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

基本信息

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
项目类别：
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

项目摘要

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，例如全身性红斑狼疮（SLE，狼疮），类风湿关节炎（RA），硬皮病和骨关节炎，在美国原住民人群中引起明显的发病率和早期死亡率。通过切诺基国家与俄克拉荷马州医学研究之间的持续合作工作基金会，我们发现其他种族风湿病患者的经典自身抗体关联在NA人群中没有诊断，在部落风湿病专利中确定了新型自身抗体发现部落患者和对照组具有独特的细胞因子特征。所有这些都导致风湿病部落成员的护理在初级保健诊所的诊断更具挑战性。令人惊讶的是，我们发现那个本地人没有自身免疫性疾病证据的美国人的自身抗体率最高所有种族的生产（10.5％），主要与狼疮，全身性硬化症或类风湿关节炎相关抗体。在这些个体中，自身抗体的产生与较低的25（OH）D相关。反对- 在NA风湿病患者和对照组中，心脂蛋白自身抗体也更加频繁。某些最高感染率，不良的结果和死亡发生在部落中社区和共同诱导许多其他健康的个体的自身抗体，包括抗与血栓形成和抗周期因子反应相关的心脂蛋白反应与较差疾病结果。在我们小组和其他人的研究中，许多自身免疫性或自身免疫性疾病长期存在症状，使人联想起风湿病，例如疲劳，关节痛，肌痛，不适，皮疹，肺和心脏参与。选择环境因素有与系统性自身免疫性风湿病的密切关联。该项目将定义环境影响，例如病毒感染（SARS-COV-2，爱泼斯坦 - 巴尔病毒，巨细胞病毒），病毒重新激活（爱泼斯坦 - 巴尔病毒），维生素D缺乏症和吸烟暴露于发展部落成员的自身抗体和自身免疫性疾病。使用单细胞质量细胞术飞行时间（细胞TOF）和单细胞基因组测序与抗体结合（Cite-Seq）合作，共享免疫导致自我耐受性，自身抗体产生和自身免疫性疾病的途径将确定。最后，通过实施远程流程学，远程计划的重点是以实践为中心，基于案例的学习，学术细节和临床研究方案的患者入学切诺基国家卫生系统内的风湿病能力将为当前和未来开发患者。该项目的总体目标是识别和确认与自身抗体产生，免疫失调和自身免疫性疾病以及持久基于部落的基础设施，提供正在进行的风湿性疾病评估和治疗，以帮助较早检测，发病率降低并改善了部落患者的结局。