the expression and function of the neonatal Fc receptor in thyrocytes of Hashimoto's thyroiditis
首发时间:2017-05-05
Abstract:Objective: Thyroglobulin (Tg) and thyroid peroxidase (TPO) antibodies (TgAb and TPOAb),which are primarily of the immunoglobulin G (IgG) class, can mediate antibody-dependent cell-mediated cytotoxicity in vitro. However, it is unclear whether any thyrocyte molecules can facilitate the transport and elimination of TgAb and TPOAb. The IgG transport receptor neonatal Fc receptor (FcRn) is a candidate mediator of these processes. In this study, we aimed to evaluate FcRn expression and function in normal and Hashimoto's thyroiditis (HT) thyrocytes. Methods: FcRn expression in primary thyrocyte cultures (four normal and four HT groups) was examined by polymerase chain reaction (PCR) and Western blotting. Localization of FcRn was demonstrated by immunoelectron microscopy. A double immunofluorescence staining method was adopted to detect FcRn and internalized human TgAb IgG. Stimulation experiments were performed to assess the regulation of FcRn expression by T helper cell 1 (Th1) (IFN-γ and TNF-α) and Th2 cytokines (IL-10 and IL-4). Results: FcRn expression was lower in HT thyrocytes than in normal thyrocytes. FcRn was located in the cytoplasm, membranes, mitochondria and transport vesicles of thyrocytes. Both human IgG and TgAb IgGwere internalized by thyrocytes in a pH-dependent manner and co-localized with FcRn in thyrocytes. FcRn expression was downregulated by Th1 and Th2 cytokines in both normal and HT thyrocytes in a dose-dependent manner. Conclusions: Our results suggest that FcRn may be associated with the transport and metabolism of IgG in thyrocytes and that transport is independent of IgG type. FcRn may be involved in HT pathogenesis
keywords: Neonatal Fc receptor, Hashimoto's thyroiditis, Th1/Th2 cytokines, TgAb, IgG
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桥本甲状腺炎甲状腺细胞中新生儿Fc受体的表达与功能
摘要:目的:甲状腺球蛋白抗体(anti-thyroglobulin antibody, TgAb)和甲状腺过氧化物酶抗体(anti-thyroid peroxidase antibody, TPOAb)是桥本甲状腺炎(Hashimoto's thyroiditis, HT)的标志性抗体,二者均以免疫球蛋白G(Immunoglobulin G, IgG)型为主。体外研究已证实,IgG型TgAb和TPOAb可通过抗体依赖的细胞介导的细胞毒作用损伤甲状腺滤泡细胞。甲状腺球蛋白(thyroglobulin, Tg)储存于滤泡腔内,甲状腺过氧化物酶(thyroid peroxidase, TPO)亦表达于甲状腺细胞顶面。因此甲状腺滤泡的组织结构决定了Tg和TPO难以与循环中相应的抗体结合而发生免疫反应。新生儿Fc受体(the neonatal Fc receptor, FcRn)是IgG Fc受体的一种,可转运IgG。因此我们推测FcRn可能通过介导IgG型TgAb和TPOAb的转运而参与HT的发病机制。本研究 拟探讨在正常和HT甲状腺细胞中FcRn的表达、位置以及影响其表达的因素。 方法:分别收集手术切除的病理为正常和HT的甲状腺组织各4例,进行体外细胞培养。采用逆转录聚合酶链反应(Reverse Transcription Polymerase Chain Reaction, RT-PCR)和蛋白免疫印迹(Western Blot, WB)法测定正常和HT细胞FcRn的表达。应用免疫电镜胶体金法定位FcRn在甲状腺细胞内的位置,采用免疫荧光法检测甲状腺细胞内吞的IgG型TgAb(TgAb IgG)及FcRn的表达位置。应用不同浓度的Th1和Th2细胞因子(IFN-γ、TNF-α和IL-10、IL-4)分别刺激甲状腺细胞以观察细胞因子对FcRn表达的调节。 结果:甲状腺组织表达FcRn。FcRn主要分布于甲状腺细胞的细胞质、细胞膜、线粒体和囊泡内。人总IgG和IgG型TgAb均可以pH依赖的方式被内吞入甲状腺细胞,并与甲状腺细胞内FcRn存在共定位。FcRn在HT甲状腺组织中的表达水平低于正常甲状腺细胞。Th1和Th2细胞因子呈剂量依赖性下调正常甲状腺细胞和HT甲状腺细胞FcRn的表达。 结论:FcRn可介导甲状腺细胞内IgG型TgAb的转运和代谢,并且FcRn的转运功能和IgG种类无关。FcRn可能通过介导IgG的转运参与了HT的发病机制。?????
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