| Project/Area Number |
15390158
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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 |
Immunology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
TSUBATA Takeshi Tokyo Medical and Dental University, Laboratory of Immunology School of Biomedical Science, Professor, 大学院・疾患生命科学研究部, 教授 (80197756)
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| Co-Investigator(Kenkyū-buntansha) |
ADACHI Takahiro Tokyo Medical and Dental University, Department of Immunology Medical Research Institute, 難治疾患研究所, 助教授 (50222625)
饗場 祐一 東京医科歯科大学, 難治疾患研究所, 助手 (00273516)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥15,100,000 (Direct Cost: ¥15,100,000)
Fiscal Year 2005: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2004: ¥5,200,000 (Direct Cost: ¥5,200,000)
Fiscal Year 2003: ¥5,500,000 (Direct Cost: ¥5,500,000)
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| Keywords | B lymphocyte / BCR / signal transduction / CD22 / CD72 / ITIM / IgG / IgE / IgA / レクチン / BCR / 免疫グロブリン / アイソタイプ / 抗体産生 |
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| Research Abstract |
CD22 is a member of the siglec family and specifically recognizes a2,6 sialic acid, whereas CD72 contains a C-type lectin domain. These membrane-bound lectin molecules contain the immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic region. Upon phosphorylation, these ITIMs recruit and activate the SH2 domain containing tyrosine phosphatase 1 (SHP1), thereby down-regulate BCR signaling. We demonstrated that CD22-mediated signal regulation depends on the immunoglobulin isotypes of BCR. Indeed, CD22 negatively regulates signaling through IgM-BCR, IgD-BCR and IgA-BCR, but not signaling through IgG-BCR or IgE-BCR. In the absence of CD22-mediated signaling inhibition, IgG-BCR and IgE-BCR transmit augmented signaling, which may be involved in rapid antibody production in memory responses. The cytoplasmic regions of membrane form of IgG and IgE are involved in abrogation of CD22-mediated signal inhibition. In contrast, CD72 regulates BCR signaling regardless of Ig isotypes. SHP-1 contains two SH2 domains, and at least two out of tree ITIMs in CD22 are suggested to be essential for recruitment of SHP-1. We demonstrated that one ITIM is sufficient for recruitment of SHP-1 to CD22 and CD22-mediated signal regulation. Moreover, tyrosine at the position 783 locating in an ITIM appears to regulate phosporylation of other tyrosines in the cytoplamic region of CD22. These findings are crucial for elucidation of the function of membrane-bound lectins, and development of new strategies for controlling B cell function.
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