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

We have used Southern's blotting technique to determine the extent to which the genes encoding the constant (C) regions of mu, alpha, gamma(1), and gamma(2b) immunoglobulin heavy (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 three mu chain-producing plasmacytomas studied there was no evidence of rearrangement of C(H) genes other than C(mu). In contrast, rearrangement and deletion of nonexpressed C(H) 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 C(H) gene deletion. Frequently, though not always, such deletions as well as other types of rearrangement occur in both allelic loci. Particularly noteworthy are three gamma(2a)-expressing tumors in which C(alpha) gene rearrangement is evident in both alleles. We incorporate these observations into a probabilistic model of B cell development: in the first phase, deletions may occur between the C(mu) gene and the variable (V(H)) gene array, which result in the formation of a productive fused V(H)-C(mu) gene. The cell may then enter a second phase, which allows deletions within the C(H) gene arrays of both homologous chromosomes. Some deletions juxtapose the expressed V(H) gene with a second C(H) gene and result in a H chain class switch; others delete or alter the context of C(H) genes without changing the phenotype of the cell. We predict that switching can be both a single-step and a multi-step process, and that 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.