Inflammation-Induced Citrullinated Glucose-Regulated Protein 78 Elicits Immune Responses in Human Type 1 Diabetes

Diabetes. 2018 Nov;67(11):2337-2348. doi: 10.2337/db18-0295.


The β-cell has become recognized as a central player in the pathogenesis of type 1 diabetes with the generation of neoantigens as potential triggers for breaking immune tolerance. We report that posttranslationally modified glucose-regulated protein 78 (GRP78) is a novel autoantigen in human type 1 diabetes. When human islets were exposed to inflammatory stress induced by interleukin-1β, tumor necrosis factor-α, and interferon-γ, arginine residue R510 within GRP78 was converted into citrulline, as evidenced by liquid chromatography-tandem mass spectrometry. This conversion, known as citrullination, led to the generation of neoepitopes, which effectively could be presented by HLA-DRB1*04:01 molecules. With the use of HLA-DRB1*04:01 tetramers and ELISA techniques, we demonstrate enhanced antigenicity of citrullinated GRP78 with significantly increased CD4+ T-cell responses and autoantibody titers in patients with type 1 diabetes compared with healthy control subjects. Of note, patients with type 1 diabetes had a predominantly higher percentage of central memory cells and a lower percentage of effector memory cells directed against citrullinated GRP78 compared with the native epitope. These results strongly suggest that citrullination of β-cell proteins, exemplified here by the citrullination of GRP78, contributes to loss of self-tolerance toward β-cells in human type 1 diabetes, indicating that β-cells actively participate in their own demise.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantigens / immunology
  • Autoantigens / metabolism*
  • Citrullination
  • Cytokines / pharmacology
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism*
  • Endoplasmic Reticulum Chaperone BiP
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Inflammation / immunology
  • Inflammation / metabolism*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / immunology
  • Islets of Langerhans / metabolism*


  • Autoantigens
  • Cytokines
  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • Heat-Shock Proteins