11050037

pubmed:Citation

5

The anti-mitochondrial antibody response in primary biliary cirrhosis (PBC) is primarily directed at E2 components of PDC, OGDC, and BCOADC, and E3BP. Previous work has shown that the immunodominant autoreactive T- cell epitope is the PDC-E2 163-176 peptide, restricted by HLA DR53. To address molecular mimicry and cross-recognition among mitochondrial autoantigens, we analyzed reactivity, including agonism and antagonism assays, to a series of single amino acid-substituted peptides using cloned T-cell lines in PBC and controls. Interestingly, fine specificities were unique for every single T-cell clone, but the clones could be categorized into two distinct groups based on recognition motifs of the T-cell receptor (TCR) ligand: group A (170)ExDK(173) and group B (168)EIExD(172). (170)E is the most critical TCR contact residue for both groups of cloned T-cell lines, whereas (173)K and (168)E are the critical TCR contact residues for group A and group B cloned T-cell lines, respectively. More importantly, some group A-cloned T-cell lines cross-reacted to human E3BP 34-47, human OGDC-E2 100-113, and several peptides derived from various microbial proteins carrying an ExDK motif, whereas group B-cloned T-cell lines reacted only to E3BP 34-47 carrying an EIExD motif. Furthermore, an RGxG motif was exclusively found in the complementarity-determining region (CDR3) of the TCR Vbeta in the group B-cloned T-cell lines, while G, S, and/or R were frequently found in the CDR3 of the TCR Vbeta in the group A-cloned T-cell lines. These data provide a framework for understanding molecular mimicry among mitochondrial antigens.

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0270-9139

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901-9

pubmed-meshheading:11050037-Amino Acid Sequence, pubmed-meshheading:11050037-Amino Acid Substitution, pubmed-meshheading:11050037-Antibody Specificity, pubmed-meshheading:11050037-Autoantigens, pubmed-meshheading:11050037-Cell Division, pubmed-meshheading:11050037-Cell Line, pubmed-meshheading:11050037-Cross Reactions, pubmed-meshheading:11050037-Dihydrolipoyllysine-Residue Acetyltransferase, pubmed-meshheading:11050037-Epitopes, pubmed-meshheading:11050037-Humans, pubmed-meshheading:11050037-Immunodominant Epitopes, pubmed-meshheading:11050037-Liver Cirrhosis, Biliary, pubmed-meshheading:11050037-Mitochondria, pubmed-meshheading:11050037-Molecular Mimicry, pubmed-meshheading:11050037-Molecular Sequence Data, pubmed-meshheading:11050037-Peptide Fragments, pubmed-meshheading:11050037-Pyruvate Dehydrogenase Complex, pubmed-meshheading:11050037-Receptors, Antigen, T-Cell, alpha-beta, pubmed-meshheading:11050037-T-Lymphocytes

Fine specificity of T cells reactive to human PDC-E2 163-176 peptide, the immunodominant autoantigen in primary biliary cirrhosis: implications for molecular mimicry and cross-recognition among mitochondrial autoantigens.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't