Receptor Revision of Immunoglobulin Heavy Chain Variable Region Genes in Normal Human B Lymphocytes

Contrary to the general precepts of the clonal selection theory, several recent studies have provided evidence for the secondary rearrangement of immunoglobulin (Ig) genes in peripheral lymphoid tissues. These analyses typically used transgenic mouse models and have only detected secondary recombination of Ig light chain genes. Although Ig heavy chain variable region (V_H) genes encode a substantial element of antibody combining site specificity, there is scant evidence for V_H gene rearrangement in the periphery, leaving the physiological importance of peripheral recombination questionable. The extensive somatic mutations and clonality of the IgD⁺Strictly-IgM⁻CD38⁺ human tonsillar B cell subpopulation have now allowed detection of the first clear examples of receptor revision of human V_H genes. The revised VDJ genes contain “hybrid” V_H gene segments consisting of portions from two separate germline V_H genes, a phenomenon previously only detected due to the pressures of a transgenic system.