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.
View: Text | PDF
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

×

Figure 4

Options: View larger image (or click on image) Download as PowerPoint
Increased levels of IL-5 and EO6 in the plasma of cholesterol-fed LDLR–/...
Increased levels of IL-5 and EO6 in the plasma of cholesterol-fed LDLR–/– mice immunized with MDA-LDL. At time of death, plasma was obtained from mice immunized with MDA-LDL (n = 10) and PBS (n = 11). (A) IL-5 levels in plasma of MDA-LDL immunized mice are increased. (B) EO6 antibody levels in plasma of MDA-LDL–immunized mice are increased. The amount of EO6 present was determined using an ELISA based capture assay with anti–idiotypic AB1-2 as described in Methods and was calculated based on an EO6 standard curve. (C) Comparison of T15/EO6 antibody titers in LDLR–/– mice immunized with MDA-LDL (current study) versus mice immunized with S. pneumoniae (R36a; n = 9) from a previous study (12). EO6 antibody titers were determined at a plasma dilution of 1:500 in the same assay. Purified EO6 was used as a positive control. Biot., biotinylated. (D) Circulating IgM/apoB ICs are increased in MDA-LDL–immunized mice. Results are expressed as IgM/apoB. All bars represent the mean ± SEM values of all mice from each intervention group.