2型糖尿病合并颈动脉粥样硬化患者外周血T淋巴细胞和相关细胞因子的变化及研究
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摘要
目的探讨2型糖尿病(type 2 diabetes mellitus, T2DM)合并颈动脉粥样硬化(carotid atherosclerosis, CAS)患者外周血T淋巴细胞比率、相关细胞因子表达及其与颈动脉内膜中层厚度(intima-media thickness, IMT)和糖化血红蛋白(glycosylated hemoglobin, HbA_1c)的相关性。方法 80例T2DM患者,其中有CAS斑块者40例为CAS组,无CAS斑块者40例为无CAS组;体检健康者40例为对照组。3组采用流式细胞仪测定外周血Th1、Th2、Th17及Treg细胞比例,采用ELISA法检测血清白细胞介素(interleukin, IL)-2、IL-4、IL-6、IL-10、IL-17、干扰素(interferon, IFN)-γ水平,并测量IMT和HbA_1c水平,分析外周血T淋巴细胞与IMT和HbA_1c的相关性。结果 CAS组Th1细胞和Th17细胞百分率[(19.47±2.45)%、(2.34±0.33)%]及IL-2[(211.24±31.49)ng/L]、IL-17[(19.54±3.27)ng/L]、IFN-γ[(19.72±3.21)ng/L]水平、HbA_1c[(11.28±1.56)%]、IMT[(1.45±0.40)mm]明显高于无CAS组[(15.24±1.62)%、(1.50±0.28)%、(184.32±25.74)ng/L、(15.76±2.08)ng/L、(15.68±2.07)ng/L、(8.92±1.09)%、(1.01±0.27)mm]和对照组[(10.02±1.14)%、(0.96±0.25)%、(128.46±17.49)ng/L、(7.32±0.99)ng/L、(10.43±1.21)ng/L、(5.22±0.84)%、(0.76±0.13)mm](P<0.05),无CAS组高于对照组(P<0.05);CAS组Th2细胞和Treg细胞百分率[(2.25±0.49)%、(4.03±0.75)%]及IL-4[(4.72±0.32)ng/L]、IL-6[(11.21±1.04)ng/L]、IL-10[(11.07±1.27)ng/L]水平低于无CAS组[(2.97±0.67)%、(5.67±1.33)%、(5.36±0.61)ng/L、(13.24±1.96)ng/L、(14.77±1.93)ng/L]和对照组[(3.36±0.83)%、(6.57±1.52)%、(7.32±0.95)ng/L、(17.75±2.36)ng/L、(22.72±2.59)ng/L](P<0.05),无CAS组低于对照组(P<0.05);CAS组患者IMT与Th1、Th17细胞水平呈正相关(r=0.809,P<0.001;r=0.648,P<0.001),与Th2、Treg细胞水平呈负相关(r=-0.580,P<0.001;r=-0.643,P<0.001),HbA_1c与Th1、Th17细胞水平呈正相关(r=0.601,P<0.001;r=0.528,P<0.001),与Th2、Treg细胞水平呈负相关(r=-0.844,P<0.001;r=-0.602,P<0.001)。结论糖尿病合并CAS患者存在Th1、Th17细胞比率上调,Th2、Treg细胞比率下调,IL-2、IL-17、IFN-γ分泌增多,IL-4、-6、-10分泌减少,且与患者疾病进展程度相关。
Objective To investigate the percentages of peripheral blood T cell subsets and the expressions of related cytokines in patients with type 2 diabetes mellitus(T2 DM) and carotid atherosclerosis(CAS) and their correlations with the carotid intima-media thickness(IMT) and glycosylated hemoglobin(HbA_1c) level. Methods Eighty patients with T2 DM were divided into CAS plague group and non-CAS plaque group, with 40 patients in each group, and another 40 healthy volunteers were as controls(control group). The percentages of Th1, Th2, Th17 and Treg cells were detected by flow cytometry. The levels of interleukin(IL)-2, IL-4, IL-6, IL-10, IL-17 and interferon(IFN)-γ were detected by ELISA technique. The IMT was measured and HbA_1c was detected. The correlations of peripheral blood T cell subsets with IMT and HbA_1c were analyzed. Results The percentages of Th1 and Th17 cells((19.47±2.45)%,(2.34±0.33)%), the levels of IL-2((211.24±31.49) ng/L), IL-17((19.54±3.27) ng/L), IFN-γ((19.72±3.21) ng/L) and HbA_1c((11.28±1.56)%) as well as IMT((1.45±0.40) mm) in CAS plaque group were significantly higher than those in non-CAS plaque group((15.24±1.62)%,(1.50±0.28)%,(184.32±25.74)ng/L,(15.76±2.08)ng/L,(15.68±2.07)ng/L,(8.92±1.09)%,(1.01±0.27)mm)and control group((10.02±1.14)%,(0.96±0.25)%,(128.46±17.49)ng/L,(7.32±0.99)ng/L,(10.43±1.21)ng/L,(5.22±0.84)%,(0.76±0.13)mm)(P<0.05),and higher in non-CAS plaque group than those in control group(P<0.05).The percentages of Th2 and Treg cells((2.25±0.49)%,(4.03±0.75)%)and the levels of IL-4,IL-6 and IL-10((4.72±0.32),(11.21±1.04),(11.07±1.27)ng/L)in CAS plaque group were significantly lower than those in non-CAS plaque group((2.97±0.67)%,(5.67±1.33)%,(5.36±0.61)ng/L,(13.24±1.96)ng/L,(14.77±1.93)ng/L)and control group((3.36±0.83)%,(6.57±1.52)%,(7.32±0.95)ng/L,(17.75±2.36)ng/L,(22.72±2.59)ng/L)(P<0.05),and lower in non-CAS plaque group than those in control group(P<0.05).In CAS plaque group,IMT was positively correlated with the levels of Th1 and Th17 cells(r=0.809,P<0.001;r=0.648,P<0.001),and negatively correlated with the levels of Th2 and Treg cells(r=-0.580,P<0.001;r=-0.643,P<0.001);HbA1 c was positively correlated with the levels of Th1 and Th17 cells(r=0.601,P<0.001;r=0.528,P<0.001),and negatively correlated with the levels of Th2 and Treg cells(r=-0.844,P<0.001;r=-0.602,P<0.001).Conclusion The percentages of Th1 and Th17 cells are up-regulated,the percentages of Th2 and Treg cells are down-regulated,the levels of IL-2,IL-17 and IFN-γincrease,and the levels of IL-4,IL-6 and IL-10 decrease,which are correlated with the severity of disease.
Objective To investigate the percentages of peripheral blood T cell subsets and the expressions of related cytokines in patients with type 2 diabetes mellitus(T2 DM) and carotid atherosclerosis(CAS) and their correlations with the carotid intima-media thickness(IMT) and glycosylated hemoglobin(HbA_1c) level. Methods Eighty patients with T2 DM were divided into CAS plague group and non-CAS plaque group, with 40 patients in each group, and another 40 healthy volunteers were as controls(control group). The percentages of Th1, Th2, Th17 and Treg cells were detected by flow cytometry. The levels of interleukin(IL)-2, IL-4, IL-6, IL-10, IL-17 and interferon(IFN)-γ were detected by ELISA technique. The IMT was measured and HbA_1c was detected. The correlations of peripheral blood T cell subsets with IMT and HbA_1c were analyzed. Results The percentages of Th1 and Th17 cells((19.47±2.45)%,(2.34±0.33)%), the levels of IL-2((211.24±31.49) ng/L), IL-17((19.54±3.27) ng/L), IFN-γ((19.72±3.21) ng/L) and HbA_1c((11.28±1.56)%) as well as IMT((1.45±0.40) mm) in CAS plaque group were significantly higher than those in non-CAS plaque group((15.24±1.62)%,(1.50±0.28)%,(184.32±25.74)ng/L,(15.76±2.08)ng/L,(15.68±2.07)ng/L,(8.92±1.09)%,(1.01±0.27)mm)and control group((10.02±1.14)%,(0.96±0.25)%,(128.46±17.49)ng/L,(7.32±0.99)ng/L,(10.43±1.21)ng/L,(5.22±0.84)%,(0.76±0.13)mm)(P<0.05),and higher in non-CAS plaque group than those in control group(P<0.05).The percentages of Th2 and Treg cells((2.25±0.49)%,(4.03±0.75)%)and the levels of IL-4,IL-6 and IL-10((4.72±0.32),(11.21±1.04),(11.07±1.27)ng/L)in CAS plaque group were significantly lower than those in non-CAS plaque group((2.97±0.67)%,(5.67±1.33)%,(5.36±0.61)ng/L,(13.24±1.96)ng/L,(14.77±1.93)ng/L)and control group((3.36±0.83)%,(6.57±1.52)%,(7.32±0.95)ng/L,(17.75±2.36)ng/L,(22.72±2.59)ng/L)(P<0.05),and lower in non-CAS plaque group than those in control group(P<0.05).In CAS plaque group,IMT was positively correlated with the levels of Th1 and Th17 cells(r=0.809,P<0.001;r=0.648,P<0.001),and negatively correlated with the levels of Th2 and Treg cells(r=-0.580,P<0.001;r=-0.643,P<0.001);HbA1 c was positively correlated with the levels of Th1 and Th17 cells(r=0.601,P<0.001;r=0.528,P<0.001),and negatively correlated with the levels of Th2 and Treg cells(r=-0.844,P<0.001;r=-0.602,P<0.001).Conclusion The percentages of Th1 and Th17 cells are up-regulated,the percentages of Th2 and Treg cells are down-regulated,the levels of IL-2,IL-17 and IFN-γincrease,and the levels of IL-4,IL-6 and IL-10 decrease,which are correlated with the severity of disease.
引文
[1] 吕何锦,刘震,李韶南,等.颈动脉超声造影及血浆T淋巴细胞亚群在急性冠状动脉综合征中的应用[J].中华实用诊断与治疗杂志,2018,32(1):80-83.
[2] MANCINI O K,SHUM-TIM D,STOCHAJ U,et al.Erratum to:age,atherosclerosis and type 2 diabetes reduce human mesenchymal stromal cell-mediated T-cell suppression[J].Stem Cell Res Ther,2017,8(1):35-37.
[3] MOCSAI A.Diverse novel functions of neutrophils in immunity,inflammation,and beyond[J].J Exp Med,2013,210(7):1283-1299.
[4] CONROY M J,DUNNE M R,DONOHOE C L,et al.Obesity-associated cancer:an immunological perspective[J].Proc Nutr Soc,2016,75(2):125-138.
[5] 王凯阳,隋晓露,陈继红.T细胞亚群与CD4+ CD25+调节性T细胞及Foxp3 mRNA在肾移植大鼠急性排斥反应中的作用[J].中华实用诊断与治疗杂志,2017,31(3):218-222.
[6] PROFUMO E,BUTTARI B,PETRONE L,et al.Actin is a target of T-cell reactivity in patients with advanced carotid atherosclerotic plaques[J].Mediators Inflamm,2013:261054.
[7] OISHI Y,MANABE I.Integrated regulation of the cellular metabolism and function of immune cells in adipose tissue[J].Clin Exp Pharmacol Physiol,2016,43(3):294-303.
[8] ANDRES-BLASCO I,VINUE A,HERRERO-CERVERA A,et al.Hepatic lipase inactivation decreases atherosclerosis in insulin resistance by reducing LIGHT/Lymphotoxin beta-receptor pathway[J].Thromb Haemost,2016,116(2):379-393.
[9] LIU M H,LI Y,HAN L,et al.Adipose-derived stem cells were impaired in restricting CD4+T cell proliferation and polarization in type 2 diabetic ApoE-/- mouse[J].Mol Immunol,2017,87(11):152-160.
[10] HEVENER A L,FEBBRAIO M A.The 2009 stock conference report:inflammation,obesity and metabolic disease[J].Obes Rev,2010,11(9):635-644.
[11] COPPIETERS K T,VON HERRATH M G.Metabolic syndrome-removing roadblocks to therapy:antigenic immunotherapies[J].Mol Metab,2014,3(3):275-283.
[12] GRACHEVA S A,BIRAGOVA M S,GLAZUNOVA A M,et al.Prevalence and risk factors of extra-coronary artery disease in patients with diabetes which confirmed atherosclerosis of coronary arteries[J].Kardiologiia,2014,54(2):18-25.
[13] 张砚,朱凌云,左维泽.肺结核合并2型糖尿病患者的T淋巴细胞亚群及其与血糖控制水平相关性研究[J].中国卫生标准管理,2015,6(23):28-29.
[14] DI MARCO E,GRAY S P,CHEW P,et al.Pharmacological inhibition of NOX reduces atherosclerotic lesions,vascular ROS and immune-inflammatory responses in diabetic Apoe(-/-) mice[J].Diabetologia,2014,57(3):633-642.
[15] KIZILAY M O,SHUM-TIM D,STOCHAJ U,et al.Age,atherosclerosis and type 2 diabetes reduce human mesenchymal stromal cell-mediated T-cell suppression[J].Stem Cell Res Ther,2015,6(8):342-347.
[16] LOHMANN C,SCHAFER N,VON LUKOWICZ T,et al.Atherosclerotic mice exhibit systemic inflammation in periadventitial and visceral adipose tissue,liver,and pancreatic islets[J].Atherosclerosis,2009,207(2):360-367.
[17] YU H T,LEE J,SHIN E C,et al.Significant association between serum monokine induced by gamma interferon and carotid intima media thickness[J].J Atheroscler Thromb,2015,22(8):816-822.
[18] DI MARCO E,GRAY S P,CHEW P,et al.Differential effects of NOX4 and NOX1 on immune cell-mediated inflammation in the aortic sinus of diabetic ApoE-/- mice[J].Clin Sci (Lond),2016,130(15):1363-1374.
[19] WANG K,JIN F,ZHANG Z,et al.Angiotensin Ⅱ promotes the development of carotid atherosclerosis in type 2 diabetes patients via regulating the T cells activities:a cohort study[J].Med Sci Monit,2016,22:4000-4008.
[20] ZHAO Y,YANG L,WANG X,et al.The new insights from DPP-4 inhibitors:their potential immune modulatory function in autoimmune diabetes[J].Diabetes Metab Res Rev,2014,30(8):646-653.
[21] YADAV A K,LAL A,JHA V.Association of circulating fractalkine (CX3CL1) and CX3CR1+ CD4+ T cells with common carotid artery intima-media thickness in patients with chronic kidney disease[J].J Atheroscler Thromb,2011,18(11):958-965.
[22] KING G L.The role of inflammatory cytokines in diabetes and its complications[J].J Periodontol,2008,79(8 Suppl):1527-1534.
[2] MANCINI O K,SHUM-TIM D,STOCHAJ U,et al.Erratum to:age,atherosclerosis and type 2 diabetes reduce human mesenchymal stromal cell-mediated T-cell suppression[J].Stem Cell Res Ther,2017,8(1):35-37.
[3] MOCSAI A.Diverse novel functions of neutrophils in immunity,inflammation,and beyond[J].J Exp Med,2013,210(7):1283-1299.
[4] CONROY M J,DUNNE M R,DONOHOE C L,et al.Obesity-associated cancer:an immunological perspective[J].Proc Nutr Soc,2016,75(2):125-138.
[5] 王凯阳,隋晓露,陈继红.T细胞亚群与CD4+ CD25+调节性T细胞及Foxp3 mRNA在肾移植大鼠急性排斥反应中的作用[J].中华实用诊断与治疗杂志,2017,31(3):218-222.
[6] PROFUMO E,BUTTARI B,PETRONE L,et al.Actin is a target of T-cell reactivity in patients with advanced carotid atherosclerotic plaques[J].Mediators Inflamm,2013:261054.
[7] OISHI Y,MANABE I.Integrated regulation of the cellular metabolism and function of immune cells in adipose tissue[J].Clin Exp Pharmacol Physiol,2016,43(3):294-303.
[8] ANDRES-BLASCO I,VINUE A,HERRERO-CERVERA A,et al.Hepatic lipase inactivation decreases atherosclerosis in insulin resistance by reducing LIGHT/Lymphotoxin beta-receptor pathway[J].Thromb Haemost,2016,116(2):379-393.
[9] LIU M H,LI Y,HAN L,et al.Adipose-derived stem cells were impaired in restricting CD4+T cell proliferation and polarization in type 2 diabetic ApoE-/- mouse[J].Mol Immunol,2017,87(11):152-160.
[10] HEVENER A L,FEBBRAIO M A.The 2009 stock conference report:inflammation,obesity and metabolic disease[J].Obes Rev,2010,11(9):635-644.
[11] COPPIETERS K T,VON HERRATH M G.Metabolic syndrome-removing roadblocks to therapy:antigenic immunotherapies[J].Mol Metab,2014,3(3):275-283.
[12] GRACHEVA S A,BIRAGOVA M S,GLAZUNOVA A M,et al.Prevalence and risk factors of extra-coronary artery disease in patients with diabetes which confirmed atherosclerosis of coronary arteries[J].Kardiologiia,2014,54(2):18-25.
[13] 张砚,朱凌云,左维泽.肺结核合并2型糖尿病患者的T淋巴细胞亚群及其与血糖控制水平相关性研究[J].中国卫生标准管理,2015,6(23):28-29.
[14] DI MARCO E,GRAY S P,CHEW P,et al.Pharmacological inhibition of NOX reduces atherosclerotic lesions,vascular ROS and immune-inflammatory responses in diabetic Apoe(-/-) mice[J].Diabetologia,2014,57(3):633-642.
[15] KIZILAY M O,SHUM-TIM D,STOCHAJ U,et al.Age,atherosclerosis and type 2 diabetes reduce human mesenchymal stromal cell-mediated T-cell suppression[J].Stem Cell Res Ther,2015,6(8):342-347.
[16] LOHMANN C,SCHAFER N,VON LUKOWICZ T,et al.Atherosclerotic mice exhibit systemic inflammation in periadventitial and visceral adipose tissue,liver,and pancreatic islets[J].Atherosclerosis,2009,207(2):360-367.
[17] YU H T,LEE J,SHIN E C,et al.Significant association between serum monokine induced by gamma interferon and carotid intima media thickness[J].J Atheroscler Thromb,2015,22(8):816-822.
[18] DI MARCO E,GRAY S P,CHEW P,et al.Differential effects of NOX4 and NOX1 on immune cell-mediated inflammation in the aortic sinus of diabetic ApoE-/- mice[J].Clin Sci (Lond),2016,130(15):1363-1374.
[19] WANG K,JIN F,ZHANG Z,et al.Angiotensin Ⅱ promotes the development of carotid atherosclerosis in type 2 diabetes patients via regulating the T cells activities:a cohort study[J].Med Sci Monit,2016,22:4000-4008.
[20] ZHAO Y,YANG L,WANG X,et al.The new insights from DPP-4 inhibitors:their potential immune modulatory function in autoimmune diabetes[J].Diabetes Metab Res Rev,2014,30(8):646-653.
[21] YADAV A K,LAL A,JHA V.Association of circulating fractalkine (CX3CL1) and CX3CR1+ CD4+ T cells with common carotid artery intima-media thickness in patients with chronic kidney disease[J].J Atheroscler Thromb,2011,18(11):958-965.
[22] KING G L.The role of inflammatory cytokines in diabetes and its complications[J].J Periodontol,2008,79(8 Suppl):1527-1534.
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