PMID- 22142810
OWN - NLM
STAT- MEDLINE
DCOM- 20120325
LR  - 20220330
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Linking)
VI  - 180
IP  - 2
DP  - 2012 Feb
TI  - Antibodies against muscle-specific kinase impair both presynaptic and 
      postsynaptic functions in a murine model of myasthenia gravis.
PG  - 798-810
LID - 10.1016/j.ajpath.2011.10.031 [doi]
AB  - Antibodies against acetylcholine receptors (AChRs) cause pathogenicity in 
      myasthenia gravis (MG) patients through complement pathway-mediated destruction 
      of postsynaptic membranes at neuromuscular junctions (NMJs). However, antibodies 
      against muscle-specific kinase (MuSK), which constitute a major subclass of 
      antibodies found in MG patients, do not activate the complement pathway. To 
      investigate the pathophysiology of MuSK-MG and establish an experimental 
      autoimmune MG (EAMG) model, we injected MuSK protein into mice deficient in 
      complement component five (C5). MuSK-injected mice simultaneously developed 
      severe muscle weakness, accompanied by an electromyographic pattern such as is 
      typically observed in MG patients. In addition, we observed morphological and 
      functional defects in the NMJs of EAMG mice, demonstrating that complement 
      activation is not necessary for the onset of MuSK-MG. Furthermore, MuSK-injected 
      mice exhibited acetylcholinesterase (AChE) inhibitor-evoked cholinergic 
      hypersensitivity, as is observed in MuSK-MG patients, and a decrease in both AChE 
      and the AChE-anchoring protein collagen Q at postsynaptic membranes. These 
      findings suggest that MuSK is indispensable for the maintenance of NMJ structure 
      and function, and that disruption of MuSK activity by autoantibodies causes MG. 
      This mouse model of EAMG could be used to develop appropriate medications for the 
      treatment of MuSK-MG in humans.
CI  - Copyright (c) 2012 American Society for Investigative Pathology. Published by 
      Elsevier Inc. All rights reserved.
FAU - Mori, Shuuichi
AU  - Mori S
AD  - Department of Geriatric Medicine, Tokyo Metropolitan Institute of Gerontology, 
      Tokyo, Japan.
FAU - Kubo, Sachiho
AU  - Kubo S
FAU - Akiyoshi, Takuyu
AU  - Akiyoshi T
FAU - Yamada, Shigeru
AU  - Yamada S
FAU - Miyazaki, Tsuyoshi
AU  - Miyazaki T
FAU - Hotta, Harumi
AU  - Hotta H
FAU - Desaki, Junzo
AU  - Desaki J
FAU - Kishi, Masahiko
AU  - Kishi M
FAU - Konishi, Tetsuro
AU  - Konishi T
FAU - Nishino, Yuri
AU  - Nishino Y
FAU - Miyazawa, Atsuo
AU  - Miyazawa A
FAU - Maruyama, Naoki
AU  - Maruyama N
FAU - Shigemoto, Kazuhiro
AU  - Shigemoto K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111203
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (Autoantibodies)
RN  - 0 (Cholinesterase Inhibitors)
RN  - 0 (Complement C5)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Recombinant Proteins)
RN  - EC 2.7.10.1 (MuSK protein, mouse)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Animals
MH  - Autoantibodies/*physiology
MH  - Cholinesterase Inhibitors/pharmacology
MH  - Complement C5/deficiency
MH  - Immunoglobulin G/*physiology
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Muscle Strength/physiology
MH  - Muscle Weakness/immunology
MH  - Myasthenia Gravis, Autoimmune, Experimental/*immunology/pathology
MH  - Neuromuscular Junction/immunology/pathology/ultrastructure
MH  - Receptor Protein-Tyrosine Kinases/*immunology
MH  - Recombinant Proteins
MH  - Signal Transduction
MH  - Synapses/*immunology/pathology/physiology
MH  - Synaptic Transmission/physiology
MH  - Weight Loss/physiology
EDAT- 2011/12/07 06:00
MHDA- 2012/03/27 06:00
CRDT- 2011/12/07 06:00
PHST- 2011/04/15 00:00 [received]
PHST- 2011/10/04 00:00 [revised]
PHST- 2011/10/25 00:00 [accepted]
PHST- 2011/12/07 06:00 [entrez]
PHST- 2011/12/07 06:00 [pubmed]
PHST- 2012/03/27 06:00 [medline]
AID - S0002-9440(11)01023-6 [pii]
AID - 10.1016/j.ajpath.2011.10.031 [doi]
PST - ppublish
SO  - Am J Pathol. 2012 Feb;180(2):798-810. doi: 10.1016/j.ajpath.2011.10.031. Epub 
      2011 Dec 3.