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：

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奥马珠单抗后浆细胞样树突状细胞抗病毒反应增强。

 背景

特应性和病毒性呼吸道感染协同促进哮喘恶化。 IgE 交联会抑制病毒诱导的浆细胞样树突状细胞 (pDC) 的关键 IFN-α 反应，而过敏性哮喘患者可能缺乏这种反应。

 客观的

我们试图确定奥马珠单抗治疗降低体内IgE 水平是否会增加市中心哮喘儿童的 pDC 抗病毒 IFN-α 反应。

 方法

在奥马珠单抗治疗前和治疗期间从患有易发作哮喘的儿童中分离出的 PBMC 和 pDC 在存在或不存在 IgE 交联的情况下用鼻病毒和流感离体刺激。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 IFN-α 途径基因的 mRNA 表达。分别使用流式细胞术和 qRT-PCR 测量未刺激细胞中的 FcεRIα 蛋白水平和 mRNA 表达。分析了这些结果的变化以及与临床结果的关联，并使用统计模型来确定哮喘恶化的危险因素。

 结果

奥马珠单抗治疗在 IgE 交联存在的情况下增加了鼻病毒和流感诱导的 PBMC 以及鼻病毒诱导的 pDC IFN-α 应答，并减少了 pDC 表面 FcεRIα 表达。奥马珠单抗诱导的 pDC FcεRIα 水平降低与结果期间哮喘急性发作率降低显着相关，并与 PBMC IFN-α 反应的增加相关。研究开始时测量的 PBMC FcεRIα mRNA 表达显着改善了现有的病情加重预测模型。

 结论

这些发现表明奥马珠单抗治疗增强了 pDC IFN-α 反应并减弱了 pDC FcεRIα 蛋白表达，并提供了这些效应相关的证据。这些结果支持了临床观察的潜在机制，即过敏性致敏与病毒引起的哮喘恶化的易感性增加有关。