Induction of myasthenia by immunization against muscle-specific kinase
Induction of myasthenia by immunization against muscle-specific kinase
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DOI：
10.1172/jci21545
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发表时间：
2006-04-01
影响因子：
15.9
通讯作者：
Matsuda, S
中科院分区：
文献类型：
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作者：
Shigemoto, K;Kubo, S;Matsuda, S
肌肉特异性激酶（Muscle-specific kinase，MuSK）是烟碱型乙酰胆碱受体（nicotinic acetylcholine receptor，AChR）的突触聚集的关键，在神经肌肉接头（NMJ）的组织和维持中起着多种作用。MuSK被从运动神经元释放的聚集蛋白激活，并诱导AChR在突触后膜聚集。尽管在部分全身性重症肌无力（MG）患者中发现了针对MuSK胞外域的自身抗体，但目前尚不清楚MuSK自身抗体是否是全身性MG的病原体。在本研究中，用MuSK胞外域蛋白免疫的兔表现出MG样肌无力，并减少了NMJ处的AChR聚集。自身抗体激活MuSK和阻断AChR集群诱导的聚集蛋白或介质，不激活MuSK。因此，MuSK自身抗体严格抑制由多种途径介导的AChR聚集，这一结果拓宽了我们对MG发病机制的一般理解。
Muscle-specific kinase (MuSK) is critical for the synaptic clustering of nicotinic acetylcholine receptors (AChRs) and plays multiple roles in the organization and maintenance of neuromuscular junctions (NMJs). MuSK is activated by agrin, which is released from motoneurons, and induces AChR clustering at the postsynaptic membrane. Although autoantibodies against the ectodomain of MuSK have been found in a proportion of patients with generalized myasthenia gravis (MG), it is unclear whether MuSK autoantibodies are the causative agent of generalized MG. In the present study, rabbits immunized with MuSK ectodomain protein manifested MG-like muscle weakness with a reduction of AChR clustering at the NMJs. The autoantibodies activated MuSK and blocked AChR clustering induced by agrin or by mediators that do not activate MuSK. Thus MuSK autoantibodies rigorously inhibit AChR clustering mediated by multiple pathways, an outcome that broadens our general comprehension of the pathogenesis of MG.