Anti-MuSK patient antibodies disrupt the mouse neuromuscular junction
Article first published online: 2 APR 2008
Copyright © 2008 American Neurological Association
Annals of Neurology
Volume 63, Issue 6, pages 782–789, June 2008
How to Cite
Cole, R. N., Reddel, S. W., Gervásio, O. L. and Phillips, W. D. (2008), Anti-MuSK patient antibodies disrupt the mouse neuromuscular junction. Ann Neurol., 63: 782–789. doi: 10.1002/ana.21371
- Issue published online: 20 JUN 2008
- Article first published online: 2 APR 2008
- Manuscript Accepted: 25 JAN 2008
- Manuscript Revised: 10 JAN 2008
- Manuscript Received: 8 OCT 2007
- Muscular Dystrophy Association of New South Wales
- Muscular Dystrophy Association, USA. Grant Number: 4172
- University of Sydney R&D
- Australian Myasthenic Association in New South Wales
A subset of myasthenia gravis patients that are seronegative for anti-acetylcholine receptor (anti-AChR) antibodies are instead seropositive for antibodies against the muscle-specific kinase (anti-MuSK–positive). Here, we test whether transfer of IgG from anti-MuSK–positive patients to mice confers impairment of the neuromuscular junction and muscle weakness.
IgG from anti-MuSK–positive myasthenia gravis patients or control IgG (seronegative for AChR and MuSK) was injected intraperitoneally (45mg daily for 14 days) into 6-week-old female FVB/NJ and C57BL/6J mice. Changes at neuromuscular junctions in the tibialis anterior and diaphragm muscles were assessed by confocal fluorescent imaging of AChRs stained with fluorescent-α-bungarotoxin. Loss of function was assessed by electromyography.
In experimental mice injected with anti-MuSK–positive patient IgG, postsynaptic AChR staining was reduced to as little as 22% of that seen in control mice. Experimental mice showed reduced apposition of the nerve terminal (labeled with antibodies against synaptophysin and neurofilament) and the postsynaptic AChR cluster (labeled with fluorescent-α-bungarotoxin). Mice injected with IgG from two of three anti-MuSK–positive patients lost weight and developed muscle weakness associated with a decremental electromyographic trace on repetitive nerve stimulation.
IgG from anti-MuSK–positive patients can cause myasthenia gravis when injected into mice. This may be explained by a progressive reduction in the density of postsynaptic AChR combined with changes in the nerve terminal and its relation to the postsynaptic structure. Ann Neurol 2008