CELLULAR MECHANISMS OF ASBESTOS-INDUCED AUTOIMMUNITY

石棉引起的自身免疫的细胞机制

• 批准号: 7720588
• 负责人: JEAN Cooper PFAU
• 金额: $ 14.36万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720588
• 关键词: Address; Amphibole Asbestos; Antigen Presentation; Antigens; Antinuclear Antibodies; Apoptosis; Asbestos; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Breathing; Clinical; Complex; Computer Retrieval of Information on Scientific Projects Database; Disease Outcome; Environmental Exposure; Fibrosis; Funding; Grant; Immune Complex Glomerulonephritis; Immune system; Institution; Knowledge; Lead; Lung; Malignant Neoplasms; Mus; Pathology; Patient Self-Report; Peripheral; Play; Pleural; Production; Proteins; Pulmonary Fibrosis; Research; Research Personnel; Resources; Role; Silicates; Silicon Dioxide; Source; Specificity; To autoantigen; United States National Institutes of Health; cell type; immunopathology; interstitial; macrophage; mouse model; novel

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Inhaled silicates such as silica and asbestos can lead to complex pathologies, including pulmonary fibrosis, pleural abnormalities, cancer and systemic autoimmune diseases (SAID). One of the major gaps of knowledge regarding environmental autoimmunity is how specific autoantibody profiles are induced by particular exposures, and whether that defines the clinical disease outcome of the autoimmune response. This proposal addresses critical questions about the cellular mechanisms leading to immunopathology following inhaled silicate exposures. Amphibole asbestos exposure is associated with pulmonary fibrosis and self-reported SAID in Libby MT. Also, C57Bl/6 mice respond to asbestos with interstitial lung fibrosis, as well as production of antinuclear antibodies (ANA) and immune complex glomerulonephritis, closely resembling SAID. This novel mouse model can therefore be used to elucidate the mechanism whereby asbestos leads to the production of pathogenic autoantibodies, and to determine whether various types of inhaled silicates lead to unique autoantibody profiles. Environmental exposures have been hypothesized to expose autoantigens to the immune system via modified protein exposure, particularly during apoptosis. However, exposure of autoantigens is not sufficient to drive an autoimmune response without a second mechanism to overcome peripheral tolerance. Inhaled silicates contact several cell types that could be activated to drive antigen presentation, including macrophages and B1a B cells. Our central hypothesis is that asbestos drives exposure of a set of autoantigens that will be reflected in the autoantibody specificities produced in asbestos-exposed mice, and that B1a B cells play a role in overcoming tolerance to these antigens.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 吸入二氧化硅和石棉等硅酸盐可导致复杂的病变，包括肺纤维化、胸膜异常、癌症和全身性自身免疫性疾病 (SAID)。关于环境自身免疫的主要知识空白之一是特定暴露如何诱导特定的自身抗体谱，以及这是否定义了自身免疫反应的临床疾病结果。 该提案解决了吸入硅酸盐暴露后导致免疫病理学的细胞机制的关键问题。利比 MT 中角闪石石棉暴露与肺纤维化和自我报告的 SAID 有关。此外，C57Bl/6 小鼠对石棉的反应会导致间质性肺纤维化，并产生抗核抗体 (ANA) 和免疫复合物肾小球肾炎，与 SAID 非常相似。因此，这种新型小鼠模型可用于阐明石棉导致致病性自身抗体产生的机制，并确定各种类型的吸入硅酸盐是否会导致独特的自身抗体谱。据推测，环境暴露会通过修饰的蛋白质暴露将自身抗原暴露给免疫系统，特别是在细胞凋亡期间。然而，如果没有第二种机制来克服外周耐受，自身抗原的暴露不足以驱动自身免疫反应。吸入的硅酸盐会接触多种可被激活以驱动抗原呈递的细胞类型，包括巨噬细胞和 B1a B 细胞。我们的中心假设是，石棉会导致一组自身抗原的暴露，这些抗原将反映在石棉暴露小鼠体内产生的自身抗体特异性中，并且 B1a B 细胞在克服对这些抗原的耐受性方面发挥着作用。