B Cell Subsets in Mouse and Human Atherosclerosis

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Abstract B cells have emerged as important immune cells in murine atherosclerosis, regulating lesion development in a subset-dependent manner. B-2 B cells promote atherosclerosis through poorly defined mechanisms, and B-1 B cells exert atheroprotective effects largely through production of natural IgM antibodies (NAb). Natural IgM to oxidation-specific epitopes (OSE) that accumulate in atherosclerosis such as malondialdehyde (MDA) and phosphorylcholine (PC) present on oxidized low-density lipoprotein can antagonize oxLDL stimulation of macrophages limiting inflammation. B-1 cells are the major source of circulating IgM in mice. A human equivalent to the murine B-1 cell was recently identified through its ability to spontaneously produce IgM and data implicates this cell in producing IgM to OSE on LDL. Plasma levels of IgM to MDA-LDL are associated with less CAD and fewer CV events in humans. As such, unraveling the pathways that lead to B-1 cell production of IgM to OSE may enable targeted immune strategies to bolster production of IgM to OSE on LDL and protect from atherosclerosis in humans. Our work has identified CXCR4 as a key regulator of B-1 NAb production in mice. Moreover, analyzing a human cohort with intravascular ultrasound (IVUS) to quantify coronary artery plaque volume, we demonstrate significant association of CXCR4 expression on B-1 cells with plasma IgM to MDA-LDL and low plaque volume. In this proposal, we will use loss and gain of function studies in murine atherosclerosis models, and analysis of well characterized human cohorts to study the role of CXCR4 and other implicated chemokine receptors in mediating B-1 cell atheroprotection.