Multiple Autoantigens, Multiple Epitopes of Type 1 Diabetes

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Project Summary The overarching goal of our research is to develop new biomarkers of islet autoimmunity and to translate these discoveries to the prevention of human type 1 diabetes (T1D). During the last funding period, we developed a multiplexed assay to detect serum autoantibodies to islet and non-islet autoantigens with excellent sensitivity and predictive value when compared to our traditional radio-binding assays. The proposed studies will broaden the spectrum of relevant autoantigens to those that are post-translationally modified (PTM) as well as provide insights into when native versus PTM binding autoantibodies develop in the natural history of T1D. Our recent findings have strengthened the evidence for autoreactive T cells responding to (pro)insulin, including those activated by hybrid insulin peptides (HIPs) and defective ribosomal insulin products (DRiPs), within the residual pancreatic islets of T1D organ donors. However, we still lack robust T cell biomarkers that could reflect the activity of autoreactive T cells, especially at the earliest stages of islet autoimmunity or during immunomodulation to prevent progression to clinical diabetes. Assays for islet autoantibodies and autoreactive T cells that measure both natural and modified islet autoantigens, combined with a better understanding of their relationship, will enhance our knowledge of T1D pathogenesis and improve prediction of progression through the stages of T1D. In specific aim 1, we will optimize and multiplex autoantibody assays to native and PTM modified islet autoantigens to determine the temporal development of these antibodies in longitudinal samples from children prospectively followed from birth to development of islet autoimmunity and clinical diabetes. Specific aim 2 focuses on developing a non-cellular T cell biomarker of islet autoimmunity measured from whole blood DNA using the T cell receptor sequences obtained from residual islets of T1D organ donors. The successful completion of this proposal will result in scalable assays for the measurement of islet autoantibodies and autoreactive T cells, and improved understanding regarding the timing of autoantibody and T cell immune responses to native and post-translationally modified islet autoantigens during the development of T1D.