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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mount Sinai School of Medicine
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
Stanca, Carmen M; Bach, Nancy; Allina, Jorge et al. (2008) Atorvastatin does not improve liver biochemistries or Mayo Risk Score in primary biliary cirrhosis. Dig Dis Sci 53:1988-93
Allina, Jorge; Stanca, Carmen M; Garber, John et al. (2008) Anti-CD16 autoantibodies and delayed phagocytosis of apoptotic cells in primary biliary cirrhosis. J Autoimmun 30:238-45
Allina, Jorge; Hu, Bin; Sullivan, Daniel M et al. (2006) T cell targeting and phagocytosis of apoptotic biliary epithelial cells in primary biliary cirrhosis. J Autoimmun 27:232-41
Stanca, Carmen M; Bach, Nancy; Krause, Cynthia et al. (2005) Evaluation of fatigue in U.S. patients with primary biliary cirrhosis. Am J Gastroenterol 100:1104-9
Bai, Jingxiang; Odin, Joseph A (2003) Apoptosis and the liver: relation to autoimmunity and related conditions. Autoimmun Rev 2:36-42
Odin, J A; Huebert, R C; Casciola-Rosen, L et al. (2001) Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis. J Clin Invest 108:223-32