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.