多发性硬化抗原特异性调节性T细胞的免疫活性

<正>多发性硬化(multiple sclerosis,MS)是一种发生于中枢神经系统的炎性脱髓鞘疾病,致残率很高,严重影响患者的生存质量[1]。其发病机制迄今尚未完全明确,多认为由于基因和环境的相互作用有关[2]。多个研究发现MS患者外周血CD4+CD25highTreg的效应功能较正常对照下降[3]。动物实验中,经静脉注射给予EAE鼠CD4+CD25+Treg可明显缓解其临床病情[4]。获取足量功能改善的Treg并自体回输无疑会为MS治疗提供一个安全有效新途径。     

星形胶质细胞在多发性硬化发病中的作用机制

星形胶质细胞是中枢神经系统中数量最多的胶质细胞,其生理功能为支持和营养神经元,参与免疫调节和神经递质代谢,支持血-脑脊液屏障,调节神经细胞内、外离子浓度等。星形胶质细胞在多发性硬化(multiple sclerosis,MS)中反应性增生,此现象称为星形胶质细胞活化。活化的星形胶质细胞一方面产生一些具有神经损伤的细胞因子,另一方面能分泌有利于神经系统恢复的因子来促进神经生长和修复。因而星形胶质细胞在MS中具有双重角色。在MS发病机制中明确星形胶质细胞在不同发病阶段的作用倾向,可能为MS的治疗提供新的治疗策略。     

糖皮质激素对多发性硬化患者外周血淋巴细胞CD80和CD4+CD25+T细胞表达的影响

目的探讨糖皮质激素(GC)对多发性硬化(MS)患者外周血淋巴细胞CD80和CD4+CD25+T细胞表达的影响。方法利用流式细胞仪检测21例MS急性期患者GC治疗前后外周血淋巴细胞CD80和CD4+CD25+T细胞阳性率,并与正常对照组比较;比较MS患者治疗前后扩展功能障碍状况量表(EDSS)评分的变化。结果MS患者急性期外周血淋巴细胞CD80的阳性率[(5.031±1.782)%]较正常对照组[(6.436±2.035)%]明显下降(P<0.05),经GC治疗后CD80的阳性率[(6.467±1.882)%]明显增高(P<0.01);CD4+CD25+T细胞阳性率治疗前后与正常对照组间差异均无统计学意义;治疗后EDSS评分[(3.64±1.79)分]较治疗前[(4.26±1.68)分]明显下降(P<0.01)。结论GC可上调MS患者淋巴细胞CD80的表达,抑制细胞免疫,促进MS病情缓解。     

多发性硬化CD8+记忆性T细胞亚群的免疫学研究进展

多发性硬化(multiple sclerosis,MS)是一种发生于中枢神经系统的炎性脱髓鞘性疾病.MS临床上多以复发和缓解为临床特征,被认为与适应性免疫应答有关,在该免疫应答过程中,机体免疫记忆功能的维持至关重要,记忆性细胞则是其主要参与者.近年来多项研究发现CD8+T细胞在MS发病过程中的重要性,其记忆性细胞亚群亦...     

miRNA对多发性硬化CD4+T淋巴细胞分化调控机制的研究进展

多发性硬化(MS)是一种免疫介导的中枢神经系统慢性炎性脱髓鞘性疾病.CD4+T细胞在MS的发病机制中具有重要作用.微小RNA(miRNA)是一类具有调控活性的内源性非编码小分子RNA,通常在转录后水平调控靶基因的表达.miRNA对MS中CD4+T细胞的增殖、分化和功能维持发挥特定的调控作用,当miR-NA表达异常时可能...     

多发性硬化治疗药物及潜在治疗药物的研究进展

多发性硬化（MS）是一种以中枢神经系统炎性脱髓鞘病变为主要特点的免疫介导性疾病，病变主要累及白质，引起神经功能障碍。目前临床上MS的治疗策略主要是疾病修正治疗，其可以减慢疾病进程，但不能治愈疾病。作为终身性疾病，MS治疗药物的合理应用对于控制患者的病情、改善患者的神经功能症状较为关键。现通过归纳总结国内外的文献报道，对MS治疗的药物进行综述，旨在为MS的合理用药和最优治疗方案提供依据。此外，进一步综述处于临床试验和临床前阶段的MS潜在治疗药物，结合MS发病机制与新靶点的研究进展，为探索靶向中枢神经系统的新型治疗策略提供文献参考。     

小胶质细胞在多发性硬化中的两面性作用

多发性硬化(multiple sclerosis,MS)是以炎症反应、脱髓鞘和轴突损伤为特征的中枢神经系统(central nervoussystem,CNS)疾病,实验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis,EAE)是MS研究的动物模型。小胶质细胞(microglia)在MS/EAE的发病过程中发挥了重要作用。它既可产生促炎产物发挥神经毒性作用,还可从产生抗炎产物、促进吞噬作用以及促进神经干细胞增殖和招募三方面发挥神经保护作用。本文将对小胶质细胞在MS/EAE发病过程中的两面性作用作一综述。     

多发性硬化患者抗髓鞘少突胶质细胞糖蛋白抗体的检测及其意义

目的　检测多发性硬化 (MS)患者抗髓鞘少突胶质细胞糖蛋白抗体并探讨其意义。方法　采用EL ISA方法测定 5 6例多发性硬化患者急性期血清和脑脊液配对标本的抗髓鞘少突胶质细胞糖蛋白 (MOG)抗体 ,30例其它神经疾病 (OND)患者为对照。结果　 MS患者血清和脑脊液均可测到抗 MOG抗体 ,血清抗 MOG抗体阳性率为 35 .7% ,脑脊液抗 MOG抗体阳性率为 4 2 .8% ,OND组血清和脑脊液抗 MOG抗体阳性率均为 6 .7% ,与 OND组比较均有显著性意义 (P<0 .0 5 ) ,但血清和脑脊液比较无显著性意义 (P>0 .0 5 )。结论　多发性硬化患者血清和脑脊液中均可检测到抗 MOG抗体 ,可为临床诊断和治疗提供指导。     

利妥昔单抗在多发性硬化中研究进展

多发性硬化(MS)一直以来认为是由T细胞介导的自身免疫性疾病,最近研究提示,B细胞介导的体液免疫在其发病过程中扮演同样重要的作用。利妥昔单抗(RTX)作为一种以CD20+B细胞为靶向的单克隆抗体,现已证实可以通过耗竭B细胞来减少MS疾病的活动性,且安全性好。本文就B细胞在MS中的作用和RTX治疗MS的研究历程进行综述。     

利妥昔单抗在多发性硬化中研究进展

多发性硬化（MS）一直以来认为是由T细胞介导的自身免疫性疾病,最近研究提示,B细胞介导的体液免疫在其发病过程中扮演同样重要的作用。利妥昔单抗（RTX）作为一种以CD20⁺B细胞为靶向的单克隆抗体,现已证实可以通过耗竭B细胞来减少MS疾病的活动性,且安全性好。本文就B细胞在MS中的作用和RTX治疗MS的研究历程进行综述。     

Total tau and S100b proteins in different types of multiple sclerosis and during immunosuppressive treatment with mitoxantrone

Bartosik‐Psujek H, Psujek M, Jaworski J, Stelmasiak Z. Total tau and S100b proteins in different types of multiple sclerosis and during immunosuppressive treatment with mitoxantrone. Acta Neurol Scand: 2011: 123: 252–256. © 2010 John Wiley & Sons A/S. Purpose – Brain‐specific proteins are biochemical markers of neurodegeneration. The aim of this study was to estimate the role of biomarkers in neuronal and glial damage as a potent marker of efficiency of immunosuppressive treatment. Material and methods – The levels of total Tau protein (tTau) and S100b protein were measured using the ELISA method in serum and cerebrospinal fluid (CSF) of 30 patients with RRMS, 24 patients with SPMS and 30 healthy subjects. Additionally, serum levels of tTau and S100b were assayed every 6 months during the 24‐month mitoxantrone therapy. Results – In CSF and serum of patients with MS, both tTau and S100b were increased compared to control group; however, no significant difference was found between respective MS types. In serum of mitoxantrone‐treated patients, both proteins showed to decrease after 24 months, yet the difference was statistically significant only for S100b. Conclusions – CSF levels of tTau and S100b are elevated in patients with MS and can reflect an axonal and glial pathology. Measurement of serum concentrations of S100b may be useful for monitoring immunosuppressive therapy and may support clinical assessment. In contrast, tTau concentration did not prove to be a useful marker of mitoxantrone therapy.     

Astrocytic activation in relation to inflammatory markers during clinical exacerbation of relapsing-remitting multiple sclerosis

Summary The study aimed to assay the cerebrospinal fluid (CSF) levels of protein S100B, a biomarker of astrocyte activation in relation to kynurenic acid (KYNA) and nitric oxide (NO) metabolites, nitrate/nitrite (NOx) concentrations in acute relapse multiple sclerosis (MS) patients. Twenty relapsing-remitting MS (RR-MS) patients and 10 controls were enrolled. RR-MS patients were assessed on the expanded disability status scale (EDSS) and underwent lumbar puncture. The CSF KYNA, NOx and S100B levels were significantly higher in RR-MS group compared to controls (p = 0.01, 0.001, 0.04, respectively). There was a significant correlation between CSF S100B and KYNA (p = 0.01) but not NOx (p > 0.05) in RR-MS. CSF KYNA, NOx or S100B concentrations did not correlate with disease characteristics of MS patients. Our study suggests the activation of the kynurenine pathway leading to the increase of neuroprotective KYNA in the CSF of MS patients during acute relapse what contrasts with chronic phases of the disease.     

血清与脑脊液S100B含量与吉兰-巴雷综合征分型及病程关系的研究

目的探讨血清与脑脊液S100B含量与吉兰-巴雷综合征(Guillain-Barr syndrome,GBS)不同亚型及病程的关系。方法选取31例吉兰-巴雷综合征患者,其中包括经典吉兰-巴雷综合征(acute inflammato-ry demyelinative polyradicul-oneuropathy,AIDP)患者18例,急性运动轴索型神经病(acute motor axon neuropathy,AMAN)患者13例,对照组血清30例,对照组脑脊液10例,用ELISA法测定其S100B的含量;对GBS患者进行1年随访,评价S100B与GBS病程的关系。结果血清S100B含量AIDP组明显高于AMAN组(P<0.05)和对照组(P<0.05),AMAN组与对照组比较无明显差异(P>0.05);而在脑脊液中S100B含量AIDP组明显高于AMAN组和对照组(P<0.05),AMAN组和对照组间亦有明显差别(P<0.05);两组GBS患者脑脊液S100B含量均高于其同组的血清S100B含量(P<0.05);AIDP组血清和脑脊液S100B含量与患者病初运动功能缺失程度(初次Hughes评分)相关,前者r=0.9155,后者r=0.5716。AMAN组血清和脑脊液S100B含量与患者病初运动功能缺失程度(初次Hughes评分)均有相关性,前者r=0.7789,后者r=0.8607。AIDP组血清和脑脊液S100B含量与患者病程一年运动功能恢复程度(末次Hughes评分)都有相关性,前者r=0.7690,后者r=0.6448。AMAN组血清和脑脊液S100B含量与患者病程一年运动功能恢复程度(末次Hughes评分)均有相关性,前者r=0.8677,后者r=0.8651。结论测定血清和脑脊液S100B含量对指导分型具有一定的临床意义,而用血清和脑脊液S100B含量的高低预测GBS病程则不可取,但是如能在结合病理和电生理等检查基础上确定GBS的分型后,血清和脑脊液S100B含量血清和脑脊液S100B含量的高低在一定程度上可以预测患者的病程。     

红藻氨酸致痫大鼠海马S100B、CGRP蛋白表达及病理改变

目的 研究红藻氨酸(KA)致痫大鼠海马S100B、降钙素基因相关肽(CGRP)的表达及病理改变.方法 雄性SD大鼠按照完全随机数字表法分成对照组(8只)和模型组(40只),模型组再根据处死时间分为造模后6 h、12 h、24 h、72 h、1周5个亚组,每组8只.模型组采用KA建立颞叶癫痫动物模型,对照组用等体积生理盐水代替KA注射.模型组造模后6 h、12 h、24 h、72 h、1周,对照组注射后24 h取大鼠海马组织行Nissl染色、Timm染色和免疫组化染色,观察S100B、CGRP蛋白的表达情况以及海马神经元和胶质细胞的病理变化.结果 Nissl染色结果显示,模型组大鼠1周后CA3区出现大量固缩的坏死神经元,胞体萎缩,尼氏体消失.Timm染色结果显示,模型组大鼠1周后CA3区始层出现条带状分布的棕色颗粒,齿状回内分子层亦可见少量棕色颗粒.免疫组化染色结果显示,模型组大鼠海马CGRP蛋白大量表达,72 h时达到高峰,同时伴随大量神经元丧失及胶质细胞增生.结论 KA致痫大鼠出现S100B、CGRP蛋白高表达,尼氏体消失,苔藓纤维发芽等一系列病理学改变,推测S100B、CGRP蛋白参与了癫痫发生.

Abstract：

Objective To investigate the expressions of S100B and calcitonin gene related peptide (CGRP) and the pathologic alterations of the hippocampus in kainic acid (KA)-induced epileptic rats. Methods Male SD rats were randomly divided into control group (n=8) and model group (n=40).Animal models of temporal lobe epilepsy were established by intracerebroventricular injection of KA; the same volume of saline was injected into the rats in the control group. Hippocampal tissues within various phases after seizures (6, 12, 24 and 72 h, and 24 h after the success of model making) were performed Nissl staining, Timm staining and immunohistochemical staining. The expressions of S100B and CGRP were observed, and the pathologic alterations of the hippocampal neurons and glial cells were studied.Results All rat models were successfully induced with epileptic seizures. Nissl staining showed that pyknotic neuronal necrosis appeared in the CA3 area of the hippocampus in the model group with cell body atrophy and disappearance of Nissl bodies 1 week after the injection. Timm staining showed that brown particles showed stripped distribution in the CA3 area of the hippocampus and some brown particles in the molecular layer of fascia dentate. Immunohistochemical staining indicated that significant neurons lost and gliosis appeared after seizures with abundant expressions of S100B and CGRP.Conclusion KA-induced epileptic rats express abundant S100B and CGRP and appear such pathological changes as disappearance of Nissl bodies and mossy fiber sprouting, indicating that both S100B and CGRP participate in the onset of epilepsy.     

硫酸镁对急性重型颅脑损伤患者血清S100B浓度和预后的影响

目的观察急性重型颅脑损伤(asTBI)后血清S100B浓度的变化及其与预后的关系,研究硫酸镁对asTBI患者血清S100B浓度和预后的影响。方法69例患者随机分为硫酸镁治疗组(n=34)和常规治疗对照组(n=35)。按入院时GCS评分分为特重组(GCS3～5分)和重型组(GCS6～8分),于入院时,伤后1、4、7、14天,检测血清镁、S100B浓度和GCS评分。治疗组首剂给予25%硫酸镁16ml静脉滴注,15分钟输完,继予25%硫酸镁60ml静脉滴注,匀速24h输完。对照组除未用硫酸镁外其余治疗与治疗组完全相同。伤后3个月时纪录GOS评分。结果与健康对照组比较,asTBI后血清镁离子浓度下降(P0.05),血清S100B浓度升高,特重组(ssTBI)S100B浓度高于重型组(sTBI)(P0.05)。伤后第4、7天,治疗组血清S100B浓度低于对照组(P0.05)。入院时血清S100B浓度高于1.2μg/L者预后不良,其敏感度为(sensitivity,SEN)为75.8%,特异度(specificity,SPE)为69.4%。治疗组与对照组预后的比较无统计学意义(P0.05)。结论asTBI后,血清镁离子浓度下降,血清S100B浓度升高,且伤情越重,血清S100B浓度越高,预后越差。早期应用硫酸镁提高asTBI患者血清镁离子浓度可降低伤后第4、7天血清S100B浓度,提示硫酸镁具有一定的神经保护作用,但并不能改善预后。     

急性缺血性脑卒中外周血生化标志物的研究进展

早期诊断急性缺血性脑卒中(acute ischemic stroke,AIS),并对其缺血性脑损伤严重性进行评估,在AIS临床十预方法的选择以及预后判断中扮演着重要角色.神经影像学检查虽然能够提供卒中定位和脑组织结构性改变的重要信息,但它对于AIS患者的脑损伤严重性判断是不允足的.     

急性液化石油气中毒大鼠血清S100B和髓鞘碱性蛋白的检测及意义

目的 研究急性液化石油气(LPG)中毒大鼠血清S100B和髓鞘碱性蛋白(MBP)的变化.方法 健康雄性成年SD大鼠54只按随机数字表法分为正常对照组(n=6)、20%LPG中毒组(n=24)和50%LPG中毒组(n=24).后2组大鼠分别吸入20%、50%LPG,对照组吸入等体积的空气.在中毒1、2、3、7 d时每组取6只大鼠进行神经功能缺损评分(NSS),ELISA法检测血清样本S100B和MBP的含量.结果 与正常对照组比较,20%LPG组中毒1 d、50%LPG组中毒1 d和2 d时NSS评分均较高,差异有统计学意义(P＜0.05);在1 d和2 d时,20%LPG组和50%LPG组大鼠血清S100B、MBP均高于正常对照组,且50%LPG组高于20%LPG组,差异有统计学意义(P＜0.05);3 d时50%LPG组血清S100B、MBP高于正常对照组和20%LPG组,差异有统计学意义(P＜0.05);大鼠LPG中毒1 d时NSS评分、血清S100B、MBP浓度最高,与其它时间点比较差异均有统计学意义(P＜0.05),后随时间延长逐渐恢复.结论 LPG中毒大鼠血清S100B和MBP同时升高,提示胶质细胞参与LPG中毒对神经系统的损害.

Abstract：

Objective To observe the changes of serum S100B and MBP in rats with liquid petroleum gas poisoning. Methods Fifty-four healthy adult male SD rats were randomized into normal control group (n=6), 20% LPG poisoning group (n=24) and 50% LPG poisoning group (n=24). Rat models of liquid petroleum gas poisoning were established in the later 2 groups, and controls were given the same volume of air. The rats of each group(n=6) were scored with neurological severity scale (NSS) and the blood serum was collected on the 1st, 2nd, 3nd and 7th d of poisoning, respectively. The levels of S100B and MBP were detected by euzymelinked immunosorbent assay (ELISA).Results As compared with the scores of NSS in the normal control group, those on the 1st d of poisoning in the 20% LPG poisoning group and those on the 1st and 2nd d of poisoning in the 50% LPG poisoning group were significantly higher (P＜0.05). The levels of Sl00B and MBP in 20% and 50% LPG poisoning groups were higher than those in the control group on the 1st and 2nd d of poisoning (P＜0.05); the levels of S100B and MBP in 50% LPG poisoning group were higher than those in 20% LPG poisoning group on the 1st and 2nd d of poisoning (P＜0.05). The levels of S 100B and MBP in 50% LPG poisoning group were higher than those in 20% LPG poisoning group and normal control group on the 3rd of poisoning (P＜0.05). The NSS scores and the levels of S100B and MBP in rats with LPG poisoning enjoyed the highest scores or levels on the 1st d of poisoning and those decreased after that. Conclusion The levels of S100B and MBP of rats with LPG poisoning increase, indicating that gliocytes participate in the mechanism of nervous system injury in rats with liquid petroleum gas poisoning.     

晚期糖基化终产物受体在脑缺血损伤中的表达及作用机制

目的 通过研究RAGE在大鼠及人的缺血脑组织中的表达情况,结合体外神经细胞OGD模型中S100B、RAGE与TNF-α的相互作用结果,探讨RAGE在脑缺血损伤中的作用及相关机制.方法 采用免疫组织化学方法检测RAGE在不同缺血时间点实验大鼠和患者脑组织中的表达;建立体外神经细胞OGD模型,用ELISA方法检测TNF-α的表达.结果 （1）大鼠永久性MCAO 1h、6h、12h、24h、2d、6d缺血侧RAGE表达均明显高于非缺血侧（P＜0.01）,脑梗死患者＜2d组、3～5d组及＞5d组脑病理切片中缺血侧与非缺血侧对比RAGE表达均有显著性差异（P＜0.05）;（2）OGD培养的神经细胞,TNF-α表达量显著增加,与正常培养组相比P＜0.01;用S100B蛋白刺激神经细胞并OGD培养,可以引起神经细胞表达TNF-α的量增加S100B（P＜0.01）;阻断神经细胞表达RAGE后,TNF-α表达量也相应地下降（P＜0.01）.结论 RAGE参与脑缺血损伤过程,缺氧缺糖培养的神经细胞其损伤过程可以通过RAGE表达上调引起TNF-α表达来实现.     

脑震荡患者血清S100B蛋白的变化与认知功能障碍的相关性

目的 分析脑震荡患者血清S100B含量变化与认知功能损害的相关性,探讨血清S100B水平在脑震荡认知障碍预后判断中的意义. 方法 采用酶联免疫法分别测定126例脑震荡患者急诊入院后6h、12h和第3天的血清S100B浓度,并和同期轻型单纯脑外伤患者比较.脑震荡患者常规治疗后,于入院后第1天、第14天及3个月后进行简易智能精神状态检查量表(MMSE)评估,将S100B浓度与MMSE评分进行相关性分析. 结果入院6 h、12 h后脑震荡组患者血清S100B浓度均明显高于对照组,差异有统计学意义(P＜0.05).入院6 h血清S100B浓度与各时段MMSE评分均具有相关性(P均＜0.05);入院12 h、第3天血清S100B浓度与各时段MMSE评分均无相关性(P均＞0.05). 结论 脑震荡患者早期(6 h)血清S100B含量异常升高,并与认知功能损害有明显相关性,可作为认知功能损害预后判断的重要指标.     

施普善对脓毒症大鼠脑保护作用的实验研究

目的 探讨施普善对脓毒症大鼠的脑保护作用及可能的机制.方法 选用96只清洁级雄性SD大鼠,按照完全随机数字表法分为对照组、脓毒症组、施普善高剂量治疗组、施普善低剂量治疗组,每组又分别按造模后不同时间分为3 h、6 h、24 h组,每组8只.脓毒症组及施普善治疗组通过腹腔注射格兰氏阴性菌脂多糖(LPS)溶液(剂量为10mg/kg)建立脓毒症大鼠模型,对照组不造模.治疗组造模后立即按高剂量组215.2mg/kg、低剂量组107.6mg/kg腹腔注射施普善(生理盐水稀释至7.5 mL),对照组和脓毒症组注射与施普善等量生理盐水.在造模后3 h、6 h、24 h抽取各组大鼠颈内静脉和腹主动脉血测定乳酸(LA)及血清超氧化物岐化酶(SOD)、丙二醛(MDA)、S100B含量.结果 与脓毒症组比较,施普善高、低剂量治疗组LA、S100B蛋白、MDA含量明显下降,SOD含量明显上升,差异有统计学意义(P＜0.05).其中高剂量治疗组各项指标较低剂量组更趋于正常,差异有统计学意义(P＜0.05).结论 施普善对脓毒症大鼠大脑具有一定的保护作用,其机制可能与施普善改善脑细胞能量代谢,降低颅内LA、S100B蛋白含量及抗自由基损伤有关,并且这种作用呈剂量依赖性.

Abstract：

Objective To investigate the protective effect of cerebrolysin on cerebral injury in septic rats, and the possible mechanism of such effect. Methods Ninety-six SD rats were equally randomized into control group, sepsis group, high-dose cerebrolysin treatment group and low-dose cerebrolysin treatment group (n=24). And each group was sub-divided into groups of 3, 6 and 24 h after the success of model making (n=8). The septic rat models in the sepsis group and cerebrolysin treatment groups were induced by intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg); cerebrolysin (215.2 mg/kg and 107.6 mg/kg), diluted with physiological saline into 7.5 mL, was also intraperitoneally administered in the 2 treatment groups, respectively; and same milliliter of physiological saline was administered into the sepsis group and control group. Blood samples via jugular vein and ventral aorta in the groups of 3, 6 and 24 h after the success of model making were obtained to measure the levels of blood lactate (LA), superoxide dismutase (SOD), malondialdehyde (MDA) and S100B. Results As compared with the sepsis group, cerebrolysin treatment groups enjoyed significantly lower levels of LA,MDA and S100B protein, obviously higher level of SOD in serum (P＜0.05); these levels in the high-dose cerebrolysin treatment group were much closer to the normal levels than those in the low-dose cerebrolysin treatment group (P＜0.05). Conclusion Cerebrolysin has a protective effect on cerebral injury in septic rats through decreasing the levels of LA and S100B protein, improving energy metabolism of brain cells, and counteracting free radical damage; this effect is dose-dependent.