Schröder Paul C, Casaca Vera I, Illi Sabina, Schieck Maximilian, Michel Sven, Böck Andreas, Roduit Caroline, Frei Remo, Lluis Anna, Genuneit Jon, Pfefferle Petra, Roponen Marjut, Weber Juliane, Braun-Fahrländer Charlotte, Riedler Josef, Lauener Roger, Vuitton Dominique Angèle, Dalphin Jean-Charles, Pekkanen Juha, von Mutius Erika, Kabesch Michael, Schaub Bianca
LMU Munich, University Children's Hospital, Munich, Germany.
Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.
Pediatr Allergy Immunol. 2016 Nov;27(7):687-695. doi: 10.1111/pai.12597. Epub 2016 Jul 12.
IL-33 polymorphisms influence the susceptibility to asthma. IL-33 indirectly induces Th2-immune responses via dendritic cell activation, being important for development of atopic diseases. Furthermore, IL-33 upregulates regulatory T cells (Tregs), which are critical for healthy immune homeostasis. This study investigates associations between IL-33 polymorphisms during the development of childhood atopic diseases and underlying mechanisms including immune regulation of Tregs.
Genotyping of IL-33-polymorphisms (rs928413, rs1342326) was performed by MALDI-TOF-MS in 880 of 1133 PASTURE/EFRAIM children. In 4.5-year-old German PASTURE/EFRAIM children (n = 99), CD4 CD25 FOXP3 Tregs were assessed by flow cytometry following 24-h incubation of PBMCs with PMA/ionomycin, LPS or without stimuli (U). SOCS3, IL1RL1, TLR4 mRNA expression and sST2 protein levels ex vivo were measured in PASTURE/EFRAIM children by real-time PCR or ELISA, respectively. Health outcomes (hay fever, asthma) were assessed by questionnaires at the age of 6 years.
rs928413 and rs1342326 were positively associated with hay fever (OR = 1.77, 95%CI = 1.02-3.08; OR = 1.79, 95%CI = 1.04-3.11) and CD4 CD25 FOXP3 Tregs (%) decreased in minor allele homozygotes/heterozygotes compared to major allele homozygotes (p(U) = 0.004; p(LPS) = 0.005; p(U) = 0.001; p(LPS) = 0.012). SOCS3 mRNA expression increased in minor allele homozygotes and heterozygotes compared with major allele homozygotes for both IL-33-polymorphisms (p(rs928413) = 0.032, p(rs1342326) = 0.019) and negatively correlated to Tregs.
IL-33-polymorphisms rs928413 and rs1342326 may account for an increased risk of hay fever with the age of 6 years. Lower Tregs and increased SOCS3 in combined heterozygotes and minor allele homozygotes may be relevant for hay fever development, pointing towards dysbalanced immune regulation and insufficient control of allergic inflammation.
白细胞介素-33（IL-33）基因多态性影响哮喘易感性。IL-33通过激活树突状细胞间接诱导Th2免疫反应，对特应性疾病的发展很重要。此外，IL-33上调调节性T细胞（Tregs），这对健康的免疫稳态至关重要。本研究调查儿童特应性疾病发展过程中IL-33基因多态性与包括Tregs免疫调节在内的潜在机制之间的关联。
采用基质辅助激光解吸电离飞行时间质谱（MALDI-TOF-MS）对1133名PASTURE/EFRAIM儿童中的880名进行IL-33基因多态性（rs928413、rs1342326）基因分型。在4.5岁的德国PASTURE/EFRAIM儿童（n = 99）中，将外周血单个核细胞（PBMCs）与佛波酯/离子霉素、脂多糖（LPS）孵育24小时或不给予刺激（U）后，通过流式细胞术评估CD4 CD25 FOXP3 Tregs。分别通过实时聚合酶链反应（PCR）或酶联免疫吸附测定（ELISA）检测PASTURE/EFRAIM儿童离体状态下的细胞因子信号转导抑制因子3（SOCS3）、白细胞介素1受体1（IL1RL1）、Toll样受体4（TLR4）信使核糖核酸（mRNA）表达和可溶性ST2（sST2）蛋白水平。通过问卷在6岁时评估健康结局（花粉症、哮喘）。
rs928413和rs1342326与花粉症呈正相关（比值比[OR] = 1.77，95%置信区间[CI] = 1.02 - 3.08；OR = 1.79，95%CI = 1.04 - 3.11），与主要等位基因纯合子相比，次要等位基因纯合子/杂合子中的CD4 CD25 FOXP3 Tregs（%）降低（p（U） = 0.004；p（LPS） = 0.005；p（U） = 0.001；p（LPS） = 0.012）。对于两种IL-33基因多态性，次要等位基因纯合子和杂合子中的SOCS3 mRNA表达均高于主要等位基因纯合子（p（rs928413） = 0.032，p（rs1342326） = 0.019），且与Tregs呈负相关。
IL-33基因多态性rs928413和rs1342326可能是6岁时花粉症风险增加的原因。杂合子和次要等位基因纯合子中较低的Tregs和升高的SOCS3可能与花粉症的发展有关，表明免疫调节失衡和对过敏性炎症的控制不足。
