An allotype-associated polymorphism in the γ3 promoter determines the germ-line γ3 transcriptional rate but does not influence switching and subsequent IgG3 production

Abstract

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-κB site of the germ-line (GL) γ3 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-κB p50/p65 or Stat6 + C/EBPγ. A low level of GL γ3 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.