Mechanism of Silica-Induced Autoimmune Responses

描述（由申请方提供）：本拟定研究使用体内和体内 体外技术探索环境诱导的小鼠模型 自身免疫，其中二氧化硅被认为导致肺泡细胞凋亡， 巨噬细胞在炎性环境中丧失外周耐受性。 凋亡巨噬细胞自身抗原的抗原呈递将导致 T辅助细胞活化和随后的自身抗体的B细胞产生。 这项研究是重要的，因为缺乏了解的机制， 环境暴露后的自身免疫，严重性和增加 环境引起的自身免疫性疾病的发病率，以及对 动物模型来研究它们。三个假设将被测试与具体的 目标。首先，初步数据显示，二氧化硅导致矽肺， Balb/c小鼠中自身抗体的发展，所以我假设这代表了 一种自身免疫综合征，其特征至少部分在于 靶抗原和同种型。将考虑其他小鼠模型， 理解遗传易感性无疑将在 反应的动力学和特征。第二，通过阻断 二氧化硅诱导的抗原呈递增加和通过改变细胞因子 在暴露过程中，我将检验反应是 在Th 1环境中通过抗原呈递细胞的抗原驱动。最后 一种假说认为，二氧化硅诱导的肺泡巨噬细胞凋亡可以 提供自身免疫反应所需的表位。这将受到考验 在对T细胞的抗原呈递分析中使用凋亡细胞作为抗原 硅暴露的老鼠身上。二氧化硅诱导的自身抗体是否 本研究中不探讨致病性，但由于自身抗体 与自身免疫性疾病相关，并且通常与自身免疫性疾病有关， 这项研究和动物模型的发展无疑将提供线索， 以及后续的病理学。

DESCRIPTION (provided by applicant): This proposed study uses in vivo and in vitro techniques to explore a murine model of environmentally induced autoimmunity, in which silica is thought to lead to apoptosis of alveolar macrophages in an inflammatory setting with loss of peripheral tolerance. Antigen presentation of the self antigens of apoptotic macrophages would lead to T helper cell activation and subsequent B cell production of autoantibodies. This study is important due to the lack of understanding of mechanisms of autoimmunity following environmental exposures, the severity and increasing incidence of environmentally induced autoimmune diseases, and the need for an animal model to study them. Three hypotheses will be tested with the specific aims. First, preliminary data shows that silica leads to silicosis and autoantibody development in Balb/c mice, so I hypothesize that this represents an autoimmune syndrome that can be at least partially characterized in terms of target antigens and isotypes. Other mouse models will be considered with the understanding that genetic susceptibility will undoubtedly play a role in the kinetics and characteristics of the response. Second, by blocking silica-induced increases in antigen presentation and by altering the cytokine profile during exposure, I will test the hypothesis that the response is antigen-driven through antigen presenting cells in a Th1 setting. Finally, the hypothesis suggests that silica-induced apoptosis of alveolar macrophages can provide the epitopes required for autoimmune responses. This will be tested using apoptotic cells as antigens in an antigen presentation assay to T cells from our silica-exposed mice. Whether the silica-induced autoantibodies are pathogenic will not be explored in this study, but since autoantibodies are correlated with, and often implicated in the process of autoimmune disease, this study and the development of the animal model will no doubt provide clues to subsequent pathology as well.