Interaction of antibodies against cytomegalovirus with heat-shock protein 60 in pathogenesis of atherosclerosis
Interaction of antibodies against cytomegalovirus with heat-shock protein 60 in pathogenesis of atherosclerosis
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DOI：
10.1016/s0140-6736(03)15016-7
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发表时间：
2003-12-13
期刊：
影响因子：
168.9
通讯作者：
Puccetti, A
中科院分区：
文献类型：
--
作者：
Bason, C;Corrocher, R;Puccetti, A
背景 感染和自身免疫与动脉粥样硬化的发病机制有关。巨细胞病毒已被证明与该疾病有关。大多数动脉粥样硬化患者体内都存在针对人热休克蛋白 (HSP) 60 的自身抗体，其滴度与疾病严重程度相关，表明抗 HSP60 可能与疾病发病机制有关。我们推测巨细胞病毒感染可能会诱导产生能够结合人类 HSP60 的抗体并导致内皮细胞损伤。 方法 我们研究了 180 名冠状动脉疾病患者，提高了高灵敏度 C 反应蛋白浓度，以及是否存在传统危险因素； 90例冠心病患者，超敏C反应蛋白正常值，无传统危险因素；和 98 个控件。使用个体血清通过 ELISA 确定 HSP60 的相关表位。亲和纯化的 IgG 用于通过蛋白质印迹鉴定内皮细胞表面配体并诱导细胞凋亡。结果我们鉴定了大多数冠状动脉疾病患者所识别的 HSP60 的 11 个氨基酸序列。该肽与巨细胞病毒衍生蛋白 UL122 和 US28 具有同源性。同一患者的血清识别出 UL122 衍生的肽和 US28 衍生的肽。针对 HSP60 的纯化 IgG 和病毒肽与非应激的人内皮细胞结合，并通过与细胞表面分子相互作用诱导内皮细胞凋亡。 解释 在巨细胞病毒感染期间，可能会产生抗病毒抗体，能够与人 HSP60 交叉反应并导致非应激内皮细胞凋亡，这被认为是动脉粥样硬化发病过程中的主要事件。
Background Infections and autoimmunity have been implicated in the pathogenesis of atherosclerosis. Cytomegalovirus has been shown to contribute to the disease. Autoantibodies against human heat-shock protein (HSP) 60 are present in most atherosclerotic patients, and their titre correlates with disease severity, suggesting that anti-HSP60 might be implicated in disease pathogenesis. We postulated that cytomegalovirus infection might induce antibodies able to bind human HSP60 and to cause endothelial-cell damage.Methods We studied 180 patients with coronary-artery disease, raised high sensitivity C-reactive protein concentrations, and presence or absence of traditional risk factors; 90 patients with coronary-artery disease, normal values for high sensitivity C-reactive protein, and no traditional risk factors; and 98 controls. Individual sera were used to define the relevant epitope of HSP60 by ELISA. Affinity purified IgGs were used to identify endothelial cell-surface ligands by western blot and to induce apoptotic cell death.Findings We identified an 11 aminoacid sequence of HSP60 that was recognised by most patients with coronary-artery disease. This peptide shares homology with cytomegalovirus-derived proteins UL122 and US28. The same patients' sera recognised UL122-derived and US28-derived peptides. Purified IgGs against HSP60 and the viral peptides bound non-stressed human endothelial cells and induced endothelial-cell apoptosis by interaction with cell-surface molecules.Interpretation During cytomegalovirus infection, antibodies against the virus can arise that are able to crossreact with human HSP60 and cause apoptosis of non-stressed endothelial cells, which is judged a primary event in the pathogenosis of atherosclerosis.