Impaired receptor editing in the primary B cell repertoire of BASH-deficient mice
Impaired receptor editing in the primary B cell repertoire of BASH-deficient mice
复制标题
DOI：
10.4049/jimmunol.173.10.5980
复制
发表时间：
2004-11-15
影响因子：
4.4
通讯作者：
Kitamura, D
中科院分区：
文献类型：
--
作者：
Hayashi, K;Nojima, T;Kitamura, D
通过使用抗自身免疫球蛋白转基因/敲入小鼠系统的研究，认为通过接连重排Ig基因编辑B细胞抗原受体(BCR)被认为是中枢B细胞耐受的主要机制，这种机制排除了自我反应性B细胞的出现。然而，受体编辑在正常B细胞库的发展中的作用仍不清楚。此外，指导这一事件的信号通路尚不清楚。在这项研究中，我们证明了在缺乏参与BCR信号转导的适配器蛋白Bash(BLNK/SLP-65)的情况下，抗DNA Ig敲入小鼠的受体编辑受到损害。值得注意的是，假设的受体编辑特征，如Iglambda链表达，Igkappa基因座的重组序列重排，以及重组序列重排失活的Igkappa 106的框内VkappaJkappa连接的存在，在具有未操纵的Ig基因座的Bash缺陷小鼠中都减少了。Bcr结扎诱导的Iglambda基因体外重组在Bash缺陷者中也受到损害。B细胞。此外，Bash缺陷小鼠对DNA载体免疫表现出过度的抗体反应，这表明外围存在未经编辑的DNA反应B细胞。这些结果不仅确定了受体编辑所需的信号通路，而且表明BCR信号的受体编辑确实在正常B细胞库的发展中起作用，并有助于建立B细胞耐受性。
The editing of B cell Ag receptor (BCR) through successive rearrangements of Ig genes has been considered to be a major mechanism for the central B cell tolerance, which precludes appearance of self-reactive B cells, through studies using anti-self-Ig transgenic/knock-in mouse systems. However, contribution of the receptor editing in the development of the normal B cell repertoire remains unclear. In addition, the signaling pathway directing this event is unknown. In this study, we demonstrate that receptor editing in anti-DNA Ig knock-in mice is impaired in the absence of an adaptor protein BASH (BLNK/SLP-65) that is involved in BCR signaling. Remarkably, the supposed hallmarks of receptor editing such as Iglambda chain expression, recombination sequence rearrangements at Igkappa loci, and presence of in-frame VkappaJkappa joins in the Igkappa 106 inactivated by the recombination sequence rearrangements, were all diminished in BASH-deficient mice with unmanipulated Ig loci. BCR ligation-induced Iglambda gene recombination in vitro was also impaired in BASH-deficient. B cells. Furthermore, the BASH-deficient mice showed an excessive Ab response to a DNA carrier immunization, suggesting the presence of unedited DNA-reactive B cells in the periphery. These results not only define a signaling pathway required for receptor editing but indicate that the BCR-signaled receptor editing indeed operates in the development of normal B cell repertoire and contributes to establishing the B cell tolerance.