Induction of myasthenia by immunization against muscle-specific kinase
Kazuhiro Shigemoto, … , Norifumi Ueda,, Seiji Matsuda
Kazuhiro Shigemoto, … , Norifumi Ueda,, Seiji Matsuda
Published April 3, 2006
Citation Information: J Clin Invest. 2006;116(4):1016-1024. https://doi.org/10.1172/JCI21545.
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Induction of myasthenia by immunization against muscle-specific kinase

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.

Authors

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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Figure 2

Reduction of the size and density of AChR clusters at the NMJs in paretic rabbits.

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Reduction of the size and density of AChR clusters at the NMJs in pareti...
(A) Cross sections from the soleus muscles of 2 paretic (M1 and M2) and 3 normal rabbits (N1, N2, and N3) were stained with 10 nM rhodamine-conjugated BTX. Bright crescents of bound BTX, indicative of endplate AChR, were smaller and less intense in the paretic rabbits’ muscle fibers than in those of the normal rabbits. Arrows indicate the small angular fibers in M2 soleus muscles. L, left; R, right. Scale bar: 50 μm. (B) Images of 10 AChR clusters at NMJs in the right and 10 in the left soleus muscles of the paretic and normal rabbits were randomly recorded by a digital imaging camera. Quantification of the area and intensity of AChR clustering in the unprocessed images were measured using NIH Image software. Bars indicate mean ± SD. *P < 0.01 versus normal rabbits.