Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33.
Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33.
复制标题
DOI：
10.1016/j.jaci.2015.01.016
复制
发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Saglani S
中科院分区：
文献类型：
--
作者：
Castanhinha S;Sherburn R;Walker S;Gupta A;Bossley CJ;Buckley J;Ullmann N;Grychtol R;Campbell G;Maglione M;Koo S;Fleming L;Gregory L;Snelgrove RJ;Bush A;Lloyd CM;Saglani S
严重哮喘伴真菌致敏（SAFS）的潜在机制尚不清楚。IL-33在真菌诱导的哮喘急性发作中很重要，但其在真菌致敏中的作用尚未研究。我们试图确定是否真菌致敏的儿童严重治疗抵抗性哮喘是由IL-33介导的。82名患有严重治疗抵抗性哮喘的儿童（中位年龄11.7岁; 63%为男性）被纳入研究。SAFS（n = 38）定义为特异性IgE或皮肤点刺试验对烟曲霉、互隔交链孢菌或草枝孢菌的反应阳性。评估临床特征和气道免疫病理学。在新生小鼠模型中比较了慢性暴露于屋尘螨和A alternata。SAFS患儿的症状发作较早（0.5 vs 1.5年，P = 0.006），总IgE水平较高（637 vs 177 IU/mL，P = 0.002），非真菌吸入性过敏原特异性IgE较高。SAFS的儿童中有更多的人接受了维持性口服类固醇治疗（42% vs 14%，P = 0.02）。SAFS与较高的气道IL-33水平相关。在新生小鼠中，A alternata暴露诱导更高的血清IgE水平，肺IL-33水平，IL-13+先天淋巴细胞（ILC）和TH 2细胞数量，但类似的气道高反应性（AHR）相比，屋尘螨暴露后。吸入布地奈德后，暴露于互隔交链孢霉期间，肺IL-33水平、IL-13+ ILC数量、TH 2细胞数量、IL-13水平和AHR仍然增加，但在缺乏IL-33功能性受体的ST 2 −/−小鼠中，所有特征均显著降低。儿童SAFS与更多的口服类固醇治疗和更高的IL-33水平相关。交替暴露导致IL-33介导的ILC 2数量、TH 2细胞数量和类固醇抗性AHR增加。IL-33可能成为SAFS治疗的新靶点。
The mechanism underlying severe asthma with fungal sensitization (SAFS) is unknown. IL-33 is important in fungus-induced asthma exacerbations, but its role in fungal sensitization is unexplored. We sought to determine whether fungal sensitization in children with severe therapy-resistant asthma is mediated by IL-33. Eighty-two children (median age, 11.7 years; 63% male) with severe therapy-resistant asthma were included. SAFS (n = 38) was defined as specific IgE or skin prick test response positivity to Aspergillus fumigatus, Alternaria alternata, or Cladosporium herbarum. Clinical features and airway immunopathology were assessed. Chronic exposure to house dust mite and A alternata were compared in a neonatal mouse model. Children with SAFS had earlier symptom onset (0.5 vs 1.5 years, P = .006), higher total IgE levels (637 vs 177 IU/mL, P = .002), and nonfungal inhalant allergen-specific IgE. Significantly more children with SAFS were prescribed maintenance oral steroids (42% vs 14%, P = .02). SAFS was associated with higher airway IL-33 levels. In neonatal mice A alternata exposure induced higher serum IgE levels, pulmonary IL-33 levels, and IL-13+ innate lymphoid cell (ILC) and TH2 cell numbers but similar airway hyperresponsiveness (AHR) compared with those after house dust mite exposure. Lung IL-33 levels, IL-13+ ILC numbers, TH2 cell numbers, IL-13 levels, and AHR remained increased with inhaled budesonide during A alternata exposure, but all features were significantly reduced in ST2−/− mice lacking a functional receptor for IL-33. Pediatric SAFS was associated with more oral steroid therapy and higher IL-33 levels. A alternata exposure resulted in increased IL-33–mediated ILC2 numbers, TH2 cell numbers, and steroid-resistant AHR. IL-33 might be a novel therapeutic target for SAFS.