Binder Christoph J, Hartvigsen Karsten, Chang Mi-Kyung, Miller Marina, Broide David, Palinski Wulf, Curtiss Linda K, Corr Maripat, Witztum Joseph L
Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla 92093-0682, USA.
J Clin Invest. 2004 Aug;114(3):427-37. doi: 10.1172/JCI20479.
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.
在动脉粥样硬化形成过程中，低密度脂蛋白（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（OxPLs）的磷酸胆碱（PC）头部基团。这些表位可被适应性T细胞依赖性（TD）免疫反应和先天性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反应并具有抗动脉粥样硬化作用。此外，一种基于PC的免疫策略可导致先天性B-1细胞的TI-2扩增，并分泌T15/EO6克隆型天然IgM抗体，该抗体可结合氧化LDL（OxLDL）中的OxPLs的PC，同样可减少动脉粥样硬化的发生。T15/EO6抗体可抑制巨噬细胞摄取OxLDL。我们现在报告，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，这些细胞大量分泌白细胞介素-5（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/EO6 IgM分泌增加。使用骨髓移植模型，我们还证明IL-5缺乏导致T15/EO6滴度降低并加速动脉粥样硬化。因此，IL-5将针对OxLDL表位的适应性免疫和天然免疫联系起来，并部分通过刺激针对OxLDL的抗动脉粥样硬化天然IgM的扩增来预防动脉粥样硬化。
