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Cholangiocytes and primary biliary cirrhosis: prediction and predication.

Although there have been descriptions of primary biliary cirrhosis (PBC) for more than 100 years, this condition first attracted the attention of immunologists in 1965, when patients’ sera were found to have antimitochondrial antibodies (AMAs) (1). The mitochondrial autoantigens, which are highly conserved among mitochondria and even chloroplasts (2) of divergent species, have been identified as the E2 components of the 2-oxo-acid dehydrogenase family — particularly the 74-kDa E2 subunit of the pyruvate dehydrogenase complex, which catalyzes the formation of acetyl CoA. The structurally and functionally related mitochondrial proteins BCOADC-E2 and OGDC-E2, as well as the E3 binding protein (3), are also found as autoantigens in PBC patients. Work with recombinant autoantigens has shown that the presence of AMAs is virtually diagnostic of PBC and that, while they may be detected in the sera of asymptomatic people years before the clinical diagnosis of PBC, they are very rarely found in non-PBC individuals (4, 5). 
 
The B cell epitope of PDC-E2 is found on the lipoyl domains, and antibody binding occurs when the antigen is complexed with lipoic acid (6). In fact, there are only five proteins in mammals that contain lipoic acid, and four of the five are autoantigens in PBC. Lipoic acid is bound to the lysine residue of the inner lipoyl domain, where it functions as a swinging arm to capture electrons during oxidative phosphorylation. Related work using cloned PDC-E2–specific T cell lines shows that the immunodominant T cell epitope also falls within the lipoyl domains. Interestingly, the frequency of PDC-E2–specific CD4+ T cell precursors is 100-fold higher in the liver than in PBMCs (7) in PBC patients, suggesting that these cells are recruited to the liver during the progression of the disease. However, the precise pathogenic role of these T cells is still under investigation. 
 
Despite the advances in the molecular characterization of immunoreactivity, a number of unexplained questions remain regarding the epidemiology and tissue specificity of this disease (3). Why is PBC overwhelmingly more common in women? Why is PBC not found in childhood? Why are granulomas found, and why is eosinophilia present in periductal inflammatory infiltrates? Why is PBC relatively more specific for small bile ducts than large bile ducts? Why should PBC recur following liver transplantation? Why is the incidence of PBC so much higher in families with an index case, even when there is no obvious MHC class I or class II association? What is the significance of the observation that some monoclonal antibodies to mitochondria appear to uniquely stain the bile duct cells in patients with PBC? Finally, why does the immune response induce damage to only a minor population of cells, those of the small ducts and ductules of the biliary and salivary epithelia?