Similar to other autoimmune diseases, there are intense humoral and cellular responses to intracytoplasmic antigens in primary biliary cirrhosis (PBC). The autoantigens against antimitochondrial antibodies (AMAs) in PBC are located on the inner mitochondrial membrane and are identified as members of the 2-oxo-acid dehydrogenase complexes (2-OADCs), of which the E2 subunit of pyruvate dehydrogenase complex (PDC-E2) is the major autoantigen; AMAs are present in approximately 90 to 95% of PBC sera. An orchestrated immune response against the intrahepatic biliary epithelial cell (BEC) through 2-OADC-specific CD4+ helper T cells and CD8+ CTL are thought to be the major players in the immunological destruction of BECs in PBC. We believe that a prior/ primary event of specific intrahepatic BEC malfunction (possibly caused by environmental insults such as xenobiotics and microorganisms) is responsible for the breaking of self-tolerance to 2-OADC and leads to BEC destruction. The generation of 2-OADC-specific T cells further accelerates the damage of BEC. In addition, immunoglobulin A AMAs may participate in the destruction of BECs by damaging mitochondria.
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