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: 9974282
• 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/9974282
• 关键词: Address; Affect; Air Pollution; American; Area; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Atmosphere; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Cell Differentiation process; Cells; Cessation of life; Chemicals; Clinical; Complex; Cytochrome P450; Data; Dendritic Cells; Development; Diagnosis; Diesel Exhaust; Diet; 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; Preventive Intervention; Process; Recommendation; Reference Standards; Regulation; Research Priority; Rest; Risk; Risk Factors; Role; Sampling; Secondary to; Services; Severities; Severity of illness; Site; Smoke; Source; T cell differentiation; T cell response; T-Lymphocyte; Testing; Translating; Veterans; aryl hydrocarbon receptor ligand; base; dietary supplements; disorder prevention; epidemiology study; experimental study; high risk; in vivo Model; interest; mouse model; oral supplementation; particle; particle exposure; persistent symptom; prevent; remediation; response; 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.

流行病学研究强烈支持暴露于空中污染的发生率和严重程度 自身免疫性，该诊断涵盖了80多种不同的疾病过程，并且影响超过 2000万美国人。患者通常会出现慢性症状，使他们在余生中生病。 令人惊讶的是，尽管吸入的颗粒物（PM）被广泛接受为自身免疫性的风险，但 尚不清楚引起疾病和涉及机制的特定暴露。这可能是因为 由具有可变化学成分的众多来源产生的污染的复杂性， 暴露的种群的各种遗传背景。缺乏理解已经努力 在监管，补救和避免失败。退伍军人可能处于特别高的风险，因为军事 人员暴露于柴油发动机和其他来源的高水平PM。另外，一些独特的 在部署部位，包括烧伤坑暴露在内，可能会特别病理性的暴露。 在过去的几年中，我们的小组研究了不同PM样本增强效应器的能力 反应并增加免疫力。我们最近发现，在实验自身免疫的鼠标模型中 脑脊髓炎（EAE），两种来自柴油排气颗粒（DEP）的标准参考材料（SRMS） 疾病严重程度显着增加。这些样品的有机馏分的分析显示芳基 碳氢化合物受体（AHR）依赖性能够增强效应子Th17细胞分化的能力 样品。此外，这些样品的多环芳烃（PAH）混合物的分析表明 该部分可能是T细胞中效应子响应增加的核心。这些发现导致我们 产生这样的假设，即暴露于兵役或与部署有关的PM可以增加自我 反应性T细胞反应以AHR依赖性方式，导致更严重的自身免疫性疾病。 我们将探讨以下目的：目标1：确定对T细胞的DEP介导的影响 EAE临床严重程度的增加。我们将检验以下假设：B6-EAE模型中的DEP暴露 通过提高抗MOG T细胞的致病潜力来提高疾病的严重程度，直接通过T 细胞或间接通过DC。该目的侧重于对免疫细胞的影响，无论AHR的作用如何 AIM 2：确定AHR，代谢和PHS驱动自身免疫中的PAH的贡献 恶化。我们将检验以下假设，即两者都通过AHR加重了EAE，并将探索 代谢和PAH含量的重要性。 AIM 3：筛选兵役或与部署有关的PM的样本，以进行免疫改变 活动。我们将使经历EAE的小鼠接触到与军事暴露有关的四个样本，并测试 假设自身免疫性加重是源依赖性的。 目标4：确定饮食干预措施减轻DEP介导的加剧的能力 B6-EAE模型中的疾病。我们将检验以下假设，即饮食配体可以特异性减少 吸入污染对自身免疫性的影响。 我们预计PM会通过对T细胞中AHR的直接影响加剧EAE。我们进一步预测 军队独有的暴露会加剧疾病，口服饮食AHR配体的补充 静音PM暴露后出现的疾病加剧。该赠款直接解决了优先研究 有关服兵役或与部署有关的职业暴露的兴趣领域。结果 格兰特将提供合理的理解，以理解哪些军事环境暴露是最致病性的， 有助于补救，回避和治疗策略。