Environmental Proteinases in Human/Experimental Asthma

这个实验室的长期目标是了解免疫学机制。 潜在的过敏性肺病。这一提议将明确地确定最早的先天免疫 由过敏原激活的信号通路，为随后的过敏性肺部疾病提供条件。 此外，我们将确定家庭环境中的过敏性蛋白酶与 儿童哮喘的发展。最近的研究表明，过敏性哮喘是药物治疗失败的结果。 免疫耐受机制通常被激活以抑制炎症反应 吸入的抗原。常用的实验性过敏原，如卵清蛋白，只能短暂地 避免耐受性和诱导强烈的呼吸道炎症，然后只有在最初给药的情况下 远离肺部，然后是呼吸道抗原攻击。相比之下，我们已经开发出了更强大的 过敏原来源于与人类过敏性疾病有关的来源。不需要特殊佐剂 或给药方案，这些真菌和花粉衍生的过敏原强烈诱发过敏性肺 通过绕过呼吸道免疫耐受机制的炎症。这些强效过敏原含有很强的 蛋白水解酶活性完全解释了它们诱发和维持哮喘的能力 表型。尽管非真菌蛋白水解酶存在并与人类哮喘和其他过敏性疾病有关 我们的数据表明，哮喘儿童家中的灰尘主要含有真菌。 蛋白酶。 因此，我们提出了一个新的假设，即蛋白酶是一种重要的环境佐剂。 过敏性疾病引起过敏性疾病的因素，尤指在生命早期这项提议的目的是 因此：1.评价真菌蛋白水解酶与儿童哮喘的关系；2. 蛋白水解性变应原激活的一种新的呼吸道天然信号通路的功能特征。 我们将进行一项病例对照研究，涉及休斯顿地区患有和不患有哮喘的儿童，以 了解房屋灰尘中的活性蛋白酶与哮喘之间的关系，并进一步做好准备 哮喘患儿家庭真菌过敏原及其天然免疫测定 它们在小鼠身上引发疾病的机制。这项提议将人类和动物研究联系起来，以解开 变态反应性炎症的基本免疫机制及其开发新途径 哮喘的治疗方法。

The broad, long-term objectives of this laboratory are to understand the immunological mechanisms underlying allergic lung disease. This proposal specifically will determine the earliest innate immune signaling pathway activated by allergens that conditions the lung for subsequent allergic lung disease. Further, we will determine the relationship between allergenic proteinases in home environments and the development of childhood asthma. Recent studies indicate that allergic asthma is the result of failure of immune tolerogenic mechanisms that are normally activated to suppress inflammatory responses to inhaled antigens. Commonly used experimental allergens such as ovalbumin are only transiently capable of avoiding tolerance and inducing robust airway inflammation and then only if administered initially remotely from the lung followed by airway antigen challenge. In contrast, we have developed more potent allergens derived from sources implicated in human allergic disease. Without requiring special adjuvants or protocols for administration, these fungal and pollen-derived allergens strongly induce allergic lung inflammation by bypassing airway immune tolerogenic mechanisms. These potent allergens contain strong proteinase activities that account entirely for their ability to induce and sustain chronically the asthma phenotype. Although non-fungal proteinases exist and are implicated in human asthma and other allergic disorders, our data indicate that dust from homes of asthmatic children contains primarily fungal proteinases. We therefore propose the novel hypothesis that proteinases represent an essential environmental adjuvant factor that is responsible for inducing allergic disease, especially in early life. The aims of this proposal are therefore to: 1. To evaluate the association between fungal proteinases and childhood asthma; and 2. To functionally characterize a novel innate signaling pathway of the airway activated by proteolytic allergen. We will conduct a case-control study involving Houston-area children with and without asthma to understand the association between active proteinase in house dust and asthma and, further, prepare allergens from fungi isolated from homes of asthmatic children and determine the innate immune mechanism by which they elicit disease in mice. This proposal links human and animal studies to unravel the fundamental immune mechanisms underlying allergic inflammation with the intent to develop novel therapies for asthma.