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

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


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.

MeSH terms

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


  • Autoantigens
  • HLA-DQ Antigens
  • Insulin
  • Peptides
  • RNA, Messenger