Fig. 6.

Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4. Anti-MuSK IgG4 is produced as monospecific bivalent antibody. Upon reaching the circulation, Fab-arm exchange renders ∼99% of IgG4 MuSK antibodies bispecific and functionally monovalent. Monovalent MuSK antibodies reach NMJs and, upon binding to MuSK, block its function and induce AChR declustering, resulting in fast-onset progressive myasthenia. Monospecific functionally bivalent MuSK antibodies dimerize and activate MuSK signaling independent of agrin. Depending on the clone, this direct effect on MuSK either results in more slowly progressing myasthenia due to depletion of AChRs, by a yet-to-be-discovered mechanism, or induces no clinical phenotype with largely intact NMJs. P: phosphorylation. This figure was created with BioRender.com.