J Immunol:哮喘疾病发生机制新突破
2016-03-17

2016年1月7日 讯 /生物谷BIOON/ --哮喘是一类以肺炎以及呼吸道超敏反应为表征的慢性呼吸道疾病。然而,临床上获得的哮喘病人样本对揭示该疾病的发生机制十分有限。对于超敏反应而言,Th2与Th17细胞具有重要的作用:分别由Th2与Th17分泌的IL13与IL17A是参与呼吸道超敏反应的效应分子。其中IL-13促进机体对类固醇的超敏反应,从而导致肺部大量嗜酸性细胞的浸润。另一方面,IL-17能够促进中性粒细胞的浸润。为了进一步揭示在哮喘疾病发生过程中Th2与Th17的作用机制,来自匹斯堡大学儿科医学中心的John F. Alcorn课题组建立了一种新的小鼠模型。相关结果发表在最近一期的《journal of immunology》杂志上。

首先,作者利用T细胞移植的方式向野生型小鼠中导入同源的OVA特异性Th2与Th17细胞,之后利用OVA进行刺激使这部分移植进入的细胞得到激活。从而得到了类固醇耐受性的呼吸道过敏疾病小鼠模型。之后,作者通过elisa手段证明这一方法能够引起肺部大量Th2/Th17细胞的聚集以及IL-13/IL-17A的积累,标志着肺部炎症的发生。
 
之后,作者利用中和抗体的方法阻断了IL-13与IL-17A的活性。结果显示,在介入中和抗体之后,肺部的炎症反应程度得到了显著的减轻。此外,作者证明在IL-13与IL17A活性受到抑制的情况下,小鼠的肺部粘液上皮化生(哮喘的一类症状)也得到了改善。
 
之后,作者通过REAL-TIME PCR的方法证明在IL-13或IL-17被抑制的情况下Th2/Th17细胞内部STAT3的表达水平显著上升,这一结果说明IL-13与IL-17A可能是通过Stat3发挥促炎症的作用的。与此相反,STAT6的表达量在两类细胞被阻断的情况下受到了抑制。最终,作者比较了野生型小鼠与STAT6缺失突变体小鼠在呼吸道炎症疾病模型中的差异。结果显示,相比于野生型,突变体小鼠II型细胞因子的表达量得到了明显的降低。这一结果说明STAT6信号通路对于介导两类细胞因子引起的呼吸道炎症反应具有关键的作用。
 
doi: 10.4049/jimmunol.1501531
 
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Molecular Mechanisms of Airway Hyperresponsiveness in a Murine Model of Steroid-Resistant Airway Inflammation
 
Michelle L. Manni, Sivanarayana Mandalapu, Kevin J. McHugh, M. Merle Elloso,
Paul L. Dudas, and John F. Alcorn
IL-13 and IL-17A, produced mainly by Th2 and Th17 cells, respectively, have an influential role in asthma pathogenesis. We examined the role of IL-13 and IL-17A in mediating airway hyperresponsiveness (AHR), lung inflammation, and mucus metaplasia in a dual Th2/Th17 model of asthma. IL-13 and/or IL-17A were neutralized using mAbs. Th2/Th17 adoptive transfer induced a mixed asthma phenotype characterized by elevated eosinophilia and neutrophilia, tissue inflammation, mucus metaplasia, and AHR that were partially reversible with steroid treatment. Pulmonary inflammation and quasi-static lung compliance were largely unaffected by neutralization of IL-13 and/or IL-17A. However, neutralization of IL-13 alone or in combination with IL-17A significantly attenuated AHR and mucus metaplasia. Further, STAT6 activation was attenuated following IL-13 and IL-13/IL-17A Ab treatment. We next assessed the role of STAT6 in Th2/Th17-mediated allergic airway disease using STAT6?/? mice. STAT6?/? mice adoptively transferred with Th2/Th17 cells had decreased AHR compared with controls. These data suggest that IL-13 drives AHR and mucus metaplasia in a STAT6-dependent manner, without directly contributing to airway or tissue inflammation. IL-17A independently contributes to AHR, but it only partially mediates inflammation and mucus metaplasia in a mixed Th2/Th17 model of steroid-resistant asthma.