Severe B cell deficiency and disrupted splenic architecture in transgenic mice expressing the E41K mutated form of Bruton's tyrosine kinase
Severe B cell deficiency and disrupted splenic architecture in transgenic mice expressing the E41K mutated form of Bruton's tyrosine kinase
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DOI：
10.1093/emboj/17.18.5309
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发表时间：
1998-09-15
期刊：
影响因子：
11.4
通讯作者：
Hendriks, RW
中科院分区：
文献类型：
--
作者：
Dingjan, GM;Maas, A;Hendriks, RW
为了鉴定体内由布鲁顿酪氨酸激酶（Btk）激活的B细胞信号传导途径，我们产生了Btk表达由MHC II类Ea基因座控制区驱动的转基因小鼠。Btk过表达对B细胞功能没有显著的不良影响，并且基本上纠正了Btk（-）小鼠中的X-连锁免疫缺陷（xid）表型。相反，表达携带E41 K功能获得性突变的组成性激活形式的Btk导致比Rid更严重的B细胞缺陷。小鼠脾脏、淋巴结、外周血和腹腔中的B细胞区室显著减少。血清中大多数免疫球蛋白亚类的水平随年龄的增长而降低，并且B细胞对T细胞非依赖性II型抗原和T细胞依赖性抗原的应答基本上不存在。E41 K Btk突变体的表达增强了体外脾B细胞对抗IgM刺激的原始细胞形成。此外，小鼠表现出脾脏中B细胞区和边缘区的紊乱。我们的研究结果表明，组成性激活Btk的表达阻断卵泡再循环B细胞的发育。
To identify B-cell signaling pathways activated by Bruton's tyrosine kinase (Btk) in vivo, we generated transgenic mice in which Btk expression is driven by the MHC class II Ea gene locus control region. Btk overexpression did not have significant adverse effects on B cell function, and essentially corrected the X-linked immunodeficiency (xid) phenotype in Btk(-) mice. In contrast, expression of a constitutively activated form of Btk carrying the E41K gain-of-function mutation resulted in a B cell defect that was more severe than rid. The mice showed a marked reduction of the B cell compartment in spleen, lymph nodes, peripheral blood and peritoneal cavity, The levels in the serum of most immunoglobulin subclasses decreased with age, and B cell responses to both T cell-independent type II and T cell-dependent antigens were essentially absent. Expression of the E41K Btk mutant enhanced blast formation of splenic B cells in vitro in response to anti-IgM stimulation. Furthermore, the mice manifested a disorganization of B cell areas and marginal zones in the spleen. Our findings demonstrate that expression of constitutively activated Btk blocks the development of follicular recirculating B cells.