CMA: Immune/Inflammatory Priming in Exacerbating Responses to GWVI Stressors: Implications for GWVI Treatments

本研究合作功绩评审奖(I01)是为响应RFA BX-18-007 退伍军人健康管理局是JJ彼得斯退伍军人医疗中心(Bronx， 纽约)项目1，阿诺德公共卫生学院和Wm Jennings Bryan Dorn VA医疗中心(哥伦比亚， SC)项目2，脑科学中心退伍军人医学中心(明尼阿波利斯，明尼苏达州)项目3。我们为 临床前研究项目的综合和多学科计划，所有这些项目都通过最终目标联系在一起 更好地描述海湾战争退伍军人持续和异常免疫活动的机制 疾病(GWVI)通过开发实验模型系统，最终目标是开发新的 治疗性干预。海湾战争退伍军人的疾病是一种多方面的疾病，其特征是 症状包括认知障碍、疲劳、疼痛、情绪障碍等。最近的证据 提示这些症状的发生和发展可能是这些细胞的不平衡的结果 受试者的免疫系统。在部署期间，GWV暴露在一种独特的各种有毒物质中 是海湾战区特有的，如吡啶硫胺溴(PB)、二异丙基氟磷酸盐 (DFP)、二氯氰菊酯和贫铀，目前的证据表明门槛较低 免疫反应，并导致免疫的某些手臂持续和增强的活动 一种最好的描述为“免疫启动”的现象。此外，他们还收到了20多份 可能会使免疫系统超载的疫苗。为了支持这些考虑，主题与 GWVI通常表现出与自身免疫性疾病相同的病理特征，并普遍存在 炎症性疾病，如血浆促炎细胞因子浓度升高，非特异性 组织退化和器官衰竭。基于这一概念，三方提出了协同研究 项目的设计是为了更好地了解免疫系统如何对GWVI型做出贡献 通过探索在动物模型中概括的多种GWI条件如何协同和 最终为翻译研究提供新的机制依据。例如，项目2旨在 了解GW毒素诱导的肠道炎症小体激活如何导致肠道生物失调，并可能导致 持续的或高度的免疫炎症反应和GWVI症状。因为项目3的目标是 设计了一种假说，即缺乏特异性免疫会导致疫苗诱导的炎症反应 大脑，项目2将与项目3合作，测试炎症小体启动和遗传的贡献 肠道生物失调和持续性免疫反应的多样性。同样，项目1旨在 测试免疫启动如何增强对心理应激源的炎症反应 通过探索NLRP3炎症小体如何有助于 肠道菌群失调或人类白细胞抗原(HLA)基因多态性引起的炎症加重。这些措施的结果 研究非常有意义，不仅是因为这将在炎性小体引发、 遗传多样性和肠道生物失调毒性反应，但它也将为测试新的治疗方法提供洞察力 以持续激活免疫系统为目标的方法，要么使用免疫疗法 针对疫苗毒素的方法，益生菌减轻肠道生物失调。我们建议的研究具有创新性。 就其范围而言，这将填补未来翻译研究所需的根本空白。多数 重要的是，我们的多尺度技术创新方法，包括基因敲除小鼠模型 GWVI，包括HLA和NLRP3蛋白，将使我们的跨学科研究团队能够 在神经科学、药理学、微生物学、化学方面的杰出专业知识，以彻底调查 GWVI病因学的分子机制。

This Collaborative Merit Review Award for Research (I01) proposed in response to RFA BX-18-007 from the Veteran Health Administration is a joint effort by investigators from the JJ Peters VA Medical Center (Bronx, NY) Project 1, Arnold School of Public Health and Wm Jennings Bryan Dorn VA Medical Center (Columbia, SC) Project 2, Brain Science Center VA Medical Center (Minneapolis, MN) Project 3. We define a vision for an integrated and multidisciplinary program of preclinical research projects all linked by the ultimate goal to better characterize the mechanism of persistent and aberrant immunological activity in Gulf War Veteran Illnesses (GWVI) by developing experimental model systems, with the ultimate goal of developing novel therapeutic interventions. Gulf War Veterans’ Illnesses is a multifaceted disorder characterized by a range of symptoms including cognitive impairment, fatigue, pain, mood disorders, among others. Recent evidence suggests that the onset and progression of these symptoms may be the result of disequilibrium in these subjects’ immune systems. During deployment GWV were exposed to a unique variety of toxic agents that were specific to the Gulf War theatre, such as pyridostigmine bromine (PB), diisopropyl fluorophosphates (DFP), permethrin, and depleted uranium which current evidence indicates lowered thresholds to immunological responses and resulted in the persistent and heightened activity of certain arms of the immune system; a phenomenon best described as “immunological priming”. In addition, they received more than 20 vaccines that could have overloaded the immune system. In support of these considerations, subjects with GWVI often have shown pathological signatures in common with autoimmune disorders and generalized inflammatory disorders, such as increased plasma concentrations of pro-inflammatory cytokines, unspecific tissue degeneration, and organ failure. Based on this concept, the three proposed collaborative research projects were designed to better understand how primed immune systems may contribute to GWVI- type phenotypes by exploring how multiple GWI conditions recapitulated in animal models may synergize and eventually provide new mechanistic evidence for translation studies. For example, Project 2 was designed to understand how GW toxin induced gut inflammasome activation causes gut dysbiosis and may lead to persistent or heightened immune-inflammatory responses and GWVI symptoms. As the goal of Project 3 is designed the hypothesis that lack of specific immunity leads to vaccine-induced inflammatory reaction in the brain, Project 2 will collaborate with project 3 to test the contribution of inflammasome priming and genetic diversity to gut dysbiosis and persistent immunological responses. Similarly, Project 1, which is designed to test how immunological priming may heighten inflammatory responses to psychological stressors, will collaborate with project 2 and project 3 by exploring how the NLRP3 inflammasome may contribute to heightened inflammation induced by gut dysbiosis or HLA polymorphisms, respectively. The outcome of these studies is of great interest not only because this will establish a novel link between inflammasome priming, genetic diversity and gut-dysbiosis toxemic response, but it will also provide insight to test novel therapeutic approaches that target the persistent activation of the immune system, either using immunotherapeutic approaches against vaccine toxins, probiotics to attenuate gut dysbiosis. Our proposed studies are innovative in terms of their scope, since it will fill the fundamental gaps needed for future translational studies. Most importantly our multiscale technological innovative approaches, which include knockout murine models of GWVI, including for the HLA and NLRP3 proteins, will enable our interdisciplinary research team with outstanding expertise in neuroscience, pharmacology, microbiology, chemistry to thoroughly investigate the molecular mechanisms underlying the etiology of GWVI.