Novel Autoantibodies to the β-Cell Surface Epitopes of ZnT8 in Patients Progressing to Type-1 Diabetes

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by autoimmune destruction of insulin-producing β -cells in pancreatic islets. Seroconversions to islet autoantibodies (IAbs) precede the disease onset by many years, but the initial factors driving the chronic phase, especially the role of humoral autoimmunity in the disease progression are unknown. In the present study, we identified a new IAb directed to the extracellular epitopes of ZnT8 (ZnT8ec) exposed on the β -cell surface. We further demonstrated immunofluorescence staining of ZnT8ec-specific autoantibodies (ZnT8Ab) on cell surface and epitope spreading from ZnT8ec to multiple intracellular or secretory self-antigens during the progression of islet autoimmunity in newly diagnosed patients with T1D. The identification of ZnT8ec as a cell surface target of humoral autoimmunity in the early phase of IAb responses opens a new avenue of investigation into IAb-mediated T1D etiology and progression. Funding Statement: This study was supported by the National Institutes of Health, R56 DK123435, RO1 DK032083, and RO1DK032493. Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: Signed written informed consents were obtained from participants and the studies were approved by the Institutional Review Board of the University of Colorado.