Nonhomologous recombination at sites within the mouse JH-C delta locus accompanies C mu deletion and switch to immunoglobulin D secretion.

Abstract

Plasma cells secrete immunoglobulins other than immunoglobulin M (IgM) after a deletion and recombination in which a portion of the immunoglobulin heavy-chain locus (IgH), from the 5'-flanking region of the ,u constant-region gene (C,e) to the 5'-flanking region of the secreted heavy-chain constant-region gene (CH), is deleted. The recombination step is believed to be targeted via switch regions, stretches of repetitive DNA which lie in the 5' flank of all CH genes except 8. Although serum levels of IgD are very low, particularly in the mouse, IgD-secreting plasmacytomas of BALB/c and C57BL/6 mice are known. In an earlier study of two BALB/c IgD-secreting hybridomas, we reported that both had deleted the C,, gene, and we concluded that this deletion was common in the normal generation of IgD-secreting cells. To learn how such switch recombinations occur in the absence of a switch region upstream of the Cr,1 exon, we isolated seven more BALB/c and two C57BL/6IgD-secreting hybridomas. We determined the DNA sequences of the switch recombination junctions in eight of these hybridomas as well as that of the C57BL/6 hybridoma B1-8.81 and of the BALB/c, IgD-secreting plasmacytoma TEPC 1033. All of the lines had deleted the C, gene, and three had deleted the C,,, exon in the switch recombination event. The delta switch recombination junction sequences were similar to those of published productive switch recombinations occurring 5' to other heavy-chain genes, suggesting that nonhomologous, illegitimate recombination is utilized whenever the heavy-chain switch region is involved in recombination. The switch from ,u, the 5'-most heavy-chain constantregion gene, to other heavy-chain classes is accomplished by another somatic rearrangement of the heavy-chain locus, the switch recombination. In switch recombination, a 5' breakpoint upstream of the C,, gene is joined to a 3' breakpoint upstream of another CH gene, and the intervening DNA is deleted. The switch recombination has been linked to switch regions: 2 to 5 kb of tandem repeats in which the tetramers AGCT and TGGG occur frequently (46). Switch regions are found in the 5'-flanking area of each CH gene except C6. Curiously, most switch recombinations do not have their 5' breakpoints in the switch ,u region (S,,), though the 3' breakpoints usually are in the switch region of the expressed CH gene (25). Since IgD is rare in human serum and very rare in mouse serum, it was believed that normal production of secreted * Corresponding author. Synthesis of immunoglobulin (IgIgD might not require switch recombination but might occur by alternative splicing of transcripts spanning the VH-D-JH and C -C. locus, the same mechanism utilized for membrane IgD (reviewed in reference 6). Although human B cells with intact C,, genes can synthesize small but significant amounts of mRNA for secreted 8 chain (30), this is not the case in mice (15). It is likely that secretion of large amounts of IgD requires some sort of recombination, since three cultured human cell lines and three human m...

Artiodactyl IgD: The Missing Link

“…In teleost fish, post-transcriptional RNA splicing is involved, resulting in a chimeric form of IgD H chain with the CH1 domain being fused to unique C␦ sequences (6 -8). Due to the absence of an authentic S␦ region, B cells expressing exclusively IgD (IgM Ϫ IgD ϩ ) are extremely rare in humans and are almost absent in mice (34). Homologous recombination mediated by two 442-bp repeats localized upstream of the S and within the C-C␦ intron, or nonhomologous recombination between S and ␦ regions has been suggested as the molecular basis for generating these rare IgM Ϫ IgD ϩ cells (35,36).…”

Discovery and Characterization of Secretory IgD in Rainbow Trout: Secretory IgD Is Produced through a Novel Splicing Mechanism

“…The tissuespecific distribution of IgD plasma cells in trout is analogous to the findings in mammals. It has been found that secretory IgD cells in the peripheral blood are rare (∼3%), but make up a substantial population of the human respiratory tract mucosal B cells (17,29). In contrast to the upper respiratory tract, there are few IgD plasma cells in the digestive system mucosae, with only trace amounts of IgD in digestive fluids (30)(31)(32)(33).…”

Clonal diversification of primary BALB/c plasmacytomas harboring T(12;15) chromosomal translocations

“…The PCR methods utilized here resulted in the detection of exchanges between c-myc and the following Igh loci: , ␥2a, ␥2b, and ␣. Exchanges with ␦ and ⑀ were not observed because dedicated PCR methods have not been developed (␦/c-myc exchanges are very rare in BALB/c plasmacytomas 13 and ⑀/c-myc exchanges have never been found).…”