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

被引:72
作者
Reijonen, H
Daniels, TL
Lernmark, Å
Nepom, GT
机构
[1] Virginia Mason Res Ctr, Benaroya Res Inst, Seattle, WA 98101 USA
[2] Univ Washington, Dept Med, Seattle, WA USA
关键词
D O I
10.2337/diabetes.49.10.1621
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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页码:1621 / 1626
页数:6
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