Interallelic class switch recombination can reverse allelic exclusion and allow trans-complementation of an IgH locus switching defect.
The predominant path of immunoglobulin class switch recombination follows the paradigm of intra-chromosomal deletion enabling expression of another heavy chain instead of micro and delta. 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 Smu-Sgamma3 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.
Dougier
Hei-Lanne
HL
Laboratoire d'Immunologie, CNRS UMR 6101, Equipe labellisée 'La Ligue', Université de Limoges, Faculté de Médecine, Limoges, France.
Reynaud
Stéphane
S
Pinaud
Eric
E
Carrion
Claire
C
Delpy
Laurent
L
Cogné
Michel
M
D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D017578:Immunoglobulin Class Switching / Q000235:genetics* / Q000276:immunology*; D007143:Immunoglobulin Heavy Chains / Q000097:blood / Q000145:classification* / Q000276:immunology*; D007134:Immunoglobulin Switch Region / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008221:Lymphoid Tissue / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics
D007143:Immunoglobulin Heavy Chains; D008070:Lipopolysaccharides