Induction of myasthenia by immunization against muscle-specific kinase

Kazuhiro Shigemoto, Sachiho Kubo, Naoki Maruyama, Naohito Hato, Hiroyuki Yamada, Chen Jie, Naoto Kobayashi, Katsumi Mominoki, Yasuhito Abe, Norifumi Ueda, Seiji Matsuda

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Abstract

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.

Original languageEnglish
Pages (from-to)1016-1024
Number of pages9
JournalJournal of Clinical Investigation
Volume116
Issue number4
DOIs
Publication statusPublished - Apr 1 2006
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Shigemoto, K., Kubo, S., Maruyama, N., Hato, N., Yamada, H., Jie, C., Kobayashi, N., Mominoki, K., Abe, Y., Ueda, N., & Matsuda, S. (2006). Induction of myasthenia by immunization against muscle-specific kinase. Journal of Clinical Investigation, 116(4), 1016-1024. https://doi.org/10.1172/JCI21545