Novel autoantibodies to the 13-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 insulinproducing 13-cells in pancreatic islets. Seroconversions to islet autoantibodies (IAbs) precede the disease onset by many years, but the role of humoral autoimmunity in the disease initiation and progression are unclear. In the present study, we identified a new IAb directed to the extracellular epitopes of ZnT8 (ZnT8ec) in newly diagnosed patients with T1D, and demonstrated immunofluorescence staining of the surface of human 13-cells by autoantibodies to ZnT8ec (ZnT8ecA). With the assay specificity set on 99th percentile of 336 healthy controls, the ZnT8ecA positivity rate was 23.6% (74/313) in patients with T1D. Moreover, 30 children in a longitudinal follow up of clinical T1D development were selected for sequential expression of four major IAbs (IAA, GADA, IA2A and ZnT8icA). Among them, 10 children were ZnT8ecA positive. Remarkably, ZnT8ecA was the earliest IAb to appear in all 10 children. The identification of ZnT8ec as a cell surface target of humoral autoimmunity in the earliest phase of IAb responses opens a new avenue of investigation into the role of IAbs in the development of 13-cell autoimmunity.

Automated summary

Type 1 diabetes is characterized by autoimmune destruction of insulin-producing β-cells, and a new autoantibody directed to ZnT8 extracellular epitopes has been identified in newly diagnosed patients. This autoantibody, ZnT8ecA, was the earliest to appear in children with T1D development, suggesting a potential role in the initiation of β-cell autoimmunity.