Neuroimmunotoxicology of mercury

人和小鼠胎儿暴露在汞(Hg)中会导致长期的行为和神经功能障碍， 但神经内分泌免疫网络活动的机械性参与，例如下丘脑-垂体- 肾上腺(HPA)轴、中央定位的免疫细胞(小胶质细胞和肥大细胞)和针对中枢的自身抗体 神经系统(CNS)抗原，还没有得到充分的解决。此外，根据他们的基因 不同的是，某些小鼠品系会出现汞诱导的免疫病理(自身免疫性疾病)，这些疾病是 推测包括自身抗体引起的神经炎症，导致神经元损伤和功能障碍。 HG诱导2型免疫增强，包括Th2细胞因子IL-4、IL-5水平升高 IL-6和IgE，以及肥大细胞、嗜酸性粒细胞和嗜碱性粒细胞释放因子的增加。一些人 小鼠品系(如BALB/c小鼠)会产生免疫复合体，这种复合体可以定位于某些器官，从而引发 炎症，而具有H-2S单倍型的小鼠(例如A.Sw小鼠)产生结合到 选择直接启动靶向损伤的抗原。我们假设，基于遗传学和 暴露在环境中，一些菌株由于抗体诱导活化的CNS炎症 微痛和肥大细胞，这会导致行为异常和神经病理结果，发生在 在发育过程中暴露于汞的成年人。以成人为结局的一系列事件 神经免疫诱导的病理被认为是：i)改变神经内分泌调节，这增强了 2型免疫；ii)增强对中枢神经系统抗原的自身免疫反应；iii)调节免疫细胞 (小胶质细胞和肥大细胞)在大脑中的分布和功能；以及iv)加重的神经炎症 会扰乱神经功能。我们将首先证明汞能增强自身抗体的产生 中枢神经系统抗原，依赖于单倍型，然后鉴定自身抗原。目标2将调查 具有自身抗体的特定脑区和存在的细胞表型。AIM 3将评估 自身抗体在没有汞的情况下是否会导致汞易感(H-2s)患者发生类似的神经炎症 和Th2易感菌株)和汞不敏感菌株。我们建议某些环境代理人可以 根据宿主的基因，增强对自身抗原的免疫力，包括大脑抗原。我们 将比较无机汞和有机汞引发上述后果的能力。

Fetal exposure of man and mice to mercury (Hg) induces long-term behavioral and neuronal dysfunctions, but the mechanistic involvement of neuroendocrine immune network activities, e.g.,hypothalamo-pituitary- adrenal (HPA) axis, centrally located immune cells (microglia and mast cells), and autoantibodies to central nervous system (CNS) antigens, have not been adequately addressed. In addition, based on their genetic differences, certain mouse strains develop Hg-induced immunopathologies (autoimmune disease), which are posited to include autoantibody-induced neuroinflammation, leading to neuronal damage and dysfunction. Hg induces enhancement of type-2 immunity, which includes heightened levels of Th2 cytokines IL-4, IL-5 and IL-6 as well as IgE and elevated release of factors from mast cells, eosinophils and basophils. Some mouse strains (e.g., BALB/c mice) develop immune complexes which can localize in certain organs eliciting inflammation whereas mice with the H-2s haplotype (e.g., A.SW mice) develop autoantibodies that bind to select antigens directly initiating targeted damage. We hypothesize that based on the genetics and environmental exposures, some strains have CNS inflammation due to antibodies inducing activation of microgia and mast cells, which leads to behavioral aberrance and neuropathological outcomes that occur in adults following developmental exposures to Hg. The sequence of events that culminate in adult neuroimmune-induced pathologies are posited to be: i) altered neuroendocrine regulation, which enhances type-2 immunity; ii) increased autoimmune responses to CNS antigens; iii)modulation of immune cell (microglia and mast cells) distribution and function in the brain; and iv) elevated neuroinflammation which disrupts neuronal functions. We will first demonstrate that Hg enhances generation of autoantibodies to CNS antigens, dependent on haplotype, and then identify the autoantigens. Aim 2 will investigate the specific brain regions with autoantibodies and the phenotype of the cells present. Aim 3 will evaluate whether autoantibodies in the absence of Hg can cause similar neuroinflammation in Hg-susceptible (H-2s and Th2-prone strains) and Hg-non-susceptible strains. We suggest that certain environmental agents can initiate heightened immunity to self-antigens, including brain antigens, based on the genetics of the host. We will compare the ability of inorganic and organic Hg to initiate the described consequences.