Artery Tertiary Lymphoid Organs (ATLOs) encode a pathogenic high affinity autoantibody driving atherosclerosis

Background/Introduction Artery tertiary lymphoid organs (ATLOs) emerge in atherosclerosis which is a chronic inflammatory artery disease with an autoimmune component. However, whether disease-relevant autoimmune B cells emerge in ATLOs and their impacts remains unknown. Purpose Map atherosclerosis-specific humoral autoimmunity and define its roles in atherosclerosis. Methods We implemented a cross-tissue and cross-genotype approach in aged WT and Apoe-/- mice; comparing B cell landscapes from ATLOs and lymph-nodes by pairing of single cell RNA sequencing and BCR profiling (scRNA-seq/scBCR-seq); expression-cloning of 60 autoantibodies from germinal-center (GC) B cells; screening the antibodies for arterial wall reactivity; identifying a pathogenic atherosclerosis-specific autoantigen/autoantibody pair; autoantigen vaccination and autoantibody transfer to examine the pathogenicity of each member of the pair; conducting a clinical study to examine whether autoantibodies directed against the newly identified murine autoantigen in the circulation correlate with those in humans and patients burdened by atherosclerosis. Results ATLO-derived autoantibodies markedly skewed to atherosclerosis-relevant autoantigens versus those of lymph-nodes. One ATLO GC-derived autoantibody bound to histone 2B (H2B) with high-affinity (~25 nM). Vaccination with H2B or adoptive transfer of its cognate autoantibody accelerated atherosclerosis suggesting that ATLOs encode pathogenic high-affinity self-reactive antibodies. In a human cohort, circulating anti H2B antibody titers were associated with aortic and coronary artery calcification, independently on traditional cardiovascular risk factors. Conclusion(s) We conclude that ATLOs harbor a dysregulated immune tolerance environment permissive for autoreactive B cells that express pathogenic autoantibodies driving atherosclerosis.