Mechanism of Silica-induced Autoimmunity

描述（由申请人提供）：二氧化硅已令人信服地与多种自身免疫性疾病相关，这些疾病与肾、肺、关节和其他器官损伤导致的主要发病率和死亡率相关。然而，目前基本上对自身免疫诱导的机制或遗传易感性的作用一无所知，并且不存在已建立的动物模型。本文提出的研究旨在填补这一关键空白。每种二氧化硅相关的自身免疫性疾病都与呼吸道暴露有关，并具有突出的体液自身免疫成分，这表明二氧化硅暴露的肺导致B细胞耐受性丧失，这是这些疾病中的基本免疫异常。因此，值得注意的是，二氧化硅已被证明在受影响的肺中诱导三级淋巴样结构。其他器官中的异位淋巴组织形成突出的B细胞滤泡，支持抗原特异性免疫应答，有利于自身反应性淋巴细胞的存活和活化。在拟定的研究中，研究者将探索以下假设：呼吸道二氧化硅通过肺三级淋巴结构的中介作用导致遗传易感个体的B细胞耐受性破坏。首先，研究人员将使用一种新的自身抗体转基因小鼠模型系统，以确定吸入二氧化硅是否会导致B细胞耐受性的丧失和四种不同疾病相关遗传背景中自身抗体的产生，并确定耐受机制的破坏和诱导的自身特异性。其次，研究人员将使用模型系统来定义环境共同暴露于Toll样受体配体在二氧化硅诱导的耐受性丧失中的作用。第三，研究者将在富集耐受性敏感B细胞的人源化模型中进行平行研究，以确定二氧化硅在何种条件下诱导人自身抗体产生。最后，研究人员将使用这些模型来确定肺淋巴组织是否是耐受性丧失和自身抗体产生的部位。这些研究中产生的信息将大大提高对吸入二氧化硅诱导自身免疫的要求和机制的理解。

DESCRIPTION (provided by applicant): Silica has been convincingly linked to multiple autoimmune diseases associated with major morbidity and mortality due to kidney, lung, joint, and other organ damage. However, at present essentially nothing is known about the mechanism of autoimmune induction or the role of genetic susceptibility, and an established animal model does not exist. The studies proposed here are intended to fill this critical void. Each of the silica-associated autoimmune disorders is associated with respiratory exposure and has a prominent humoral autoimmune component, implicating silica-exposed lung in loss of B cell tolerance, the fundamental immune abnormality in these diseases. It is thus notable that silica has been demonstrated to induce tertiary lymphoid structures in affected lungs. Ectopic lymphoid tissue in other organs develops prominent B cell follicles that support antigen-specific immune responses and favor survival and activation of autoreactive lymphocytes. In the proposed studies the investigators will explore the hypothesis that respiratory silica leads to a breach in B cell tolerance in genetically susceptible individuals through the intermediary of pulmonary tertiary lymphoid structures. First, the investigators will use a novel autoantibody transgenic mouse model system to determine whether inhaled silica induces loss of B cell tolerance and autoantibody production in each of four distinct disease-relevant genetic backgrounds, and identify the tolerance mechanism breached and the autospecificities induced. Second, the investigators will use the model system to define the role of environmental co-exposure to Toll-like receptor ligands in silica-induced loss of tolerance. Third, the investigator will conduct parallel studies in a humanized model that enriches for tolerance-susceptible B cells to determine under what conditions silica induces human autoantibody production. Last, the investigators will use the models to determine whether lung lymphoid tissue is the site of loss of tolerance and autoantibody production. The information generated in these studies will substantially heighten understanding of the requirements for and mechanisms by which inhaled silica induces autoimmunity.