Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques
Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques
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DOI：
10.4049/jimmunol.174.10.6509
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发表时间：
2005-05-15
影响因子：
4.4
通讯作者：
Del Prete, G
中科院分区：
文献类型：
--
作者：
Benagiano, M;D'Elios, MM;Del Prete, G
流行病学研究表明炎症成分在动脉粥样硬化中具有潜在的重要性，并支持这样的假设：由于分子拟态，对病原体抗原的免疫反应与同源宿主蛋白发生交叉反应。所涉及的候选蛋白质可能是应激诱导的蛋白质，称为热休克蛋白（HSP）。在这项研究中，我们报告动脉粥样硬化斑块含有体内激活的 CD4(+) T 细胞，可识别人类 60-kDa HSP。在外周血中检测不到这种体内激活的 60 kDa HSP 特异性 T 细胞。在肺炎衣原体 DNA 血清学和 PCR 呈阳性的患者中，但在两者均为阴性的患者中，大多数针对人 60-kDa HSP 的噬菌斑衍生 T 细胞也能识别肺炎衣原体 60-kDa HSP。我们表征了这种 60 kDa HSP 特异性斑块衍生 T 细胞的亚分子特异性，并鉴定了该自身抗原的自身反应表位和交叉反应表位。在用人 60-kDa HSP 攻击时，大多数斑块衍生的 T 细胞表达 Th 1 型功能，包括细胞毒性和帮助单核细胞组织因子产生。我们认为，经历经典动脉粥样硬化危险因素并受到 Th 1 型细胞因子调节的动脉内皮细胞表达自身 60-kDa HSP，通过分子拟态机制成为自身反应性 T 细胞和与微生物 60-kDa HSP 交叉反应性 T 细胞的靶标。这一假说与 HSP 免疫会加剧动脉粥样硬化的观点一致，而免疫抑制和 T 细胞耗竭则可防止实验动物动脉粥样硬化病变的形成。
Epidemiological studies suggest the potential importance of an inflammatory component in atherosclerosis and support the hypothesis that immune responses to Ags of pathogens cross-react with homologous host proteins due to molecular mimicry. Protein candidates involved may be the stress-induced proteins known as heat shock proteins (HSP). In this study, we report that atherosclerotic plaques harbor in vivo-activated CD4(+) T cells that recognize the human 60-kDa HSP. Such in vivo-activated 60-kDa HSP-specific T cells are not detectable in the peripheral blood. In patients with positive serology and PCR for Chlamydia pneumoniae DNA, but not in patients negative for both, most of plaque-derived T cells specific for human 60-kDa HSP also recognized the C. pneumoniae 60-kDa HSP. We characterized the submolecular specificity of such 60-kDa HSP-specific plaque-derived T cells and identified both the self- and cross-reactive epitopes of that autoantigen. On challenge with human 60-kDa HSP, most of the plaque-derived T cells expressed Th type 1 functions, including cytotoxicity and help for monocyte tissue factor production. We suggest that arterial endothelial cells, undergoing classical atherosclerosis risk factors and conditioned by Th type 1 cytokines, express self 60-kDa HSP, which becomes target for both autoreactive T cells and cross-reactive T cells to microbial 60-kDa HSP via a mechanism of molecular mimicry. This hypothesis is in agreement with the notion that immunization with HSP exacerbates atherosclerosis, whereas immunosuppression and T cell depletion prevent the formation of arteriosclerotic lesions in experimental animals.