In gMG, the mechanisms that control the adaptive immune system do not function properly, as the adaptive immune system targets healthy tissues. With gMG, the pathology includes the generation of antibodies against acetylcholine receptors (AChRs). Anti-AChR antibodies disrupt signal transmission at the NMJ by blocking and reducing the number of functioning AChRs.¹

• AChRs are found on the surface of muscle cells and are important for the generation of muscle contraction¹
• On average, approximately 85% of patients with gMG are anti-AChR antibody positive²

At least 3 pathogenic mechanisms are believed to be responsible for disrupting the NMJ in anti-AChR antibody-positive gMG^3,4:

1. 1. Complement-mediated postsynaptic membrane destruction
2. 2. Antigenic modulation
3. 3. Blockage of AChRs

Overview^3-5: All 3 mechanisms are believed to be active in anti-AChR antibody-positive gMG, but complement-mediated postsynaptic membrane destruction could be a cause of functional AChR loss and consequent failure of neuromuscular transmission.

Anti-AChR antibody binding to AChRs activates the complement cascade, resulting in the downstream production of terminal complement components, including protein C5a (leading to inflammation) and C5b. C5b is the first protein included in the formation of the membrane attack complex (MAC) at the postsynaptic membrane.

MAC is composed of complement proteins C5b through C9 and damages the postsynaptic membrane and its associated structures, such as the membrane folds and dense clusters of AChRs. This causes a simplification and distortion of the postsynaptic membrane that reduces the overall number of AChRs.

Alteration of folds in the muscle membrane reduces the efficiency of neuromuscular transmission.