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

Abstract

Myasthenia gravis (MG) is a severely debilitating autoimmune disease that is due to a decrease in the efficiency of synaptic transmission at neuromuscular synapses. MG is caused by antibodies against postsynaptic proteins, including (i) acetylcholine receptors, the neurotransmitter receptor, (ii) muscle-specific kinase (MuSK), a receptor tyrosine kinase essential for the formation and maintenance of neuromuscular synapses, and (iii)

Mechanisms controlling neuromuscular junction stability

“…LRP4 has been proposed to be a novel congenital myasthenic syndrome disease gene [64]. In myasthenia gravis (MG), a severely debilitating autoimmune disease that is due to a decrease in the efficiency of synaptic transmission at neuromuscular synapses, antibodies are generated against post-synaptic proteins, including acetylcholine receptors, MuSK, and (Lrp4), which prevent binding between MuSK and Lrp4, and inhibit agrin-stimulated MuSK phosphorylation [65].…”

Guidelines for pre-clinical animal and cellular models of MuSK-myasthenia gravis

“…IgG from MuSK-MG patients was able to disperse pre-existing AChR clusters in as little as one hour (Cole et al, 2010;Koneczny et al, 2013). IgG4 from MuSK-MG patients blocked the binding of LRP4 to MuSK, either on a solid support or when the proteins were expressed together in HEK cells (Huijbers et al, 2013;Koneczny et al, 2013). This indicates an important role of IgG4 autoantibodies.…”

“…Myoblasts exposed to a high concentration of MuSK-MG IgG from one patient showed marked co-internalization of human IgG and MuSK-GFP within one hour (Cole et al, 2010). By contrast, HEK or 3T3 cells exposed to MuSK-MG IgG (for 6-or 24 h respectively) revealed no reduction in cell surface expression of MuSK-GFP (Huijbers et al, 2013;Koneczny et al, 2013). Whether this difference was due to the different experimental set-ups, or differences in the patients' antibodies is not clear.…”

“…Cultured myotubes express on their surface the key components of the MuSK signaling pathway: LRP4, MuSK and AChR. Several groups have shown that, when added to cultured myotubes, plasma or IgG from MuSK-MG patients can inhibit the formation of AChR clusters and/or cause disassembly of pre-existing AChR clusters (Cole et al, 2010;Farrugia et al, 2007;Hoch et al, 2001;Huijbers et al, 2013;Koneczny et al, 2013). Cell culture assays using multiwell trays lend themselves to the testing of plasma/serum samples from large numbers of MuSK-MG patients.…”

Peripheral plasmablasts in anti-MuSK myasthenia gravis

“…It is interesting to note that in anti-MuSK myasthenia gravis antibodies are directly pathogenic [9] , whereas in IgG4-related disease they are probably not [7,10] . We recently stressed that the sphere of IgG4-mediated neurological autoimmune disorders is an expanding one [10] .…”