Recognition of post-translationally modified glutamic acid decarboxylase 65 epitopes in subjects with type 1 diabetes

  1. Eddie A. James*
  1. *Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
  2. Department of Medicine, University of Washington, Seattle, WA, USA
  1. Corresponding Author: Eddie A. James E-mail: ejames{at}


Post-translational modification 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 post-translationally 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 non-responsive to their unmodified counterparts. Our findings suggest that post-translational modification 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.

  • Received December 27, 2013.
  • Accepted March 28, 2014.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See for details.

Articles citing this article