Mismatch repair deficiency interferes with the accumulation of mutations in chronically stimulated B cells and not with the hypermutation process.
Primary responses to the hapten phenyloxazolone and chronic responses to environmental antigens occurring in Peyer's patches were analyzed in two different mismatch repair-deficient backgrounds. Paradoxically, whereas primary responses were found normal in MSH2- and only slightly diminished in PMS2-deficient mice, mutations in Peyer's patch B cells from both k.o. animals were reduced three times, the subset of Peyer's patch B cells with highly mutated sequences being specifically missing in the mismatch repair-deficient context. Strikingly, germinal center B cells from Peyer's patches of k.o. animals showed microsatellite instability at an unprecedented level. We thus propose that the amount of DNA damages generated prevents these cells from recycling in germinal centers and that mismatch repair deficiency is only the indirect cause of the lower mutation incidence observed.
Frey
S
S
INSERM U373, Faculté de Médecine Necker-Enfants Malades, Paris, France.
Bertocci
B
B
Delbos
F
F
Quint
L
L
Weill
J C
JC
Reynaud
C A
CA
D000251:Adenosine Triphosphatases; D000818:Animals; D001402:B-Lymphocytes; D001483:Base Sequence; D002460:Cell Line; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D005803:Genes, Immunoglobulin; D018858:Germinal Center; D006241:Haptens / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D018895:Microsatellite Repeats; D000070976:Mismatch Repair Endonuclease PMS2; D008969:Molecular Sequence Data; D051718:MutS Homolog 2 Protein; D009154:Mutation; D010081:Oxazolone / Q000008:administration & dosage / Q000031:analogs & derivatives; D010581:Peyer's Patches; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D006241:Haptens; D011506:Proteins; D011518:Proto-Oncogene Proteins; C018361:2-phenyloxazolone; D010081:Oxazolone; D000251:Adenosine Triphosphatases; C499533:Pms2 protein, mouse; D000070976:Mismatch Repair Endonuclease PMS2; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes