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 B 27+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 B 27+IgM+CD24hi cells (MZB) in patients inversely correlates with coronary artery disease severity.