The molecular basis and biological significance of V H replacement

Summary:  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.