Autoimmunity and primary biliary cirrhosis

The history of primary biliary cirrhosis (PBC) began in 1851, with autoimmunity introduced in 1958 and expanded from the 1960s on. In PBC, autoantibodies are present to mitochondria-located antigens (AMA) and to nuclear-located antigens (ANA). The AMA react with E2 subunits of three members of the 2-oxoacid dehydrogenase complex family, but most frequently with pyruvate dehydrogenase complex (PDC); the inner lipoyl domain of PDC-E2 contains a major B- and T-cell epitope. The ANA react with three nuclear components, centromeric proteins, nuclear dot proteins and nuclear pore complex. Autoimmune diseases including PBC reflect a failure in mechanisms of self-tolerance which is developed in central lymphoid tissues in embryonic life by deletion of self-reactive lymphocytes, and maintained in peripheral tissues in post-natal life by regulatory processes. Primary biliary cirrhosis has not yet been identified with failure in any one particular tolerance mechanism. Genetic influences are revealed by familial occurrences and by associations with HLA alleles, and environmental influences by epidemiological data. A lead to pathogenesis is the accumulation uniquely in PBC of PDC-E2-like material at the plasma membrance of biliary epithelial cells (BECs). Although the origin of this accumulation of PDC-E2 at the surface of BECs is uncertain, it provides a credible ‘tissue-specific’ target for an autoimmune attack by T and B lymphocytes at the site of the actual pathology.