王圣元,肖枫林,李航,张禹
WANG Shengyuan,XIAO Fenglin,LI Hang,ZHANG Yu

• 1:中国人民解放军海军总医院高压氧科
• 2:中国人民解放军海军总医院肾脏病科

摘要(Abstract)：

目的:观察重症肌无力(MG)患者免疫治疗前后自身免疫性调节因子(AIRE)及Tfr/Tfh比值变化,分析其与MG严重程度的相关性。方法:收集16例全身型MG(GMG)患者、14例眼肌型MG(OMG)患者、10例健康体检者(对照组)的外周血标本,并收集10例接受免疫抑制治疗1个月并获得随访的GMG患者(治疗组)外周血标本;采用流式细胞术检测AIRE阳性细胞、Tfr细胞及Tfh细胞数量,计算Tfr/Tfh比值;观察治疗组治疗前后AIRE及Tfr/Tfh比值变化,分析AIRE阳性表达率、Tfr/Tfh比值与MG严重程度的相关性。结果:治疗组GMG患者治疗后AIRE阳性表达率及Tfr/Tfh比值较治疗前均有显著提高(P<0.01),治疗组AIRE阳性表达率与OMG组及对照组比较差异均无统计学意义(P=0.164,P=0.862);治疗组Tfr/Tfh比值低于对照组(P<0.001),而与OMG组比较差异无统计学意义(P=0.685);GMG患者AIRE阳性表达率及Tfr/Tfh比值与MG定量评分(QMG)评分及临床绝对评分均呈负相关(P<0.05)。结论:AIRE阳性表达率及Tfr/Tfh比值与MG严重程度呈负相关,免疫治疗可提高AIRE及Tfr/Tfh比值。
Objective: To analyse the ratio changes of AIRE and Tfr/Tfh in patients with myasthenia gravis( MG) before and after immunotherapy. Methods: Peripheral blood samples of 16 cases with generalised MG( GMG group),14 cases with ocular MG( OMG group) and 10 cases as the control group from Jan. 2016 to Jan. 2017 were collected from Tangdu Hospital of Airforce Military Medical University,China. 10 cases wth GMG as the experiment group were followed up after immunotherapy.The expression of autoimmune regulator( AIRE),Tfr cell and Tfh cells were measured by flow cytometry. Results: The AIRE expression and Tfr/Tfh ratio of 10 GMG patients were significantly improved after treatment( P = 0. 01,P = 0. 009). The expression of AIRE in the treatment group was higher than that in GMG group( P < 0. 001),while the difference between OMG group and the control group were not statistically significant( P = 0. 164,P = 0. 862). The Tfr/Tfh ratio in the treatment group was higher than that of GMG group( P < 0. 01),lower than that of the control group( P < 0. 001),but with no significant difference from OMG group( P = 0. 685). The expression of AIRE and Tfr/Tfh ratio were negatively correlated with the quantitative MG( QMG) score and clinical absolute score in all GMG group( P < 0. 001,P < 0. 001,P < 0. 05,P = 0. 002). Conclusion: The AIRE and Tfr/Tfh ratio increased in different degrees after immunotherapy,and there might be an interactive mechanism between AIRE and Tfr,Tfh cells.

关键词(KeyWords)： 重症肌无力;自身免疫性调节因子;T淋巴细胞亚群;免疫治疗
myasthenia gravis;autoimmune regulator;T lymphocyte subsets;immunotherapy

Abstract:

Keywords:

基金项目(Foundation): 国家自然青年科学基金项目(81500669)

作者(Author): 王圣元,肖枫林,李航,张禹
WANG Shengyuan,XIAO Fenglin,LI Hang,ZHANG Yu

DOI: 10.19367/j.cnki.1000-2707.2018.08.014

参考文献(References)：

• [1]RICHARDS J,HOWARD J F.Seronegative myasthenia gravis associated with malignant thymoma[J].Neuromuscul Disord,2017,27(5):417-418.
• [2]KUSHAGRA B,HIDEYUKI Y,CHRISTOPHE B,et al.The transcriptional regulator Aire binds to and activates super-enhancers[J].Nature Immunology,2017,18(3):263-273.
• [3]闫斌,朱明振,李卫君,等.自身免疫调节因子在重症肌无力患者胸腺内的表达及作用分析[J].中风与神经疾病杂志,2017,34(10):913-915.
• [4]ANNE K,BASTIAN G,DAVID N,et al.Generation of T follicular helper cells in vitro:requirement for B-cell receptor cross-linking and cognate B-and T-cell interaction[J].Immunology,2018,153(2):214-224.
• [5]YANG G,YANG X S,ZHANG J M,et al.Transcriptional repressor Blimp1 regulates follicular regulatory T-cell homeostasis and function[J].Immunology,2018,153(1):105-117.
• [6]王圣元,张慜,李柱一,等.重症肌无力患者外周血AIRE、Tfh细胞和Tfr细胞与病情严重性相关分析[J].中国神经免疫学和神经病学杂志,2017,24(3):170-173.
• [7]汪杰,李宏增,李川,等.重症肌无力患者的免疫指标与临床疗效分析[J].现代生物医学进展,2016,16(31):6162-6191.
• [8]YI J S,DECROOS E C,SANDERS D B,et al.Prolonged B-cell depletion in Mu SK myasthenia gravis following rituximab treatment.[J].Muscle Nerve,2013,48(6):992-993.
• [9]PEZZI N,ASSIS A F,COTRIM-SOUSA L C,et al.Aire knockdown in medullary thymic epithelial cells affects Aire protein,deregulates cell adhesion genes and decreases thymocyte interaction[J].Molecular Immunol,2016,77:157-173.
• [10]ANDREW S K,ERIK L M,GERALD R C,et al.Rapid chromatin repression by Aire provides precise control of immune tolerance[J].Nature Immunology,2018,19(2):162-172.
• [11]PERNIOLA R.MUSCO G.The biophysical and biochemical properties of the autoimmune regulator(AIRE)protein[J].Biochimicaet Biophysica Acta:Molecular Basis of Disease,2014,1842(2):326-337.
• [12]金伯泉.T-B细胞协作研究的重大突破——滤泡辅助性T细胞的发现,一个新的CD4+效应T细胞亚群[J].细胞与分子免疫学杂志,2009,25(1):1-5.
• [13]ZHU Y,ZOU L,LIU Y.T follicular helper cells,T follicular regulatory cells and autoimmunity[J].International Immunology,2016,28(4):173-179.
• [14]DEENICK E K,MA C S,BRINK R,et al.Regulation of T follicular helper cell formation and function by antigen presenting cells[J].Curr Opin Immunol,2011,23(1):111-118.
• [15]SAGE P T T,SHARPE A H.T follicular regulatory cells[J].Immunol Rev,2016,271(1):246-259.
• [16]MALCHOW S,LEVENTHAL D S,LEE V,et al.Aire enforces immune tolerance by directing autoreactive T cells into the regulatory T cell lineage[J].Immunity,2016,44(5):1102-1113.
• [17]YONATAN H,SHIR N,CHAMUTAL B,et al.Transcriptional programs that control expression of the autoimmune regulator gene Aire[J].Nature Immunology,2017,18(2):161-172.

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