2004 Fiscal Year Final Research Report Summary
Functional analysis of AIRE, a gene responsible for the hereditary type of autoimmune disease.
| Project/Area Number |
15390315
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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 |
膠原病・アレルギー・感染症内科学
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| Research Institution | The University of Tokushima |
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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)
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| 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)
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| Project Period (FY) |
2003 – 2004
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| Keywords | AIRE / autoimmune disease / immunoregulatory T cell / self-tolerance / thymus / PHD / E3 ligase |
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| 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.
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