1997 Fiscal Year Final Research Report Summary
MOLECULAR MECHANISM OF IMMUNE REGULATION IN PRIMARY BILIARY CIRRHOSIS
| Project/Area Number |
08457155
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
内科学一般
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
ISHIBASHI Hiromi KYUSHU UNIVERSITY,FACULTY OF MEDICINE,ASSOCIATE PROFESSOR, 医学部, 助教授 (80127969)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIMURA Yasuharu KUMAMOTO UNIVERSITY,FACULTY OF MEDICINE,PROFESSOR, 医学部, 教授 (10156119)
HAYASHIDA Kazuhiro KYUSHU UNIVERSITY,FACULTY OF MEDICINE,INSTRUCTOR, 医学部, 助手 (60180981)
NAKAMURA Minoru KYUSHU UNIVERSITY,FACULTY OF MEDICINE,INSTRUCTOR, 医学部, 助手 (40217906)
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| Project Period (FY) |
1996 – 1997
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| Keywords | Primary biliary cirrhosis / Autoimmune disease / Immune regulation / T cell / T cell receptor / T cell epitope / Molecular mimicry / Immune response |
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| Research Abstract |
1.Mapping of B cell epitope of mitochondrial antigen.
Using anti-mitochondrial antibody obtained from the oatient with primary biliary cirrhosis (PBC), we performed epitope mapping of a major mitochondrial antigen, E2 component of pyruvate dehydrogenase complex (PDC-E2). The epitopes are mapped in the regions around lipoic acid-bound lysine in the outer and innner lypoil domains. Each Asp of the N-terminal side is important to bind antibody. Lypoic acid did not influence immunoreactivity with the antibody.
2.Cloning of T cell specific for mitochondrial antigen epitope mapping.
We established six T cell clones specific for PDC-E2 peptides from four different patients with PBC using 33 different peptides of 17-20 amino acid residues corresponding to human PDC-E2 as stimulating antigens (Ags). The minimal T cell of these six T cell clones were all mapped to the same region of the PDC-E2 peptide 163-176 (GDLLAEIETDKATI). The common essential amino acids of this epitope for these T cell clones
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were E,D and K at positions 170,172 and 173, respectively. One T cell clone cross-reacted to exogenous Ags such as E.coli PDC-E2 peptide which has an EXDK sequence. This is the definite demonsration of the presence of molecular mimicry at the T cell clonal level in human autoimmune diseases.
T cell receptor
We found that frequency of the T cells reactive to the human PDC-E2 163-176 peptide is significantly increased in the peripheral blood of patients with PBC as compared to healthy subjects. We also confirmed that these T cells were all restricted with HLA-DRB4^<**>01 (DR53). These results together with the evidence that the immunodominant B cell epitope overlaps with the human T cell epitope of the PDC-E2 antigen indicate that the T cells reactive to this epitope are closely associated with the pathogenesis of PBC.The Vbeta-and the Jbeta-gene usages were diverse among the T cell clones (Vbeta11-Lbeta1.4, Vbeta8-Jb1.2, Vbeta12-Jb2.1, Vbeta10-Jbeta1.5 and Vbeta20-Jbeta2.1). By contrast, in the third complementarity determining region (CDR3), G was frequently found and GXG or GXS motif was identified in all T cell clones. Moreover, RGXG motif was found in three clones generated from two patients.These results indicate that the T cells may recognize the ligand (the human PDC-E2 163-176 peptide/HLA-DR53 complex) using the limited motif in the CDR3 region and that the design of CDR3-specific immunotherapy wouled be possible using these motifs. Less
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[Publications] Ichiki, Y., Shimoda, S., Hara, H., Sigemats, K., Nakamura, M., Hayashida.K, .Ishibashi, H., Niho, Y.: "Analysis of T Cell Receptor β of the T Cell Clones Reactive to the Human PDC-E2 163-176 Peptide in the context of HLA-DR53 in Patients with Primary Biliary Cirrhosis" Hepatology. 26. 728-733 (1997)
Description
「研究成果報告書概要(和文)」より
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[Publications] Shimoda, S., Van de Water, J., Ichiki, Y., Shigematsu, H., Nakamura, M., Ansari, A.A., Ishibashi, H., Gershwin, M.E.: "The T cell immunobiology of primary biliary cirrhosis." Molecular and genetic approaches to Diseases-Immunology,Hematology and Oncology,edit.Y,Niho,Kyushu University Press,Fukuoka. (in press). (1998)
Description
「研究成果報告書概要(和文)」より
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[Publications] Ichiki, Y., Shimoda, S., Hara, H., Sigematsu, K., Nakamura, M., Hayashida, K., Ishibashi, H M., Niho, Y.: "Analysis of T cell receptor of the T cell clones reactive to the human PDC-E2 163-176 peptide in the context of HLA-DR53 in patients with primary biliary cirrhosis." Hepatology. 26(3). 728-733 (1997)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Ichiki, Y., Shimoda, S., Sigematsu, K., Nakamura, M., Hayashida, K., Ishibashi, H., Niho, Y.: "PDC-E2 reptide reactive T cells and molecular mimicry in primary biliary cirrhosis." Gastroenterology and Immunology 33, My Life. 177-180 (1997)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Shimoda, S., Van de Water, J., Ichiki, Y., Shigematsu, H., Nakamura, M., Ansari, A.A., Ishibashi, H., Gershwin, M.E.: "The T cell immunobiology of primary biliary cirrhosis" Molecular and genetic approaches to Diseases-Immunology, Hematology and Oncology, edit. Y.Niho, Kyushu University Press, Fukuoka. (1998)
Description
「研究成果報告書概要(欧文)」より
