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）：全球特应性和哮喘患病率呈上升趋势。与特应性和哮喘的诱导相关，暴露于抗原、内毒素和其他病原体相关的分子模式（PAMPs）可诱导先天和适应性免疫反应。事实上，强效过敏原与生物制剂的共同暴露，通过先天免疫系统的受体触发，可能是适应性过敏致敏的必要途径。这些免疫反应受到暴露和基因的双重控制。在成人中，职业暴露估计占新哮喘病例的15%，而职业性哮喘是成人发病哮喘发展的极好模型。与动物打交道的研究科学家和技术人员对实验动物（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，可以检查与过敏致敏和哮喘相关的暴露、遗传学和生物学机制的相互作用。我们最近证明，内毒素是小鼠症状的最强预测因子，特别是在对小鼠不过敏的工人中。志愿者的内毒素挑战再现了职业暴露引起的上呼吸道和下呼吸道症状。在动物中，与过敏原接触的内毒素会增强过敏致敏作用，这取决于内毒素的时间和剂量。因此，内毒素既可作为呼吸道刺激物，也可作为过敏性致敏的辅助剂。toll样受体4 （TLR4）和CD14是人类内毒素反应的两个主要因子。人类TLR4编码区和CD14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，TLR4/896G变体降低了人支气管对内毒素的反应性和细胞因子释放。CD14/-159 C变异与过敏性疾病标志物相关，尽管在较高内毒素暴露的情况下，CD14/-159 T变异与气流限制和血清IgE升高有关。其他新描述的TLR4和CD14基因变异也可能在这些免疫事件中被证明是重要的，被其他已知的过敏和哮喘基因β -腺受体、tnf - α、IL-4、IL-4 α和IL-13的作用所修饰。该建议的中心假设是，内毒素和过敏原与TLR4和CD14以及其他过敏和哮喘相关基因的特异性宿主遗传变异的相互作用决定了与工作相关的症状、气流限制和对实验室小鼠的致敏风险。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，并在新雇佣工人的试点初始队列纵向研究中得到解决。研究实验室和动物设施的内毒素和小鼠过敏原取样将测量所有研究对象的暴露水平，并表征颗粒大小和分布。作为其主要目标，拟议的研究将评估野生型TLR4/896 G变体或CD14/-156 C或T变体，与空气中内毒素或小鼠过敏原结合，是否与气流限制、症状或小鼠致敏有关。作为次要目标，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。在一项巢式病例对照研究中，根据CD14和TLR4等位基因分类的受试者，通过检测pbmc对内毒素的体外细胞因子反应，研究基因多态性的功能意义。因此，该研究将确定对LA的症状和致敏所必需的暴露和遗传风险因素，为限制暴露和减少过敏性疾病的结果提供关键信息，并为过敏致敏和哮喘的过程提供更广泛的见解。