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Functional analysis of AIRE, a gene responsible for the hereditary type of autoimmune disease.

Research Project

Project/Area Number 15390315
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 膠原病・アレルギー・感染症内科学
Research InstitutionThe University of Tokushima

Principal Investigator

MATSUMOTO Mitsuru  The University of Tokushima, Institute for Enzyme Research, M.D., Ph.D., Professor, 分子酵素学研究センター, 教授 (60221595)

Co-Investigator(Kenkyū-buntansha) KURODA Noriyuki  The University of Tokushima, Institute for Enzyme Research, Ph.D., Assistant Professor, 分子酵素学研究センター, 助手 (50359915)
MATSUSHIMA Akemi  The University of Tokushima, Institute for Enzyme Research, Ph.D., Lecturer, 分子酵素学研究センター, 教務員 (70116862)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 2004: ¥6,400,000 (Direct Cost: ¥6,400,000)
Fiscal Year 2003: ¥7,400,000 (Direct Cost: ¥7,400,000)
KeywordsAIRE / autoimmune disease / immunoregulatory T cell / self-tolerance / thymus / PHD / E3 ligase
Research Abstract

Autoimmune regulator (AIRE) gene mutation is responsible for the development of organ-specific autoimmune disease with monogenic autosomal recessive inheritance. Although Aire has been considered to regulate the elimination of autoreactive T cells through transcriptional control of tissue-specific antigens in thymic epithelial cells, other mechanisms of AlRE-dependent tolerance remain to be investigated. We have established Aire-deficient mice, and examined the mechanisms underlying the breakdown of self-tolerance. The production and/or function of immunoregulatory T cells were retained in the Aire-deficient mice. The mice developed Sjogren's syndrome-like pathologic changes in the exocrine organs, and this was associated with autoimmunity against a ubiquitous protein, a-fodrin. Remarkably, transcriptional expression of α-fodrin was retained in the Aire-deficient thymus. These results suggest that Aire regulates the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus, at least against this ubiquitous protein. Rather, Aire may regulate the processing and/or presentation of self-proteins so that the maturing T cells can recognize the self-antigens in a form capable of efficiently triggering autoreactive T cells. We also show that the first PHD (PHD1) of AIRE mediates E3 ligase activity. The significance of this finding was underscored by the fact that disease-causing missense mutations in the PHD1 (C311Y and P326Q) abolished its E3 ligase activity. These results add a novel enzymatic function for AIRE, and suggest an indispensable role of the ubiquitin-proteasome pathway in the establishment of self-tolerance in which AIRE is involved.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (10 results)

All 2005 2004 Other

All Journal Article (7 results) Publications (3 results)

  • [Journal Article] Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice.2005

    • Author(s)
      Kuroda N, et al.
    • Journal Title

      Journal of Immunology 174

      Pages: 1862-1870

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Dependence of self tolerance on TRAF6-directed development of thymic stroma.2005

    • Author(s)
      Akiyama T, et al.
    • Journal Title

      Science (10.1126/science.1105677) (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Dependence of self-tolerance on TRAF6-directed development of thymic stroma.2005

    • Author(s)
      Akiyama T, et al.
    • Journal Title

      Science

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Dependence of self-tolerance on TRAF6-directed development of thymic stroma.2005

    • Author(s)
      Akiyama T, et al.
    • Journal Title

      Science, (10,1126/science.1105677) (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] AIRE functions as an E3 ubiquitin ligase.2004

    • Author(s)
      Uchida D, et al.
    • Journal Title

      Journal of Experimental Medicine 199

      Pages: 167-172

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] NF-κB-inducing kinaseestablishes self-tolerance in a thymic stroma dependent manner.2004

    • Author(s)
      Kajiura F, et al.
    • Journal Title

      Journal of Immunology 172

      Pages: 2067-2075

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Subcellular expression of autoimmune regulator is organized in a spatiotemporal manner.2004

    • Author(s)
      Akiyoshi H, et al.
    • Journal Title

      Journal of Biological Chemistry 279

      Pages: 33984-33991

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Publications] Minami A, et al.: "Increased insulin sensitivity and hypoinsulinemia in APS knockout mice"Diabetes. 52. 2657-2665 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Uchida D, et al.: "AIRE functions as an E3 ubiquitin ligase"Journal of Experimental Medicine. 199. 167-172 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kajiura F, et al.: "NF-κB-inducing kinaseestablishes self-tolerance in a thymic stroma dependent manner"Journal of Immunology. 172. 2067-2075 (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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