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Abstract

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 (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.

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-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.

Interpretation

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