Autoreactive responses to pyruvate dehydrogenase complex in the pathogenesis of primary biliary cirrhosis

Primary biliary cirrhosis (FBC) is a cholestatic liver disease characterise d by immune-mediated destruction of the biliary epithelial cells (BEC) Lini ng the intrahepatic bile ducts (non-suppurative destructive cholangitis (NS DC)). Autoantibody and autoreactive T-cell responses specific for the self- antigen pyruvate dehydrogenase: complex (PDC) are almost ubiquitous in PBC patients, leading to the view that the disease has an autoimmune aetiology. Autoreactive responses in PBC appear to be directed at the E2 and at the E 3-binding protein (E3BP) (protein X) components of PDC, with the dominant B -cell and T-cell epitopes in E2 (fewer data are available for E3BP) spannin g the inner (of two) lipoic acid-binding domains. The causal link between t he breakdown of self-tolerance to PDC (particularly at the T-cell level) an d the development of NSDC has been emphasised by the demonstration, in a mu rine model (experimental autoimmune cholangitis), that sensitisation with P DC of mammalian origin results in a breakdown of both B-cell and T-cell tol erance to murine PDC accompanied by the development of NSDC. An increasing understanding of the role played by PDC-specific autoreactive T cells in th e pathogenesis of FBC has led us to examine the role played by the target c ells in PBC (BEC) in both the inducer and effector mechanisms responsible f or PBC.