Identification of novel immune phenotypes for allergic and nonallergic childhood asthma
Identification of novel immune phenotypes for allergic and nonallergic childhood asthma
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DOI：
10.1016/j.jaci.2014.07.046
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发表时间：
2015-01-01
影响因子：
14.2
通讯作者：
Schaub, Bianca
中科院分区：
文献类型：
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作者：
Raedler, Diana;Ballenberger, Nikolaus;Schaub, Bianca
背景资料：儿童哮喘分为过敏性哮喘（AA）和非过敏性哮喘（NA），但两者治疗相同，只有部分成功。目的：我们试图确定新的免疫表型的儿童AA和NA。方法：临床哮喘研究协会队列研究包括275类固醇初治4- 15岁的德国儿童（健康对照组[HC]，AA患者，NA患者）。在PBMC中，在抗CD 3/CD 28、脂质A和肽聚糖刺激之前/之后，对调节性T（Treg）和T（H）17细胞（流式细胞术/Treg细胞抑制）进行定量和功能分析。细胞因子和基因表达，通过使用Luminex或转录组学/定量实时RT-PCR评估，通过回归分析进行分析。结果：采用线性判别分析方法，对3种表型进行免疫芯片和蛋白质分析，均能很好地区分。与HC相比，AA患者的特征是Treg细胞增加，但与NA患者相比则不然。来自AA患者而非NA患者的Treg细胞显著抑制IL 5、IL-13和IFN-γ分泌。AA患者的细胞内氯离子通道4（CLIC 4）和结节性硬化症1（TSC 1）的表达减少，这两种基因是重要的先天免疫调节因子。NA患者的特征为促炎性IL-1 β水平、中性粒细胞计数和IL-17转移免疫增加。与此同时，NA患者的抗炎性IL 37、脯氨酸-丝氨酸-苏氨酸磷酸酶相互作用蛋白2（PSTPIP 2）、嗜中性粒细胞相关基因CD 93、髓样细胞表达触发受体1（TREM 1）和G蛋白信号转导调节因子13（RGS 13）的表达增加。一个共享的T（H）2免疫存在于两个哮喘phenotype.Conclusion：新的免疫调节机制在儿童哮喘确定增加Treg细胞与AA患者相比，在HC，但不是那些在NA和先天免疫基因减少AA患者，第一个潜在的反调节机制，以抑制细胞因子，但不足以控制过敏性炎症。非常明显，NA患者显示IL-17转移的促炎免疫，促进中性粒细胞炎症和功能性Treg细胞减少。这些独特途径的鉴定为未来个体化预测哮喘发展、病程和预防策略提供了深刻的基础。
Background: Childhood asthma is classified into allergic asthma (AA) and nonallergic asthma (NA), yet both are treated identically, with only partial success. Objective: We sought to identify novel immune phenotypes for childhood AA and NA.Methods: The Clinical Asthma Research Association cohort study includes 275 steroid-naive 4-to 15-year-old German children (healthy control subjects [HCs], patients with AA, and patients with NA). In PBMCs both quantitative and functional analysis of regulatory T (Treg) and T(H)17 cells (flow cytometry/Treg cell suppression) before/after anti-CD3/CD28, lipid A, and peptidoglycan stimulation were performed. Cytokines and gene expression, as assessed by using Luminex or transcriptomics/quantitative real-time RT-PCR, were analyzed by means of regression analysis. Linear discriminant analysis was applied to discriminate between phenotypes.Results: The 3 phenotypes were immunologically well discriminated by means of microarray and protein analysis with linear discriminant analysis. Patients with AA were characterized by increased Treg cells compared with those in HCs but not those in patients with NA. Treg cells from patients with AA, but not patients with NA, significantly suppressed IL5, IL-13, and IFN-gamma secretion. Patients with AA had decreased expression of chloride intracellular channel 4 (CLIC4) and tuberous sclerosis 1 (TSC1), important innate immunity regulators. Patients with NA were characterized by increased proinflammatory IL-1 beta levels, neutrophil counts, and IL-17-shifted immunity. In parallel, expressions of anti-inflammatory IL37, proline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2), and the neutrophil-associated genes CD93, triggering receptor expressed on myeloid cells 1 (TREM1), and regulator of G-protein signaling 13 (RGS13) were increased in patients with NA. A shared T(H)2 immunity was present in both asthma phenotypes.Conclusion: Novel immune-regulatory mechanisms in childhood asthma identified increased Treg cells in patients with AA compared with those in HCs but not those in NA and decreased innate immunity genes for patients with AA, the first potentially indicating a counterregulatory mechanism to suppress cytokines yet not sufficient to control allergic inflammation. Very distinctly, patients with NA showed an IL-17-shifted proinflammatory immunity, promoting neutrophil inflammation and less functional Treg cells. Identification of these unique pathways provides a profound basis for future strategies for individualized prediction of asthma development, disease course, and prevention.