GAD65-specific autoantibodies enhance the presentation of an immunodominant T-cell epitope from GAD65.
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-DRB 1*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.
Reijonen
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Virginia Mason Research Center, Benaroya Research Institute, Seattle, Washington 981010, USA. reijonen@vmresearch.org
Daniels
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TL
Lernmark
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A
Nepom
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D000293:Adolescent; D000595:Amino Acid Sequence; D017951:Antigen Presentation; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D007527:Isoenzymes / Q000737:chemistry / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D011961:Receptors, Fc / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*
D001323:Autoantibodies; D000939:Epitopes; D007527:Isoenzymes; D010446:Peptide Fragments; D011961:Receptors, Fc; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2