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.

Autoreactive T cells in type 1 diabetes

“…The generation of defective ribosomal products (DRiPs) from the proinsulin gene is another recently discovered mechanism leading to production of T cell-targeted β cell neoepitopes. β Cells generate DRiP neoepitopes using an alternative initiation site for translation and by translating the 3′ UTR (176). T cell reactivity against proinsulin DRiPs was tested in peripheral blood samples from T1D patients, and proliferative responses were observed in most.…”

“…Proinsulin DRiPs were formed under thapsigargin-induced experimental ER stress, a form of stress characterized by calcium depletion in the ER and increased cytoplasmic calcium levels, in contrast to classical ER stress caused by accumulation of misfolded proteins. Thus, in the T1D pancreas, ER stress and inflammation impair β cell function by increasing production of autoantigens (147), and DRiPs could trigger and enhance T cell-mediated killing of β cells (176).…”

Tools to define the melanoma‐associated immunopeptidome

“…These neoantigens represent highly attractive targets when these peptides derive from public mutations, although they may be also highly suitable for the design of personalized therapies. Moreover, mutations may result in non‐canonical reading frames additionally representing an important source for neoantigens, as shown for autoimmune diseases and cancer . In addition, post‐translational modifications may produce aberrantly processed peptides potentially representing neoantigens .…”

Type 1 Diabetes: Disease Stratification

“…Beta cell stress has been demonstrated to generate modifications (posttranslational modifications, generation of hybrid proteins arising from fusion of beta cell peptides, defective ribosomal proteins with altered reading frames) of beta cell proteins that elicit either antibody or T cell responses in established T1D [62][63][64][65][66] . Of interest to stratifying subjects at risk of progressing to stage 1 T1D is detection of antibodies to beta cell protein modifications prior to detection of antibodies to native beta cell epitopes.…”