Primary biliary cirrhosis (PBC) is a chronic cholestatic
liver disease characterized by the presence of antimitochondrial
autoantibodies in the serum. The major
antigens recognized by the
antibodies are the E2 components of the 2-oxo
acid dehydrogenase complexes, all of which possess covalently attached
lipoic acid cofactors. A bacterial etiology has been proposed for the disease, and patients'
antibodies are known to recognize the E2 subunits (E2p) of both mammalian and bacterial
pyruvate dehydrogenase complexes. Immunoblotting and ELISA inhibition techniques using extracts of Escherichia coli deletion strains, genetically restructured E2
polypeptides, and isolated lipoyl domains demonstrate that (i) the E2o subunit of the E. coli
2-oxoglutarate dehydrogenase complex is recognized by patients'
antibodies; (ii) the main immunogenic region of E2p lies within the lipoly domains; (iii) the presence of a lipoly residue within the domain is crucial for effective recognition by the
antibodies; and (iv) octanoylated E2p, octanoylated E2o, and octanoylated lipoyl domain, produced by a mutant deficient in lipoate biosynthesis, are recognized by patients'
antibodies but not as effectively as their lipoylated counterparts. These findings indicate that
antibodies in PBC patients' sera bind to a unique
peptide-cofactor conformation within the lipoyl domains of the E2
polypeptides and that this
epitope is partially mimicked by substituting the lipoyl cofactor with an octanoyl group.