CLASS SWITCH CONTROL REGION AT THE 3' END OF THE IMMUNOGLOBULIN HEAVY-CHAIN LOCUS

We replaced the IgH 3' enhancer (3'E(H)) region with a neomycin resistance gene in ES cells and generated chimeric mice in which all mature lymphocytes were either heterozygous (3'E(H)(+/-)) or homozygous (3'E(H)(-/-)) for the mutation. In vitro activated 3'E(H)(-/-) B cells responded similarly to 3'E(H)(+/-) B cells with respect to proliferation and secretion of IgM and IgG1 but were specifically deficient in IgG2a, IgG2b, IgG3, and IgE secretion. These isotype deficiencies correlated with a deficiency in accumulation of transcripts from and class switching to affected C-H genes. In vivo, chimeric mice containing only 3'E(H)(-/-) B cells were deficient in serum IgG2a and IgG3. We propose that the 3'E(H)(-/-) mutation disrupts the activity of a regulatory region that influences heavy chain class switching to several different C-H genes that lie as far as 100 kb upstream of the mutation.