| Co-Investigator(Kenkyū-buntansha) |
NISHIMURA Yasuharu Kumamoto University, Graduate School of Medical Sciences, Professor, 大学院・医学系研究科, 教授 (10156119)
FUKUI Yoshinori Kyushu University, Graduate School of Medical Sciences, Associate Professor, 医学研究院, 助教授 (60243961)
SASAZAKI Takehiko Kyushu University, Graduate School of Medical Sciences, Professor, 医学研究院, 教授 (50014121)
MATSUSHITA Sho Kumamoto University, Graduate School of Medical Sciences, Associate Professor, 大学院・医学系研究科, 助教授 (50167649)
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| Research Abstract |
In patients with primary biliary cirrhosis (PBC), the anti-mitochondrial antibody response is primarily directed against E2 components of the pyruvate dehydrogenase complex (PDC-E2), 2-oxoglutarate dehydrogenase complex (OGDC-E2), the branched chain 2 oxo-acid dehydrogenase complex (BCOADC-E2), and the E3 binding protein (E3BP) of PDC. We have previously demonstrated that the PDC-E2 163-176 peptide (GDLLAEIETDKATI) is the immunodominant autoreactive T cell epitope which is restricted by HLA DR53 (DRA1^*0101/DRB4^*0101). To address the issue of molecular mimicry and cross-recognition among mitochondrial antigens, we analyzed the reactivity to a series of single amino acid substituted peptides of ten cloned T cell lines derived from both healthy subjects and patients with PBC which recognize a single T cell receptor (TCR) ligand, PDC-E2 163-176 peptide/HLA DR53. In addition, we performed antagonism and agonism assays using analogue peptides to determine the most critical TCR contact resi
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due(s). Our data demonstrate that the overall fine specificities are unique for every single T cell clone but that these T cell clones are roughly categorized into two distinct groups based on their recognition motifs of TCR ligand ; the ^<170>ExDK^<173> (group A) and the ^<168>EIExD^<172> (group B). ^<170>E is the most critical TCR contact residue for both groups of cloned T cell lines whereas ^<173>K and ^<168>E are critical TCR contact residues for group A and group B cloned T cell lines, respectively. Importantly, both group A and group B T cell clones were established from the peripheral blood of both patients with PBC and healthy subjects. Most importantly, some of the group A cloned T cell lines cross-react to human E3BP 34-47, human OGDC-E2 100-113, and several peptides derived from various microbial proteins carrying an ExDK motif, while group B cloned T cell lines react 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 may provide a molecular basis for understanding molecular mimicry and cross-recognition among mitochondrial antigens in PBC. Less
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