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
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DOI：
10.1172/jci200420479
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发表时间：
2004-08-01
影响因子：
15.9
通讯作者：
Witztum, JL
中科院分区：
文献类型：
--
作者：
Binder, CJ;Hartvigsen, K;Witztum, JL
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，如丙二醛修饰的（MDA修饰的）LDL（MDA-LDL）或氧化磷脂（OxPL）的磷酸胆碱（PC）头基。这些表位被适应性T细胞依赖性（TD）和先天性T细胞非依赖性2型（TI-2）免疫应答识别。我们先前表明，用MDA-LDL免疫小鼠诱导TD反应和动脉粥样硬化保护。此外，导致先天性B-1细胞的TI-2扩增和T15/E0 6克隆型天然IgM抗体的分泌的基于PC的免疫策略也减少了动脉粥样硬化的发生，所述T15/E0 6克隆型天然IgM抗体结合氧化LDL（OxLDL）内OxPL的PC。T15/E06抗体抑制巨噬细胞对OxLDL的摄取。我们现在报道，用不含OxPL的MDA-LDL免疫，意外地导致T15/E06抗体的扩增。MDA-LDL免疫引起MDA-LDL特异性Th 2细胞的优先扩增，其显著分泌IL-5。反过来，IL-5对先天性B-1细胞提供非同源刺激，导致T15/EO 6 IgM分泌增加。使用骨髓移植模型，我们还证明了IL-5缺乏导致T15/EO 6滴度降低和加速动脉粥样硬化。因此，IL-5将特异于OxLDL表位的适应性和天然免疫联系起来，并部分通过刺激特异于OxLDL的动脉粥样硬化保护性天然IgM的扩增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.