The antibody immune response in atherosclerosis

Résumé

Atherosclerosis is a chronic inflammatory disease in which both innate and adaptive immunity are involved in disease initiation and progression, most likely through their response to endogenously modified structures generated in the context of the disease. However, the B cell response during atherosclerosis development is very far from being understood, and the extent, quality and function of the antibody repertoire associated to atherosclerosis remain unknown. In this work, we have addressed the antibody response associated to atherosclerosis using low density lipoprotein‐receptor deficient (LDLR‐/‐) mice fed with high fat diet (HFD). We have found that atherosclerosis promotes a germinal center (GC) response, accompanied by generation of specific antibodies. In order to study the atherosclerosisassociated antibody repertoire, we have performed an unprecedented high‐throughput single cell analysis by isolating individual B cells and sequencing the heavy and light chains of antibody genes. We have found that atherosclerotic mice have a distinct antibody repertoire and identified a collection of clones associated to atherosclerosis. Cloning and expression of these antibodies allowed the evaluation of their antigen specificity and functional properties. Among atherosclerosis‐associated antibodies, we selected A12 antibody for further analysis, since it revealed atheroma plaque reactivity in both atherogenic mice and carotid atherosclerosis human patients. Pull down experiments followed by proteomics analysis allowed the identification of the specific antigen for A12 antibody, the mitochondrial protein aldehyde dehydrogenase 4 family member A1 (ALDH4A1), that acts as a novel self‐antigen in the context of atherosclerosis. We have found that ALDH4A1 accumulates in atheroma plaques and that its protein levels were increased in plasma from both atherogenic mice and human carotid atherosclerosis patients, becoming a new biomarker for atherosclerotic disease. Finally, treatment of atherogenic mice with A12 revealed that this antibody is atheroprotective. Thus, the data presented here have broadened our understanding of the atherosclerosis‐associated humoral response and has revealed ALDH4A1 as a putative novel biomarker and A12 as potential therapeutic tool