IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis

被引:351
作者
Binder, CJ
Hartvigsen, K
Chang, MK
Miller, M
Broide, D
Palinski, W
Curtiss, LK
Corr, M
Witztum, JL
机构
[1] Univ Calif San Diego, Dept Med, Div Endocrinol & Metab, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Dept Med, Div Rheumatol Allergy & Immunol, La Jolla, CA 92093 USA
[3] Scripps Res Inst, Dept Immunol, La Jolla, CA USA
关键词
D O I
10.1172/jci200420479
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
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页码:427 / 437
页数:11
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