When an action potential travels down a motor nerve and reaches the nerve terminal, acetylcholine (ACh) molecules are released from the presynaptic vesicles and adhere to AChR at the peaks of postsynaptic folds. Channels in the AChR open, allowing Na+ and other cations to enter into the muscle fiber endplate and depolarize it. The multiple depolarizations will sum up, and if large enough, trigger an action potential, which travels along the muscle fiber to produce contraction. With every nerve impulse, the amount of ACh released by the presynaptic motor neuron normally decreases due to a temporal depletion of the presynaptic ACh stores (presynaptic rundown).

In Myasthenia Gravis (MG), there is a reduction in the number of AChR available at the muscle endplate and flattening of the postsynaptic folds. The fewer endplate potentials produced by the yet normal amount of ACh released might fail to be translated into an action potential. The end result is an inefficient neuromuscular transmission. This inefficient neuromuscular transmission together with the normally present presynaptic rundown phenomenon results in a decremental amount of nerve fibers being activated by successive nerve fiber impulses. This explains the fatigability in the involved patients.

The decrease in number of the postsynaptic AChR is believed to be due to an autoimmune process whereby anti-AChR antibodies are produced and act to block the target receptors, increase their turnover, and damage the postsynaptic membrane in a complement-mediated manner. Although the primary etiology remains speculative, there is increasing evidence that the thymus might play an important role.

Histopathologic studies showed prominent germinal centers. Epithelial myoid cells normally present in the thymus do resemble skeletal muscle cells and possess AChR on their surface membrane. These cells may become antigenic and unleash an autoimmune attack on the muscular endplate AChR by molecular mimicry.

Why the disease afflicts first and predominantly the extraocular muscles remains unanswered. It probably has to do with the physiology and antigenicity of the muscles in question.