GAD65-specific antoantibodies enhance the presentation of an immunodominant T-cell epitope from GAD65
GAD65-specific antoantibodies enhance the presentation of an immunodominant T-cell epitope from GAD65
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DOI：
10.2337/diabetes.49.10.1621
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发表时间：
2000-10-01
期刊：
影响因子：
7.7
通讯作者：
Nepom, GT
中科院分区：
文献类型：
--
作者：
Reijonen, H;Daniels, TL;Nepom, GT
GAD 65自身抗体（GAD 65 Ab）在1型糖尿病中非常普遍，但其在疾病发病机制中的功能作用及其与T细胞对GAD 65反应性的关系仍不清楚。我们测试了GAD 65 Ab调节GAD 65向T细胞的呈递的假设，将识别HLA-DRB 1 *0401背景下的GAD 65 274-286表位的T细胞杂交瘤T33.1与暴露于单独的重组人GAD 65或与GAD 65 Ab（+）或GAD 65 Ab（-）血清复合的重组人GAD 65的抗原呈递细胞一起孵育。多个GAD 65 Ab（+）血清极大地增强了T33.1杂交瘤的刺激。增强效应在来自具有高GAD 65自身抗体水平的患者的血清中最为突出。GAD 65 Ab（-）受试者的血清没有影响。T细胞刺激和GAD 65抗体水平之间的相关性不是绝对的，这表明其他变量，如GAD 65不同区域的自身抗体识别和对274-286表位加工的可变影响可能有贡献。抗体复合的GAD 65的摄取是Fc受体（FcR）介导的，因为针对FcR的单克隆抗体抑制了呈递的增强。我们的结果支持GAD 65 Ab调节GAD 65向T细胞的呈递的假设。增加的抗原摄取和自身抗体特异性的异质性可能为抗体促进的T细胞反应提供了影响1型糖尿病进展的机制。
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.