Do Xenobiotics Exacerbate Idiopathic Autoimmunity?

异生素会加剧特发性自身免疫吗？

• 批准号: 9506204
• 负责人: Kenneth Michael Pollard
• 金额: $ 29.03万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9506204
• 关键词: Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Cell Development; B-Lymphocytes; Biological Markers; Biological Response Modifiers; Characteristics; Chronic; Classification; Clinical; Coupling; Data; Deposition; Development; Diagnosis; Diagnostic; Discrimination; Disease; Environmental Exposure; Event; Exposure to; Genetic; Human; Immune; Immune Cell Activation; Immune Sera; Immunologics; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Investigation; Knowledge; Laboratories; Lead; Lymphoid; Measurement; Measures; Mercuric chloride; Morphology; Mouse Strains; Nuclear Antigens; Organ; Pathogenesis; Pathology; Pharmaceutical Preparations; Play; Population; Rheumatoid Arthritis; Risk; Role; Serological; Serum Immunologic; Silicon Dioxide; Site; Structure; Syndrome; Systemic Lupus Erythematosus; Systemic Scleroderma; Testing; Time; Tissues; Xenobiotics; autoreactive B cell; clinical Diagnosis; clinical development; clinically relevant; disease phenotype; environmental agent; individual patient; lupus-like; response; serological marker; specific biomarkers; systemic autoimmune disease; systemic autoimmunity; tool

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.

7。项目摘要/摘要 自身免疫性被认为是由遗传学，环境触发器和随机事件的结合而产生的。 尽管环境/异种剂在触发自身免疫性中的作用尚不清楚 如果特发性和诱发疾病是通过共同机制引起的。分类标准已开发到 有助于诊断特发性自身免疫性疾病，但是缺乏实验室工具来识别 环境引起的自身免疫。这是由于缺乏研究识别特定生物标志物的研究 特定的环境暴露会导致自身免疫性。这是我们理解的重要障碍 异种生物引起的自身免疫的诊断和治疗。最近的研究表明，异生物暴露 结果产生局部炎症反应，其中可能包括异位淋巴结结构（ELS）样细胞 积累。 Els出现在非分辨，慢性炎症的部位，在目标器官中发现 特发性自身免疫性疾病可能支持完全差异化的自动反应性的发展 B细胞。在特发性自身免疫性中，先天性和适应性炎症介体发生在或同时发生之前 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，调查炎症介体与 自身抗体不仅可以区分自身抗体阳性健康个体和患者 疾病，但在临床相关疾病的发展中也是阶段。此类信息不存在 与特定异种生物的暴露以及异生物诱导的自身免疫的发展有关。我们 假设异种生物诱导的炎症介质有助于异位淋巴结构形成 以及在异种生物中产生自身抗体谱的完全分化的自动反应性B细胞的发展 和暴露地点特定的响应。为了测试这一点，我们将实现两个不同但重叠的目标。在目标1中 我们将测试以下假设：炎症介质和自身抗体的概况可以区分 异源生物诱导的，异源生物效果和特发性系统性自身免疫性通过确定，随着时间的推移， 与特发性和诱导的自身抗体和免疫介质的血清学特征 自身免疫性并将其与包括先天和适应性在内的疾病特征的发展相关 免疫细胞激活，组织病理和免疫沉积。在AIM 2中，我们将检验以下假设 异生物诱导的EL是通过识别条件来产生B细胞发育的自身抗体的部位 对于居民B细胞的ELS形成和自身抗体谱所必需的。从中生成的数据 提案将有助于确定特定的异种生物暴露是否导致炎症介质，EL和 可以用作环境引起的自身免疫性的诊断标准的自身抗体轮廓。这会 提高我们对可以发展为慢性炎症的潜在机制的了解 自身免疫性。