Causes/Inheritance

What causes myasthenia gravis (MG)?

The immune system in myasthenia gravis
Normally (A), the immune system releases antibodies to attack foreign invaders, such as bacteria. In autoimmune diseases (B), the antibodies mistakenly attack a person’s own tissues. In myasthenia gravis, they attack and damage muscle cells.
Packets of ACh in the nerve cell
Myasthenia gravis occurs when the immune system makes antibodies that destroy the ACh receptor (AChR), a docking site for the nerve chemical acetylcholine (ACh). Some treatments block acetylcholinesterase (AChE), an enzyme that breaks down ACh, while others target the immune system.

The immune system normally defends the body against diseases, but sometimes it can turn against the body, leading to an autoimmune disease. MG is just one of many autoimmune diseases, which include arthritis and type 1 diabetes.

In all of these diseases, an army of immune cells that would normally attack bacteria and disease-causing "germs" mistakenly attacks cells and/or proteins that have essential functions in the body. In most cases of MG, the immune system targets the acetylcholine receptor — a protein on muscle cells that’s required for muscle contraction (see illustration to the right).

At the normal neuromuscular junction, a nerve cell tells a muscle cell to contract by releasing the chemical acetylcholine (ACh). ACh attaches to the ACh receptor — a pore or "channel" in the surface of the muscle cell — twisting it open and allowing an inward flux of electrical current that triggers muscle contraction. These contractions enable someone to move a hand, to dial the telephone, walk through a door or complete any other voluntary movement.

About 85 percent of people with MG have antibodies against the ACh receptor in their blood. The antibodies (Y-shaped missiles that immune cells called B cells use to attack bacteria and viruses) target and destroy many of the ACh receptors on muscle. Consequently, the muscle’s response to repeated nerve signals declines with time, and the muscles become weak and tired.

About 15 percent of people with MG are seronegative for antibodies to the ACh receptor, meaning the antibodies aren’t detectable in their blood (serum). Recently, it’s been discovered that a large fraction of these people have antibodies to muscle-specific kinase (MuSK), a protein that helps organize ACh receptors on the muscle cell surface.

Scientists don’t know what triggers most autoimmune reactions, but they have a few theories. One possibility is that certain viral or bacterial proteins mimic "self-proteins" in the body (such as the ACh receptor), stimulating the immune system to unwittingly attack the self-protein.

There's also evidence that an immune system gland called the thymus plays a role in MG (see illustration below). Located in the chest just below the throat, the thymus is essential to the development of the immune system. From fetal life through childhood, the gland teaches immune cells called T cells to recognize self from non-self.

thymus
The thymus, a small gland in the upper chest, seems to play a role in myasthenia gravis.

About 15 percent of people with MG have a thymic tumor, called a thymoma, and another 65 percent have overactive thymic cells, a condition called thymic hyperplasia. When the thymus doesn’t work properly, the T cells might lose some of their ability to distinguish self from non-self, making them more likely to attack the body’s own cells.

What is the genetic susceptibility in MG?

Although MG and other autoimmune diseases are not hereditary, genetic susceptibility does appear to play a role.

Most studies suggest that if you have a relative with an autoimmune disease, your risk of getting an autoimmune disease is increased — the closer the relative, the higher the risk.

Even for identical twins, however, that risk is relatively small. Most studies suggest that when one twin has an autoimmune disease, the other has less than a 50 percent chance of getting the same disease.

Also, people who already have one autoimmune disease have a greater risk of developing another one. It’s estimated that 5 to 10 percent of people with MG have another autoimmune disease, which appeared before or after the onset of MG. The most common of these are autoimmune thyroid disease, rheumatoid arthritis and systemic lupus erythematosus (a disease that affects multiple organs).

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