IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis
Christoph J. Binder, … , Maripat Corr, Joseph L. Witztum
Christoph J. Binder, … , Maripat Corr, Joseph L. Witztum
Published August 1, 2004
Citation Information: J Clin Invest. 2004;114(3):427-437. https://doi.org/10.1172/JCI20479.
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Article Cardiology

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

Abstract

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.

Authors

Christoph J. Binder, Karsten Hartvigsen, Mi-Kyung Chang, Marina Miller, David Broide, Wulf Palinski, Linda K. Curtiss, Maripat Corr, Joseph L. Witztum

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Decreased atherosclerosis and dominant Th2 response in immunized LDLR–/–...
Decreased atherosclerosis and dominant Th2 response in immunized LDLR–/– mice. Mice were immunized with homologous MDA-LDL (n = 10) or PBS (n = 11) in Freund’s adjuvant, and then fed a high-cholesterol diet for 13 weeks, during which they received further booster immunizations. (A) Lipoprotein profiles at time of death in pooled plasma of all mice immunized with MDA-LDL (filled circles) or PBS (open circles) as determined by FPLC. (B) Decreased atherosclerotic lesion size in cross-sections through the aortic origin in mice immunized with MDA-LDL. Values are mean ± SEM in mm2/section. (C and D) Plasma IgG1 (filled circles) and IgG2a (open circles) dilution curves of binding to MDA-LDL of mice immunized with (C) MDA-LDL or (D) PBS. Values are the mean ± SEM of all final plasma samples for each group measured in duplicate. (E and F) ELISpot assay of frequencies of MDA-LDL–specific cytokine-secreting cells in the spleens of mice immunized with (E) MDA-LDL or (F) PBS. Splenocytes were incubated overnight in the absence or presence of murine MDA-LDL with and without anti-CD28, and the frequencies of MDA-LDL–specific IFN-γ (white bars) or IL-5 (black bars) SFCs were assessed. Bars represent the mean SFCs ± SEM of 2 × 106 cells of all mice for each group. P < 0.01, Student’s paired t test.