IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis.
IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis.
复制标题
DOI：
10.1172/jci20479
复制
发表时间：
2004-08
期刊：
影响因子：
--
通讯作者：
C. Binder;K. Hartvigsen;Mi-Kyung Chang;Marina Miller;D. Broide;W. Palinski;L. Curtiss;M. Corr;J. Witztum
中科院分区：
文献类型：
--
作者：
C. Binder;K. Hartvigsen;Mi-Kyung Chang;Marina Miller;D. Broide;W. Palinski;L. Curtiss;M. Corr;J. Witztum
在动脉粥样硬化形成过程中，LDL 被氧化，产生各种氧化特异性新表位，例如丙二醛修饰（MDA 修饰）LDL (MDA-LDL) 或氧化磷脂 (OxPL) 的磷酸胆碱 (PC) 头基。这些表位可被适应性 T 细胞依赖性 (TD) 和先天性 T 细胞非依赖性 2 型 (TI-2) 免疫反应识别。我们之前表明，用 MDA-LDL 免疫小鼠可诱导 TD 反应和动脉粥样硬化保护。此外，基于 PC 的免疫策略可导致先天 B-1 细胞的 TI-2 扩增和 T15/EO6 克隆型天然 IgM 抗体的分泌，这些抗体与氧化 LDL (OxLDL) 内的 OxPL 的 PC 结合，也可减少动脉粥样硬化形成。 T15/EO6 抗体抑制巨噬细胞摄取 OxLDL。我们现在报道，使用不含 OxPL 的 MDA-LDL 免疫意外地导致了 T15/EO6 抗体的扩增。 MDA-LDL 免疫导致 MDA-LDL 特异性 Th2 细胞优先扩增，这些细胞显着分泌 IL-5。反过来，IL-5 为先天 B-1 细胞提供非同源刺激，导致 T15/EO6 IgM 分泌增加。使用骨髓移植模型，我们还证明 IL-5 缺乏会导致 T15/EO6 滴度降低并加速动脉粥样硬化。因此，IL-5 将 OxLDL 表位特异性的适应性免疫和天然免疫联系起来，并通过刺激 OxLDL 特异性的动脉粥样硬化天然 IgM 的扩张来防止动脉粥样硬化。
During atherogenesis, LDL is oxidized, generating various oxidation-specific neoepitopes, such as malondialdehyde-modified (MDA-modified) LDL (MDA-LDL) or the phosphorylcholine (PC) headgroup of oxidized phospholipids (OxPLs). These epitopes are recognized by both adaptive T cell-dependent (TD) and innate T cell-independent type 2 (TI-2) immune responses. We previously showed that immunization of mice with MDA-LDL induces a TD response and atheroprotection. In addition, a PC-based immunization strategy that leads to a TI-2 expansion of innate B-1 cells and secretion of T15/EO6 clonotype natural IgM antibodies, which bind the PC of OxPLs within oxidized LDL (OxLDL), also reduces atherogenesis. T15/EO6 antibodies inhibit OxLDL uptake by macrophages. We now report that immunization with MDA-LDL, which does not contain OxPL, unexpectedly led to the expansion of T15/EO6 antibodies. MDA-LDL immunization caused a preferential expansion of MDA-LDL-specific Th2 cells that prominently secreted IL-5. In turn, IL-5 provided noncognate stimulation to innate B-1 cells, leading to increased secretion of T15/EO6 IgM. Using a bone marrow transplant model, we also demonstrated that IL-5 deficiency led to decreased titers of T15/EO6 and accelerated atherosclerosis. Thus, IL-5 links adaptive and natural immunity specific to epitopes of OxLDL and protects from atherosclerosis, in part by stimulating the expansion of atheroprotective natural IgM specific for OxLDL.