An allotype-associated polymorphism in the gamma3 promoter determines the germ-line gamma3 transcriptional rate but does not influence switching and subsequent IgG3 production.
The human IgG3 (b) allotype is associated with a high and the (g) allotype with a low mean serum level of IgG3 which is due to a low frequency of B cell switching in the latter. In the present study, we found a polymorphism in position -73 (C --> A), located in the 4th NF-kappaB site of the germ-line (GL) gamma3 promoter, resulting in a significant decrease of both the basal and induced activity in the (g) allotype-associated promoter. Over-expression experiments also showed that this polymorphism reduced the synergistic activation of the promoter by Stat6 + NF-kappaB p50 / p65 or Stat6 + C / EBPgamma. A low level of GL gamma3 transcripts was also observed in individuals carrying the (g) allotype-associated promoter region. However, an individual homozygous for a crossover between the promoter and switch region, i. e. with a (g) allotype-associated promoter and a (b) allotype-associated switch region, showed a normal level of switching and IgG3 serum level. This suggests that although the (g) allotype-associated promoter is functionally inferior to that of the (b) allotype-associated promoter, these differences do not affect switching and final production of IgG3 and that polymorphisms in the switch region are more important in controlling this process.
Pan
Q
Q
Division of Clinical Immunology, IMPI, Karolinska Institutet at Huddinge Hospital, Huddinge, Sweden.
Petit-Frére
C
C
Hammarström
L
L
D001402:B-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007126:Immunoglobulin Allotypes / Q000235:genetics*; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000145:classification / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
D007126:Immunoglobulin Allotypes; D007074:Immunoglobulin G