Muehlberg Tina, Gilbert Jacqueline A, Rao Prakash V, McGregor Alan M, Banga J Paul
Guy's, King's and St Thomas' School of Medicine, Division of Medicine, London SE5 9PJ, United Kingdom.
Endocrinology. 2004 Apr;145(4):1539-45. doi: 10.1210/en.2003-1456. Epub 2004 Feb 5.
Graves' disease is characterized by the presence of autoantibodies to the TSH receptor (TSHR). There are multiple antibodies to the TSHR, with thyroid-stimulating antibodies (TSAbs) and TSH-stimulating blocking antibodies (TSBAbs), which in patients can fluctuate over time, resulting in changes in disease activity. Recently, animal models of Graves' disease have been developed, but it is not known whether the induced TSAbs and TSBAbs change spontaneously with time to influence disease. We used fibroblasts expressing major histocompatability complex (MHC) class II and human TSHR murine model to study anti-TSHR antibody patterns in serial bleeds of 23 animals. Anti-TSHR antibody responses were first detectable after 7-8 wk of first immunization. Moreover, the pattern of the TSAbs or TSBAbs was selected early in the response. The majority of the animals showed anti-TSHR antibodies that were either TSAb or TSBAb responses and were maintained throughout the course of 17-24 wk of the experiment. Remarkably, a proportion of mice (13%) displayed presence of antibodies with both TSAbs and TSBAbs, which appeared to cycle over time and thus mimic the fluctuations described in some hyperthyroid patients. Analyses of the linear epitopes to TSHR by peptide scanning showed that there was no early restricted epitope response. Thus, despite using an inbred strain, the initial response appears to target different regions of the receptor in different animals. Our data show that anti-TSHR antibody epitopes in the model display heterogeneity in TSHR epitopes, which vary in individual animals as well as in their regulation.
格雷夫斯病的特征是存在针对促甲状腺激素受体（TSHR）的自身抗体。针对TSHR有多种抗体，包括甲状腺刺激抗体（TSAbs）和促甲状腺激素刺激阻断抗体（TSBAbs），在患者体内，这些抗体水平会随时间波动，导致疾病活动度发生变化。最近，已建立了格雷夫斯病的动物模型，但尚不清楚诱导产生的TSAbs和TSBAbs是否会随时间自发变化从而影响疾病。我们使用表达主要组织相容性复合体（MHC）II类分子和人TSHR的成纤维细胞小鼠模型，研究了23只动物连续采血中的抗TSHR抗体模式。首次免疫7 - 8周后首次检测到抗TSHR抗体反应。此外，TSAbs或TSBAbs的模式在反应早期就已确定。大多数动物显示出的抗TSHR抗体要么是TSAb反应，要么是TSBAb反应，并且在整个17 - 24周的实验过程中保持稳定。值得注意的是，一部分小鼠（13%）同时出现了TSAbs和TSBAbs两种抗体，它们似乎随时间循环变化，从而模拟了一些甲状腺功能亢进患者中描述的波动情况。通过肽扫描对TSHR线性表位进行分析表明，早期没有受限的表位反应。因此，尽管使用的是近交系，不同动物的初始反应似乎针对受体的不同区域。我们的数据表明，该模型中的抗TSHR抗体表位在TSHR表位方面表现出异质性，在个体动物及其调节方面都有所不同。
