anti-ALDH4A1 autoreactive B cells accumulate as age associated B cells and expand in atherosclerosis

Autoreactive antibodies are the hallmark of many autoimmune diseases. Atherosclerosis is a disease of the arteries that underlies most cardiovascular deaths and has a strong autoimmune component. Some atherosclerosis-associated antibodies can have protective roles, such as those recognizing oxidized low-density lipoprotein or the ALDH4A1 mitochondrial protein. However, whether autoreactive atherosclerosis antibodies arise from B cells that escape tolerance checkpoints or from responses to disease-induced neo-epitopes not subject to central tolerance, is not known. Here we have addressed this question by generating a BCR mouse model expressing A12, an atherosclerosis-associated antibody recognizing ALDH4A1 (IghA12/+ mice). We found that the majority of A12-expressing cells are subject to classical tolerance checkpoints. Peripheral A12-expressing cells accumulated as aged-associated B cells (ABC), a subset of memory-like B cells linked to age and autoimmune diseases, and efficiently differentiated into anti-ALDH4A1 antibody-secreting plasma cells. Finally, induction of atherosclerosis in IghA12/+ mice promoted expansion of A12-expressing cells and increased A12 antibody titers. Collectively, our work identifies a mechanistic link between autoimmunity, atherosclerosis, and ageing through the generation and expansion of ABCs.