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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：
10438444
负责人：
JUDITH A JAMES
金额：
$ 37.21万
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/10438444
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 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 Outcome Dissemination and Implementation Early Diagnosis Early Intervention Early treatment Enrollment 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 Mentors Methods Morbidity - disease rate Myalgia Native American Research Center for Health Native Americans Oklahoma Outcome Pathway interactions Patients Population Prevention Primary Health Care Production Provider Race Rheumatism Rheumatoid Arthritis Rheumatology Rivers SARS-CoV-2 infection Scleroderma Self Tolerance Symptoms Systemic Lupus Erythematosus Systemic Scleroderma Testing Thrombosis Time Vaccines Viral Virus Diseases Vitamin D Deficiency Work autoimmune rheumatologic disease base care providers coronavirus disease cytokine immunoregulation improved outcome infection rate mortality multiple omics novel participant enrollment 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 项目概要风湿性疾病，例如系统性红斑狼疮（SLE，狼疮）、类风湿性关节炎（RA）、硬皮病和骨关节炎导致美洲原住民显着发病和早期死亡。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基金会，我们发现其他种族的风湿病患者中存在经典的自身抗体关联无法在 NA 人群中进行诊断，在部落风湿病专利中鉴定出新型自身抗体，并且发现部落患者和对照者具有独特的细胞因子特征；所有这些都会导致风湿病在初级保健诊所诊断部落成员的护理更具挑战性。令人惊讶的是，我们发现 Native 没有自身免疫性风湿病证据的美国人的自身抗体率最高所有种族的产量（10.5%），主要与狼疮、系统性硬化症或类风湿性关节炎相关抗体。这些个体中自身抗体的产生与 25(OH)D 水平较低有关。反对- 心磷脂自身抗体在 NA 风湿病患者和对照中也更常见。一些因新冠肺炎感染率、不良后果和死亡人数最高的地区发生在部落社区，而新冠病毒会在许多其他方面健康的个体中诱发自身抗体，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患有自身免疫性疾病的新冠肺炎患者自身免疫性疾病有长期的症状，这让人想起风湿病，例如疲劳、关节痛、肌痛、不适、皮疹、肺和心脏受累。选择环境因素有与系统性自身免疫性风湿病密切相关。该项目将定义以下影响：环境影响，例如病毒感染（SARS-CoV-2、Epstein-Barr 病毒、巨细胞病毒）、病毒感染再激活（Epstein-Barr 病毒）、维生素 D 缺乏和吸烟暴露对发展的影响部落成员的自身抗体和自身免疫性疾病。使用单细胞质谱流式细胞仪飞行时间 (CyTOF) 和单细胞基因组测序与抗体结合 (CITE-seq) 相结合，共享免疫导致自我耐受性丧失、自身抗体产生和自身免疫性风湿病的途径将被确定。最后，通过实施远程风湿病学、远程指导计划，重点关注以实践为中心、基于案例的学习、学术细节以及临床研究方案的患者登记切罗基国家卫生系统内的风湿病治疗能力将针对当前和未来进行发展患者。该项目的总体目标是识别和确认与以下因素相关的环境影响：自身抗体的产生、免疫失调和自身免疫性风湿病，以及建立持久的基于部落的基础设施，提供持续的风湿病评估和治疗，以帮助早期治疗检测、降低发病率并改善部落患者的预后。