Zhang Zhixin, Burrows Peter D, Cooper Max D
Division of Developmental and Clinical Immunology, University of Alabama at Birmingham, Birmingham, AL 35294-3300, USA.
Immunol Rev. 2004 Feb;197:231-42. doi: 10.1111/j.0105-2896.2004.0107.x.
First observed in mouse pre-B-cell lines and then in knock-in mice carrying self-reactive IgH transgenes, VH replacement has now been shown to contribute to the primary B-cell repertoire in humans. Through recombination-activating gene (RAG)-mediated recombination between a cryptic recombination signal sequence (RSS) present in almost all VH genes and the flanking 23 base pair RSS of an upstream VH gene, VH replacement renews the entire VH-coding region, while leaving behind a short stretch of nucleotides as a VH replacement footprint. In addition to extending the CDR3 region, the VH replacement footprints preferentially contribute charged amino acids. VH replacement rearrangement in immature B cells may either eliminate a self-reactive B-cell receptor or contribute to the generation of self-reactive antibodies. VH replacement may also rescue non-productive or dysfunctional VHDJH rearrangement in pro-B and pre-B cells. Conversely, VH replacement of a productive immunoglobulin H gene may generate non-productive VH replacement to disrupt or temporarily reverse the B-cell differentiation process. VH replacement can thus play a complex role in the generation of the primary B-cell repertoire.
VH替换首先在小鼠前B细胞系中被观察到，随后在携带自身反应性IgH转基因的敲入小鼠中被发现，现在已证明其在人类初级B细胞库的形成中发挥作用。通过重组激活基因（RAG）介导几乎所有VH基因中存在的隐蔽重组信号序列（RSS）与上游VH基因侧翼的23个碱基对RSS之间的重组，VH替换更新了整个VH编码区，同时留下一小段核苷酸作为VH替换足迹。除了扩展互补决定区3（CDR3）区域外，VH替换足迹还优先贡献带电荷的氨基酸。未成熟B细胞中的VH替换重排可能消除自身反应性B细胞受体，也可能有助于自身反应性抗体的产生。VH替换还可能挽救前B细胞和前B细胞中无功能或功能失调的VHDJH重排。相反，有功能的免疫球蛋白H基因的VH替换可能产生无功能的VH替换，从而破坏或暂时逆转B细胞分化过程。因此，VH替换在初级B细胞库的形成中可能发挥复杂的作用。
