Age-associated B cells predict coronary events in humans and aggravate murine atherosclerosis 2257113

Abstract

Abstract Introduction Aging is a major risk factor for cardiovascular disease (CVD) and is linked to a functional decline of the immune system. B cells contribute to atherosclerosis progression by antibody secretion, antigen presentation and T cell regulation. During aging, CD11c+CD21low B cells accumulate, but it is unclear whether these age-associated B cells (ABCs) are linked with incident cardiovascular events in humans and if they contribute to atherosclerosis progression. Methods To investigate associations with first-time coronary events, circulating B cells were phenotyped with flow cytometry in a case-control study (N = 604) nested in the Malmö Diet and Cancer Study cohort with a median of 14 years follow up. Splenic B cells in young (5 months) and aged (21 months) female Ldlr-/- mice were characterized with single-cell RNA-sequencing coupled with BCR-sequencing. Atherogenicity was determined by transfer of ABCs to Ldlr-/- and Ldlr-/-Rag1-/- mice. Results ABCs were distinctly expanded in older (≥66 years), compared to middle-aged (≤52 years) individuals (P = 0.002) and accumulated in aged atherosclerotic mice. Coronary event cases had higher ABC counts than controls and regression analysis revealed an association to incident coronary events, independent of cardiovascular risk factors [odds ratio: 1.80 (95% CI 1.05-3.07), P = 0.032, comparing the 4th vs 1st quartile]. Adoptive transfer of ABCs promoted atherosclerotic lesion development. In Ldlr-/- Rag1-/- mice, ABCs also increased necrotic cores (P < 0.05). After transfer, B cells recovered from recipient mice expressed CD138 and secreted antibodies. Accordingly, we demonstrated that ABCs expressed plasma cell differentiation genes and showed the greatest clonal expansion within the B cell compartment, with extensive clonal overlap with plasma cells. Conclusion We show that ABCs predict first-time coronary events in humans and contribute to atherosclerosis in mice. ABCs may serve as potential prognostic and therapeutic targets for CVD. Funding Source Fondation Leducq Network (CHECKPOINT ATHERO); European Union (B-specific; Grant Agreement No. 101115159); ERA-CVD B-eatATHERO consortium, Dutch Heart Foundation (2019T107) and ERA4HEALTH MARGINALIZE MI consortium. Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)