Depletion of B2 but Not B1a B Cells in BAFF Receptor-Deficient ApoE−/− Mice Attenuates Atherosclerosis by Potently Ameliorating Arterial Inflammation

Abstract

We have recently identified conventional B2 cells as atherogenic and B1a cells as atheroprotective in hypercholesterolemic ApoE−/− mice. Here, we examined the development of atherosclerosis in BAFF-R deficient ApoE−/− mice because B2 cells but not B1a cells are selectively depleted in BAFF-R deficient mice. We fed BAFF-R−/− ApoE−/− (BaffR.ApoE DKO) and BAFF-R+/+ApoE−/− (ApoE KO) mice a high fat diet (HFD) for 8-weeks. B2 cells were significantly reduced by 82%, 81%, 94%, 72% in blood, peritoneal fluid, spleen and peripheral lymph nodes respectively; while B1a cells and non-B lymphocytes were unaffected. Aortic atherosclerotic lesions assessed by oil red-O stained-lipid accumulation and CD68+ macrophage accumulation were decreased by 44% and 50% respectively. B cells were absent in atherosclerotic lesions of BaffR.ApoE DKO mice as were IgG1 and IgG2a immunoglobulins produced by B2 cells, despite low but measurable numbers of B2 cells and IgG1 and IgG2a immunoglobulin concentrations in plasma. Plasma IgM and IgM deposits in atherosclerotic lesions were also reduced. BAFF-R deficiency in ApoE−/− mice was also associated with a reduced expression of VCAM-1 and fewer macrophages, dendritic cells, CD4+ and CD8+ T cell infiltrates and PCNA+ cells in lesions. The expression of proinflammatory cytokines, TNF-α, IL1-β and proinflammatory chemokine MCP-1 was also reduced. Body weight and plasma cholesterols were unaffected in BaffR.ApoE DKO mice. Our data indicate that B2 cells are important contributors to the development of atherosclerosis and that targeting the BAFF-R to specifically reduce atherogenic B2 cell numbers while preserving atheroprotective B1a cell numbers may be a potential therapeutic strategy to reduce atherosclerosis by potently reducing arterial inflammation.

Molecular Biology of Atherosclerosis

“…Deletion of the BAFF receptor (BAFFR), necessary for B2 development, was also recently shown to be protective in at least two studies (968,1528). Like the anti-CD20 antibody infusion studies, BAFFR deficiency resulted in marked selective reduction of B2 cells with little effect on B1a cells.…”

Adaptive immunity in atherogenesis: new insights and therapeutic approaches

“…On the other hand, use of anti-CD20 to deplete B-2 cells in mice, which spared B-1 cells in the peritoneum, reduced atherosclerosis, as well as activation and proliferation of DCs and CD4 + T cells, suggesting that B-2 cells were proatherogenic by several mechanisms (60,94). Furthermore B cell-activating factor receptor (BAFF-R) deficiency, which causes a reduction in B-2 but not B-1 cells, also reduced lesion development and macrophage and T cell infiltration (95,96). However, recent data demonstrated a role for the Id3-CCR6 pathway in mediating aortic B cell homing, and demonstrated that resident adventitial B cells mediated protection from early atherosclerosis in part through inhibiting intimal macrophage accumulation (97).…”

High Levels of (Un)Switched Memory B Cells Are Associated With Better Outcome in Patients With Advanced Atherosclerotic Disease

“…To date, it is generally accepted that (auto)antibody‐producing B1 B cells are atheroprotective26, 27 and this protective effect depends on IgM secretion,28 whereas conventional B2 B cells are generally considered proatherogenic 29. This proatherogenic phenotype in mice has mainly been attributed to the production of pathogenic IgG antibodies against oxidized low‐density lipoprotein (oxLDL) and the immune effector function of these B cells 27, 28, 30, 31, 32, 33. In human atherosclerosis, however, there is conflicting evidence about the role of autoantibodies directed against oxLDL.…”