Interallelic class switch recombination can reverse allelic exclusion and allow trans-complementation of an IgH locus switching defect
✍ Scribed by Hei-Lanne Dougier; Stéphane Reynaud; Eric Pinaud; Claire Carrion; Laurent Delpy; Michel Cogné
- Publisher
- John Wiley and Sons
- Year
- 2006
- Tongue
- English
- Weight
- 397 KB
- Volume
- 36
- Category
- Article
- ISSN
- 0014-2980
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✦ Synopsis
Abstract
The predominant path of immunoglobulin class switch recombination follows the paradigm of intra‐chromosomal deletion enabling expression of another heavy chain instead of µ and δ. This was, however, challenged by observations of inter‐allelic class switch recombination in rabbit or mouse IgG3‐ or IgA‐producing B cells. Assuming that the conditions of inter‐chromosomal exchange are likely present at any target S regions in stimulated B cells, we explored trans‐association of VH and C genes in a model allowing all C genes to be checked simultaneously. Heterozygous mutant mice are thus studied, which carry one non‐functional IgH allele inactivated by a non‐translatable mutation of VDJ‐CH transcripts, while the functional allele is deficient for class switching due to a truncated 3′regulatory region. A fair level of switching to all Ig classes is restored in heterozygous mice despite the fact that cis‐recombination is either non productive on one allele or deficient on the other. Molecular evidence at the DNA level of trans‐CSR to IgG3 was demonstrated by cloning and sequencing S__µ__‐S__γ__3 hybrid junctions. These data demonstrate that inter‐allelic recombination may broadly rescue the production of various class‐switched isotypes and allow complementation between mutations located at both ends of the IgH constant gene cluster.