A subclass of serum anti-ZnT8 antibodies directed to the surface of live pancreatic β-cells

Chengfeng Merriman, Qiong Huang, Wei Gu, Liping Yu, Dax Fu

Research output: Contribution to journalArticle

Abstract

The islet-specific zinc transporter ZnT8 is a major self-antigen found in insulin granules of pancreatic β-cells. Frequent insulin secretion exposes ZnT8 to the cell surface, but the humoral antigenicity of the surface-displayed ZnT8 remains unknown. Here we show that a membrane-embedded human ZnT8 antigen triggered a vigorous immune response in ZnT8 knock-out mice. Approximately 50% of serum immunoreactivities toward ZnT8 were mapped to its transmembrane domain that is accessible to extracellular ZnT8 antibody (ZnT8A). ZnT8A binding was detected on live rat insulinoma INS-1E cells, and the binding specificity was validated by a CRISPR/ Cas9 mediated ZnT8 knock-out. Applying established ZnT8A assays to purified serum antibodies from patients with type 1 diabetes, we detected human ZnT8A bound to live INS-1E cells, whereas a ZnT8 knock-out specifically reduced the surface binding. Our results demonstrate that ZnT8 is a cell surface self-antigen, raising the possibility of a direct involvement in antibody-mediated β-cell dysfunction and cytotoxicity.

Original languageEnglish (US)
Pages (from-to)579-587
Number of pages9
JournalJournal of Biological Chemistry
Volume293
Issue number2
DOIs
StatePublished - Jan 12 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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