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Abstract 21: B-1b Cells Secrete Atheroprotective IgM and Attenuate Atherosclerosis

S. Morris-Rosenfeld,H. Perry,P. Srikakulapu,Chantel C. McSkimming,A. Gonen,T. Prohaska,S. Tsimikas,J. Witztum,T. Bender,Angela M Taylor,C. McNamara

Published 2015 in Arteriosclerosis, Thrombosis and Vascular Biology

ABSTRACT

Rationale: B cells contribute to atherosclerosis through subset specific mechanisms. Whereas some controversy exists about the role of B-2 B cells, B-1a B cells are atheroprotective. The function of B-1b B cells, a unique subset of B-1 cells that can produce T cell-independent (TI) memory, has 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 in vitro in response to activating stimulation. Additionally, we demonstrate that B-1b cells provide direct atheroprotection after adoptive transfer into B and T cell deficient (Rag1-/-Apoe-/-) hosts. To support these findings, we utilize a B cell specific Id3 knockout mouse model (Id3BKO), which develops increased numbers of B-1b cells systemically, to demonstrate that these mice develop attenuated atherosclerosis and increased OSE IgM antibodies compared to wild-type controls (Id3WT) after being fed a Western diet for 16 weeks. Finally, we report that the presence of a functionally relevant homozygous SNP in ID3 in humans associates with increased proportion of circulating B-1 cells and anti-MDA-LDL IgM and that the percentage of circulating B-1 cells is directly associated with the amount of anti-MDA-LDL IgM suggesting clinical relevance. Conclusions: These results provide novel evidence that B-1b B cells produce atheroprotective OSE IgM antibodies and protect against atherosclerosis in mice, and suggest that similar mechanisms may occur in humans.

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