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

被引：186

作者：

Kracht, Maria J. L. ^{[1
,2
,3
]}

van Lummel, Menno ^{[2
,3
]}

Nikolic, Tatjana ^{[2
,3
]}

Joosten, Antoinette M. ^{[2
,3
]}

Laban, Sandra ^{[2
,3
]}

van der Slik, Arno R. ^{[2
,3
]}

van Veelen, Peter A. ^{[4
]}

Carlotti, Francoise ^{[5
]}

de Koning, Eelco J. P. ^{[5
]}

Hoeben, Rob C. ^{[1
]}

Zaldumbide, Arnaud ^{[1
]}

Roep, Bart O. ^{[2
,3
,6
]}

机构：

[1] Leiden Univ, Med Ctr, Dept Mol Cell Biol, Leiden, Netherlands

[2] Leiden Univ, Med Ctr, Dept Immunohematol, Leiden, Netherlands

[3] Leiden Univ, Med Ctr, Dept Blood Transfus, Leiden, Netherlands

[4] Leiden Univ, Med Ctr, Ctr Prote & Metab, Leiden, Netherlands

[5] Leiden Univ, Med Ctr, Dept Internal Med, Leiden, Netherlands

[6] City Hope Natl Med Ctr, Dept Diabet Immunol, Diabet & Metab Res Inst, Beckman Diabet Res Inst, Duarte, CA USA

来源：

NATURE MEDICINE | 2017年 / 23卷 / 04期

关键词：

CD8; T-CELLS; UNFOLDED PROTEIN RESPONSE; MESSENGER-RNA; RECENT-ONSET; POSTTRANSLATIONAL MODIFICATION; HUMAN ISLETS; BETA-CELLS; ER STRESS; TRANSLATION; BINDING;

D O I：

10.1038/nm.4289

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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(1,2). 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.

引用

页码：501 / +

页数：10

共 53 条

[1] CD8 T cell autoreactivity to preproinsulin epitopes with very low human leucocyte antigen class I binding affinity [J].