Posttranslational Modification of HLA-DQ Binding Islet Autoantigens in Type 1 Diabetes

  1. Bart O. Roep1
  1. 1Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
  2. 2Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
  3. 3Department of Immunobiology, School of Medicine, King’s College London, London, U.K.
  1. Corresponding author: Bart O. Roep, boroep{at}lumc.nl.

Abstract

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.

Footnotes

  • Received September 5, 2012.
  • Accepted September 23, 2013.

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  1. Diabetes vol. 63 no. 1 237-247
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