南方医科大学学报

南方医科大学学报 ›› 2022, Vol. 42 ›› Issue (5): 733-739.doi: 10.12122/j.issn.1673-4254.2022.05.15

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类风湿关节炎血清学标志物的筛选：基于细胞因子蛋白芯片

韩奕芃，卢小希，赖伟男，梁人戈，杨 敏，欧阳晴晴   

  1. 南方医科大学南方医院风湿免疫科，广东 广州 510515
  • 出版日期:2022-05-20 发布日期:2022-06-02

Identification of serological biomarkers for diagnosis of rheumatoid arthritis using a protein array-based approach

HAN Yipeng, LU Xiaoxi, LAI Weinan, LIANG Renge, YANG Min, OUYANG Qingqing   

  1. Department of Rheumatology and Immunology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
  • Online:2022-05-20 Published:2022-06-02

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摘要： 目的 探讨多项血清中细胞因子及可溶性细胞因子受体蛋白在类风湿关节炎临床诊断中的应用价值。方法 选择2015年~2019年在本院确诊为类风湿关节炎（RA）的患者59例作为RA组，并以在我院接受定期体检的年龄和性别匹配的健康受试者46例作为健康对照组。通过人细胞因子蛋白芯片检测其中5例RA组及5例健康对照组血清样本，选取4种差异表达细胞因子LIMPII、ROBO3、Periostin、IGFBP-4及可溶性受体蛋白2B4、Tie-2，于另外54例RA组及41例健康对照组血清样本中，对其六者血清水平进行 ELISA验证。Spearman 相关分析检测细胞因子及可溶性细胞因子受体蛋白与临床指标（包括：类风湿因子（RF）、红细胞沉降率（ESR）、C反应蛋白（CRP）、疾病活动评分（DAS28）及健康评估问卷（HAQ））的关系；受试者工作特征曲线（ROC）分析评估其诊断价值。结果 与健康对照相比，2B4、LIMPII、Tie-2、ROBO3、Periostin和IGFBP-4在RA血清中的表达显著升高（P<0.01）。同时，RA血清中LIMPII、ROBO3和Periostin血清水平与类风湿因子、C反应蛋白、疾病活动评分及健康评估问卷等反映疾病活动程度评价指标正相关（P<0.01）。血清2B4、LIMPⅡ、Periostin、ROBO3、IGFBP-4和Tie-2表达水平均对RA的诊断有显著意义（P<0.05），其中2B4曲线下面积为最大（AUC：0.861，P<0.001），其次依顺序LIMPII、ROBO3、Periostin、Tie-2、 和IGFBP-4。结论 血清LIMPII、ROBO3和Periostin的表达水平可反映RA的疾病活动度，此外血清2B4、LIMPⅡ、Periostin、ROBO3、IGFBP-4和Tie-2可能作为RA的诊断的生物标记物。

关键词: 类风湿关节炎；细胞因子；细胞因子受体；生物标志物；蛋白芯片

Abstract: Objective To study the cytokine patterns in patients with rheumatoid arthritis (RA) and healthy individuals and identify candidate serum biomarkers for clinical diagnosis of RA. Methods This study was conducted among 59 patients diagnosed with RA in our hospital from 2015 to 2019 with 46 age- and gender-matched healthy subjects who received regular physical examinations in our hospital as the control group. Serological autoimmune profiles of 5 RA patients and 5 healthy control subjects were obtained from human cytokine microarrays. We selected 4 differentially expressed cytokines (LIMPII, ROBO3, Periostin and IGFBP-4) and 2 soluble cytokine receptors of interest (2B4 and Tie-2) and examined their serum levels using enzyme-linked immunosorbent assay in 54 RA patients and 41 healthy control subjects. Spearman correlation test was performed to assess the correlation of serum cytokine and soluble receptor expression levels with the clinical features including rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), disease activity score (DAS28) and health assessment questionnaire (HAQ). Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic capability of these cytokines. Results We identified 6 dysregulated cytokines and soluble receptors (2B4, LIMPII, Tie- 2, ROBO3, periostin and IGFBP- 4) in RA patients (P<0.01). The serum levels of LIMPII, ROBO3 and periostin were significantly correlated with the disease activity indicators including RF (P<0.001), CRP (P<0.001), DAS28 (P<0.001) and HAQ (P<0.001) in RA patients. Among the 6 candidate cytokines, 2B4 showed the largest area under the curve (AUC) of 0.861 for RA diagnosis (P<0.001), followed then by LIMPII, ROBO3, periostin, Tie-2 and IGFBP-4. Conclusion Serum levels of LIMPII, ROBO3 and periostin can be indicative of the disease activity of RA, and serum 2B4, LIMPII, periostin, ROBO3, IGFBP-4 and Tie-2 levels may serve as biomarkers for the diagnosis of RA.

Key words: rheumatoid arthritis; cytokine; cytokine receptor; biomarkers; protein chip