浆样树突状细胞通过IFN-α调控Th分化失衡在Graves病致病机制中的作用

Graves' disease (GD), an autoimmunity disease, is charactered by disturbed balance of helper T cells subsets which are regulated by dendritic cells. Our previous study had displayed that the plasmacytoid dendritic cells (pDC) in GD patients were significantly elevated than that in healthy controls. Increased proliferation and differentiation of Th cells induced by GD pDC were also observed. Furthermore, supernatant concentration of interferon-α(IFN-α) in GD-pDC were higher than in controls. It is hypothesis that pDC might affect the disturbed balance of Th cells subsets by IFN-α prodution, and might play a role in the pathogenesis of GD. The studies will be conduct to identify ：1.the percentage of the Th subsets and pDC in controls and in GD patients, before and 6, 12 months after the commencement；and the association between Th subsets, pDC, thyroid functionand（FT3，FT4，TSH）and auto-antibody(TRAb,TPOAb,TGAb)；2. whether the disturbed balance of Th cells subsets induced by GD-pDC can be blockade anti-IFN-α neutralized antibody in vitro，and what is the mechanism；3.whether the incidence of GD or the disturbed balance of Th cells can be ameliorated by neutralization of IFN-α or depletion of pDC in vivo.The results will be helpful to further understand the pathogenosis of GD, and provide new target for GD treatment.

Graves病（GD）是一种自身免疫性疾病，常伴有Th细胞亚群失衡，而T细胞的分化是受体内树突状细胞（DC）调控。我们的前期工作中发现GD患者外周血DC发生了向pDC偏移，且伴有诱导na?ve T细胞增殖和分化能力的异常,IFN-α的分泌增多。为此，我们推测pDC可能通过分泌IFN-α影响T细胞的分化格局在GD致病中起作用。为进一步验证我们的设想，我们拟进行如下研究：①通过观察GD患者外周血pDC亚群比例和Th细胞分化格局，在抗甲状腺药物治疗过程中的动态变化，及与免疫学、临床生化指标的相关性；②体外实验，观察GD-pDC在阻断或未阻断IFN-α的情况下对na?ve T细胞分化的影响及机制；③ 建立GD小鼠模型，利用阻断性抗体等，体内阻断IFN-α合成和作用，观察对Th细胞分化及GD发病的影响。通过上述研究，将有望深入研究GD的发病机制，为GD的免疫调节和靶向治疗奠定新的理论基础。

Graves’病是一种自身免疫性疾病，常伴有Th细胞亚群失衡，而T细胞的分化受体内树突状细胞（DC）调控。本研究中，进行了：（1）观察GD患者外周血pDC和Th细胞分化格局，及其动态变化，结果发现初发GD患者外周血pDC及IFN-a显著性升高，Th1/Th2和Th17/Treg的比值显著性升高，随着药物治疗病情好转，pDC、IFN-a水平和Th1/Th2及Th17/Treg的比值均趋于正常，pDC和Th1及Th17存在显著相关性；pDC和免疫性指标（TRAb、TPOAb、TGAb）存在相关性，IFN-a和 pDC存在正相关。提示GD患者pDC通过分泌IFN-a影响Th1和Th17的优势分化。（2）体外GD患者pDC和naïve T细胞培养，也表现促进增殖抑制凋亡，诱导Th1和Th17的优势分化，该作用被anti-IFN-a 抗体所拮抗，进一步提示GD患者pDC通过IFN-a在诱导Th分化中的作用。GD-pDC能促进Th1（T-bet）和Th17（RORγt）的mRNA表达，抑制Th2（GATA-3）和Treg(FOXP3)mRNA表达，anti-IFN-a 抗体能部分拮抗该作用。总而言之， pDC显著升高，并通过分泌IFN-a影响Th1和Th17的优势分化，促进GD的发生发展。