Viral and allergen-driven immunity in chronic lung disease

摘要 严重过敏性哮喘病的特征是显著的气道结构改变和慢性 炎症以嗜酸性粒细胞、单核细胞和淋巴细胞为主，并伴有粘液 取决于免疫反应的性质的分泌过多。最严重的呼吸道疾病 从可控制的气道功能障碍到类固醇， 抵抗状态，通常是难以控制的严重恶化的结果。在超过25 经过多年的研究，我的实验室已经确定了许多细胞因子和趋化因子的作用， 启动和驱动肺部免疫反应，确定先天免疫分子，塑造 免疫表型（TLR，Notch）定义了呼吸道病毒感染的作用， 疾病，检查免疫细胞功能的表观遗传调节，以及最近确定的代谢控制 先天性免疫细胞激活。我们以前的许多发现揭示了潜在的治疗靶点 包括我们的第二个NHLBI RO 1中检查干细胞因子和ILC 2的研究。一 我们目前的NHLBI RO 1赠款正在研究自噬和细胞代谢在先天性免疫缺陷中的作用。 免疫细胞功能我们最近的研究正在解决与训练有关的其他机制。 肺内的免疫力，以及改变肺结构和功能的肺反应的发展， 肺的完整性。虽然我们将把2个RO 1与不同的主题结合起来，但我们的总体目标是 了解疾病期间肺部免疫环境是如何发展和维持的， 我们所有的研究。总之，我们过去和正在进行的调查显示， 不仅是疾病发展过程中的免疫反应，而且是早期免疫反应的长期后果。 疾病及其与肺功能和发育改变的关系。使用R35机制，我们将 继续扩大这些研究领域，这将是范式转变。我们将专注于具体目标 包括1）确定肺中RSV诱导的早期应答如何改变先天免疫细胞表型 并诱导肺结构变化，使肺易于发生后来的过敏/哮喘反应; 2）检查 干细胞因子（SCF）在改变慢性肺疾病患者ILC 2群体活化中作用 疾病;和3）研究细胞代谢如何改变疾病期间的免疫细胞发育，以维持 并延长疾病的严重程度。完成这些研究将提供新的见解，建立新的范例， 和完整的概念验证研究，以推进知识和验证新的， 临床疾病的相关机制。

Abstract Severe allergic asthmatic disease is characterized by significant airway structure changes and chronic inflammation predominated by eosinophils, mononuclear cells, and lymphocytes, and accompanied by mucus hypersecretion that depends upon the nature of the immune response. The most severe airways disease progresses through a continuum of responses ranging from manageable airway dysfunction to a steroid resistant state that is often a result of a severe exacerbation that is difficult to control. Over the more than 25 years of work in this area my laboratory has defined the role of numerous cytokines and chemokines that initiate and drive the pulmonary immune responses, identified innate immune molecules that shape the immune phenotype (TLRs, Notch), defined a role for respiratory viral infections that induce and exacerbate disease, examined epigenetic regulation of immune cell function, and more recently identified metabolic control of innate immune cell activation. Many of our previous discoveries have revealed potential therapeutic targets for pulmonary diseases, including studies in our 2nd NHLBI RO1 that examine stem cell factor and ILC2. One of our present NHLBI RO1 grants is examining the role of autophagy and cellular metabolism for innate immune cell function. Our most recent studies are addressing additional mechanisms linked to trained immunity within the lung, as well as development of lung responses that alter the structural and functional integrity of the lung. While we will be combining 2 RO1 with divergent themes, our overall objective of understanding how the pulmonary immune environment is developed and maintained during disease is central to all of our studies. Together, our past and ongoing investigations are revealing an integrated understanding of not only the immune responses during disease development, but also the long-term consequence of early disease and its relationship to altered lung function and development. Using this R35 mechanism, we will continue expanding on these areas of research that will be paradigm shifting. We will focus on specific goals including 1) determine how early RSV-induced responses in the lung alter the innate immune cell phenotype and induce lung structural changes that predisposes the lung to later allergic/asthmatic responses; 2) examine the role that stem cell factor (SCF) has on altering the activation of ILC2 populations in chronic pulmonary disease; and 3) investigate how cell metabolism alters immune cell development during disease to maintain and extend disease severity. Completion of these studies will provide new insights, establish new paradigms, and complete proof of concept studies needed to advance knowledge and validate new, therapeutically relevant mechanisms in clinical disease.