B-la cells are atheroprotective;an effect dependent on secreted IgM. Yet, the factors that regulate the B-la subset are unknown. Recent data from our group demonstrates that Id3 is essential for B cell-mediated atheroprotection, and that loss of ld3 resulted in reduced B-la cell number and reduced serum levels of E06 (an atheroprotective natural antibody made by Bla cells). In vivo proliferation assays demonstrated that ld3 was essential for B-la, but not B2 cell homeostatic proliferation and cell culture studies suggest that this effect may be mediated by ld3 regulation of cyclin D2 expression. Accordingly, we hypothesize that Id3 in B cells is necessary for B-la cell atheroprotection through promoting B-la cell cycle progression and self renewal resulting in increased levels of atheroprotective natural antibodies such as E06. This hypothesis and the molecular and cellular mechanisms mediating these effects will be studied in aims 1 and 2. Moreover, we will translate these novel findings in mice into testable hypotheses in humans with type 2 diabetes (T2DM). We have recently identified a single nucleotide polymorphism (SNP) in the human ID3 gene at rs 11574 that encodes an Id3 protein with attenuated function. This SNP was present in 46% of participants in the Diabetes Heart Study and was associated with an increase in carotid intima medial thickness (cIMT) in this diabetic population, suggesting a potential link between loss of Id3 function and atherosclerosis in humans. Recent identification of a novel circulating subset of B cells in humans with the unique properties of murine B-la cells and our new preliminary data suggesting an association of the 1D3 SNP at rsl 1574 with levels of circulating IgM to modified lipids in humans with diabetes, support the hypothesis that Id3 polymorphism at rsl 1574 is associated with reduced circulating B-la-like cells and reduced atheroprotective IgM to modified lipids in humans. Through collaborations with projects 1 and 2 and our human core, we are uniquely poised to test these innovative hypotheses to identify molecular mechanisms regulating atheroprotective B cells in mice and humans, potentially leading to identification of novel biomarkers and novel strategies to bolster innate immune protection against atherosclerosis.

Public Health Relevance

Identification of the mechanisms regulating B-la cells in mice may provide important insights into pathways that could be manipulated to bolster immune protection from atherosclerosis. Moreover, characterization of the humans equivalent of murine B-la cells will lay essential groundwork for novel and potentially more effective strategies to limit atherogenesis and its clinical sequelae in humans

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Verbeek, Rutger; Boekholdt, S Matthijs; Stoekenbroek, Robert M et al. (2016) Population and assay thresholds for the predictive value of lipoprotein (a) for coronary artery disease: the EPIC-Norfolk Prospective Population Study. J Lipid Res 57:697-705
Yang, Xiaohong; Lee, Sang-Rok; Choi, Yun-Seok et al. (2016) Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results. J Lipid Res 57:706-13
Harmon, Daniel B; Srikakulapu, Prasad; Kaplan, Jennifer L et al. (2016) Protective Role for B-1b B Cells and IgM in Obesity-Associated Inflammation, Glucose Intolerance, and Insulin Resistance. Arterioscler Thromb Vasc Biol 36:682-91
Choi, Soo-Ho; Kim, Jungsu; Gonen, Ayelet et al. (2016) MD-2 binds cholesterol. Biochem Biophys Res Commun 470:877-80
Park, Kiwon; Mikulski, Zbigniew; Seo, Goo-Young et al. (2016) The transcription factor NR4A3 controls CD103+ dendritic cell migration. J Clin Invest 126:4603-4615
Choi, Soo-Ho; Sviridov, Dmitri; Miller, Yury I (2016) Oxidized cholesteryl esters and inflammation. Biochim Biophys Acta :
Yeang, Calvin; Cotter, Bruno; Tsimikas, Sotirios (2016) Experimental Animal Models Evaluating the Causal Role of Lipoprotein(a) in Atherosclerosis and Aortic Stenosis. Cardiovasc Drugs Ther 30:75-85
Tsimikas, Sotirios (2016) Lipoprotein(a): novel target and emergence of novel therapies to lower cardiovascular disease risk. Curr Opin Endocrinol Diabetes Obes 23:157-64
Leibundgut, Gregor; Lee, Jun-Hee; Strauss, Bradley H et al. (2016) Acute and long-term effect of percutaneous coronary intervention on serially-measured oxidative, inflammatory, and coagulation biomarkers in patients with stable angina. J Thromb Thrombolysis 41:569-80
Cheng, Hsin-Yuan; Gaddis, Dalia E; Wu, Runpei et al. (2016) Loss of ABCG1 influences regulatory T cell differentiation and atherosclerosis. J Clin Invest 126:3236-46

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