Abstract 13062: Pathogenic IgG Antibodies in Hyperlipidemic Mice Promote Atherosclerosis

Abstract

Background: B2 cells promote atherosclerosis, but the exact mechanisms by which they promote atherosclerosis are not known. Antibodies can be pathogenic in a number of chronic inflammatory diseases. Here, we examined the role of antibodies in the development of atherosclerosis in hyperlipidemic mice. Methods and Results: As an interaction between B cells and CD4 T cells is important for plasma cell development and antibody production, we generated mixed chimeric LDLR -/- mice with B cells selectively deficient in MHC II or CD40 molecules. B cells deficient in either molecule decreased atherosclerosis by ~30-40%. This was associated with reduced spleen germinal centre B cells and plasma cells, markedly reduced plasma total immunoglobulins, reduced spleen CD4 T cell activation and decreased IFN-γ+ CD4 T cells. To confirm that the observed effects on atherosclerosis were largely due to impaired plasma cell generation and antibody production, we also deleted B cell-specific Blimp-1, a transcription factor critically important for B cell differentiation into antibody-producing plasma cells. Chimeric LDLR -/- mice transplanted with CD23 CRE -Blimp-1 fl/fl bone marrow were completely devoid of spleen plasma cells and plasma total immunoglobulins but CD4+ T cell activation was unaffected; atherosclerosis in these mice was reduced by nearly 50%. To exclude the possibility that the reduction in atherosclerosis was due to deletion of plasma cells, we then purified IgG from hyperlipidemic mice with atherosclerosis and transferred the IgG into immunoglobulin/plasma cell-deficient CD23 CRE -Blimp-1 fl/fl bone marrow transplanted LDLR -/- mice. Atherosclerotic lesions doubled in size in mice that received IgG from atherosclerotic mice, compared to transfer of IgG purified from non-atherosclerotic mice. Conclusions: Our study indicates that IgG antibodies generated in hyperlipidemic mice during atherosclerosis development accelerates growth of atherosclerotic lesions. Targeting pathogenic IgG antibodies in atherosclerosis has a potential to reduce lesion progression and the incidence of heart attacks and strokes.