The molecular basis and biological significance of V_H replacement

First observed in mouse pre-B-cell lines and then in knock-in mice carrying self-reactive IgH transgenes, V_H 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 V_H genes and the flanking 23 base pair RSS of an upstream V_H gene, V _H replacement renews the entire V_H-coding region, while leaving behind a short stretch of nucleotides as a V_H replacement footprint. In addition to extending the CDR3 region, the V_H replacement footprints preferentially contribute charged amino acids. V _H replacement rearrangement in immature B cells may either eliminate a self-reactive B-cell receptor or contribute to the generation of self-reactive antibodies. V_H replacement may also rescue non-productive or dysfunctional V_HDJ_H rearrangement in pro-B and pre-B cells. Conversely, V_H replacement of a productive immunoglobulin H gene may generate non-productive V_H replacement to disrupt or temporarily reverse the B-cell differentiation process. V _H replacement can thus play a complex role in the generation of the primary B-cell repertoire.