甲状腺相关性眼病新进展最终课件

,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Changzheng Hospital,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Changzheng Hospital,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Changzheng Hospital,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Changzheng Hospital,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Changzheng Hospital,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Changzheng Hospital,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Changzheng Hospital,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Changzheng Hospital,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Changzheng Hospital,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Changzheng Hospital,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Changzheng Hospital,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Changzheng Hospital,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,甲状腺相关性眼病临床与基础研究,上海长征医院 石勇铨,甲状腺相关性眼病临床与基础研究上海长征医院 石勇铨,内容提要,临床表现与分级评分,2,病理改变与发病机制,1,实验室与影像学检查,3,治疗方法与疗效转归,4,内容提要临床表现与分级评分2病理改变与发病机制1实验室与影像,一种器官特异性自身免疫性疾病,发病率较高，约占眼眶病的,20,近年来在我国有增高趋势,甲状腺相关性眼病,(TAO),一种器官特异性自身免疫性疾病甲状腺相关性眼病(TAO),TAO,病理改变,眼外肌,眶脂肪,TAO病理改变眼外肌眶脂肪,单个核细胞,、,CDR-阳性淋巴细胞浸润,CD45RO阳性的T细胞和巨噬细胞在,浸润,TAO,眼眶组织免疫组化,单个核细胞、CDR-阳性淋巴细胞浸润CD45RO阳性的T细胞,TAO,眼眶组织免疫组化,anti-IFNy-antibody;(B)anti-TNFa-antibody;,(C)anti-11-la-antibody;(D)isotype control IgG-antibody,TAO眼眶组织免疫组化anti-IFNy-antibody;,TAO,发病机制,细胞免疫为主：,TSHR,、,CD40,等激活,T,淋巴细胞,体液免疫参与：,TSHR,、,Tg,、,IGF-1,、,G2S,蛋白、黄素蛋白,Fp,等抗原刺激,B,细胞产生抗体；,其他致病因子：如,C/EBP,及,PPAR,途径等，正向调控脂肪细胞分化增殖；,危险因素：遗传因素、年龄、吸烟等，吸烟者,TAO,发病率增加,1.3,倍，突眼增加,2.6,倍，复视增加,3.1,倍，疗效显著降低,TAO发病机制细胞免疫为主：TSHR、CD40等激活T淋巴细,体液免疫途径,体液免疫途径,细胞免疫途径,Cawood TJ.J Clin Endocrinol Metab 2007;92:59.,Eckstein AK.J Clin Endocrinol Metab 2006;91:3464.,眼眶后组织,高,表达,TSHR,T,淋巴细胞,细胞因子,成纤维细胞,脂肪细胞,识别,浸润眼眶,球后软组织炎症,糖胺聚糖,球后眼外肌水肿,球后脂肪浸润,分泌,释放,刺激,转化,TAO,？,？,细胞免疫途径Cawood TJ.J Clin Endocr,甲状腺相关性眼病眼眶成纤维细胞,microRNA,调控促甲状腺激素受体表达的机制研究,上海市科委基础重点项目（,08JC1407400,）,甲状腺相关性眼病眼眶成纤维细胞microRNA调控促甲状腺激,TAO,患者眼眶成纤维细胞,TSHR,表达升高,0.0,.1,.2,.3,.4,TAO,患者,正常对照者,TSHR,表达水平,标准系数,t值,P值,CAS,评分,0.459,3.258,0.035*,TSHR,表达水平与,CAS,评分正相关,TAO患者眼眶成纤维细胞TSHR表达升高0.0.1.2.3.,结果,qRT-PCR,检测两组差异结果,miRNA,芯片筛查,眼眶成纤维细胞,Am ID,AliGnmenT,眼眶成纤维细胞,Am ID,AliGnmenT,hsA-miR-519e,UUGUGAGAUUUUCC-UCCGUGAA,hsA-miR-626,UUCUGU-AAAAGUCUGUCGA,hsA-miR-518A-5p,CUUUCCCGAAG-GGAAACGUC,hsA-miR-567,CAAGACAGG-ACCUUCUUGUAUGA,mmU-miR-878-5p,ACAGAACUGUAGGUUGAUCUAU,mmU-miR-717,UCUCUUCCAUAGAGACAGACUC,hsA-miR-143,CUCAACCUAUUAAUCAUCUCU,hsA-miR-592,UGUAGUAGCGUAU-AACUGUGUU,hsA-miR-22*,AUUUCGAACGGUGACUUCUUGA,mmU-miR-669b,UGUACGUGUACGUGUGUUUUGA,hsA-miR-302d,UGUGAGUUUGUACCUUCGUGAAU,hsA-miR-376A*,AUGAGUAUCUUCC-UCUUAGAUG,mmU-miR-669C,UGUGUGUAGGUGUGUGUUGAUA,hsA-miR-33A*,CACUACGUGACACCUUUGUAAC,hsA-miR-374b*,UUACUAUUAUGUUGGACGAUUC,hsA-miR-371-5p,UCACGGGGGUGUCAAACUCA,hsA-miR-143,CUCAACCUAUUAAUCAUCUCU,预测以,TSHR,为靶基因的,miRNAs,第,42,位,结果qRT-PCR检测两组差异结果miRNA芯片筛查眼眶成纤,启动子,信号通路,STAT3,IL2/IL6-STAT3-miR-143-|TSHR,NFKB,IL1/TNF-alpha-IL1R-NFKB-miR-143-|TSHR,Myc,TGF-beta-SMAD2/3-E2F4/5-|,Myc-miR-143-|TSHR,Sp1,TGF-beta-SMAD2/3-p300/Sp1-miR-143-|TSHR,PREB1,EGF/VEGF/FGF/HGF/IGF-RAS-PREB1-|miR-143-|TSHR,注：,-,促进，,-|,抑制。,生物信息学分析,国家自然基金面上项目（,81170728,）,miR-143,靶向调控,TSHR,基因促进甲状腺相关性眼病发病的机制研究,启动子信号通路STAT3IL2/IL6-STAT3-mi,内容提要,临床表现与分级评分,2,病理改变与发病机制,1,诊断标准与辅助检查,3,治疗方法与疗效转归,4,内容提要临床表现与分级评分2病理改变与发病机制1诊断标准与辅,根据甲状腺功能临床分型,功能正常型,功能亢进型,95%,功能低下型,TAO,临床分型,根据甲状腺功能临床分型TAO临床分型,广泛累及眼眶软组织（眼外肌、脂肪、泪腺）,表现为突眼、眼睑退缩、球结膜水肿，眶周水肿和眼球运动障碍等,严重时会导致暴露性角膜炎、复视、及视神经受压等,居致盲性眼眶疾病之首,TAO,临床表现,广泛累及眼眶软组织（眼外肌、脂肪、泪腺）TAO临床表现,由于,TAO,严重程度不同，与其治疗密切相关，常用,TAO,的严重程度及活动度来评价病情：,眼病分级标准，即,NO SPECS,标准,眼部病变的临床活动性评分，即,CAS,评分,复视的主观评分标准,由于TAO严重程度不同，与其治疗密切相关，常用,Nospecs 分级标准,相当于,TES积分,0级,无症状和体征,0,1级,只有症状,+眼睑退缩、回落,1,2级（软组织受累）,Grade 0 无,0,Grade a 微小,2,Grade b中等,4,Grade c显著,6,3级,(突眼度),Grade 0-,9,4级(眼外肌受累),Grade 0 无,0,Grade a 运动略有影响,4,Grade b 运动明显受限,8,Grade c 眼球运动障碍,12,5级(角膜受累),Grade 0 无,0,Grade a 角膜点彩,5,Grade b 角膜溃疡,10,Grade c 角膜云翳/坏死/穿孔,15,6级,(视力丧失),Grade 0 20/30,0,Grade a 20/30-20/60,6,Grade b 20/60-20/200,12,Grade c 20/200,18,TAO,严重程度评分,Nospecs 分级标准相当于TES积分0级无症