抑郁症患者Th17免疫调节相关炎性细胞因子与抑郁严重程度的相关性

Relationship between inflammatory cytokines related with Th17 immunoregulatory and depression severity in patients with depression

目的:探讨Th17免疫调节系统与抑郁症的关系,从神经免疫角度揭示抑郁症发病的机制,寻找可用于抑郁症诊断及预测复发的生物标志物。方法:收集2019年3月至2020年5月就诊于郑州大学第一附属医院精神科门诊及住院的抑郁症患者91例,包括首发患者45例(FED组),反复发作患者46例(RMDD组),和性别、年龄、受教育年限相匹配的40名健康对照者(HC组)。采用酶联免疫法(ELISA)测定血浆中Th17免疫调节系统8个相关炎性细胞因子(五个促炎细胞因子:IL-1β、IL-6、IL-17A、IL-21、IL-23;三个抗炎细胞因子:TGF-β1、IL-10、IL-27)的水平;采用汉密尔顿抑郁量表-24项(HAMD-24项)对所有抑郁症患者进行抑郁严重程度的评估。采用SPSS 23.0统计学软件进行统计分析。组间比较采用两独立样本t检验、单因素方差分、Mann-Whitney U检验和Kruskal-Wallis H检验。结果:(1)FED组、RMDD组、HC组三组比较发现血浆中促炎细胞因子IL-1β[5.321(1.317,21.287)ng/L、11.277(4.315,26.167)ng/L、8.126(1.179,9.287)ng/L]、IL-6[7.787(2.077,16.778)ng/L、5.290(2.364,14.475)ng/L、4.389(1.453,4.491)ng/L]、IL-21[6.777(6.293,9.198)ng/L、7.261(6.293,25.058ng/L、5.097(3.033,6.507)ng/L)]和抗炎细胞因子TGF-β1[59.098(13.491,125.368)ng/L、46.230(18.852,122.559)ng/L、25.292(2.716,31.874)ng/L]、IL-10[226.930(105.117,449.444)ng/L、193.929(109.014,468.269)ng/L、131.429(77.587,157.497)ng/L]、IL-27[0.968(0.651,1.879)ng/L、1.859(0.690,6.221)ng/L、0.865(0.679,1.287)ng/L]的水平差异均有统计学意义(H=7.219,9.482,18.989,16.166,11.511,6.262,均P<0.05),而促炎细胞因子IL-17A[2.175(1.031,7.975)ng/L、3.576(1.896,11.611)ng/L、3.807(1.301,4.710)ng/L]、IL-23[15.708(2.898,114.175)ng/L、26.893(9.282,58.592)ng/L、17.041(5.027,23.613)ng/L]的水平均差异无统计学意义(H=2.179,4.305,均P>0.05);进一步两两比较发现,FED组血浆中促炎细胞因子IL-6、IL-21和抗炎细胞因子TGF-β1、IL-10水平均高于HC组,差异均有统计学意义(均P<0.05);RMDD组血浆中促炎细胞因子IL-1β、IL-6、IL-21和抗炎细胞因子TGF-β1、IL-10、IL-27水平均高于HC组,均差异有统计学意义(均P<0.05);FED组与RMDD组八个炎性细胞因子的比较均差异无统计学意义(均P>0.05)。(2)Spearman相关分析发现,IL-1β与HAMD-24项总分呈正相关(r=0.286,P<0.05);IL-6与HAMD-24项总分及焦虑/躯体化因子分均呈正相关(r=0.390,0.291,P<0.05);TGF-β1与HAMD-24项总分及焦虑/躯体化和认知障碍分均呈负相关(r=-4.200,-0.321,-0.361,P<0.05);IL-21与睡眠因子分呈正相关(r=0.319,P<0.05);IL-10与HAMD-24项总分及认知障碍因子分均呈负相关(r=-0.306,-0.270,均P<0.05);其余炎性细胞因子与HAMD-24项总分及七类因子分之间无明显相关性(均P>0.05)。结论:抑郁症患者存在Th17免疫系统促炎细胞因子和抗炎细胞因子的失衡,且在反复发作抑郁症患者中更明显;Th17免疫系统的免疫激活水平可能与抑郁症临床症状的严重程度关联,促炎细胞因子IL-6可成为重性抑郁症的生物标志物,而TGF-β1、IL-21则分别与抑郁症认知障碍和睡眠关联。

Objective To explore the relationship between Th17 immunoregulatory system and depression and reveal the mechanism of depression from the perspective of neuroimmunity,as well to look for biomarkers that can be used to diagnose,evaluate and predict recurrence of depression.Methods A total of 91 patients with depression including 45 first-episode patients(FED group)and 46 recurrent episodes patients(RMDD group)were collected who were admitted to Psychiatry Department of the First Affiliated Hospital of Zhengzhou University from March 2019 to May 2020.And 40 healthy controls matched with depression patients in age,gender and education level were collected as control group(HC group).The levels of eight inflammatory cytokines in Th17 immunoregulatory system(five pro-inflammatory cytokines:IL-1β,IL-6,IL-17A,IL-21,IL-23;three anti-inflammatory cytokines:TGF-β1,IL-10,and IL-27)were measured by enzyme-linked immunosorbent assay(ELISA).Hamilton depression scale-24(HAMD-24)was used to evaluate the severity of depressive symptoms.Data analyses were performed with SPSS 23.0.Two independent samples t-test,one-way ANOVA,Mann Whitney U test and Kruskal Wallis H test were used for comparison between groups.Results(1)Comparison of FED group,RMDD group and HC group showed that the levels of pro-inflammatory cytokines IL-1β(5.321(1.317,21.287)ng/L,11.277(4.315,26.167)ng/L,8.126(1.179,9.287)ng/L),IL-6(7.787(2.077,16.778)ng/L,5.290(2.364.14.475)ng/L,4.389(1.453,4.491)ng/L),IL-21(6.777(6.293,9.198)ng/L,7.261(6.293,25.058)ng/L,5.097(3.033,6.507)ng/L)and anti-inflammatory cytokines TGF-β1(59.098(13.491,125.368)ng/L,46.230(18.852,122.559)ng/L,25.292(2.716,31.874)ng/L),IL-10(226.930(105.117,449.444)ng/L,193.929(109.014,468.269)ng/L,131.429(77.587,157.497)ng/L)and IL-27(0.968(0.651,1.879)ng/L,1.859(0.690,6.221)ng/L,0.865(0.679,1.287)ng/L)in plasma were statistically different(H=7.219,9.482,18.989,16.166,11.511,6.262,all P<0.05),while the levels of pro-inflammatory cytokines IL-17A(2.175(1.031,7.975)ng/L,3.576(1.896,11.611)ng/L,3.807(1.301,4.710)ng/L)and IL-23(15.708(2.898,114.175)ng/L,26.893(9.282,58.592)ng/L,17.041(5.027,23.613)ng/L)were not statistically significant(H=2.179,4.305,both P>0.05).Further pairwise comparisons showed that the levels of pro-inflammatory cytokines IL-6,IL-21 and anti-inflammatory cytokines TGF-β1 and IL-10 in plasma of FED group were higher than those of HC group,and the differences were statistically significant(all P<0.05).The levels of pro-inflammatory cytokines IL-1β,IL-6,IL-21 and anti-inflammatory cytokines TGF-β1,IL-10,IL-27 in RMDD group were higher than those in HC group,and the differences were statistically significant(all P<0.05).There were no significant differences in the eight inflammatory cytokines between FED group and RMDD group(all P>0.05).(2)Spearman correlation analysis showed that IL-1βwas positively correlated with total score of HAMD-24(r=0.286,P<0.05).IL-6 was positively correlated with total score of HAMD-24 and factor score of anxiety or somatization(r=0.390,0.291,both P<0.05).TGF-β1 was negatively correlated with total score of HAMD-24 and factor scores of anxiety or somatization and cognitive impairment(r=-4.200,-0.321,-0.361,all P<0.05).IL-21 was positively correlated with factor score of sleep(r=0.319,P<0.05);IL-10 was negatively correlated with total score of HAMD-24 and factor score of cognitive impairment(r=-0.306,-0.270,both P<0.05).There was no significant correlation between other inflammatory cytokines and total score of HAMD-24 and seven factor scores(all P>0.05).Conclusion There is an imbalance in pro-and anti-inflammatory cytokines of Th17 immunoregulatory system in patients with depression,which is more obvious in recurrent episodes patients.The level of immune activation of Th17 immunoregulatory system may be associated with the severity of clinical symptoms,in which the inflammatory cytokine IL-6 may be a biomarker of major depressive disorder;TGF-β1 and IL-21 may be associated with depressive cognitive impairment and sleep.