What is the pathophysiology of myasthenia gravis?

Pathophysiology of Myasthenia Gravis

Myasthenia gravis is a B-cell mediated autoimmune disorder where antibodies attack components of the neuromuscular junction—primarily the acetylcholine receptor—disrupting normal nerve signal transmission to muscles and causing the characteristic fatigable weakness. 1

Mechanism of Normal Neuromuscular Transmission

• Acetylcholine is released at the neuromuscular junction during an action potential and crosses the synapse to bind acetylcholine receptors on muscle fibers, triggering muscle contraction. 1

Autoimmune Attack at the Neuromuscular Junction

The pathogenesis depends on the specific autoantibody target and isotype involved:

Acetylcholine Receptor (AChR) Antibodies

• AChR antibodies are found in nearly all patients with generalized myasthenia gravis and in 40-77% of patients with ocular myasthenia gravis. 1
• These antibodies are predominantly IgG1 and IgG3 isotypes, which activate complement-mediated destruction of the postsynaptic membrane. 2
• Two primary mechanisms cause loss of functional AChRs: complement-mediated damage to the postsynaptic membrane and increased rate of AChR turnover through antibody-induced receptor internalization and degradation. 2
• The net result is a reduced number of available acetylcholine receptors, preventing proper nerve signal transmission even when acetylcholine is released normally. 1

Muscle-Specific Kinase (MuSK) Antibodies

• MuSK antibodies are detected in approximately 6% of myasthenia gravis patients who lack AChR antibodies. 3
• These antibodies are predominantly IgG4 isotype and cause disassembly of the neuromuscular junction by disrupting MuSK's physiological function in synapse maintenance and adaptation. 2
• Unlike AChR antibodies, MuSK antibodies do not activate complement but instead interfere with the structural organization of the neuromuscular junction. 2

Other Autoantibody Targets

• Low-density lipoprotein receptor-related protein 4 (LRP4) has been identified as a third autoantigen in myasthenia gravis. 3
• Additional antibodies against agrin, collagen Q, titin, ryanodine receptor, Kv1.4 potassium channels, and cortactin have been found in some patients and serve as useful biomarkers. 3

Muscle-Specific Vulnerability

• Extraocular muscles are particularly susceptible to fatigue due to their unique twitch fiber composition and fewer acetylcholine receptors compared to other skeletal muscles. 1
• This explains why ocular symptoms (ptosis and diplopia) are often the first manifestations, occurring in 50% of patients at initial presentation. 1

Thymic Involvement

• The thymus gland plays a central role in the pathogenesis, particularly in AChR-positive myasthenia gravis, with thymic abnormalities and defects in immune regulation contributing to the failure of immune tolerance to the AChR. 4, 2
• Thymoma is present in approximately 10-20% of patients with AChR-positive myasthenia gravis and represents a significant risk factor for disease development. 5, 6

Clinical Consequence of Pathophysiology

• The impaired neuromuscular transmission results in fluctuating muscle weakness that worsens with repetitive activity (as acetylcholine stores deplete and fewer functional receptors are available) and improves with rest (allowing time for acetylcholine replenishment). 1
• Proximal muscles are affected more than distal muscles due to their higher metabolic demands and greater reliance on sustained neuromuscular transmission. 5
• Respiratory muscle involvement represents the most serious manifestation, as severe impairment of neuromuscular transmission in these muscles can lead to respiratory failure requiring ventilatory support (myasthenic crisis). 1, 5