Role of Apoptotic Cholangiocytes in PBC

Mount Sinai School Of Medicine Of Nyu, New York NY

Investigators

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Abstract

DESCRIPTION (adapted from the application) My academic and clinical experience of the past fourteen years have laid the foundation for success in studying the pathogenesis of PBC. The combination of a Ph.D. and M.D. allows one to more easily take insights from the bedside to the research bench and back again. Working within a newly established PBC research center at Mount Sinai Medical Center will give me the intellectual and technical support necessary for the transition to an independent investigative career. Initially, I will focus on the role of apoptotic cholangiocytes in the pathogenesis of PBC. Later, I plan to use these findings to develop an animal model of PBC in which potential treatment strategies can be tested. Additionally, I intend to investigate in greater detail the role of protein sulfhydryl oxidation in apoptotic signaling pathways. My clinical and teaching activities will increase over time, but I will remain focused on a translational research career. Our preliminary results suggest that in patients with PBC, apoptotic cholangiocytes are the source of immunogenic PDC-E2, the major PBC autoantigen, that is responsible for the activation of autoreactive B cells. Autoantibodies recognize only the reduced sulfhydryl form of PDC-E2, yet persistence of PDC-E2, in a reduced state occurs only in select cell types, such as cholangiocytes, following apoptosis. Whether or not presentation by antigen presenting cells of novel peptides derived from reduced PDC-E2 in apoptotic cholangiocytes is similarly responsible for the activation of autoreactive T cells is unknown. This issue is important since autoreactive T cells are thought to be pathogenic in PBC and not simple secondary to cholangiocyte damage. To account for this paradox, we have developed a model of PBC pathogenesis in which an initial subclinical episode of biliary inflammation leads to self sustaining biliary inflammation following activation of PDC-E2 specific T cells in susceptible individuals. The crux of this model is whether or not healthy cholangiocytes engulf apoptotic cholangiocytes and present novel peptides derived from this exogenous source of reduced PDC-E2. In this proposal, we aim to determine the following: 1) whether autoreactive T cells from patients with PBC preferentially respond to peptides derived from reduced, rather than oxidized, PDC-E2;2) the antigen presenting cell that most effectively activates autoreactive T cells following incubation with exogenous sources of reduced PDC-E2; and 3) whether PBC patient cholangiocytes engulf apoptotic cells in vivo. Together, these studies will help determine whether autoreactive T cells in patients with PBC are truly pathogenic or simply secondary to idiopathic cholangiocyte destruction.