Mechanisms associated with the pathogenicity of antibodies against muscle-specific kinase in myasthenia gravis

• Autoantibodies to MuSK cause MG in experimental animal models.
• Anti-MuSK antibodies in patients are predominantly of the IgG4 subclass.
• Th2 cytokines may regulate anti-MuSK antibody production.
• Divalent and monovalent antibodies impair MuSK functions by distinct mechanisms.
• A murine MuSK-MG model may be useful to identify more effective medications.

The presence of autoantibodies against muscle-specific kinase (MuSK) at the neuromuscular junction (NMJ) results in myasthenia gravis (MG). MuSK antibody-associated MG (MuSK MG) patients often have severe symptoms, including bulbar dysfunction, respiratory insufficiency and atrophy of the facial and tongue muscles. MuSK antibodies in MG patients predominantly belong to the IgG4 subclass, and the unique properties of IgG4 antibodies are directly associated with the pathogenic mechanisms of MuSK MG. Histopathological studies in animal models of MuSK MG have revealed that anti-MuSK antibodies cause contraction of motor terminals, significant loss of acetylcholine receptor (AChR) expression, and a reduction in synaptic folds at the postsynaptic membrane in the absence of complement involvement. Failure of neuromuscular transmission at pre- and postsynaptic membranes of the NMJs has been observed in both patients and animal models of MuSK MG. A murine model of MuSK-MG revealed the mechanisms underlying cholinergic hypersensitivity after administration of acetylcholinesterase inhibitors, which has also been observed in MuSK-MG patients. Further studies of this model have provided evidence suggesting that 3,4-diaminopyridine may be effective as a symptomatic therapy for MuSK MG.