Neuroimmunotoxicology of mercury

描述（由申请人提供）：人类和小鼠胎儿暴露于汞（Hg）可诱导长期行为和神经功能障碍，但神经内分泌免疫网络活动的机制参与，例如，下丘脑-垂体-肾上腺（HPA）轴、位于中枢的免疫细胞（小胶质细胞和肥大细胞）和针对中枢神经系统（CNS）抗原的自身抗体尚未得到充分解决。此外，基于它们的遗传差异，某些小鼠品系发展汞诱导的免疫病理学（自身免疫性疾病），其被假定为包括自身抗体诱导的神经炎症，导致神经元损伤和功能障碍。汞可增强2型免疫力，包括Th 2细胞因子IL-4、IL-5和IL-6以及IgE水平升高，以及肥大细胞、嗜酸性粒细胞和嗜碱性粒细胞释放因子增加。一些小鼠品系（例如，BALB/c小鼠）产生免疫复合物，其可以定位于某些器官中引发炎症，而具有H-2s单倍型的小鼠（例如，SW小鼠）产生与选择的抗原结合的自身抗体，直接引发靶向损伤。我们假设，根据遗传和环境暴露，一些菌株有中枢神经系统炎症由于抗体诱导激活的microgia和肥大细胞，导致行为畸变和神经病理学的结果，发生在成年人以下发育暴露于汞。在成人神经免疫诱导的病理中达到高潮的事件顺序被假定为：i）改变的神经内分泌调节，其增强2型免疫; ii）对CNS抗原的自身免疫应答增加; iii）脑中免疫细胞（小胶质细胞和肥大细胞）分布和功能的调节;以及iv）升高的神经炎症，其破坏神经元功能。我们将首先证明，汞增强生成的自身抗体中枢神经系统抗原，依赖于单倍型，然后确定自身抗原。目的2将研究具有自身抗体的特定脑区域和存在的细胞的表型。目的3将评估在汞不存在的情况下，自身抗体是否可以在汞敏感株（H-2s和Th 2倾向株）和汞非敏感株中引起类似的神经炎症。我们认为，某些环境因素可以启动提高免疫力的自身抗原，包括脑抗原，根据宿主的遗传。我们将比较无机汞和有机汞引发上述后果的能力。

DESCRIPTION (provided by applicant): 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.