Immunoglobulin Gene Rearrangements

Abstract

Abstract V(D)J and class switch recombination are two deoxyribonucleic acid (DNA) recombination processes that occur at immunoglobulin genes during the generation of B cells and the attendant rearrangement of immunoglobulin heavy and light chain loci. V(D)J occurs during early B‐ and T‐cell development whereas class switch recombination occurs exclusively in mature B cells. V(D)J recombination achieves the assembly of new exons that encode the portion of the antigen receptor that binds antigen. Class switch recombination changes the constant portion of the heavy chain of the antibody from IgM to IgG, IgA or IgE. V(D)J recombination occurs in the bone marrow for pre‐B cells and in the thymus for pre‐T cells. Class switch recombination occurs in the germinal centres in the spleen, lymph nodes and Peyer's patches. Key Concepts: V(D)J recombination occurs only in vertebrates, because these are the only organisms that have lymphocytes and that generate B and T cells with antigen receptors. V(D)J recombination is done by the RAG1 and RAG2 proteins, which bind at recombination signal sequences (RSS) that consist of heptamer and nonamer recognition sequences. The RAG complex (consisting of RAG1 and RAG2, along with HMGB1) is only expressed in pre‐B cells and pre‐T cells. Class switch recombination requires activation‐induced deaminase (AID). AID acts only on single‐stranded DNA. For class switch regions, single‐stranded DNA is generated by the formation of R‐loops at the switch regions. Switch regions consist of unit repeats (25–80 bp in length) that are 40–50% G on the nontemplate strand, making them prone to form R‐loops. Occasionally, the RAG complex or AID act at off‐target sites, thereby triggering double‐strand breaks that can cause the chromosomal translocations that initiate many types of lymphomas or lymphoid leukaemias.