Self-Reactive B Cells in Artery Tertiary Lymphoid Organs Encode Pathogenic High Affinity Autoantibody in Atherosclerosis

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. To map atherosclerosis-specific humoral autoimmunity and define its roles, we isolated germinal-center (GC) B cells from ATLOs and lymph-nodes, expression-cloned 60 autoantibodies and screened them for arterial wall reactivity. 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). Moreover, vaccination with H2B or adoptive transfer of its cognate autoantibody markedly accelerated atherosclerosis suggesting that ATLOs fail to delete pathogenic high-affinity self-reactive B cells. In a human cohort, total circulating anti H2B antibody titers positively correlated with aortic and coronary artery calcification. We conclude that ATLOs harbor a dysregulated immune tolerance environment permissive for autoreactive B cells that express pathogenic autoantibodies driving atherosclerosis.