The Complement Cascade in gMG Pathophysiology

Key Takeaways:

• Complement drives destruction in AChR-positive gMG but is not involved in MuSK-positive cases.
• The Membrane Attack Complex (MAC) physically destroys the muscle membrane, leading to permanent loss of neuromuscular junction architecture.
• Inhibiting the terminal cascade (C5) prevents this physical damage, preserving the integrity of the neuromuscular junction.

Generalized myasthenia gravis (gMG) is characterized by fluctuating muscle weakness resulting from impaired neuromuscular transmission. While the clinical hallmark is fatigability, the underlying pathology is a sophisticated autoimmune assault on the neuromuscular junction (NMJ). Structural damage to the postsynaptic membrane contributes to disease severity.¹

For decades, the primary focus rested specifically on the presence of autoantibodies. However, contemporary understanding reveals that in the most common form of gMG, these antibodies are triggers for downstream complement activation rather than being the only mediators of postsynaptic dysfunction. The actual destruction of the NMJ is largely executed by the complement system.¹

For clinicians managing gMG, moving beyond a "blockade" model of pathophysiology to one that incorporates complement-mediated structural damage is essential for understanding disease severity and the rationale behind emerging targeted therapies. This conceptual shift is particularly important for explaining severe, fixed, or treatment-refractory symptoms observed in a subset of patients. This article outlines the mechanistic role of the complement cascade in gMG pathophysiology.¹

The immunoglobulin trigger

The involvement of the complement system in gMG is largely determined by the patient's serological profile. Approximately 85 percent of gMG patients harbor antibodies against the acetylcholine receptor (AChR).^1,2

These anti-AChR antibodies are predominantly of the IgG1 and IgG3 subclasses. IgG1 and IgG3 antibodies are the most potent IgG subclasses for activating the classical complement pathway. When bound to AChRs tightly clustered on the postsynaptic membrane, the Fc regions of adjacent IgG1 or IgG3 molecules provide a docking site for the C1 complex, initiating the cascade.¹

Crucially, this mechanism does not apply to all gMG variants. Patients with antibodies against muscle-specific kinase (MuSK) typically express IgG4 subclass antibodies. IgG4 does not effectively activate complement.³

Therefore, the pathophysiology of MuSK-MG is functionally distinct, relying on interference with AChR clustering rather than complement-mediated destruction. Recognizing this dichotomy is fundamental to clinical decision-making, particularly regarding therapeutic agents targeting complement.¹

The cascade in action: From activation to destruction

In AChR-positive gMG, once the C1 complex binds to the antibody-antigen complex at the NMJ, the classical complement pathway is triggered. This leads to a proteolytic cascade generating C3 convertase, which cleaves C3 into C3a and C3b. C3b deposits on the postsynaptic membrane in a process known as opsonization, marking the area for further immune response and facilitating phagocytosis of damaged membrane debris by macrophages.^1,4

The critical turning point in pathophysiology occurs with the subsequent formation of C5 convertase, which cleaves C5 into C5a and C5b. C5a is a potent anaphylatoxin that promotes inflammation and attracts immune cells to the NMJ, exacerbating local damage.^1,4

C5b, however, initiates the terminal steps of the cascade. C5b rapidly recruits components C6, C7, C8, and multiple molecules of C9 to form the Membrane Attack Complex (MAC), also known as C5b-9.^1,4

The Membrane Attack Complex (MAC)

The assembly of the MAC is the definitive destructive event in AChR-positive gMG pathophysiology. The MAC forms a pore-like structure that inserts itself directly into the lipid bilayer of the postsynaptic muscle membrane. This results in focal lysis and osmotic damage to the muscle fiber surface. Repeated MAC insertion results in cumulative, irreversible damage to the postsynaptic membrane rather than transient dysfunction.^1,4

The consequence of repeated MAC insertion is severe structural alteration of the NMJ. Electron microscopy of affected NMJs reveals a characteristic simplification of the postsynaptic membrane, with flattened junctional folds and a widened synaptic cleft. These morphologic changes correlate with disease severity.^1,4

This destruction leads to a massive loss of functional AChRs and voltage-gated sodium channels, severely compromising the safety factor of neuromuscular transmission and resulting in clinical weakness. Studies have confirmed that MAC deposition colocalizes precisely with AChR loss at the junctional folds in patient tissue.^1,4

Modern therapeutics

In the pathophysiology of AChR-positive gMG, the autoantibody pulls the trigger, but the complement system – specifically the terminal MAC – inflicts the critical damage. Terminal complement activation represents the final common pathway of postsynaptic membrane injury in AChR-positive gMG. The transition from viewing gMG solely as an antibody-mediated receptor blockade to recognizing it as a complement-mediated destructive process is clinically significant.¹

This understanding explains why therapies that solely reduce antibody levels may sometimes be insufficient in acute crises and provides the mechanistic basis for modern therapeutics designed to inhibit terminal complement activation, thereby preserving NMJ architecture and function.¹