Rearrangement of immunoglobulin heavy chain genes during B-lymphocyte development as revealed by studies of mouse plasmacytoma cells

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Abstract
The Southern blotting technique was used to determine the extent to which the genes encoding the constant (C) regions of .mu., .alpha., .gamma.1 and .gamma.2b immunoglobulin H chains are altered in number and context from their germline (embryo) state in a series of 14 plasmacytomas expressing various H chain classes. In the 3 .mu. chain-producing plasmacytomas studied there was no evidence of rearrangement of CH genes other than C.mu.. Rearrangement and deletion of nonexpressed CH genes was frequent in plasmacytomas that produce .gamma. or .alpha. chains. The observed pattern of deletions is consistent with the idea that the ontogenetic switch in H chain class requires CH gene deletion. Frequently, though not always, such deletions and other types of rearrangement occur in both allelic loci. Particularly noteworthy are 3 .gamma.2a-expressing tumors in which C.alpha. gene rearrangement is evident in both alleles. A probabilistic model of B [bone marrow-derived] cell development was developed in which deletions occurring between the C.mu. gene and the variable (VH) gene array in the 1st phase may result in the formation of a productive fused VH-C.mu. gene. The cell may then enter a 2nd phase, which allows deletions within the CH gene arrays of both homologous chromosomes. Some deletions juxtapose the expressed VH gene with a 2nd CH gene and result in a H chain class switch; others delete or alter the context of CH genes without changing the phenotype of the cell. Switching may be both a single-step and a multi-step process. In the latter case, those rearrangements that do not result in a switch may be physiologically significant in that they may limit the options of further switching.