The molecular basis and biological significance of VH 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(H)DJ(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.