B cell-specific knockout of AID protects against atherosclerosis

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. We sought to define whether AID affects atherosclerotic plaque formation. 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 ± 0.03mm(2)) compared with Ldlr(-/-)WT (0.30 ± 0.04mm(2), 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. AID depletion directly inhibits atherosclerotic plaque formation.