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

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

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Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
Benaroya Research Institute, Seattle, WA.
Yale University School of Medicine, New Haven, CT.
Pisa University, Pisa, Italy.
Division of Pediatric Surgery, University of Pittsburgh, Pittsburgh, PA.
Laboratory of Protein Phosphorylation and Proteomics, KU Leuven, Leuven, Belgium.
SyBioMa, KU Leuven, Leuven, Belgium.
INSERM, U1016, CNRS, UMR8104, Paris Descartes University, Sorbonne Paris Cité, Cochin Institute, Paris, France.
Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium


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.


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