Epstein-Barr病毒相关噬血细胞综合征患者细胞因子/趋化因子表达谱及其临床意义

Expression Profile and Clinical Significance of Cytokines and Chemokines in Patients with Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis

目的:观察Epstein-Barr病毒(EBV)相关噬血细胞综合征(HLH)患者细胞因子/趋化因子表达谱,探讨其对生存结局的预测效能。方法:采用多细胞因子检测方法对EBV相关HLH患者、EBV感染者和对照者血清中38种细胞因子/趋化因子进行检测,比较各组之间细胞因子/趋化因子的表达差异。比较EBV相关HLH患者活动期和缓解期细胞因子/趋化因子的表达变化,评估其对生存结局的预测效能。结果:EBV相关HLH患者血清干扰素-α2(IFN-α2)、白细胞介素(IL)-6和IL-7水平分别为33.67(23.23-68.78)pg/ml、(74.95±25.53)pg/ml、35.35(19.50-63.55)pg/ml,显著高于EBV感染者[IFN-α2:16.07(9.87-29.63);IL-6:55.91±20.29;IL-7:20.40(13.35-31.40)]和对照者[IFN-α2:11.02(4.67-21.25);IL-6:42.64±13.41;IL-7:16.95(14.95-33.78)](均P<0.05)。EBV相关HLH患者血清IL-8、IL-9和巨噬细胞来源趋化因子(MDC)水平分别为11.00(7.50-15.27)pg/ml、81.30(40.79-111.0)pg/ml和(512.6±128.7)pg/ml,均显著高于对照者[IL-8:6.80(5.56-8.38);IL-9:41.30(29.82-67.91);MDC:384.1±156.6](均P<0.05),但与EBV感染者比较无统计学差异(P>0.05)。对EBV相关HLH患者存活组和死亡组血清IFN-α2、IL-6、IL-7、IL-8、IL-9、MDC水平进行ROC曲线分析,曲线下面积分别为0.781、0.778、0.633、0.805、0.562、0.657,P值分别为0.019、0.021、0.269、0.015、0.607、0.190,其中IFN-α2、IL-6、IL-8生存结局预测效能良好。EBV相关HLH患者缓解期血清IFN-α2、IL-6、MDC水平显著低于疾病活动期(P<0.05),而IL-7、IL-8、IL-9水平在疾病活动期和缓解期患者中的差异无统计学意义(P>0.05)。结论:IFN-α2、IL-6、IL-7、IL-8、IL-9、MDC可能参与了EBV相关HLH的发病过程。

Objective: To investigate the cytokine/chemokine profile in patients with Epstein-Barr virus(EBV)-related hemophagocytic lymphohistiocytosis(HLH), and assess the prognostic value of survival. Methods: Serum levels of thirty-eight cytokines/chemokines were measured by multiple cytokine assay kit in EBV-related HLH patients, EBV-infected patients, and controls. The expression profile of cytokines/chemokines was compared among groups. The changes of cytokine/chemokine expression in active and remission stage of EBV-related HLH patients were also compared, and the prognostic values for survival were evaluated. Results: Serum levels of interferon-α2(IFN-α2), interleukin(IL)-6, and IL-7 in EBV-related HLH patients were 33.67(23.23-68.78) pg/ml,(74.95±25.53) pg/ml, and 35.35(19.50-63.55) pg/ml, respectively, which were significantly higher than those in EBV-infected patients[IFN-α2: 16.07(9.87-29.63);IL-6: 55.91±20.29;IL-7: 20.40(13.35-31.40)] and controls [IFN-α2: 11.02(4.67-21.25);IL-6:42.64±13.41;IL-7: 16.95(14.95-33.78)](all P<0.05). Serum levels of IL-8, IL-9, and marcophage-derived chemokine(MDC) in EBV-related HLH patients were 11.00(7.50-15.27) pg/ml, 81.30(40.79-111.0) pg/ml, and(512.6±128.7) pg/ml, respectively, which were significantly higher than those in controls [IL-8: 6. 80( 5. 56-8. 38);IL-9: 41. 30( 29. 82-67. 91);M DC: 384. 1 ± 156. 6]( all P < 0. 05),but there w as no remarkable differences compared w ith EBV-infected patients( P > 0. 05). Serum IFN-α2,IL-6,IL-7,IL-8,IL-9,and M DC in survival and death groups of EBV-related HLH patients w ere analyzed by receiver operating characteristic curve w ith area under curve of 0. 781,0. 778,0. 633,0. 805,0. 562,and 0. 657,respectively( P = 0. 019,0. 021,0. 269,0. 015,0. 607,and 0. 190). IFN-α2,IL-6,and IL-8 had good predictive effect on survival. Serum level of IFN-α2,IL-6,and M DC of EBV-related HLH patients in remission stage w ere significantly low er than those in active stage( P < 0. 05),w hile IL-7,IL-8,and IL-9 w ere not different( P > 0. 05). Conclusion: IFN-α2,IL-6,IL-7,IL-8,IL-9,and M DC may take part in the pathogenesis of EBV-related HLH.