Neuroimmunotoxicology: autoimmunity, inflammation, age,

免疫系统和神经系统（以及与生殖系统的可能相互作用）之间存在许多联系，包括：1）两个系统的出生后发育/成熟延长。2)妊娠母亲的感染和促炎级联因子（TNF α、白细胞介素-6）可能转移至后代，以及与免疫介导的应答相关的对儿童的长期影响。3)将活性病毒转移到脑中（例如，疱疹、HIV、西尼罗河病毒）和认知缺陷/痴呆的表现。4)与自身免疫性疾病相关的人类病例中认知缺陷的增加（例如，艾滋病、多发性硬化症、色氨酸诱导的自身免疫），5）使用抗炎剂治疗认知障碍的治疗性干预缺乏成功，表明系统之间的相互作用比先前预期的更复杂。脑中炎性细胞的局部激活可能导致急性脑损伤后发生的神经元死亡以及更渐进的退行性过程。在这个网络中，各种细胞沟通和调节免疫和炎症反应的启动，传播和抑制的复杂过程。通过常驻免疫细胞网络和神经元与神经胶质之间的细胞-细胞相互作用，在损伤时发生级联反应，其发出可能导致神经元死亡的信号事件。大脑中的炎症反应与外周中的炎症反应大致相同。作为宿主的防御反应，它可以保护大脑，然而，当反应变得失调时，这可能导致不良事件。在这个框架下，我们已经报道了小胶质细胞不仅在损伤反应的初始阶段而且在损伤后的修复过程中都是至关重要的。该项目的目的是确定可能导致或加剧正在进行的神经元死亡过程的神经胶质反应的关键特征，以及这些特征如何随着化学暴露，免疫系统完整性和生命阶段而变化。这些特征不仅包括单个细胞应答，还包括可能影响这些应答结果的细胞外环境。在暴露于环境因子的框架内，有大量数据表明，免疫系统的急性反应可能是化学品暴露的结果。通常，有能力改变免疫系统的药剂或因素也会改变神经系统。因此，本项目的目的是试图确定两种系统之间的相互作用，这些相互作用不仅可能导致急性不良反应，而且可能导致长期不良结局。了解大脑的常驻免疫细胞，全身免疫系统，神经退行性疾病的表现，以及安装再生反应的能力/能力之间的联系，将为确定治疗这些疾病的方法提供关键的一步。

There have been a number of proposed links between the immune system and the nervous system (and possible interactions with the reproductive system) including: 1) prolonged post-natal development/maturation of both systems. 2) infection in the pregnant mother and possible transfer of factors of the pro-inflammatory cascade (TNFalpha, Interleukin-6) to the offspring and long-term effects on the child as related to an immune-mediated response. 3) transfer of active virsus into the brain (e.g., Herpes, HIV, West-Nile) and the manifestation of cognitive deficits/dementia. 4) increase of cognitive deficits in human cases related to autoimmune disease (e.g., AIDs, Multiple Sclerosis, Tryptophan-induced autoimmunity), 5) the lack of success with therapeutic intervention with anti-inflammatory agents for cognitive impairment suggesting a more complicated interactions between the systems than previously anticipated. Local activation of inflammatory cells in the brain may contribute to neuronal death that occurs following acute brain injury as well as more progressive degenerative processes. In this network, various cells communicate and regulate complex processes of initiation, propagation, and suppression of immune and inflammatory responses. Through the resident immune cell network and the cell-cell interactions between the neurons and glia, a cascade of responses occur upon insult that signal events that may lead to neuronal death. The inflammatory response in the brain serves much the same was as that in the periphery. As a host defense response it serves to protect the brain however, when the response becomes dysregulated this can lead to adverse events. Under this framework we have reported that microglia cells are critical not only in the initial phase of the damage response but also in the repair process following injury. The purpose of this project is to identify the critical features of the glia response that may either cause or exacerbate an ongoing process of neuronal death and how these features change with chemical exposure, immune system integrity, and life stage. These features include not only the individual cell response but also the extracellular environment that may influence the outcome of such responses. Within the framework of exposure to environmental agents, there exists a substantial database to suggest that acute responses of the immune system can occur as a result of chemical exposure. Quite often, the agents or factors that have the capacity to alter the immune system are shown to also alter the nervous system. Thus, it is the purpose of this project to attempt to identify interactions between the two systems that may contribute not only to acute adverse effects but also to long-term adverse outcomes. Understanding the link between the resident immune cells of the brain, the systemic immune system, manifestation of neurodegenerative disease, and the ability/inability to mount a regenerative response will provide a critical step toward identifying approaches to treat such conditions.