Investigating a Model for PM-Induced Exacerbation of Autoimmunity

研究 PM 诱发的自身免疫恶化模型

• 批准号: 10266063
• 负责人: Joshua D Mezrich
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266063
• 关键词: Address; Affect; Air Pollution; American; Area; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Atmosphere; Autoimmune; Autoimmune Diseases; Autoimmunity; Cell Differentiation process; Cells; Cessation of life; Chemicals; Clinical; Complex; Cytochrome P450; Data; Dendritic Cells; Development; Diagnosis; Diesel Exhaust; Dietary Intervention; Dietary Supplementation; Disease; Dust; Environmental Exposure; Enzymes; Experimental Autoimmune Encephalomyelitis; Exposure to; Face; General Population; Genetic; Goals; Grant; Health; Immune; Immunity; In Vitro; Incidence; Inhalation; Knowledge; Lead; Ligands; Mediating; Metabolism; Military Personnel; Modeling; Multiple Sclerosis; Mus; Null Lymphocytes; Occupational Exposure; Particulate Matter; Pathogenicity; Pathologic; Patients; Play; Pollution; Population; Prevention; Process; Recommendation; Reference Standards; Regulation; Research Priority; Rest; Risk; Risk Factors; Role; Sampling; Secondary to; Severities; Severity of illness; Site; Smoke; Source; T cell differentiation; T cell response; T-Lymphocyte; Testing; Translating; Veterans; active duty; aryl hydrocarbon receptor ligand; autoreactive T cell; base; burn pit; dietary; dietary supplements; disorder prevention; epidemiology study; experimental study; high risk; in vivo Model; interest; military service; military veteran; mouse model; oral supplementation; particle; particle exposure; persistent symptom; prevent; preventive intervention; remediation; response; risk prediction; treatment strategy

Epidemiologic studies strongly support that exposure to airborne pollution increases the incidence and severity autoimmunity, a diagnosis that encompasses more than 80 different disease processes and affects more than 20 million Americans. Patients typically suffer chronic symptoms that leave them ill for the rest of their lives. Surprisingly, despite the fact that inhaled particulate matter (PM) is well accepted as a risk for autoimmunity, the specific exposures that cause disease and the mechanisms involved are not known. This is likely because of the complexity of pollution that is generated by numerous sources with variable chemical composition, and the diverse genetic background of populations that are exposed. This lack of understanding has made efforts at regulation, remediation, and avoidance unsuccessful. Veterans may be at particularly high risk, as military personnel are exposed to high levels of PM from diesel engines and other sources. In addition, some unique exposures that may be particularly pathologic are found at sites of deployment, including burn pit exposures. Our group has spent the last few years examining the ability of different samples of PM to enhance an effector response and increase immunity. We have recently found that in a mouse model of experimental autoimmune encephalomyelitis (EAE), two Standard Reference Materials (SRMs) from diesel exhaust particles (DEP) significantly increased severity of disease. Analysis of the organic fractions of these samples show aryl hydrocarbon receptor (AHR)-dependent ability for enhancement of effector Th17 cell differentiation by these samples. In addition, analysis of polycyclic aromatic hydrocarbon (PAH) mixtures from these samples suggest this fraction may be central to the increased effector response in T cells. These findings have led us to generate the hypothesis that exposure to military service or deployment-related PM can increase self- reactive T-cell responses in an AHR-dependent manner, resulting in more severe autoimmune disease. We will explore the following aims: Aim 1: Identify DEP-mediated effects on T cells that lead to an increase in EAE clinical severity. We will test the hypothesis that DEP exposure in the B6-EAE model enhances disease severity by increasing the pathogenic potential of anti-MOG T cells, either directly through T cells or indirectly through DCs. This aim focuses on effects on immune cells irrespective of a role for the AHR Aim 2: Determine the contribution of the AHR, metabolism, and the PAHs in PM-driven autoimmune exacerbation. We will test the hypothesis that both DEPs aggravate EAE via the AHR, and will explore the importance of metabolism and PAH content. Aim 3: Screen source samples of military service or deployment-related PM for immune-altering activity. We will expose mice undergoing EAE to four samples relevant to military exposures, testing the hypothesis that aggravation of autoimmunity is source dependent. Aim 4: Determine the capacity of dietary interventions to mitigate DEP-mediated aggravation of disease in the B6-EAE model. We will test the hypothesis that dietary ligands can specifically reduce the effects of inhaled pollution on autoimmunity. We anticipate that PM will aggravate EAE through a direct effect on the AHR in T cells. We further predict that exposures unique to the military will aggravate disease, and oral supplementation with dietary AHR ligands will mute the aggravation of disease seen after PM exposure. This grant directly addresses the priority research area of interest regarding military service or deployment-related occupational exposures. Results from this grant will provide a rational for understanding which military environmental exposures are most pathogenic and aid in remediation, avoidance, and treatment strategies.

流行病学研究有力地支持了暴露在空气污染中会增加发病率和严重性 自身免疫，一种包含80多种不同疾病过程的诊断，并影响超过 2000万美国人。患者通常会出现慢性症状，导致他们终生患病。 令人惊讶的是，尽管吸入颗粒物(PM)被广泛接受为自身免疫的风险， 导致疾病的具体暴露和涉及的机制尚不清楚。这很可能是因为 由多种化学成分不同的来源产生的污染的复杂性；以及 受感染人群的不同遗传背景。这种缺乏理解的做法使人们努力 在监管、补救和规避方面不成功。退伍军人的风险可能特别高，因为军人 工作人员暴露在柴油发动机和其他来源的高水平PM中。此外，一些独一无二的 可能特别病理性的暴露是在部署地点发现的，包括烧伤坑暴露。 我们的团队在过去的几年里一直在研究不同的PM样本增强效应器的能力 应对并提高免疫力。我们最近在一种实验性自身免疫的小鼠模型中发现 脑脊髓炎(EAE)，柴油机尾气颗粒物(DEP)中的两种标准物质(SRM) 显著增加了疾病的严重性。对这些样品的有机馏分进行了分析，结果显示芳基 这些化合物依赖于烃受体(AHR)促进效应分子Th17细胞分化的能力 样本。此外，对这些样品中的多环芳烃(PAH)混合物的分析表明 这一组分可能是T细胞增加效应反应的中心。这些发现使我们得以 建立这样一种假设，即接触兵役或与部署相关的PM会增加自我 以AHR依赖方式的反应性T细胞反应，导致更严重的自身免疫性疾病。 我们将探索以下目标：目标1：确定DEP对T细胞的影响，从而导致 EAE临床严重程度增加。我们将在B6-EAE模型中检验DEP暴露的假设 通过增加抗MOG T细胞的致病潜能来增强疾病的严重性，或者直接通过T细胞 细胞或间接通过DC。这一目标侧重于对免疫细胞的影响，而不考虑AHR的作用 目的2：确定AHR、代谢和多环芳烃在PM驱动的自身免疫中的作用 病情恶化。我们将检验这两种DEP通过AHR加重EAE的假设，并将探索 代谢和多环芳烃含量的重要性。 目标3：筛选兵役或部署相关PM的来源样本以进行免疫改变 活动。我们将让接受EAE的小鼠接触四个与军事暴露相关的样本，测试 假设自身免疫的加重是来源依赖的。 目的4：确定饮食干预缓解DEP介导的糖尿病加重的能力 B6-EAE模型中的疾病。我们将检验这一假设，即饮食配体可以特别地减少 吸入性污染对自身免疫的影响 我们预计PM将通过直接影响T细胞中的AHR而加重EAE。我们进一步预测， 军队独有的暴露会加重疾病，口服补充膳食AHR配体将 减少PM暴露后出现的疾病恶化。这笔拨款直接用于优先研究 关于服兵役或与部署有关的职业暴露的感兴趣领域。由此产生的结果 格兰特将为了解哪些军事环境暴露最具致病性和 协助补救、避免和治疗策略。