Effect of autoantibodies on lung fibroblast phenotype

描述（由申请方提供）：砷暴露与肺纤维化以及自身免疫反应（包括抗核抗体增加）相关。我们最近完成了一项对利比MT石棉暴露人群的初步研究，表明这些自身抗体可能与疾病进展有关。这项建议的具体目标是基于这样一种假设，即石棉暴露导致肺内细胞对免疫系统独特抗原的表达和呈递发生改变，然后产生抗体反应。然后，这些抗体可能通过与成纤维细胞结合并增加其促纤维化活性而加剧导致石棉相关疾病（ARD）的慢性炎症性疾病。该方法首先证明石棉暴露受试者中产生的自身抗体对成纤维细胞的识别，然后确定石棉暴露于成纤维细胞是否导致靶抗原表达改变，最后证明靶向成纤维细胞的抗体可以影响促炎活性。长期目标是了解自身抗体在暴露于已知环境因子石棉的个体中肺部疾病发病机制中的可能作用。这种理解可能与其他自身免疫性疾病有关，其中没有已知的激发剂是已知的，因此这些研究将有可能提供一种预防和治疗方式的方法。

DESCRIPTION (provided by applicant): Asbestos exposure is associated with pulmonary fibrosis as well as autoimmune responses, including increased antinuclear antibodies. We have recently completed a pilot study of the asbestos-exposed population of Libby MT that suggests that these autoantibodies may be associated with disease progression. The specific aims of this proposal are based on the hypothesis that asbestos exposure leads to the altered expression and presentation by cells within the lung of unique antigens to the immune system, which then mounts an antibody response. These antibodies may then exacerbate chronic inflammatory conditions responsible for asbestos-related disease (ARD) by binding to fibroblasts and increasing their pro-fibrotic activities. The approach is to first demonstrate recognition of fibroblasts by autoantibodies generated in asbestos exposed subjects, then to determine whether asbestos exposure to fibroblasts leads to altered expression of target antigens, and finally to demonstrate that antibodies targeting the fibroblasts can affect pro-inflammatory activities. The long-term goal will be to understand the possible role of autoantibodies in the pathogenesis of lung disease in individuals exposed to a known environmental agent, asbestos. This understanding may be of relevance to other autoimmune diseases where no known inciting agent is known, and therefore these studies will have the potential to provide an approach to prevention and therapeutic modalities.