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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.

Author information

1
Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
2
Benaroya Research Institute, Seattle, WA.
3
Yale University School of Medicine, New Haven, CT.
4
Pisa University, Pisa, Italy.
5
Division of Pediatric Surgery, University of Pittsburgh, Pittsburgh, PA.
6
Laboratory of Protein Phosphorylation and Proteomics, KU Leuven, Leuven, Belgium.
7
SyBioMa, KU Leuven, Leuven, Belgium.
8
INSERM, U1016, CNRS, UMR8104, Paris Descartes University, Sorbonne Paris Cité, Cochin Institute, Paris, France.
9
Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium lutgart.overbergh@kuleuven.be.

Abstract

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.

PMID:
30348823
DOI:
10.2337/db18-0295

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