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

doi:10.1038/nm.4289

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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

191 Citations (Scopus)

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 language	English
Pages (from-to)	501-507
Number of pages	7
Journal	Nature Medicine
Volume	23
Issue number	4
DOIs	https://doi.org/10.1038/nm.4289
Publication status	Published - 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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10.1038/nm.4289

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title = "Autoimmunity against a defective ribosomal insulin gene product in type 1 diabetes",

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.",

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AU - van Lummel, Menno

AU - Nikolic, Tatjana

AU - Joosten, Antoinette M

AU - Laban, Sandra

AU - van der Slik, Arno R

AU - van Veelen, Peter A

AU - Carlotti, Françoise

AU - de Koning, Eelco J P

AU - Hoeben, Rob C

AU - Zaldumbide, Arnaud

AU - Roep, Bart O

PY - 2017/4

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AB - 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.

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

Abstract

Keywords

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