Animal models of antimuscle‐specific kinase myasthenia

Abstract

Antimuscle specific kinase (anti-MuSK) myasthenia (AMM) differs from antiacetylcholine receptor myasthenia gravis in exhibiting more focal muscle involvement (neck, shoulder, facial, and bulbar muscles) with wasting of the involved, primarily axial, muscles. AMM is not associated with thymic hyperplasia and responds poorly to anticholinesterase treatment. Animal models of AMM have been induced in rabbits, mice, and rats by immunization with purified xenogeneic MuSK ectodomain, and by passive transfer of large quantities of purified serum IgG from AMM patients into mice. The models have confirmed the pathogenic role of the MuSK antibodies in AMM and have demonstrated the involvement of both the presynaptic and postsynaptic components of the neuromuscular junction. The observations in this human disease and its animal models demonstrate the role of MuSK not only in the formation of this synapse but also in its maintenance.

The expanding field of IgG4‐mediated neurological autoimmune disorders

“…These experiments unequivocally proved their pathogenicity [14]. Active immunization of mice, rats or rabbits with MuSK causes a myasthenic phenotype [15][16][17][18][19]. Moreover, monovalent antibodies, generated by papain digestion, inhibited acetylcholine receptor (AChR) clustering and MuSK phosphorylation in vitro [20].…”

“…or control IgG4, was able to bind neuromuscular junctions in whole mount mouse muscle and upon passive transfer induced a myasthenic phenotype in immune-compromised mice [11][12][13]. Active immunization of mice, rats or rabbits with MuSK causes a myasthenic phenotype [15][16][17][18][19]. Active immunization of mice, rats or rabbits with MuSK causes a myasthenic phenotype [15][16][17][18][19].…”

Altered Active Zones, Vesicle Pools, Nerve Terminal Conductivity, and Morphology during Experimental MuSK Myasthenia Gravis

“…This goal is made possible by active [31] – [33] , [46] – [48] as well as passive [33] – [36] , [45] , [49] immunization models of MuSK-MG [50] . Herein, we immunized mice with rat MuSK ectodomain and evaluated functional, morphological, and biochemical properties of NMJs in respiratory muscles of mice exhibiting MuSK-MG. Our data suggest that the following presynaptic changes contribute to reduced neuromuscular transmission during MuSK-MG: 1) reduced number of active zones, 2) reduced probability of quantal release, 3) reduced number of quanta, and 4) altered nerve terminal conductivity and morphology.…”

Structure and function of neuromuscular junction, centered on muscle‐specific tyrosine kinase and related proteins

“…) have been determined largely as the IgG4 isotype, which does not activate complement differently from AChR antibodies (IgG1 and IgG3), and is detected in ~70% of MG patients who are mostly negative for AChR antibodies, although it has become appreciated that the cell‐based assay raises the anti‐AChR antibody detection rate in MG patients seronegative for AChR antibodies . The pathogenicity of MuSK antibodies was confirmed by the induction of animal models in which pre‐ and postsynaptic dysfunctions were proven . Also, it is worth noting that MuSK antibodies impair not only Lrp4‐MuSK interaction, but also agrin‐independent AChR clustering …”

“…In AChR antibody‐positive MG patients and animal models, the presynaptic ACh quantal release increases to compensate postsynaptic dysfunctions in ACh sensitivity, while the MG patients and animal models positive for MuSK and Lrp4 antibodies showed a defect in ACh‐release upregulation to compensate the postsynaptic dysfunctions . The compensatory mechanisms are provided by the fast‐mode of endocytosis to promote the synaptic vesicle recycling and the trans‐synaptic retrograde signaling.…”