Drabek D, Raguz S, De Wit T P, Dingjan G M, Savelkoul H F, Grosveld F, Hendriks R W
Department of Cell Biology and Genetics, Faculty of Medicine, Erasmus University Rotterdam, The Netherlands.
Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):610-5. doi: 10.1073/pnas.94.2.610.
Bruton tyrosine kinase (Btk) is essential for the development of pre-B cells to mature B cell stages. Btk-deficient mice manifest an X-linked immunodeficiency (xid) defect characterized by a reduction of peripheral IgMlow IgDhigh B cells, a lack of peritoneal CD5+ B cells, low serum levels of IgM and IgG3, and impaired responses to T cell independent type II (TI-II) antigens. We have generated transgenic mice in which expression of the human Btk gene is driven by the murine class II major histocompatibility complex Ea gene locus control region, which provides gene expression from the pre-B cell stage onwards. When these transgenic mice were mated onto a Btk- background, correction of the xid B cell defects was observed: B cells differentiated to mature IgMlowIgDhigh stages, peritoneal CD5+ B cells were present, and serum Ig levels and in vivo responses to TI-II antigens were in the normal ranges. A comparable rescue by transgenic Btk expression was also observed in heterozygous Btk+/- female mice in those B-lineage cells that were Btk-deficient as a result of X chromosome inactivation. These findings indicate that the Btk- phenotype in the mouse can be corrected by expression of human Btk from the pre-B cell stage onwards.
布鲁顿酪氨酸激酶（Btk）对于前B细胞发育至成熟B细胞阶段至关重要。Btk缺陷小鼠表现出X连锁免疫缺陷（xid）缺陷，其特征为外周IgM低IgD高B细胞减少、缺乏腹膜CD5+B细胞、血清IgM和IgG3水平低以及对T细胞非依赖性II型（TI-II）抗原的反应受损。我们构建了转基因小鼠，其中人类Btk基因的表达由小鼠II类主要组织相容性复合体Ea基因座控制区驱动，该控制区从pre-B细胞阶段起提供基因表达。当这些转基因小鼠与Btk-背景小鼠交配时，观察到xid B细胞缺陷得到纠正：B细胞分化至成熟的IgM低IgD高阶段，存在腹膜CD5+B细胞，血清Ig水平以及对TI-II抗原的体内反应均在正常范围内。在因X染色体失活而Btk缺陷的B系细胞中，杂合Btk+/-雌性小鼠中也观察到转基因Btk表达产生了类似的拯救作用。这些发现表明，从小鼠的前B细胞阶段起表达人类Btk可纠正小鼠中的Btk-表型。
