VH replacement in mice and humans

Heavy chain variable segment (VH) replacement refers to recombination activating gene (RAG) product-mediated secondary recombination between a previously rearranged VH gene and an upstream unrearranged VH gene. VH replacement was first observed in mouse pre-B cell lines and later demonstrated in knock-in mouse models carrying immunoglobulin heavy chain (IgH) genes encoding self-reactive or mono-specific antibodies or non-functional IgH rearrangements on both IgH alleles. Despite these findings, it is still difficult to find VH replacement intermediates during normal murine B cell development. In humans, ongoing VH replacement was found in a clonal B lineage EU12 cell line and in human bone marrow immature B cells. The identification of potential VH replacement products also suggested a potential contribution of VH replacement to the antibody repertoire. Here, I review the evidence for whether VH replacement genuinely offers an in vivo RAG-mediated recombinatorial mechanism to alter preformed IgH genes in mice and humans.