Myasthenia gravis: antibodies against postsynaptic acetylcholine receptors

Myasthenia gravis is an autoimmune disease. The immune system makes IgG antibodies against the nicotinic acetylcholine receptor, the protein on the muscle surface that acetylcholine binds to in order to trigger contraction. These receptors sit on the postsynaptic membrane, the muscle side of the neuromuscular junction (the gap where a motor nerve passes its signal to a muscle fibre).

The antibodies block acetylcholine from binding, increase receptor turnover (receptors are removed faster) and activate complement, a cascade of immune proteins that damages the membrane it settles on. Acetylcholine is then broken down by acetylcholinesterase (the enzyme that clears it from the gap) before enough receptors are activated, so neuromuscular transmission fails.

The result is fatigable weakness: strength falls with repeated use and recovers with rest, and it is often worse towards the end of the day. Ptosis (drooping of the upper eyelid) and diplopia (double vision) are the commonest symptoms. Sensation and reflexes are normal, because the fault lies at the junction.

In around 10% of patients the antibodies target MuSK (muscle-specific tyrosine kinase, a protein on the muscle membrane) instead, giving a related but distinct picture. The thymus is abnormal in around 75% of patients, with hyperplasia (overgrowth) in young patients and thymoma (a tumour of the thymus) in 10 to 15%.

Lambert-Eaton syndrome is the presynaptic look-alike: its antibodies are against calcium channels on the nerve ending, so less acetylcholine is released.