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.
Division of Clinical Immunology, IMPI, Karolinska Institutet at Huddinge Hospital, Huddinge, Sweden.
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Pan
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Petit-Frére
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Hammarström
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