Mechanism of Silica-Induced Autoimmune Responses

二氧化硅诱导自身免疫反应的机制

• 批准号: 6405143
• 负责人: JEAN Cooper PFAU
• 金额: $ 4.19万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6405143
• 关键词: T lymphocyte; alveolar macrophages; antigen presentation; apoptosis; autoantibody; autoimmune disorder; cytokine; environmental exposure; genetic susceptibility; laboratory mouse; pathologic process; pneumoconiosis; postdoctoral investigator; silicates

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.

描述（由申请人提供）：本提议的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会导致肺泡细胞凋亡 炎症环境中的巨噬细胞丧失外周耐受性。 凋亡巨噬细胞自身抗原的抗原呈递会导致 T 辅助细胞激活以及随后 B 细胞产生自身抗体。 由于缺乏对机制的了解，这项研究很重要 环境暴露后的自身免疫，其严重程度和增加 环境诱发的自身免疫性疾病的发生率，以及需要 动物模型来研究它们。三个假设将根据具体情况进行检验 目标。首先，初步数据表明，二氧化硅会导致硅肺病， Balb/c 小鼠中出现自身抗体，所以我假设这代表 一种自身免疫综合征，其至少部分特征在于 目标抗原和同种型。其他鼠标型号将被考虑 了解遗传易感性无疑会在 反应的动力学和特征。二、通过拦截 二氧化硅诱导抗原呈递增加并通过改变细胞因子 在暴露期间的轮廓，我将测试响应的假设 在 Th1 环境中通过抗原呈递细胞进行抗原驱动。最后， 假设表明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。这将被测试 在 T 细胞抗原呈递测定中使用凋亡细胞作为抗原 来自我们暴露于二氧化硅的小鼠。二氧化硅诱导的自身抗体是否 本研究不会探讨致病性，但由于自身抗体是 与自身免疫性疾病相关，并且经常参与其过程， 这项研究和动物模型的开发无疑将提供线索 以及随后的病理学。

项目成果

Silica accelerated systemic autoimmune disease in lupus-prone New Zealand mixed mice.

二氧化硅会加速患有狼疮的新西兰混合小鼠的系统性自身免疫性疾病。

• 发表时间: 2003-03
• 影响因子: 4.6
• 作者: Brown, J M;Archer, A J;Pfau, J C;Holian, A
• 通讯作者: Holian, A

Environmental oxygen tension affects phenotype in cultured bone marrow-derived macrophages.

环境氧张力影响培养的骨髓源性巨噬细胞的表型。

• 发表时间: 2004-02
• 作者: Pfau, Jean C;Schneider, Jordan C;Archer, Amy J;Sentissi, Jami;Leyva, Francisco J;Cramton, Jennifer
• 通讯作者: Cramton, Jennifer