Anti-MuSK patient antibodies disrupt the mouse neuromuscular junction.
OBJECTIVE
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.


METHODS
IgG from anti-MuSK-positive myasthenia gravis patients or control IgG (seronegative for AChR and MuSK) was injected intraperitoneally (45 mg 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-alpha-bungarotoxin. Loss of function was assessed by electromyography.


RESULTS
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-alpha-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.


CONCLUSIONS
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.
Cole
Rebecca N
RN
School of Medical Sciences (Physiology) and Bosch Institute, University of Sydney, Sydney, Australia.
Reddel
Stephen W
SW
Gervásio
Othon L
OL
Phillips
William D
WD
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001323:Autoantibodies / Q000276:immunology* / Q000633:toxicity; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology* / Q000633:toxicity; D051379:Mice; D018908:Muscle Weakness / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology; D009157:Myasthenia Gravis / Q000276:immunology* / Q000503:physiopathology; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000276:immunology* / Q000503:physiopathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000276:immunology*; D013570:Synaptic Membranes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000276:immunology
D001323:Autoantibodies; D007074:Immunoglobulin G; D011950:Receptors, Cholinergic; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000109:Acetylcholine