IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation

Abstract

Genetic factors are known to strongly influence susceptibility to allergic inflammation. The Th2 cytokine IL-13 is a central mediator of allergy and asthma, and common single-nucleotide polymorphisms in IL13 are associated with allergic phenotypes in several ethnically diverse populations. In particular, IL13+2044G→A is expected to result in the nonconservative replacement of arginine 130 (R130) with glutamine (Q). We examined the impact of IL13+2044G→A on the functional properties of IL-13 by directly comparing the activity of WT IL-13 and IL-13 R130Q on primary human cells involved in the effector mechanisms of allergic inflammation. Our results show that IL-13 R130Q was significantly more active than WT IL-13 in inducing STAT6 phosphorylation and CD23 expression in monocytes and hydrocortisone-dependent IgE switching in B cells. Notably, IL-13 R130Q was neutralized less effectively than WT IL-13 by an IL-13Rα2 decoy. Decreased neutralization of the minor variant could contribute to its enhanced in vivo activity. Neither IL-13 variant was able to engage T cells, which suggests that increased allergic inflammation in carriers of IL13+2044A depends on enhanced IL-13-mediated Th2 effector functions rather than increased Th2 differentiation. Collectively, our data indicate that natural variation in the coding region of IL13 may be an important genetic determinant of susceptibility to allergy.

Polymorphisms in IL13 pathway genes in asthma and chronic obstructive pulmonary disease

“…Vladich et al (34) reported that an R fi Q replacement may amplify IL13 activity (e.g., STAT6 phosphorylation and CD23 expression in monocytes), particularly when associated with other SNPs in the IL13 pathway, such as -1111CT (often found in LD) or V50R551 of IL4Ra (35). It is important to note that, while both the asthma/atopy and COPD analyses highlighted a role for IL13 SNPs in disease mechanisms, the asthma/atopy associations involved SNPs in the promoter, intron and exon regions, whereas the COPD signal was localized to intronic and coding region SNPs.…”

Mouse genetic model for antigen-induced airway manifestations of asthma

“…37 The groups of Bleecker and Postma showed an association between a polymorphism in the IL-13 promoter and bronchial hyper-reactivity in a Dutch population of asthmatics. 38 Vladich et al 39 recently demonstrated that the IL-13 2044GA polymorphism, which is associated with allergy and asthma, encodes for a form of IL-13, which is more active and less effectively neutralized. In our experiments, a significant correlation is seen between IL-13 and airway reactivity at low doses of methacholine (below 25 mg/ml), but not at high doses.…”

Th2 Cell-Selective Enhancement of HumanIL13Transcription byIL13-1112C>T, a Polymorphism Associated with Allergic Inflammation

“…This block includes IL13-2044GϾA, a coding SNP resulting in the expression of a gain-offunction variant (IL-13 R130Q; Ref. 13) strongly associated with allergic inflammation in several ethnically distinct populations (14). This polymorphism is also in high, albeit not complete, LD with two promoter polymorphisms, IL13-1512AϾC and IL13-1112CϾT (rs1800925, also referred to as Ϫ1055 and Ϫ1111) (12).…”

“…The effect was strengthened after adjusting for ethnicity and IL13-2044 genotype in a multivariate linear regression (Ϫ1112TT vs CC, p ϭ 0.007; Ϫ1112TT vs CT, p ϭ 0.003). The latter adjustment was required because IL13-2044GϾA, a common coding SNP in strong LD with IL13-1112CϾT in the Tucson population (12), results in the expression of an IL-13 variant (IL-13 R130Q) with increased biological activity and altered antigenic properties that decrease its ELISA-based detection by a factor of 25.7% (13). Therefore, the data shown in Fig.…”