Background

Atopy and viral respiratory tract infections synergistically promote asthma exacerbations. IgE cross-linking inhibits critical virus-induced IFN-α responses of plasmacytoid dendritic cells (pDCs), which can be deficient in patients with allergic asthma.

Objective

We sought to determine whether reducing IgE levels in vivo with omalizumab treatment increases pDC antiviral IFN-α responses in inner-city children with asthma.

Methods

PBMCs and pDCs isolated from children with exacerbation-prone asthma before and during omalizumab treatment were stimulated ex vivo with rhinovirus and influenza in the presence or absence of IgE cross-linking. IFN-α levels were measured in supernatants, and mRNA expression of IFN-α pathway genes was determined by using quantitative RT-PCR (qRT-PCR) in cell pellets. FcεRIα protein levels and mRNA expression were measured in unstimulated cells by using flow cytometry and qRT-PCR, respectively. Changes in these outcomes and associations with clinical outcomes were analyzed, and statistical modeling was used to identify risk factors for asthma exacerbations.

Results

Omalizumab treatment increased rhinovirus- and influenza-induced PBMC and rhinovirus-induced pDC IFN-α responses in the presence of IgE cross-linking and reduced pDC surface FcεRIα expression. Omalizumab-induced reductions in pDC FcεRIα levels were significantly associated with a lower asthma exacerbation rate during the outcome period and correlated with increases in PBMC IFN-α responses. PBMC FcεRIα mRNA expression measured on study entry significantly improved an existing model of exacerbation prediction.

Conclusions

These findings indicate that omalizumab treatment augments pDC IFN-α responses and attenuates pDC FcεRIα protein expression and provide evidence that these effects are related. These results support a potential mechanism underlying clinical observations that allergic sensitization is associated with increased susceptibility to virus-induced asthma exacerbations.

中文翻译：

---

omalizumab后增强的浆细胞样树突状细胞抗病毒反应。

背景

特应性疾病和病毒性呼吸道感染协同促进哮喘发作。IgE交联抑制了浆细胞样树突状细胞（pDC）的关键病毒诱导的IFN-α反应，这在过敏性哮喘患者中可能是不足的。

客观的

我们试图确定用奥马珠单抗治疗可降低体内IgE水平是否增加内城区哮喘儿童的pDC抗病毒IFN-α反应。

方法

在存在或不存在IgE交联的情况下，用鼻病毒和流感病毒离体刺激在奥马珠单抗治疗之前和期间从易加重哮喘患儿中分离的PBMC和pDC 。测量上清液中的IFN-α水平，并使用定量RT-PCR（qRT-PCR）测定细胞沉淀中的IFN-α途径基因的mRNA表达。使用流式细胞仪和qRT-PCR分别测量未刺激细胞中的FcεRIα蛋白水平和mRNA表达。分析了这些结局的变化以及与临床结局的关系，并使用统计模型确定了哮喘加重的危险因素。

结果

在IgE交联的情况下，奥马珠单抗治疗增加了鼻病毒和流感诱导的PBMC和鼻病毒诱导的pDCIFN-α反应，并降低了pDC表面FcεRIα表达。奥马珠单抗诱导的pDCFcεRIα水平降低与预后期间哮喘急性发作率降低显着相关，并与PBMCIFN-α反应增加相关。在研究开始时测得的PBMCFcεRIαmRNA表达显着改善了加重预测的现有模型。

结论

这些发现表明，奥马珠单抗治疗可增强pDCIFN-α反应并减弱pDCFcεRIα蛋白表达，并提供这些作用相关的证据。这些结果支持了潜在的机制，潜在的临床观察表明，过敏性致敏与对病毒引起的哮喘加重的易感性增加有关。