Dust Mite, Cockroach and Cat Allergens in Asthma

描述(由申请人提供)：这项资助中建议的研究旨在提供对室内过敏原暴露和针对这些蛋白质的特异性IgE抗体在哮喘患病率和严重程度方面的作用的新理解。我们最近对一种新形式的过敏反应的研究发现，IgE抗体是针对扁虱叮咬诱导的低聚半乳糖-1，3-半乳糖(α-GAL)的。这些反应在美国东南部很常见，与食用红肉3-4小时后出现迟发性过敏反应有关。与此一致，这里提出的实验利用了这样一个事实，即有两种过敏原(阿尔法-半乳糖和花生)致敏似乎变得更加常见，并且i)产生高滴度的IgE抗体，ii)被认为通过皮肤诱导IgE抗体，iii)与哮喘无关。我们的中心假设是，抗蛋白质抗原的IgE抗体是哮喘的重要诱因，如果它们被长期吸入，而且这些IgE抗体效价较高会增加这种风险。拟议的实验从几个方面解决了这一问题：i.在发展中国家或“卫生前”地区进行的研究，旨在了解为什么这些国家的儿童既没有针对吸入性过敏原的高滴度IgE抗体，也没有过敏性哮喘。这些研究将包括厄瓜多尔、哥斯达黎加和弗吉尼亚州的家庭环境、过敏反应、临床症状和粪便微生物群的比较。在西方“后卫生”环境中的研究集中于不同暴露途径影响IgE抗体反应的证据。这些研究将调查在有或没有破坏皮肤屏障的情况下，变应原对皮肤诱导Th2相关反应的影响。这些研究还将探讨婴儿过度清洁造成的皮肤变化是否会导致IgE抗体的增加。我们将使用两种不同的方法来研究高滴度IgE抗体与了解哮喘急性加重的相关性。这些研究将首先研究在医院急诊室出现急性加重的儿童，其次，使用新的RV-16池，对患有哮喘的成人受试者进行RV挑战。这些研究将集中在鼻病毒导致过敏性哮喘恶化的机制上。综上所述，这里提出的实验有可能：i)解释高滴度对哮喘患病率和严重性的影响；ii)确定旨在降低疾病严重性和恶化风险的治疗目标；iii)提供有关过敏性疾病患病率持续上升的信息。

DESCRIPTION (provided by applicant): The studies proposed in this grant are designed to provide new understanding of the role of both indoor allergen exposure and IgE antibodies specific for these proteins in relation to the prevalence and severity of asthma. Our recent investigation of a novel form of anaphylaxis identified IgE antibodies specific for the oligosaccharide galactose-¿-1,3-galactose (alpha-gal) that are induced by tick bites. Those responses are common in the southeastern United States and are associated with delayed anaphylaxis following 3-4 hours after consumption of red meat. In keeping with that, the experiments proposed here take advantage of the fact that there are two allergens (alpha-gal and peanut) where sensitization appears to have become more common and which i) give rise to high titer IgE antibodies, ii) are thought to induce IgE antibodies by going through the skin, and iii) are not associated with asthma. Our central hypothesis is that IgE antibodies to protein antigens are an important contributor to asthma if they are chronically inhaled, and also that higher titers of these IgE antibodies increase that risk. The proposed experiments address several aspects of the problem from: I. Studies in developing or "pre-hygiene" regions, designed to understand why children in those countries do not have either high titer IgE antibodies to inhalant allergens or allergic asthma. These studies will include a comparison of home environments, allergic sensitization, clinical symptoms, and stool microbiome in Ecuador, Costa Rica, and Virginia. II. Studies within a Western "post-hygiene" environment focused on the evidence that different routes of exposure influence IgE antibody responses. These studies will investigate the effects of allergens on the skin in inducing Th2-related responses, with or without disruption of the skin barrier. The studies will also address the question whether changes in the skin due to excessive cleaning of infants could have contributed to the increase in IgE antibodies. III. We will use two different approaches to investigate the relevance of high titer IgE antibodies to understanding acute exacerbations of asthma. Those studies will first study children presenting with acute exacerbations to the hospital emergency room, and second, carry out RV challenges on adult subjects with asthma, using a new RV-16 pool. These studies will focus on the mechanisms by which Rhinovirus acts to cause exacerbation of allergic asthma. Taken together, the experiments proposed here have the potential to: i) explain the effects of high titer on prevalence and severity of asthma, ii) identify targets for treatment designed to reduce the severity of disease and the risk of exacerbations, and iii) provide information about why allergic diseases are continuing to increase in prevalence.