Primary biliary cirrhosis (PBC) is a human autoimmune liver disease characterized by progressive destruction of the intrahepatic biliary epithelial cells (BECs) eventually leading to cirrhosis and liver failure. The major autoantigen of PBC has been identified as the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), which is located in the mitochondria matrix. The thesis that intact PDC-E2 can be presented by BECs and/or interact with IgA via trancytosis and thereby initiate BEC specific injury in PBC is supported by the unique metabolic process of PDC-E2 (i.e. non-glutathiolated PDC-E2) during apoptosis of BECs, together with the capacity of BECs as antigen presenting cells and IgA trancytosis in BECs. Recent experimental evidence gives partial support for this thesis when it demonstrated the triad of BEC apoptopes, macrophages from PBC patients, and anti-mitochondrial antibodies (AMAs) interact to stimulate a burst of proinflammatory cytokines. An obstacle in the further exploration of pathogenesis in PBC is the absence of appropriate animal models. Our laboratory has developed a xenobiotic induced model of PBC following immunization of mice with 2-octynoic acid coupled to bovine serum albumin (2OA-BSA), an antigen selected following quantitative structure-activity relationship analysis of the PDC-E2. Recent data in humans with PBC has suggested that a major component of liver pathology is due to activation of innate immunity. We took advantage of our 2OA-BSA model and immunized mice with and without the addition of polyinosinic-polycytidylic acid (poly I:C), a viral RNA mimetic and TLR3 agonist. Importantly, our investigation revealed that 2OA-BSA-immunized mice exposed to poly I:C develop a profound exacerbation of their autoimmune cholangitis, including significant increases in CD8+infiltrating T cells, NK cells, Gr-1highCD11b+cells and proinflammatory cytokines. In addition, treated mice have evidence of fibrosis. These findings lend support to the concept that besides breakdown of self-tolerance, there is a requirement of a second "hit" during the breakdown process that leads to the perpetuation of disease and its exacerbation which more faithfully mimics human PBC. Our data also become a logical explanation for the recurrence of PBC following liver transplantation in the absence of major histocompatability complex compatibility.
|Advisor:||Gershwin, Merrill E.|
|Commitee:||Bowlus, Christopher L., Leung, Patrick S.C.|
|School:||University of California, Davis|
|School Location:||United States -- California|
|Source:||DAI-B 73/03, Dissertation Abstracts International|
|Keywords:||Autoimmune cholangitis, Innate immunity, Liver fibrosis, Primary biliary cirrhosis, Toll-like receptors, Xenobiotics|
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