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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
Author(s) -
Shigematsu Hirohisa,
Shimoda Shinji,
Nakamura Minoru,
Matsushita Sho,
Nishimura Yasuharu,
Sakamoto Norihiro,
Ichiki Yasunori,
Niho Yoshiyuki,
Gershwin M. Eric,
Ishibashi Hiromi
Publication year - 2000
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2000.18714
Subject(s) - molecular mimicry , t cell receptor , epitope , primary biliary cirrhosis , t cell , biology , complementarity determining region , microbiology and biotechnology , antigen , antibody , immunology , monoclonal antibody , immune system
Abstract 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 Vβ in the group B–cloned T‐cell lines, while G, S, and/or R were frequently found in the CDR3 of the TCR Vβ in the group A–cloned T‐cell lines. These data provide a framework for understanding molecular mimicry among mitochondrial antigens.