Do Xenobiotics Exacerbate Idiopathic Autoimmunity?

7.项目总结/摘要 自身免疫性被认为是遗传、环境触发和随机事件的综合结果。 虽然环境/外源性物质在触发自身免疫中的作用已经得到了很好的证实，但目前还不清楚 如果自发性和诱发性疾病是由共同机制引起。已制定分类标准， 但是，缺乏用于鉴定的实验室工具 环境诱导的自身免疫这是由于缺乏研究，确定生物标志物的特异性， 特定的环境暴露导致自身免疫。这是我们理解的一个重大障碍， 异源性自身免疫的诊断和治疗。最近的研究表明， 导致局部炎症反应，包括异位淋巴样结构（ELS）样细胞 积累。ELS出现在非消退的慢性炎症部位，并已在靶器官中发现 在这些疾病中，它们可能支持完全分化的自身反应性 B细胞。在特发性自身免疫中，先天性和适应性炎症介质发生在 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，炎症介质和炎症介质之间的时间关系的调查， 自身抗体不仅可以区分自身抗体阳性的健康个体和患有 疾病，而且在临床相关疾病的进展阶段。此类信息不存在于 与暴露于特定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 假设外源性诱导炎症介质有助于异位淋巴结构形成 以及完全分化的自身反应性B细胞在异生物质中产生自身抗体谱的发展 和暴露部位特异性反应。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 我们将检验炎症介质和自身抗体谱可以区分 外源性诱导的、外源性加重的和特发性全身性自身免疫，通过测定，随着时间的推移， 与特发性和诱导性免疫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，包括先天性和适应性 免疫细胞活化、组织病理学和免疫沉积。在目标2中，我们将检验以下假设： 外源性物质诱导的ELS是通过鉴定条件产生自身抗体的B细胞发育的位点 ELS形成和常驻B细胞的自身抗体谱所必需。由此产生的数据 该提案将有助于确定特定的外源性暴露是否会导致炎症介质，ELS， 自身抗体谱，可作为环境诱导的自身免疫的诊断标准。这将 增加我们对慢性炎症的潜在机制的了解， 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.