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Myasthenia Gravis

Causes of Myasthenia Gravis

The underlying cause of myasthenia gravis is unknown. However, there is likely a genetic component, and clear evidence exists that the disease is somehow related to abnormalities in the thymus gland. Even though an exact cause has not been determined, the disease course is fairly well understood.

Myasthenia gravis affects the neuromuscular junction, or the area where nerve endings communicate with skeletal muscles. At the neuromuscular junction, nerve endings transmit impulses across a tiny space (synapse) to the muscle, causing it to contract. When a nerve impulse travels down the nerve, a neurotransmitter (ie, acetylcholine) is released from vesicles in the nerve ending into the synapse and bathes acetylcholine receptors located on the muscle side of the synapse, causing the muscle to be stimulated and contract.

The reaction is short-lived; in a very brief time, acetylcholine in the receptor is metabolized into its components (acetate and choline) by the enzyme acetylcholinesterase. Any remaining acetylcholine diffuses away from the receptors.

With myasthenia gravis, this normal impulse transmission is disrupted by T-cell-mediated autoantibodies that target and block the body’s own acetylcholine receptors. If enough receptors are blocked by autoantibodies, then the muscle contraction will be weak, causing the principal symptoms of myasthenia gravis.

The disease also affects the synapse in other ways besides blocking the acetylcholine receptors. On the muscle side of the synapse, acetylcholine receptors are normally grouped closely in tight synaptic folds. In myasthenia gravis, however, the autoantibodies work in concert with complement proteins (also part of the immune system) to damage and spread out the receptors and widen the synaptic folds. The result is fewer receptors.

In recent years, several interesting theories have been advanced to explain myasthenia gravis. Up to 90% of people with myasthenia gravis suffer from some form of abnormality in the thymus gland. The thymus gland is where T cells—the chief immune cell involved in myasthenia gravis—are produced and “schooled.” About 70% percent of people with myasthenia gravis have an enlarged thymus gland (hyperplasia), and 20% have usually benign thymic tumors (ie, thymomas) (Onodera 2005). By studying cells from thymomas and tissue from the thymus gland, scientists have begun to develop a unified theory that might one day explain the cause of myasthenia gravis.

According to this theory, myoid cells in the thymus might be responsible for the autoimmune reaction seen in myasthenia gravis. Myoid cells are muscle-like cells within the thymus gland. Recent studies have shown that T cells are first sensitized against myoid cells within the thymus. This has two effects. First, it causes the microscopic thymus changes seen in early-onset myasthenia gravis, which occurs before the age of 40 years. These changes resemble those eventually seen in skeletal muscles. Second, the sensitization of T cell antibodies to myoid cells causes the formation of germinal centers, which are key facilitators in the autoimmune reaction against acetylcholine receptors (Shiono 2003; Roxanis 2002).

Building on this work, researchers have looked more recently at the role of inflammatory cytokines in myasthenia gravis. In several studies, scientists have discovered that the expression of acetylcholine receptors is modified by inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α). These pro-inflammatory chemicals have been implicated in other autoimmune diseases (eg, multiple sclerosis and Lou Gehrig’s disease). In one study, researchers found that cytokine activity was enhanced in the myasthenia gravis thymus, possibly influencing acetylcholine-receptor expression and contributing to initiation of the autoimmune response (Poea-Guyon 2005). While this research is still preliminary, it offers novel therapeutic targets for the treatment of myasthenia gravis.