TARGETING AND REGULATION OF IMMUNOGLOBULIN GENE SOMATIC HYPERMUTATION AND ISOTYPE SWITCH RECOMBINATION

This chapter discusses some of the recent work that has addressed the mechanisms of these two processes, with particular emphasis on the use of engineered constructs, to identify genetic elements critical to activation or targeting. Somatic hypermutation introduces single-base changes in the rearranged variable regions, resulting in the production of immunoglobulin molecules, with dramatically increased affinity for antigen. Isotype switch recombination joins to the expressed variable region a constant region of a different class or isotype that increases the efficiency, with which antigen is destroyed or cleared, from the system after being bound, by antibody. Most of the current understanding of somatic hypermutation depends on extensive sequence analysis that has been carried out on hypermutated V regions. In certain antihapten responses in inbred mice, a limited number of germ-line genes gives rise to most of the antibodies and this makes it possible to study somatic hypermutation independent of V-region repertoire use. Somatic hypermutation and switch recombination occurs during a restricted stage of B-cell development. Although these two processes are not necessarily coupled, most B cells that have undergone somatic hypermutation have also carried out switch recombination and vice versa. © 1995, Academic Press Inc.