IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis.
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.
Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla 92093-0682, USA.
Christoph J
CJ
Binder
Karsten
K
Hartvigsen
Mi-Kyung
MK
Chang
Marina
M
Miller
David
D
Broide
Wulf
W
Palinski
Linda K
LK
Curtiss
Maripat
M
Corr
Joseph L
JL
Witztum
D000818:Animals; D000917:Antibody Formation; D001161:Arteriosclerosis / Q000517:prevention & control*; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology*; D005260:Female; D007113:Immunity, Innate; D007075:Immunoglobulin M / Q000378:metabolism; D015848:Interleukin-5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008315:Malondialdehyde / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018418:Th2 Cells / Q000276:immunology
D000939:Epitopes; D007075:Immunoglobulin M; D015848:Interleukin-5; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D008315:Malondialdehyde