From the Rheumatology Service (N.B., C.P.-S., P.R.-L., C.C.-V., M.A.A., R.C., Y.J.-G., M.S., A.R.-A., E.C.-E., A.E., C.L.-P.) and Radiology Service (P.S.), Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia University Hospital, Cordoba, Spain; and Department of Biomedical Sciences and Centre of Excellence for Biotechnology, Development and Biodiversity Research, University of Sassari, Italy (M.S.).
Arterioscler Thromb Vasc Biol. 2014 Dec;34(12):2706-16. doi: 10.1161/ATVBAHA.114.304475. Epub 2014 Sep 25.
Previous studies have suggested a relationship between anticyclic citrullinated protein (CCP) levels and development of cardiovascular disease in rheumatoid arthritis (RA). However, a limited number of studies have demonstrated an involvement of anti-CCPs in those processes. This study was aimed to define the specific role of these auto-antibodies in the pro-oxidative, inflammatory, and proatherogenic profile observed in leukocytes from RA patients.
Seventy-five RA patients and 31 healthy donors were enrolled. Carotid intima media thickness was evaluated as atherosclerosis marker. Several procoagulant and inflammatory factors, leukocyte activation, and oxidative stress markers were analyzed in plasma and leukocyte subsets. Anti-CCPs were purified from plasma of RA patients, and in vitro treatment of healthy leukocytes was conducted. High titers of anti-CCPs were associated to altered expression of prothrombotic and inflammatory markers, high oxidative stress, and pathological carotid intima media thickness in RA patients. Notably, gene expression analysis showed that lymphocytes were major players in altered inflammatory profile, monocytes were responsible for the protrombotic and atherogenic status, and neutrophils mainly displayed a pro-oxidative feature. In vitro treatment with purified anti-CCPs fully recapitulated that pathogenic profile, promoting the activation of leukocytes.
Anti-CCPs are key players in the inflammatory and proatherogenic status of RA patients. The effects are specific of the immune cell targeted, promoting overexpression of thrombotic, inflammatory, and pro-oxidative markers in monocytes; pro-oxidative status in neutrophils; and proinflammatory profile in lymphocytes. Targeting these autoantibodies would be an excellent strategy to prevent the development of cardiovascular disease in RA.
先前的研究表明，抗环瓜氨酸肽（CCP）水平与类风湿关节炎（RA）患者心血管疾病的发展之间存在关联。然而，有限数量的研究表明抗 CCPs 参与了这些过程。本研究旨在确定这些自身抗体在 RA 患者白细胞中观察到的促氧化、炎症和促动脉粥样硬化特征中的具体作用。
共纳入 75 例 RA 患者和 31 名健康对照者。颈动脉内膜中层厚度被评估为动脉粥样硬化标志物。分析了血浆和白细胞亚群中的几种促凝和炎症因子、白细胞活化和氧化应激标志物。从 RA 患者的血浆中纯化出抗 CCPs，并对健康白细胞进行体外处理。高滴度的抗 CCPs 与 RA 患者的促血栓形成和炎症标志物表达改变、高氧化应激和病理性颈动脉内膜中层厚度相关。值得注意的是，基因表达分析显示，淋巴细胞是改变炎症谱的主要参与者，单核细胞负责促血栓形成和动脉粥样硬化状态，而中性粒细胞主要表现出促氧化特征。体外用纯化的抗 CCPs 处理可完全再现该致病谱，促进白细胞的激活。
抗 CCPs 是 RA 患者炎症和促动脉粥样硬化状态的关键因素。这些作用是针对免疫细胞特异性的，促进单核细胞中血栓形成、炎症和促氧化标志物的过度表达；中性粒细胞中的促氧化状态；以及淋巴细胞中的促炎谱。靶向这些自身抗体将是预防 RA 患者心血管疾病发展的理想策略。
