B cells regulate atherosclerosis with adaptive B-2 cells aggravating atherosclerosis and innate B-1 cells attenuating atherosclerosis. B-1 cell production of IgM to oxidation specific epitopes (OSE) on LDL such as MDA-LDL is thought to occur in the bone marrow and spleen and serve to block the inflammatory effects of these modified lipids. However, we and others demonstrated that atheroprotective B-1 cells reside in the outer layer of the vessel wall including perivascular adipose tissue (PVAT), a region known to play an important role in vascular inflammation and atherosclerosis. Preliminary data provide the first evidence for B-1 cell derived IgM production in the PVAT of mice and demonstrates that adipose tissue B-1-derived IgM limits M1 macrophage production of inflammatory cytokines, a potential mechanism whereby PVAT IgM may attenuate atherosclerosis. Preliminary murine data implicates the chemokine receptors (CR) CCR6 and CXCR4 in B-1 cell-mediated IgM production in PVAT and atheroprotection. Consistent with murine findings, we identified B-1 cells and IgM production in coronary artery PVAT of humans. Moreover, utilizing our well phenotyped human cohort at UVA, preliminary data suggests that CXCR4 expression on circulating human B-1 cells positively associates with plasma levels of IgM to MDA-LDL and inversely associates with human coronary artery plaque volume and indices of plaque instability as measured by intravascular ultrasound-virtual histology (IVUS- VH). Accordingly, we hypothesize that specific CR expression on B-1 cells leads to increased numbers of B-1 cells in PVAT and these B-1 cells inhibit inflammatory cytokine production by M1 macrophages and attenuate diet-induced atherosclerosis in an IgM- dependent manner. We further hypothesize that expression of specific CRs on human B- 1 cells is positively associated with plasma IgM to OSE and is inversely associated with coronary artery plaque volume and indices of plaque instability. To test this hypothesis, we propose the following aims:
Specific Aim 1 : Test the hypothesis that the expression of specific CRs (CXCR4, CCR6 and CXCR5) on B-1 cells promotes their recruitment to the PVAT and enhances local IgM production.
Specific Aim 2 : Test the hypothesis that CR-mediated B-1 production of IgM in PVAT reduces PVAT and lesional inflammation and diet-induced atherosclerosis.
Specific Aim 3 : Identify CRs on human circulating CD20+CD27+CD43+ B cells that are inversely associated with plaque burden and plaque instability in humans as measured by IVUS-VH and determine if these unique B-1 subsets spontaneously produce IgM to OSE and are associated with plasma levels.
Cardiovascular disease 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. Studies clearly show 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, broad- based immunosuppression 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 for the development of strategies that could promote immune protection from atherosclerosis and limit inflammation. Perivascular adipose tissue (PVAT) has been implicated in regulating plaque build-up in arteries. We identified immune cells that protect from atherosclerosis (B-1 cells) in the PVAT of mouse and humans. Chemokine receptors (CR) control the trafficking of immune cells and we demonstrate that CR expression on B cells regulate the amount of atheroprotective IgM produced by B cells in PVAT. A fuller understanding and the identification of the mechanisms whereby these CR regulate atherosclerosis in mice and testing for relevance in humans has the potential to lead to novel immune cell targeted therapy for atherosclerosis protection. Our group is uniquely poised to address these important questions and translate these findings rapidly to humans as we have all the animal models and expertise in hand and have an established translational program with the infrastructure needed to test these hypotheses in humans.
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