HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases.

Abstract

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.

• Authors: S Shimoda, M Nakamura, H Ishibashi, K Hayashida, Y Niho
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 181 Issue 5 Pg. 1835-45 (May 01 1995) ISSN: 0022-1007 [Print] United States
• PMID: 7536796 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Epitopes
• HLA-DR Antigens
• HLA-DRB4 Chains
• Peptide Fragments
• Pyruvate Dehydrogenase Complex

Topics

• Adult
• Aged
• Amino Acid Sequence
• Autoimmune Diseases (immunology)
• Binding Sites
• Epitopes
• HLA-DR Antigens (immunology)
• HLA-DRB4 Chains
• Humans
• Liver Cirrhosis, Biliary (immunology)
• Lymphocyte Activation
• Middle Aged
• Molecular Sequence Data
• Peptide Fragments (immunology)
• Pyruvate Dehydrogenase Complex (immunology)
• T-Lymphocytes (immunology)