【作者】 赵宇；

【导师】 关海霞；

【作者基本信息】 中国医科大学 ， 内分泌与代谢病学， 2018， 硕士

【摘要】 目的:桥本甲状腺炎(HT)是一种器官特异性自身免疫疾病,是甲减的常见原因。TAM受体信号通路的缺乏可以造成人类慢性炎症和自身免疫性疾病。在成人组织中,TAM受体信号通路对于吞噬和清除凋亡细胞至关重要,还对天然免疫反应起到反馈抑制作用,与多种自身免疫疾病有着密切联系,如系统性红斑狼疮、炎症性肠病、类风湿关节炎、干燥综合征及多发性硬化症等。然而其在HT中的作用仍不为人知,本研究旨在揭示TAM受体信号通路在HT发病中的作用。研究方法:1、纳入HT患者和年龄性别相匹配的对照各40例,收集他们的甲状腺组织,分别通过实时荧光定量PCR、western blot、免疫荧光检测TAM受体及配体在甲状腺组织中的m RNA表达、蛋白表达及定位。2、纳入90例HT患者及30例对照,HT患者被分为了三组:临床甲状腺功能减退组(OH)、亚临床甲状腺功能减退组(SCH)及单纯高抗体组(Isolated Ab),收集他们的血清,通过ELISA法测定s Tyro3,s Axl,s Mer TK,Gas6和Pro S的血清水平,评估它们的表达与一些临床指标的关系。3、纳入15例HT患者及18例对照,收集PBMC,流式细胞术检测TAM受体及配体在T淋巴细胞、B淋巴细胞及单核细胞上的表达。结果:1、在HT患者的甲状腺组织中,Gas6的m RNA表达水平较对照组相比明显减低,差异具有统计学意义(P<0.01),Tyro3、Axl、Mer TK及Pro S的m RNA表达水平较对照组相比无显著差异(P>0.05)。Gas6的蛋白表达水平较对照组相比明显减低,差异具有统计学意义(P<0.05),Mer TK和Pro S的蛋白表达水平较对照组相比无显著差异(P>0.05)。Gas6表达在HT患者非淋巴细胞浸润区的甲状腺滤泡上。2、在HT患者中,s Mer TK的血清水平明显升高,特别是在OH组和SCH组,且其血清水平与TPOAb和TSH水平呈正相关。此外,在HT患者中,Pro S血清水平明显降低,且与TPOAb呈负相关。5、TAM受体及配体在T淋巴细胞上的表达量较低,在HT患者中,Tyro3、Axl、Pro S在T淋巴细胞上的表达量较对照组相比降低,差异有统计学意义(P<0.05)。TAM受体及配体在B淋巴细胞及单核细胞上的表达量较对照组相比无统计学差异(P>0.05)。结论:在HT患者的甲状腺组织中,Gas6的m RNA及蛋白表达水平均降低。在HT患者的血清中,s Mer TK的表达水平升高而Pro S的表达水平降低。TAM受体信号通路可能在HT发病中起到一定作用。更多还原

【Abstract】 Objective:Hashimoto thyroiditis(HT)is an organ-specific autoimmune disease which can cause hypothyroidism.The lack of TAM receptor signaling pathway can lead to chronic inflammation and autoimmune diseases in humans.In adult tissues,the TAM signaling pathway is crucial for the phagocytosis and clearance of apoptotic cells.It also plays a role in feedback inhibition of innate immune responses.It has a close connection with a lot of autoimmune diseases,such as systemic lupus erythematosus,inflammatory bowel disease,rheumatoid arthritis,Sjogren’s syndrome and multiple sclerosis.However,the role of TAM receptor signaling in HT remains unknown.This study aimed to reveal the role of TAM receptor signaling pathway in the pathogenesis of HT.Methods:1.In this study,40 cases of thyroid tissues from HT patients and age-and sex-matched controls were collected respectively.The m RNA,protein expression and location of TAM signaling in thyroid tissue were detected by real-time fluorescent quantitative PCR,western blot and immunofluorescence.2.We included 90 HT patients and 30 controls.HT patients were divided into three groups which were overt hypothyroidism group,subclinical hypothyroidism group and isolated thyroid specific autoantibodies group.Serum levels of s Tyro3,s Axl,s Mer TK,Gas6 and Pro S were measured by ELISA and the correlation between their expressions and some clinical features were assessed.3.We included 15 HT patients and 18 controls.PBMC were collected and the expressions of TAM receptors and ligands on T lymphocytes,B lymphocytes and monocytes were detected by flow cytometry.Results:1.In the thyroid tissues of HT patients,the m RNA expressions of Gas6 were significantly lower than those of the control group which has statisitical significance(P<0.01),and the m RNA expressions of Tyro3,Axl,Mer TK and Pro S had no significant differences from the control group(P> 0.05).The protein expressions of Gas6 were significantly lower than the control group with statisitical significance(P <0.05).The protein expressions of Mer TK and Pro S were not significantly different from those of the control group(P>0.05).Gas6 located in thyroid follicles of non-lymphocyte infiltrated area in patients with HT.2.Serum levels of s Mer TK in patients with HT were significantly elevated,especially in the overt hypothyroidism and subclinical hypothyroidism groups,and the serum levels of s Mer TK were positively correlated with TPOAb and TSH levels.In addition,serum levels of Pro S in HT patients were significantly lower and negatively correlated with TPOAb.3.The expressions of TAM receptors and ligands on T lymphocytes were low,and in HT patients,the expressions of Tyro3,Axl and Pro S on T lymphocytes were lower than those in the control group which has statisitical significance(P <0.05).The expressions of TAM receptors and ligands on B lymphocytes and monocytes were not significantly different in comparision to control group(P> 0.05).Conclution:The m RNA and protein expressions of Gas6 are reduced in thyroid tissues of HT patients,and we can find increased serum levels of s Mer TK and decreased levels of Pro S.TAM receptor signaling pathway may play a role in the pathogenesis of HT.更多还原