Autoimmune diseases of the neuromuscular synapse
Autoimmune myasthenia gravis with acetylcholine receptor (AChR) antibodies is an acquired disorder of the neuromuscular junction. At each neuromuscular junction one nerve cell and one muscle cell form a complex structure that enables bidirectional communication. In addition to AChR, MuSK, LRP4, Agrin, ColQ and VGCC are other antigens at this synapse that are accessible to antibodies. Remarkable, each of these antibodies is associated with a distinct clinical phenotype. Antibodies to the postsynaptic muscle membrane cause MG in which ocular or bulbar weakness predominates. Antibodies to the presynaptic VGCCs cause Lambert-Eaton myasthenic syndrome (LEMS), in which proximal leg weakness is the main clinical feature. Early onset AChR MG shares the same HLA genetic background with LEMS. In both a high prevalence of HLA-A1B8DR3 is found. On the other hand, within AChR MG, patients with late-onset disease show no association with this HLA type.
The immunopathogenesis of the different types of myasthenia is also significantly different. AChR MG is caused by complement activating IgG1 antibodies, while MuSK antibodies are IgG4, which cannot activate complement, but mechanically block the MuSK-LRP4 complex. These insights are important for the choice of therapy. Although several symptomatic or immunosuppressive treatments are available, about 15% of MG patients has been found refractory to immunotherapy or suffer from severe side effects. Symptomatic therapy includes acetylcholinesterase inhibitors. Thymectomy has been shown to be beneficial in early-onset AChR MG. Plasma exchange or intravenous immunoglobulin are used for treating myasthenic crisis, while corticosteroids and several immunosuppressive drugs are used for chronic treatment. The number of new drugs for myasthenia is increasing fast, and soon several new drugs will be available for treatment of this group of autoimmune diseases. This might drastically change the current treatment algorithms and give an opportunity to diminish the role of chronic corticosteroid treatment and avoid long-term side effects.