2001 Fiscal Year Final Research Report Summary
Genetic factors Involved in the Pathogenesis of Autoimmune Disea
| Project/Area Number |
11357003
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Experimental pathology
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| Research Institution | JUNTENDO UNIVERSITY |
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Principal Investigator |
SHIRAI Toshikazu Department of Pathology, Juntendo University School of Medicine, Professer, 医学部, 教授 (30115860)
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| Co-Investigator(Kenkyū-buntansha) |
HAMANO Yoshitomo Department of Pathology, Juntendo University School of Medicine, Instructor, 医学部, 助手 (10281354)
JIANG Yi Department of Pathology, Juntendo University School of Medicine, Instructor, 医学部, 助手 (50276466)
HIROSE Sachiko Department of Pathology, Juntendo University School of Medicine, Assiclate Professer, 医学部, 助教授 (00127127)
NISHIMURA Hiroyuki Department of Biomedical Enginee, Toin Human Science and Technolog Center, Toin University of Yokoh, Professor, 工学部, 教授 (60189313)
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| Project Period (FY) |
1999 – 2001
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| Keywords | Autoimmunity / Genetics / Genome / Genome screening / Microsatellite / Multigeneic disease / SLE / Susceptibility genes |
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| Research Abstract |
Systemic lupus erythematosus (SLE) is a complex, multigenic autoimmune disease with a wide spectrum of clinical manifestations. Much of the pathology is attributed to deposition to various tissues of immune complexes continuously formed with autoantibodies ; thus, the pathogenesis is related to genetic dysregulation of self-reactive B cells. However. as the complexity of polygenic inheritance of SLE phenotypes is considerable, susceptibility loci and genes have not been identified precisely. To solve some such difficulties, we designed genetic studies on SLE using murine lupus models. Major difficulties were related to the fact that each specific aspect of diverse SLE phenotypes(clinical manifestations and immunological abnormalities)is mostly controlled separately by a different set of susceptibility loci. Involvement of positive and negative epistatic gene interactions often puzzles genetic analyses of SLE phenotypes. Studies on genetic regulations of emergence, clonal expansion, differentiation and maturation of self-reactive B cells showed that they are regulated at different stages by different of SLE-susceptibility. There were several positional candidate polymorphic genes that were potentially responsible for the abnormal B cell phenotypes. Further studies on the identification of susceptibility genes and their functions are ongoing using genetically manipulated and recombinant mice. Such knowledge will lead to elucidation of genetic and cellular mechanisms involved in dysregulation of self-reactive lymphocytes in the pathogenesis of SLE.
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[Publications] Jiang, Y., Hirose, S., Sanokawa-Akakura, R., Abe, M., Mi, X., Li, N., Miura, Y., Shirai, J., Zhang, D., Hamano, Y.&Shitai, T.: "Genetically-determined aberrant downreguration of FCRIIBI in germinal center B cells associated with hyper-IgG and IgG autoantibodies in murine systemic Iupus erythematosus"Int. Immunol.. 11. 1685-1691 (1999)
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[Publications] Shirai, J., Iba, A., Jiang, Y., Sanokawa-Akikura, R., Miura, Y., Yan, K., Hamano, Y., Hirose, S.&Shirai, T.: "Genetic polymorphism of murine tissue plasminogen activator associated with antiphospoligid syndrome"Genes and Immunity. 1. 130-136 (1999)
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[Publications] Jiang, Y., Hirose, S., Abe, M., Sanokawa-Akikura, R., Ohtsuji, M., Mi, X., Li, N., Xiu, Y., Zhang, D., Shirai, J., Hamano, Y., Fujii, H.&Shirai, T.: "Polymorphisms in IgG Fc receptor IIB regulatory regions associated with autoimmune susceptibility."Immunogenetics. 51. 429-435 (2000)
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[Publications] Jiang, Y., Ohtsuji, M., Abe, M., Li, N., Xiu, Y., Wen, X-S., Shirai, T.&Hirose, S: "Polymorphisms and chromosomal mapping of the murien gene for B-cell activating factor belonging to the tumor factor family (BAFF) and association with the autoimmune phenotype."Immunogenetics. 53. 810-813 (2001)
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