B-1B Cells are a Novel Atheroprotective B Cell Subset and are Negatively Regulated by ID3

Morris-Rosenfeld, Samuel, Experimental Pathology - Graduate School of Arts and Sciences, University of Virginia
McNamara, Coleen, Department of Medicine, Cardiovascular Medicine, University of Virginia

Vascular disease remains the leading cause of death globally through its sequelae myocardial infarction and stroke. The primary contributor to vascular disease, atherosclerosis, is defined by intimal plaque formation in response to lipid deposition. Atherosclerosis is a chronic, progressive disease of the medium to large size arteries and has been well described as a product of low grade inflammation.
B cells are highly involved in the development and progression of atherosclerosis, responding to atherogenic antigen and aggregating in the vascular adventitia. The contributions of B cells to atherosclerosis are subset dependent. Adaptive B-2 cells are considered atherogenic though they can also have atheroprotective function based on the context and model used to study them. Innate B-1a cells are atheroprotective through the secretion of IgM natural antibodies reactive to oxidized LDL. B-1b cells, a unique subset of B-1 cells that are able to provide T cell-independent immune memory, are also atheroprotective and secrete IgM reactive to oxidation-specific epitopes on oxidized LDL.
Inhibitor of differentiation 3 (Id3) is a helix-loop-helix transcription factor known to regulate B cell development and homeostasis as well as atherosclerosis. Studies in a B cell specific Id3 knockout model (Id3BKO) revealed that these mice have a
significantly expanded B-1b cell population in all compartments without a difference in B-1a or B-2 numbers. Additional studies demonstrated that Id3BKO mice developed attenuated atherosclerosis and increased titers of atheroprotective IgM supporting B-1b cells as atheroprotective and suggesting Id3 selectively negatively regulates their numbers. Attempts to define a mechanism by which Id3 regulates B-1b cells have been inconclusive.
Given their contributions to T cell independent memory, B-1b cells are a novel target for immunization strategies against atherosclerosis and Id3 could be an important target for B-1 directed therapies

PHD (Doctor of Philosophy)
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