V-H replacement in mice and humans

Heavy chain variable segment NO replacement refers to recombination activating gene (RAG) product-mediated secondary recombination between a previously rearranged V-H gene and an upstream unrearranged V-H gene. V-H 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 allelles. Despite these findings, it is still difficult to find V-H replacement intermediates during normal murine B cell development. In humans, ongoing V-H replacement was found in a clonal B lineage EU12 cell line and in human bone marrow immature B cells. The identification of potential V-H replacement products also suggested a potential contribution of V-H replacement to the antibody repertoire. Here, I review the evidence for whether V-H replacement genuinely offers an in vivo RAG-mediated recombinatorial mechanism to alter preformed IgH genes in mice and humans.