AChR抗体阳性重症肌无力合并舌肌萎缩2例报道并文献分析

目的 探讨重症肌无力(MG)患者合并舌肌萎缩的发病特点及机制。方法 分析武汉同济医院神经内科住院部2例乙酰胆碱受体(AChR)抗体阳性MG患者合并舌肌萎缩的临床资料,检索MG合并舌肌萎缩的文献报道,总结此类疾病的特点、萎缩机制、治疗方法及预后。结果 在临床上MG合并舌肌萎缩并不多见,大多数患者伴有血清肌肉特异性酪氨酸肌酶(MuSK)抗体阳性,伴AChR抗体阳性者较为罕见,肌肉萎缩的发病机制具体不详; 该类患者除发病时间较长外,通常提示更严重的病情、更差的治疗反应、更不良的预后。结论 MG舌肌萎缩临床少见,严重影响着患者的言语、咀嚼和吞咽等功能,除病程较长外,其肌肉萎缩机制暂不清楚,有待临床进一步探索,以改善此类患者预后和生活质量。     

重组白细胞介素2及T细胞亚群对重症肌无力患者AChR—ab的影响

对１９例全身型重症肌无力（ＭＧ）患者周围血Ｂ细胞分化能力进行了研究，并观察重组白细胞介素２（ｒＩＬ－２）及Ｔ细胞亚群对其影响。方法分离外周血纯Ｂ细胞，体外与电鳗乙酰胆碱受体（ＡＣｈＲ）一起培养，并分别加入去ＣＤ４＋Ｔ细胞，去ＣＤ８＋Ｔ细胞及ｒＩＬ－２。用酶联免疫－生物素法检测其上清液的乙酰胆碱受体抗体（ＡＣｈＲ－ａｂ）。同时以１０例健康人为对照组。结果去ＣＤ８＋Ｔ细胞后ＡＣｈＲ－ａｂ的产生无明显增加；去ＣＤ４＋Ｔ细胞加入ｒＩＬ－２后ＡＣｈＲ－ａｂ产生减少。结论提示ｒＩＬ－２对ＭＧ患者有潜在治疗价值。     

d-Penicillamine-induced neuromuscular disease in guinea pigs

We found that chronic d-penicillamine administration in guinea pigs may induce a variety of electrophysiologic, histologic, and serologic changes that are reminiscent of features of both experimental allergic myositis and experimental allergic myasthenia gravis. These include (i) electromyographic decrement following repetitive stimulation that is reversible with edrophonium, and augmentation of twitch tension with edrophonium; (ii) nonspecific inflammatory and necrotic changes in muscle; and (iii) significant elevation of acetylcholine receptor antibody. The guinea-pig model raises several questions that must be answered before it can be regarded as a reliable model of d-penicillamine-induced neuromuscular disease in humans.     

Regenerated EDL muscle of rats requires innervation to maintain AChE molecular forms

Extensores digitorum longi of rats, infarcted and denervated by different surgical procedures, were used to analyze by biochemical and cytochemical methods the acetylcholinesterase (AChE) changes during muscle degeneration, regeneration, and early or delayed reinnervation. Biochemical tests showed that the regenerating muscle produces globular AChE forms (36% of controls) and small amounts of A12 (16S) asymmetric form (5% of controls); at the end of the regeneration, innervation and electromechanical function are required for the complete recovery of globular forms, and are absolutely critical to prevent A12 (16S) disappearance. Cytochemical observations showed that, unlike nicotinic receptor, AChE deposited at the neuromuscular junction before ischemic necrosis is protected from breakdown, as is the basal lamina of muscle fibers. Taken together, these observations contribute to the understanding of the factors that play a critical role in muscle repair and are, therefore, of clinical relevance.     

Properties of junctional acetylcholine receptors that appear rapidly after denervation

It was previously found that the number of junctional acetylcholine receptors of rat diaphragm, as measured with [¹²⁵I]alphabungarotoxin binding, suddenly increased 2 days after denervation in vivo or in vitro. Organ culture was used here to characterize further this unusual class of junctional receptors. The ‘new’ acetylcholine receptors were physiologically functional and were functionally located only in the junctional region. The rate of degradation of new receptors was slower than that of extrajunctional receptors and similar (in the first 24 h) to that of typical junctional receptors. In addition, the appearance of new junctional receptors was inhibited by cycloheximide and actinomycin D given at critical periods, implicating a protein synthetic step. Finally, nerve stimulation in the presence of a post-synaptic blocker (pancuronium) advanced the time of appearance of new junctional receptors.This last finding coupled with our previous report of nerve stump length effects on junctional acetylcholine receptors²⁶ reinforces the suggestion that under certain conditions the level of junctional receptors can be regulated by the motor neuron.     

自身免疫性自主神经节病的诊治新进展

自身免疫性自主神经节病（AAG）为一种与自身抗体相关、由免疫介导的自主神经功能障碍疾病。多为急性或亚急性起病,常见临床表现为体位性昏厥、汗液分泌异常、膀胱功能障碍、胃肠动力下降与性功能障碍等植物神经受累等。体格检查和实验室检查提示相应的自主神经功能异常,但缺乏特异性。如排除副肿瘤性、多脏器萎缩或糖尿病等所致的自主神经功能障碍,可诊断为AAG;如患者血清中抗自主神经节乙酰胆碱受体抗体滴度升高则可明确诊断。临床上以免疫抑制治疗为主,主要应用静脉注射丙种球蛋A（IWG）、血浆置换、激素、免疫抑制剂等免疫调节治疗,但剂量与疗程目前只能依靠医生个人经验及患者临床缓解情况而决定。如疗效不佳则用IVIG、血浆置换与免疫抑制剂联合治疗。     

Activation of the adenosine A2A receptor attenuates experimental autoimmune myasthenia gravis severity

The adenosine A2A receptor (A2AR) is the major cellular adenosine receptor commonly associated with immunosuppression. Here, we investigated whether A2AR activation holds the potential for impacting the severity of experimental autoimmune myasthenia gravis (EAMG) induced following immunization of Lewis rats with the acetylcholine receptor (AChR) R97-116 peptide. This report demonstrates reduced A2AR expression by both T cells and B cells residing in spleen and lymph nodes following EAMG induction. A2AR stimulation inhibited anti-AChR antibody production and proliferation of AChR-specific lymphocytes in vitro. Inhibition was blocked with the A2AR antagonists or protein kinase A inhibitor. We also determined that the development of EAMG was accompanied by a T-helper cell imbalance that could be restored following A2AR stimulation that resulted in increased Treg cell levels and a reduction in Th1-, Th2-, and Th17-cell subtypes. An EAMG-preventive treatment regimen was established that consisted of (2-(p-(2-carbonylethyl)phenylethylamino)-5-N-ethylcarboxamidoadenosine) (CGS21680; A2AR agonist) administration 1 day prior to EAMG induction. Administration of CGS21680 29 days post EAMG induction (therapeutic treatment) also ameliorated disease severity. We conclude that A2AR agonists may represent a new class of compounds that can be developed for use in the treatment of myasthenia gravis or other T-cell- and B-cell-mediated autoimmune diseases.     

The role of the innate immune recognition system in the pathogenesis of primary biliary cirrhosis: a conceptual view

The aetiology of primary biliary cirrhosis (PBC) remains unknown. Infectious and non‐infectious noxious insults in combination with tissue‐specific factors may precipitate PBC. Activation of innate immune response because of impending danger signals seems to be a key event in early PBC, as evidenced by granuloma formation, eosinophilic reaction and IgM elevation. Aberrant mitophagy in ‘stressed’ biliary epithelia cells may initiate the immune response against mitochondrial antigens. Antimitochondrial autoantibodies recognize evolutionarily conserved molecules. The question arises, whether they are pathogenic or rather an expression of beneficial autoimmunity. The generally stable course of PBC suggests that stimulatory and inhibitory autoimmune reactions govern the inflammatory biliary process. Tissue repair and defense are the heart of innate immunity. But continuous exposure of exogenous stimuli may precipitate functional antireceptor autoantibodies that are no more protective but rather harmful. Mitophagy, apoptosis and bile duct proliferation define the inflammatory response within bile ducts. Autoantigens may be clustered in different blebs on the surface of apoptotic cells targeting a variety of membrane and non‐membrane‐associated antigens. Thus, the autoantibody response in PBC may target, for instance, the pro‐ and anti‐apoptotic proteins of the Bcl‐2 family or receptors of the adrenergic or cholinergic system, hereby interfering with the programme of apoptosis and the proliferation of biliary epithelial cells. Consideration of there being functional autoantibodies into the pathogenesis of PBC may help to improve our understanding of the aetiopathogenesis of PBC.     

Tyrosine phosphatase STEP61 negatively regulates amyloid β‐mediated ERK/CREB signaling pathways via α7 nicotinic acetylcholine receptors

Striatal‐enriched phosphatase 61 (STEP₆₁) plays an essential role in synaptic plasticity and has recently been implicated in neurodegenerative disease. Here we characterized a possible role of STEP₆₁ in Alzheimer's disease (AD) pathology using a mouse model of AD (Tg‐APPswe/PSEN1dE9, APP/PS1 mice) and an in vitro model of AD [cortical neurons treated with amyloid β (Aβ)_1–42 peptides]. Our data indicate age‐related elevation of STEP₆₁ levels and the proportion of dephosphorylated STEP₆₁ (active STEP₆₁) in wild‐type mice, which was enhanced in APP/PS1 mice. Furthermore, the increased STEP₆₁ levels and active STEP₆₁ were observed in the hippocampus and cortex from 12‐month‐old APP/PS1 mice and in Aβ_1–42‐treated cortical neurons. An α7 nicotinic acetylcholine receptors (nAChRs) antagonist, α‐bungarotoxin (BTX), inhibited the Aβ_1–42‐induced increase of STEP₆₁ expression and activation. In addition, extracellular signal‐regulated kinase 1/2 (ERK1/2) and cAMP response element binding (CREB) were impaired in Aβ_1–42‐treated cortical neurons, and knockdown of STEP₆₁ enhanced the activation of ERK1/2 and CREB. Collectively, these findings indicate two alternate pathological pathways effecting STEP₆₁ regulation in AD. First, Aβ regulating STEP₆₁ activity is mediated by Aβ binding to α7 nAChRs. Second, STEP₆₁ negatively regulates Aβ‐mediated ERK/CREB pathway, an important signaling cascade involved in memory formation. © 2013 Wiley Periodicals, Inc.