Immune Cell Interactions in Atherosclerosis

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Overall Abstract Our PPG will test the hypothesis that the lipid and protein components of lipoproteins trigger innate and adaptive immune responses that control human atherosclerosis. We will study the immune cell cross-talk that occurs during human atherosclerosis progression. Immunity plays an important role in coronary artery disease (CAD), as recent clinical trials have clearly demonstrated. However, these trials also taught us that systemic treatments of the immune system, by their very nature, impair host defense. Thus, it is imperative to find new, more specific interventions that modulate immune cell function in atherosclerosis, yet spare host defense. We will study immune cells and plasma from human subjects from 3 well-characterized clinical cohorts, 1-our existing CAVA cohort (Coronary Assessment at Virginia), where subjects are enrolled from the UVA cardiac catheterization laboratory that undergo quantitative coronary analysis for disease quantification; 2- Computerized Tomography (CT)-CAVA cohort, where subjects undergoing noninvasive CT angiography for cardiovascular disease assessment in years 1 and 2 of the PPG renewal (baseline measures) will be followed up at 3 years to allow for determination of coronary plaque progression and changes in markers of plaque vulnerability, and 3- The Multi-Ethnic Study of Atherosclerosis (MESA), a large NHLBI-sponsored longitudinal cohort that has been ongoing since 2000. In this synergistic program, Project 1 CD9+ Monocyte and Macrophage Immune Functions in Atherosclerosis has identified new monocyte subsets expressing the tetraspanin CD9, and will study how CD9 impacts metabolism and immune modulation of monocytes and macrophages in CAD. Project 2 Cholesterol Regulation of Inflammatory Macrophages in Atherosclerosis will study how specialized lipid raft signaling drives transcriptional and metabolic reprogramming in macrophages. Project 3 Regulation of Atheroprotective IgM-producing B cells in Murine and Human Atherosclerosis will study how CD24 and CCR6 on newly identified human B-1 cell subsets modulate atheroprotective IgM production. Project 4 ApoB-Specific CD4 and CD8 T cells Exacerbate Atherosclerosis will identify and study immunodominant human apolipoprotein B (apoB) epitopes to investigate how these activate CD4 and CD8 T cell using mouse models to address mechanisms. An important synergistic aspect to our PPG is that it is highly interactive, in that B cells, T cells, monocytes and macrophages communicate with each other in the artery wall and in lymphoid tissues. Unique aspects of our program are the focus on studying human immune cells, the link to biospecimens and clinical data from 3 complementary cardiovascular cohorts, the use of unbiased high dimensional protein and RNA-sequencing at the single cell level for all human immune cells from the same human subjects, and our ability to link all of our group’s discoveries with extensive clinical data on each subject. The human studies are complemented by murine mechanistic models where applicable. The end goal of our studies is to identify safe new therapeutic strategies targeting immune cell function to limit CAD.