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Roles of CD40/CD40 ligand molecules in human immunological disorders

CD40/CD40配体分子在人类免疫疾病中的作用

基本信息

批准号：
11670745
负责人：
NONOYAMA Shigeaki
金额：
$ 2.5万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670745/
关键词：
CD40 CD40 ligand Primary immunodefidciency AID

项目摘要

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.

1)人CD 40配体缺陷的特征：35例新发现的X连锁高IgM综合征（XHIM）患者，并检查其CD 40配体突变与临床表型的相关性。用SSCP和ELISA检测sCD 40配体，建立了CD 40配体缺陷的筛查方法。发现XHIM的携带者具有减少的sCD 40配体的量，并且所有患者具有不可检测的sCD 40配体水平。2）高IgM综合征2型的表征：9名患有高IgM综合征2型的日本患者被表征。所有患者都有AID突变。7例患者均来自非血缘家系，其中6例在同一密码子上发生错义突变，提示该密码子是AID突变的热点。在所有患者中，血清中的IgG、伊加和IgE水平均检测不到，外周血B细胞中的体细胞超突变受损。如果用抗-CD 40和IL-4培养，B细胞不能产生可检测量的IgE。这些结果表明AID在人B细胞的类转换和体细胞超突变中起着不可或缺的作用。3）Ku在CD 40信号通路中的作用：Ku被鉴定为参与CD 40信号通路的分子，我们发现Ku与CD 40的胞浆内区域相关联，CD 40刺激可诱导Ku的酪氨酸磷酸化。此外，CD 40刺激通过Ku依赖性方式诱导B细胞中的DNA-PK活性。