Biliary atresia (BA) is a progressive, inflammatory, sclerosing cholangiopathy that presents in infancy and leads to bile duct obstruction, biliary cirrhosis and the need for liver transplantation in the majority of patients. The etiology of BA is not known;a proposed theory is that the bile duct injury is initiated by a viral infection, followd by a progressive, autoimmune-mediated response targeting bile duct epithelia. Our laboratory and others have established the contribution of T cell-mediated inflammation and autoimmunity to bile duct injury in the rotavirus-induced mouse model of BA and in limited human studies. Recent data from our laboratory reveals that B cell-deficient mice are protected from BA, suggesting that B cells are essential to the development of bile duct injury. Research in murine models and humans have demonstrated the significant contribution of B cells to the onset and progression of many different autoimmune diseases, despite the fact that the organ-specific injury in these diseases was traditionally thought to be solely due to T cell-mediated inflammation. The specific hypotheses to be tested in this proposal are two-fold: 1. B cells play a critical role in the development and progression of bile duct injury and obstruction in murine BA;and 2. BA patients have circulating serum autoantibodies that may provide clues to disease pathogenesis and serve as prognostic biomarkers of disease severity.
Specific Aim 1 : Establish the contribution of B cells to development of bile duct injury in murine BA through use of B cell knockout and transgenic mice. Investigations of knockout and transgenic mice will establish the B cell mechanism involved in bile duct injury, specifically B cell antigen presentation versus immunoglobulin production.
Specific Aim 2 : Determine the contribution of B cells to progression of bile duct injury in murine BA through administration of B cell-depleting agents.
This aim has direct translational implications to potential new therapies for human BA.
Specific Aim 3 : Define serum autoantibodies in BA patients and determine correlation with disease severity. Serum autoantibodies will be identified from a protein autoantigen microarray. The utility of autoantibodies in BA as serum biomarkers of disease severity will also be assessed. Significance: These investigations will add a unique perspective and increase our understanding of how B cells function in the setting of virus-induced autoimmunity. Discovery of autoantibodies in BA would provide clues to autoimmune mechanisms of pathogenesis and function as useful biomarkers to gauge severity of disease or response to novel therapies. The potential benefit of B cell depleting agents in alleviating progression of disease could change the paradigm of how physicians care for BA patients.
Biliary atresia is the number one indication for liver transplantation in children, yet the cause of this devastating disease is not known. Knowledge gained regarding the role of the humoral immunity (specifically, B cell antigen presentation function and autoantibodies) in bile duct injury will lead to an enriched understanding of the cause of this disease and offer insight into new therapies aimed at stopping the immune-mediated attack on bile ducts. Autoantibodies identified may also function as biomarkers of disease and may be used as tools to measure progression of disease and response to new therapies.