Monoclonal pathogenic antibodies to the thyroid-stimulating hormone receptor in Graves' disease with potent thyroid-stimulating activity but differential blocking activity activate multiple signaling pathways
Monoclonal pathogenic antibodies to the thyroid-stimulating hormone receptor in Graves' disease with potent thyroid-stimulating activity but differential blocking activity activate multiple signaling pathways
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DOI：
10.4049/jimmunol.176.8.5084
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发表时间：
2006-04-15
影响因子：
4.4
通讯作者：
Banga, J. Paul
中科院分区：
文献类型：
--
作者：
Gilbert, Jacqueline A.;Gianoukakis, Andrew G.;Banga, J. Paul
Graves病中致病自身抗体的甲状腺靶标抗原是促甲状腺激素(TSH)的受体，但对这种致病抗体反应的分子基础知之甚少。我们描述了两种高亲和力单抗的特征，这两种单抗是从甲亢Graves病的实验性小鼠模型发展而来的，表现出强大的甲状腺刺激活性。纳克浓度的Ig G单抗KSAb1和KSAb2及其Fab诱导与TSH配基匹配的TSH受体的完全刺激，从而作为该受体的完全激动剂。然而，KSAb1和KSAb2在阻断TSH介导的受体刺激的能力上表现出不同的活性，这表明它们的生物学特性存在细微的差异。在置换研究中，KSAb1和KSAb2的IgG和Fabs与Graves病自身抗体以及一些甲状腺功能减退患者中存在的甲状腺阻断抗体竞争，表明这些受体上的自身免疫决定因素之间存在密切关系。在被动转移研究中，单次注射微克量的KSAb1或KSAb2免疫球蛋白导致血清甲状腺激素迅速升高，并持续数天的甲亢状态。甲状腺有细胞坏死的迹象，但没有伴发的单个核细胞浸润。在研究其受体激活途径时，KSAb1和KSAb2均可引起原代甲状腺细胞内ERK1/2通路的磷酸化，提示多条信号通路可能参与了Graves病的发病机制。总之，我们的发现强调了实验小鼠模型在复制人类疾病方面的相似性，并为表征这种致病反应的分子基础提供了改进的手段。
The thyroid target Ag for disease-inducing autoantibodies in Graves' disease is the receptor for thyroid-stimulating hormone (TSH), but little is known about the molecular basis of this pathogenic Ab response. We describe the characteristics of two high-affinity mAbs developed from an experimental murine model of hyperthyroid Graves' disease that exhibit potent thyroid-stimulating activity. Nanogram concentrations of the IgG mAbs KSAb1 and KSAb2 and their Fab induce full stimulation of the TSH receptor that is matched by the ligand TSH and, thus, act as full agonists for the receptor. However, KSAb1 and KSAb2 display differential activities in their ability to block TSH-mediated stimulation of the receptor, indicating subtle differences in their biological properties. In displacement studies, IgG and Fabs of KSAb1 and KSAb2 compete with Graves' disease autoantibodies as well as thyroid-blocking Abs present in some hypothyroid patients, indicating a close relationship between these autoimmune determinants on the receptor. In passive transfer studies, single injections of microgram quantities of KSAb1 or KSAb2 IgG led to rapid elevation of serum thyroxine and a hyperthyroid state that was maintained for a number of days. The thyroid glands showed evidence of cell necrosis, but there was no accompanying mononuclear cell infiltrate. In studying their receptor activation pathways, both KSAb1 and KSAb2 provoked phosphorylation of the intracellular ERK1/2 pathway in primary thyrocytes, indicating that multiple signaling pathways may participate in the pathogenesis of Graves' disease. In summary, our findings emphasize the similarities of the experimental mouse model in reproducing the human disorder and provide improved means for characterizing the molecular basis of this pathogenic response.