重症肌无力的治疗进展

重症肌无力是一种由补充和抗体介导的神经肌肉接头传递功能障碍的获得性自身免疫性疾病,重症肌无力发病机制至今尚未完全阐明。随着对重症肌无力发病机制研究的不断深入,治疗方面也是日益取得进展,但重症肌无力的多样性可以影响治疗效果,对症药物用于病情较轻患者,病情严重者可结合长期免疫抑制剂和胸腺切除治疗,生物制剂目前仅用于难治性重症肌无力治疗,但随着科技发展生物制剂的用途将会更广泛。文中综述近年来国内外重症肌无力对症及免疫抑制治疗、胸腺切除方面的治疗进展。     

血清阴性重症肌无力研究进展

乙酰胆碱受体(acetylcholine receptor,AChR)抗体阴性的重症肌无力(myasthenia gravis,MG)称为血清阴性重症肌无力(SNMG)。SNMG在发病机制、临床表现和治疗上都与AChR抗体阳性MG不同。近年来研究者在SNMG患者血清中发现多种MG相关抗体,如肌肉特异性酪氨酸激酶(muscle-specific receptor tyro-sine kinase,MuSK)抗体、低亲和力AChR抗体、低密度脂蛋白受体相关蛋白4(low density lipoprotein receptor-related protein 4,LRP4)抗体等。本文就SNMG发病机制与临床表现的研究进展做一简要综述。     

滤泡辅助性T细胞在重症肌无力发病机制中的研究进展

重症肌无力是自身抗体介导的免疫性疾病,其发病机制与滤泡辅助性T细胞(Tfh)及其分泌的相关细胞因子密不可分。胸腺生发中心(GC)的发现对重症肌无力的研究意义重大,源于GC的Tfh细胞是辅助B细胞迁移、增殖、分化为浆细胞并产生高亲和力抗体的主要效应T细胞,在免疫调节过程中发挥核心作用。近年来,越来越多研究报道Tfh细胞参与重症肌无力发生的病理过程;同时,靶向或被动转移Tfh细胞的治疗策略及临床试验已成为相关研究热点。本综述围绕Tfh细胞的表型、分化与调节及其与重症肌无力发病机制研究的最新进展进行阐述。     

AChR胸腺中异位表达异常导致MG发病的研究

<正>重症肌无力(myasthenia gravis,MG)是一种自身免疫性疾病,由抗体介导,主要攻击神经肌肉接头处的乙酰胆碱受体,引起全身骨骼肌无力和易疲劳。经研究分析,胸腺内的免疫耐受异常在发病机制中占重要作用,本研究将讨论在重症肌无力发病中胸腺内的自身免疫反应以及编码乙酰胆碱自身抗原α亚基的基因——CHRNA1基因位点多态性在重症肌无力发病机制中的相关作用。     

抗ω—芋螺毒素结合蛋白抗体在重症肌无力中的意义

目的:探讨ω－芋螺毒素(ω－ｃｏｎｏｔｏｘｉｎ)结合蛋白抗体在重症肌无力发病机制中的作用。方法:用ＥＬＩＳＡ方法检测３４例重症肌无力病人、２０例正常人和２１例其他神经系统疾病病人血清中抗ω－芋螺毒素结合蛋白、抗突触前膜和抗乙酰胆碱受体抗体。结果:重症肌无力病人血清中存在抗ω－芋螺毒素结合蛋白抗体,其阳性为３５．３%;突触前膜及乙酰胆碱受体抗体阳性分别为５２．９%和５０%,抗ω－芋螺毒素结合蛋白抗体与另两种抗体间有良好线性关系。结论:部分重症肌无力病人血清中存在抗ω－芋螺毒素结合蛋白抗体,提示重症肌无力是一种突触前膜,包括Ｃａ２＋通道蛋白,和突触后膜均受累及的神经肌肉接头病。     

重症肌无力发病机制和治疗的回顾与展望

重症肌无力(MG)是一种由乙酰胆碱受体(AChR)抗体介导、细胞免疫依赖、补体系统参与,主要累及神经肌肉接头突触后膜AChR的自身免疫性疾病。随着免疫学研究的不断进展,对重症肌无力的发病机制、诊断与治疗特点有了更加深入的认识,笔者就此简要概述。一、历史回顾英国生理学家Thomas Willis于1672年首先描述了首例重症肌无力患者的临床表现,1879年英国     

胸腺切除治疗儿童型重症肌无力(附10例报告)

目的:探讨儿童重症肌无力患者胸腺切除疗效。方法:对儿童重症肌无力患者进行胸腺切除,手术前后采取静脉血2ml,进行抗乙酰胆碱受体抗体(AchRab)、抗骨骼肌抗体(ASA)、抗平滑肌抗体(SMA)、抗线粒体抗体(AMA)、抗核抗体(ANA)检测,并与正常健康儿童作对照,随访观察1～1．5年。结果:10例儿童重症肌无力患者,女性8例,男性2例,均为眼肌型;血清AchRab水平手术前后无显著性变化;术后ASA、SMA、ANA均转阴;胸腺病理改变以胸腺增生为主;随访发现术前病程越长,术后疗效越差。结论:儿童重症肌无力眼肌型多见,女性发病较多;眼肌型重症肌无力AchRab变化不明显;ASA、SMA阳性有助于MG的诊断;儿童重症肌无力眼肌型胸腺病理改变以增生为主;术前病程长短,影响术后疗效。     

眼肌型重症肌无力进展为全身型重症肌无力的临床相关因素分析

目的 :探讨眼肌型重症肌无力进展为全身型重症肌无力的临床相关预测因素。方法 :33例初诊为眼肌型重症肌无力的患者经过3年随访,根据疾病进展结局分为眼肌型重症肌无力组(13例)和进展为全身型重症肌无力组(20例)。对与疾病进展可能相关的临床因素进行分析。结果 :进展为全身型重症肌无力组患者初诊时的定量重症肌无力评分、乙酰胆碱受体抗体阳性率、抗核抗体阳性率、合并胸腺瘤的比例以及合并糖尿病的比例均高于眼肌型重症肌无力组(P值均0.05)。结论 :定量重症肌无力评分高、乙酰胆碱受体抗体阳性、抗核抗体阳性以及合并胸腺瘤和糖尿病可能是眼肌型重症肌无力进展为全身型重症肌无力的预测指标。     

重症肌无力发病的非乙酰胆碱受体抗体机制

重症肌无力 (ＭＧ)是一种主要由乙酰胆碱受体 (ＡＣｈＲ)抗体介导的自身免疫性疾病。然而 ,约有 1 5 %的ＭＧ患者血清中未检测到ＡＣｈＲ抗体 ,这些患者被称为抗体阴性重症肌无力 (ｓｅｒｏｎｅｇａｔｉｖｅＭＧ ,ＳＮＭＧ) [1 ] 。由于ＳＮＭＧ患者的临床表现与抗体阳性的ＭＧ患者基本相似 ,对免疫抑制剂治疗亦敏感 ,而且给小鼠注射ＳＮＭＧ患者的血清或ＩｇＧ亦能复制出ＭＧ模型[2 ] ,因此 ,对ＭＧ发病机制而言 ,除ＡＣｈＲ抗体的介导外 ,可能还有其他的抗体或分子参与。近年来对ＭＧ发病的非ＡＣｈＲ抗体机制研究取得了一系列的进展 ,综…     

重症肌无力的发病机制

重症肌无力(MG)是一种神经-肌肉接头传递功能障碍的自身免疫性疾病。MG的发病机制主要涉及免疫因素和遗传因素。免疫因素包括多种致病抗体、细胞免疫、细胞因子、补体及胸腺等。随着免疫学研究的不断进展,MG的发病机制也有了更深入的研究。     

重症肌无力患者外周血T淋巴细胞亚群凋亡的研究

目的探讨外周血T淋巴细胞亚群凋亡在重症肌无力(MG)免疫发病机制中的作用及临床意义。方法采用流式细胞术结合免疫荧光抗体法测定了45例MG患者和40例正常对照组外周血CD4~ T淋巴细胞、CD8~ T淋巴细胞百分数及其凋亡状况,并对24例MG患者在应用糖皮质激素治疗后外周血T淋巴细胞亚群凋亡状况进行了观察。结果MG患者组外周血CD8~ T淋巴细胞百分率较正常对照组明显降低,CD4~ /CD8~ 比值较正常对照组明显升高：MG患者组外周血CD4~ T淋巴细胞凋亡程度较正常对照组明显降低；MG患者外周血CD4~ T淋巴细胞凋亡程度与MG类型、预后密切相关：应用糖皮质激素治疗后MG患者外周血CD4~ T淋巴细胞凋亡程度明显增强。结论MG患者存在T淋巴细胞亚群的分布异常及CD4~ T淋巴细胞凋亡功能障碍,其凋亡程度可能与MG类型、预后密切相关,糖皮质激素对MG患者外周血CD4~ T淋巴细胞凋亡缺陷具有纠正作用。     

Muscle histopathology in myasthenia gravis with antibodies against MuSK and AChR

Aims: We compared myopathological features in myasthenia gravis (MG) patients with antibodies against AChR (seropositive) and muscle-specific tyrosin-kinase (MuSK). While the immunopathogenesis of seropositive MG is well known, there is a lack of pathological studies in anti-MuSK antibody-positive (MuSK+) MG. Methods: We analysed skeletal muscle biopsy features of 13 MG patients: 6 MuSK+ (all women) and 7 anti-AchR antibody-positive (AChR+) (2 women and 5 men). In our histopathological examination, we quantified the atrophy factor of both fibre types, and the extent of minicores, myofibrillar disarray, cytochrome c oxidase (COX)-negative fibres, mitochondrial aggregates and fibre type grouping. Results: Mean muscle fibre atrophy factor was higher in AChR+ MG than MuSK+ MG, both in type I fibres (494 vs. 210) and particularly in type II fibres (1023 vs. 300). Fibre type grouping was observed in AChR+ MG whereas COX-negative fibres were common in MuSK+ MG. Bulbar muscles were more severely affected in MuSK+ MG and the disease was more severe: the onset was usually earlier (39 years) with Myasthenia Gravis Foundation of America score III in MuSK+ MG, and score II was found in AChR+ MG (62 years). Conclusions: Muscle biopsies of MuSK+ MG show myopathic signs with prominent mitochondrial abnormalities, whereas neurogenic features and atrophy are more frequently found in AChR+ MG. The mitochondrial impairment could explain the oculo-bulbar involvement in MuSK+ MG.     

Purified IgG from seropositive and seronegative patients with myasthenia gravis reversibly blocks currents through nicotinic acetylcholine receptor channels

The mechanism of block of nicotinic acetylcholine receptor (nAChR) channels by purified antibodies from patients with myasthenia gravis (MG) was investigated by using an ultrafast system for solution exchange at outside-out patches. IgG of MG patients and controls was purified by using protein A–Sepharose columns. Probes from 9 seropositive MG patients and 3 seronegative MG patients were tested. As a preparation, cultured mouse myotubes expressing the embryonic-type nAChR channels were used. Twenty-millisecond pulses of 1.0 mM ACh were applied repetitively to outside-out patches. Outside-out patches were preexposed with IgG in concentrations between 0.1 and 200 mg/L during application of ACh pulses. The peak current amplitude was reduced to values between 6% and 71% of control for the 9 seropositive and 3 seronegative MG patients. The block was concentration dependent and fully reversible after washout of antibodies. Incubation with IgG from different control patients did not reduce the peak current amplitude. In addition, our findings with purified IgG from seronegative MG patients support the idea of the immunopathogenesis of this disorder and may allow the development of a diagnostic test for seronegative MG patients.     

Modulation by tumor necrosis factor-alpha of human astroglial cell production of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF).

Phagocyte survival and function are enhanced by GM-CSF and G-CSF. The production of both CSFs can be induced in mesenchymal cells by tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1). We have recently demonstrated that IL-1 alpha and beta induced the production of GM-CSF and G-CSF by two human astroglial cell lines. In the present study, we examined the effects of TNF-alpha on the production of GM-CSF and G-CSF by U87MG, a human astroglial cell line that constitutively expresses GM-CSF and G-CSF, and U373MG, a second human astroglial cell line that does not produce CSF. We demonstrate that U87MG can be induced to increase its production of GM-CSF and G-CSF by exposure to TNF-alpha while U373MG is induced to produce GM-CSF but not G-CSF. These responses, measured by accumulation of elevated levels of CSF protein and mRNA, are rapid and sensitive. The implications of these findings to the immunopathogenesis of central nervous system infections are discussed.     

Current Treatment,Emerging Translational Therapies,and New Therapeutic Targets for Autoimmune Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune disease associated with the production of autoantibodies against 1) the skeletal muscle acetylcholine receptor; 2) muscle-specific kinase, a receptor tyrosine kinase critical for the maintenance of neuromuscular synapses; 3) low-density lipoprotein receptor-related protein 4, an important molecular binding partner for muscle-specific kinase; and 4) other muscle endplate proteins. In addition to the profile of autoantibodies, MG may be classified according the location of the affected muscles (ocular vs generalized), the age of symptom onset, and the nature of thymic pathology. Immunopathologic events leading to the production of autoantibodies differ in the various disease subtypes. Advances in our knowledge of the immunopathogenesis of the subtypes of MG will allow for directed utilization of the ever-growing repertoire of therapeutic agents that target distinct nodes in the immune pathway relevant to the initiation and maintenance of autoimmune disease. In this review, we examine the pathogenesis of MG subtypes, current treatment options, and emerging new treatments and therapeutic targets.     

Myasthenia gravis: T and B cell reactivities to the beta-bungarotoxin binding protein presynaptic membrane receptor.

Antibodies against acetylcholine receptor (AChR) can be detected in most patients with myasthenia gravis (MG) and are considered to be involved in the immunopathogenesis of this disease. AChR are isolated from crude receptor preparations by binding to alpha-bungarotoxin (alpha-BuTx). Patients with MG have also antibodies against a second protein tentatively named presynaptic membrane receptor (PsmR), which has been isolated from crude receptor utilizing beta-bungarotoxin (beta-BuTx). PsmR could represent another antigen besides AChR relevant for the development of MG. We have now evaluated the T cell reactivity to PsmR in MG and controls by analysing the frequencies of cells which in response to PsmR in short-term cultures secreted interferon-gamma (IFN-gamma). The B cell response to PsmR was analysed in parallel by counting cells secreting anti-PsmR antibodies. Most patients with MG had PsmR reactive T cell in blood with a median number of about 1 per 44,000 mononuclear cells. Cells secreting anti-PsmR antibodies belonging to the IgG and IgA isotypes, less frequently of the IgM isotype were detected in most MG patients. A positive correlation was found between T cells reactive with PsmR and anti-PsmR IgG antibody secreting cells. PsmR reactive T and B cells were also detected in control patients, but at much lower numbers. Our results indicate that MG is accompanied by T as well as B cell responses to PsmR, in addition to the previously recognized responses to AChR. It remains to be shown whether these PsmR reactivities are of pathogenetic importance in MG.     

Modulation by tumor necrosis factor-α of human astroglial cell production of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF)

Phagocyte survival and function are enhanced by GM-CSF and G-CSF. The production of both CSFs can be induced in mesenchymal cells by tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). We have recently demonstrated that IL-1α and β induced the production of GM-CSF and G-CSF by two human astroglial cell lines. In the present study, we examined the effects TNF-α on the production of GM-CSF and G-CSF by U87MG, a human astroglial cell line that constitutively expresses GM-CSF and G-CSF, and U373MG, a second human astroglial cell line does not produce CSF. We demonstrate that U87MG can be induced to increase its production of GM-CSF and G-CSF by exposure to TNF-α while U373MG is induced to produce GM-CSF but not G-CSF. These responses, measured by accumulation of elevated levels of CSF protein and mRNA, are rapid and sensitive. The implications of these findings to the immunopathogenesis of central nervous system infections are discussed.     

T-cell tumor necrosis factor-alpha receptor binding in myasthenic patients.

Myasthenia gravis (MG) is a T-cell-dependent and antibody-mediated autoimmune disease of the neuromuscular junction, in which the cytokine network may be deranged. Specific receptors for tumor necrosis factor (TNF)-alpha, a cytokine with several effects on the neuroimmune system, were found on human lymphocytes. In the present study, we assayed TNF-alpha binding on peripheral blood T-cells from MG patients, finding that T-cells from patients have significantly more TNF-alpha receptors than those from controls (Bmax: 654 +/- 12 vs. 133 +/- 4 (mean +/- SEM) receptors/cell). Such TNF-alpha binding sites are of the same type in patients and healthy subjects (Kd: 68.7 +/- 4.3 vs. 70.1 +/- 4.8 (mean +/- SEM) pM). The enhanced T-cell TNF-alpha binding is due to an increased number of TNF-alpha receptors on T-helper lymphocytes. These results are discussed in terms of MG immunopathogenesis, since it has been reported that activated T-cells have increased amounts of TNF-alpha receptors.     

Ptosis and mastication disorders revealing concurrent myasthenia gravis and chronic polyradiculoneuritis

Although myasthenia gravis (MG) has frequently been associated with other autoimmune disorders, it has only rarely been reported in conjunction with diseases of the nervous system. A 74-year-old patient with hypertension suddenly presented left unilateral ptosis and mastication disorders. Clinical examination showed a concomitant loss of strength distally and reduced deep tendon reflex. Electrophysiologic data indicated a diagnosis of MG and chronic inflammatory demyelinating polyneuropathy; acetylcholine receptor antibody was elevated at 4.1 nmol/L (normal < 2 nmol/L). Improvement was rapid after initiation of pyridostigmine in association with corticosteroid (1 mg/kg/day). One month later, the cranial nerve deficit disappeared and strength was normal. It is likely that a basic abnormality of immune regulation was responsible for the emergence of diseases with different clinical presentations, but similar immunopathogenesis. Corticosteroid seemed to be the most effective treatment.