B Cells and Humoral Immunity in Atherosclerosis from Mice to Human

Author: ORCID icon orcid.org/0000-0003-0994-1491
Pattarabanjird, Tanyaporn, Biomedical Engineering - School of Engineering and Applied Science, University of Virginia
Advisor:
McNamara, Coleen, Cardiovascular Medicine, University of Virginia
Abstract:

Atherosclerotic cardiovascular disease is a chronic inflammatory disease and a number one cause of death in the United States. It is characterized by accumulation of oxidized low-density lipoprotein (OxLDL) in the artery wall initiating a cascade of inflammatory responses as well as macrophage uptake of OxLDL leading to formation of foam cells, a hallmark of atherosclerotic plaque formation. Despite the ubiquitous use of lipid lowering medications as a standard care to treat hyperlipidemia and cardiovascular diseases, the prevalence of cardiovascular disease still remains high indicating that lipid modification is not sufficient as a stand-alone treatment for cardiovascular diseases. The completion of the Canakinumab anti-inflammatory thrombosis outcome study (CANTOS) is the first evidence proving that inhibiting inflammation in the absence of lipid modifications can also improve atherosclerotic outcomes. This finding highlights the importance of immune-modulatory therapy in managing atherosclerosis.

B cells have emerged as important immune cells in modulating atherosclerosis through subtype dependent mechanisms. In murine, B1 cells are atheroprotective, while B2 cells are pro-atherogenic. B1 cells can be further subtyped into B1a and B1b cells based on CD5 expression. B1 cells are self-renewed and produce anti-inflammatory antibody IgM that recognizes and helps clear oxidation specific epitopes (OSEs), such as malondialdehyde LDL (MDA-LDL), which ameliorates atherosclerosis. Therefore, understanding of factors regulating self-renewal of B1 cells, IgM production can help identify targets for atherosclerosis immunotherapy. Additionally, identification of human B cells equivalent to murine B1 cells is also crucial as the discovery will facilitate translating findings from mice to humans.

In this dissertation, I present the evidences that p62, an autophagy and cell proliferative adaptor protein, regulates self-renewal of murine B1b cells. Lentiviral-mediated overexpression of p62 in murine B1 cells leads to an increase in B1b cell number, higher IgM production, and reduction of atherosclerotic plaque. More importantly, expression of p62 can be promoted through activation of E2A transcription factor or loss of inhibitor of differentiation 3 (Id3), an inhibitory binding partner of E2A.

To allow translation of this discovery to human, I seek to identify IgM producing human B cells. Through utilizing mass cytometry, I identified human IgM producing B cells to be marked by CD27+/IgM+. Additionally, CD24 is shown to promote IgM production in these cells through interacting with CCR6 to reduce ligand induced CCR6 internalization. This allows higher level of CCR6 to be on the surface to mediate trafficking to the spleen where these CD27+IgM+ B cells produce IgM antibody. Use of CD24 blocking monoclonal antibody also leads to an increase in vascular inflammation in hyperlipidemic humanized mice model. This second discovery does not only allow identification of human equivalent murine B1 cells, but also suggests that CD24 and CCR6 might also be promising targets for B cell targeted therapy for atherosclerosis.

Degree:
PHD (Doctor of Philosophy)
Keywords:
B cells, Atherosclerosis, CD24, P62, IgM
Language:
English
Issued Date:
2021/11/08