Autoantibodies to mitochondria (AMA, anti-M2) are a serologic hallmark of
primary biliary cirrhosis (PBC). These react with three structurally and functionally related multienzymic complexes, the 2-oxoacid
dehydrogenase complexes, but chiefly with the E2 subunit of
pyruvate dehydrogenase complex (PDC-E2). Their very dose (95%) and specific association with PBC underpins the autoimmune concept of pathogenesis of that disease, notwithstanding several non-congruent features. Detailed studies, including structural analysis of
epitopes, do not disclose how these
autoantibodies originate. Their ubiquity in PBC has overshadowed the existence of a second set of relatively PBC-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 the promyelocytic
leukemia antigen; and a recently identified
autoantigen, SOX13. Certain of these reactants are
DNA-binding proteins with transcriptional regulatory activity. Thus serum from individuals with the same clinical syndrome can have autoimmune reactivity to disparate mitochondrial and nuclear constituents in different cellular compartments. Antibody probing of phage displayed
random peptide libraries, together with
epitope scanning using overlapping sequential octameric
peptides from the PDC-E2 sequence, showed that the discontinuous motifs MH, FV(E) and SYP contributed to a predicted conformational antibody
epitope in the inner lipoyl domain of PDC-E2.