來自上海交通大學醫(yī)學院免疫學研究所，中科院上海生科院健康科學研究所,，瑞金醫(yī)院內(nèi)分泌研究所的研究人員發(fā)現(xiàn)了一種自身免疫性疾病的重要調(diào)控機制,，不僅揭示了這種疾病免疫失衡機制和關(guān)鍵調(diào)控靶點，也為形成免疫干預(yù)治療的新策略提供了重要的理論基礎(chǔ)和實驗依據(jù),。這一研究成果公布在 The Journal of Immunology 雜志上,。
領(lǐng)導這一研究的是張雁云教授，其早年畢業(yè)于蘇州醫(yī)學院,，曾在日本東京大學醫(yī)學部進修學習,，這項研究由張雁云研究員課題組，博士研究生毛朝明,，與上海交通大學醫(yī)學院附屬瑞金醫(yī)院內(nèi)分泌研究所王曙,、寧光教授等共同合作。
Graves病(毒性彌漫性甲狀腺腫,，GD)是一種自身免疫性疾病,。1835年，Graves首次報告了該病,。GD臨床主要表現(xiàn)為：彌漫性甲狀腺腫伴甲亢癥狀,、浸潤性突眼、脛前粘液性水腫,。研究發(fā)現(xiàn)GD的發(fā)病原因主要是在多基因遺傳基礎(chǔ)上,，未確定的外因(如精神刺激)等應(yīng)激因素而誘發(fā)自體免疫反應(yīng)所致。目前認為GD是由于甲狀腺細胞表面受體作為抗原,，所產(chǎn)生的抗體與TSH受體結(jié)合,，使甲狀腺細胞持續(xù)激發(fā)，產(chǎn)生高水平的甲狀腺素所致,。但是Graves病導致人體免疫失衡的分子機制尚不清楚,，臨床治療缺少有效的免疫干預(yù)手段。
在這篇文章中,，研究人員發(fā)現(xiàn)Graves病患者體內(nèi)重要免疫調(diào)節(jié)細胞(Treg細胞)數(shù)量明顯下降,，而其樹突狀細胞(DC)發(fā)生極化偏移,，DC亞型漿細胞樣DC(pDC)比例明顯升高,。更重要的是,，研究發(fā)現(xiàn)這種pDC極化偏移引起分泌IFN-alpha增加，導致Treg細胞發(fā)生凋亡,，提示pDC誘導的Treg細胞凋亡是導致Graves病免疫失衡的重要機制之一,。進一步的研究發(fā)現(xiàn)，寡核苷酸UDP通過P2Y6受體途徑能夠抑制pDC的功能,，可恢復(fù)Treg細胞的免疫抑制活性(圖解2),。
此項研究不僅揭示了Graves病免疫失衡機制和關(guān)鍵調(diào)控靶點,，也為形成免疫干預(yù)治療的新策略提供了重要的理論基礎(chǔ)和實驗依據(jù),。這項研究得到了國家重點基礎(chǔ)研究發(fā)展規(guī)劃項目973重大科學計劃、中科院知識創(chuàng)新工程重大項目,、重大新藥創(chuàng)制專項,、國家自然科學基金,、上海市科委重點項目和上海市教委重點學科基金等的支持。（生物谷Bioon.com）
生物谷推薦原文出處：
The Journal of Immunology March 11, 2011 doi: 10.4049/jimmunol.0904135
Impairment of Regulatory Capacity of CD4+CD25+ Regulatory T Cells Mediated by Dendritic Cell Polarization and Hyperthyroidism in Graves’ Disease
Chaoming Mao* ,1, Shu Wang§,1, Yichuan Xiao* , Jingwei Xu* , Qian Jiang?, Min Jin*?, Xiaohua Jiang§?, Hua Guo§?, Guang Ning§? and Yanyun Zhang*
Graves’ disease (GD) is one of the most common autoimmune diseases. The immune dysfunction in GD involves the generation of thyroid-stimulating hormone receptor (TSHR) autoantibodies that presumably arise consequent to interactions among dendritic cells (DCs), T cells, and regulatory T (Treg) cells. However, the immunological mechanisms of interactions between them that lead to the induction and regulation of this autoimmune disease are poorly defined. In this study, we investigated whether DCs are the main cause of the defective activity of Treg cells in GD patients. We found a significant decrease in the percentage of circulating CD4+CD25+FOXP3+ Treg cells in untreated GD patients (uGD), which was negatively correlated with the concentration of TSHR autoantibodies. uGD-derived DCs were polarized to increase the number of plasmacytoid DCs (pDCs) and conferred the ability to abrogate the suppressive function of Treg cells through inducing apoptosis of CD4+CD25+ Treg cells in an IFN-α–dependent manner, and elevated thyroid hormones further exacerbated the effect. The nucleotide UDP, which inhibits IFN-α secretion of pDCs through P2Y6 receptor signaling, restored the suppressive function of CD4+CD25+ Treg cells. Collectively, uGD-derived DCs through pDC polarization and elevated thyroid hormones act in concert to impair the regulatory capacity of Treg cells, facilitating the production of TSHR autoantibodies in the pathogenesis of GD.
