Genetic/Biological Determinants of Environmental Disease

肺中先天免疫和适应性免疫之间的相互作用对于宿主对感染的反应的发展至关重要，并且可能在许多形式的肺部疾病（包括哮喘、纤维化和肺移植排斥）的发展中很重要。吸入空气污染中常见的毒素有助于哮喘和环境气道损伤的发展和进展。这项研究计划的总体目标是在环境气道疾病的小鼠模型和人群中鉴定介导宿主对一些环境毒素和过敏原反应的基因。具体的环境挑战包括脂多糖（LPS）、过敏原（屋尘螨和卵清蛋白）、臭氧和颗粒物。 在环境哮喘遗传学项目中，目标是鉴定参与哮喘患者气流阻塞和气道炎症发展的基因，并确定这些差异表达基因的多态性是否使个体易患哮喘。哮喘是一种复杂的遗传性疾病，由许多独特的基因-基因和基因-环境相互作用引起。吸入的环境因子在哮喘患者中诱导几种非常特异性的生物反应，包括诱导获得性和先天性免疫，其导致急性和慢性形式的气道炎症和气道重塑。新出现的证据表明，获得性和先天性免疫反应在肺部可能受到多态性基因的影响。在这个项目中，我们假设在特定的亚段气道挑战后，哮喘患者气道细胞表达的基因多态性使个体易患哮喘。为了验证这一假设，我们计划确定差异表达的基因，细胞在气道上皮细胞后，特定的亚段气道挑战与刺激，诱导获得性（屋尘螨）或先天性（LPS）免疫反应，然后确定这些基因的多态性是否与哮喘的发展在一个单独的，充分表征，家族性哮喘患者队列。除了人类亚段激发研究外，我们正在长期过敏原暴露的小鼠模型中更密切地研究内毒素暴露与过敏性哮喘之间的关系。 在另一项研究中，我们正在使用完善的环境气道疾病小鼠模型来研究Toll样受体4（TLR 4）在宿主对特定环境毒素的反应中的作用。肺部经常暴露于广泛的环境毒素，包括微生物病原体及其产物，颗粒物和臭氧。宿主对这些毒素的反应的共同特征是急性嗜酸性炎症和促炎细胞因子的上调。一些证据表明，TLR 4是需要从革兰氏阴性细菌的LPS的先天免疫应答，但TLR 4在宿主对其他毒素，如臭氧的反应中的作用目前还不清楚。 最后，我们正在研究移植生物学背景下先天免疫和适应性免疫之间的相互作用。慢性排斥反应表现为气道纤维化时限长吗？人类肺移植后的长期存活率。尽管排斥被认为是由于受体对同种异体肺组织的适应性免疫应答而发生的，但肺同种异体移植物也暴露于吸入毒素、感染和其他环境刺激形式的显著先天免疫刺激。我们的假设是先天免疫激活促进了肺移植急性和慢性排斥反应的发生。为了验证这一假设，我们从200多名肺移植受者及其各自的供体中分离了遗传物质和组织样本，并描述了他们在移植排斥反应方面的临床结果。我们还试图开发一种新的基于免疫学的慢性肺排斥小鼠移植模型，以进一步验证我们的假设。

The interplay between innate and adaptive immunity in the lung is central to the development of host response to infection and likely important in the development of many forms of lung disease including asthma, fibrosis, and lung transplant rejection. Inhalation of toxins commonly found in air pollution contributes to the development and progression of asthma and environmental airway injury. The overall goal of this research program is to identify genes that mediate the host response to a number of environmental toxins and allergens both in mouse models of environmental airway diseases and in human populations. Specific environmental challenges include lipopolysacharide (LPS), allergens (house dust mite and ovalbumin), ozone, and particulate matter. In the genetics of environmental asthma project, the goal is to identify genes that are involved in the development of airflow obstruction and airway inflammation in asthmatics, and to determine whether polymorphisms in these differentially expressed genes predispose individuals to develop asthma. Asthma is a complex genetic disorder that is caused by a number of unique gene-gene and gene-environment interactions. Inhaled environmental agents induce several very specific biologic responses in asthmatics, including the induction of acquired and innate immunity that leads to acute and chronic forms of airway inflammation and airway remodeling. Emerging evidence indicates that both acquired and innate immune responses in the lung may be influenced by polymorphic genes. In this project, we hypothesize that polymorphisms of genes expressed by airway cells in asthmatics following specific subsegmental airway challenges predispose individuals to the development of asthma. To test this hypothesis, we plan to identify the genes that are differentially expressed by cells in the airway epithelia following specific subsegmental airway challenge with stimuli that induce acquired (house dust mite) or innate (LPS) immune responses, and then determine whether polymorphisms in these genes are associated with the development of asthma in a separate, well characterized, familial cohort of asthmatics. In addition to subsegmental challenge studies in humans, we are investigating more closely the relationship between endotoxin exposure and allergic asthma in a mouse model of long term allergen exposure. In another line of investigation, we are using well-established mouse models of environmental airway disease to study the role of the Toll-like receptor 4 (TLR4) in the host response to specific environmental toxins. The lung is constantly exposed to a broad spectrum of environmental toxins, including microbiologic pathogens and their products, particulate matter, and ozone. A common feature of the host response to these toxins is both acute neutrophilic inflammation and upregulation of proinflammatory cytokines. Several lines of evidence demonstrate that TLR4 is required for innate immune responses to LPS from gram-negative bacteria but the role of TLR4 in the host response to other toxins such as ozone is at present unclear. Finally, we are examining the interplay between innate and adaptive immunity in the context of transplant biology. Chronic rejection manifest as airway fibrosis limit long?term survival after human lung transplant. Although rejection is thought to occur as a result of the recipient adaptive immune response to the allogenic lung tissue, the lung allograft is also exposed to significant innate immune stimuli in the form of inhalational toxins, infections, and other environmental stimuli. Our hypothesis in this line of investigation is that innate immune activation promotes the development of acute and chronic lung allograft rejection. In order to test this hypothesis we have isolated genetic material and tissue samples from over 200 lung transplant recipients and their respective donors and characterized their clinical outcomes with regards to graft rejection. We have also sought to develop a novel immunologically based murine transplant model of chronic lung rejection to pursue further testing of our hypothesis.