Control of Immunoglobulin Class Switch Recombination

Abstract

The comparative analysis of Ig class switch recombination in a priori IgG/IgA-expressing myelomas and hybridomas, in switch variants and in activated normal B cells shows the following characteristics of class switch recombination in activated B cells: It is prevented during most of B cell ontogeny. It happens on both IgH loci of activated and switched B cells. The recombination is programmed in that on both IgH loci of switched cells the same switch regions recombine with Smu. This is true at least for the IgG1 pathway. IgM-expressing cells show no class switch recombination on the inactive IgH locus. Thus, physiological class switch recombination is a programmed rather than a random event and is controlled as such. The initial stages of class switching and the molecules involved in these are largely unclear: What is the nature of the protection of switch regions and how is this protection abrogated? Do specific recombinases exist? What is the role of large transcription units? Is the specificity of class switch recombination a result of specific "opening" of the DNA for transcription? Do all B cells use the same switch mechanism? What is the role of switch factors (such as lymphokines)? These and more questions await answers and although a variety of switch scenarios could be discussed at present a detailed speculation seems premature.

Deletional remodeling of c-myc-deregulating chromosomal translocations

“…One possibility we consider envisions the Ighm/ c-myc exchange in a mature, class switch competent Bcell that has encountered antigen and other appropriate signals and prepares itself for isotype switching. In this situation, the initial lesion that provokes illegitimate recombination between Ighm and c-myc may be a DNA double-strand break in Sm due to internal rearrangements of Sm, mostly deletions and occasionally inversions, known to occur prior to class switching (Radbruch et al, 1986;Dunnick et al, 1989). The interruption of Sm may lead to Ighm/c-myc recombination and chromosomal translocation t(12;15) on the non-productive Igh allele, followed by deletional remodeling' of the t(12;15) by aberrant class switch recombination and normal class switching on the productive Igh allele (see Figure 7 for more details).…”

Directed Ig class switch recombination in activated murine B cells.

“…Conclusions Switch recombination in proliferating myeloma and hybridoma cells is usually less frequent than 10-/cell/generation (Radbruch et al, 1980;Radbruch, 1986). Upon activation of normal splenic B-cells, however, switch recombination occurs at frequencies of 100-101/cell/generation, and in >50% of the switched cells on both IgH loci (Coutinho and Fomi, 1982;Radbruch et al, 1986a). Class switch recombination is directed to mostly the same switch regions on the two chromosomes of a cell.…”

Lymph nodes and Peyer's patches of IL-6 transgenic BALB/c mice harbor T(12;15) translocated plasma cells that contain illegitimate exchanges between the immunoglobulin heavy-chain μ locus and c-myc

“…The observation that the 5Ј-C /cmyc exchanges were accompanied invariably by large deletions in S was consistent with this hypothesis, since S deletions are common in B cells undergoing isotype switching. 14,15 Furthermore, the average length of deletions in S was 2.7 kb and thus considerably longer than the average deletion in c-myc, which was just 171 bp (calculated from Table 2, last two columns). This suggested that S was targeted by a deletional mechanism (switch recombinase?)…”