新生儿缺氧缺血性脑病机体免疫功能变化的研究
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摘要
【目的】
探讨缺氧缺血性脑病(Hypoxic ischemic encephalopathy,HIE)新生儿外周血T淋巴细胞亚群和血清免疫球蛋白的改变以及二者之间的关系,综合分析细胞免疫和体液免疫在新生儿HIE发病中的特点,为HIE的发病机制和免疫治疗提供理论依据。
【资料和方法】
30名不同程度HIE患儿作为HIE组。其中轻度14例,中重度16例；男13例,女17例。同期出生的正常新生儿18名作为正常对照组。其中男11例,女7例。两组胎龄均为37-42周,出生体重2500～4000g。HIE组于出生24小时内分别取外周静脉血2ml于乙二胺四乙酸二钾(EDTA-K2)真空采血管和普通生化管。正常对照组即于出生时分别取脐血2ml于EDTA-K2真空采血管和普通生化管,均室温放置,1小时内送检。流式细胞术测定外周血T细胞亚群,免疫比浊法测定血清免疫球蛋白。SPSS16.0统计分析软件处理结果。数据以均数±标准差(X±S)表示。HIE组和正常组间比较采用两独立样本t检验；对照组、HIE轻度和HIE中重度间比较采用单因素方差分析。
【结果】
1.T细胞亚群的比较
①HIE组和正常对照组间比较HIE组CD3+、CD4+较正常对照组明显降低,差异有显著性(P<0.05);CD8+、CD4+/CD8+无显著性差异(P>0.05)。
②对照组、轻度HIE和中重度HIE组间比较：CD3+、CD4+在HIE轻度与中重度间的表达均低于对照组,差异有显著性(P<0.05);CD8+、CD4+/CD8+较对照组均无显著性差异(P>0.05)。HIE轻度和中重度之间比较,CD3+、CD4+、CD8+及CD4+/CD8+均无显著性差异,(P>0.05)。
2.血清免疫球蛋白的比较：
①HIE组和正常对照组相比较：HIE组IgM较正常对照组偏低,差异有显著性(P< 0.05); IgG和IgA均无显著性差异(P>0.05)。
②对照组、轻度HIE和中重度HIE间比较：IgM在轻度HIE与中重度HIE的表达均较对照组明显偏低,差异有显著性(P<0.05).IgG、IgA较对照组均无显著性差异(P>0.05);HIE轻度和中重度HIE间相比较,IgG、IgA及IgM均无显著性差异(P>0.05)。
【结论】
1.新生儿缺氧缺血性脑病对细胞免疫的影响主要表现在总T细胞(CD3+)和辅助/诱导T细胞(CD4+)的降低,但两者的降低幅度与HIE程度无明显相关。
2.新生儿缺氧缺血性脑病对体液免疫的影响主要表现在血清免疫球蛋白IgM的降低,但其降低幅度与HIE程度无明显相关。
[Objective]
To probe into the changes of T-lymphocyte subsets and serum immunoglobulins and the relation between them in neonates with hypoxic-ischemic encephalopathy (HIE),which can comprehensively analyze the features of cellular immunity and humoral immunity to provide theoretical evidences for pathogenesis and immunotherapy of HIE.
[Methods]
Thirty neonates with HIE is named as HIE group, which is divided into mild group including fourteen neonates and moderate-severe group including sixteen neonates.There are thirteen male neonates and sixteen female neonates in the HIE group. Eighteen normal neonates born at the same time is named as control group which includes eleven male neonates and seven female neonates. The gestation age of all the neonates ranges from thirty-seven to forty-two weeks. All of the birth weight ranges from 2500g to 4000g. Four milliliter of peripheral blood is collected from the neonates of HIE group within their 24h, of which two milliliter of peripheral blood is collected with EDTA-K2 tube and the other two milliliter with biochemical tube. Accordingly, four millilitre of cord blood is collected from control group while born, of which two milliliter of cord blood is collected with EDTA-K2 tube and the other two milliliter with biochemical tube too. The sample of the both two groups is conserved at ordinary temperature and sent to chemical examination in an hour. T-lymphocyte subsets including CD3+,CD4+,CD8+ and CD4+/CD8+ ratio are detected by Flow Cytometr (FCM) and serum immunoglobulins including IgG、IgA and IgM are detected by 722 Spectrophotometer. The results are analyzed by SPSS 16.0 and the data are expressed with mean±tandard deviation(X±S). Independent-Samples T test is used in the comparison between HIE group and control group.One-Way ANONA is used in the comparison among mild HIE、moderate-severe HIE and control group.
[Results]
1.Comparisions of the T subset:
(1)Comparision between HIE group and control group
Percentages of CD3+ and CD4+ cells in neonates with HIE are obviously lower than those in control group, the difference is significiant(P<0.05); There is no obvious difference of the CD8+ and CD4+/CD8+ in the both two groups, (P>0.05).
(2)Comparision among mild HIE、moderate-severe HIE and control group
Percentages of CD3+ and CD4+ cells in neonates with mild HIE or moderate-severe HIE are obviously lower than those in control group, the difference is significiant (P<0.05); There is no obvious difference of the percentages of CDg+ and CD4+/CD8+ between mild HIE and control group、moderate-severe HIE and control group(P>0.05). There is no obvious difference of CD3+\CD4+, CD8+ and CD4+/CD8+ between mild HIE and moderate-severe HIE the (P>0.05)。
2.Comparisions of the serum immune globulins:
(1)Comparision between HIE group and control group
Contents of IgM in neonates with HIE are lower than those in control group(P< 0.05); There is no obvious difference of the IgA and IgG in the both two groups, (P>0.05).
(2)Comparision among mild HIE、moderate-severe HIE and control group
Contents of IgM in neonates with mild HIE or moderate-severe HIE are obviously lower than those in control group, the difference is significiant (P< 0.05); There is no obvious difference of content of IgA and IgG between mild HIE and control group、moderate-severe HIE and control group(P>0.05).There is no obvious difference of the IgA、IgG and IgM between mild HIE and moderate-severe HIE (P>0.05)。
[Conclusion]
1.The influence of HIE on cellular immunity is mainly expressed by the decrease of the total mount of T-lymphocyte subsets (CD3+) and helper T-cell (CD4+), but there is no dependability with the degree of HIE.
2.The influence of HIE on humoral immunity is mainly expressed by the decrease of serum IgM, but there is no dependability with the degree of HIE.
探讨缺氧缺血性脑病(Hypoxic ischemic encephalopathy,HIE)新生儿外周血T淋巴细胞亚群和血清免疫球蛋白的改变以及二者之间的关系,综合分析细胞免疫和体液免疫在新生儿HIE发病中的特点,为HIE的发病机制和免疫治疗提供理论依据。
【资料和方法】
30名不同程度HIE患儿作为HIE组。其中轻度14例,中重度16例；男13例,女17例。同期出生的正常新生儿18名作为正常对照组。其中男11例,女7例。两组胎龄均为37-42周,出生体重2500～4000g。HIE组于出生24小时内分别取外周静脉血2ml于乙二胺四乙酸二钾(EDTA-K2)真空采血管和普通生化管。正常对照组即于出生时分别取脐血2ml于EDTA-K2真空采血管和普通生化管,均室温放置,1小时内送检。流式细胞术测定外周血T细胞亚群,免疫比浊法测定血清免疫球蛋白。SPSS16.0统计分析软件处理结果。数据以均数±标准差(X±S)表示。HIE组和正常组间比较采用两独立样本t检验；对照组、HIE轻度和HIE中重度间比较采用单因素方差分析。
【结果】
1.T细胞亚群的比较
①HIE组和正常对照组间比较HIE组CD3+、CD4+较正常对照组明显降低,差异有显著性(P<0.05);CD8+、CD4+/CD8+无显著性差异(P>0.05)。
②对照组、轻度HIE和中重度HIE组间比较：CD3+、CD4+在HIE轻度与中重度间的表达均低于对照组,差异有显著性(P<0.05);CD8+、CD4+/CD8+较对照组均无显著性差异(P>0.05)。HIE轻度和中重度之间比较,CD3+、CD4+、CD8+及CD4+/CD8+均无显著性差异,(P>0.05)。
2.血清免疫球蛋白的比较：
①HIE组和正常对照组相比较：HIE组IgM较正常对照组偏低,差异有显著性(P< 0.05); IgG和IgA均无显著性差异(P>0.05)。
②对照组、轻度HIE和中重度HIE间比较：IgM在轻度HIE与中重度HIE的表达均较对照组明显偏低,差异有显著性(P<0.05).IgG、IgA较对照组均无显著性差异(P>0.05);HIE轻度和中重度HIE间相比较,IgG、IgA及IgM均无显著性差异(P>0.05)。
【结论】
1.新生儿缺氧缺血性脑病对细胞免疫的影响主要表现在总T细胞(CD3+)和辅助/诱导T细胞(CD4+)的降低,但两者的降低幅度与HIE程度无明显相关。
2.新生儿缺氧缺血性脑病对体液免疫的影响主要表现在血清免疫球蛋白IgM的降低,但其降低幅度与HIE程度无明显相关。
[Objective]
To probe into the changes of T-lymphocyte subsets and serum immunoglobulins and the relation between them in neonates with hypoxic-ischemic encephalopathy (HIE),which can comprehensively analyze the features of cellular immunity and humoral immunity to provide theoretical evidences for pathogenesis and immunotherapy of HIE.
[Methods]
Thirty neonates with HIE is named as HIE group, which is divided into mild group including fourteen neonates and moderate-severe group including sixteen neonates.There are thirteen male neonates and sixteen female neonates in the HIE group. Eighteen normal neonates born at the same time is named as control group which includes eleven male neonates and seven female neonates. The gestation age of all the neonates ranges from thirty-seven to forty-two weeks. All of the birth weight ranges from 2500g to 4000g. Four milliliter of peripheral blood is collected from the neonates of HIE group within their 24h, of which two milliliter of peripheral blood is collected with EDTA-K2 tube and the other two milliliter with biochemical tube. Accordingly, four millilitre of cord blood is collected from control group while born, of which two milliliter of cord blood is collected with EDTA-K2 tube and the other two milliliter with biochemical tube too. The sample of the both two groups is conserved at ordinary temperature and sent to chemical examination in an hour. T-lymphocyte subsets including CD3+,CD4+,CD8+ and CD4+/CD8+ ratio are detected by Flow Cytometr (FCM) and serum immunoglobulins including IgG、IgA and IgM are detected by 722 Spectrophotometer. The results are analyzed by SPSS 16.0 and the data are expressed with mean±tandard deviation(X±S). Independent-Samples T test is used in the comparison between HIE group and control group.One-Way ANONA is used in the comparison among mild HIE、moderate-severe HIE and control group.
[Results]
1.Comparisions of the T subset:
(1)Comparision between HIE group and control group
Percentages of CD3+ and CD4+ cells in neonates with HIE are obviously lower than those in control group, the difference is significiant(P<0.05); There is no obvious difference of the CD8+ and CD4+/CD8+ in the both two groups, (P>0.05).
(2)Comparision among mild HIE、moderate-severe HIE and control group
Percentages of CD3+ and CD4+ cells in neonates with mild HIE or moderate-severe HIE are obviously lower than those in control group, the difference is significiant (P<0.05); There is no obvious difference of the percentages of CDg+ and CD4+/CD8+ between mild HIE and control group、moderate-severe HIE and control group(P>0.05). There is no obvious difference of CD3+\CD4+, CD8+ and CD4+/CD8+ between mild HIE and moderate-severe HIE the (P>0.05)。
2.Comparisions of the serum immune globulins:
(1)Comparision between HIE group and control group
Contents of IgM in neonates with HIE are lower than those in control group(P< 0.05); There is no obvious difference of the IgA and IgG in the both two groups, (P>0.05).
(2)Comparision among mild HIE、moderate-severe HIE and control group
Contents of IgM in neonates with mild HIE or moderate-severe HIE are obviously lower than those in control group, the difference is significiant (P< 0.05); There is no obvious difference of content of IgA and IgG between mild HIE and control group、moderate-severe HIE and control group(P>0.05).There is no obvious difference of the IgA、IgG and IgM between mild HIE and moderate-severe HIE (P>0.05)。
[Conclusion]
1.The influence of HIE on cellular immunity is mainly expressed by the decrease of the total mount of T-lymphocyte subsets (CD3+) and helper T-cell (CD4+), but there is no dependability with the degree of HIE.
2.The influence of HIE on humoral immunity is mainly expressed by the decrease of serum IgM, but there is no dependability with the degree of HIE.
引文
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[51]许建文,陈艳霞.大剂量免疫球蛋白治疗重度新生儿缺氧缺血性脑病的效果[J].实用儿科临床杂志,2008；23(2)：140-141.
[1]Bennet L, Roelfsema V, Pathipati P, et al. Relationship between evolving epilep-tiform activity and delayed loss of mitochondrial activity after asphyxia measured by near infrared spectroscopy in preterm fetal sheep [J]. J Physiol,2006,572 (1) 141-154.
[2]Miller JA,Miller FS. Effects of drugs and anaesthetics on reanimation of ice-cold mice[J]. J Physiol,1958,140 (1):23-24.
[3]Westin B, Miller JA, Nyberg R, et al. Neonatal asphysia pallida treated with hypothermia alone or with hypothermia transfusion of oxygenated blood [J]. Surgery, 1959,45:868-879.
[4]Lap took AR, Corbett RJ, Sterett R, et al. Modest hypothermia provides partial neuroprotection for ischemic neonatal brain[J]. Pediatr Res,1994,35 (4 Pt 1) 436-442.
[5]EicherDJ,Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy:efficacy outcomes[J]. Pediatr Neurol,2005,32 (1):11-17.
[6]Gluckman PD,Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy:multicentre randomised trial[J]. Lancet,2005,365 (9460):663-670.
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[8]选择性头部亚低温治疗新生儿HIE多中心协作组.亚低温治疗新生儿缺氧缺血性脑病临床多中心研究阶段性疗效分析[J].中国循证儿科杂志,2006,1(2)99-105.
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[1]Bennet L, Roelfsema V, Pathipati P, et al. Relationship between evolving epilep-tiform activity and delayed loss of mitochondrial activity after asphyxia measured by near infrared spectroscopy in preterm fetal sheep [J]. J Physiol,2006,572 (1) 141-154.
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[4]Lap took AR, Corbett RJ, Sterett R, et al. Modest hypothermia provides partial neuroprotection for ischemic neonatal brain[J]. Pediatr Res,1994,35 (4 Pt 1) 436-442.
[5]EicherDJ,Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy:efficacy outcomes[J]. Pediatr Neurol,2005,32 (1):11-17.
[6]Gluckman PD,Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy:multicentre randomised trial[J]. Lancet,2005,365 (9460):663-670.
[7]Shankaran S,Lap took AR, Ehrenkranz RA, et al. Whole body hypothermia for neonates with hypoxic ischemic encephalopathy[J].N Engl J Med,2005,353 (15): 1574-1584.
[8]选择性头部亚低温治疗新生儿HIE多中心协作组.亚低温治疗新生儿缺氧缺血性脑病临床多中心研究阶段性疗效分析[J].中国循证儿科杂志,2006,1(2)99-105.
[9]孙莉,胡小平.新生儿缺氧缺血性脑病亚低温治疗进展[J].中国新生儿科杂 志,2008,23(4)：248-250.
[10]Azzopardi D, Brocklehurst P, Edwards D, et al. The TOBY Study.Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy:a randomised controlled trial [J]. BMC Pediatr,2008,20 (8):17.
[11]Sutton LN, Clark BJ,Norwood CR, et al. Global cerebral ischemia in piglets under conditions of mild and deep hypothermia [J]. Stroke,1991,22 (12):1567-1573.
[12]KaderA, Frazzini V I, Barker CJ, et al. Effect of mild hypothermia on nitric-oxide synthesis during focal cerebral ischemia[J]. Neurosurgery,1994,35 (2) 272-277.
[13]Tooley JR, Satas S, Porter HS, et al. Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective [J].Ann Neurol,2003,53 (1): 65-72.
[14]ColombelM,Olsson CA,Ng PY, et al. Hormone-regulated apoptosis results from reentry of differentiated prostate cells onto a defective cell cycle[J]. Cancer Res, 1992,52 (16):4313-4319.
[15]Chopp M,Li Y, Zhang ZG, et al p53 expression in brain after middle cerebral artery occlusion in the rat[J]. Biochem Biophys Res Commun,1992,182 (3) 1201-1207.
[16]Zhang Z, Sobel RA, Cheng D, et al. Mild hypothermia increases Bcl-2 protein expression following global cerebral ischemia [J].Brain ResMol Brain Res,2001,95 (1 12):75-85.
[17]SlikkerW,DesaiVG,Duhart H, et al. Hypothermia enhances Bcl-2 expression and protects against oxidative stress-induced cell death in Chinese hamster ovary cells[J]. Free Radic BiolMed,2001,31(3):405-411.
[18]Phanithi PB, Yoshida Y, Santana A, et al. Mild hypothermia mitigates post-ischemic neuronal death following focal cerebral ischemia in rat brain: immunohistochemical study of Fas, Caspase23 and TUNEL [J]. Neuropathology,2000, 20 (4):273-282.
[19]王来栓,于立君,邵肖梅.亚低温减轻新生大鼠缺氧缺血脑细胞凋亡的作用 及机制研究[J].中国当代儿科杂志,2007,1(9)：37-41.
[20]YenariMA, Iwayama S, Cheng D, et al. Mild hypothermia attenuates cytochrome C release but does not alter Bcl-2 expression or caspase activation after experimental stroke [J]. Cereb Blood Flow Metab,2002,22 (1):29-38.
[21]Maclellan CL,Davies LM, FingasMS, et al. The influence of hypothermia on outcome after intracerebral hemorrhage in rats [J].Stroke,2006,37 (5):1266-1270.
[22]Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal asphyxia:a safety study[J]. Pediatrics,1998,102 (4Pt1):885-892.
[23]Maier CM,Ahern KB, ChengML, et al. Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia effects on neurologic outcome, infarct size, apoptosis, and inflammation[J]. Neuro Report,1998,5 (26): 2171-2180.
[24]Yager J, Towfighi J, Vannucci RC. Influence of mild hypothermia on hypoxic ischemic brain damage in the immature rat[J]. Pediatr Res,1993,34 (4):525-529.
[25]Jaramillo A, Illanes S, Diaz V. Is hypothermia useful in malignant ischemic stroke? Current status and future perspectives [J]. J Neurol Sci,2008,266 (112):128.
[26]Thoresen M, Hobbs CE, Wood T, et al. Cooling combined with immediate or delayed xenon inhalation provides equivalent long term neuroprotection after neonatal hypoxia-ischemia [J]. J Cereb Blood Flow Metab,2009,29 (4):707-714.
[27]姜敏,朱长速,程秀永.新生儿缺氧缺血性脑损伤的亚低温治疗方案研究进展[J].国外医学儿科学分册,2003,30(1)：16-17.
[28]周文浩,邵肖梅.亚低温治疗新生儿缺氧缺血性脑损伤的临床应用前景[J].中华围产医学杂志,2002,5(2)：158-160.
[29]Gunn AJ, Gunn TR, de Haan HH, et al. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs[J]. J Clin Invest,1997, 99 (2):248-256.
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