TY - JOUR
T1 - Divalent and monovalent autoantibodies cause dysfunction of MuSK by distinct mechanisms in a rabbit model of myasthenia gravis
AU - Mori, Shuuichi
AU - Yamada, Shigeru
AU - Kubo, Sachiho
AU - Chen, Jie
AU - Matsuda, Seiji
AU - Shudou, Masachika
AU - Maruyama, Naoki
AU - Shigemoto, Kazuhiro
N1 - Funding Information:
Our studies were supported by grants from the Health Science Research Grants for Research on Psychiatric and Neurological Diseases and Mental Health ( H19-Psycho-General-19 ), and Comprehensive Research of Aging and Health ( H22-Aging-General-002 ) from the Ministry of Health, Labor, and Welfare, Japan , and Grants-in-Aid for Scientific Research on Innovative Area ( 21200023 ), Grant-in-Aid for Scientific Research (C) ( 21591102 ), and Grant-in-aid for Young Scientists (B) ( 23791009 ) from the Ministry of Education, Science, and Culture, Japan, and Intramural Research Grant (22-5) for Neurological and Psychiatric Disorders of National Center of Neurology and Psychiatry.
PY - 2012/3
Y1 - 2012/3
N2 - Muscle-specific kinase (MuSK), a receptor tyrosine kinase, is required for the formation and maintenance of neuromuscular junctions (NMJs). Although autoantibodies against MuSK have been demonstrated to cause myasthenia gravis (MG), the underlying pathogenic mechanism remains unclear because a major subclass of these antibodies is functionally monovalent. We investigated the pathogenic role of MuSK antibodies in the onset of MG in vivo and in vitro. Ultrastructural visualization of NMJs in paretic rabbits with MuSK antibodies indicated that postsynaptic membranes were preserved, despite a significant loss of complexity in the convoluted synaptic folds. In addition, an in vitro assay indicated that both divalent and monovalent antibodies from paretic rabbits could interfere with agrin-induced acetylcholine receptor (AChR) clustering in cultured myotubes. Furthermore, in the absence of agrin, divalent antibodies induced MuSK phosphorylation and accelerated downregulation of Dok-7, an essential intracellular MuSK binding protein, while monovalent antibodies inhibited agrin-induced phosphorylation of MuSK, thus demonstrating distinct molecular mechanisms underlying the MuSK dysfunction induced by these two types of antibodies. Taken together, these findings suggest that complement activation is not necessary for the MG onset and that both divalent and monovalent antibodies may cause MG in vivo by inducing MuSK dysfunction.
AB - Muscle-specific kinase (MuSK), a receptor tyrosine kinase, is required for the formation and maintenance of neuromuscular junctions (NMJs). Although autoantibodies against MuSK have been demonstrated to cause myasthenia gravis (MG), the underlying pathogenic mechanism remains unclear because a major subclass of these antibodies is functionally monovalent. We investigated the pathogenic role of MuSK antibodies in the onset of MG in vivo and in vitro. Ultrastructural visualization of NMJs in paretic rabbits with MuSK antibodies indicated that postsynaptic membranes were preserved, despite a significant loss of complexity in the convoluted synaptic folds. In addition, an in vitro assay indicated that both divalent and monovalent antibodies from paretic rabbits could interfere with agrin-induced acetylcholine receptor (AChR) clustering in cultured myotubes. Furthermore, in the absence of agrin, divalent antibodies induced MuSK phosphorylation and accelerated downregulation of Dok-7, an essential intracellular MuSK binding protein, while monovalent antibodies inhibited agrin-induced phosphorylation of MuSK, thus demonstrating distinct molecular mechanisms underlying the MuSK dysfunction induced by these two types of antibodies. Taken together, these findings suggest that complement activation is not necessary for the MG onset and that both divalent and monovalent antibodies may cause MG in vivo by inducing MuSK dysfunction.
KW - Antibodies
KW - Dok-7
KW - MuSK
KW - Myasthenia gravis
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U2 - 10.1016/j.jneuroim.2011.12.005
DO - 10.1016/j.jneuroim.2011.12.005
M3 - Article
C2 - 22222307
AN - SCOPUS:84857914720
SN - 0165-5728
VL - 244
SP - 1
EP - 7
JO - Advances in Neuroimmunology
JF - Advances in Neuroimmunology
IS - 1-2
ER -