Do Xenobiotics Exacerbate Idiopathic Autoimmunity?

7. 项目总结/摘要 自身免疫被认为是遗传、环境触发因素和随机事件共同作用的结果。 尽管环境/外源物质在引发自身免疫方面的作用已得到充分证实，但尚不清楚 特发性疾病和诱发性疾病是否由共同机制引起。已制定分类标准 有助于诊断特发性自身免疫性疾病，但缺乏用于识别的实验室工具 环境诱发的自身免疫。这是由于缺乏识别特定生物标志物的研究。 导致自身免疫的特定环境暴露。这是我们理解的一个重大障碍， 外源性自身免疫性疾病的诊断和治疗。最近的研究表明，外源性物质暴露 导致局部炎症反应，包括异位淋巴结构 (ELS) 样细胞 积累。 ELS 出现在未消退的慢性炎症部位，并且已在靶器官中发现 特发性自身免疫性疾病，它们可能支持完全分化的自身反应性的发展 B细胞。在特发性自身免疫性疾病中，先天性和适应性炎症介质先于或同时发生 自身抗体和这些免疫学特征可预测临床自身免疫性疾病的发展。 这些研究表明，对炎症介质和炎症介质之间时间关系的研究 自身抗体不仅可以区分自身抗体阳性的健康个体和患有自身抗体的患者 疾病，而且还包括进展为临床相关疾病的阶段。此类信息不存在于 与接触特定的外源性物质和外源性物质诱导的自身免疫的发展有关。我们 假设异生素诱导的炎症介质有助于异位淋巴结构的形成 以及在异生素中产生自身抗体谱的完全分化的自身反应性 B 细胞的开发 和暴露部位的特定反应。为了测试这一点，我们将实现两个不同但重叠的目标。目标 1 我们将检验以下假设：炎症介质和自身抗体的特征可以区分 随着时间的推移，通过确定异生素诱导的、异生素加剧的和特发性全身性自身免疫， 与特发性和诱导性相关的自身抗体和免疫介质的血清学特征 自身免疫并将其与疾病特征的发展相关联，包括先天性和适应性 免疫细胞激活、组织病理学和免疫沉积。在目标 2 中，我们将检验以下假设： 异生素诱导的 ELS 是通过识别条件产生自身抗体的 B 细胞发育位点 ELS 形成和驻留 B 细胞自身抗体谱所必需的。由此生成的数据 该提案将有助于确定特定的异生素暴露是否会导致炎症介质、ELS 和 自身抗体谱可作为环境引起的自身免疫的诊断标准。这将 增加我们对慢性炎症潜在机制的了解，慢性炎症可以发展为 自身免疫。

7. Project Summary/Abstract Autoimmunity is thought to result from a combination of genetics, environmental triggers, and stochastic events. Although the role of environmental/xenobiotic agents in triggering autoimmunity is well established, it is unclear if idiopathic and induced disease arise by common mechanisms. Classification criteria have been developed to aid in the diagnosis of idiopathic autoimmune diseases however there is a lack of laboratory tools for identifying environmentally induced autoimmunity. This is due to the paucity of studies identifying biomarkers specific for a particular environmental exposure that leads to autoimmunity. This is a significant barrier to our understanding, diagnosis and treatment of xenobiotic-induced autoimmunity. Recent studies show that xenobiotic exposure results in a localized inflammatory response that can include ectopic lymphoid structure (ELS)-like cellular accumulations. ELS arise at sites of non-resolving, chronic inflammation and have been found in target organs of idiopathic autoimmune diseases where they may support the development of fully differentiated autoreactive B cells. In idiopathic autoimmunity innate and adaptive inflammatory mediators occur prior to or concurrent with autoantibodies and these immunological profiles are predictive of development of clinical autoimmune disease. These studies reveal that investigation of the temporal relationships between inflammatory mediators and autoantibodies can distinguish not only between autoantibody positive healthy individuals and patients with disease but also stages in the progression to clinically relevant disease. Such information does not exist in relation to exposure to a specific xenobiotic and the development of xenobiotic-induced autoimmunity. We hypothesize that xenobiotic-induced inflammatory mediators contribute to ectopic lymphoid structure formation and the development of fully differentiated autoreactive B cells producing autoantibody profiles in a xenobiotic and exposure site specific response. To test this we will undertake two distinct, yet overlapping, aims. In Aim 1 we will test the hypothesis that profiles of inflammatory mediators and autoantibodies can discriminate between xenobiotic-induced, xenobiotic-exacerbated, and idiopathic systemic autoimmunity by determining, over time, the serological profiles of autoantibodies and immune mediators relevant to both idiopathic and induced autoimmunity and correlate them with the development of features of disease including innate and adaptive immune cell activation, tissue pathology and immune deposits. In Aim 2 we will test the hypothesis that xenobiotic-induced ELS are sites of autoantibody producing B cell development by identifying conditions necessary for ELS formation and the autoantibody profiles of resident B cells. The data generated from this proposal will help determine whether specific xenobiotic exposures lead to inflammatory mediators, ELS, and autoantibody profiles that can serve as diagnostic criteria for environmental-induced autoimmunity. This will increase our knowledge of the underlying mechanisms of chronic inflammation that can progress to autoimmunity.