Posttranslational Modification of HLA-DQ Binding Islet Autoantigens in Type 1 Diabetes
- Menno van Lummel1,
- Gaby Duinkerken1,
- Peter A. van Veelen1,
- Arnoud de Ru1,
- Robert Cordfunke1,
- Arnaud Zaldumbide2,
- Iria Gomez-Touriño3,
- Sefina Arif3,
- Mark Peakman3,
- Jan W. Drijfhout1 and
- Bart O. Roep1⇑
- 1Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
- 2Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
- 3Department of Immunobiology, School of Medicine, King’s College London, London, U.K.
- Corresponding author: Bart O. Roep, .
Posttranslational modification (PTM) of islet autoantigens can cause lack of central tolerance in type 1 diabetes (T1D). Tissue transglutaminase (tTG), involved in PTM of gluten antigens in celiac disease, creates negatively charged peptides favored by T1D-predisposing HLA-DQ molecules, offering an attractive candidate modifying islet autoantigens in T1D. The highly predisposing HLA-DQ8cis/trans molecules share preferences for negatively charged peptides, as well as distinct peptide-binding characteristics that distinguish their peptide-binding repertoire. We screened islet autoantigens with the tTG substrate motif for candidate-modified epitopes binding to HLA-DQ8cis/trans and identified 31 candidate islet epitopes. Deamidation was confirmed for 28 peptides (90%). Two of these epitopes preferentially bound to HLA-DQ8cis and six to HLA-DQ8trans upon deamidation, whereas all other peptides bound equally to HLA-DQ8cis/trans. HLA-DQ8cis–restricted T cells from a new-onset T1D patient could only be generated against a deamidated proinsulin peptide, but cross-reacted with native proinsulin peptide upon restimulation. The rate of T-cell autoreactivity in recent-onset T1D patients extended from 42% to native insulin to 68% adding responses to modified proinsulin, versus 20% and 37% respectively, in healthy donors. Most patients responded by interferon-γ, whereas most healthy donors produced interleukin-10 only. Thus, T-cell autoreactivity exists to modified islet epitopes that differs in quality and quantity between patients and healthy donors.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1214/-/DC1.
- Received September 5, 2012.
- Accepted September 23, 2013.
- © 2014 by the American Diabetes Association.
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