Myasthenia gravis

Myasthenia gravis comes from the Greek word ‘myasthenia’, meaning muscle weakness; and the Latin word ‘gravis’, meaning severe. So, myasthenia gravis is an autoimmune condition that causes serious muscle weakness.

First, let's focus on physiology and how muscles normally work. Whether you’re reaching for a slice of pizza or sinking that perfect shot in basketball, it all starts in the brain. The upper motor neuron of the cerebral cortex fires an action potential down the spinal cord to activate lower motor neurons. Next, lower motor neurons pick up these signals and pass them along their axons toward terminal branches and axon terminals, all the way to skeletal muscle fibers.

This communication site between the lower motor neuron and the skeletal muscle fiber is known as the neuromuscular junction, which consists of three main parts. First, there’s the presynaptic membrane, which is the axon terminal of the lower motor neuron packed with acetylcholine vesicles. Acetylcholine is actually the neurotransmitter that enables muscle contraction. Next, there’s the postsynaptic membrane, which is the membrane of the skeletal muscle fiber, rich in nicotinic acetylcholine receptors.

Finally, this tiny space between two membranes is called the synaptic cleft and contains the enzyme acetylcholine esterase.

Now, the arrival of the action potential at the axon terminal triggers the opening of voltage-gated calcium channels in the presynaptic membrane, allowing calcium ions to rush in. This triggers the acetylcholine vesicles to fuse with the presynaptic membrane and release acetylcholine into the synaptic cleft. Once inside the cleft, acetylcholine moves across to bind nicotinic acetylcholine receptors on the postsynaptic membrane. Eventually, this binding triggers the muscle cell to depolarize, setting off a chain of intracellular events that lead to contraction. Once the contraction is over, acetylcholine is broken down by acetylcholine esterase, allowing the muscle to relax and prepare for the next signal.

In myasthenia gravis, the immune system produces antibodies that disrupt the normal function of nicotinic acetylcholine receptors. Now, there are three types of autoantibodies. First, we have blocking antibodies, which bind and block acetylcholine receptors, so acetylcholine can’t activate them. Next, there are binding antibodies, which bind the receptors and activate the complement system, eventually destroying them. Finally, the third type includes modulating antibodies, which bind the receptors and trigger the muscle cell to pull the entire receptor inside.

As more receptors are blocked, destroyed, or removed from the postsynaptic membrane, it becomes harder for muscles to receive signals, leading to muscle weakness.

But that's not all. Sometimes, the immune system does not directly attack the acetylcholine receptors. Instead, it targets other important proteins that help neuromuscular junctions work properly, like Muscle Specific Kinase and Lipoprotein Related Protein 4. When they are disrupted, the connection between nerves and muscles becomes unstable or weak, making it even harder for signals to reach the muscle and causing further muscle weakness.

Now, several risk factors contribute to myasthenia gravis, including thymic abnormalities and genetics. In thymic hyperplasia, the thymus enlarges and forms reactive B-cell follicles that produce autoantibodies. Next up is thymoma, which is a tumor that arises from the epithelial cells of the thymus. Both conditions can cause the thymus to misguide the immune system into attacking acetylcholine receptors.

Next up are genetic factors. Certain HLA subtypes, which are genes that help control the immune system, can make someone more likely to develop autoimmune conditions like myasthenia gravis. Moreover, myasthenia gravis often shows up alongside other autoimmune diseases, such as thyroiditis, lupus, or rheumatoid arthritis.

Now, moving to clinical manifestations. As the immune system blocks, destroys or removes receptors from the postsynaptic membrane, muscles have a hard time receiving signals. Ultimately this leads to muscle weakness and fatigue, which is more pronounced in the proximal muscles.

Remember when you were a kid and spent the whole day in the backyard shooting basketballs? Imagine that after a few throws your muscles start to feel weak. You’d have to stop and rest before you could keep playing. Well, that’s what it’s like for someone with myasthenia gravis. Their muscles get tired quickly, even with simple things like brushing their teeth or combing their hair.