Pathophysiology of Myasthenia Gravis

Myasthenia gravis represents a chronic T-cell–dependent, B-cell–mediated autoimmune disorder that disrupts neuromuscular transmission through pathogenic autoantibodies targeting the neuromuscular junction. The disease impairs the normal cascade of acetylcholine release, binding to nicotinic receptors, and subsequent muscle contraction, resulting in the hallmark symptoms of fluctuating weakness and fatigability. Understanding this pathophysiology is crucial for developing targeted therapeutic interventions.

Three primary autoantibody types drive myasthenia gravis pathogenesis: acetylcholine receptor (AChR) antibodies, muscle-specific kinase (MuSK) antibodies, and, less commonly, LRP4 antibodies, with some patients remaining seronegative. AChR antibodies, primarily IgG1 and IgG3 subtypes, trigger complement activation through the classical pathway, leading to membrane attack complex formation and destruction of the postsynaptic membrane. This complement-mediated damage involves cleaving C3 into C3a and C3b, then C5 into C5a and C5b, ultimately forming the membrane attack complex that destroys neuromuscular junction architecture.

MuSK antibodies operate through a different mechanism, representing IgG4-mediated responses that disrupt acetylcholine receptor clustering at the motor endplate without activating complement cascades. This distinction has significant therapeutic implications, as complement-targeting treatments prove ineffective in MuSK-positive patients. The specific autoantibody profile determines both disease phenotype and treatment response, making accurate serological classification essential for optimal patient management and therapeutic selection in myasthenia gravis care.