Immunoglobulin class-switch recombination in mice devoid of any Sμ tandem repeat

Immunoglobulin heavy-chain class-switch recombination (CSR) occurs between highly repetitive switch sequences located upstream of the constant region genes. However, the role of these sequences remains unclear. Mutant mice were generated in which most of the Imu-Cmu intron was deleted, including all the repeats. Late B-cell development was characterized by a severe impairment, but not a complete block, in class switching to all isotypes despite normal germ line transcription. Sequence analysis of the Imu-Cmu intron in in vitro activated-mutant splenocytes did not reveal any significant increase in activation-induced cytidine deaminase (AID)-induced somatic mutations. Analysis of switch junctions showed that, in the absence of any Smu repeat, the Imu exon was readily used as a substrate for CSR. In contrast to the sequence alterations downstream of the switch junctions, very few, if any, mutations were found upstream of the junction sites. Our data suggest that the core Emu enhancer could be the boundary for CSR-associated somatic mutations. We propose that the core Emu enhancer plays a central role in the temporal dissociation of somatic hypermutation from class switching. (C) 2004 by The American Society of Hematology.