What is the pathogenesis of myasthenia gravis?

Pathogenesis of Myasthenia Gravis

Myasthenia gravis is a B-cell mediated autoimmune disorder where pathogenic autoantibodies attack postsynaptic components of the neuromuscular junction, primarily acetylcholine receptors, leading to impaired neuromuscular transmission and characteristic fatigable muscle weakness. 1

Autoimmune Mechanism

The fundamental pathogenic process involves autoantibodies targeting critical components of the neuromuscular junction:

• Acetylcholine receptor (AChR) antibodies are the primary culprit, found in nearly all patients with generalized myasthenia gravis and in 40-77% of patients with ocular myasthenia gravis 2, 1
• These antibodies are predominantly IgG1 and IgG3 subtypes that produce complement-mediated damage to the postsynaptic membrane 3
• The antibodies increase the rate of AChR turnover, causing progressive loss of acetylcholine receptors from the postsynaptic membrane 3

Neuromuscular Junction Disruption

The normal physiology is disrupted through specific mechanisms:

• Acetylcholine is released at the neuromuscular junction during an action potential and migrates across the synapse to reach striated muscle 2, 1
• Autoantibodies prevent proper nerve signal transmission by blocking, degrading, or destroying acetylcholine receptors 1, 3
• This results in failed neuromuscular transmission despite normal acetylcholine release from the presynaptic terminal 4, 3

Alternative Antibody Targets

In patients without AChR antibodies (approximately 15-20% of cases), other pathogenic antibodies exist:

• Muscle-specific kinase (MuSK) antibodies are found in approximately 30% of AChR-negative patients 5, 6
• MuSK antibodies are predominantly IgG4 subtype and cause disassembly of the neuromuscular junction by disrupting MuSK's physiological role in synapse maintenance 3
• LRP4 antibodies (against low-density lipoprotein receptor-related protein 4) have been identified as another cause in some seronegative patients 4, 6
• These antibodies disrupt the MuSK signaling complex required for development and maintenance of the postsynaptic membrane 4, 5

Selective Muscle Vulnerability

Extraocular muscles show particular susceptibility to this pathogenic process:

• Twitch fibers in extraocular muscles are especially vulnerable to fatigue 2, 1
• These muscles have fewer acetylcholine receptors compared to other skeletal muscles, making them more susceptible to antibody-mediated receptor loss 2, 7
• This explains why ocular symptoms (ptosis, diplopia, variable strabismus) are often the first manifestations, occurring in 50% of patients initially 1, 8

Role of the Thymus

The thymus gland plays a central role in disease pathogenesis:

• The thymus is involved in the failure of immune tolerance to the AChR 9, 3
• Thymoma is present in approximately 10-20% of patients and represents a significant risk factor 8, 6
• Thymectomy can substantially reduce clinical symptoms, particularly in specific age-based and immune-based patient subgroups 2

Clinical Consequences of Pathogenic Mechanisms

The antibody-mediated damage produces characteristic clinical features:

• Fluctuating weakness results from variable degrees of neuromuscular junction impairment that worsen with continued activity as remaining functional receptors become exhausted 1, 7
• Fatiguability occurs because repetitive nerve stimulation depletes the already reduced safety margin for neuromuscular transmission 7, 8
• Proximal muscles are affected more than distal muscles due to differences in neuromuscular junction density and receptor reserve 7, 8

Disease Subtypes Based on Pathogenesis

Different antibody patterns create distinct disease subgroups with varying pathogenic mechanisms:

• AChR-positive MG involves complement-mediated destruction and accelerated receptor degradation 3
• MuSK-positive MG involves functional disruption of synapse maintenance without complement activation 5, 3
• LRP4-positive MG disrupts the agrin-LRP4-MuSK signaling pathway essential for postsynaptic differentiation 4, 6
• Seronegative MG may involve antibodies to other unidentified neuromuscular junction components or low-titer antibodies below detection thresholds 6, 9

Critical Pathogenic Pitfall

The most dangerous consequence of this pathogenic process is respiratory muscle involvement, where antibody-mediated loss of neuromuscular transmission in respiratory muscles can rapidly progress to life-threatening respiratory failure requiring ventilatory support 1, 7, 8