MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4

MuSK myasthenia gravis (MG) is a debilitating autoimmune disease: one-third of MuSK MG patients experience a life-threatening respiratory crisis, and long-term immunosuppression is the only current treatment option. Here we show that pathogenic human IgG4 MuSK antibodies bind to the first Ig-like domain in MuSK and prevent Lrp4 from binding MuSK, thereby inhibiting Agrin-stimulated MuSK phosphorylation. This inhibitory mechanism is likely responsible for disrupting the structure of the synapse, compromising synaptic transmission and causing disease. Our findings therefore suggest that therapeutic strategies designed to increase MuSK activity may prove effective in treating MuSK MG. Moreover, our studies provide mechanistic understanding of an IgG4-mediated autoimmune disease and may shed light on the mechanisms of other IgG4-mediated autoimmune diseases.