Novel genetic variation of human interleukin-21 receptor is associated with elevated IgE levels in females

Abstract

The interleukin-21 receptor (IL21R) was recently discovered as a novel member of the class-I-cytokine-receptor family and is selectively expressed in lymphoid tissues. IL21R shows strong sequence homologies to the interleukin-4 receptor a chain gene (IL4RA). In addition, both genes are adjacent and share structural similarity. We analyzed all the exons of the human IL21R gene and its 5 0 flanking region for sequence variation. We identified four novel single nucleotide polymorphisms (SNPs) and genotyped 300 healthy blood donors. Total serum IgE levels were measured in all subjects and associated with IL21R SNPs. Results revealed a significant association of one IL21R polymorphism (T-83C) with elevated IgE levels (4100 kU/I) in females (OR ¼ 3.000, CI ¼ [1.163;8.385], P ¼ 0.015, n ¼ 138). This was confirmed in a second prospectively collected group of female blood donors (OR ¼ 2.535, CI ¼ [0.927;6.733], P ¼ 0.046, n ¼ 123). In contrast, no effects were observed in male subjects in either population. These findings identify IL21R as a possible novel target locus influencing IgE synthesis in female individuals.

IFN-γ-Mediated Inhibition of Human IgE Synthesis by IL-21 Is Associated with a Polymorphism in theIL-21RGene

“…These results indicate that polyclonal stimulation of B cells through CD40, although of physiologic relevance, delivers a strong polyclonal activation signal that, because of its intensity, is likely to mask the potential inhibitory effects of IL- 21 The results presented in this study indicate that healthy, as well as atopic, individuals respond with a differential sensitivity to the modulatory effects of IL-21 on the synthesis of IgE. Moreover, this differential sensitivity was found to be associated with the presence of a polymorphism in the gene encoding the IL-21R, which is the consequence of a nucleotide substitution in the 5Ј flanking region of exon 1B (T-83C) (14). We focused on this polymorphism, because among the four IL-21R gene variants that were reported in the literature, only the presence of the T-83C variant was found to be associated with enhanced IgE serum levels in healthy and, to a greater extent, in atopic individuals (14).…”

“…Moreover, in a different study, injection of IL-21 into mice was found to inhibit Ag-specific IgE, but not IgG2a, responses and this effect was reportedly due to the inhibition of IL-4-induced germline C transcription by IL-21 (13). Recently, an association between a single nucleotide polymorphism (T-83C) in the IL-21R and the presence of elevated IgE serum levels has been reported (14), suggesting a negative regulatory function of IL-21 in the production of this istoype in humans as well.…”

“…Moreover, this differential sensitivity was found to be associated with the presence of a polymorphism in the gene encoding the IL-21R, which is the consequence of a nucleotide substitution in the 5Ј flanking region of exon 1B (T-83C) (14). We focused on this polymorphism, because among the four IL-21R gene variants that were reported in the literature, only the presence of the T-83C variant was found to be associated with enhanced IgE serum levels in healthy and, to a greater extent, in atopic individuals (14). As presented here, T or NK cells from individuals who carry one allele of this IL-21R gene variant produce less IFN-␥ following stimulation with IL-21, compared with those from individuals carrying the wild-type gene.…”

“…It has been reported that the presence of a polymorphism (T-83C) in the gene encoding the human IL-21R is associated with elevated serum levels of IgE, in both healthy and, to a greater extent, atopic individuals (14). Because of the differential sensitivity of PBMC to respond to the effects of rIL-21, as described above, we therefore determined, in a sizeable cohort of donors consisting of both healthy and atopic individuals, whether their clinical status, as well as the presence of this polymorphism, might affect the capacity of IL-21 to modulate IL-4-induced IgE synthesis in vitro.…”

IL-21 Induces Inhibitor of Differentiation 2 and Leads to Complete Abrogation of Anaphylaxis in Mice

“…Skewing of the balance between IL-4 and IL-21 signals could etiologically be associated with allergic hypersensitivities. Hecker et al (49) analyzed genetic polymorphisms in the human IL-21R gene and found that the presence of the T-83C variant was associated with elevated IgE serum levels in healthy and, to a greater extent, in atopic female individuals. Supplementation of the IL-21 signal may be a reasonable strategy to correct Id2 expression and in turn alleviate allergic symptoms in allergic patients.…”