IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation.
IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation.
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DOI：
10.1172/jci22818
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发表时间：
2005-03
期刊：
影响因子：
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通讯作者：
F. Vladich;Susan M. Brazille;D. Stern;Michael L Peck;R. Ghittoni;D. Vercelli
中科院分区：
文献类型：
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作者：
F. Vladich;Susan M. Brazille;D. Stern;Michael L Peck;R. Ghittoni;D. Vercelli
已知遗传因素强烈影响过敏性炎症的易感性。Th 2细胞因子IL-13是过敏和哮喘的中心介质，IL-13中常见的单核苷酸多态性与几个不同种族人群中的过敏表型相关。特别地，预期IL 13 + 2044 GA导致精氨酸130（R130）被谷氨酰胺（Q）非保守性取代。我们通过直接比较WT IL-13和IL-13 R130 Q对参与变应性炎症效应机制的原代人细胞的活性来检查IL-13 + 2044 GA对IL-13的功能性质的影响。我们的结果表明，IL-13 R130 Q在诱导单核细胞中的STAT 6磷酸化和CD 23表达以及B细胞中的氢化可的松依赖性IgE转换方面比WT IL-13显著更有活性。值得注意的是，IL-13 R130 Q被IL-13 R2诱饵比WT IL-13更不有效地中和。次要变体的中和作用降低可能有助于其体内活性增强。两种IL-13变体都不能接合T细胞，这表明IL-13 + 2044 A携带者中增加的过敏性炎症取决于增强的IL-13介导的Th 2效应子功能，而不是增加的Th 2分化。总的来说，我们的数据表明，IL-13编码区的自然变异可能是过敏易感性的一个重要遗传决定因素。
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+2044GA is expected to result in the nonconservative replacement of arginine 130 (R130) with glutamine (Q). We examined the impact of IL13+2044GA 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-13R2 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.