HLA DRB4 0101-RESTRICTED IMMUNODOMINANT T-CELL AUTOEPITOPE OF PYRUVATE-DEHYDROGENASE COMPLEX IN PRIMARY BILIARY-CIRRHOSIS - EVIDENCE OF MOLECULAR MIMICRY IN HUMAN AUTOIMMUNE-DISEASES

We established six T cell clones specific for pyruvate dehydrogenase c omplex (PDC)-E2 peptides from four different patients with primary bil iary cirrhosis using 33 different peptides of 17-20 amino acid residue s corresponding to human PDC-E2 as stimulating antigens. The minimal T cell epitopes of these six T cell clones were all mapped to the same region of the PDC-E2 peptide 163-176 (GDLLAEIETDKATI), which correspon ds to the inner lipoyl domain of PDC-E2. The HLA restriction molecules for this epitope were all identified as HLA DRB4 0101. The common ess ential amino acids of this epitope for these T cell clones were E, D, and K at positions 170, 172, and 173, respectively; other crucial amin o acids for this epitope differed in each T cell clone. In addition, t he alanine-substituted peptides at positions 170 and 173, but not 172, inhibited the proliferation of all T cell clones induced by the origi nal peptide of human PDC-E2 163-176, indicating that amino acid D at p osition 172 is a critical MHC-binding site for all T cell clones teste d. Interestingly, all T cell clones reacted to PDC-E2 peptide 36-49 (G DLIAEVETDKATV), which corresponds to the outer lipoyl domain of human PDC-E2. Furthermore, one T cell clone cross-reacted with exogenous ant igens such as Escherichia coli PDC-E2 peptide 31-44/134-147/235-248 (E QSLITVEGDKASM), which has an EXDK sequence. This is a definite demonst ration of the presence of molecular mimicry at the T cell clonal level in human autoimmune diseases. It is also considered possible to desig n peptide-specific immunotherapy based on the findings of T cell autoe pitopes in primary biliary cirrhosis.