Investigating the pathogenic role and its novel intervention of virus-associated double-stranded RNA in asthma

尽管治疗方法有所改善，但仍有相当数量的过敏性哮喘新诊断患者。这种发病机制通常与病毒感染有关。许多引起呼吸道感染的病毒以单链RNA作为自己的基因组，然后产生双链RNA(DsRNA)，作为复制的中间产物。因此，靶向dsRNA是阐明病毒相关哮喘发病机制的合理途径。分子免疫学的最新进展表明，dsRNA可诱导强烈的先天免疫反应。这些短暂的反应可能会影响正在进行的获得性免疫反应，包括过敏反应。为了阐明dsRNA在哮喘发生发展中的作用，我们研究了在变应原致敏过程中，多聚胞苷(PolyIC)(一种病毒dsRNA的合成模拟物)治疗是否会影响以下哮喘表型。当每次卵清蛋白致敏时给予聚IC，曙红…与生理盐水组相比，吸入OVA后BALF中的亲和力和气道高反应性增强。这种增强需要同时和重复地给予Poly IC和OVA增敏，这表明Poly IC可能影响致敏过程。Poly IC组小鼠在OVA攻击后BALF中IL-13浓度选择性高于生理盐水组。当在每次OVA激发前给予IL-13抑制剂时，没有发现哮喘表型的增加。对OVA攻击的肺细胞进行的流式细胞术分析表明，CD8+T细胞亚群ET是过量产生IL-13的主要来源。因此，CD8~+T细胞亚群选择性过度产生IL-13可能是Poly IC治疗后哮喘表型增强的重要原因。有趣的是，这些表型是肥大细胞依赖的，因为肥大细胞缺陷小鼠哮喘的增加表型不是在肥大细胞缺陷小鼠中诱导的，而是在多聚IC治疗前经过肥大细胞转移处理的小鼠中发生的。多聚IC与D-氨基半乳糖(D-GAL)联合应用时，哮喘的表型增加，IL-10和干扰素-γ的产生下调。暴露于过敏原的小鼠肺中的Foxp3+调节性T细胞也减少。经抗IL-10受体抗体处理的小鼠不能诱导聚IC/D-半乳糖诱导的哮喘表型增强，但在干扰素-γ缺陷小鼠中却能诱导。这些结果提示，双链RNA可能通过肥大细胞/CD8+T细胞/IL-13途径和调节性T细胞/IL-10途径等多种机制促进哮喘表型的诱导。较少

Despite a therapeutic improvement, there has been considerable number of newly diagnosed patients of allergic asthma. Such pathogenesis is frequently associated with viral infection. Many viruses causing airway infection have single-stranded RNA as their own genome and then generate double-stranded RNA (dsRNA), as intermediates for replication. Hence, it is rational approach to target dsRNA for elucidating the mechanisms of virus-associated pathogenesis of asthma. Recent progress in molecular immunology revealed that dsRNA induces strong innate immune responses. Those temporal responses may affect the ongoing acquired immune responses, including allergic sensitization. To elucidate the role of dsRNA on the development of asthma, we examined whether treatment of polyinocinic polycytidilic acid (poly IC), a synthetic mimetic of viral dsRNA, during allergen sensitization affects or not the following asthma phenotype. When poly IC was administered at every sensitization with OVA, the eosin … More ophilia in BALF and the airway hyperresponsiveness after OVA inhalation challenge were augmented in comparison with those of saline-treated mice. This augmentation required simultaneous and repeated administration of poly IC with OVA sensitization, suggesting that poly IC may affect the process of sensitization. The concentration of IL-13 in BALF after OVA challenge in poly IC-treated mice was selectively higher than that in saline-treated mice. When an IL-13 inhibitor was administered before every OVA challenge, no augmentation of asthma phenotype was found. Flow cytometric analysis of OVA-challenged lung cells revealed that CD8^+T-cell subs et was a major source of over-produced IL-13. Thus, the selective over-production of IL-13 from CD8^+T-cell subset may be crucial for the augmented phenotype of asthma induced by poly IC treatment. Interestingly, these phenotypes were mast cell-dependent since the augmented phenotype of asthma was not induced in mast cell-deficient mice but done in the mice pretreated with mast cell-transfer before poly IC treatment. When poly IC was administered with D-galactosamine (D-gal), the augmented phenotype of asthma accompanied with the down-regulation of production of IL-10 and IFN-gamma. The Foxp3+regulatory T cells also decreased in the lungs of allergen-exposed mice. The poly IC/D-gal-induced augmentation of asthma phenotype was not induced in the mice pretreated with anti-IL-10 receptor antibody, but done in IFN-gamma-deficient mice. These results suggest that double-stranded RNA may enhance the induction of asthma phenotype by multiple mechanisms including mast cell/CD8+T-cell/IL-13 pathway and regulatory T-cell/IL-10 pathway. Less