The presence of V H mutations in the clones that had undergone replacement indicated that these B cells were immunocompetent and could receive and respond to diversification signals. The identification of blunt-ended double-stranded DNA breaks at the embedded heptamers and the demonstration of recombinase activating gene (RAG) expression suggested that these rearrangements could occur in the synovial tissues, presumably in pseudo-germinal centers, and that they could be mediated by RAG in a recognition signal sequence–specific manner. These secondary V H rearrangements were documented at both the cDNA and genomic DNA levels and involved several heptamer-like sequences at four distinct locations within V H (three sites in framework region 3 and one in complementarity determining region 2). Examples of multiple independent V H replacement events occurring in distinct progeny clones were also identified. While studying the B lymphocytes that expand in the synovial tissues of patients with rheumatoid arthritis (RA), clones with V HDJ H variants that were apparently generated by V H replacement were identified with surprising frequency (∼8%).
This exchange can involve cryptic heptamer-like sequences embedded in the coding regions of V H genes. This process changes the antigen combining site by replacing a portion of the original V H/diversity/heavy chain joining region (V HDJ H) rearrangement with a corresponding portion of a new V H segment. Mature B cells can alter their antibody repertoires by several mechanisms, including immunoglobulin heavy chain variable region (V H) replacement.
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