gMG resources

For patients with the chronic autoimmune disorder, myasthenia gravis (or MG), signals from the brain to the muscles get interrupted, resulting in muscle fatigue and weakness.

Normal nerve-to-muscle communication (known as neuromuscular transmission) occurs when an action potential travels from the brain along a motor neuron to its ending, called a nerve terminal. This terminal is located at the neuromuscular junction (or NMJ), the connection between the nerves and muscle fibers where the action potential is converted to a chemical signal (known as neurotransmission), ultimately leading to muscle contraction.

First, the nerve terminal communicates to the muscle through the release of a neurotransmitter called acetylcholine.

Acetylcholine binds to acetylcholine receptors on the muscle membrane, transmitting the signal. Once enough acetylcholine is bound and the signal reaches a threshold, an action potential triggers a muscle contraction.

On the surface of junctional folds in the muscle, specialized proteins known as muscle-specific kinase (or MuSK) and low-density lipoprotein receptor-related protein 4 (or LRP4) interact to organize and anchor the receptors near the nerve terminal. This process is known as clustering and it facilitates communication between nerves and muscles.

But how is communication at the NMJ interrupted in patients with MG?

Normally, B cells of the immune system produce antibodies that bind to pathogens, marking them for destruction.

But for patients with a chronic autoimmune disorder like MG, certain B cells of the immune system become autoreactive and produce autoantibodies.

Specifically, CD19-expressing plasmablasts and some plasma cells produce autoantibodies that target the acetylcholine receptor and MuSK.

These types of autoreactive B cells are the primary source of the autoantibodies that attack and degrade components of the NMJ involved in nerve-to-muscle communication, leading to impaired neuromuscular transmission over time.

There are 3 mechanisms of disease associated with autoantibodies that target the acetylcholine receptor in MG. Autoantibodies can: 1, block acetylcholine from binding to its receptors; 2, promote cross-linking and internal degradation of the receptors; and 3, lead to complement-mediated damage to the neuromuscular morphology at the NMJ.

Autoantibodies that target MuSK disrupt neuromuscular transmission by inhibiting the interaction between MuSK and LRP4, leading to reduced receptor clustering and a lower likelihood of acetylcholine binding.

Approximately 80% to 85% of patients with MG have autoantibodies that target the acetylcholine receptor, whereas about 5% to 10% of patients with MG have autoantibodies that target MuSK.

Approximately 2% of patients with MG have autoantibodies against LRP4, while about 5% to 10% of patients are considered seronegative, meaning they don’t have detectable autoantibodies against the acetylcholine receptor, MuSK, or LRP4.

Since these autoantibodies interrupt nerve-to-muscle communication, the muscles of the respiratory system, limbs, neck, face, and eyes are often impacted in patients with MG.

Patients with MG frequently experience muscle weakness leading to reduced strength in the arms and legs, drooping eyelids, and difficulty chewing or swallowing.

These core symptoms are the result of MuSK autoantibody-mediated disruption of receptor clustering, as well as acetylcholine receptor autoantibody-mediated binding and blocking, crosslinking and degradation, and complement-mediated damage to the NMJ.

While there are multiple mechanisms of disease that lead to interrupted neuromuscular transmission in patients with MG, the underlying pathophysiology can be traced upstream to the production of autoantibodies from pathogenic B cells.