B cell-specific knockout of AID protects against atherosclerosis

Abstract

Rationale: Antigen-naive IgM-producing B cells are atheroprotective, whereas mature B cells producing class-switched antibodies promote atherosclerosis. Activation-induced cytidine deaminase (AID), which mediates class switch recombination (CSR), would thus be expected to foster atherosclerosis. Yet, AID also plays a major role in the establishment of B cell tolerance. Objective: We sought to define whether AID affects atherosclerotic plaque formation. Methods and Results: In Ldlr-/- mice, a high fat diet (HFD) increased aortic expression of AID compared with chow diet. We generated Ldlr-/- chimeras transplanted with bone marrow from Aicda-/- or wild-type (WT) mice, fed a HFD for 14 weeks. Decreased B cell maturation in Ldlr-/-Aicda-/- mice was demonstrated by 50% reduction in splenic and aortic BAFFR expression, a key signaling component of B2 cell maturation. This was associated with increased plasma IgM in Ldlr–/-Aicda-/- compared with Ldlr-/-WT animals. Importantly, Ldlr-/-Aicda-/- mice had reduced atherosclerotic lesion area (0.20±0.03mm2) compared with Ldlr-/-WT (0.30±0.04mm2, P<0.05), although no differences in plaque composition were noted between groups. In addition, immunofluorescence analysis revealed increased splenic B and T cell areas independent of cell number. Conclusions: AID activity directly promotes atherosclerotic plaque formation.