Identification of the dihydrolipoamide acetyltransferase subunit of the human pyruvate dehydrogenase complex as an autoantigen in halothane hepatitis: Molecular mimicry of trifluoroacetyl‐lysine by lipoic acid

Trifluoroacetylated (CF₃CO‐) proteins, elicited upon exposure of animals or humans to halothane, were recognized by anti‐CF₃CO antibody, monospecific for the hapten derivative N⁶‐trifluoroacetyl‐l‐lysine. Anti‐CF₃CO antibodies cross‐reacted with the dihydrolipoamide acetyltransferase (E2 subunit) of pyruvate dehydrogenase, indicating that epitopes on the E2 subunit of pyruvate dehydrogenase molecularly mimic those on CF₃CO‐proteins. Lipoic acid, the prosthetic group of the E2 subunit of pyruvate dehydrogenase was essential in this process, in that only the lipoylated form of the recombinantly expressed inner lipoyl domain of the human E2 subunit of pyruvate dehydrogenase, but not the unlipoylated form, was recognized by anti‐CF₃CO antibody. Furthermore, based on a high degree of structural relatedness, both CF₃CO‐Lys and (6RS)‐lipoic acid, as well as the lipoylated peptide ETDK_lipoylATIG specifically inhibited the recognition by anti‐CF₃CO antibody of the E2 subunit of pyruvate dehydrogenase, of trifluoroacetylated rabbit serum albumin and of human liver CF₃CO‐proteins. In sera of patients was halothane hepatitis, autoantibodies with properties identical to those of anti‐CF₃CO antibody were identified which could not discriminate between CF₃CO‐proteins and the E2 subunit of pyruvate dehydrogenase. These data suggest that the E2 subunit pyruvate of dehydrogenase is an autoantigen in halothane hepatitis and that molecular mimicry of CF₃CO‐proteins by the E2 subunit of pyruvate dehydrogenase is due to the similar structures of CF₃CO‐Lys and lipoic acid.