来自上海交通大学医学院免疫学研究所,中科院上海生科院健康科学研究所,瑞金医院内分泌研究所的研究人员发现了一种自身免疫性疾病的重要调控机制,不仅揭示了这种疾病免疫失衡机制和关键调控靶点,也为形成免疫干预治疗的新策略提供了重要的理论基础和实验依据。这一研究成果公布在 The Journal of Immunology 杂志上。
领导这一研究的是张雁云教授,其早年毕业于苏州医学院,曾在日本东京大学医学部进修学习,这项研究由张雁云研究员课题组,博士研究生毛朝明,与上海交通大学医学院附属瑞金医院内分泌研究所王曙、宁光教授等共同合作。
Graves病(毒性弥漫性甲状腺肿,GD)是一种自身免疫性疾病。1835年,Graves首次报告了该病。GD临床主要表现为:弥漫性甲状腺肿伴甲亢症状、浸润性突眼、胫前粘液性水肿。研究发现GD的发病原因主要是在多基因遗传基础上,未确定的外因(如精神刺激)等应激因素而诱发自体免疫反应所致。目前认为GD是由于甲状腺细胞表面受体作为抗原,所产生的抗体与TSH受体结合,使甲状腺细胞持续激发,产生高水平的甲状腺素所致。但是Graves病导致人体免疫失衡的分子机制尚不清楚,临床治疗缺少有效的免疫干预手段。
在这篇文章中,研究人员发现Graves病患者体内重要免疫调节细胞(Treg细胞)数量明显下降,而其树突状细胞(DC)发生极化偏移,DC亚型浆细胞样DC(pDC)比例明显升高。更重要的是,研究发现这种pDC极化偏移引起分泌IFN-alpha增加,导致Treg细胞发生凋亡,提示pDC诱导的Treg细胞凋亡是导致Graves病免疫失衡的重要机制之一。进一步的研究发现,寡核苷酸UDP通过P2Y6受体途径能够抑制pDC的功能,可恢复Treg细胞的免疫抑制活性(图解2)。
此项研究不仅揭示了Graves病免疫失衡机制和关键调控靶点,也为形成免疫干预治疗的新策略提供了重要的理论基础和实验依据。这项研究得到了国家重点基础研究发展规划项目973重大科学计划、中科院知识创新工程重大项目、重大新药创制专项、国家自然科学基金、上海市科委重点项目和上海市教委重点学科基金等的支持。(生物谷Bioon.com)
生物谷推荐原文出处:
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.