Muscle-specific
kinase (
MuSK), a
receptor tyrosine kinase, is required for the formation and maintenance of neuromuscular junctions (NMJs). Although
autoantibodies against
MuSK have been demonstrated to cause
myasthenia gravis (MG), the underlying pathogenic mechanism remains unclear because a major subclass of these
antibodies is functionally monovalent. We investigated the pathogenic role of
MuSK antibodies in the onset of MG in vivo and in vitro. Ultrastructural visualization of NMJs in paretic rabbits with
MuSK antibodies indicated that postsynaptic membranes were preserved, despite a significant loss of complexity in the convoluted synaptic folds. In addition, an in vitro assay indicated that both divalent and monovalent
antibodies from paretic rabbits could interfere with
agrin-induced
acetylcholine receptor (AChR) clustering in cultured myotubes. Furthermore, in the absence of
agrin, divalent
antibodies induced
MuSK phosphorylation and accelerated downregulation of Dok-7, an essential intracellular
MuSK binding protein, while monovalent
antibodies inhibited
agrin-induced phosphorylation of
MuSK, thus demonstrating distinct molecular mechanisms underlying the
MuSK dysfunction induced by these two types of
antibodies. Taken together, these findings suggest that complement activation is not necessary for the MG onset and that both divalent and monovalent
antibodies may cause MG in vivo by inducing
MuSK dysfunction.