Predicting Systemic Autoimmunity through Follow-up of Blood Relatives

描述（由申请人提供）：本项目解决的挑战领域是领域9：健康差异研究。此应用程序的具体主题是“针对不成比例影响狼疮和硬皮病患者群体的预防策略”。系统性红斑狼疮是一种典型的系统性自身免疫性疾病，在过去的50多年里，FDA没有批准新的治疗方法。识别SLE发展的“高风险”人群将允许采用预防性治疗进行干预。系统性狼疮有一个已知的遗传易感性和家庭成员携带增加的风险发展临床疾病。在过去的15年里，我们的研究联盟收集了近6000名SLE患者未受影响的血亲，这些患者的血清样本平均在7.6年前收集和保存。这些人在当时临床表现良好，但许多人在此期间可能转变为临床狼疮。重新联系这些个体（他们已经同意为未来的研究重新联系）将为我们提供一个独特的机会，在临床疾病发病前和发病时/发病后快速收集一组SLE患者的标本。此外，将汇编具有一些增加的遗传风险和可能的自身抗体的个体队列，这些个体不会转变为临床疾病。选择血清学生物标志物，包括选择自身抗体谱和血清α干扰素活性，将测试与过渡到临床狼疮的关系。其他与狼疮相关的环境因素，如维生素D缺乏的标志物和对常见病原体的异常体液免疫反应，将作为狼疮发病的预测因素进行测试。对遗传风险多态性与SLE风险增加的评价有待进一步研究。最后，大量的临床、人口统计和治疗信息，结合历史收集和后续研究的生物标本，将为未来的调查提供帮助。该项目将有助于识别SLE发展的“高风险”个体，确定针对这些或未来生物标志物的潜在预防性治疗的杰出人群。据估计，有多达5000万美国人患有自身免疫性疾病。

DESCRIPTION (provided by applicant): The Challenge Area addressed by this project is Area 9: Health Disparities Research. The specific topic for this application is "Prevention Strategies that Target Disproportionately Affected Lupus and Scleroderma Patient Populations". Systemic lupus erythematosus is a prototypic systemic autoimmune disease for which no new FDA treatment has been approved in over 50 years. Identification of "high risk" groups for SLE development would allow intervention with preventive therapies. Systemic lupus has a known genetic predisposition and family members are carry an increased risk of developing clinical disease. Over the past 15 years, our consortium of investigators has assembled a collection of nearly 6,000 unaffected blood relatives of SLE patients who had serum samples collected and stored on average 7.6 years ago. These individuals were clinically well at that time, but many have potentially transitioned to clinical lupus in the interim. Re-contacting these individuals (who have provided consent for re-contact for future studies) will provide us with a unique opportunity to rapidly assemble a group of SLE patients with specimens before and at/after clinical disease onset. In addition, cohorts of individuals with some increased genetic risk, and likely autoantibodies, who do not transition to clinical disease will be compiled. Select serological biomarkers, including select autoantibody profiles and serum alpha interferon activity, will be tested for association with transition to clinical lupus. Additional lupus- associated environmental factors, such as markers of vitamin D deficiency and abnormal humoral immune responses to common pathogens, will be tested as predictors of SLE disease onset. Evaluation of genetic risk polymorphisms with increased risk of SLE can be further studied. Finally, a large collection of clinical, demographic, and therapeutic information, in combination with biospecimens from historical collections and follow-up studies, will be available for future investigation. This project will help to identify "high risk" individuals for SLE development, defining outstanding populations for potential preventative therapies directed toward these or future biomarkers. Autoimmune diseases are estimated to afflict as many as 50,000,000 Americans. PUBLIC HEALTH RELEVANCE: This application tests genetic and serologic biomarkers of autoimmunity, cytokine activity, and abnormal environmental responses as predictors of autoimmune disease onset. ARRA funds would allow rapid generation of a SLE transition cohort by follow-up of historical, at-risk individuals to establish disease predictors to aid in prevention strategies. Biospecimens and associated clinical data will be biobanked to test future alternate hypotheses.