Autoimmune diseases affect up to 1 in 12 individuals, and the etiology and pathogenesis of disease processes remain poorly understood. Lack of essential understanding of disease mechanisms results in limited and inferior diagnostic approaches, may often lead to misdiagnoses, and hinders the development of directed immunotherapeutics. Therefore, our research is unified by a single goal: To improve the lives of patients with systemic autoimmune diseases by providing knowledge and tools for earlier, more precise treatment. By focusing our patient-oriented research on the initiating and pathogenic factors in systemic autoimmune rheumatic diseases, our laboratory has delineated immunologic processes, genetic factors, and environmental exposures that contribute to the onset and progression of autoimmunity. Using systemic lupus erythematosus (SLE) as a prototype, our research group showed for the first time that autoantibodies occur before clinical disease onset (NEJM 2003) and before associated clinical symptoms (A&R 2007), identified the initial targets of key lupus autoantibodies (Nature Med 2005), and established the concept of humoral epitope spreading in human disease (JEM 1995, SJI 1999). We have also identified a progression of systemic cytokine, chemokine, and soluble mediator dysregulation that precedes SLE transition and identifies people at high risk of future SLE onset, and showed that hydroxychloroquine use is associated with delayed lupus onset. By following large, diverse, well-characterized cohorts of patients after disease classification, we have identified immune disturbances that correspond with disease activity. These studies have revealed distinct cellular phenotypes that may contribute to disease flares in different patients or at different times, established molecular signatures that distinguish subsets of SLE patients based on patterns of immune activation, and defined a robust soluble mediator score that predicts impending disease flare in SLE patients, regardless of the specific immune pathways involved. Together, these studies provide a path toward understanding the heterogeneity of autoimmune diseases, as well as mechanisms that are common across diagnoses. Finally, we have partnered with local tribes to better understand and treat these diseases in American Indian populations, where rheumatic diseases are highly prevalent and often more aggressive. Our collaborative studies with tribal nations were among the first to describe unique serological and clinical features of rheumatic diseases in American Indians in Oklahoma and surrounding communities, and our ongoing work is defining antigenic specificities and soluble mediators in greater detail as a route to facilitating diagnosis in American Indian patients. Our research is supported by an NIAID Autoimmunity Center of Excellence, NIAMS Center grant, NIGMS Clinical and Translational Research Center, NIGMS Native American Research Center for Health, and other NIH awards.