Autoimmunity against a defective ribosomal insulin gene product in type 1 diabetes

Maria J L Kracht, Menno van Lummel, Tatjana Nikolic, Antoinette M Joosten, Sandra Laban, Arno R van der Slik, Peter A van Veelen, Françoise Carlotti, Eelco J P de Koning, Rob C Hoeben, Arnaud Zaldumbide, Bart O Roep

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Identification of epitopes that are recognized by diabetogenic T cells and cause selective beta cell destruction in type 1 diabetes (T1D) has focused on peptides originating from native beta cell proteins. Translational errors represent a major potential source of antigenic peptides to which central immune tolerance is lacking. Here, we describe an alternative open reading frame within human insulin mRNA encoding a highly immunogenic polypeptide that is targeted by T cells in T1D patients. We show that cytotoxic T cells directed against the N-terminal peptide of this nonconventional product are present in the circulation of individuals diagnosed with T1D, and we provide direct evidence that such CD8+ T cells are capable of killing human beta cells and thereby may be diabetogenic. This study reveals a new source of nonconventional polypeptides that act as self-epitopes in clinical autoimmune disease.

Original languageEnglish
Pages (from-to)501-507
Number of pages7
JournalNature Medicine
Volume23
Issue number4
DOIs
Publication statusPublished - Apr 2017

Keywords

  • Adolescent
  • Adult
  • Autoantigens
  • Autoimmunity
  • CD8-Positive T-Lymphocytes
  • Child
  • Dendritic Cells
  • Diabetes Mellitus, Type 1
  • Female
  • HLA-DQ Antigens
  • Humans
  • Immunohistochemistry
  • Insulin
  • Insulin-Secreting Cells
  • Male
  • Open Reading Frames
  • Peptides
  • Protein Biosynthesis
  • RNA, Messenger
  • T-Lymphocytes, Cytotoxic
  • Young Adult
  • Journal Article

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