EXCEED THE SPACE PROVIDED. Primary biliary cirrhosis (PBC) is a progressive autoimmune disease characterized by intrahepatic bile duct destruction and antimitochondrial antibodies (AMA) directed to the 2-oxoacid dehydrogenase enzymes, most commonly PDC-E2. PBC is one of a group of autoimmune diseases characterized by a localized immune attack on a specific cell type, even though the autoantigens are ubiquitous. A detailed understanding of the induction and pathogenesis of PBC will lead to new avenues for therapeutic modalities and provide insights into the etiology of this group of conditions. Our work has documented specific functional abnormalities in the innate and adaptive immune system, including hyper-responding IgM memory B cells, increases in both hepatic NK-T cells and autoantigen-specific CD4 and CD8 T cells. We have also demonstrated that autoantigen-specific IgA induces early biliary epithelial cells (BEC) apoptotic changes and that BEC have unique properties that alter the immunogenicity of mitochondrial autoantigens. These data lead to a model in which PBC is produced by a mucosally-driven response, with pathology mediated by both innate and adaptive immune mechanisms. We will continue our original three aims with a focus on mechanisms. First, we hypothesize that innate immunity plays critical roles in the breakdown of tolerance and that signaling pathways by which B cells secrete abnormally high IgM levels is the earliest disease event; unraveling this process is critical for defining the earliest pathogenic events. Second, the adaptive arm of the immune system will be examined for phenotypic and functional capacity of antigen-specific CD4 and CDS T cells. Third, we will examine the BEC biology using human BEC and our surrogate IgA-receptor transfected MDCK cells and ask whether the expression and/or processing of PDC-E2 in cells transiting IgA AMA is affected in a way that might give rise to immunogenic autopeptides. Use of FRET will determine where in the cell transcytosed anti-PDC-E2 IgA binds and the consequences for mitochondrial survival by measurements of autophagy. We will take advantage of our unique reagents, including recombinant autoantigens, recombinant IgA AMA, purified dimeric IgA,human BEC, autoreactive CD4 and CDST cell lines and MHC Class I tetramers. These studies will advance our understanding of the molecular basis of the immune response in PBC, particularly adaptive and innate pathways, and suggest possible means of therapeutic intervention.
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