Gounopoulos P, Merki E, Hansen L F, Choi S-H, Tsimikas S
Division of Cardiovascular Diseases, University of California, San Diego, San Diego, La Jolla, CA 92093-0682, USA.
Minerva Cardioangiol. 2007 Dec;55(6):821-37.
The pathogenesis of atherosclerosis is mediated by genetic susceptibility along with a variety of cardiovascular risk factors and environment influences. As atherosclerotic lesions progress, they manifest several features typical of chronic inflammation, such as the presence of monocyte/macrophages, T-cells and inflammatory cytokines. This inflammatory response is fueled and enhanced by oxidative stress, which may be the link between lipid disorders and inflammation. Oxidation of lipoproteins is intimately involved in all stages of atherosclerosis and oxidative byproducts co-localize with inflammatory cells. When low density lipoprotein enters the subintimal space, it is oxidized by several mechanisms, including both enzymatic and non-enzymatic pathways and becomes a ligand for scavenger receptors on macrophages leading to generation of foam cells. Oxidized LDL is not only pro-inflammatory and pro-atherogenic, but several of the neoepitopes generated during oxidation are highly immunogenic and result in the generation of autoantibodies. Autoantibodies to OxLDL are found within atherosclerotic lesions and in apparently healthy subjects, as well as patients with various manifestations of cardiovascular disease. In this article, the role of circulating autoantibodies to OxLDL in cardiovascular disease will be reviewed. Although controversy still exists, the overall evidence supports the notion that IgG autoantibodies to OxLDL are associated with pro-atherogenic properties and IgM autoantibodies to OxLDL with atheroprotective properties. Whether such antibodies have a modulating role or are merely reflectors of atherogenesis has not been fully determined. Data is also emerging on the role of natural antibodies, which are primarily of the IgM class, that recognize oxidation-specific epitopes. Among other properties, these antibodies may be involved in housekeeping functions in binding and clearing pro-inflammatory oxidized lipids and therefore may be atheroprotective. Several studies have also recently evaluated the potential therapeutic role of antibodies to OxLDL either through active immunization using OxLDL or model oxidation-specific epitopes as immunogens or through passive immunization with human antibodies directed to oxidation-specific epitopes. Although these investigation are at an early stage, they show promise that immune modulation may lead to novel approaches to treat atherosclerosis and cardiovascular disease.
动脉粥样硬化的发病机制由遗传易感性以及多种心血管危险因素和环境影响共同介导。随着动脉粥样硬化病变的进展，它们表现出几种慢性炎症的典型特征，如单核细胞/巨噬细胞、T细胞和炎性细胞因子的存在。氧化应激加剧并增强了这种炎症反应，氧化应激可能是脂质紊乱与炎症之间的联系。脂蛋白的氧化与动脉粥样硬化的各个阶段密切相关，氧化副产物与炎症细胞共定位。当低密度脂蛋白进入内膜下空间时，它通过多种机制被氧化，包括酶促和非酶促途径，并成为巨噬细胞上清道夫受体的配体，导致泡沫细胞的产生。氧化型低密度脂蛋白不仅具有促炎和促动脉粥样硬化作用，而且氧化过程中产生的几种新表位具有高度免疫原性，可导致自身抗体的产生。在动脉粥样硬化病变内以及明显健康的受试者以及患有各种心血管疾病表现的患者中都发现了抗氧化型低密度脂蛋白自身抗体。在本文中，将综述循环抗氧化型低密度脂蛋白自身抗体在心血管疾病中的作用。尽管仍存在争议，但总体证据支持这样的观点，即抗氧化型低密度脂蛋白IgG自身抗体与促动脉粥样硬化特性相关，而抗氧化型低密度脂蛋白IgM自身抗体具有抗动脉粥样硬化特性。这些抗体是具有调节作用还是仅仅是动脉粥样硬化发生的反映尚未完全确定。关于天然抗体（主要是IgM类）识别氧化特异性表位的作用的数据也在不断涌现。除其他特性外，这些抗体可能参与结合和清除促炎氧化脂质的管家功能，因此可能具有抗动脉粥样硬化作用。最近也有几项研究评估了抗氧化型低密度脂蛋白抗体的潜在治疗作用，要么通过使用氧化型低密度脂蛋白或模型氧化特异性表位作为免疫原进行主动免疫，要么通过用针对氧化特异性表位的人抗体进行被动免疫。尽管这些研究尚处于早期阶段，但它们显示出免疫调节可能会带来治疗动脉粥样硬化和心血管疾病新方法的前景。
