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.
Cardiovascular disease (CVD) remains the leading global cause of death, accounting for at least 17.3 million deaths annually. The risk of atherosclerotic cardiovascular disease (CVD) varies significantly even in individuals with similar traditional risk factors. Moreover, despite aggressive modification of these risk factors the CVD event rate remains high, suggesting that CVD could be further prevented by additional strategies targeting other pathways. A wealth of studies have clearly shown that atherosclerosis is a chronic inflammatory disease. As such, immunomodulatory therapy has been proposed as the next stage for improving prevention of atherosclerotic CVD. Yet, immunosuppressive strategies in humans may have deleterious effects on CVD, likely due in part to the fact that not all immune cells are pro-inflammatory. In fact, several immune cell subsets have anti-inflammatory properties and are atheroprotective. Clearly a more comprehensive understanding of immune mechanisms in atherosclerosis is needed. Our group has recently discovered that the B-1b B cell subset produces natural antibodies (NAb) that protect from diet-induced atherosclerosis in mice. Notably, plasma levels of NAbs in humans are associated with less CVD and fewer CV events. We have identified a surface molecule on these cells (CXCR4) that mediates NAb production in mice and is associated with plasma levels of NAb and less coronary artery plaque in humans. In this proposal, we seek to further identify mechanisms whereby CXCR4 and similar surface molecules (chemokine receptors, CR) on B-1 cells mediate this NAb production and identify their role in preventing diet-induced atherosclerosis. Furthermore, we propose to study CXCR4 and other CR in two well characterized human cohorts to translate this knowledge to human disease. Results may provide critical insight and enable targeted immune strategies to bolster production of NAbs and protect from atherosclerosis in humans.
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