T cell epitope spreading to myelin oligodendrocyte glycoprotein in HLA-DR4 transgenic mice during experimental autoimmune encephalomyelitis

Epitope spreading has been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and human multiple sclerosis (MS). T cell epitope spreading has been demonstrated in rodents for myelin basic protein (MBP) and proteolipid protein (PLP) determinants, but not for myelin oligodendrocyte glycoprotein (MOG), another important myelin antigen. Moreover, the role of human autoimmunity-associated MHC molecules in epitope spreading, including HLA-DR2 and DR4, has not been formally examined. To address these questions, we investigated epitope spreading to MOG determinants in HLA-DR4 (DRB1*0401) transgenic mice during EAE. The data show that upon induction of EAE in HLA-DR4 transgenic mice with the immunodominant HLA-DR4-restricted MOG peptide 97-108 (MOG(97-108); TCFFRDHSYQEE), the T cell response diversifies over time to MOG(181-200) (core: MOG(183-191); FVIVPVLGP) and MBP. The spreading epitope MOG(181-200) binds with high affinity to HLA-DRB1*0401 and is presented by human HLA-DRB1*0401+antigen presenting cells. Moreover, this epitope is encephalitogenic in HLA-DRB1*0401 transgenic mice. This study demonstrates intra- and intermolecular epitope spreading to MOG and MBP in "humanized" HLA-DR4 transgenic mice.     

Wistar大鼠实验性变态反应性脑脊髓炎病理探讨

目的研究缓解-复发型EAE大鼠的基本病理改变。方法对缓解-复发型EAE大鼠进行HE染色、Weil髓鞘染色和改良的Bielschowsky染色,以免疫组化方法标记GFAP和MMP-2、MMP-9。结果组织内可见多个血管周围淋巴细胞浸润呈袖套样分布,伴有大片状脱髓鞘,部分脱失的髓鞘内有炎细胞浸润,轴索呈空泡样缺失,GFAP染色证明在旧病灶的周围部分可见星形胶质细胞增生,MMP-2、MMP-9在血管内皮细胞、细胞外基质、炎细胞及脑(脊)膜内呈阳性表达。结论①缓解-复发型EAE大鼠的组织病理学改变与临床表现一致,有活动性和非活动性病灶并存的现象。②MMP-2、MMP-9在活动性病灶内表达,参与疾病的发生。③缓解-复发型EAE病理改变与MS相似,是理想的动物模型。     

地塞米松对实验性自身免疫性脑脊髓炎大鼠MCP-1表达的影响

目的为探讨地塞米松(DXM)对实验性自身免疫性脑脊髓炎(EAE)大鼠临床指标和单核细胞趋化蛋白1(MCP1)mRNA的影响。方法将正常大鼠、完全抗原和百日咳毒素原液免疫后的大鼠免疫后7d,分成:正常大鼠、EAE组和DXM组。DXM组给予DXM腹腔注射,另外两组给予生理盐水注射。取脑和脊髓制成石蜡切片,进行苏木素伊红(HE)染色和MCP1mRNA的原位杂交(ISH),并比较各项临床指标。结果DXM组的发病率、临床评分和MCP1mRNA的阳性细胞数显著性降低(P<0.01)。结论进一步证实DXM的使用可对EAE有治疗作用。     

手足口病并发脑脊髓炎63例临床分析

目的研究手足15病并发脑脊髓炎的临床和检验检查特点，以提高诊治水平。方法对63例手足口病并发脑脊髓炎患儿的临床资料进行回顾性分析及随访研究。结果发病年龄1～11岁，平均（3．36±1．13）岁。肢体活动障碍59例（93．7％），脑脊液常规异常63例（100％），脑脊液蛋白升高20例（31．7％）平均住院日为（16．8±1．94）d，较脑脊液蛋白正常患儿平均住院13长。磁共振异常45例（71．4％），以脑桥或脊髓斑片状及条状长T1、长T2信号为主。脑电图异常30例（47．6％），肌电图检查四肢神经传导异常40例（63．5％），提示F波出波率低。63例均予激素治疗，60例同时合用大剂量人血丙种球蛋白，疗效显著，所有患儿均好转。经6个月随访，1例左下肢稍有跛行，54例恢复正常，8例失随防。结论脑脊髓炎是重症手足口病中枢神经系统损害的表现之一，好发年龄3～4岁。脑脊液、MRI、肌电图检查四肢神经传导功能，有助于早期诊断。脑脊液蛋白升高提示恢复慢、住院时间长。糖皮质激素及大剂量丙种球蛋白有一定疗效，预后良好。     

Experimental Autoimmune Encephalomyelitis in the Wistar Rat: Dependence of MBP-specific T Cell Responsiveness on B7 Costimulation

Experimental autoimmune encephalomyelitis (EAE) is an animal model of human multiple sclerosis that requires the activation of autoreactive T cells for the expression of pathology. EAE has been most frequently studied in the Lewis rat model as well as in several murine models of EAE including the PLJ and B10PL strains. In the present study we describe a novel model of EAE induced in the Wistar rat strain by immunization with guinea pig spinal cord antigens and pertussis toxin (PT). T cell responses were induced to myelin basic protein. Autoreactive T cells could be totally blocked by the in vitro treatment with CTLA4Ig, a protein that blocks the costimulation of autoreactive T cells. The addition of IL-2 could reverse the inhibition seen in vitro with CTLA4Ig. The effects of inhibition of B7 costimulation were also examined by an analysis of cytokine responses and IL-2 receptor on T cells. CTLA4Ig treatment in vitro reduced the expression of IL-2 receptor on T cells, enhanced T cell apoptosis and decreased the synthesis of IL-2, IFN- &#110 and TNF- &#102 . CTLA4Ig treatment had no effect on IL-10 synthesis by T cells, a cytokine implicated in the functions of regulatory T cell subsets. Overall, our studies support the rationale of B7 blocking therapies as a potential treatment for models of multiple sclerosis. The induction of EAE in the Wistar rat provides yet another novel model in which to examine the regulation of T cell autoimmunity.     

T-cell vaccination prevents EAE effector cell development but does not inhibit priming of MBP responsive cells

Cell recipients which have recovered from adoptively transferred Experimental Allergic Encephalomyelitis (EAE) mediated by encephalitogenic T-cell lines do not develop clinical disease following subsequent challenge with myelin basic protein (MBP) emulsified in CFA (MBP-CFA), a recipient response termed vaccination. The immune mechanism(s), which accounts for the vaccination-induced resistance response, is not known. We have used an adoptive transfer system to investigate the point(s) of control within the pathway of EAE effector cell development from MBP-specific naive precursors that prevents clinical disease in T-cell line vaccinated, MBP-CFA challenged Lewis rats. Although EAE effector cells do not develop in T-cell line vaccinated recipients, our data shows that MBP precursor cells are primed in T-cell line vaccinated MBP-CFA challenged animals, and these MBP-specific precursor cells can be stimulated in culture to the EAE effector cell level. MBP-memory cells also arise in T-cell line vaccinated MBP-CFA challenged donors, as demonstrated by the early and rapid onset of EAE in MBP-CFA challenged recipients of lymphnode cells from T-cell line vaccinated MBP-CFA challenged donors. We also found that it was possible to adoptively transfer resistance to MBP-CFA challenge using spleen cells from donors previously vaccinated with encephalitogenic T-cells. These results show that although EAE effector cells do not develop in T-cell line vaccinated animals, T-cell vaccination does not inhibit the initial MBP precursor cell response and does not prevent the development of MBP memory cells. © 1996 Wiley-Liss, Inc.     

急性播散性脑脊髓炎与经典多发性硬化的临床对比分析

目的 寻找临床上鉴别急性播散性脑脊髓炎(acute disseminated encephalumyelitis,ADEM)与经典多发性硬化(classical multiple sclerosis,CMS)的方法.方法 回顾性分析20例ADEM和24例CMS患者的流行病学特点、临床症状、实验室检查和MRI,对各定性资料进行卡方检验,定量资料进行两独立样本的Wilcoxon秩和检验.结果 ADEM患者起病年龄[(27±15)岁]较CMS患者[(37±13)岁,Z=-2.218,P=0.027]小.ADEM患者通常有前驱感染史(75%),发热(65%)、脑膜刺激征(40%)、癫痫(25%),较CMS者常见(x2=23.652、18.609、9.189、4.514,均P＜0 05),脑病更多见于ADEM患者.ADEM患者血白细胞[(11 9±5.8)×109/L,Z=-2.030,P=0.042]、C反应蛋白(2.74 mg/L,Z=-3.028,P=0.002)、红细胞沉降率(11.00 mm/h,Z=-2 406,P=0.016)、脑脊液白细胞(9×106/L,Z=-2.781,P=0.005)较CMS患者[上述指标分别为(8.0±3.2)×109/L、0.49 mg/L、7.00 mm/h、2 ×106/L]高,脑脊液蛋白(ADEM组0.19 g/L,CMS组0.17 g/L)及寡克隆带(OCB)阳性率(ADEM组4/20,CMS组11/24)在两者间差异无统计学意义.在MRI上,ADEM患者更多见皮质灰质病灶(14/20,x2=15.213,P=0.000)、基底节区灰质病灶(14/20,x2=8.910,P=0.003)和脑干病灶(14/20,x2=5.867,P=0.015),脊髓病灶多近中央分布(83%,x2=11.542,P=0 001),病灶边界模糊(95%,x2=21.787,P=0.000);CMS患者更多见近皮质白质病灶(21/24,x2=17.628,P=0.000)、侧脑室旁病灶(21/24,x2=15.213,P=0.000)和胼胝体病灶(14/24,x2=8.640,P=0.003),脊髓病灶多呈偏心分布(85%),病灶边界清楚(75%).结论 ADEM与CMS无论在流行病学特点、临床症状,还是在脑脊液和MRI检查方面都有一定差异.

Abstract：

Objective To improve differential diagnosis between acute disseminated encephalomyelitis ( ADEM) and classical multiple sclerosis ( CMS).Methods All 20 cases of ADEM and 24 cases of CMS were examined.Their epidemiological and clinical findings,laboratory features and magnetic resonance imaging ( MRI) data were analyzed using x2 test for categorical variables,Wilcoxon Rank-Sum tests for continuous variables.Results ADEM and CMS showed no sex predominance.Patients with ADEM ((27 ±15) years) were younger than CMS ((37 ±13) years,Z= -2.218,P =0.027).The following findings were more commonly seen in ADEM compared with CMS:predemyelinating infectious disease (75% vs 4%,x2 =23.652,P = 0.000),fever (65% vs 4%,x2 =18.609,P = 0.000),meningeal irritation sign (40% vs 0,x2 = 9.189,P =0.002),seizure (25% vs 0,x2 =4.514,P = 0.034),and encephalopathy.ADEM patients were more likely to present with blood leucocytosis ( (11.9 ± 5.8) ×109/L vs (8.0±3.2) ×109/L,Z= -2.030,P=0.042),high C-reactive protein (2.74 mg/L vs 0.49 mg/L,Z = - 3.028,P = 0.002),increased erythrocyte sedimentation rate (11.00 mm/h vs 7.00 mm/h,Z= -2.406,P =0.016),and cerebrospinal fluid leucocytosis (9 × 106/L vs 2×106/L,Z =- 2.781,P = 0.005).There were no differences in cerebrospinal fluid protein and oligoclonal band between the two groups.The following MRI lesions were more commonly seen in ADEM patients:cortical gray matter lesions (14/20,x2=15.213,P=0.000),basal ganglia gray matter lesions (14/20,x2 =8.910,P = 0.003),and brainstem lesions ( 14/20,x2 = 5.867,P = 0.015).In contrast,lesions in subcortical white matter (21/24,x2 = 17.628,P =0.000),periventricular area (21/24,x2 =15.213,P=0.000) and corpus callosum ( 14/24,x2 = 8.640,P = 0.003 ) were more common in the MRI image of CMS patients.The lesions in spinal cord were usually centrally distributed in ADEM (83% ),while peripherally in CMS (85%,x2 = 11.542,P = 0.001).The lesions had poorly defined margins in ADEM (95%),but well defined margins in CMS (75%,x2 =21.787,P = 0.000).Conclusion There are differences in epidemiological and clinical findings,laboratory features and MRI appearances between ADEM and CMS.     

实验性变态反应性脑脊髓炎大鼠模型的复制

目的：观察不同的遗传背景（远交系和近交系）和饲养环境对Wistar大鼠实验性变态反应性脑脊髓炎（EAE）发病率的影响，摸索EAE模型制作的实验方法与技术。方法： 采用动物行为学、常规HE和LFB染色方法，观察不同的遗传背景和饲养环境下豚鼠全脊髓匀浆诱导大鼠EAE的发病情况与中枢神经系统（CNS）的病理变化。结果： （1）动物行为学的改变：各组大鼠EAE发病率、潜伏期和症状评分无显著差异，但近交系组发病大鼠可出现四肢瘫痪。（2）病理学改变：每组发病大鼠CNS内可见不同程度的炎性细胞浸润；髓鞘染色可见广泛的神经髓鞘变性、脱失；而其中近交系组的5只EAE大鼠髓鞘脱失部位大多局限在炎症改变明显的血管套周围的白质区。结论： 远交系与近交系，或清洁级与普通级的Wistar大鼠的EAE的发病率无明显差异，而远交系与近交系的不同遗传背景可能会影响大鼠EAE的体征和病理表现。     

Retrograde transport of horseradish peroxidase is specifically impaired in bulbospinal serotonin axons during experimental allergic encephalomyelitis

Bulbospinal monoamine-containing axons appear to be severely damaged in rats with the inflammatory and demyelinating disease, experimental allergic encephalomyelitis (EAE). This paper reports that although bulbospinal serotonin axons are damaged in the disease, cell bodies of origin in the medulla oblongata retain normal morphology. However, these serotonin cells are not able to retrogradely transport the enzyme horseradish peroxidase (HRP) from terminals in the lumbar spinal cord. Most non-serotonin-containing cells in the medulla which project to the lumbar spinal cord retain the ability to retrogradely transport HRP from the lumbar cord during the disease. These findings suggest that there is some specificity to spinal cord axonal damage during EAE.     

急性播散性脑脊髓炎的MRI表现与临床分析

目的 :探讨急性播散性脑脊髓炎 (ADEM)脑部MRI及临床表现、病程、预后间的关系。方法 :回顾性分析 43例的MRI表现及临床资料 ,按病灶大小、数目分组 ,分析病灶大小、数目与临床表现、病程及预后间的关系。结果 :双侧脑室周围及额、颞、顶、枕白质区见多发、不对称长T1长T2 信号灶 ,部分T1WI为等信号。 18例见环形强化 ,3例轻度至中度占位效应。病灶大小与临床分级组间差异有显著性意义 (P <0 .0 5 ) ;病灶大小与病程、预后无明显相关性 ;病灶数目与临床分级、病程均无明显相关性。结论 :综合分析ADEM的脑部MRI表现 ,可在一定程度上为临床诊断、病情评估、治疗监测及评估预后提供依据。