PMID- 22326541
OWN - NLM
STAT- MEDLINE
DCOM- 20120504
LR  - 20220330
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Linking)
VI  - 234
IP  - 2
DP  - 2012 Apr
TI  - Passive and active immunization models of MuSK-Ab positive myasthenia: 
      electrophysiological evidence for pre and postsynaptic defects.
PG  - 506-12
LID - 10.1016/j.expneurol.2012.01.025 [doi]
AB  - Antibodies directed against the post-synaptic neuromuscular junction protein, 
      muscle specific kinase (MuSK) are found in a small proportion of generalized 
      myasthenia gravis (MuSK-MG) patients. MuSK is a receptor tyrosine kinase which is 
      essential for clustering of the acetylcholine receptors (AChRs) at the 
      neuromuscular junction, but the mechanisms by which MuSK antibodies (MuSK-Abs) 
      affect neuromuscular transmission are not clear. Experimental models of MuSK-MG 
      have been described but there have been no detailed electrophysiological studies 
      and no comparisons between the MuSK-MG and the typical form with AChR-Abs 
      (AChR-MG). Here we studied the electrophysiology of neuromuscular transmission 
      after immunization against MuSK compared with immunization against AChR, and also 
      after passive transfer of IgG from MuSK-MG or AChR-MG patients. Overt clinical 
      weakness was observed in 6/10 MuSK-immunized and 3/9 AChR-immunized mice but not 
      in those injected with patients' IgG. Miniature endplate potentials (MEPPS) were 
      reduced in all weak mice consistent with the reduction in postsynaptic AChRs that 
      was found. However, whereas there was an increase in the quantal release of 
      acetylcholine (ACh) in the weak AChR-immunized mice, no such increase was found 
      in the weak MuSK-immunized mice. Similar trends were found after the passive 
      transfer of purified IgG antibodies from MuSK-MG or AChR-MG patients. Preliminary 
      results showed that MuSK expression was considerably higher at the neuromuscular 
      junctions of the masseter (facial) than in the gastrocnemius (leg) with no 
      reduction in MuSK immunostaining at the neuromuscular junctions. Overall, these 
      results suggest that MuSK antibodies act in at least two ways. Firstly by 
      indirectly affecting MuSK's ability to maintain the high density of AChRs and 
      secondly by interfering with a compensatory presynaptic mechanism that regulates 
      quantal release and helps to preserve neuromuscular function. These results raise 
      questions about how MuSK is involved in retrograde signaling, and the combination 
      of post-synaptic defects with lack of presynaptic compensation may begin to 
      explain the more severe disease in MuSK-MG patients.
CI  - Copyright A(c) 2012 Elsevier Inc. All rights reserved.
FAU - Viegas, Stuart
AU  - Viegas S
AD  - Weatherall Institute of Molecular Medicine and Nuffield Department of Clinical 
      Neurosciences, John Radcliffe Hospital, Oxford OX3 9DS, UK.
FAU - Jacobson, Leslie
AU  - Jacobson L
FAU - Waters, Patrick
AU  - Waters P
FAU - Cossins, Judith
AU  - Cossins J
FAU - Jacob, Saiju
AU  - Jacob S
FAU - Leite, M Isabel
AU  - Leite MI
FAU - Webster, Richard
AU  - Webster R
FAU - Vincent, Angela
AU  - Vincent A
LA  - eng
GR  - Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120203
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 0 (Autoantibodies)
RN  - 0 (Receptors, Cholinergic)
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/*immunology
MH  - Disease Models, Animal
MH  - Immunization, Passive
MH  - Mice
MH  - Motor Activity/immunology
MH  - Muscle Weakness/immunology/*physiopathology
MH  - Myasthenia Gravis, Autoimmune, Experimental/immunology/*physiopathology
MH  - Neuromuscular Junction/immunology/*physiopathology
MH  - Receptor Protein-Tyrosine Kinases/immunology/*metabolism
MH  - Receptors, Cholinergic/immunology/*metabolism
MH  - Synapses/immunology/*metabolism
MH  - Vaccination
EDAT- 2012/02/14 06:00
MHDA- 2012/05/05 06:00
CRDT- 2012/02/14 06:00
PHST- 2011/09/30 00:00 [received]
PHST- 2012/01/21 00:00 [revised]
PHST- 2012/01/27 00:00 [accepted]
PHST- 2012/02/14 06:00 [entrez]
PHST- 2012/02/14 06:00 [pubmed]
PHST- 2012/05/05 06:00 [medline]
AID - S0014-4886(12)00045-3 [pii]
AID - 10.1016/j.expneurol.2012.01.025 [doi]
PST - ppublish
SO  - Exp Neurol. 2012 Apr;234(2):506-12. doi: 10.1016/j.expneurol.2012.01.025. Epub 
      2012 Feb 3.