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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
Thomas F. Nealon, III Postdoctoral Research Fellowship Honoring Zachery Rue
Project Title: Role of B cells in the pathogenesis of autoimmune hepatitis
Autoimmune hepatitis (AIH) is a disease of unknown etiology, characterized by a loss of tolerance against hepatocytes leading to the progressive destruction of the hepatic parenchyma. Even with treatment, progression to cirrhosis and endstage liver disease may occur in 10-20% of cases and liver transplantation may be necessary. Recently, B cells were found to be involved in the pathogenesis of several autoimmune pathologies including T-cell mediated diseases such as Type 1 diabetes and multiple sclerosis. In AIH, a T cell mediated disease, Dr. Lapierre found, in an experimental model, that the development of the autoreactive B-cell response against hepatic proteins correlated with the subsequent onset of AIH. Furthermore, at CHU Sainte-Justine, two patients with AIH are currently in remission following treatment with rituximab, a B-cell depleting humanized monoclonal antibodies.
These, and several other observations in AIH patients and in experimental models, leads Dr. Lapierre to propose that B cells are involved at various stages of development of an autoimmune response against the liver and are either directly or indirectly implicated in the immune-mediated damage to hepatocytes. Experimental models of AIH developed in Dr. Lapierre’s laboratory allowed to identify three stages in the development of an AIH; 1) initiating events in which a primary activation of autoreactive T and B cells occurs following a “triggering event”, 2) a lag period where autoreactive T and B cells proliferate but no clinical signs of AIH are apparent and; 3) Active AIH when massive infiltration of the liver by autoreactive lymphocytes occurs. Dr. Lapierre believes that B cells could be implicated during these three stages and play an active part in sustaining the autoreactive T cell response against the liver. The proposed experiments, based on promising preliminary results and clinical observations, could lead to a new and innovative treatment for autoimmune hepatitis patients and help us understand the underpinning immune molecular mechanisms responsible for a break of immune tolerance toward hepatocytes.