Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Dr. Bryan Heit

Abstract

CD93 is a transmembrane C-type lectin expressed on myeloid, endothelial, and B cells. First identified as a developmental B cell marker and a phagocytic C1q receptor, little is known about the role and mechanism of CD93 in efferocytosis (the phagocytosis of apoptotic cells). CD93 knockout mice develop chronic inflammatory diseases characterized by a lack of efferocytosis such as atherosclerosis and a lupus-like autoimmune disease. In humans, a cleaved form of CD93 (sCD93) is elevated during inflammation and autoimmune responses, and CD93 polymorphisms are associated with enhanced susceptibility to atherosclerosis and lupus. Despite these clinical associations, no comprehensive bioinformatic analysis of CD93’s evolution and regulation have been performed to date. To this end evolutionary analysis of CD93 was performed, demonstrating that CD93 evolution is characterized by conservation but with several amino acid residues showing recent positive selection. Promoter analysis of CD93 revealed several interactions with transcription factors involved in regulation of cell growth, differentiation, and apoptosis, consistent with the known expression profile of CD93 and cell types known to engage in efferocytosis. Shedding assays using human monocytes and monocyte-like THP-1 cells show that CD93 expression is lost during monocyte-to-macrophage differentiation and in response to PMA stimulation. The cleavage was not dependent on the TAPI-2-inhibitable proteases which includes select MMPs and other proteases such as ADAMs and ACE secretases. Importantly, apoptotic cell mimics opsonized with sCD93 containing supernatants show increased phagocytic uptake, suggesting that sCD93 acts as an opsonin for apoptotic cells.

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