Th17细胞与多发性硬化/实验性自身免疫性脑脊髓炎

多发性硬化(multiple sclerosis,MS)及其理想动物模型实验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis,EAE)是主要累及中枢神经系统的自身免疫性疾病.     

树突状细胞在实验性自身免疫性脑脊髓炎和多发性硬化中的作用

树突状细胞(Dendritic cells,DC)作为一种专职的抗原呈递细胞(antigen-presenting cell,APC),既能激活机体免疫系统,又可以诱导免疫耐受,是许多自身免疫性疾病和肿瘤免疫研究的热点。本文介绍树突状细胞在实验性自身免疫性脑脊髓炎和多发性硬化发病及治疗过程中所发挥的作用。1树突状细胞的特点DC是一种专职的APC,能激活静止的T细胞和B细胞。DC遇到抗原刺激后迅速表达趋化因子受体(CCR)7,它们能从组织间隙,如肠粘膜、呼吸道粘膜下移行到附近的淋巴结并成熟。人和鼠不同的DC亚群的特性是不一样的,DC既能针对外界的感染作出反应,对机…     

多发性硬化和实验性自身免疫性脑脊髓炎中的轴突损伤

本文综述了多发性硬化和实验性自身免疫性脑脊髓炎中轴突损伤的研究进展,包括疾病早期、起始阶段的轴突损伤及其机制,影像及组织学表现正常的白质内的轴突变性,多发性硬化灰质内的轴突损伤,长病程多发性硬化病变内的轴突缺失等方面,并提出可能的干预措施及存在的问题。     

树突状细胞在自身免疫性脑脊髓炎发病及耐受中作用的研究

目的　研究树突状细胞 ( dendritic cells,DCs)在实验性自身免疫性脑脊髓炎 ( experimental allergicencephalomyelitis,EAE)发病及免疫耐受中的作用。方法　诱导 EAE和口服耐受 EAE模型 ,采用流式细胞仪和直接免疫荧光法观察 EAE不同阶段、不同疾病程度外周淋巴结和中枢神经系统 ( CNS)中 DCs数量的变化。结果　免疫后第 4、7、9天外周淋巴结 DCs数量逐渐增多 ,第 9天脑、脊髓中开始有 DCs浸润 ,第 1 5天 DCs数量达高峰 ,第 1 5、2 3天 DCs数量与疾病症状严重程度相一致。口服耐受组与 EAE组差异无显著性。结论　外周淋巴结和 CNS局部 DCs在 EAE的发生、发展、转归尤其在触发发病中起重要作用。 DCs作为免疫反应的始动者 ,其数量变化在口服免疫耐受的产生机制中具次要作用     

他汀类药物治疗实验性变态反应性脑脊髓炎和多发性硬化研究进展

多发性硬化（multiple sclerosis，MS）是常见的中枢神经系统（central nervous system，CNS）炎性脱髓鞘疾病。根据已证实的体液和细胞免疫反应、与白细胞抗原（HLA）单倍型的遗传联合，以及对免疫调节治疗的临床反应，认为MS是一种自身免疫性疾病。MS的治疗选择很有限，治疗方法包括促皮质激素、皮质激素、细胞毒性药物、抗淋巴细胞球蛋白、血浆交换等，     

实验性自身免疫性脑脊髓炎的历史和现状

<正> 多发性硬化(multiple sclerosis,MS)是一种中枢神经系统(central nervous system,CNS)炎性脱髓鞘性自身免疫性疾病,其确切的发病机制仍不清楚,研究MS的实验动物模型成为探索该病病因学的最佳途径和方法。MS的实验动物模型主要分为免疫介导模型和病毒诱导模型两种,其中以免疫介导模型多用,该模型主要是通过注射CNS髓鞘蛋白(或分子肽段)与抗原佐剂的乳化复合物诱导动物对抗原反     

实验性自身免疫性脑脊髓炎中细胞凋亡的研究进展

实验性自身免疫性脑脊髓炎 (ex perimentalautoimmuneencephalomyelitis ,EAE)已被公认为人类中枢神经系统(CNS)脱髓鞘疾病———多发性硬化(multiplesclerosis ,MS)的经典动物模型 ,是T细胞介导的脱髓鞘疾病。EAE中的细胞凋亡现象既可发生于CNS ,也可发生于外周淋巴器官 ;不仅会发生T细胞凋亡 ,而且巨噬细胞、少突胶质细胞及小胶质细胞均可发生凋亡。因此 ,细胞凋亡对于EAE病程的进展、临床表现及治疗研究等都有重要意义。1　CNS与外周淋巴器官中细胞凋亡的研究概况1.1　CNS的细胞凋亡多种细胞均可在CNS发生凋亡 ,其中自身反应…     

自身抗原冲击的树突状细胞抑制实验性自身免疫性脑脊髓炎具有抗原特异性(简报)

树突状细胞(dendritic cells，DC)不仅有免疫刺激作用．而且能通过诱导中枢和外周耐受而调节免疫反应。近年发现，在诱发自身免疫性疾病动物模型如实验性自身免疫性脑脊髓炎(EAE)之前，皮下注射致病抗原碱性髓鞘蛋白68-86(MBP68-86)体外冲击的DC，对该抗原诱导的EAE模型有明显抑制作用。此研究采用皮下注射3种不同的致脑炎肽MBP68-86、蛋白脂质蛋白139-151(PLP139-151)和髓鞘少突胶质细胞糖蛋白肽(MOG35-55)体外冲击DC，对EAE进行研究。     

实验性自身免疫性脑脊髓炎模型的建立和长期观察研究

目的 建立实验性自身免疫性脑脊髓炎小鼠模型(EAE)并长期观察研究.方法 C57BL/6小鼠30只,随机分为EAE模型组、PBS对照组和正常对照组.应用神经功能评分进行临床评估,通过HE和髓鞘染色观察组织病理变化.结果 小鼠在诱导后的12±3d急性起病,16±2d内达到高峰,严重度评分为3.2±0.6分.半年观察期内复发1次,复发率为25%.光镜下可见EAE组以脊髓组织病变为主,表现为大量炎性细胞浸润和白质脱髓鞘.结论 采用MOG_(35-55)诱导C57BL/6小鼠建立的模型既往被认为是一种慢性迁延EAE模型,本研究通过长期观察发现其存在缓解复发现象.

Abstract：

Objective To establish a mice model of experimental autoimmune encephalomyelitis (EAE) and perform a long term study. Methods C57BL/6 mice were immunized with 300μg MOG_(35-55) in complete Freund' s adjuvant (CFA) to establish EAE model in EAE group (n = 10). Mice in adjuvant group( n = 10)were treated with CFA without MOG_(35-55) and control group( n = 10)were treated with normal saline. The pathologic changes of the central nervous system were studied by HE staining and myelin staining. Results The clinic symptoms of EAE were present in the 12±3th day post-immunization,and went to the peek in the 16±2 th day post-immunization. The severity score was 3.2±0.6. One relapse was observed in the term of 6 months, and the rate was 25%. Light microscopy showed there were abundant inflammatory cells infiltrated especially in spinal cord tissues in EAE mice,with evident demyelination in white matter. Conclusion The relapse of this EAE model was observed in the study, though it was believed to be a chronic persistent model without relapse.     

调节性T细胞在实验性变态反应性脑脊髓炎和多发性硬化发病中的作用

调节性T细胞(regulatory T cells,Treg)是一类具有免疫调节功能的T细胞哑群.近年来,Treg细胞在实验性变态反应性脑脊髓炎(experimental allergical encephalomyelitis,EAE)、多发性硬化(multiple sclerosis,MS)发病中的作用越来越受到关注,小鼠Treg细胞缺失可导致特异性自身免疫性疾病,增加Treg细胞的功能可以减轻或抑制EAE.最近的研究结果表明,MS本身也伴随着成熟Treg细胞的受损或功能障碍.     

黏附分子CD44在实验性自身免疫性脑脊髓炎中的作用

目的探讨黏附分子CD44在实验性自身免疫性脑脊髓炎(EAE)发病中的作用。方法将20只大鼠随机分为正常对照组及EAE组,EAE组采用粗制髓鞘碱性蛋白(MBP)抗原注入大鼠后足掌皮下(0. 2 ml/100 g)制作EAE模型,观察大鼠的发病情况及病理表现;并采用免疫组织化学法检测两组大鼠脑组织CD44的含量。结果正常对照组大鼠未发病,EAE组大鼠均有不同程度的发病。HE染色后,光镜下观察,正常对照组大鼠脑和脊髓无异常; EAE组大鼠可见脑及脊髓实质内小血管充血,小静脉周围有大量炎性细胞浸润,血管周围白质脱髓鞘改变。免疫组化显示,正常对照组大鼠脑和脊髓组织未发现CD44阳性细胞; EAE组大鼠中枢神经系统(CNS)白质及灰白质交界处可见大量CD44阳性细胞。结论 EAE模型中存在黏附分子CD44的高表达,其对EAE的发病可能起到促进作用。     

Lesional accumulation of RhoA(+) cells in brains of experimental autoimmune encephalomyelitis and multiple sclerosis

Aim: Infiltration of autoantigen-specific T cells and monocytes into the central nervous system is essential for the development of both experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). RhoA is one of the best-known members of Rho GTPases, and inhibition of RhoA has been shown to attenuate the progression of EAE. The aim of this study was to investigate the expression of RhoA in brains of EAE rats and MS tissue. Methods: EAE was induced by immunization with the synthetic peptide gpMBP68-84 in rats, and clinical severity was scored. RhoA expression pattern was investigated in brains of EAE rats at different time points and in different lesions of brain tissue specimens from six MS brains and five neuropathologically unaffected controls by immunohistochemistry. Methods: In EAE rat brains, accumulation of RhoA⁺ cells reached maximal levels around Day 13, correlating to the clinical severity of EAE, and up-regulation lasted until the recovery stage of the disease. Double-labelling experiments showed that the major cellular sources of RhoA were reactive macrophages/microglia. While RhoA⁺ cells in normal human brain parenchyma were rarely observed, RhoA expression was found to be spatially associated with MS lesions, showing a marked decrease from active lesions via chronic stages to its near absence in normal-appearing white matter. In addition, major RhoA⁺ cells in brain parenchyma of MS were identified to be activated macrophages/microglia. Conclusion: Our present data indicated that RhoA may play an important role during the effector phase of EAE and MS. Therefore, RhoA inhibitors might be a therapeutic option for MS patients.     

Suppression of experimental autoimmune encephalomyelitis by sulfasalazine

It has recently been suggested that the sulfidopeptide leukotriene C4 (LTC4), a 5-lipoxygenase product of the arachidonic acid metabolism and one of the most potent mediators of vascular permeability, might be involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). Subsequently, 20 guinea pigs with EAE were treated with sulfasalazine, a substance with a proved leukotriene inhibiting effect, which has previously been described as exerting beneficial effects in patients with inflammatory bowel disease and rheumatoid arthritis. The sulfasalazine-treated guinea pigs showed a significantly better clinical outcome, as well as a significantly lower histological inflammation score compared with 19 controls.     

一氧化氮供体对实验性自身免疫性脑脊髓炎的作用

目的探讨一氧化氮供体3-吗啉-斯德酮亚胺(3-morpholinosydnonimine,SIN-1)对实验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis,EAE)大鼠的作用。方法应用豚鼠髓鞘碱性蛋白68-86(myelin basic protein 68-86,MBP68-86)主动免疫制作EAE实验动物模型。将大鼠随机分为SIN-1组和对照组,SIN-1组大鼠于致敏后第0~7天给予SIN-1药物干预,动态观察两组大鼠的临床症状及体质量变化,致敏后第14天采用ELISA方法检测各组大鼠单个核细胞(mononuclear cells,MNC)培养上清中γ干扰素(IFN-γ)和白细胞介素-4(IL-4)水平,并观察大鼠脑组织病理变化。结果与对照组比较,SIN-1组大鼠发病时间延迟,恢复时间提前,体质量明显增加,临床症状明显减轻;疾病症状最高评分明显降低。SIN-1组大鼠MNC培养上清中IFN-γ水平为(90.29±9.07)pg/mL,较对照组的(121.57±10.44)pg/mL明显降低(P<0.05);IL-4水平为(18.14±3.98)pg/mL,较对照组的(8.14±1.95)pg/mL明显增加(P<0.05)。SIN-1组大鼠组织病理损伤较对照组明显减轻。结论一氧化氮供体SIN-1可抑制EAE大鼠病情发展,对EAE具有保护作用。     

Variation in experimental autoimmune encephalomyelitis scores in a mouse model of multiple sclerosis

Multiple sclerosis (MS) is a common demyelinating central nervous system disease associated with progressive physical impairment. To study the mechanism underlying disease pathogenesis and develop potential treatments, experimental autoimmune encephalomyelitis (EAE) is often used as an animal model. EAE can be induced in various species by introducing specific antigens, which ultimately result in motor dysfunction. Although the severity of the paralysis is indicated using the EAE score, there is no standard scoring system for EAE signs, and there is variability between research groups with regard to the exact EAE scoring system utilized. Here, we describe the criteria used for EAE scoring systems in various laboratories and suggest combining EAE score with another quantitative index to evaluate paralysis, such as the traveled distance, with the goal of facilitating the study of the mechanisms and treatment of MS.     

Ginsenoside Rd ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice

Multiple sclerosis (MS) is a common disabling autoimmune disease without an effective treatment in young adults. Ginsenoside Rd, extracted from Panax notoginseng, has multiple pharmacological effects and potential therapeutic applications in diseases of the central nervous system. In this study, we explore the efficacy of ginsenoside Rd in experimental autoimmune encephalomyelitis (EAE), an established model of MS. EAE was induced by myelin oligodendrocyte glycoprotein 35–55‐amino‐acid peptide. Ginsenoside Rd (10–80 mg/kg/day) or vehicle was intraperitoneally administered on the disease onset day, and the therapy persisted throughout the experiments. The dose of 40 mg/kg/day of ginsenoside Rd was selected as optimal. Ginsenoside Rd effectively ameliorated the clinical severity in EAE mice, reduced the permeability of the blood–brain barrier, regulated the secretion of interferon‐gamma and interleukin‐4, promoted the Th2 shift in vivo (cerebral cortex) and in vitro (splenocytes culture supernatants), and prevented the reduction in expression of brain‐derived neurotrophic factor and nerve growth factor in both cerebral cortex and lumbar spinal cord of EAE mice. This study establishes the potency of ginsenoside Rd in inhibiting the clinical course of EAE. These findings suggest that ginsenoside Rd could be a promising agent for amelioration of neuroimmune dysfunction diseases such as MS. © 2014 Wiley Periodicals, Inc.     

Chronic exercise confers neuroprotection in experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is an autoimmune disease that affects the CNS, resulting in accumulated loss of cognitive, sensory, and motor function. This study evaluates the neuropathological effects of voluntary exercise in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Two groups of C57BL/6J mice were injected with an emulsion containing myelin oligodendrocyte glycoprotein and then randomized to housing with a running wheel or a locked wheel. Exercising EAE mice exhibited a less severe neurological disease score and later onset of disease compared with sedentary EAE animals. Immune cell infiltration and demyelination in the ventral white matter tracts of the lumbar spinal cord were significantly reduced in the EAE exercise group compared with sedentary EAE animals. Neurofilament immunolabeling in the ventral pyramidal and extrapyramidal motor tracts displayed a more random distribution of axons and an apparent loss of smaller diameter axons, with a greater loss of fluorescence immunolabeling in the sedentary EAE animals. In lamina IX gray matter regions of the lumbar spinal cord, sedentary animals with EAE displayed a greater loss of α‐motor neurons compared with EAE animals exposed to exercise. These findings provide evidence that voluntary exercise results in reduced and attenuated disability, reductions in autoimmune cell infiltration, and preservation of axons and motor neurons in the lumbar spinal cord of mice with EAE. © 2014 Wiley Periodicals, Inc.     

Keratan sulfate exacerbates experimental autoimmune encephalomyelitis

Proteoglycans (PGs) are the components of extracellular matrices in the central nervous system (CNS). Keratan sulfate (KS) is a glycosaminoglycan that is included in the KSPG that acts as an inhibitory factor in nerve regeneration after CNS injury. To investigate the role of KS in immune diseases, we induced experimental autoimmune encephalomyelitis (EAE) in mice that were deficient in the N‐acetylglucosamine (GlcNAc)‐6‐O‐sulfotransferase 1 (GlcNAc6ST1) gene (KS‐KO). KS‐KO mice developed less severe EAE and showed repressed recall response in the induction phase. Furthermore, GlcNAc6ST1 might have roles in the passage of the pathogenic lymphocytes through the blood–brain barrier via adhesion molecules. Thus, modulation of KS may become a treatment for neuroimmunological diseases. © 2015 Wiley Periodicals, Inc.     

Serum pro-inflammatory and anti-inflammatory cytokines and the pathogenesis of experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) as an experimental model of multiple sclerosis (MS) is characterized by demyelination, infiltration of inflammatory cells into the nervous system and dysregulation of serum inflammatory cytokines. We investigated the correlation of serum cytokines and other inflammatory markers with the EAE pathogenesis. After EAE induction, the levels of different serum cytokine/inflammatory mediators were measured. Furthermore, motor functions, myelination, and lymphocyte infiltration in EAE mice were also assessed. Our results revealed that the serum concentrations of T-helper 1 (Th1) and Th17 cytokines, interleukin (IL)-6, IL-1β, IL-1α and prostaglandin E2 in EAE mice were significantly higher than controls. The ratios of pro- to anti-inflammatory cytokines were different between the EAE and the control group. A statistically significant positive correlation was found between the IL-6/IL-10 ratio and the EAE severity, demyelination rate, and lymphocyte infiltration in EAE mice. Results indicate that the profiles of serum pro- and anti-inflammatory cytokines might be useful as biomarkers for monitoring the pathological manifestation of EAE. Furthermore, evaluating the dynamic interplay of serum cytokine levels and the correlation with pathogenic mechanisms of EAE may provide diagnostic and therapeutic insights for MS and some other inflammatory disorders.