Environmental Influences Driving Autoimmunity and Autoimmune Disease in Tribal Members

OMRF项目摘要 风湿性疾病，如系统性红斑狼疮(SLE)、类风湿性关节炎(RA)、 硬皮病和骨性关节炎在美洲原住民人口中造成显著的发病率和早期死亡率。 通过切诺基民族和俄克拉荷马医学研究中心之间的持续合作 基金会，我们发现在其他种族的风湿病患者中经典自身抗体的相关性 在NA人群中不能诊断，在部落风湿病患者中发现新的自身抗体，以及 发现部落患者和对照组有独特的细胞因子信号；所有这些都会导致风湿病 部落成员的医疗保健在初级保健诊所诊断起来更具挑战性。令人惊讶的是，我们发现当地人 没有自身免疫性风湿病证据的美国人的自身抗体比率最高。 产生(10.5%)所有种族，主要与狼疮、系统性硬化症或类风湿性关节炎相关 抗体。在这些个体中，自身抗体的产生与较低的25(OH)D水平有关。反- 心磷脂自身抗体在NA风湿病患者和对照组中也更常见。 一些最高的感染率、不良结局和COVID死亡发生在部落。 社区，COVID在许多其他健康的人中诱导自身抗体，包括抗 与血栓形成相关的心磷脂反应和与不良相关的抗细胞因子反应 疾病后果。在我们小组和其他人的研究中，许多患有自身免疫性或 自身免疫性疾病具有延长的症状，这让人想起风湿性疾病，例如 疲劳、关节痛、肌痛、不适、皮疹、肺和心脏受累。选定的环境因素有 与系统性自身免疫性风湿病有很强的相关性。该项目将定义 环境影响，如病毒感染(SARS-CoV-2、Epstein-Barr病毒、巨细胞病毒)、病毒 重新激活(爱泼斯坦-巴尔病毒)，维生素D缺乏和吸烟暴露，对 部落成员的自身抗体和自身免疫性疾病。用单细胞质量细胞术测定飞行时间 (CyTOF)和单细胞基因组测序与抗体结合(CITE-SEQ)，共享免疫 导致自身耐受性丧失、自身抗体产生和自身免疫性风湿病的途径 将会被确定。最后，通过远程医疗的实施，重点介绍了远程医疗方案 以实践为中心、以病例为基础的学习、学术细节和临床研究方案的患者登记 切诺基国家卫生系统内的风湿病能力将在当前和未来得到发展 病人。该项目的总体目标是确定和确认与以下内容相关的环境影响 自身抗体的产生，免疫失调和自身免疫性风湿病，以及持久的构建 以部落为基础的基础设施，提供持续的风湿病评估和治疗，帮助更早 检测，降低了发病率，改善了部落患者的预后。

OMRF Project Summary Rheumatic diseases, such as systemic lupus erythematosus (SLE, lupus), rheumatoid arthritis (RA), scleroderma and osteoarthritis, cause significant morbidity and early mortality in Native American populations. Through ongoing collaborative work between the Cherokee Nation and the Oklahoma Medical Research Foundation, we have found that classic autoantibody associations in rheumatic disease patients of other races are not diagnostic in NA populations, identified novel autoantibodies in tribal rheumatic disease patents and found that tribal patients and controls have unique cytokine signatures; all of which make rheumatic disease care in tribal members more challenging to diagnose in primary care clinics. Surprisingly, we found that Native American individuals without evidence of autoimmune rheumatic disease had the highest rate of autoantibody production (10.5%) of all races, primarily with lupus, systemic sclerosis or rheumatoid arthritis associated antibodies. Autoantibody production is associated with lower levels of 25(OH)D in these individuals. Anti- cardiolipin autoantibodies are also more frequent in NA rheumatic disease patients and controls. Some of the highest rates of infection, poor outcomes and deaths from COVID have occurred in tribal communities, and COVID induces autoantibodies in many otherwise healthy individuals, including anti- cardiolipin responses that associate with thrombosis and anti-cytokine responses that associate with poor disease outcomes. In studies from our group and others, many COVID patients with autoimmunity or autoimmune disease are having prolonged symptoms, which are reminiscent of rheumatic diseases, such as fatigue, arthralgias, myalgias, malaise, rashes, lung and heart involvement. Select environmental factors have strong associations with systemic autoimmune rheumatic diseases. This project will define the impact of environmental influences, such as viral infections (SARS-CoV-2, Epstein-Barr virus, Cytomegalovirus), viral reactivation (Epstein-Barr virus), vitamin D deficiency and smoking exposure, on the development of autoantibodies and autoimmune disease in tribal members. Using single cell mass cytometry time of flight (CyTOF) and single cell genomic sequencing partnered with antibody binding (CITE-seq), shared immune pathways contributing to loss of self-tolerance, autoantibody production and autoimmune rheumatic disease will be determined. Finally, through implementation of a telerheumatology, telementoring program focused on practice-centric, case-based learning, academic detailing, and patient enrollment to clinical research protocols rheumatology capacity within the Cherokee Nation Health System will be developed for current and future patients. The overall goals of this project are to identify and confirm environmental influences associated with autoantibody production, immune dysregulation and autoimmune rheumatic disease, as well as build lasting tribal-based infrastructure to provide ongoing rheumatic disease evaluation and treatment that aid earlier detection, decreased morbidity and improved outcomes in tribal patients.