慢性炎症和自身免疫会导致心血管 (CV) 疾病。最近，已经鉴定出针对 CXC 基序趋化因子受体 3 (CXCR3) 的自身抗体 (aAb)，CXCR3 是一种在动脉粥样硬化中起关键作用的 G 蛋白偶联受体。抗 CXCR3 aAb 对 CV 风险和疾病的作用尚不清楚。抗 CXCR3 aAb 通过市售酶联免疫吸附测定法对基于人群的古腾堡健康研究的 5000 名参与者（可用性：97.1%）进行了量化，该研究具有广泛的临床研究表型分析。进行回归分析以确定抗 CXCR3 aAb 的决定因素以及与临床结果的相关性（即全因死亡率、心源性死亡、心力衰竭和主要不良心脏事件，包括突发冠状动脉疾病、心肌梗塞和心源性死亡）。最后，在 ApoE(-/-) 小鼠中进行 CXCR3 免疫和 aAb 被动转移以进行临床前验证。排除患有自身免疫性疾病的个体后，分析样本包括 4195 名个体（48% 女性，平均年龄 55.5 ± 11 岁），免疫调节药物、急性感染和癌症病史。与年龄、性别、肾功能和传统心血管危险因素无关，抗 CXCR3 aAb 浓度的增加会转化为更高的内膜中层厚度、左心室质量和 N 末端 B 型利钠肽前体。根据年龄和性别进行调整后，高于 75% 的抗 CXCR3 aAb 可预测全因死亡[风险比 (HR)（95% 置信区间）1.25 (1.02, 1.52)，P = .029]，这是由过高的心脏死亡率驱动的[ HR 2.51 (1.21, 5.22)，P = .014]。主要不良心脏事件风险较高的趋势 [HR 1.42 (1.0, 2.0), P = .05]，同时心力衰竭事件风险增加 [抗 CXCR3 aAb 的每标准差增加的 HR：1.26 (1.02, 1.56) ), P = .03] 可能有助于这一观察。靶向蛋白质组学揭示了抗 CXCR3 aAb 的分子特征，反映了与正在进行的 T 辅助细胞 1 反应相关的免疫细胞激活和细胞因子-细胞因子受体相互作用。最后，与未免疫对照相比，针对 CXCR3 免疫的 ApoE(-/-) 小鼠表现出抗 CXCR3 aAb 增加，并表现出更高的动脉粥样硬化负担，这与被动转移模型中抗 CXCR3 aAb 的浓度相关。自身免疫性疾病中，抗 CXCR3 aAb 丰富，与 CV 终末器官损伤相关，并可预测全因死亡以及心脏发病率和死亡率以及实验性动脉粥样硬化的加速。© 作者 2023。出版者牛津大学出版社代表欧洲心脏病学会。

Chronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear.Anti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in 5000 participants (availability: 97.1%) of the population-based Gutenberg Health Study with extensive clinical phenotyping. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcome (i.e. all-cause mortality, cardiac death, heart failure, and major adverse cardiac events comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE(-/-) mice for preclinical validation.The analysis sample included 4195 individuals (48% female, mean age 55.5 ± 11 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional CV risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima-media thickness, left ventricular mass, and N-terminal pro-B-type natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) (95% confidence interval) 1.25 (1.02, 1.52), P = .029], driven by excess cardiac mortality [HR 2.51 (1.21, 5.22), P = .014]. A trend towards a higher risk for major adverse cardiac events [HR 1.42 (1.0, 2.0), P = .05] along with increased risk of incident heart failure [HR per standard deviation increase of anti-CXCR3 aAbs: 1.26 (1.02, 1.56), P = .03] may contribute to this observation. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine-cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE(-/-) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared to non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model.In individuals free of autoimmune disease, anti-CXCR3 aAbs were abundant, related to CV end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis.© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.