Mature B cells can alter their antibody repertoires by several mechanisms, including immunoglobulin heavy chain variable region (VH) replacement. This process changes the antigen combining site by replacing a portion of the original VH/diversity/heavy chain joining region (VHDJH) rearrangement with a corresponding portion of a new VH segment. This exchange can involve cryptic heptamer-like sequences embedded in the coding regions of VH genes. While studying the B lymphocytes that expand in the synovial tissues of patients with rheumatoid arthritis (RA), clones with VHDJH variants that were apparently generated by VH replacement were identified with surprising frequency (∼8%). Examples of multiple independent VH replacement events occurring in distinct progeny clones were also identified. These secondary VH rearrangements were documented at both the cDNA and genomic DNA levels and involved several heptamer-like sequences at four distinct locations within VH (three sites in framework region 3 and one in complementarity determining region 2). The identification of blunt-ended double-stranded DNA breaks at the embedded heptamers and the demonstration of recombinase activ
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