Pollution Aggravates Autoimmunity Through the Aryl Hydrocarbon Receptor

污染通过芳基烃受体加剧自身免疫

• 批准号: 8872438
• 负责人: Joshua D Mezrich
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8872438
• 关键词: Acute; Area; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Binding; Biological Assay; Breathing; Bronchiolitis Obliterans; Cells; Chronic; Clinical; Control Groups; Cytokine Receptors; Data; Development; Disease; Dose; Educational workshop; Environment; Environmental Exposure; Equilibrium; Experimental Autoimmune Encephalomyelitis; Future; Generations; Grant; Immune; Immune system; Immunomodulators; In Vitro; Incidence; Inflammation; Interleukin-17; Laboratories; Lead; Ligands; Lung; Lung Transplantation; Mediating; Modeling; Mus; National Institute of Environmental Health Sciences; Onset of illness; Organ Transplantation; Outcome; Particulate Matter; Pathology; Pathway interactions; Patients; Pharmacologic Substance; Play; Pollution; Proteins; Public Health; Publications; Recombinants; Reference Standards; Regulatory T-Lymphocyte; Reporting; Risk; Risk Factors; Role; Sampling; Solid; Symptoms; Syndrome; T cell response; Testing; Therapeutic; To autoantigen; Transplant Recipients; Transplantation; aryl hydrocarbon receptor ligand; base; cell type; epidemiologic data; experience; high risk; interest; lymph nodes; mouse model; novel; novel strategies; pollutant; public health relevance; receptor expression; remediation; research study; response

 DESCRIPTION (provided by applicant): Airborne pollution is well documented as a risk factor for multiple airway diseases, and is implicated in aggravating autoimmunity, both in the lung and systemically. In this grant we investigate the importance of inhaled particulate matter (PM), and specifically polycyclic aromatic hydrocarbons (PAHs) in PM, to enhance Th17 differentiation systemically and aggravate autoimmunity in a murine model of experimental autoimmune encephalomyelitis (EAE). We will present preliminary data that inhaled PM increases Th17 differentiation in remote lymph nodes and worsens EAE. Based on these findings and previous data, we have developed the hypothesis that patients at risk for development of autoimmunity experience a dysregulation of their Treg/Th17 balance when confronted with prolonged or acute airborne exposures that can aggravate existing disease or stimulate new onset disease. The recent finding that the aryl hydrocarbon receptor (AHR) plays a central role in the regulatory T cell (Treg)/Th17 balance, where some ligands of the AHR can enhance Treg differentiation and other ligands can enhance Th17 differentiation led us to predict that PAHs (which are known AHR ligands) in PM are responsible for pollution induced Th17 deviation. Our model is that PAHs in pollution, encountered through inhalation, bind to the AHR on immune cells, leading to increased Th17 differentiation, decreased Treg generation, and enhanced autoimmunity. If this model is correct, we postulate that a number of environmentally induced autoimmune diseases may be influenced by a similar mechanism. We will explore the following aims: Aim 1: Determine the lower limits of PM capacity to exacerbate EAE and examine the associated changes in the T cell responses to MOGp35-55. Aim 2: Determine the component(s) of PM responsible for aggravation of EAE after inhalation. Aim 3: Determine the requirements for AHR expression in PM- mediated EAE aggravation. The unique features of this grant and future studies are the ability we have based on our expertise to examine specific components of PM and their interaction with the AHR, the numerous recombinant mouse models at our disposal, and our ability to compare standard reference materials to real world samples to develop and test the components of PM that enhance autoimmunity. The connections of this project to public health are supported by the high incidence of autoimmunity, the known connection of these morbid diseases to environmental exposures, and the lack of understanding of mechanisms of disease or adequate treatments for those suffering from them. We predict that our findings will allow development of avoidance strategies, more focused remediation, and identify the cell types, receptor, and cytokines to target with immunomodulators.

 描述（由申请人提供）：空气污染是多种气道疾病的危险因素，并与肺和全身自身免疫加重有关。在这项研究中，我们调查的重要性，吸入颗粒物（PM），特别是多环芳烃（PAH）在PM中，以提高Th 17分化系统和加重自身免疫性实验性自身免疫性脑脊髓炎（EAE）的小鼠模型。我们将提出吸入PM增加远端淋巴结和EAE中Th 17分化的初步数据。基于这些发现和以前的数据，我们提出了一个假设，即当面临长期或急性空气暴露时，有发生自身免疫风险的患者会经历Treg/Th 17平衡失调，这可能会加重现有疾病或刺激新发疾病。最近的研究发现，芳烃受体（AHR）在调节性T细胞（Treg）/Th 17平衡中起着核心作用，其中AHR的一些配体可以增强Treg分化，而其他配体可以增强Th 17分化，这使我们预测PM中的多环芳烃（已知的AHR配体）是污染诱导的Th 17偏离的原因。我们的模型是，污染中的多环芳烃，通过吸入遇到，结合免疫细胞上的AHR，导致增加Th 17分化，减少Treg生成，并增强自身免疫。如果这个模型是正确的，我们假设，一些环境诱导的自身免疫性疾病可能受到类似机制的影响。我们将探索以下目标：目标1：确定PM加剧EAE的能力下限，并检查T细胞对MOGp 35 -55反应的相关变化。目的2：确定吸入后导致EAE加重的PM组分。目的3：确定PM介导的EAE加重中AHR表达的要求.这项资助和未来研究的独特之处在于，我们能够根据我们的专业知识来检查PM的特定成分及其与AHR的相互作用，我们可以使用的众多重组小鼠模型，以及我们将标准参考材料与真实的世界样本进行比较以开发和测试增强自身免疫的PM成分的能力。该项目与公共卫生的联系得到了自身免疫的高发病率，这些病态疾病与环境暴露的已知联系，以及对疾病机制或对患者的适当治疗缺乏了解的支持。我们预测，我们的研究结果将允许开发避免策略，更集中的补救措施，并确定免疫调节剂靶向的细胞类型，受体和细胞因子。