Pathophysiology Of Myasthenia Gravis

Myasthenia gravis is an autoimmune channelopathy: it features antibodies directed against proteins that are naturally present in the body. While various similar diseases have been linked to immunologic cross-reaction with an infective agent, there is no known causative pathogen that could account for myasthenia. There is a slight genetic predisposition: particular HLA types seem to predispose for MG (B8 and DR3 with DR1 more specific for ocular myasthenia). Up to 75% of patients have an abnormality of the thymus; 10% have a thymoma, a tumor (either benign or malignant) of the thymus, and other abnormalities are frequently found. The disease process generally remains stationary after thymectomy (removal of the thymus).

In MG, the autoantibodies most commonly act against the nicotinic acetylcholine receptor (nAChR),[6] the receptor in the motor end plate for the neurotransmitter acetylcholine that stimulates muscular contractions. Some forms of the antibody impair the ability of acetylcholine to bind to receptors. Others lead to the destruction of receptors, either by complement fixation or by inducing the muscle cell to eliminate the receptors through endocytosis.

The antibodies are produced by plasma cells, derived from B-cells. B-cells convert into plasma cells by T-helper cell stimulation. To carry out this activation, T-helpers must first be activated themselves, which is done by binding of the T-cell receptor (TCR) to the acetylcholine receptor antigenic peptide fragment (epitope) resting within the major histocompatibility complex of antigen presenting cells. Since the thymus plays an important role in the development of T-cells and the selection of TCR, myasthenia gravis is closely associated with thymoma. The exact mechanisms are, however, not convincingly clarified, although resection of the thymus (thymectomy) in MG patients without a thymus neoplasm often have positive results.

In normal muscle contraction, cumulative activation of the nAChR leads to influx of sodium ions, which in turn causes the depolarization of muscle cell and subsequent opening of voltage-gated sodium channels. This ion influx then travels down the cell membranes via T-tubules and, via calcium channel complexes, leads to the release of calcium from the sarcoplasmic reticulum. Only when the levels of calcium inside the muscle cell are high enough will it contract. Decreased numbers of functioning nAChRs therefore impairs muscular contraction by limiting depolarization. In fact, MG causes the motor neuron action potential to muscular twitch ratio to vary from the nonpathological one to one ratio.

A second category of gravis is due to autoantibodies against the MuSK protein (muscle specific kinase), a tyrosine kinase receptor which is required for the formation of the neuromuscular junction. Antibodies against MuSK inhibit the signaling of MuSK normally induced by its nerve-derived ligand, agrin. The result is a decrease in patency of the neuromuscular junction, and the consequent symptoms of MG.

People treated with penicillamine can develop MG symptoms. Their antibody titer is usually similar to that of MG, but both the symptoms and the titer disappear when drug administration is discontinued.

MG is more common in families with other autoimmune diseases. A familial predisposition found in 5% of the cases is associated with certain genetic variations, such as an increased frequency of HLA-B8 and DR3. People with MG suffer from coexisting autoimmune diseases at a higher frequency than members of the general population. Of particular mention is coexisting thyroid disease, where episodes of hypothyroidism may precipitate a severe exacerbation.

The acetylcholine receptor is clustered and anchored by the Rapsyn protein, research into which might eventually lead to new treatment options.