Neuroimmunotoxicology of mercury

描述（由申请人提供）：人类和小鼠胎儿暴露于汞（Hg）诱导长期的行为和神经元功能障碍，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，中央定位的免疫细胞（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，基于遗传差异，某些小鼠品系会出现hg诱导的免疫病理（自身免疫性疾病），其中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。汞诱导2型免疫增强，包括Th2细胞因子IL-4、IL-5和IL-6以及IgE水平升高，肥大细胞、嗜酸性粒细胞和嗜碱性粒细胞因子释放升高。一些小鼠菌株（如BALB/c小鼠）产生免疫复合物，可以定位于某些器官，引发炎症，而具有H-2s单倍型的小鼠（如A.SW小鼠）产生自身抗体，与选择的抗原结合，直接启动靶向损伤。我们假设，基于遗传和环境暴露，一些毒株由于抗体诱导微肌细胞和肥大细胞的激活而产生中枢神经系统炎症，这导致成人在发育暴露于汞后出现行为异常和神经病理结果。最终导致成人神经免疫诱导病理的事件序列被假设为：1)神经内分泌调节改变，增强2型免疫；ii)对中枢神经系统抗原的自身免疫反应增强；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；iv)神经炎症升高，破坏神经元功能。我们将首先证明汞增强了CNS抗原自身抗体的产生，依赖于单倍型，然后鉴定自身抗原。目的2将研究具有自身抗体的特定大脑区域和存在的细胞表型。目的3将评估在没有汞的情况下，自身抗体是否会在Hg易感菌株（H-2s和th2易感菌株）和Hg不易感菌株中引起类似的神经炎症。我们认为，某些环境因素可以根据宿主的基因启动对自身抗原（包括脑抗原）的增强免疫力。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.