Mechanisms of atopic disease development in the lung

 描述（由申请人提供）：哮喘和特应性疾病是西方世界的主要健康负担。导致这些疾病发展和恶化的机制尚不清楚。呼吸道病毒感染与特应性疾病的发展和恶化有关。我们已经利用了副粘病毒感染的小鼠模型，其中仙台病毒（SeV）感染导致具有气道高反应性和粘液细胞化生的长期病毒后特应性疾病。这种“亲特应性”范例依赖于表达CD 49 d的中性粒细胞（PMN）的募集，其通过未知的机制驱动肺树突细胞上IgE的高亲和力受体的表达。制备抗SeV IgE，其交联该受体，最终导致产生IL 13的Th 2细胞的募集。中性粒细胞亚群的调节是否会影响疾病尚不清楚，也不清楚IgE在抗病毒免疫应答中起什么作用。我们假设肺对病毒免疫反应的特定成分（即，CD 49 d + PMN和IgE）驱动特应性疾病的发展，并且可以被调节以降低特应性疾病风险。为了验证这一假设，我们提出了这些具体的目标：1）确定是否操纵表达CD 49 d的PMN可以预防病毒后特应性疾病。2)确定表达CD 49 d的PMN诱导cDC FceRI的机制。3)确定抗病毒免疫应答期间IgE的功能相关性。在这个项目完成后，我们将确定CD 49 d + PMN与CD 49 d-PMN的不同，它们的募集是否会影响病毒后特应性疾病的发展，以及人类中是否存在类似的细胞。CD 49 d + PMN驱动树突状细胞表达FceRI的机制将是已知的，并且我们将确定IgE在抗病毒免疫应答中的功能相关性。总之，这些研究将帮助我们在未来完善和集中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.