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Åke Lernmark

Principal investigator

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GAD65-specific autoantibodies enhance the presentation of an immunodominant T-cell epitope from GAD65

Author

  • Charlotta af Hällström-Reijonen
  • Terri L Daniels
  • A. Lernmark
  • Gerald T Nepom

Summary, in English

GAD65 autoantibodies (GAD65Ab) are highly prevalent in type 1 diabetes, but their functional role in the pathogenesis of the disease and their relationship to T-cell reactivity to GAD65 is still unclear. We tested the hypothesis that GAD65Ab modulate presentation of GAD65 to T-cells. T-cell hybridoma T33.1, which recognizes the GAD65 274-286 epitope in the context of HLA-DRB1*0401, was incubated with antigen-presenting cells exposed to recombinant human GAD65 alone or complexed with GAD65Ab+ or GAD65Ab- sera. Stimulation of the T33.1 hybridoma was greatly enhanced by multiple GAD65Ab+ sera. The enhancement effect was most prominent with sera from patients with high GAD65 autoantibody levels. Sera from GAD65Ab- subjects had no effect. The correlation between T-cell stimulation and GAD65Ab levels was not absolute, suggesting that other variables such as autoantibody recognition of different regions of GAD65 and variable effects on processing of the 274-286 epitope may contribute. Uptake of antibody-complexed GAD65 was Fc receptor (FcR)-mediated because the enhancement of presentation was inhibited by monoclonal antibodies against FcR. Our results support the hypothesis that GAD65Ab modulate presentation of GAD65 to T-cells. Increased antigen uptake and heterogeneity in the autoantibody specificity may provide a mechanism for antibody-facilitated T-cell response influencing the progression of type 1 diabetes.

Publishing year

2000

Language

English

Pages

1621-1626

Publication/Series

Diabetes

Volume

49

Issue

10

Document type

Journal article

Publisher

American Diabetes Association Inc.

Status

Published

ISBN/ISSN/Other

  • ISSN: 0012-1797