Shaw Peter X
University of California, San Diego, La Jolla, CA 92093, USA.
Arch Immunol Ther Exp (Warsz). 2004 Jul-Aug;52(4):225-39.
Atherosclerosis is a chronic inflammatory disease, resulting from hyperlipidemia and a complex interplay of many environmental, metabolic, and genetic risk factors. The unregulated macrophage uptake of cholesterol and lipids through modified forms of low-density lipoprotein (LDL), such as "OxLDL", transforms macrophages into "foam cells" to form the initial morphological lesion (the fatty streak). The modification of LDL not only enhances its uptake by macrophages, but also changes the natural structures of these otherwise ubiquitous molecules to generate a variety of modified lipids and proteins that represent highly immunogenic neo-determinants. For example, in ApoE-/- mice, autoantibody titers to epitopes on OxLDL are correlated with the extent of atherosclerosis. Similarly, oxidative stress on cellular membranes could also give rise to "oxidation-specific" epitopes and common autoantibodies. However, OxLDL is not uniform, but rather contains complex structures, ranging from a small conformational change in surface lipids to the breakdown of the peptide chain. Therefore, the immune responses to the variety of OxLDL and their association to atherosclerosis progression are very different. For example, phosphorylcholine (PC) is a natural component of phospholipids and exists in LDL and plasma membranes. "Natural" antibodies against PC can distinctively react to PC on bacteria, OxLDL and apoptotic cells, but not to those on unoxidized phospholipids, native LDL and viable cells, which suggests the broader role of such autoantibodies in maintaining the homeostasis of the host. While malondialdehyde-modified structures resemble more the exogenous changes and associate with advanced stage of lesion, they are more likely to associate with adaptive immunity.
动脉粥样硬化是一种慢性炎症性疾病，由高脂血症以及许多环境、代谢和遗传风险因素的复杂相互作用引起。巨噬细胞通过修饰形式的低密度脂蛋白（LDL），如“氧化型低密度脂蛋白（OxLDL）”，无节制地摄取胆固醇和脂质，将巨噬细胞转化为“泡沫细胞”，形成初始形态病变（脂肪条纹）。LDL的修饰不仅增强了巨噬细胞对其的摄取，还改变了这些原本普遍存在的分子的天然结构，产生了多种修饰脂质和蛋白质，这些代表了高度免疫原性的新抗原决定簇。例如，在载脂蛋白E基因敲除（ApoE-/-）小鼠中，针对OxLDL表位的自身抗体滴度与动脉粥样硬化的程度相关。同样，细胞膜上的氧化应激也可能产生“氧化特异性”表位和常见自身抗体。然而，OxLDL并非均匀一致，而是包含复杂结构，范围从表面脂质的微小构象变化到肽链的断裂。因此，针对各种OxLDL的免疫反应及其与动脉粥样硬化进展的关联差异很大。例如，磷酸胆碱（PC）是磷脂的天然成分，存在于LDL和质膜中。针对PC的“天然”抗体可特异性地与细菌、OxLDL和凋亡细胞上的PC发生反应，但不与未氧化磷脂、天然LDL和活细胞上的PC发生反应，这表明此类自身抗体在维持宿主内环境稳态方面具有更广泛的作用。虽然丙二醛修饰的结构更类似于外源性变化，并与病变的晚期相关，但它们更可能与适应性免疫相关。
