Environmental Influences Driving Autoimmunity and Autoimmune Disease in Tribal Members

环境影响导致部落成员发生自身免疫和自身免疫疾病

• 批准号: 10707068
• 负责人: JUDITH A JAMES
• 金额: $ 37.54万
• 依托单位: CHEROKEE NATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707068
• 关键词: 2019-nCoV; Academic Detailing; Algorithms; Antibodies; Arthralgia; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; Automobile Driving; Binding; COVID-19; COVID-19 impact; COVID-19 patient; Cardiolipins; Caring; Case Based Learning; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Cessation of life; Cherokee Indian; Cherokee Nation, Oklahoma; Cities; Clinic; Clinical Research; Clinical Research Protocols; Cotinine; Cytomegalovirus; Cytometry; Data; Degenerative polyarthritis; Development; Diagnosis; Disease; Disease Outcome; Dissemination and Implementation; Early Diagnosis; Early Intervention; Early treatment; Environmental Exposure; Environmental Impact; Environmental Risk Factor; Epstein-Barr virus early antigen; Evaluation; Exanthema; Fatigue; Foundations; Future; Genomics; Goals; Grant; Health; Health system; Heart; Human Herpesvirus 4; Immune; Immune System Diseases; Immunophenotyping; Individual; Infection; Infrastructure; Legal patent; Long COVID; Lung; Lupus; Malaise; Measures; Medical Research; Methods; Morbidity - disease rate; Myalgia; Native American Research Center for Health; Native Americans; Oklahoma; Outcome; Pathway interactions; Patients; Population; Prevention; Production; Provider; Race; Rheumatism; Rheumatoid Arthritis; Rheumatology; Rivers; SARS-CoV-2 infection; Scleroderma; Self Tolerance; Symptoms; Systemic Lupus Erythematosus; Systemic Scleroderma; Testing; Thrombosis; Time; Tribes; Vaccines; Viral; Virus Diseases; Vitamin D Deficiency; Work; autoimmune rheumatologic disease; coronavirus disease; cytokine; immunoregulation; improved outcome; infection rate; mortality; multiple omics; novel; participant enrollment; patient engagement; primary care clinic; primary care provider; programs; proteogenomics; response; rheumatologist; single-cell RNA sequencing; smoking exposure; systemic autoimmune disease; tribal community; tribal member

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.

OMRF项目摘要 风湿性疾病，如系统性红斑狼疮（SLE，lupus），类风湿性关节炎（RA）， 硬皮病和骨关节炎在美洲土著人群中引起显著的发病率和早期死亡率。 通过切罗基族和俄克拉荷马州医学研究中心之间持续的合作 在此基础上，我们发现其他种族的风湿性疾病患者的经典自身抗体联合 在NA人群中不具有诊断性，在部落风湿病患者中发现了新的自身抗体， 发现部落患者和对照组有独特的细胞因子特征;所有这些都使风湿性疾病 部落成员的护理在初级保健诊所诊断更具挑战性。令人惊讶的是，我们发现， 没有自身免疫性风湿病证据的美国个体的自身抗体率最高 生产（10.5%）的所有种族，主要与狼疮，系统性硬化症或类风湿性关节炎相关 抗体的自身抗体的产生与这些个体中25（OH）D水平较低有关。反 心磷脂自身抗体在NA风湿病患者和对照中也更常见。 一些最高的感染率，不良后果和死亡的COVID发生在部落 社区，COVID在许多其他健康个体中诱导自身抗体，包括抗- 与血栓形成相关的心磷脂反应和与不良反应相关的抗细胞因子反应 疾病结果。在我们小组和其他人的研究中，许多患有自身免疫或 自身免疫性疾病有长期的症状，这让人想起风湿性疾病，如 疲劳、关节痛、肌痛、不适、皮疹、肺和心脏受累。选择环境因素有 与全身性自身免疫性风湿性疾病密切相关。该项目将确定的影响 环境影响，如病毒感染（SARS-CoV-2，EB病毒，巨细胞病毒），病毒感染 再激活（EB病毒），维生素D缺乏和吸烟暴露，对发展的影响， 自身抗体和自身免疫性疾病。使用单细胞质量细胞仪飞行时间 （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 将被确定。最后，通过实施远程血液流变学，远程监护计划的重点是 以实践为中心，以案例为基础的学习，学术细节和临床研究方案的患者登记 切罗基国家卫生系统内的流变学能力将在当前和未来得到发展 患者本项目的总体目标是识别和确认与以下方面相关的环境影响： 自身抗体的产生，免疫失调和自身免疫性风湿病，以及建立持久的 以部落为基础的基础设施，提供持续的风湿性疾病评估和治疗， 检测，降低发病率和改善部落患者的结果。