Journal
DIABETES
Volume 67, Issue 11, Pages 2337-2348Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db18-0295
Keywords
-
Categories
Funding
- Innovative Medicines Initiative Joint Undertaking [115797]
- European Union's Horizon 2020 research and innovation program
- European Federation of Pharmaceutical Industries and Associations
- Leona M. and Harry B. Helmsley Charitable Trust
- KU Leuven [GOA14/010]
- JDRF [2-SRA-2015-52-Q-R, 1-INO-2018-638-A-N, 3-PDF-2018-593-A-N]
- Fonds Wetenschappelijk Onderzoek [1189518N, 11Y6716N]
- JDRF
Ask authors/readers for more resources
The beta-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 auto-antigen in human type 1 diabetes. When human islets were exposed to inflammatory stress induced by interleukin-1 beta, tumor necrosis factor-alpha, and interferon-gamma, 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 beta-cell proteins, exemplified here by the citrullination of GRP78, contributes to loss of self-tolerance toward beta-cells in human type 1 diabetes, indicating that beta-cells actively participate in their own demise.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available