Antibodies against Muscle-Specific Kinase Impair Both Presynaptic and Postsynaptic Functions in a Murine Model of Myasthenia Gravis

Abstract

Antibodies against acetylcholine receptors (AChRs) cause pathogenicity in myasthenia gravis (MG) patients through complement pathway-mediated destruction of postsynaptic membranes at neuromuscular junctions (NMJs). However, antibodies against muscle-specific kinase (MuSK), which constitute a major subclass of antibodies found in MG patients, do not activate the complement pathway. To investigate the pathophysiology of MuSK-MG and establish an experimental autoimmune MG (EAMG) model, we injected MuSK protein into mice deficient in complement component five (C5). MuSK-injected mice simultaneously developed severe muscle weakness, accompanied by an electromyographic pattern such as is typically observed in MG patients. In addition, we observed morphological and functional defects in the NMJs of EAMG mice, demonstrating that complement activation is not necessary for the onset of MuSK-MG. Furthermore, MuSK-injected mice exhibited acetylcholinesterase (AChE) inhibitor-evoked cholinergic hypersensitivity, as is observed in MuSK-MG patients, and a decrease in both AChE and the AChE-anchoring protein collagen Q at postsynaptic membranes. These findings suggest that MuSK is indispensable for the maintenance of NMJ structure and function, and that disruption of MuSK activity by autoantibodies causes MG. This mouse model of EAMG could be used to develop appropriate medications for the treatment of MuSK-MG in humans.

The Role of Acalypha Indica Linn. Extract on Heart Rates With Myasthenia Gravis Rat Model

“…Animal experiments show that MuSK immunoglobulin G (IgG) can cause MG. Mice that received repeated daily injections of patient IgG showed impaired neuromuscular transmission, with reductions in endplate AChR [18][19][20]. Similar changes to endplates were reported in mice, rats, and rabbits that were actively immunized with MuSK [21,22].…”

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

“…An increase in quantal content, however, is not evident in MuSK MG (12,16,45). These findings suggest that MuSK plays an important role in this homeostatic response.…”

“…These studies have shown that bivalent MuSK antibodies activate MuSK phosphorylation and inhibit Agrindependent AChR clustering (16,36), whereas monovalent Fab fragments, generated from these antibodies, inhibit MuSK phosphorylation and AChR clustering (37). Because rabbits lack the equivalent of human IgG4 antibodies, and mouse IgG binds complement (38,39), the active immunization models lead to the production of classic, bivalent antibodies that cross-link antigens, deplete cell-surface expression, and engage complement.…”

Antibodies against low-density lipoprotein receptor–related protein 4 induce myasthenia gravis

“…Ecto-LRP4 was emulsified with CFA and injected into female A/J mice, a strain that has been used successfully to establish MuSK EAMG (33,36). Mice received 3 boost injections (at weeks 4, 7, and 16) with ecto-LRP4 emulsified with incomplete Freund adjuvant (IFA); control mice were injected with emulsified PBS.…”

“…Approximately 40%-70% of seronegative patients have antibodies against MuSK (28)(29)(30). Immunization with the extracellular domain of MuSK causes MG in rodents and rabbits (31)(32)(33)(34)(35)(36). Passive transfer of IgG from antiMuSK-positive MG patients causes MG in adult animals (37)(38)(39)(40)(41).…”