Unknown

Dataset Information

0

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


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.

SUBMITTER: McGinty JW 

PROVIDER: S-EPMC4392921 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

McGinty John W JW   Chow I-Ting IT   Greenbaum Carla C   Odegard Jared J   Kwok William W WW   James Eddie A EA  

Diabetes 20140404 9


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 p  ...[more]

Similar Datasets

| S-EPMC8982141 | biostudies-literature
| S-EPMC10341784 | biostudies-literature
| S-EPMC6859290 | biostudies-literature
| S-EPMC5508727 | biostudies-literature
| S-EPMC2630690 | biostudies-literature
| S-EPMC11324298 | biostudies-literature
2021-05-29 | E-MTAB-10323 | biostudies-arrayexpress
| S-EPMC6437014 | biostudies-literature
| S-EPMC8274489 | biostudies-literature
| S-EPMC4718521 | biostudies-literature