Rheumatology Service (A.M.P.-T., C.P.-S., L.P.-S., M.L.-T., M.C.A.-A., L.A.-R., I.A.-d.l.R., C.R.-R., P.F., N.B., A.E.-C., E.C.-E., M.Á.A.-Z., C.L.-P.), Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Cordoba/University of Cordoba, Spain.
Deparment of Cell Biology, Immunology and Physiology, University of Córdoba, Campus de Excelencia Internacional Agroalimentario ceiA3, Spain (C.P.-S., J.A.G.-R., J.M.V.).
Arterioscler Thromb Vasc Biol. 2021 Sep;41(9):2417-2430. doi: 10.1161/ATVBAHA.121.315928. Epub 2021 Jul 29.
Systemic lupus erythematosus (SLE) is associated to boosted atherosclerosis development and a higher cardiovascular disease risk. This study aimed to delineate the role of anti-double stranded DNA (anti-dsDNA) antibodies on the molecular profile and the activity of immune and vascular cells, as well as on their enhanced cardiovascular risk.
Eighty SLE patients were included. Extensive clinical/analytical evaluation was performed, including cardiovascular disease parameters (endothelial function, proatherogenic dyslipidemia, and carotid intima-media thickness). Gene and protein expression profiles were evaluated in monocytes from patients diagnosed positive or negative for anti-dsDNA antibodies by using NanoString and cytokine arrays, respectively. NETosis and circulating inflammatory profile was assessed in both neutrophils and plasma. Positivity and persistence of anti-dsDNA antibodies in SLE patients were associated to endothelial dysfunction, proatherogenic dyslipidemia, and accelerated atherosclerosis. In parallel, anti-dsDNA antibodies were linked to the aberrant activation of innate immune cells, so that anti-dsDNA(+) SLE monocytes showed distinctive gene and protein expression/activity profiles, and neutrophils were more prone to suffer NETosis in comparison with anti-dsDNA(−) patients. Anti-dsDNA(+) patients further displayed altered levels of numerous circulating mediators related to inflammation, NETosis, and cardiovascular risk. In vitro, Ig-dsDNA promoted NETosis on neutrophils, apoptosis on monocytes, modulated the expression of inflammation and thrombosis-related molecules, and induced endothelial activation, at least partially, by FcR (Fc receptor)-binding mechanisms.
Anti-dsDNA antibodies increase the cardiovascular risk of SLE patients by altering key molecular processes that drive a distinctive and coordinated immune and vascular activation, representing a potential tool in the management of this comorbidity.
系统性红斑狼疮（SLE）与动脉粥样硬化发展加速和心血管疾病风险增加有关。本研究旨在阐明抗双链 DNA（anti-dsDNA）抗体在免疫和血管细胞的分子谱、活性及其增强的心血管风险中的作用。
纳入 80 例 SLE 患者。进行了广泛的临床/分析评估，包括心血管疾病参数（内皮功能、致动脉粥样硬化性血脂异常和颈动脉内膜中层厚度）。通过 NanoString 和细胞因子阵列分别评估抗 dsDNA 抗体阳性和阴性患者单核细胞的基因和蛋白质表达谱。在中性粒细胞和血浆中评估 NETosis 和循环炎症谱。SLE 患者抗 dsDNA 抗体的阳性和持续存在与内皮功能障碍、致动脉粥样硬化性血脂异常和动脉粥样硬化加速有关。与此同时，抗 dsDNA 抗体与固有免疫细胞的异常激活有关，因此抗 dsDNA（+）SLE 单核细胞表现出独特的基因和蛋白质表达/活性谱，与抗 dsDNA（−）患者相比，中性粒细胞更容易发生 NETosis。抗 dsDNA（+）患者进一步显示与炎症、NETosis 和心血管风险相关的众多循环介质的水平发生改变。在体外，Ig-dsDNA 通过 Fc 受体（FcR）结合机制促进中性粒细胞的 NETosis、单核细胞的凋亡、调节炎症和血栓形成相关分子的表达，并诱导内皮细胞激活。
抗 dsDNA 抗体通过改变驱动独特和协调的免疫和血管激活的关键分子过程，增加 SLE 患者的心血管风险，这代表了管理这种合并症的潜在工具。
