Protracted clinical and inflammatory response to rhinovirus challenge in human asthmatics

鼻病毒(RV)感染是哮喘恶化的最常见原因，我们之前的研究 RV-A16的实验接种证明了该模型能够概括生理和 自然感染的免疫后果。以前从未被认识到的是，哮喘患者 持续显示上呼吸道和下呼吸道症状复发，在2-3周后达到高峰 接种疫苗。哮喘患者接种RV与嗜酸性粒细胞反应的快速发展有关 感染后2-4天(Dpi)达到高峰的呼吸道。嗜酸性炎症的这种增加也会发生。 然而，适应性免疫反应很快就可以解释，先天免疫系统 加重已建立的2型炎症状态是公认的。这反映了一代人的不成熟 2型促炎环境的上皮细胞(EPC)隔室，包括细胞因子的释放 白介素25、白介素33和TSLP。IL-25最近被认为是由一家 分化的EPC称为孤立性化学感觉细胞(SCC)。这三种细胞因子都能激活小鼠的免疫细胞 呼吸道，包括先天淋巴2细胞(ILC2)。但包括肥大细胞在内的其他细胞表达它们的受体 并将以分泌IL-5和IL-13作为反应。伴随着其他上皮来源的表达增强 嗜酸性粒细胞激活细胞因子，这解释了嗜酸性炎症和症状的加重 在接种后2-3天内观察。在拟议的研究中，我们特别渴望探索 导致呼吸道症状和炎症持续恶化的机制。这一增长 IL-13的产生将促进杯状细胞和干细胞的进一步分化，我们预测这些将 在2-3周内，呼吸道内皮祖细胞的比例越来越高。鳞状细胞癌来源的IL-25(和其他 细胞因子)将促进肥大细胞和ILC2的扩张。然而，这种晚期哮喘的复发 症状发生在持续暴露于空气变应原的情况下。我们的研究已经证明 RV增强对旁观者空气变应原的适应性免疫反应的能力。过敏原的相互作用 随着肥大细胞和过敏原特异的CD4+组织驻留记忆(TRM)淋巴细胞数量的增加 将建立一种我们建议的环境，这是炎症和症状长期恶化的基础。在……里面 综上所述，我们假设RV感染会通过一种新的方式快速诱导炎症反应 不成熟的上皮室，这会导致2型炎症状态的恶化 负责快速发展的轮状病毒诱发的哮喘恶化。更重要的是，我们建议 这种轮状病毒感染将导致SCCs、ILC2、CD4+TRM淋巴细胞和肥大细胞的延迟扩张， 这会导致呼吸道症状反复/旷日持久的恶化，并增加对进一步 病情加重。因此，这种前馈环路形成了严重哮喘表型的基础，其特征是 经常恶化，在某些情况下，导致不可逆转的肺功能丧失。 1

Rhinovirus (RV) infections are the most common cause of asthma exacerbations and our previous studies with experimental RV-A16 inoculations demonstrate the ability of this model to recapitulate the physiological and immune consequences of natural infections. What has never previously been appreciated is that asthmatics consistently also demonstrate recurrence of upper and lower airway symptoms peaking 2-3 weeks post- inoculation. RV inoculation in asthmatics is associated with rapid development of an eosinophilic response in the airway that peaks at 2-4 days post-infection (dpi). This increase in eosinophilic inflammation evolves too rapidly to be explained by an adaptive immune response, however, the ability of the innate immune system to exacerbate an established type 2 inflammatory state is recognized. This reflects generation by a dysmatured epithelial cells (EpC) compartment of a type 2 inflammation-promoting milieu including release of the cytokines interleukin (IL)-25, IL-33, and TSLP. IL-25 has recently been recognized to be exclusively produced by a differentiated EpC termed the solitary chemosensory cell (SCC). All 3 cytokines activate immune cells of the airway, including innate lymphoid 2 cells (ILC2s). But other cells including mast cells express their receptors and will respond with secretion of IL-5 and IL-13. Along with enhanced expression of other epithelial-derived eosinophil-activating cytokines, this explains the exacerbation of eosinophilic inflammation and symptoms observed within 2-3 days of the inoculation. In the proposed studies, we are particularly eager to explore mechanisms responsible for the protracted worsening of airway symptoms and inflammation. The increase in IL-13 production will promote the further differentiation of goblet cells and SCCs and we predict that these will comprise an increasingly high proportion of airway EpCs over 2-3 weeks. SCC-derived IL-25 (and other cytokines) will then promote the expansion of mast cells and ILC2s. However, this late recurrence of asthma symptoms is occurring in the presence of ongoing aeroallergen exposure. Our studies have demonstrated the ability of RV to enhance adaptive immune responses to bystander aeroallergens. The interaction of allergens with expanded populations of mast cells and allergen-specific CD4+ tissue resident memory (TRM) lymphocytes will establish a milieu that we propose underlies the protracted worsening of inflammation and symptoms. In summary, we hypothesize that RV infection results in the rapid induction of an inflammatory response by a dysmatured epithelial compartment, which leads to the exacerbation of a type 2 inflammatory state that is responsible for the rapid development RV-induced asthma exacerbations. More importantly, we propose that this RV infection will lead to the delayed expansion of SCCs, ILC2s, CD4+ TRM lymphocytes, and mast cells, that leads to the recurrent/protracted worsening of respiratory symptoms and enhances susceptibility to further exacerbations. This feedforward loop thereby forms the basis for a severe asthma phenotype characterized by frequent exacerbations and, in some situations, to the irreversible loss of lung function. 1