PMID- 22222307
OWN - NLM
STAT- MEDLINE
DCOM- 20120508
LR  - 20120309
IS  - 1872-8421 (Electronic)
IS  - 0165-5728 (Linking)
VI  - 244
IP  - 1-2
DP  - 2012 Mar
TI  - Divalent and monovalent autoantibodies cause dysfunction of MuSK by distinct 
      mechanisms in a rabbit model of myasthenia gravis.
PG  - 1-7
LID - 10.1016/j.jneuroim.2011.12.005 [doi]
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.
CI  - Copyright A(c) 2011 Elsevier B.V. All rights reserved.
FAU - Mori, Shuuichi
AU  - Mori S
AD  - Department of Geriatric Medicine, Tokyo Metropolitan Institute of Gerontology, 
      Tokyo 173-0015, Japan.
FAU - Yamada, Shigeru
AU  - Yamada S
FAU - Kubo, Sachiho
AU  - Kubo S
FAU - Chen, Jie
AU  - Chen J
FAU - Matsuda, Seiji
AU  - Matsuda S
FAU - Shudou, Masachika
AU  - Shudou M
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 - 20120104
PL  - Netherlands
TA  - J Neuroimmunol
JT  - Journal of neuroimmunology
JID - 8109498
RN  - 0 (Agrin)
RN  - 0 (Autoantibodies)
RN  - 0 (Receptors, Cholinergic)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Agrin/pharmacology
MH  - Animals
MH  - Autoantibodies/*immunology
MH  - Disease Models, Animal
MH  - Muscle, Skeletal/drug effects/*enzymology/ultrastructure
MH  - Myasthenia Gravis/*immunology
MH  - Neuromuscular Junction/drug effects/immunology
MH  - Rabbits
MH  - Receptor Protein-Tyrosine Kinases/*immunology
MH  - Receptors, Cholinergic/metabolism
EDAT- 2012/01/10 06:00
MHDA- 2012/05/09 06:00
CRDT- 2012/01/07 06:00
PHST- 2011/08/26 00:00 [received]
PHST- 2011/11/07 00:00 [revised]
PHST- 2011/12/05 00:00 [accepted]
PHST- 2012/01/07 06:00 [entrez]
PHST- 2012/01/10 06:00 [pubmed]
PHST- 2012/05/09 06:00 [medline]
AID - S0165-5728(11)00343-2 [pii]
AID - 10.1016/j.jneuroim.2011.12.005 [doi]
PST - ppublish
SO  - J Neuroimmunol. 2012 Mar;244(1-2):1-7. doi: 10.1016/j.jneuroim.2011.12.005. Epub 
      2012 Jan 4.