Abstract 9224: Depletion of Mature B cells by Deletion of BAFF Receptor Reduces Atherosclerosis in ldlr Knockout Mice

Abstract

Innate-like B1a cells may protect against atherosclerosis via production of natural anti-oxLDL IgM antibodies. However, we recently demonstrated that anti-CD20 antibody-mediated B cell depletion reduced murine atherosclerosis, suggesting some subsets of B cells could promote atherosclerosis. B cell activating factor (BAFF) and its cognate receptors, are important regulators of B cell survival and activation. Increased BAFF levels are associated with a number of autoimmune diseases. This study aims to characterise the effects of mature B cell loss on atherosclerosis. We analysed aortic root atherosclerosis, serum anti-oxLDL antibody levels and immune cell phenotypes in male ldlr-/- mice transplanted with control (WT) or BAFF receptor (BAFFR)-/- bone marrow and fed a high fat diet for 6 weeks. Ldlr/BAFFR-/- chimeric mice had significantly reduced levels of mature B cells (B220+ IgM+) in the spleen, blood, bone marrow and peritoneum, but no difference in peritoneal B1a cells (B220+ IgM+ CD11b+ CD5+). Despite a non-significant trend towards increased serum total cholesterol (6.65±0.72 g/l vs 6.03±0.72 in controls), aortic root atherosclerosis levels were reduced by 33% in ldlr/BAFFR-/- mice, an effect accompanied by a reduction in IgG but not IgM antibodies to malonaldehyde modified-LDL and reduced CD4+ T cell proliferation in vitro. However, there was no apparent difference in Treg levels or function, and no changes in blood Ly6C monocyte subsets. Splenic dendritic cells from ldlr/BAFFR-/- mice displayed reduced CD40 and MHC Class II expression, suggesting impaired activation in the absence of B cells. Deficiency in mature B cell levels reduced atherosclerosis and circulating levels of anti-oxLDL IgG, potentially linked to impaired pro-inflammatory dendritic cell maturation and T cell activation. These results support the notion that whereas B1a cells may protect against atherosclerosis by production of protective natural anti-oxLDL IgM antibodies, other B cell subsets could play pathogenic roles. This study provides important insight into the potential effects of therapies targeting B cells and/or BAFF on atherosclerosis.