身抗原释放、自身抗体产生和自身反应性,这在类风湿性关节炎、系统性红斑狼疮、斯约格伦综合征和系统性硬化症等注意力缺失症中尤为显著。从本质上讲,这种方法旨在让人们深刻理解暴露于空气污染会如何引发或导致注意力缺失症,从而为更有针对性的预防和治疗策略提供潜在的途径。
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引用次数: 0
Extrafollicular CD19lowCXCR5−CD11c− double negative 3 (DN3) B cells are significantly associated with disease activity in females with systemic lupus erythematosus 卵泡外 CD19lowCXCR5-CD11c- 双阴性 3 (DN3) B 细胞与系统性红斑狼疮女性患者的疾病活动显著相关
IF 4.7 Q2 IMMUNOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.jtauto.2024.100252

Objective

B cells play a major role in the development and maintenance of systemic lupus erythematosus (SLE). Double negative (DN) B cells defined by the lack of surface expression of IgD and CD27 have attracted recent interest for their sensitivity to Toll-like receptor 7 (TLR7) ligands and their potential role in the production of autoantibodies. Here we aimed at investigating the possible association of DN B cells and their subsets with SLE disease activity specifically in female patients, in which TLR7 gene has been reported to escape X chromosome inactivation.

Methods

Peripheral blood mononuclear cells were purified from woman participating to the clinically well-characterized Swiss SLE Cohort Study (SSCS). PBMC from age-matched healthy females were used as controls. PBMC were stained for cell surface markers, intracellular Tbet and analyzed by multicolor cytofluorimetry. Single nucleotide TLR7 polymorphisms were assessed by polymerase chain reaction.

Results

The median SLE disease activity index of the 86 females was 2, IQR [0–6], all but 8 were under chronic SLE treatment. B cells co-expressing CD11c and Tbet were increased, the mean fluorescence intensity (MFI) of CD19 was considerably reduced and we observed a large increase in CD11c + CXCR5-and CD11c-CXCR5-concomitantly with a reduction of CD11c-CXCR5+ B cells in SLE compared to 40 healthy donors (HD). When focusing on the DN B cell subset, we found a reduction of DN1 (CD11c-CXCR5+) and an increase of DN2 (CD11c + CXCR5-) and most impressively of DN3 (CD11c-CXCR5-) cells. The DN subset, particularly DN3, showed the lowest level of CD19 expression. Both DN1 and DN3 percentages as well as the CD19 MFI of DN cells were associated with SLE disease activity. The use of glucocorticoids, immunosuppressants, and antimalarials impacted differentially on the frequencies of DN B cell subsets. CD19 MFI in B cells and the percentage of DN3 were the strongest biomarkers of disease activity. The TLR7 snp3858384 G allele was associated with increased percentages of B cells and CD19+CD11c-CXCR5+ and decreased CD19+CD11c-CXCR5-.

Conclusions

DN3 B cells are strongly associated with SLE clinical activity pointing to their potential involvement in disease pathogenesis, and CD19 expression level performs accurately as disease activity biomarker.
目的B细胞在系统性红斑狼疮(SLE)的发生和维持中起着重要作用。双阴性(DN)B细胞的定义是缺乏 IgD 和 CD27 的表面表达,它们对 Toll 样受体 7(TLR7)配体的敏感性及其在自身抗体产生中的潜在作用最近引起了人们的兴趣。在此,我们旨在研究 DN B 细胞及其亚群与系统性红斑狼疮疾病活动的可能关联,特别是在女性患者中,有报道称 TLR7 基因可逃避 X 染色体失活。方法:从参与临床特征良好的瑞士系统性红斑狼疮队列研究(SSCS)的女性患者中纯化外周血单核细胞。以年龄匹配的健康女性的外周血单核细胞为对照。对 PBMC 进行细胞表面标记物和细胞内 Tbet 染色,并用多色细胞荧光测定法进行分析。结果86名女性的系统性红斑狼疮疾病活动指数中位数为2,IQR[0-6],除8名女性外,其余女性均接受过慢性系统性红斑狼疮治疗。与 40 名健康供体(HD)相比,我们观察到系统性红斑狼疮患者 CD11c + CXCR5 和 CD11c-CXCR5 大量增加,同时 CD11c-CXCR5+ B 细胞减少。当关注 DN B 细胞亚群时,我们发现 DN1(CD11c-CXCR5+)细胞减少,DN2(CD11c + CXCR5-)细胞增加,最令人印象深刻的是 DN3(CD11c-CXCR5-)细胞。DN 亚群,尤其是 DN3,CD19 表达水平最低。DN1和DN3的百分比以及DN细胞的CD19 MFI都与系统性红斑狼疮的疾病活动有关。使用糖皮质激素、免疫抑制剂和抗疟药会对 DN B 细胞亚群的频率产生不同程度的影响。B 细胞中 CD19 MFI 和 DN3 的百分比是疾病活动性最强的生物标志物。TLR7 snp3858384 G等位基因与B细胞和CD19+CD11c-CXCR5+百分比升高和CD19+CD11c-CXCR5-百分比降低有关。
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引用次数: 0
Mitochondrial DNA copy number and the risk of autoimmune diseases: A Mendelian randomization study with meta-analysis 线粒体 DNA 拷贝数与自身免疫性疾病的风险:带有荟萃分析的孟德尔随机研究
IF 4.7 Q2 IMMUNOLOGY Pub Date : 2024-10-02 DOI: 10.1016/j.jtauto.2024.100251

Background

Mitochondrial DNA plays a crucial role in the pathophysiology of autoimmune diseases (ADs). However, the association between mitochondrial DNA copy number (mtDNA-CN) and ADs risk is controversial. In this study, Mendelian randomization (MR) analysis and meta-analysis were performed using three sets of independent instrumental variables (IVs) to investigate the potential association between mtDNA-CN and 20 types of ADs.

Methods

The three sets of IVs were drawn primarily from participants in the UK Biobank and the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium using different methods. Outcome data for ADs were investigated using summary statistics from the FinnGen cohort. The potential causal associations were assessed using inverse-variance weighting (IVW), MR-Egger, and weighted median methods. Sensitivity analysis and the Steiger test were used to verify the robustness of the MR estimates. In addition, a meta-analysis was conducted to pool the results from three IV groups.

Results

Overall, genetically predicted mtDNA-CN was not associated with ADs risk (OR = 1.046, 95 % CI: 0.964–1.135, P = 0.283). However, subgroup analyses showed positive causal associations of mtDNA-CN with autoimmune hypothyroidism (OR = 1.133, 95 % CI: 1.016–1.262, P = 0.024) and rheumatoid arthritis (OR = 1.219, 95 % CI: 1.028–1.445, P = 0.023). In contrast, there was no causal association between mtDNA-CN and atopic dermatitis as well as psoriasis, ulcerative colitis, adult-onset Still disease, type1 diabetes, Crohn disease, sarcoidosis, ankylosing spondylitis, multiple sclerosis, autoimmune hyperthyroidism, primary sclerosing cholangitis, systemic lupus erythematosus, systemic sclerosis, alopecia areata, myasthenia gravis, Guillain-Barre syndrome, dermatopolymyositis, and vitiligo.

Conclusions

This MR analysis showed mtDNA-CN is causally associated with an increased risk of autoimmune hypothyroidism and rheumatoid arthritis at the genetic level. The findings have important implications for the use of mtDNA-CN as a biomarker for risk assessment of autoimmune hypothyroidism and rheumatoid arthritis in clinical practice.
背景线粒体 DNA 在自身免疫性疾病(ADs)的病理生理学中起着至关重要的作用。然而,线粒体DNA拷贝数(mtDNA-CN)与自身免疫性疾病风险之间的关系却存在争议。本研究使用三组独立的工具变量(IV)进行了孟德尔随机化(MR)分析和荟萃分析,以研究 mtDNA-CN 与 20 种 ADs 之间的潜在关联。使用芬兰基因队列的汇总统计数据调查了AD的结果数据。使用逆方差加权(IVW)、MR-Egger 和加权中位数方法评估了潜在的因果关系。敏感性分析和 Steiger 检验用于验证 MR 估计值的稳健性。结果总体而言,基因预测的 mtDNA-CN 与 ADs 风险无关(OR = 1.046,95 % CI:0.964-1.135,P = 0.283)。然而,亚组分析显示,mtDNA-CN 与自身免疫性甲状腺功能减退症(OR = 1.133,95 % CI:1.016-1.262,P = 0.024)和类风湿性关节炎(OR = 1.219,95 % CI:1.028-1.445,P = 0.023)存在正向因果关系。相比之下,mtDNA-CN 与特应性皮炎、银屑病、溃疡性结肠炎、成人型静止病、1 型糖尿病、克罗恩病、肉样瘤病、强直性脊柱炎、多发性硬化症、自身免疫性关节炎和类风湿性关节炎(OR = 1.219,95 % CI:1.028-1.445,P = 0.023)之间没有因果关系、多发性硬化症、自身免疫性甲状腺功能亢进症、原发性硬化性胆管炎、系统性红斑狼疮、系统性硬化症、斑秃、重症肌无力、格林-巴利综合征、皮肌炎和白癜风。结论这项磁共振分析表明,mtDNA-CN 与自身免疫性甲状腺功能减退症和类风湿性关节炎的遗传风险增加有因果关系。这些发现对于在临床实践中使用 mtDNA-CN 作为自身免疫性甲状腺功能减退症和类风湿性关节炎风险评估的生物标志物具有重要意义。
{"title":"Mitochondrial DNA copy number and the risk of autoimmune diseases: A Mendelian randomization study with meta-analysis","authors":"","doi":"10.1016/j.jtauto.2024.100251","DOIUrl":"10.1016/j.jtauto.2024.100251","url":null,"abstract":"<div><h3>Background</h3><div>Mitochondrial DNA plays a crucial role in the pathophysiology of autoimmune diseases (ADs). However, the association between mitochondrial DNA copy number (mtDNA-CN) and ADs risk is controversial. In this study, Mendelian randomization (MR) analysis and meta-analysis were performed using three sets of independent instrumental variables (IVs) to investigate the potential association between mtDNA-CN and 20 types of ADs.</div></div><div><h3>Methods</h3><div>The three sets of IVs were drawn primarily from participants in the UK Biobank and the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium using different methods. Outcome data for ADs were investigated using summary statistics from the FinnGen cohort. The potential causal associations were assessed using inverse-variance weighting (IVW), MR-Egger, and weighted median methods. Sensitivity analysis and the Steiger test were used to verify the robustness of the MR estimates. In addition, a meta-analysis was conducted to pool the results from three IV groups.</div></div><div><h3>Results</h3><div>Overall, genetically predicted mtDNA-CN was not associated with ADs risk (OR = 1.046, 95 % CI: 0.964–1.135, P = 0.283). However, subgroup analyses showed positive causal associations of mtDNA-CN with autoimmune hypothyroidism (OR = 1.133, 95 % CI: 1.016–1.262, P = 0.024) and rheumatoid arthritis (OR = 1.219, 95 % CI: 1.028–1.445, P = 0.023). In contrast, there was no causal association between mtDNA-CN and atopic dermatitis as well as psoriasis, ulcerative colitis, adult-onset Still disease, type1 diabetes, Crohn disease, sarcoidosis, ankylosing spondylitis, multiple sclerosis, autoimmune hyperthyroidism, primary sclerosing cholangitis, systemic lupus erythematosus, systemic sclerosis, alopecia areata, myasthenia gravis, Guillain-Barre syndrome, dermatopolymyositis, and vitiligo.</div></div><div><h3>Conclusions</h3><div>This MR analysis showed mtDNA-CN is causally associated with an increased risk of autoimmune hypothyroidism and rheumatoid arthritis at the genetic level. The findings have important implications for the use of mtDNA-CN as a biomarker for risk assessment of autoimmune hypothyroidism and rheumatoid arthritis in clinical practice.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142427001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Vascular injury derived apoptotic exosome-like vesicles trigger autoimmunity 血管损伤衍生的凋亡外泌体样囊泡引发自身免疫
IF 4.7 Q2 IMMUNOLOGY Pub Date : 2024-08-11 DOI: 10.1016/j.jtauto.2024.100250

According to a central tenet of classical immune theory, a healthy immune system must avoid self-reactive lymphocyte clones but we now know that B cells repertoire exhibit some level of autoreactivity. These autoreactive B cells are thought to rely on self-ligands for their clonal selection and survival. Here, we confirm that healthy mice exhibit self-reactive B cell clones that can be stimulated in vitro by agonists of toll-like receptor (TLR) 1/2, TLR4, TLR7 and TLR9 to secrete anti-LG3/perlecan. LG3/perlecan is an antigen packaged in exosome-like structures released by apoptotic endothelial cells (ApoExos) upon vascular injury. We demonstrate that the injection of ApoExos in healthy animals activates the IL-23/IL-17 pro-inflammatory and autoimmune axis, and produces several autoantibodies, including anti-LG3 autoantibodies and hallmark autoantibodies found in systemic lupus erythematosus. We also identify γδT cells as key mediators of the maturation of ApoExos-induced autoantibodies in healthy mice. Altogether we show that ApoExos released by apoptotic endothelial cells display immune-mediating functions that can stimulate the B cells in the normal repertoire to produce autoantibodies. Our work also identifies TLR activation and γδT cells as important modulators of the humoral autoimmune response induced by ApoExos.

根据经典免疫理论的核心原则,健康的免疫系统必须避免自我反应性淋巴细胞克隆,但我们现在知道,B 细胞复合物表现出一定程度的自我反应性。这些自反应性 B 细胞被认为依赖于自身配体进行克隆选择和存活。在这里,我们证实了健康小鼠表现出的自反应性 B 细胞克隆可在体外受到收费样受体(TLR)1/2、TLR4、TLR7 和 TLR9 激动剂的刺激而分泌抗 LG3/perlecan。LG3/perlecan是一种抗原,在血管损伤时由凋亡的内皮细胞(ApoExos)释放的类外泌体结构中包装。我们证明,在健康动物体内注射 ApoExos 会激活 IL-23/IL-17 促炎症和自身免疫轴,并产生多种自身抗体,包括抗 LG3 自身抗体和系统性红斑狼疮中的标志性自身抗体。我们还发现γδT细胞是ApoExos诱导的自身抗体在健康小鼠体内成熟的关键介质。总之,我们的研究表明,凋亡的内皮细胞释放的 ApoExos 具有免疫介导功能,可刺激正常细胞群中的 B 细胞产生自身抗体。我们的研究还发现 TLR 激活和 γδT 细胞是 ApoExos 诱导的体液自身免疫反应的重要调节因子。
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引用次数: 0
Unlocking therapeutic potential: Targeting lymphocyte activation Gene-3 (LAG-3) with fibrinogen-like protein 1 (FGL1) in systemic lupus erythematosus 释放治疗潜力:用纤维蛋白原样蛋白 1 (FGL1) 靶向淋巴细胞活化基因-3 (LAG-3) 治疗系统性红斑狼疮
IF 4.7 Q2 IMMUNOLOGY Pub Date : 2024-07-27 DOI: 10.1016/j.jtauto.2024.100249

Systemic lupus erythematosus (SLE) represents an autoimmune disorder that affects multiple systems. In the treatment of this condition, the focus primarily revolves around inflammation suppression and immunosuppression. Consequently, targeted therapy has emerged as a prevailing approach. Currently, the quest for highly sensitive and specifically effective targets has gained significant momentum in the context of SLE treatment. Lymphocyte activation gene-3 (LAG-3) stands out as a crucial inhibitory receptor that binds to pMHC-II, thereby effectively dampening autoimmune responses. Fibrinogen-like protein 1 (FGL1) serves as the principal immunosuppressive ligand for LAG-3, and their combined action demonstrates a potent immunosuppressive effect. This intricate mechanism paves the way for potential SLE treatment by targeting LAG-3 with FGL1. This work provides a comprehensive summary of LAG-3's role in the pathogenesis of SLE and elucidates the feasibility of leveraging FGL1 as a therapeutic approach for SLE management. It introduces a novel therapeutic target and opens up new avenues of therapeutic consideration in the clinical context of SLE treatment.

系统性红斑狼疮(SLE)是一种影响多个系统的自身免疫性疾病。治疗这种疾病的重点主要是抑制炎症和免疫抑制。因此,靶向治疗已成为一种主流方法。目前,在系统性红斑狼疮的治疗中,寻找高灵敏度和特异性有效靶点的工作取得了显著的进展。淋巴细胞活化基因-3(LAG-3)是一种重要的抑制受体,它能与 pMHC-II 结合,从而有效抑制自身免疫反应。纤维蛋白原样蛋白 1(FGL1)是 LAG-3 的主要免疫抑制配体,它们的联合作用显示出强大的免疫抑制效果。这一错综复杂的机制为通过 FGL1 靶向 LAG-3 治疗系统性红斑狼疮铺平了道路。这项研究全面总结了 LAG-3 在系统性红斑狼疮发病机制中的作用,阐明了利用 FGL1 作为系统性红斑狼疮治疗方法的可行性。它引入了一个新的治疗靶点,为系统性红斑狼疮的临床治疗开辟了新的治疗途径。
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引用次数: 0
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Journal of Translational Autoimmunity
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