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Detection of HLA Predominance and Novel HLA Shared Epitopes in Biliary Atresia

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Project Summary/Abstract Biliary atresia (BA) is a progressive, inflammatory, sclerosing cholangiopathy which presents in infancy and leads to bile duct obstruction, biliary cirrhosis and the need for liver transplantation in the majority of patients. A current theory regarding the pathogenesis of BA entails a virus-induced autoimmune-mediated destruction of the biliary tree leading to cirrhosis. Evidence for a disease being autoimmune in nature includes identification of predominant human leukocyte antigens (HLA) alleles associated with the disease. The hypothesis being examined is that BA is associated with an increased frequency of certain HLA genotypes and novel shared HLA epitopes, suggesting a role for autoimmunity in the pathogenesis of disease. In Specific Aim I we will determine predominant HLA genotypes with increased frequency in BA patients compared to normal controls by high resolution genotyping of class I and class II HLA molecules. Furthermore, analysis of HLA predominance in the severe form of BA (death or transplant by 2 years of age) will be compared to the mild form (>5 years old and alive with native liver) in order to identify disease severity-specific HLA associations. Specific Aim II entails identification of BA-specific epitopes within HLA alleles utilizing a computer algorithm that permits screening large numbers of alleles to search for shared epitopes. Apparently disparate HLA alleles may have similar antigen-binding sites, known as shared epitopes, and thereby overlap in their capacity to present antigens. Thus in autoimmune and immune-mediated diseases, the incidence and severity of the disease may be related to the number of shared epitopes present. The significance of this project is that it will decisively answer the question of HLA predominance in BA in the United States. Furthermore, it is now clear that epitopes shared between HLA alleles are the actual susceptibility markers. Dr. Freed and colleagues have developed a computer program that can quantitate epitope differences based on the stereochemical effects of amino acid substitutions. This algorithm can be used to search millions of possible epitopes in order to discover those that are shared within BA patients. These studies will revolutionize the way in which HLA data are analyzed and will have the capability to predict possible peptides that are triggering the autoimmune response in BA.
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