Neuroimmunotoxicology--autoimmunity/inflammation/age

免疫系统和神经系统(以及可能与生殖系统的相互作用)之间有许多联系，包括：1)两个系统出生后发育/成熟的时间延长。2)孕妇的感染和可能的促炎性级联因子(肿瘤坏死因子α、白介素6)转移到后代，以及与免疫介导性反应有关的对儿童的长期影响。3)活动性病毒进入大脑(如疱疹、艾滋病毒、西尼罗河)和认知缺陷/痴呆的表现。4)与自身免疫性疾病(如艾滋病、多发性硬化症、色氨酸诱导的自身免疫)有关的人类病例中认知缺陷的增加；5)抗炎剂对认知障碍的治疗干预缺乏成功，这表明这些系统之间的相互作用比之前预期的更复杂。脑内炎症细胞的局部激活可能导致急性脑损伤后的神经元死亡以及更进行性的退变过程。在这个网络中，不同的细胞交流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以及神经元和胶质细胞之间的细胞间相互作用，当受到侮辱时，会发生一连串的反应，发出可能导致神经元死亡的信号。大脑的炎症反应与外周的炎症反应大致相同。作为一种宿主防御反应，它起到保护大脑的作用，然而，当反应变得失调时，这可能会导致不良事件。在这一框架下，我们已经报道，小胶质细胞不仅在损伤反应的初始阶段起关键作用，而且在损伤后的修复过程中也是至关重要的。本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胶质细胞反应的关键特征，以及这些特征如何随着化学物质暴露、免疫系统完整性和生命阶段的变化而变化。这些特征不仅包括单个细胞的反应，还包括可能影响这种反应结果的细胞外环境。在暴露于环境制剂的框架内，有一个大量的数据库表明，化学暴露可导致免疫系统的急性反应。通常情况下，有能力改变免疫系统的试剂或因素被证明也会改变神经系统。因此，本项目的目的是试图确定这两个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，而且还可能导致长期不良后果。了解大脑的常驻免疫细胞、系统免疫系统、神经退行性疾病的表现以及启动再生反应的能力/能力之间的联系，将为确定治疗此类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.