Recognition of Posttranslationally Modified GAD65 Epitopes in Subjects With Type 1 Diabetes

Diabetes. 2014 Sep;63(9):3033-40. doi: 10.2337/db13-1952. Epub 2014 Apr 4.

Abstract

Posttranslational modification (PTM) of self-proteins has been shown to elicit clinically relevant immune responses in rheumatoid arthritis and celiac disease. Accumulating evidence suggests that recognition of modified self-proteins may also be important in type 1 diabetes. Our objective was to identify posttranslationally modified GAD65 peptides, which are recognized by subjects with type 1 diabetes, and to assess their disease relevance. We show that citrullination and transglutamination of peptides can enhance their binding to DRB1*04:01, a diabetes-susceptible HLA allele. These and corresponding modifications to amino acids at T-cell contact positions modulated the recognition of multiple GAD65 peptides by self-reactive T cells. Using class II tetramers, we verified that memory T cells specific for these modified epitopes were detectable directly ex vivo in the peripheral blood of subjects with type 1 diabetes at significantly higher frequencies than healthy controls. Furthermore, T cells that recognize these modified epitopes were either less responsive or nonresponsive to their unmodified counterparts. Our findings suggest that PTM contributes to the progression of autoimmune diabetes by eliciting T-cell responses to new epitope specificities that are present primarily in the periphery, thereby circumventing tolerance mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • CD4-Positive T-Lymphocytes / immunology
  • Diabetes Mellitus, Type 1 / immunology*
  • Epitopes, T-Lymphocyte / immunology*
  • Glutamate Decarboxylase / immunology*
  • Glutamate Decarboxylase / metabolism
  • HLA-DRB1 Chains / immunology
  • Humans
  • Insulin-Secreting Cells / immunology
  • Protein Processing, Post-Translational

Substances

  • Epitopes, T-Lymphocyte
  • HLA-DRB1 Chains
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2