Secrete Atheroprotective IgM and Attenuate Atherosclerosis

Rationale: B cells contribute to atherosclerosis through subset specific mechanisms. Whereas some controversy exists about the role of B-2 cells, B-1a cells are atheroprotective due to secretion of atheroprotective IgM antibodies independent of antigen. B-1b cells, a unique subset of B-1 cells that respond specifically to T cell-independent antigens, have not been studied within the context of atherosclerosis. Objective: To determine whether B-1b cells produce atheroprotective IgM antibodies and function to protect against diet induced atherosclerosis. Methods and Results: We demonstrate that B-1b cells are sufficient to produce IgM antibodies against oxidation specific epitopes (OSE) on LDL both in vitro and in vivo. Additionally, we demonstrate that B1b cells provide atheroprotection after adoptive transfer into B and T cell deficient (Rag1-/-Apoe-/-) hosts. We implicate Id3 in the regulation of B-1b cells as B cell-specific Id3 knockout mice (Id3BKOApoe-/-) have increased numbers of B-1b cells systemically, increased titers of OSE-reactive IgM antibodies, and significantly reduced diet-induced atherosclerosis compared to Id3WTApoe-/controls. Finally, we report that the presence of a homozygous SNP in ID3 in humans that attenuates Id3 function is associated with an increased percentage of circulating B-1 cells and anti-MDA-LDL IgM suggesting clinical relevance. Conclusions: These results provide novel evidence that B-1b cells produce atheroprotective OSE-reactive IgM antibodies and protect against atherosclerosis in mice, and suggest that similar mechanisms may occur in humans.