葛瑞夫茲氏症 (Graves’ disease, GD) 是一種特定器官的自體免疫疾病，病癥包括甲狀腺過度釋放甲狀腺素以及甲狀腺的腫大。一般而言，葛瑞夫茲氏症的致病機制過去認知主要經由血液循環中的促甲狀腺刺激素受體自體抗體所造成。近來的研究發現葛瑞夫茲氏症病患血清中類胰島素生長因子1受體自體抗體可導致細胞激素包括介白素16及化學趨化激素RANTES的生成。然而，其病理機制以及臨床上的研究證據仍不清楚。除了免疫致病機制外，遺傳性因子及代謝性因子也參與其中。本研究中我們收集葛瑞夫茲氏症及甲狀腺乳突瘤病患甲狀腺組織及健康者血清，測試促發炎性細胞激素及自體抗體的生成以探討其參與葛瑞夫茲氏症致病機制的角色。研究的特定目標一為測量是否有異常的自體抗體結合至甲狀腺組織。免疫組織染色法結果顯示在葛瑞夫茲氏症病患甲狀腺組織相較於甲狀腺乳突瘤病患的正常甲狀腺組織部位有較多的自體抗體結合。特定目標二係針對類胰島素生長因子1受體表現量以及病患生成纖維母細胞自體抗體及類胰島素生長因子1受體自體抗體的研究。經由免疫組織染色法、流式細胞儀及ELISA測得類胰島素生長因子1受體表現量以及纖維母細胞自體抗體及類胰島素生長因子1受體自體抗體，結果顯示在葛瑞夫茲氏症病患有較高的表現量。特定目標三探討異常促發炎細胞素的生成。藉由ELISA的測定結果顯示介白素16在葛瑞夫茲氏症病患的血清有顯著較多的表現，而介白素6及腫瘤壞死因子並無此現象。然而，介白素16的表現與自體抗體的表現並無正向的關連性。綜合以上的結果顯示在葛瑞夫茲氏症病患血清中不僅是有促甲狀腺刺激素受體自體抗體的生成，我們的結果證實血清中亦出現纖維母細胞以及類胰島素生長因子1受體自體抗體並且有異常增加的介白素16表現，這些因子都可能參與在葛瑞夫茲氏症的制病機轉。然而，類胰島素生長因子1受體自體抗體與遺傳性因子可能共同導致介白素16過度的表現。

Graves' disease (GD) is an organ-specific autoimmune disease, which characterized by excessive production of thyroid hormone by the thyroid gland and by its diffuse enlargement. In general, GD is caused by circulating autoantibodies (autoAbs) directed against the thyroid-stimulating hormone (TSH) receptor. Current findings show that autoAbs against insulin-like growth factor-1 receptor (IGF-1R) are able to cause cytokine production, including IL-16 and RANTES. However, the mechanisms and clinical implications are still unclear. In addition to the involvement of immunopathogenesis, genetic and metabolic effects are also involved. In this project, we recruited patients with GD and healthy subjects, and measured the levels of inflammatory cytokines and autoAbs that might be involved in the pathogenesis of GD. Specific Aim 1 of this study is to determine the abnormal expression of autoAbs against thyroid tissues. Immunohistochemistry demonstrated that the generation of autoAbs against thyroid tissue antigens was higher in GD patients than in non-GD groups, including papillary thyroid carcinoma patients and healthy volunteers. Specific Aim 2 is to examine the expression of IGF-1R and autoAbs against fibroblasts and IGF-1R. Immunohistochemistry, flow cytometry analysis, and ELISA demonstrated that high levels of IGF-1R and autoAbs against fibroblasts and IGF-1R were detected in GD patients. However, there are no correlations between these two autoAbs. Specific Aim 3 is to study the deregulated production of pro-inflammatory cytokines. We provide evidence obtained from ELISA that the serum levels of IL-16, but not TNF-α and IL-6, were increased in GD. However, there are no association between cytokine levels and the generation of autoAbs. Taken together, these results show that the generation of autoAbs against not only TSHR but also fibroblasts and IGF-1R and the deregulated IL-16 are present in GD pathogenesis. The mechanisms for IGF-1R autoAb-induced IL-16 and other genetic factors involved in the dysregulated IL-16 expression are currently being investigated.

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