Nonhomologous Recombination at Sites within the Mouse J_H-C_δ Locus Accompanies Cμ 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 μ constant-region gene (C_μ) to the 5′-flanking region of the secreted heavy-chain constant-region gene (C_H), 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 C_H genes except δ. 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_μ 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 C_δ1 exon, we isolated seven more BALB/c and two C57BL/6 IgD-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.δ1 and of the BALB/c, IgD-secreting plasmacytoma TEPC 1033. All of the lines had deleted the C_μ gene, and three had deleted the C_δ1 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.