Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans
Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans
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DOI：
10.1172/jci36800
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发表时间：
2009-05-01
影响因子：
15.9
通讯作者：
Binder, Christoph J.
中科院分区：
文献类型：
--
作者：
Chou, Meng-Yun;Fogelstrand, Linda;Binder, Christoph J.
动脉粥样硬化是一种以氧化脂蛋白和凋亡细胞积累为特征的慢性炎症性疾病。对各种氧化特异性表位的适应性免疫反应在动脉粥样硬化发生中起重要作用。然而，越来越多的证据表明，这些表位也被先天受体（如巨噬细胞上的清道夫受体）和血浆蛋白（如c反应蛋白（CRP））识别。在这里，我们提供了多条证据，证明氧化特异性表位在小鼠和人类中都是天然抗体（nab）的主要、以前未被识别的靶标。使用仅表达IgM抗体的重组小鼠，我们发现大约30%。所有nab结合到模型氧化特异性表位，以及动脉粥样硬化病变和凋亡细胞。由于氧化过程无处不在，我们假设这些表位施加选择性压力来扩大nab，这反过来在介导炎症和细胞死亡导致的稳态功能中发挥重要作用，正如它们促进凋亡细胞清除的能力所证明的那样。这些发现为nab在介导宿主稳态中的功能及其在健康和疾病（如慢性炎症性疾病和动脉粥样硬化）中的作用提供了新的见解。
Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of oxidized lipoproteins and apoptotic cells. Adaptive immune responses to various oxidation-specific epitopes play an important role in atherogenesis. However, accumulating evidence suggests that these epitopes are also recognized by innate receptors, such as scavenger receptors on macrophages, and plasma proteins, such as C-reactive protein (CRP). Here, we provide multiple lines of evidence that oxidation-specific epitopes constitute a dominant, previously unrecognized target of natural Abs (NAbs) in both mice and humans. Using reconstituted mice expressing solely IgM NAbs, we have shown that approximately 30%. of all NAbs bound to model oxidation-specific epitopes, as well as to atherosclerotic lesions and apoptotic cells. Because oxidative processes are ubiquitous, we hypothesized that these epitopes exert selective pressure to expand NAbs, which in turn play an important role in mediating homeostatic functions consequent to inflammation and cell death, as demonstrated by their ability to facilitate apoptotic cell clearance. These findings provide novel insights into the functions of NAbs in mediating host homeostasis and into their roles in health and diseases, such as chronic inflammatory diseases and atherosclerosis.