Soliman M, Kaplan E, Yanagawa T, Hidaka Y, Fisfalen M E, DeGroot L J
Department of Medicine, University of Chicago, Illinois 60637.
J Clin Endocrinol Metab. 1995 Mar;80(3):905-14. doi: 10.1210/jcem.80.3.7533773.
In Graves' disease (GD), the TSH receptor (TSHR) is believed to be the major target of an autoimmune response. T-Lymphocytes regulate the immune system. To assess the interaction of T-cells with TSHR in the pathogenesis of GD, we tested the T-cell response of peripheral blood mononuclear cells and T-cell lines to the recombinant human TSHR extracellular domain (rhTSHR-ECD) and 31 synthetic peptides corresponding to the entire TSHR-ECD in 20 patients with GD, 8 patients with Hashimoto's thyroiditis, 7 with colloid nodular goiter (CNG), and 20 normal controls. Comparing patients from different groups with normal subjects, there was a significant response to rhTSHR-ECD and thyroglobulin in GD patients (P < 0.001) and HT patients (P < 0.05), but not in CNG patients (P > 0.1). All 20 patients with GD responded to at least one peptide. The reactivity in GD patients was heterogeneous and spanned the entire TSHR-ECD. However, the reactivity was significantly different from that in controls for peptide regions 44-88, 119-176, 227-263, and 343-376, and the stimulation index (SI) values were significantly different for peptides 272-291 and 301-320. Significant differences were confined to peptides 158-176 and 343-362 and the region 227-263 for comparison of the number of positive responses in patients and controls to individual peptides. Forty-six percent of human leukocyte antigen-DQA1 0501 allele-positive Graves' patients responded to peptides 158-176 and 248-263 (SI = 3 or more) compared to 14% of allele-negative patients. In HT and CNG patients, the response was mainly to peptides in the carboxy-terminal half of the TSHR-ECD. Concordance of the reactivity in T-cell lines and peripheral blood mononuclear cells was observed in 36% of direct comparisons in GD. Eighty-five percent and 90% of GD patients were positive for microsomal antibody and TSHR antibody, respectively, and 59% of microsomal antibody-positive and 67% of TSHR antibody-positive patients responded to rhTSHR-ECD (SI = 2 or more). However, there was no significant correlation between antibody-positive patients and reactivity to specific peptides. Using multiple criteria to define immunodominance, peptides 158-176, 237-252, 248-263, and 343-362 seem to be important epitopes and may be critical for T-cell triggering in GD.
在格雷夫斯病（GD）中，促甲状腺激素受体（TSHR）被认为是自身免疫反应的主要靶点。T淋巴细胞调节免疫系统。为了评估T细胞与TSHR在GD发病机制中的相互作用，我们检测了20例GD患者、8例桥本甲状腺炎患者、7例胶样结节性甲状腺肿（CNG）患者和20例正常对照者的外周血单个核细胞和T细胞系对重组人TSHR细胞外结构域（rhTSHR-ECD）以及对应于整个TSHR-ECD的31种合成肽的T细胞反应。将不同组的患者与正常受试者进行比较，GD患者（P < 0.001）和HT患者（P < 0.05）对rhTSHR-ECD和甲状腺球蛋白有显著反应，而CNG患者则无（P > 0.1）。所有20例GD患者至少对一种肽有反应。GD患者的反应具有异质性，涵盖整个TSHR-ECD。然而，对于肽段44 - 88、119 - 176、227 - 263和343 - 376，其反应性与对照组显著不同，并且肽段272 - 291和301 - 320的刺激指数（SI）值也有显著差异。在比较患者和对照对单个肽的阳性反应数量时，显著差异局限于肽段158 - 176和343 - 362以及区域227 - 263。46%的人类白细胞抗原-DQA1 0501等位基因阳性的格雷夫斯病患者对肽段158 - 176和248 - 263有反应（SI = 3或更高），而等位基因阴性患者的这一比例为14%。在HT和CNG患者中，反应主要针对TSHR-ECD羧基末端一半的肽段。在GD的36%的直接比较中观察到T细胞系和外周血单个核细胞反应性的一致性。85%和90%的GD患者分别为微粒体抗体和TSHR抗体阳性，59%的微粒体抗体阳性患者和67%的TSHR抗体阳性患者对rhTSHR-ECD有反应（SI = 2或更高）。然而，抗体阳性患者与对特定肽的反应性之间没有显著相关性。使用多种标准来定义免疫优势，肽段158 - 176、237 - 252、248 - 263和343 - 362似乎是重要的表位，可能对GD中T细胞的触发至关重要。
