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 complex (PDC)-E2 peptides from four different patients with primary biliary cirrhosis using 33 different peptides of 17-20 amino acid residues 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 corresponds to the inner lipoyl domain of PDC-E2. The HLA restriction molecules for this epitope were all identified as HLA DRB4 0101. The common essential amino acids of this epitope for these T cell clones were E, D, and K at positions 170, 172, and 173, respectively; other crucial amino acids for this epitope differed in each T cell clone. In addition, the alanine-substituted peptides at positions 170 and 173, but not 172, inhibited the proliferation of all T cell clones induced by the original peptide of human PDC-E2 163-176, indicating that amino acid D at position 172 is a critical MHC-binding site for all T cell clones tested. Interestingly, all T cell clones reacted to PDC-E2 peptide 36-49 (GDLIAEVETDKATV), which corresponds to the outer lipoyl domain of human PDC-E2. Furthermore, one T cell clone cross-reacted with exogenous antigens such as Escherichia coli PDC-E2 peptide 31-44/134-147/235-248 (EQSLITVEGDKASM), which has an EXDK sequence. This is a definite demonstration of the presence of molecular mimicry at the T cell clonal level in human autoimmune diseases. It is also considered possible to design peptide-specific immunotherapy based on the findings of T cell autoepitopes in primary biliary cirrhosis.
Shimoda
S
S
First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Nakamura
M
M
Ishibashi
H
H
Hayashida
K
K
Niho
Y
Y
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001327:Autoimmune Diseases / Q000276:immunology*; D001665:Binding Sites; D000939:Epitopes; D006684:HLA-DR Antigens / Q000276:immunology*; D059845:HLA-DRB4 Chains; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D008213:Lymphocyte Activation; D008875:Middle Aged; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D011768:Pyruvate Dehydrogenase Complex / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D000939:Epitopes; D006684:HLA-DR Antigens; D059845:HLA-DRB4 Chains; D010446:Peptide Fragments; D011768:Pyruvate Dehydrogenase Complex