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

TY - JOUR

T1 - Autoimmunity against a defective ribosomal insulin gene product in type 1 diabetes

AU - Kracht, Maria J L

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

Y1 - 2017/4

N2 - 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.

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.

KW - Adolescent

KW - Adult

KW - Autoantigens

KW - Autoimmunity

KW - CD8-Positive T-Lymphocytes

KW - Child

KW - Dendritic Cells

KW - Diabetes Mellitus, Type 1

KW - Female

KW - HLA-DQ Antigens

KW - Humans

KW - Immunohistochemistry

KW - Insulin

KW - Insulin-Secreting Cells

KW - Male

KW - Open Reading Frames

KW - Peptides

KW - Protein Biosynthesis

KW - RNA, Messenger

KW - T-Lymphocytes, Cytotoxic

KW - Young Adult

KW - Journal Article

U2 - 10.1038/nm.4289

DO - 10.1038/nm.4289

M3 - Article

C2 - 28263308

SN - 1078-8956

VL - 23

SP - 501

EP - 507

JO - Nature Medicine

JF - Nature Medicine

IS - 4

ER -