The immunology of primary biliary cirrhosis: the end of the beginning?

The chronic liver disease primary biliary cirrhosis (PBC) is characterised by autoreactive B-cell and T-cell responses directed against mitochondrial antigens. In recent years these responses have been extensively characterised and the principal PBC associated autoantigen identified as pyruvate dehydrogenase complex (PDC). The identification of anti-PDC responses (present in over 95% of PDC patients) has given rise to important questions pertinent to our understanding of the pathogenesis of PBC. What specific role to anti-PDC responses play in target cell damage? How and why does immune tolerance break down to as highly conserved and ubiquitously expressed self-antigen as PDC? Why does breakdown in tolerance to an antigen present in all nucleated cells result in damage restricted to the intra-hepatic bile ducts? In attempting to answer these key questions we have, in this review, proposed a unifying hypothesis for the pathogenesis of PBC.