血浆Dickkopf-1在类风湿关节炎患者中的表达及其与外周血T细胞亚群的相关性

doi:10.19723/j.issn.1671-167X.2021.02.004

北京大学学报（医学版） ›› 2021, Vol. 53 ›› Issue (2): 255-260. doi: 10.19723/j.issn.1671-167X.2021.02.004

血浆Dickkopf-1在类风湿关节炎患者中的表达及其与外周血T细胞亚群的相关性

曹迪¹,王燕^1,^Δ(),王柳青¹,孙晓麟²,黄妃³,孟洋¹,任丽丽¹,张学武^2,^Δ()

1.郑州大学第五附属医院风湿免疫科, 郑州 450000
2.北京大学人民医院风湿免疫科, 北京 100044
3.遵义医科大学附属医院肾病风湿科, 贵州遵义 563000

收稿日期:2020-03-16 出版日期:2021-04-18 发布日期:2021-04-21
通讯作者: 王燕,张学武 E-mail:wangyanh_1963@163.com;xuewulore@163.com
基金资助:
国家自然科学基金(81771678);河南省教育厅重点科技攻关项目(19A320016)

Expression of plasma Dickkopf-1 in patients with rheumatoid arthritis and its correlation with peripheral blood T cell subsets

CAO Di¹,WANG Yan^1,^Δ(),WANG Liu-qing¹,SUN Xiao-lin²,HUANG Fei³,MENG Yang¹,REN Li-li¹,ZHANG Xue-wu^2,^Δ()

1. Department of Rheumatology and Immunology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
2. Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing 100044, China
3. Department of Rheumatology and Immunology,Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou, China

Received:2020-03-16 Online:2021-04-18 Published:2021-04-21
Contact: Yan WANG,Xue-wu ZHANG E-mail:wangyanh_1963@163.com;xuewulore@163.com
Supported by:
National Natural Science Foundation of China(81771678);Key Scientific and Technological Project of Education Department of Henan Province(19A320016)

摘要/Abstract

摘要：

目的: 检测类风湿关节炎(rheumatoid arthritis,RA)患者血浆Dickkopf-1(DKK-1)水平,并分析其与外周血T细胞亚群、临床指标之间的相关性。方法: 采用酶联免疫吸附法(enzyme linked immunosorbent assay,ELISA)检测32例RA患者及20例健康对照者的血浆DKK-1的水平,并记录RA患者的各项临床表现和实验室指标。流式细胞仪检测RA患者外周血T细胞亚群(包括Treg、nTreg、aTreg、sTreg、Teff、Tfh、CD4⁺CD161⁺T、CD8⁺T、CD8⁺CD161⁺T细胞)。比较两组血浆DKK-1的水平,并分析其与外周血T细胞亚群、临床指标的相关性。结果: (1)RA患者血浆DKK-1浓度为(124.97±64.98) ng/L,健康对照组血浆DKK-1浓度为(84.95±13.74) ng/L,RA患者血浆DKK-1水平显著高于健康对照组(P<0.05),RA患者外周血CD8⁺CD161⁺T细胞百分比显著高于健康对照组(P<0.05)。(2)血浆DKK-1水平与红细胞沉降率(r=0.406,P=0.021)、DAS28评分(r=0.372,P=0.036)、免疫球蛋白G(r=0.362,P=0.042)、免疫球蛋白A(r=0.377,P=0.033)呈正相关;与年龄、病程、C-反应蛋白、类风湿因子、抗环瓜氨酸肽抗体、免疫球蛋白M、补体C3、补体C4、白细胞计数、中性粒细胞百分比无相关性。(3)RA患者血浆DKK-1水平与外周血CD8⁺CD161⁺T细胞百分比呈正相关(r=0.413,P=0.019);与Treg、nTreg、aTreg、sTreg、Teff、Tfh、CD4⁺CD161⁺T、CD8⁺T细胞无相关性。(4)外周血CD161⁺CD8⁺T细胞百分比与红细胞沉降率(r=-0.415,P=0.004)、C-反应蛋白(r=-0.393,P=0.007)、DAS28评分(r=-0.392,P=0.007)、类风湿因子(r=-0.535,P<0.001)、抗环瓜氨酸肽抗体(r=-0.589,P<0.001)、免疫球蛋白G(r=-0.368,P=0.012)、免疫球蛋白M(r=-0.311,P=0.035)呈负相关;与年龄、病程、免疫球蛋白A、补体C3、补体C4、白细胞计数、中性粒细胞百分比无相关性。结论: RA患者血浆DKK-1水平和外周血T细胞亚群中的CD8⁺CD161⁺T细胞百分比均升高,可能与患者体内促炎细胞因子的分泌有关;DKK-1参与骨稳态的调节,可用作RA骨破坏的标志物。

关键词: 类风湿关节炎, Dickkopf-1蛋白, T细胞

Abstract:

Objective: To detect the levels of Dickkopf-1 (DKK-1) in the plasma of patients with rheumatoid arthritis (RA), and to analyze their correlation with peripheral blood T cell subsets and clinical indicators. Methods: Enzyme-linked immunosorbent assay (ELISA) was used to detect plasma DKK-1 levels in 32 RA patients and 20 healthy controls, and to record the various clinical manifestations and laboratory indicators of the RA patients, and flow cytometry to detect peripheral blood T cell subsets in the RA patients (Including Treg, nTreg, aTreg, sTreg, Teff, Tfh, CD4⁺CD161⁺T, CD8⁺T, CD8⁺CD161⁺T cells). The plasma DKK-1 levels between the two groups were ompared, and its correlation with peripheral blood T cell subsets and clinical indicators analyzed. Results: (1) The plasma DKK-1 concentration of the RA patients was (124.97±64.98) ng/L. The plasma DKK-1 concentration of the healthy control group was (84.95±13.74) ng/L. The plasma DKK-1 level of the RA patients was significantly higher than that of the healthy control group (P<0.05), and the percentage of CD8⁺CD161⁺T cells in the peripheral blood of the RA patients was significantly higher than that of the healthy control group (P<0.05). (2) The plasma DKK-1 level was positively correlated with erythrocyte sedimentation rate (r=0.406, P=0.021),DAS28 score (r=0.372, P=0.036), immunoglobulin G(r=0.362, P=0.042), immunoglobulin A(r=0.377, P=0.033) ; it had no correlation with age, course of disease, C-reactive protein, rheumatoid factor, anti-cyclic citrullinated peptide antibody, immunoglobulin M, complement C3, complement C4, white blood cell, neutrophil ratio. (3) The plasma DKK-1 level in the RA patients was positively correlated with the percentage of peripheral blood CD161⁺CD8⁺T cells (r=0.413, P=0.019);it had no correlation with Treg, nTreg, aTreg, sTreg, Teff, Tfh, CD4⁺CD161⁺T, CD8⁺T cells. (4) The percentage of CD161⁺CD8⁺T cells was negatively correlated with erythrocyte sedimentation rate (r=-0.415, P=0.004), C-reactive protein (r=-0.393, P=0.007), DAS28 score(r=-0.392, P=0.007),rheumatoid factor (r=-0.535, P<0.001), anti-citrullinated protein antibody (r=-0.589, P<0.001), immunoglobulin G(r=-0.368, P=0.012) immunoglobulin M (r=-0.311, P=0.035); it had no correlation with age, disease course, immunoglobulin A, complement C3, complement C4,white blood cell,and neutrophil ratio. Conclusion: RA patients’ plasma DKK-1 levels and the percentage of CD8⁺CD161⁺T cells in T cell subsets in peripheral blood increase, which may be related to the secretion of proinflammatory cytokines in patients; DKK-1 is involved in the regulation of bone homeostasis and can be used as a marker of bone destruction in RA.

Key words: Rheumatoid arthritis, Dickkopf-1, T cells

中图分类号:

R593.2

曹迪,王燕,王柳青,孙晓麟,黄妃,孟洋,任丽丽,张学武. 血浆Dickkopf-1在类风湿关节炎患者中的表达及其与外周血T细胞亚群的相关性[J]. 北京大学学报（医学版）, 2021, 53(2): 255-260.

CAO Di,WANG Yan,WANG Liu-qing,SUN Xiao-lin,HUANG Fei,MENG Yang,REN Li-li,ZHANG Xue-wu. Expression of plasma Dickkopf-1 in patients with rheumatoid arthritis and its correlation with peripheral blood T cell subsets[J]. Journal of Peking University (Health Sciences), 2021, 53(2): 255-260.

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参考文献 12

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[7]	Fujita K, Janz S. Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF[J]. Mol Cancer, 2007,6(1):71.
[8]	Diarra D, Stolina M, Polzer K, et al. Dickkopf-1 is a master regulator of joint remodeling[J]. Nat Med, 2007,13(2):156-163. pmid: 17237793
[9]	Gómez-Vaquero C, Martín I, Loza E, et al. Effect of osteoprotegerin and Dickkopf-related protein 1 on radiological progression in tightly controlled rheumatoid arthritis[J]. PLoS One, 2016,11(12):e0166691.
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[11]	Mitsuo A, Morimoto S, Nakiri Y, et al. Decreased CD161⁺CD8⁺ T cells in the peripheral blood of patients suffering from rheumatic diseases[J]. Rheumatology (Oxford), 2006,45(12):1477-1484.
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Characteristics	RA (n=32)
Age/years, $\bar{x} \pm s$	63.09 ±11.07
Duration/years, M (Min, Max)	10.0 (5.0, 17.3)
ESR/(mm/h), $\bar{x} \pm s$	47.53±22.76
CRP/(mg/L), M (Min, Max)	24.4 (7.2, 56.4)
DAS28, $\bar{x} \pm s$	5.29±1.40
RF/(IU/mL), M (Min, Max)	350.0 (134.3, 657.5)
CCP/(U/mL), M (Min, Max)	178.8 (134.3, 230.7)
IgG/(g/L), $\bar{x} \pm s$	14.06±3.93
IgA/(g/L), $\bar{x} \pm s$	3.35±1.28
IgM/(g/L), $\bar{x} \pm s$	1.37±0.70
C3/(g/L), $\bar{x} \pm s$	0.93±0.24
C4/(g/L), $\bar{x} \pm s$	0.18±0.08
WBC/(×10⁹/L), $\bar{x} \pm s$	6.61±2.33
Neu/%, $\bar{x} \pm s$	63.92±13.15

血浆Dickkopf-1在类风湿关节炎患者中的表达及其与外周血T细胞亚群的相关性

Expression of plasma Dickkopf-1 in patients with rheumatoid arthritis and its correlation with peripheral blood T cell subsets

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