自噬在多发性硬化中的研究进展

多发性硬化(MS)是一种自身免疫性疾病,其发病机制尚不明确,可能是多因素共同致病的结果。自噬,即细胞内的"自食"现象,可清除细胞内多余的细胞器和蛋白质,是维持机体正常生理功能的重要机制。近年研究发现,自噬参与了MS和实验性自身免疫性脑脊髓炎(EAE)的发生发展过程,EAE是一种用中枢神经系统髓鞘抗原免疫易感动物的自身免疫性疾病模型,是目前最常用于研究MS的动物模型。对自噬的干预有望能为阐明MS的发病机制和开发更多治疗措施提供新的依据,文中就自噬在MS中的研究进展做一综述。     

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，     

雌激素在多发性硬化中的免疫调节作用

多发性硬化（MS）是一种CNS慢性脱髓鞘疾病，实验性自身免疫性脑脊髓炎（EAE）是研究MS的理想动物模型。目前已证实雌激素在MS和EAE中可从细胞免疫、体液免疫和抗原呈递等各方面发挥广泛的免疫调节作用，但雌激素复杂的免疫调节机制仍待探讨。     

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.     

细胞凋亡在多发性硬化中的作用及其机制

多发性硬化(MS)是一种以中枢神经系统脱髓鞘病变为特征的自身免疫性疾病。在MS及其动物模型—实验性自身免疫性脑脊髓炎,细胞凋亡参与了自身反应性T细胞的清除和脑细胞(少突胶质细胞、巨噬细胞、小胶质细胞等)的损伤、修复,其机制可能是通过Fas/FasL系统、内源性皮质醇等途径。对凋亡过程的干预有可能成为一种治疗MS的新策略。     

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。     

Th17细胞在多发性硬化发病过程中的作用

多发性硬化被认为是Th1细胞介导的自身免疫病。近年来,一种以分泌IL-17为特征的Th17细胞被发现与自身免疫反应有关。越来越多的证据表明,Th17细胞参与自身免疫性炎症的病理过程,在实验性自身免疫性脑脊髓炎和多发性硬化的发生发展过程中发挥着重要作用。其介导多发性硬化的具体机制仍不清楚,可能与破坏血脑屏障、诱导单核细胞扩增并分化为髓样树突状细胞以及促进炎性细胞因子网络的形成等有关。本文综述了关于Th17细胞的发现、分化以及在多发性硬化发病机制中的作用。     

蠕虫对多发性硬化动物模型的保护作用

一、多发性硬化(MS)和实验性自身免疫性脑脊髓炎多发性硬化是中枢神经系统(CNS)白质炎症脱髓鞘性自身免疫性疾病,临床主要表现为缓解复发和阶梯进展的视力、运动和平衡障碍。MS按疾病的病程分为以下几种类型:缓解复发型、原发进展和继发进展型。MS病情的进展是髓鞘抗原特异性T细胞,以髓鞘为靶,导致CNS的炎症浸润,最后导     

甲基维生素B12对多发性硬化模型大鼠的作用

研究甲基维生素B12 对脱髓鞘的修复作用。以实验性自身免疫性脑脊髓炎作为多发性硬化的动物模型。用豚鼠脊髓匀浆和完全弗氏佐剂诱导Lewis大鼠发生实验性自身免疫性脑脊髓炎 (experimentalauto immuneen cephalomyelitis,EAE) ,给予不同剂量的甲基维生素B12 ,观察体重变化、神经系统评分和组织学检查。注射甲基维生素B12 (2 6 6 μg/kg ,5 32 μg/kg)增加大鼠的缓解比例 ,由 35 .7%增至 6 0 %。降低死亡率 ,由 5 2 .3%降为 16 .70 % ,减少体重 (g)下降量 ,由 18.9± 15 .6降到 4 .8± 9.5。组织学检查证实甲基维生素B12 有促进髓鞘修复的作用。提示 ,较大剂量甲基维生素B12 对多发性硬化模型大鼠有确切良好作用。     

甲基维生素B12对多发性硬化模型大鼠的作用

研究甲基维生素Bi2对脱髓鞘的修复作用.以实验性自身免疫性脑脊髓炎作为多发性硬化的动物模型.用豚鼠脊髓匀浆和完全弗氏佐剂诱导Lewis大鼠发生实验性自身免疫性脑脊髓炎(experimental auto-immuneencephalomyelitis,EAE),给予不同剂量的甲基维生素B12,观察体重变化、神经系统评分和组织学检查.注射甲基维生素B12(266 μg/kg,532μg/kg)增加大鼠的缓解比例,由35.7%增至60%.降低死亡率,由52.3%降为16.70%,减少体重(g)下降量,由18.9±15.6降到4.8±9.5.组织学检查证实甲基维生素B12有促进髓鞘修复的作用.提示,较大剂量甲基维生素B12对多发性硬化模型大鼠有确切良好作用.     

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.     

Tissue Transglutaminase contributes to experimental multiple sclerosis pathogenesis and clinical outcome by promoting macrophage migration

Multiple sclerosis is a serious neurological disorder, resulting in e.g., sensory, motor and cognitive deficits. A critical pathological aspect of multiple sclerosis (MS) is the influx of immunomodulatory cells into the central nervous system (CNS). Identification of key players that regulate cellular trafficking into the CNS may lead to the development of more selective treatment to halt this process. The multifunctional enzyme tissue Transglutaminase (TG2) can participate in various inflammation-related processes, and is known to be expressed in the CNS. In the present study, we question whether TG2 activity contributes to the pathogenesis of experimental MS, and could be a novel therapeutic target.In human post-mortem material, we showed the appearance of TG2 immunoreactivity in leukocytes in MS lesions, and particular in macrophages in rat chronic-relapsing experimental autoimmune encephalomyelitis (cr-EAE), an experimental MS model. Clinical deficits as observed in mouse EAE were reduced in TG2 knock-out mice compared to littermate wild-type mice, supporting a role of TG2 in EAE pathogenesis. To establish if the enzyme TG2 represents an attractive therapeutic target, cr-EAE rats were treated with TG2 activity inhibitors during ongoing disease. Reduction of TG2 activity in cr-EAE animals dramatically attenuated clinical deficits and demyelination. The mechanism underlying these beneficial effects pointed toward a reduction in macrophage migration into the CNS due to attenuated cytoskeletal flexibility and RhoA GTPase activity. Moreover, iNOS and TNFα levels were selectively reduced in the CNS of cr-EAE rats treated with a TG2 activity inhibitor, whereas other relevant inflammatory mediators were not affected in CNS or spleen by reducing TG2 activity. We conclude that modulating TG2 activity opens new avenues for therapeutic intervention in MS which does not affect peripheral levels of inflammatory mediators.     

Axonal and neuronal pathology in multiple sclerosis: What have we learnt from animal models

Axonal and neuronal injury and loss are of critical importance for permanent clinical disability in multiple sclerosis patients. Axonal injury occurs already early during the disease and accumulates with disease progression. It is not restricted to focal demyelinated lesions in the white matter, but also affects the normal appearing white matter and the grey matter. Experimental studies show that many different immunological mechanisms may lead to axonal and neuronal injury, including antigen-specific destruction by specific T-cells and auto-antibodies as well as injury induced by products of activated macrophages and microglia. They all appear to be relevant for multiple sclerosis pathogensis in different patients and at different stages of the disease. However, in MS lesions a major mechanism of axonal and neuronal damage appears to be related to the action of reactive oxygen and nitrogen species, which may induce neuronal injury through impairment of mitochondrial function and subsequent energy failure.     

Neuroinflammation responses and neurodegeneration in multiple sclerosis

Diffuse neurodegeneration is now considered to be the main cause of irreversible neurological disability in multiple sclerosis (MS). Demonstration of a diffuse inflammatory reaction in the MS brain led to the assumption that diffuse neuroinflammation induces diffuse neurodegeneration. Macrophages/microglia accumulate throughout the MS brain and are, therefore, considered the main culprits implicated in the development of neurodegeneration. However, recent advances in the understanding of macrophage/microglia functions and origins have now challenged that view. This report is a summary of these advances, and discusses their contribution to the perception of macrophage/microglia functions in MS-associated neurodegeneration.     

Chronic relapsing experimental allergic encephalomyelitis: its value as an experimental model for multiple sclerosis

Summary Comparison of the pathohistology of chronic relapsing experimental allergic encephalomyelitis (CR-EAE) and multiple sclerosis (MS) reveals a close similarity. Thus, CR-EAE appears to be a valuable model for the study of pathogenetic factors leading to the formation of MS lesions, although the induction of the disease may be different (active sensitization with CNS antigens and adjuvant in CR-EAE versus unknown etiology in MS). CR-EAE furthermore mimicks the pathohistological patterns of other related human inflammatory demyelinating diseases (i.e., acute perivenous leukoencephalomyelitis and acute hemorrhagic leukoencephalomyelitis). The expression of an acute, predominantly inflammatory versus chronic inflammatory demyelinating disease in this model depends upon the time interval between sensitization and sampling of the animals. Recent evidence is discussed that a cooperation between cellular and humoral immune mechanisms, directed against multiple CNS antigens, is responsible for the formation of large demyelinated plaques in EAE and MS.Supported by Austrian Science Research Fund, Project S25/07     

Neurophysiology of synaptic functioning in multiple sclerosis

Multiple sclerosis (MS) is an inflammatory immune-mediate disorder of the central nervous system (CNS), primarily affecting the myelin sheath and followed by neurodegeneration. Synaptic alterations are emerging as critical determinants of early neurodegeneration in MS.Inflammation-induced alterations of synaptic transmission and plasticity have been investigated in vitro and also in human MS using transcranial magnetic stimulation (TMS) techniques. Specific inflammatory cytokines alter glutamatergic and GABAergic transmission, resulting in synaptic hyperexcitability. In both experimental autoimmune encephalomyelitis (EAE) and MS, excitotoxic damage and neurodegeneration are found even in the early phases of disease, conversely inflammation persists in the progressive phases.Inflammatory cytokines also affect synaptic plasticity, as both long-term potentiation (LTP) and long-term depression (LTD) are altered in EAE and in MS patients. In particular, inflammation profoundly subverts plasticity and influence both clinical recovery after a relapse and disease course. Regulation of neuronal activity by cytokines plays important roles in the neuro-immune crosstalk involved in inflammation-associated excitotoxic neuronal damage, and in the chance of developing compensatory plasticity.Innate and adaptive immunity interact with the CNS in MS, in line with the concept that cytokines and chemokines, in concert with neurotransmitters and neuropeptides, represent a major communication system in the CNS.     

Crotoxin down-modulates pro-inflammatory cells and alleviates pain on the MOG35-55-induced experimental autoimmune encephalomyelitis,an animal model of multiple sclerosis

Multiple sclerosis (MS) is a Central Nervous System inflammatory demyelinating disease that has as primary symptoms losses of sensory and motor functions, including chronic pain. To date, however, few studies have investigated the mechanisms of chronic pain in animal models of MS since locomotor impairments render difficult its evaluation. It was previously demonstrated that in the MOG_35-55-induced EAE, an animal model of MS, the hypernociception appears before the onset of motor disability, allowing for the study of these two phenomena separately. Here, we evaluated the effect of crotoxin (CTX), a neurotoxin isolated from the Crotalus durissus terrificus snake venom that displays, at non-toxic dose, antinociceptive, anti-inflammatory and immunomodulatory effects, in the pain and in symptoms progression of EAE. The pain threshold of female C57BL/6 mice decreased at the 4th day after immunization, while the first sign of disease appeared around the 11st–12nd days, coinciding with the onset of motor abnormalities. CTX (40 µg/kg, s.c.) administered in a single dose on the 5th day after immunization, induced a long-lasting analgesic effect (5 days), without interfering with the clinical signs of the disease. On the other hand, when crotoxin was administered for 5 consecutive days, from 5th–9th day after immunization, it induced analgesia and also reduced EAE progression. The antinociceptive effect of crotoxin was blocked by Boc-2 (0.5 mg/kg, i.p.), a selective antagonist of formyl peptide receptors, by NDGA (30 μg/kg, i.p.), a lipoxygenase inhibitor and by atropine sulfate (10 mg/kg, i.p.), an antagonist of muscarinic receptors, administered 30 min before CTX. CTX was also effective in decreasing EAE clinical signs even when administered after its onset. Regarding the interactions between neurons and immunocompetent cells, CTX, in vitro, was able to reduce T cell proliferation, decreasing Th1 and Th17 and increasing Treg cell differentiation. Furthermore, in EAE model, the treatment with 5 consecutive doses of CTX inhibited IFN-γ-producing T cells, GM-CSF-producing T cells, reduced the frequency of activated microglia/macrophages within the CNS and decreased the number of migrating cell to spinal cord and cerebellum at the peak of the disease.These results suggest that CTX is a potential treatment not only for pain alteration but also for clinical progression induced by the disease as well as an useful tool for the development of new therapeutic approaches for the multiple sclerosis control.