The hallmark clinical feature of myasthenia gravis (MG) is fatigable, fluctuating muscle weakness that declines with repetitive use and improves with rest.2,3 This is caused by the impairment of neuromuscular transmission as a result of the activity of autoantibodies against key molecules functioning at the NMJ.4–6
The binding of autoantibodies to AChRs at the postsynaptic membrane is thought to reduce the functionality of the receptors via three key mechanisms that ultimately reduce their capacity to generate action potentials, causing muscle weakness:7
1. Complement-mediated NMJ destruction
2. Functional AChR blockade
3. Cross-linking of AChRs resulting in their internalisation and destruction (so-called antigenic modulation)
- The binding of anti-AChR antibodies to the AChR triggers the activation of the complement system7
- Terminal complement activation results in the cleavage of C5 into C5a and C5b8
- C5a leads to inflammation, while C5b binds to other complement proteins to form the membrane attack complex (MAC)8
- MAC formation results in destruction of the NMJ7,8
Unlike anti-AChR antibodies, antibodies against the muscle-specific kinase (MuSK) are unable to activate complement directly, but are thought to reduce the numbers of AChR clusters at the postsynaptic membrane by preventing the interaction of MuSK with the low-density lipoprotein receptor-related protein 4 (LRP4).6,9
The underlying cause for the production of autoantibodies in MG is not fully understood.4 In patients seropositive for anti-AChR antibodies, it is widely acknowledged that impairment of the thymus may favour an autoimmune T cell-mediated B cell activation and subsequent synthesis of anti-AChR autoantibodies.4,6
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