| Project/Area Number |
11670745
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
NONOYAMA Shigeaki TOKYO MEDICAL AND DENTAL UNIVERSITY, DEPARTMENT OF PEDIATRICS, ASSISTANT PROFESSOR, 大学院・医歯学総合研究科, 講師 (40280961)
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| Co-Investigator(Kenkyū-buntansha) |
MORIO Tomohiro TOKYO MEDICAL AND DENTAL UNIVERSITY, DEPARTMENT OF GENERAL MEDICINE, ASSOCIATE PROFESSOR, 医学部・附属病院, 助教授 (30239628)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2001: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2000: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1999: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | CD40 / CD40 ligand / Primary immunodefidciency / AID |
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| Research Abstract |
1) Characterization of human CD40 ligand deficiency : 35 x-linked hyper IgM syndrome (XHIM) patients were newly identified and their correlation of CD40 ligand mutation and the clinical phenotypes was examined. Screening methods of CD40 ligand deficiency using SSCP and ELISA that measures sCD40 ligand have been established. Carriers of XHIM were found to have decreased amounts of sCD40 ligand and all patients had non-detectable levels of sCD40 ligand.
2) Characterization of hyper IGM syndrome type 2 : Nine Japanese patients with hyper IgM syndrome type 2 were characterized. All patients had mutations in AID. Seven patients were from non-consanguineous families, and six of them had a missense mutation in the same codon, suggesting that this codon is the hot spot of AID mutation. In all patients, IgG, IgA and IgE levels in the sera were undetectable, and somatic hyper mutations were impaired in their peripheral blood B cells. B cells failed to produce detectable amounts of IgE if cultured with anti-CD40 and IL-4. These results indicate that AID plays indispensable roles in class switch and somatic hypermutation in human B cells.
3) Roles of Ku in the signaling pathway of CD40 : Ku was identified as the molecule that is involved in the CD40 signaling, we found that Ku associates with intracytoplasmic region of CD40, and CD40 stimulation induces tyrosine phosphorylation of Ku. In addition, CD40 stimulation induces DNA-PK activity in B cells by Ku dependent fashion.
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