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.     

Glomus tumours: an immunohistochemical profile of 11 cases

We studied 11 glomus tumours immunohistochemically, with a panel of connective tissue and epithelial markers. Most tumours contained small nerve fibres located in connective tissue septae between groups of glomus cells, thus accounting for the frequent occurrence of pain associated with glomus tumours. All tumours stained positively for muscle-specific actin and vimentin. Immunostaining for high and low molecular weight cytokeratins, desmin, myoglobin, S-100 protein, neurofilaments and Factor VIII related antigen was negative. Our findings confirm and amplify the proposed smooth muscle histogenesis of glomus tumours. This immunohistochemical profile may be of diagnostic value in the differential diagnosis of atypical glomus tumours.     

重症肌无力患者酪氨酸激酶抗体的检测

目的探讨酪氨酸激酶抗体（MuSKAb）在血清阴性重症肌无力（SNMG）发病中的作用。方法采用放射免疫法检测198例重症肌无力（MG）患者血清中抗乙酰胆碱受体抗体（AChRAb）水平，筛选出SNMG血清样本再行MuSKAb水平检测。结果MG患者血清AChRAb浓度明显高于对照组（P〈0．05），其阳性率为81．3％，SNMG患者血清MuSKAb均为阴性。结论MuSKAb可能在中国SNMG患者中的检出率较低。     

Heparin Inhibits Acetylcholine Receptor Aggregation at Two Distinct Steps in the Agrin-induced Pathway

Muscle cells depend on motoneurons for the initiation of postsynaptic differentiation during early development of the neuromuscular junction. Motoneurons secrete specific isoforms of the extracellular matrix protein agrin which trigger the aggregation of acetylcholine receptors (AChRs) on the muscle surface. Both motoneuron- and agrin-induced AChR aggregation are inhibited by heparin. Here we show that this inhibition is due to two separate and distinguishable mechanisms. At high concentrations, heparin directly binds to agrin isoforms which contain the peptide KSRK, resulting in a virtually complete inhibition of AChR clustering. Heparin and other polyanions do not bind to agrin splicing variants without KSRK insert. Isoforms containing or lacking the KSRK insert have a high potency to induce AChR aggregation in the presence of an activating eight-amino-acid insert. This activity is inhibited by low concentrations of heparin even in the absence of any binding of heparin to agrin. Therefore, this second type of inhibition is due to the interaction of heparin with a downstream component of the agrin-induced clustering pathway. Binding of heparin to this yet unidentified component substantially decreases, but does not completely abolish AChR aggregation. The inhibition is particularly strong on myotubes which have not completely matured in culture.     

Thymectomy may not be associated with clinical improvement in MuSK myasthenia gravis

Introduction: A randomized trial demonstrated benefit from thymectomy in nonthymomatous acetylcholine receptor (AChR)-antibody positive myasthenia gravis (MG). Uncontrolled observational and histologic studies suggest thymectomy may not be efficacious in anti–muscle-specific kinase (MuSK)-MG. Methods: The therapeutic impact of thymectomy was evaluated from data collected for a multicenter, retrospective blinded review of rituximab in MuSK-MG. Results: Baseline characteristics were similar between thymectomy (n = 26) and nonthymectomy (n = 29) groups, including treatment with rituximab (42% vs. 45%). At last visit, 35% of thymectomy subjects reached the primary endpoint, a Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) score of minimal manifestations (MM) or better, compared with 55% of controls (P = 0.17). After controlling for age at onset of MG, rituximab, prednisone, and intravenous immunoglobulin/plasma exchange treatment, thymectomy was not associated with greater likelihood of favorable clinical outcome (odds ratio = 0.43, 95% confidence interval 0.12–1.53, P = 0.19). Discussion: Thymectomy was not associated with additional clinical improvement in this multicenter cohort of MuSK-MG patients. Muscle Nerve 59:404–410, 2019     

Myasthenia gravis: A comprehensive review of immune dysregulation and etiological mechanisms

Autoimmune myasthenia gravis (MG) is characterized by muscle weakness caused by antibodies directed against proteins of the neuromuscular junction. The main antigenic target is the acetylcholine receptor (AChR), but the muscle Specific Kinase (MuSK) and the low-density lipoprotein receptor-related protein (LRP4) are also targets. This review summarizes the clinical and biological data available for different subgroups of patients, who are classified according to antigenic target, age of onset, and observed thymic abnormalities, such as follicular hyperplasia or thymoma.Here, we analyze in detail the role of the thymus in the physiopathology of MG and propose an explanation for the development of the thymic follicular hyperplasia that is commonly observed in young female patients with anti-AChR antibodies. The influence of the pro-inflammatory environment is discussed, particularly the role of TNF-α and Th17-related cytokines, which could explain the escape of thymic T cells from regulation and the chronic inflammation in the MG thymus. Together with this immune dysregulation, active angiogenic processes and the upregulation of chemokines could promote thymic follicular hyperplasia.MG is a multifactorial disease, and we review the etiological mechanisms that could lead to its onset. Recent global genetic analyses have highlighted potential susceptibility genes. In addition, miRNAs, which play a crucial role in immune function, have been implicated in MG by recent studies. We also discuss the role of sex hormones and the influence of environmental factors, such as the viral hypothesis. This hypothesis is supported by reports that type I interferon and molecules mimicking viral infection can induce thymic changes similar to those observed in MG patients with anti-AChR antibodies.     

卵巢切除对高胰岛素血症MKR小鼠糖脂代谢的影响

目的 探讨正常或高胰岛素血症情况下卵巢切除对小鼠血糖、脂肪组织含量和肝脏脂质沉积的影响。 方法 6周龄雌性骨骼肌特异性胰岛素样生长因子1受体功能缺失（MKR）高胰岛素血症小鼠20只随机分为MKR假手术组（MKR组）和MKR卵巢切除组（MKR OVX组）,每组10只;野生型（WT）FVB/N小鼠20只随机分为WT假手术组（WT组）和WT卵巢切除组（WT OVX组）,每组10只。术后恢复饲养2周,监测各组小鼠体质量和血糖水平;葡萄糖耐量试验（GTT）和胰岛素耐量试验（ITT）检测小鼠葡萄糖耐受能力和胰岛素敏感性;术后12周处死小鼠,称量各组小鼠肝脏和脂肪组织质量,HE染色、糖原染色和油红O染色观察各组小鼠肝脏和性腺脂肪组织病理形态表现,实时荧光定量PCR（RT-qPCR）法检测各组小鼠性腺脂肪组织中脂代谢相关基因mRNA表达水平,Western blotting法检测各组小鼠性腺脂肪组织中激素敏感脂肪酶（HSL）蛋白表达水平。 结果 与WT组比较,MKR组小鼠体质量明显降低（P<0.05）;与MKR组比较,MKR OVX组小鼠体质量明显增加（P<0.05）,但与WT组和WT OVX组比较,MKR OVX组小鼠体质量降低（P<0.05）。MKR OVX组小鼠血糖逐渐升高,出现严重葡萄糖不耐受和胰岛素抵抗。与WT组比较,WT OVX组小鼠肝脏出现脂肪变性,糖原减少,MKR OVX组小鼠肝脂肪变性程度增加且糖原减少。与WT组比较,WT OVX组小鼠性腺脂肪和肠系膜脂肪系数明显升高（P<0.05）;与MKR组比较,MKR OVX组小鼠皮下脂肪、性腺脂肪和肾周脂肪系数明显升高（P<0.05）。HE染色,与WT组比较,MKR组小鼠脂肪细胞明显缩小,WT OVX组和MKR OVX组小鼠脂肪细胞均增大,但与WT组和WT OVX组比较, MKR OVX组小鼠脂肪细胞仍缩小。RT-qPCR和Western blotting法检测,与WT组比较,MKR组小鼠性腺脂肪组织中HSL mRNA和蛋白表达水平升高（P<0.05）;与MKR组比较,MKR OVX组小鼠性腺脂肪组织中HSL mRNA和蛋白表达水平降低（P<0.05）。 结论 卵巢切除会导致小鼠糖代谢紊乱、脂肪组织质量增加和肝脏脂质沉积,而高内源性胰岛素水平和胰岛素抵抗会进一步加重因卵巢切除导致的糖脂代谢紊乱。     

Concurrent inflammatory myopathy and myasthenia gravis with or without thymic pathology: A case series and literature review

Objectives

The association of myasthenia gravis (MG) and inflammatory myositis (IM) is rare and typically only one of the diseases is present. The management of the 2 diseases differs, therefore it is important to recognize the concomitant presentation. Here, we report a case series of 7 patients with co-existing MG and IM with review of the literature.

The role of muscle-specific tyrosine kinase (MuSK) and mystery of MuSK myasthenia gravis

MuSK myasthenia gravis is a rare, severe autoimmune disease of the neuromuscular junction, only identified in 2001, with unclear pathogenic mechanisms. In this review we describe the clinical aspects that distinguish MuSK MG from AChR MG, review what is known about the role of MuSK in the development and function of the neuromuscular junction, and discuss the data that address how the antibodies to MuSK lead to neuromuscular transmission failure.     

肌细胞特异性microRNAs对收缩舒张生物学效应调控机制的研究进展

 肌细胞特异性microRNAs (muscle-specific microRNAs,myomiRs)是一类特异性表达在肌组织中的内源性非编码小分子RNA,通过转录后水平负调控相关基因的表达,广泛参与到一系列生物学过程中,影响疾病的发生发展。肌细胞相关疾病(如慢性阻塞性肺炎、肥厚型心肌病等)的发生、发展可引起myomiRs及其下游靶基因表达改变,从而进一步影响疾病的发展、预后及转归。本文将综述miR-1、miR-133、miR-206、miR-208和miR-499等常见myomiRs在横纹肌和非横纹肌收缩舒张机制中的作用,重点关注myomiRs对肌细胞收缩舒张生物学效应的影响,以期为肌细胞相关疾病治疗提供新思路。