Myasthenia gravis is a paralytic disorder with
autoantibodies against
acetylcholine receptors at the neuromuscular junction. A proportion of patients instead has
antibodies against muscle-specific
kinase, a
protein essential for
acetylcholine receptor clustering. These are generally of the immunoglobulin-G4 subclass and correlate with disease severity, suggesting specific myasthenogenic activity. However, immunoglobulin-G4 subclass
antibodies are generally considered to be 'benign' and direct proof for their pathogenicity in muscle-specific
kinase myasthenia gravis (or other
immunoglobulin-G4-associated disorders) is lacking. Furthermore, the exact electrophysiological synaptic defects caused at neuromuscular junctions by human anti-muscle-specific
kinase autoantibodies are hitherto unknown. We show that purified immunoglobulin-G4, but not immunoglobulin-G1-3, from patients with muscle-specific
kinase myasthenia gravis binds to mouse neuromuscular junctions in vitro, and that injection into immunodeficient mice causes
paralysis. Injected immunoglobulin-G4 caused reduced density and fragmented area of neuromuscular junction
acetylcholine receptors. Detailed electrophysiological synaptic analyses revealed severe reduction of postsynaptic
acetylcholine sensitivity, and exaggerated depression of presynaptic
acetylcholine release during high-rate activity, together causing the (fatigable)
muscle weakness. Intriguingly, compensatory transmitter release upregulation, which is the normal homeostatic response in
acetylcholine receptor myasthenia gravis, was absent. This conveys extra vulnerability to neurotransmission at muscle-specific
kinase myasthenia gravis neuromuscular junctions. Thus, we demonstrate that patient anti-muscle-specific
kinase immunoglobulin-G4 is myasthenogenic, independent of additional immune system components, and have elucidated the underlying electrophysiological neuromuscular junction abnormalities.