The effect of age on xenobiotic-induced autoimmunity

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 前炎性细胞因子(IL-6、肿瘤坏死因子-α)的存在是免疫状态下降和 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。 以及一些自身免疫性疾病。环境因素在发展中起着重要作用。 然而，在关于环境-免疫的研究中，年龄并没有显著地被考虑在内 诱导的自身免疫，而不是观察到职业性暴露是显著的 因素。汞暴露与人类自身免疫的表达有关， 实验动物模型。面临风险的人口数量可观，而且种类繁多。我们有 小鼠汞诱导自身免疫(MHgIA)作为一种 研究系统性自身免疫启动和发展的实验模型。这只动物 在这些研究中，暴露的年龄从4到12周不等，暴露的时间通常是 已经4周了。疾病的严重程度取决于干扰素-γ和IL-6的存在，并局限于 与IL-1、β、干扰素等促炎细胞因子升高相关的炎症反应 γ和肿瘤坏死因子-α。目前尚不清楚汞诱导的自身免疫是否会因 两人的年龄相关性慢性炎症和促炎细胞因子的表达 还有老鼠。促炎症细胞因子IL-6、肿瘤坏死因子-α和干扰素-γ在衰老中的重要性 而在mHgIA和特发性自身免疫中，衰老会导致mHgIA的加重 与更年轻的动物相比。这个应用程序将检验“高龄”这一假设 MHgIA用于环境诱导研究对实验结果的影响 成人人群中的自身免疫。“拟议的研究将分两个阶段进行 在FOA(RFA-AG-16-020)中概述。UH2阶段将把重点放在繁育动物种群上 B10.S、B10.S/IFNG-/-和B10.S/IL6-/-小鼠的存活水平高达75%，并包括一组 用于用老龄动物诱导mHgIA的可行性的初步试验。UH3 阶段将比较中心假说，即动物年龄的增大会影响实验 通过比较和对比老年和青年男女B10.S的mHgIA 老鼠。我们还将使用B10.S/IFNG-/-和B10.S/IL6-/-小鼠来检测IL-6和 干扰素-γ与AGE相关的促炎反应及其是否需要 年龄相关自身免疫的发展，以及接触氯化汞是否会加剧 IL-6或干扰素-γ缺乏的老年动物的自身免疫。

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.