The pathophysiology of MuSK myasthenia gravis

Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disease that is hallmarked by fatigable muscle weakness of in particular the cranial and bulbar muscles. The disease is caused by auto-antibodies binding MuSK on the post-synaptic muscle membrane. MuSK orchestrates formation, differentiation and maintenance of neuromuscular synapses. The research outlined in this thesis aimed at identifying the pathomechanism of MuSK MG. In passive transfer studies with immune incompetent mice we showed that IgG4 subclass antibodies from these patients exclusively induced myasthenia. We furthermore showed that anti-MuSK IgG4 causes the disease by inhibiting MuSK-Lrp4 interaction which results in loss of acetylcholine receptor clustering and synaptic disassembly. Our retrospective longitudinal study in 53 patients from three different cohorts identified the N-terminal Ig-like domain of MuSK as the main immunogenic region of the protein and showed that titers against this domain correlate with disease severity. Epitope patterns did not correlate with sensitivity to acetylcholine esterase inhibitors. Lastly we observed that, next to MuSK MG, 12 other antibody-mediated autoimmune diseases are hallmarked by predominant involvement of IgG4 antibodies. As IgG4 antibody-mediated autoimmune diseases differ in several aspects from other autoimmune disease they might form a new niche in antibody-mediated autoimmune diseases