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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 114 Issue 3 Pg. 427-37 (Aug 2004) ISSN: 0021-9738 [Print] United States
• PMID: 15286809 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Epitopes
• Immunoglobulin M
• Interleukin-5
• Lipoproteins, LDL
• oxidized low density lipoprotein
• Malondialdehyde

Topics

• Animals
• Antibody Formation
• Arteriosclerosis (prevention & control)
• Bone Marrow Transplantation
• Disease Models, Animal
• Epitopes (immunology)
• Female
• Immunity, Innate
• Immunoglobulin M (metabolism)
• Interleukin-5 (deficiency, genetics, metabolism)
• Lipoproteins, LDL (drug effects, immunology, metabolism)
• Malondialdehyde (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Th2 Cells (immunology)