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

尽管治疗上有所改善，但仍有相当数量的新诊断的过敏性哮喘患者。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具有单链RNA作为其自身的基因组，然后产生双链RNA（dsRNA）作为复制的中间体。因此，以dsRNA为靶点，研究病毒相关的哮喘发病机制是一条合理的途径。分子免疫学的最新进展表明，dsRNA可诱导强烈的先天免疫应答。这些暂时的反应可能会影响正在进行的获得性免疫反应，包括过敏性致敏。为了阐明dsRNA在哮喘发展中的作用，我们研究了在过敏原致敏过程中，多聚肌苷酸多胞苷酸（polyIC）（一种病毒dsRNA的合成模拟物）的治疗是否会影响以下哮喘表型。当在每次用OVA致敏时施用聚IC时，伊红 ...更多信息 与盐水处理的小鼠相比，BALF中的嗜中性粒细胞增多和OVA吸入激发后的气道高反应性增强。这种增强需要同时和重复施用聚IC与OVA致敏，表明聚IC可能影响致敏过程。经poly IC处理的小鼠在OVA激发后BALF中IL-13的浓度选择性地高于盐水处理的小鼠。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激发的肺细胞进行流式细胞术分析，发现CD 8 ^+ T细胞亚群是过量产生IL-13的主要来源。因此，CD 8 ^+ T细胞亚群选择性过量产生IL-13可能是poly IC治疗诱导哮喘表型增强的关键。有趣的是，这些表型是肥大细胞依赖性的，因为哮喘的增强表型不是在肥大细胞缺陷小鼠中诱导的，而是在多聚IC治疗前用肥大细胞转移预处理的小鼠中诱导的。当多聚IC与D-半乳糖胺（D-gal）联合给药时，哮喘表型增强，伴有IL-10和IFN-γ产生的下调。Foxp 3+调节性T细胞在过敏原暴露小鼠的肺中也减少。在用抗IL-10受体抗体预处理的小鼠中没有诱导poly IC/D-gal诱导的哮喘表型增强，但在IFN-γ缺陷小鼠中进行。这些结果表明，双链RNA可能通过多种机制增强哮喘表型的诱导，包括肥大细胞/CD 8 + T细胞/IL-13途径和调节性T细胞/IL-10途径。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