Thyrotropin receptor epitopes and their relation to histocompatibility leukocyte antigen-DR molecules in Graves' disease
Thyrotropin receptor epitopes and their relation to histocompatibility leukocyte antigen-DR molecules in Graves' disease
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DOI：
10.1210/jc.2005-2537
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发表时间：
2006-06-01
影响因子：
5.8
通讯作者：
De Groot, Leslie J.
中科院分区：
文献类型：
--
作者：
Inaba, Hidefumi;Martin, William;De Groot, Leslie J.
内容：Graves病（Graves' disease，GD）是一种以TSH受体（TSH receptor，TSHR）自身免疫为特征的疾病。目的：研究TSHR中启动这种免疫反应的T细胞表位及其与GD易感的人类组织相容性白细胞抗原（human histocompatibility leukocyte antigen，HLA）分子的相互作用。DRB 1 *0101（DR1）、DRB 1 *1501（DR2）、DRB 1 *0301（DR3）、DRB 1 *1101（DR5）和DRB 1 *0701（DR7）。我们使用T细胞表位映射算法EpiMatrix扫描TSHR胞外结构域。我们将这些结果与GD患者测量体外T细胞对肽反应的临床研究进行比较。设置：该研究在大学实验室进行。患者：患者包括200名连续的成人GD临床患者。干预：没有干预。主要结果测量：测量表位的结合亲和力，预测亲和力和报告的T细胞刺激数据。结果：大多数肽以中等或高亲和力结合一个或多个HLA-DR分子。与容易患GD的HLA-DR 3和HLA-DR 5结合的肽总体上表现出中等的结合亲和力，而与GD保护性HLA-DR 7结合的大多数肽以高亲和力结合。这些差异可能与胸腺中的T细胞选择有关。肽的结合亲和力与EpiMatrix预测的HLA-DRB 1 * 0101、DRB 1 *1501、DR 3和DRB 1 *0701的亲和力强烈相关，但与HLA-DR 5无关。平均IC 50值与临床T细胞刺激data.Conclusions显着相关：三种不同的方法识别免疫原性肽没有提供一个统一的图片的重要TSHR表位。然而，肽132-150（GIFNTGLKMFPDLTKVYST）通过三种方法鉴定为GD中的重要表位;还鉴定了肽145-163、158-176、207-222、248-263、272-291和343-362的可能重要性。
Context: Graves' disease (GD) is characterized by autoimmunity to the TSH receptor (TSHR).Objective: We sought to identify T cell epitopes in TSHR that initiate this immune response and their interaction with human histocompatibility leukocyte antigen (HLA) molecules predisposing to GD.Design: We examined the affinity of 31 overlapping peptides spanning the TSHR extracellular domain for binding in vitro to five purified HLA-DR molecules; DRB1*0101 (DR1), DRB1*1501 (DR2), DRB1*0301 (DR3), DRB1*1101 (DR5), and DRB1*0701 (DR7). We scanned the TSHR extracellular domain using a T cell epitope-mapping algorithm, EpiMatrix. We compared these results with clinical studies of GD patients measuring in vitro T cell responses to the peptides.Setting: The study was conducted at a university laboratory.Patients: Patients included 200 serial adult clinic patients with GD.Intervention: There were no interventions.Main Outcome Measurements: Binding affinity of epitopes, predicted affinity, and reported T cell stimulation data were measured.Results: Most peptides bound with intermediate or high affinity to one or more HLA-DR molecule. Peptides binding to HLA-DR3 and HLA-DR5, which predispose to GD, exhibited moderate binding affinities overall, whereas most peptides binding to GD-protective HLA-DR7 bound with high affinity. These differences may relate to T cell selection in the thymus. Binding affinity of peptides correlated strongly with EpiMatrix-predicted affinity for HLA-DRB1* 0101, DRB1*1501, DR3, and DRB1*0701 but not HLA-DR5. Average IC50 values correlated significantly with clinical T cell stimulation data.Conclusions: Three different methods for identifying immunogenic peptides did not provide a uniform picture of important TSHR epitopes. However, peptide 132-150 (GIFNTGLKMFPDLTKVYST) was identified by three methods as an important epitope in GD; the possible importance of peptides 145-163, 158-176, 207-222, 248-263, 272-291, and 343-362 was also identified.