SUMMARY Autoimmune disease results from a combination of immunologic missteps involving multiple genes, cell types and environmental factors. In the proposed studies, we will study how these factors promote the transition from sub-clinical autoimmunity to autoimmune disease by comparing individuals at risk for type 1 diabetes, a disease with a well-defined natural history of sub-clinical autoimmunity, and individuals with Down syndrome (DS), a condition with extremely high risk of developing autoimmune disease. The central hypothesis is that the naïve T cell compartment of at-risk individuals is enriched for potentially pathogenic precursors “poised” to transition to autoreactive effector T cells, and the failure of regulatory mechanisms to restrain this process ultimately results in autoimmune disease. The approach leverages access to cross sectional and longitudinal cohorts at high risk or known to progress to autoimmunity; expertise in the genetics and autoantigen-specific T cells in the context of autoimmunity and expertise in single cell multi-modal analyses. Together, this expertise will allow us to probe T cell states in a manner not yet applied to autoimmunity. In our first two Aims, we will deeply characterize T cells across platforms from at risk subjects and address the role of epigenetics. In Aims 3 and 4 we address the role of external triggers using longitudinal cohorts prospectively tracking trigger events and determine whether autoimmune features are exaggerated in subjects acquiring a second autoimmune disease Aim 1 will determine whether pathogenic precursors are present in the naïve T cell compartment of individuals at risk for autoimmune disease compared to non-risk individuals. Aim 2 will identify cell types that harbor the genetic risk for disease transitions and identify underlying pathways that support pathogenic precursor T cells. Aim 3 will identify external factors that contribute to the transition of pathogenic precursors to effectors, including a prospective longitudinal high-risk cohort with intense at home sample collection to track immune variation bridging trigger events. Aim 4 will determine whether features seen in individuals who transition to T1D are exaggerated in individuals who develop additional autoimmune diseases. Ultimately, the knowledge gained from this work will contribute to staging of disease, selective therapies and establish biomarkers to determine risk of progression and response to therapy.

NARRATIVE Autoimmune disease presents a major health hazard to our population and can be devastating to individual patients. To date, there is no therapy that can prevent or cure autoimmune disease. The proposed studies will investigate how naïve T cells promote the transition from sub-clinical autoimmunity to autoimmune disease, focusing on this transition in individuals at-risk for type 1 diabetes and in individuals with Down syndrome, which is a genetic condition at high-risk for developing autoimmune disease.