The peculiar autoimmunity of primary biliary cirrhosis

Autoantibodies to mitochondria (AMA, anti-M2) are a serologic hallmark of p rimary biliary cirrhosis (PBC). These react with three structurally and fun ctionally related multienzymic complexes, the 2-oxoacid dehydrogenase compl exes, but chiefly with die E2 subunit of pyruvate dehydrogenase complex (PD C-E2). Their very dose (95%) and specific association with PBC underpins th e autoimmune concept of pathogenesis of that disease, notwithstanding sever al non-congruent features. Detailed studies, including structural analysis of epitopes, do nor disclose how these autoantibodies originate. Their ubiq uity in PBC has overshadowed the existence of a second set of relatively PB C-specific autoantibodies to nuclear antigens for which reactants have been . cloned and characterized. These include centromeric proteins; proteins of the nuclear pore complex; nuclear dot proteins, which include Sp-100 and t he promyelocytic leukemia antigen; and a recently identified autoantigen, S OX13. Certain of these reactants are DNA-binding proteins with transcriptio nal regulatory activity Thus serum from individuals with the same clinical syndrome can have autoimmune reactivity to disparate mitochondrial and nucl ear constituents in different cellular compartments. Antibody probing of ph age displayed random peptide libraries, together with epitope scanning usin g overlapping sequential octameric peptides from the PDC-E2 sequence, showe d that the discontinuous motifs MH, FV(E) and SIP contributed to a predicte d conformational antibody epitope in the inner lipoyl domain of PDC-E2.