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自身免疫性疾病患者T淋巴细胞线粒体损伤定量分析及其临床价值探讨

吴子燕 奉福泰 李昊隆 徐洪琳 张蜀澜 李永哲

吴子燕, 奉福泰, 李昊隆, 徐洪琳, 张蜀澜, 李永哲. 自身免疫性疾病患者T淋巴细胞线粒体损伤定量分析及其临床价值探讨[J]. 协和医学杂志, 2023, 14(5): 991-998. doi: 10.12290/xhyxzz.2023-0256
引用本文: 吴子燕, 奉福泰, 李昊隆, 徐洪琳, 张蜀澜, 李永哲. 自身免疫性疾病患者T淋巴细胞线粒体损伤定量分析及其临床价值探讨[J]. 协和医学杂志, 2023, 14(5): 991-998. doi: 10.12290/xhyxzz.2023-0256
WU Ziyan, FENG Futai, LI Haolong, XU Honglin, ZHANG Shulan, LI Yongzhe. Quantitative Analysis of Mitochondrial Damage in T Lymphocytes from Patients with Autoimmune Diseases and Evaluation of Its Clinical Value[J]. Medical Journal of Peking Union Medical College Hospital, 2023, 14(5): 991-998. doi: 10.12290/xhyxzz.2023-0256
Citation: WU Ziyan, FENG Futai, LI Haolong, XU Honglin, ZHANG Shulan, LI Yongzhe. Quantitative Analysis of Mitochondrial Damage in T Lymphocytes from Patients with Autoimmune Diseases and Evaluation of Its Clinical Value[J]. Medical Journal of Peking Union Medical College Hospital, 2023, 14(5): 991-998. doi: 10.12290/xhyxzz.2023-0256

自身免疫性疾病患者T淋巴细胞线粒体损伤定量分析及其临床价值探讨

doi: 10.12290/xhyxzz.2023-0256
基金项目: 

国家重点研发计划 2018YFE0207300

国家自然科学基金 81871302

中央高水平医院临床科研专项 2022-PUMCH-B-124

详细信息
    通讯作者:

    李永哲,E-mail: yongzhelipumch@126.com

  • 中图分类号: R593.2;R446

Quantitative Analysis of Mitochondrial Damage in T Lymphocytes from Patients with Autoimmune Diseases and Evaluation of Its Clinical Value

Funds: 

National Key Research and Development Program of China 2018YFE0207300

National Natural Science Foundation of China 81871302

National High Level Hospital Clinical Research Funding 2022-PUMCH-B-124

More Information
  • 摘要:   目的  评估自身免疫性疾病(autoimmune disease,AID)患者外周血T淋巴细胞线粒体损伤情况,以期为AID病因学研究提供思路。  方法  回顾性收集2023年3—4月北京协和医院诊治的AID患者及同期体检健康人群的临床资料,并依据外周血辅助性T淋巴细胞(T helper cell, Th)百分比/杀伤性T淋巴细胞(T cytotoxic cell, Tc)百分比比值,将AID患者分为免疫功能低下亚组和免疫功能正常亚组。采用流式细胞术评估AID患者T淋巴细胞线粒体损伤情况,以线粒体膜电位偏低细胞百分比(mitochondrial membrane potential low percentage,MMP-low%)表示线粒体功能障碍程度并分析其与AID的相关性。  结果  共入选符合纳入与排除标准的AID患者70例,健康人群20名。AID患者中,免疫功能低下者20例(Th/Tc比值<0.70),免疫功能正常者50例(Th/Tc比值≥0.70);系统性红斑狼疮(systemic lupus erythematosus,SLE)患者33例,类风湿关节炎(rheumatoid arthritis,RA)患者19例,干燥综合征(Sjögren syndrome,SS)患者18例。SLE、RA、SS患者CD3+T淋巴细胞线粒体膜电位偏低细胞百分比(T MMP-low%)、CD3+CD4+T淋巴细胞线粒体膜电位偏低细胞百分比(Th MMP-low%)、CD3+CD8+T淋巴细胞线粒体膜电位偏低细胞百分比(Tc MMP-low%)均低于健康人群(P均<0.05)。AID患者中,免疫功能低下亚组和免疫功能正常亚组T MMP-low%、Th MMP-low%、Tc MMP-low%均低于健康人群(P均<0.05);相较于免疫功能正常亚组,免疫功能低下亚组T MMP-low%、Th MMP-low%、Tc MMP-low%均呈降低趋势,但差异无统计学意义(P均>0.05)。Spearman相关性分析显示,线粒体损伤指标中,仅发现Th MMP-low%/Tc MMP-low%比值与AID患者免疫功能(Th/Tc比值)具有相关性(r=-0.39,P=0.001)。受试者工作特征曲线显示,T MMP-low%、Tc MMP-low%、Th MMP-low%在AID的识别中均具有良好效能,曲线下面积分别为0.83(95% CI: 0.74~0.92)、0.82(95% CI: 0.73~0.92)、0.77(95% CI: 0.67~0.88)。  结论  AID患者存在一定程度的外周血T淋巴细胞线粒体损伤, 尤其在免疫功能低下者中此现象更显著。T淋巴细胞线粒体损伤相关指标或可作为AID辅助诊断的分子标志物。
    作者贡献:吴子燕负责论文撰写;李昊隆负责实验研究;奉福泰、徐洪琳负责数据分析;张蜀澜、李永哲负责研究设计。
    利益冲突:所有作者均声明不存在利益冲突
  • 图  1  AID患者与健康人群CD3+T淋巴细胞、CD3+CD4+T淋巴细胞、CD3+CD8+T淋巴细胞线粒体质量比较

    T MMP-low%、Th MMP-low%、Tc MMP-low%、AID、SLE、RA、SS:同表 1

    图  2  AID患者Th MMP-low%/Tc MMP-low%比值与Th/Tc比值的相关性

    Th MMP-low%、Tc MMP-low%、AID:同表 1;Th/Tc:Th百分比与Tc百分比的比值

    图  3  T淋巴细胞及其亚群线粒体功能障碍相关指标识别AID的ROC曲线图

    ROC:受试者工作特征;Th/Tc:同图 2;T MMP-low%、Th MMP-low%、Tc MMP-low%、AID:同表 1

    表  1  AID患者与健康人群外周血T淋巴细胞及其亚群线粒体质量比较[M(P25, P75), %]

    组别 T MMP-low% Th MMP-low% Tc MMP-low%
    SLE患者(n=33) 20.91(11.96,28.17)* 14.52(10.18,18.75)* 22.83(13.49,32.95)*
    RA患者(n=19) 25.51(21.59,36.07)*# 18.20(12.31,27.46)* 35.64(24.12,41.97)*#
    SS患者(n=18) 19.92(11.09,34.50)* 19.09(4.78,30.85)* 26.56(11.99,43.09)*
    健康人群(n=20) 38.24(31.35,48.54) 25.05(23.47,33.32) 48.41(35.59,65.41)
    P <0.0001 0.0006 <0.0001
    AID:自身免疫性疾病;SLE:系统性红斑狼疮;RA:类风湿关节炎;SS:干燥综合征;T MMP-low%:CD3+T淋巴细胞线粒体膜电位偏低细胞百分比;Th MMP-low%:CD3+CD4+T淋巴细胞线粒体膜电位偏低细胞百分比;Tc MMP-low%:CD3+CD8+T淋巴细胞线粒体膜电位偏低细胞百分比;与健康人群比较,* P<0.05;与SLE患者比较,# P<0.05
    下载: 导出CSV

    表  2  不同免疫状态的AID患者与健康人群T淋巴细胞及其亚群线粒体质量比较[M(P25, P75)]

    组别 T MMP-low%(%) Th MMP-low%(%) Tc MMP-low%(%) Th MMP-low%/Tc MMP-low%比值
    AID组(n=70)
       免疫功能低下亚组(n=20) 17.15 (10.71,31.16)* 15.36 (10.62,25.46)* 18.07 (10.99,35.85)* 0.86(0.59,1.27)
       免疫功能正常亚组(n=50) 23.88 (17.16,32.52)* 16.27 (10.30,22.67)* 30.61 (18.15,38.85)* 0.56(0.38,0.85)
    健康人群(n=20) 38.24 (31.35,48.54) 25.05(23.47,33.32) 48.41(35.59,65.41) 0.60(0.43,0.72)
    P 0.0002 0.005 0.0001 0.056
    T MMP-low%、Th MMP-low%、Tc MMP-low%、AID:同表 1;与健康人群比较,* P<0.05
    下载: 导出CSV

    表  3  T MMP-low%、Tc MMP-low%、Th MMP-low% 识别AID的临床价值

    诊断指标 T MMP-low% Th MMP-low% Tc MMP-low%
    AUC 0.83 0.77 0.82
    最佳临界值(%) 24.07 21.95 42.57
    灵敏度(%) 100 85.00 70.00
    特异度(%) 57.14 72.86 82.86
    阴性预测值(%) 100 94.44 90.63
    阳性预测值(%) 40.00 47.22 53.85
    假阳性率(%) 42.86 27.14 17.14
    假阴性率(%) 0 15.00 30.00
    准确度(%) 66.67 75.56 80.00
    Youden指数 0.57 0.58 0.53
    AUC:曲线下面积;T MMP-low%、Th MMP-low%、Tc MMP-low%、AID:同表 1
    下载: 导出CSV
  • [1] Pisetsky DS. Pathogenesis of autoimmune disease[J]. Nat Rev Nephrol, 2023, 19: 509-524.
    [2] Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythe-matosus[J]. Arthritis Rheumatol, 2019, 71: 1400-1412. doi:  10.1002/art.40930
    [3] Kay J, Upchurch KS. ACR/EULAR 2010 rheumatoid arthritis classification criteria[J]. Rheumatology, 2012, 51: vi5-vi9. doi:  10.1093/rheumatology/ker193
    [4] Shiboski CH, Shiboski SC, Seror R, et al. 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjögren's Syndrome: A Consensus and Data-Driven Methodology Involving Three International Patient Cohorts[J]. Arthritis Rheumatol, 2017, 69: 35-45. doi:  10.1002/art.39859
    [5] Soriano BL, Brenner D. Metabolism and epigenetics at the heart of T cell function[J]. Trends Immunol, 2023, 44: 231-244. doi:  10.1016/j.it.2023.01.002
    [6] Becker YLC, Duvvuri B, Fortin PR, et al. The role of mitochondria in rheumatic diseases[J]. Nat Rev Rheumatol, 2022, 18: 621-640. doi:  10.1038/s41584-022-00834-z
    [7] Chen PM, Tsokos GC. Mitochondria in the Pathogenesis of Systemic Lupus Erythematosus[J]. Curr Rheumatol Rep, 2022, 24: 88-95. doi:  10.1007/s11926-022-01063-9
    [8] Clayton SA, MacDonald L, Kurowska SM, et al. Mitochondria as Key Players in the Pathogenesis and Treatment of Rheumatoid Arthritis[J]. Front Immunol, 2021, 12: 673916. doi:  10.3389/fimmu.2021.673916
    [9] Faas MM, de Vos P. Mitochondrial function in immune cells in health and disease[J]. Biochim Biophys Acta Mol Basis Dis, 2020, 1866: 165845. doi:  10.1016/j.bbadis.2020.165845
    [10] Jiao Y, Yan Z, Yang A. Mitochondria in innate immunity signaling and its therapeutic implications in autoimmune diseases[J]. Clin Exp Immunol, 2023, 14: 1160035.
    [11] Saadh MJ, Kazemi K, Khorramdelazad H, et al. Role of T cells in the pathogenesis of systemic lupus erythematous: Focus on immunometabolism dysfunctions[J]. Int Immunopharmacol, 2023, 119: 110246. doi:  10.1016/j.intimp.2023.110246
    [12] Shu P, Liang H, Zhang J, et al. Reactive oxygen species formation and its effect on CD4(+) T cell-mediated inflammation[J]. Front Immunol, 2023, 14: 1199233. doi:  10.3389/fimmu.2023.1199233
    [13] Quintero GDC, Muñoz UM, Vásquez G. Mitochondria as a key player in systemic lupus erythematosus[J]. Autoimmunity, 2022, 55: 497-505. doi:  10.1080/08916934.2022.2112181
    [14] Chávez MD, Tse HM. Targeting Mitochondrial-Derived Reactive Oxygen Species in T Cell-Mediated Autoimmune Diseases[J]. Front Immunol, 2021, 12: 703972. doi:  10.3389/fimmu.2021.703972
    [15] Weyand CM, Wu B, Huang T, et al. Mitochondria as disease-relevant organelles in rheumatoid arthritis[J]. Clin Exp Immunol, 2023, 211: 208-223. doi:  10.1093/cei/uxac107
    [16] Gergely PJ, Grossman C, Niland B, et al. Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus[J]. Arthritis Rheum, 2002, 46: 175-190. doi:  10.1002/1529-0131(200201)46:1<175::AID-ART10015>3.0.CO;2-H
    [17] Wahl DR, Petersen B, Warner R, et al. Characterization of the metabolic phenotype of chronically activated lymphocytes[J]. Lupus, 2010, 19: 1492-1501. doi:  10.1177/0961203310373109
    [18] Lee HT, Lin CS, Lee CS, et al. Increased 8-hydroxy-2'-deoxyguanosine in plasma and decreased mRNA expres-sion of human 8-oxoguanine DNA glycosylase 1, anti-oxidant enzymes, mitochondrial biogenesis-related proteins and glycolytic enzymes in leucocytes in patients with systemic lupus erythematosus[J]. Clin Exp Immunol, 2014, 176: 66-77. doi:  10.1111/cei.12256
    [19] Lee HT, Lin CS, Pan SC, et al. Alterations of oxygen consumption and extracellular acidification rates by glutamine in PBMCs of SLE patients[J]. Mitochondrion, 2019, 44: 65-74. doi:  10.1016/j.mito.2018.01.002
    [20] Lee HT, Wu TH, Lin CS, et al. Oxidative DNA and mitochondrial DNA change in patients with SLE[J]. Front Biosci, 2017, 22: 493-503. doi:  10.2741/4497
    [21] Warner LM, Adams LM, Sehgal SN. Rapamycin prolongs survival and arrests pathophysiologic changes in murine systemic lupus erythematosus[J]. Arthritis Rheum, 1994, 37: 289-297. doi:  10.1002/art.1780370219
    [22] Hajizadeh S, DeGroot J, TeKoppele JM, et al. Extracellular mitochondrial DNA and oxidatively damaged DNA in synovial fluid of patients with rheumatoid arthritis[J]. Arthritis Res Ther, 2003, 5: R234-R240. doi:  10.1186/ar787
    [23] Li Y, Shen Y, Jin K, et al. The DNA Repair Nuclease MRE11A Functions as a Mitochondrial Protector and Prevents T Cell Pyroptosis and Tissue Inflammation[J]. Cell Metab, 2019, 30: 477-492. e476. doi:  10.1016/j.cmet.2019.06.016
    [24] Yang Z, Fujii H, Mohan SV, et al. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells[J]. J Exp Med, 2013, 210: 2119-2134. doi:  10.1084/jem.20130252
    [25] Li N, Li Y, Hu J, et al. A Link Between Mitochondrial Dysfunction and the Immune Microenvironment of Salivary Glands in Primary Sjögren's Syndrome[J]. Front Immunol, 2022, 13: 845209. doi:  10.3389/fimmu.2022.845209
    [26] Mankowski RT, Wohlgemuth SE, Bresciani G, et al. Intraoperative Hemi-Diaphragm Electrical Stimulation Demons-trates Attenuated Mitochondrial Function without Change in Oxidative Stress in Cardiothoracic Surgery Patients[J]. Antioxidants (Basel), 2023, 12: 1009. doi:  10.3390/antiox12051009
    [27] Yennemadi AS, Keane J, Leisching G. Mitochondrial bioenergetic changes in systemic lupus erythematosus immune cell subsets: Contributions to pathogenesis and clinical applications[J]. Lupus, 2023, 32: 603-611. doi:  10.1177/09612033231164635
    [28] Nanto HF, Yamazaki M, Murakami H, et al. Chronic heat stress induces renal fibrosis and mitochondrial dysfunction in laying hens[J]. J Anim Sci Biotechnol, 2023, 14: 81. doi:  10.1186/s40104-023-00878-5
    [29] Zhang S, Lv Y, Luo X, et al. Homocysteine promotes atherosclerosis through macrophage pyroptosis via endoplasmic reticulum stress and calcium disorder[J]. Mol Med, 2023, 29: 73.
    [30] Ren X, Zhou H, Sun Y, et al. MIRO-1 interacts with VDAC-1 to regulate mitochondrial membrane potent ial in Caenorhabditis elegans[J]. EMBO Rep, 2023, 24: e56297. doi:  10.15252/embr.202256297
    [31] Clifton LA, Wacklin KHP, Ådén J, et al. Creation of distinctive Bax-lipid complexes at mitochondrial membrane surfaces drives pore formation to initiate apoptosis[J]. Sci adv, 2023, 9: eadg7940. doi:  10.1126/sciadv.adg7940
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出版历程
  • 收稿日期:  2023-03-27
  • 录用日期:  2023-04-21
  • 刊出日期:  2023-09-30

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