Myasthenia gravis is an
autoimmune disease of the neuromuscular junction (NMJ) caused by
antibodies that attack components of the postsynaptic membrane, impair neuromuscular transmission, and lead to weakness and
fatigue of skeletal muscle. This can be generalised or localised to certain muscle groups, and involvement of the bulbar and respiratory muscles can be life threatening. The pathogenesis of
myasthenia gravis depends upon the target and isotype of the
autoantibodies. Most cases are caused by
immunoglobulin (Ig)G1 and
IgG3 antibodies to the
acetylcholine receptor (AChR). They produce
complement-mediated damage and increase the rate of AChR turnover, both mechanisms causing loss of AChR from the postsynaptic membrane. The thymus gland is involved in many patients, and there are experimental and genetic approaches to understand the failure of immune tolerance to the AChR. In a proportion of those patients without AChR
antibodies,
antibodies to muscle-specific
kinase (
MuSK), or related
proteins such as
agrin and
low-density lipoprotein receptor-related
protein 4 (LRP4), are present.
MuSK antibodies are predominantly
IgG4 and cause disassembly of the neuromuscular junction by disrupting the physiological function of
MuSK in synapse maintenance and adaptation. Here we discuss how knowledge of neuromuscular junction structure and function has fed into understanding the mechanisms of AChR and
MuSK antibodies.
Myasthenia gravis remains a paradigm for
autoantibody-mediated conditions and these observations show how much there is still to learn about synaptic function and pathological mechanisms.