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Nat Med. 2017 Apr;23(4):501-507. doi: 10.1038/nm.4289. Epub 2017 Feb 27.

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

Author information

1
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
2
Departments of Immunohematology &Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
3
Center for Proteomics &Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.
4
Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.
5
Department of Diabetes Immunology, Diabetes &Metabolism Research Institute at the Beckman Diabetes Research Institute, City of Hope, Duarte, California, USA.

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.

PMID:
28263308
DOI:
10.1038/nm.4289
[Indexed for MEDLINE]

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