Primary biliary cirrhosis (PBC) has been considered to be a 'model auto-immune disease' for more than two decades. However, the underlying pathophysiology of PBC and the relationship with the associated serological abnormalities have been hitherto elusive. Beginning in 1987 with the cloning and subsequent identification of the mitochondrial autoantigens of PBC, progress has come rapidly and we can now sketch several potential pathogenic pathways through which disease occurs. More than 90% of patients with PBC produce autoantibodies to mitochondria, and the antoantigens involved have been identified as related components of the 2-oxo-acid dehydrogenase complexes (OADC), including the E2 subunits of the pyruvate dehydrogenase complex (PDC-E2), the branched chain 2-oxo-acid dehdrogenase complex and 2-oxo-glutarate dehydrogenase complex, Protein X and E1 alpha. The cDNAs of each of the E2 subunits of OADC have been cloned and characterized. Moreover, the epitopes of the antimitochondrial antibodies (AMA) have been mapped at the highly conserved lipoyl domain E2 subunits. The use of recombinant peptides produced by these clones has greatly facilitated the detection of AMA. In addition, nucleotide sequence analysis of PDC-E2 specific human monoclonals and combinatorial Fabs strongly suggests that these autoantibodies are derived from clonal selection of a restricted set of somatically mutated immunoglobulin germline genes. Most interestingly, however, the use of monoclonal reagents to PDC-E2 has demonstrated that there is an increased expression of either PDC-E2, or a cross-reactive molecule, on the luminal surface of biliary epithelial cells in patients with PBC. These data provide a scenario to explain the tissue specific pathology associated with PBC and several interesting underlying pathophysiological mechanisms.
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