Mechanisms of Atopic Disease Development in the Lung

 描述(申请人提供)：哮喘和特应性疾病是西方人的主要健康负担。导致这些疾病发展和恶化的机制(S)尚不清楚。呼吸道病毒感染与特应性疾病的发展和恶化有关。我们利用了副粘病毒感染的小鼠模型，在该模型中，仙台病毒(SeV)感染会导致一种长期的病毒后特应性疾病，伴有呼吸道高反应性和粘液细胞化生。这种“前特应性”模式依赖于CD49d表达的中性粒细胞(PMN)的募集，PMN通过一种未知的机制驱动肺树突状细胞上高亲和力的IgE受体的表达。产生抗SeV IgE，使该受体交联，最终导致产生IL13的Th2细胞的募集。PMN亚群的调节是否会影响疾病尚不清楚，也不清楚IgE在抗病毒免疫反应中扮演什么角色。我们假设，肺对病毒的免疫反应的特定成分(即CD49d+PMN和IgE)驱动特应性疾病的发生，并且可以被调节以降低特应性疾病的风险。为了验证这一假设，我们提出了以下具体目标：1)确定操纵表达CD49d的PMN是否可以预防病毒后特应性疾病。2)探讨CD49d表达的PMN诱导CDC FceRI的机制。3)确定IgE在抗病毒免疫应答中的功能相关性。这个项目完成后，我们将确定CD49d+PMN与CD49d-PMN的不同之处，它们的招募调节是否影响病毒后特应性疾病的发展，以及人类是否存在类似的细胞。CD49d+PMN驱动树突状细胞表达FceRI的机制将被了解，我们将确定IgE在抗病毒免疫反应中的功能相关性。总之，这些研究将帮助我们改进和集中未来潜在的治疗干预措施，以防止病毒后特应性疾病的发展和恶化。

 DESCRIPTION (provided by applicant): Asthma and atopic diseases are major health burdens in the westernized world. The mechanism(s) responsible for the development and exacerbation of these diseases are not well understood. Respiratory viral infections have been implicated in development and exacerbation of atopic disease. We have utilized a mouse model of paramyxoviral infection where infection with Sendai virus (SeV) leads to a long-lasting post-viral atopic disease with airway hyperreactivity and mucous cell metaplasia. This "pro-atopic" paradigm depends upon recruitment of CD49d expressing neutrophils (PMN), which, through an unknown mechanism, drive expression of the high-affinity receptor for IgE on lung dendritic cells. Anti-SeV IgE is made which crosslinks this receptor, ultimately leading to recruitment of IL13 producing Th2 cells. Whether modulation of the PMN subsets can impact disease is not known, nor is it clear what role IgE plays during the antiviral immune response. We hypothesize that specific components of the pulmonary immune response to viruses (i.e., CD49d+ PMN and IgE) drive development of atopic disease, and can be modulated to reduce the atopic disease risk. To test this hypothesis we propose these specific aims: 1) Determine if manipulation of CD49d expressing PMN can prevent post-viral atopic disease. 2) Determine the mechanism through which CD49d expressing PMN induce cDC FceRI. 3) Determine the functional relevance of IgE during the antiviral immune response. Upon completion of this project, we will have determined how CD49d+ PMN differ from CD49d- PMN, whether modulation of their recruitment affects the development of post-viral atopic disease, and whether similar cells exist in humans. The mechanism through which CD49d+ PMN drive dendritic cell expression of FceRI will be known, and we will have determined the functional relevance of IgE in the antiviral immune response. Together, these studies will help us refine and focus potential therapeutic interventions in the future to prevent the development and exacerbation of post-viral atopic disease.