Induction of myasthenia by immunization against muscle-specific kinase.
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.
Department of Preventive Medicine, Ehime University School of Medicine, Ehime, Japan. shigemot@m.ehime-u.ac.jp
Kazuhiro
K
Shigemoto
Sachiho
S
Kubo
Naoki
N
Maruyama
Naohito
N
Hato
Hiroyuki
H
Yamada
Chen
C
Jie
Naoto
N
Kobayashi
Katsumi
K
Mominoki
Yasuhito
Y
Abe
Norifumi
N
Ueda
Seiji
S
Matsuda
D018171:Agrin / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007114:Immunization; D051379:Mice; D008954:Models, Biological; D009123:Muscle Hypotonia / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D009157:Myasthenia Gravis / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D009439:Neuraminidase / Q000378:metabolism; D009469:Neuromuscular Junction / Q000276:immunology; D017434:Protein Structure, Tertiary; D011817:Rabbits; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000276:immunology* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013045:Species Specificity
D018171:Agrin; D001323:Autoantibodies; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D009439:Neuraminidase