Study of Allergen, Genetics and Endotoxin (SAGE)

过敏原、遗传学和内毒素研究 (SAGE)

• 批准号: 7564684
• 负责人: Cecile S Rose
• 金额: $ 36.28万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7564684
• 关键词: ADRB2 gene; Address; Adjuvant; Adrenergic Receptor; Adult; Adult asthma; Affect; Alleles; Allergens; Allergic; Allergic rhinitis; Animal Experimentation; Animal Model; Animal Technicians; Animals; Antigens; Asthma; Binding; Biological; Biological Models; Biological Products; Bronchial Hyperreactivity; CD14 gene; Cereals; Chest; Child; Code; Cross-Sectional Studies; Disease; Disease Outcome; Dose; Endotoxins; Environment; Environmental Risk Factor; Event; Exposure to; Flour; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Health; Human; Hypersensitivity; IgE; Immune response; Immune system; Immunologics; In Vitro; Interleukin-12; Interleukin-13; Interleukin-4; Irritants; Laboratory Animals; Laboratory Technicians; Laboratory mice; Latex; Light; Link; Longitudinal Studies; Measures; Molecular; Molecular Weight; Mus; Nested Case-Control Study; Occupational; Occupational Asthma; Occupational Exposure; Organism; Outcome; Particle Size; Pathway interactions; Pattern; Persons; Pilot Projects; Population Study; Prevalence; Process; Promoter Regions; Reporting; Research; Research Personnel; Response Elements; Risk; Sampling; Scientist; Serum; Signal Transduction; Study Subject; Surface; Symptoms; Time; Tumor Necrosis Factor-alpha; Variant; Work; Workplace; animal facility; atopy; cohort; cytokine; genetic risk factor; genetic variant; human TLR4 protein; human TNF protein; in vitro testing; insight; model development; pathogen; pet animal; programs; receptor; respiratory; response; toll-like receptor 4; volunteer

DESCRIPTION (provided by applicant): Thct worldwide prevalence of atopy and asthma is on the rise. Relevant to the induction of atopy and asthma, exposures to antigens, endotoxin and other pathogen-associated molecular patterns (PAMPs) induce both innate and adaptive immune responses. Indeed, co-exposure of potent allergens with biological agents, triggering through receptors of the innate immune system, may be the necessary pathway for adaptive allergic sensitization. These immune responses are controlled both by exposures and genes. In adults, occupational exposures are estimated to contribute 15% of new asthma cases, and occupational asthma serves as an excellent model for the development of adult onset asthma. Research scientists and technicians who work with animals have high rates of symptoms and sensitization to laboratory animals (LA), and are exposed to airborne animal allergens and endotoxin in the workplace. We propose to study this population because it is a model system in which to examine the interaction of exposures, genetics, and the biological mechanisms relevant to allergic sensitization and asthma. We recently demonstrated that endotoxin is the strongest predictor of symptoms to mice, particularly in workers who are not mouse allergic. Endotoxin challenge in volunteers reproduces upper and lower respiratory symptoms reported from occupational exposures. In animals, endotoxin exposure with allergen potentiates allergic sensitization, depending on the timing and dose of endotoxin. Endotoxin may thus act as both a respiratory irritant and as an adjuvant in allergic sensitization. Toll-like receptor 4 (TLR4) and CD14 are two major human endotoxin response elements. Polymorphisms in the human TLR4 coding region and in the CD14 promoter region dictate different functional responses to endotoxin and to allergen, respectively. The TLR4/896G variant reduces human bronchial responsiveness and cytokine release to endotoxin compared to the wild type. The CD14/-159 C variant is associated with markers of allergic disease, although in the context of higher endotoxin exposure, the CD14/-159 T variant is linked to airflow limitation and increased serum IgE. Other, newly described TLR4 and CD14 gene variants may also prove important in these immunologic events, modified by the effect of the other known allergy and asthma genes beta2-adenoreceptor, TNF-alpha, IL-4, IL-4alpha, and IL-13. The central hypothesis of this proposal is that the interaction of endotoxin and allergen with specific host genetic variants of TLR4 and CD14 and other allergy- and asthma-associated genes determines risk for work-related symptoms, airflow limitation, and sensitization to laboratory mice. This hypothesis will be addressed in a cross-sectional study of research scientists, laboratory technicians, and animal handlers, and in a pilot inception cohort longitudinal study of newly hired workers. Sampling for endotoxin and mouse allergen in research laboratories and the animal facility will measure exposure levels for all study subjects, and characterize particle size and distribution. As its primary objective, the proposed study will assess whether the wild type TLR4/896 G variant or the CD14/-156 C or T variant, in combination with airborne endotoxin or mouse allergen, are associated with airflow limitation, symptoms or sensitization to mice. As a secondary objective, the study will assess the contribution of other known asthma and allergy-related gene variants to these health outcomes. A sub-aim will examine the functional significance of gene polymorphisms, by testing in vitro cytokine responses of PBMCs to endotoxin in a nested case control study of subjects categorized by CD14 and TLR4 alleles. As such, the study will determine those exposures and genetic risk factors necessary for symptoms and sensitization to LA, supply information critical for limiting exposures and reducing allergic disease outcomes, and provide broader insight into the process of allergic sensitization and asthma.

描述（由申请人提供）：特应性和哮喘的全球患病率正在上升。与诱导特应性和哮喘相关，暴露于抗原、内毒素和其他病原体相关分子模式（PAMP）诱导先天性和适应性免疫应答。事实上，通过先天免疫系统的受体触发的强效过敏原与生物制剂的共同暴露可能是适应性过敏致敏的必要途径。这些免疫反应受暴露和基因控制。在成人中，职业暴露估计占新发哮喘病例的15%，职业性哮喘是成人发作哮喘发展的一个很好的模型。与动物一起工作的研究科学家和技术人员对实验室动物（LA）的症状和致敏率很高，并且在工作场所暴露于空气传播的动物过敏原和内毒素。我们建议研究这一人群，因为它是一个模型系统，在其中检查暴露的相互作用，遗传学和相关的过敏性致敏和哮喘的生物学机制。我们最近证明，内毒素是小鼠症状的最强预测因子，特别是在不对小鼠过敏的工人中。志愿者的内毒素挑战再现了职业暴露报告的上呼吸道和下呼吸道症状。在动物中，内毒素暴露与过敏原增强过敏性致敏作用，这取决于内毒素的时间和剂量。因此，内毒素可作为呼吸道刺激物和过敏性致敏的佐剂。Toll样受体4（TLR 4）和CD 14是两种主要的人体内毒素应答元件。人TLR 4编码区和CD 14启动子区的多态性分别决定了对内毒素和过敏原的不同功能反应。与野生型相比，TLR 4/896 G变体降低人支气管对内毒素的反应性和细胞因子释放。CD 14/-159 C变异体与过敏性疾病的标志物相关，尽管在较高内毒素暴露的情况下，CD 14/-159 T变异体与气流限制和血清IgE升高相关。其他新描述的TLR 4和CD 14基因变体也可能在这些免疫事件中证明是重要的，其被其他已知的过敏和哮喘基因β 2-腺受体、TNF-α、IL-4、IL-4 α和IL-13的作用修饰。该建议的中心假设是，内毒素和过敏原与TLR 4和CD 14的特定宿主遗传变异体以及其他过敏和哮喘相关基因的相互作用决定了实验室小鼠出现工作相关症状、气流受限和致敏的风险。这一假设将在研究科学家，实验室技术人员和动物处理人员的横断面研究中得到解决，并在新雇用工人的试点初始队列纵向研究中得到解决。在研究实验室和动物设施中对内毒素和小鼠过敏原进行采样，测量所有研究受试者的暴露水平，并表征粒度和分布。作为其主要目的，拟议的研究将评估野生型TLR 4/896 G变体或CD 14/-156 C或T变体与空气传播的内毒素或小鼠过敏原的组合是否与小鼠的气流限制、症状或致敏性相关。作为次要目的，该研究将评估其他已知的哮喘和过敏相关基因变异对这些健康结果的贡献。一个子目标是通过在按CD 14和TLR 4等位基因分类的受试者的巢式病例对照研究中测试PBMC对内毒素的体外细胞因子应答来检查基因多态性的功能意义。因此，该研究将确定LA症状和致敏所需的暴露和遗传风险因素，提供限制暴露和减少过敏性疾病结局的关键信息，并提供对过敏性致敏和哮喘过程的更广泛了解。