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

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01HL055798-18
Application #
8707525
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2014
Total Cost
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
Tsimikas, Sotirios; Duff, Gordon W; Berger, Peter B et al. (2014) Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J Am Coll Cardiol 63:1724-34
Willeit, Peter; Kiechl, Stefan; Kronenberg, Florian et al. (2014) Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J Am Coll Cardiol 64:851-60
Ai, Ding; Jiang, Hongfeng; Westerterp, Marit et al. (2014) Disruption of mammalian target of rapamycin complex 1 in macrophages decreases chemokine gene expression and atherosclerosis. Circ Res 114:1576-84
Manichaikul, Ani; Rich, Stephen S; Perry, Heather et al. (2014) A functionally significant polymorphism in ID3 is associated with human coronary pathology. PLoS One 9:e90222
Lazic, Milos; Inzaugarat, Maria Eugenia; Povero, Davide et al. (2014) Reduced dietary omega-6 to omega-3 fatty acid ratio and 12/15-lipoxygenase deficiency are protective against chronic high fat diet-induced steatohepatitis. PLoS One 9:e107658
Cheng, Hsin-Yuan; Wu, Runpei; Hedrick, Catherine C (2014) Gammadelta (??) T lymphocytes do not impact the development of early atherosclerosis. Atherosclerosis 234:265-9
Morris-Rosenfeld, Samuel; Lipinski, Michael J; McNamara, Coleen A (2014) Understanding the role of B cells in atherosclerosis: potential clinical implications. Expert Rev Clin Immunol 10:77-89
Fang, Longhou; Liu, Chao; Miller, Yury I (2014) Zebrafish models of dyslipidemia: relevance to atherosclerosis and angiogenesis. Transl Res 163:99-108
Ge, Shuwang; Hertel, Barbara; Koltsova, Ekaterina K et al. (2013) Increased atherosclerotic lesion formation and vascular leukocyte accumulation in renal impairment are mediated by interleukin-17A. Circ Res 113:965-74
Cheng, Hsin-Yuan; Wu, Runpei; Gebre, Abraham K et al. (2013) Increased cholesterol content in gammadelta (ýýýý) T lymphocytes differentially regulates their activation. PLoS One 8:e63746

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