Table 5.

An overview of the accepted knowledge and unresolved questions about MuSK MG pathophysiology and the involvement of IgG4.

Accepted knowledge Polyclonal patient IgG4 induces MG-like features in vitro and in vivo Polyclonal patient IgG1–3 sometimes induce MG-like features in vitro MuSK antibodies cause MG by inhibiting LRP4–MuSK signalling, resulting in AChR declustering MuSK antibodies in some cases induce MuSK internalization and MuSK–ColQ interaction inhibition Polyclonal IgG4 MuSK patient antibodies exchange Fab-arms The N-terminal Ig-like domain 1 is the main immunogenic region, and epitopes outside this domain exist Unresolved questions Do IgG4 and IgG1 MuSK autoantibodies recognize similar epitopes? Can IgG1–3 MuSK autoantibodies cause MG in vivo? Is the valency of the autoantibodies relevant to their pathogenicity? Do MuSK MG patients have dysgammaglobulinemia? Do non-pathogenic MuSK antibodies exist? Are antibodies binding different epitopes on MuSK equally pathogenic? Do MuSK-specific IgE, IgA and IgM exist? What is their role? What causes the (IgG4) MuSK autoimmune response? Do IgG4-mediated autoimmune disease share a similar aetiology? Why is rituximab such an effective therapy in MuSK MG? Why do some patients remain in stable remission while other relapse?