Autoantibodies directed to islet cell surface antigens and their pathologic roles in type-1 diabetes

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Islet autoantibodies (AAs) are reliable biomarkers of pancreatic autoimmunity. Serum AAs against four major biochemical antigens (insulin, GAD, IA-2, and ZnT8) are routinely used in clinical research as key metrics for diagnostics and prognostics in patients with type-1 diabetes (T1D), and for disease prediction in at-risk individuals before T1D onset. Robust biochemical assays have been developed to detect AAs recognizing soluble antigens or soluble domains of membrane-bound antigens. Detection of AAs to membrane-bound antigens, however, is challenged by technical difficulties in adaption of their insoluble transmembrane domains (TMD) to solution-based assay platforms. At present, we have no knowledge of the prevalence and first appearance of AAs targeting any TMD antigens. Among the four major biochemical antigens, the islet-specific ZnT8 is unique in having a major TMD that encompasses two thirds protein sequence in a full-length ZnT8. Our recent works showed that ZnT8 is trafficked to the surface of pancreatic β-cells following insulin secretion, and the surfaced TMD is highly antigenic, recognized by serum ZnT8 AAs in patients with T1D. These findings suggest that the TMD in ZnT8 is a novel immunogenic domain for surfaced-targeted AAs, and its display on the cell surface may promote antibody-mediated cytotoxicity contributing directly to β-cell autoimmune destruction. To test these hypotheses, we will (i) validate AAs directed to the TMD of ZnT8 (TMDAs) in patients progressing to T1D, and (ii) establish TMDAs as direct-targeting AAs, as such, bind directly to live pancreatic β cells to modulate their functions and survival. The proposed research is expected to validate a completely new class of AAs targeting a recently identified islet cell surface antigen, illuminating the roles of TMDAs in the natural history of T1D (Aim 1) and disease pathogenesis (Aim 2). The knowledge gained will be translated to novel diagnostic tools and potential therapeutic interventions.