Figure 3.

Pathogenic mechanisms of MG autoantibodies at the NMJ. (A) At the healthy NMJ, neural Agrin stimulation induces interaction between Lrp4 and MuSK, leading to MuSK autophosphorylation and activation and the phosphorylation and clustering of AChRs. A retrograde signal for presynaptic development is sent via Lrp4. (B) MG antibodies of IgG1 and IgG3 subclass against AChR have three pathogenic mechanisms: (1) Cross-linking and increased turnover of AChR lead to reduced AChR levels at the NMJ, (2) activation of the classical complement cascade, formation of the membrane attack complex (MAC) and complement-mediated damage of the postsynaptic membrane, and (3) direct block of function by preventing the binding of acetylcholine. (C) Bispecific IgG4 antibodies of IgG4 subclass against MuSK bind monovalently to MuSK and block Lrp4-MuSK interaction, thus interrupting the agrin-Lrp4-MuSK-Dok7 signaling axis and causing reduced densities of AChR at the synapse. A further effect is the disruption of a retrograde signal from Lrp4 to the motor neuron. Divalent binding of MuSK IgG leads to dimerization, autophosphorylation, and activation of MuSK independent of Agrin stimulation and causes the formation of ectopic AChR clusters. Created with BioRender.