Human circulating CD24^hi marginal zone B cells produce IgM targeting atherogenic antigens and confer protection from vascular disease

IgMs that inactivate oxidation-specific epitopes (IgM(OSE)), which are secondary products of lipid peroxidization, protect against inflammatory diseases, including diet-induced atherosclerosis. However, the human B cell subtype that produces IgM(OSE) remains unknown. In this study, we used single-cell mass cytometry and adoptive transfer of B cell subtypes to NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NSG) mice to identify B27+IgM+CD24hi cells as the major producers of IgM(OSE) in humans. Notably, these cells have characteristics of human circulatory marginal zone B (MZB) cells, which are known to be atheoroprotective IgM producers in mice. CD24 antibody treatment to reduce MZB cells and IgM in a hyperlipidemic humanized mouse model provides the evidence that MZB cells protect against vascular inflammation. Consistent with these findings, the frequency of B27+IgM+CD24hi cells (MZB) in patients inversely correlates with coronary artery disease severity.