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.