The effect of age on xenobiotic-induced autoimmunity

年龄对异生素诱导的自身免疫的影响

• 批准号: 10002226
• 负责人: Kenneth Michael Pollard
• 金额: $ 9.99万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002226
• 关键词: Acute; Address; Adult; Age; Aging; Air; Animal Model; Animals; Atherosclerosis; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Benchmarking; Biological Process; Breeding; Chemicals; Chronic; Chronic Disease; Cohort Studies; Complex; Development; Diabetes Mellitus; Disease; Dose; Eating; Elderly; Environment; Environmental Exposure; Environmental Risk Factor; Epidemiology; Experimental Animal Model; Experimental Models; Exposure to; Female; Food; GTP-Binding Protein alpha Subunits, Gs; Gold; Human; Immune; Immune system; Infection; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Interferon Type II; Interleukin-1 beta; Interleukin-6; Length; Liquid substance; Longevity; Membranous Glomerulonephritis; Mercuric chloride; Mercury; Mining; Mus; Nerve Degeneration; Occupational Exposure; Outcome; Phase; Phenotype; Physiological; Play; Population; Populations at Risk; Predisposition; Production; Radiation; Research; Risk; Risk Factors; Role; Severities; Severity of illness; Skin Care; Specificity; TNF gene; Testing; Xenobiotics; age effect; age related; aged; carcinogenesis; cohort; cytokine; experience; experimental study; immune function; immunological status; juvenile animal; lupus prone mice; male; manufacturing process; mortality; response; senescence; systemic autoimmunity

Aging is associated with dysregulation of immune function manifested by increased susceptibility to infections and an increase in chronic inflammation. Such chronic inflammation, especially the presence of proinflammatory cytokines (IL-6, TNF-α), are predictors of failing immune status and mortality in the elderly. Associated with these changes is an increase in autoantibody responses and some autoimmune diseases. Environmental factors play a significant role in the development of human autoimmunity, however age has not figured significantly in studies on environmentally- induced autoimmunity other than the observation that occupational exposure is a significant factor. Mercury exposure has been implicated in the expression of autoimmunity in humans and experimental animal models. The human populations at risk are sizable and diverse. We have extensive experience in the use of murine mercury-induced autoimmunity (mHgIA) as an experimental model to study the initiation and development of systemic autoimmunity. The animal age at exposure in these studies have ranged from 4-12 weeks with the length of exposure usually being 4 weeks. Disease severity is dependent upon the presence of IFN-γ and IL-6, and localized inflammatory response associated with increased proinflammatory cytokines including IL-1β, IFN- γ and TNF-α. It remains unknown if induction of autoimmunity by mercury is exacerbated by the age-related chronic inflammation and proinflammatory cytokine expression found in both humans and mice. The importance of proinflammatory cytokines such as IL-6, TNF-α and IFN-γ in aging and in mHgIA and idiopathic autoimmunity suggests that aging will lead to exacerbation of mHgIA compared to younger animals. This application will test the hypothesis that "advanced age impacts the experimental outcomes of mHgIA used to study environmentally-induced autoimmunity in adult human populations." The proposed research will proceed in two phases as outlined in the FOA (RFA-AG-16-020). The UH2 phase will focus on breeding cohorts of animals up to the 75% survival level of B10.S, B10.S/Ifng-/- and B10.S/Il6-/- mice and includes a cohort to be used for a preliminary test of the feasibility of using aged animals to induce mHgIA. The UH3 phase will compare the central hypothesis that “older ages of animals impact experimental outcomes” by comparing and contrasting mHgIA in old versus young male and female B10.S mice. We will also use B10.S/Ifng-/- and B10.S/Il6-/- mice to examine the contribution of IL-6 and IFN-γ to age associated proinflammatory responses and whether they are requited for development of age-related autoimmunity, and whether exposure to HgCl2 exacerbates autoimmunity in aged animals deficient in either IL-6 or IFN-γ.

衰老与免疫功能失调有关，表现为易感性增加 感染和慢性炎症的增加。这种慢性炎症，尤其是 促炎细胞因子（IL-6、TNF-α）的存在是免疫状态衰竭的预测因子， 老年人的死亡率。与这些变化相关的是自身抗体反应的增加 和一些自身免疫性疾病环境因素在发展中起着重要作用 人类自身免疫，然而，年龄并没有在环境研究中显着， 除了观察到职业暴露是一个显着的 因子汞暴露与人类自身免疫的表达有关， 实验动物模型。面临风险的人群数量庞大，而且多种多样。我们有 在使用小鼠汞诱导的自身免疫（mHgIA）作为 研究系统性自身免疫的起始和发展的实验模型。动物 在这些研究中，接触的年龄范围为4-12周，接触的时间通常为 4周。疾病的严重程度取决于IFN-γ和IL-6的存在，并且局部化。 与促炎细胞因子（包括IL-1β、IFN-γ）增加相关的炎症反应 γ和TNF-α。目前尚不清楚汞诱导的自身免疫是否会因以下因素而加剧： 在两个人类中发现的与年龄相关的慢性炎症和促炎细胞因子表达 和老鼠。促炎细胞因子如IL-6、TNF-α和IFN-γ在衰老中的重要性 而在mHgIA和特发性自身免疫中提示增龄会导致mHgIA加重 与年轻的动物相比。这个应用程序将测试假设，“高龄” 影响用于研究环境诱导的mHgIA的实验结果 成人群体中的自身免疫性。“建议的研究将分两个阶段进行， 在FOA（RFA-AG-16-020）中概述。UH 2阶段将重点关注动物的繁殖队列 B10.S、B10.S/Ifng-/-和B10.S/I16-/-小鼠的高达75%的存活水平，并包括一个队列， 用于初步测试使用老年动物诱导mHgIA的可行性。UH3 阶段将比较中心假设，即“年龄较大的动物影响实验 通过比较和对比老年与年轻男性和女性B10.S 小鼠我们还将使用B10.S/Ifng-/-和B10.S/I16-/-小鼠来检查IL-6和IL-16对小鼠的作用。 IFN-γ与年龄相关的促炎反应以及它们是否需要 与年龄相关的自身免疫的发展，以及暴露于HgCl 2是否会加剧 在IL-6或IFN-γ缺陷的老年动物中的自身免疫。