Antibodies against Muscle-Specific Kinase Impair Both Presynaptic and Postsynaptic Functions in a Murine Model of Myasthenia Gravis
Antibodies against Muscle-Specific Kinase Impair Both Presynaptic and Postsynaptic Functions in a Murine Model of Myasthenia Gravis
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DOI：
10.1016/j.ajpath.2011.10.031
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发表时间：
2012-02-01
影响因子：
6
通讯作者：
Shigemoto, Kazuhiro
中科院分区：
文献类型：
--
作者：
Mori, Shuuichi;Kubo, Sachiho;Shigemoto, Kazuhiro
针对乙酰胆碱受体（AChRs）的抗体通过补体途径介导的神经肌肉连接（NMJs）突触后膜的破坏引起重症肌无力（MG）患者的致病性。然而，针对肌肉特异性激酶（MuSK）的抗体（在MG患者中发现的抗体的主要亚类）不会激活补体途径。为了研究麝香-MG的病理生理机制并建立实验性自身免疫性MG （EAMG）模型，我们将麝香蛋白注射到补体成分5 （C5）缺乏的小鼠体内。注射麝香的小鼠同时出现严重的肌肉无力，并伴有肌电图模式，如在MG患者中典型观察到的。此外，我们在EAMG小鼠的NMJs中观察到形态和功能缺陷，证明补体激活不是MuSK-MG发病的必要条件。此外，注射麝香的小鼠表现出乙酰胆碱酯酶（AChE）抑制剂引起的胆碱能超敏反应，正如麝香mg患者所观察到的那样，AChE和突触后膜上AChE锚定蛋白胶原Q都有所下降。这些发现表明，MuSK对于维持NMJ的结构和功能是必不可少的，而自身抗体破坏MuSK活性会导致MG的发生。该小鼠EAMG模型可用于开发治疗人类麝香- mg的合适药物。（中国病理杂志，2012,180:798-810;DOI: 10.1016/ j.j ajpath.2011.10.031）
Antibodies against acetylcholine receptors (AChRs) cause pathogenicity in myasthenia gravis (MG) patients through complement pathway-mediated destruction of postsynaptic membranes at neuromuscular junctions (NMJs). However, antibodies against muscle-specific kinase (MuSK), which constitute a major subclass of antibodies found in MG patients, do not activate the complement pathway. To investigate the pathophysiology of MUSK-MG and establish an experimental autoimmune MG (EAMG) model, we injected MuSK protein into mice deficient in complement component five (C5). MuSK-injected mice simultaneously developed severe muscle weakness, accompanied by an electromyographic pattern such as is typically observed in MG patients. In addition, we observed morphological and functional defects in the NMJs of EAMG mice, demonstrating that complement activation is not necessary for the onset of MuSK-MG. Furthermore, MUSK-injected mice exhibited acetylcholinesterase (AChE) inhibitor-evoked cholinergic hypersensitivity, as is observed in MuSK-MG patients, and a decrease in both AChE and the AChE-anchoring protein collagen Q at postsynaptic membranes. These findings suggest that MuSK is indispensable for the maintenance of NMJ structure and function, and that disruption of MuSK activity by autoantibodies causes MG. This mouse model of EAMG could be used to develop appropriate medications for the treatment of MuSK-MG in humans. (Am J Pathol 2012, 180:798-810; DOI: 10.1016/j.ajpath.2011.10.031)