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

Recognition of posttranslationally modified GAD65 epitopes in subjects with type 1 diabetes.

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Benaroya Research Institute at Virginia Mason, Seattle, WA.
Benaroya Research Institute at Virginia Mason, Seattle, WA Department of Medicine, University of Washington, Seattle, WA.
Benaroya Research Institute at Virginia Mason, Seattle, WA


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.

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