Regulation of Class Switch Recombination

This chapter focuses on the regulation of class-switch recombination (CSR) to all non-m isotypes, except for delta. The expression of immunoglobulin D (IgD) results from alternative splicing that regularly occurs as part of B-cell maturation, and only rarely involves Cμ deletion. In contrast, deoxyribonucleic acid (DNA) recombination is constantly needed for the other isotypes, and there are a number of elements that are now known to be essential. For example, a critical first step in CSR is germline transcription (GT), whose production for several isotypes is dependent on at least two of the 3 immunoglobulin H (IgH) enhancers. GT of individual isotypes requires cell-cell interaction involving CD40 and CD40L, various B cell transcription factors, including NFkB and specific T cell cytokines. A predilection to switch to particular classes, especially immunoglobulin E (IgE) in allergic individuals can be harmful for human health, and most likely is fostered by the T cell cytokine profile associated with particular Th subsets. Mistakes in CSR have been associated with chromosomal translocations involving "c-myc" and are regularly detected in murine plasmacytomas, human myeloma, and Burkitt's lymphoma. Current challenges are to identify the signals that trigger 3 enhancer activity during B-cell development and the mechanisms that engage these enhancers with I promoters for GT. The formation of GT clearly involves both positive and negative regulation, providing an additional arena for critical investigation.