Abstract
Myasthenia gravis (MG) with antibodies to the muscle-specific receptor tyrosine kinase (MuSK) is a distinct sub-group of MG, affecting 5–8% of all MG patients. MuSK, a receptor tyrosine kinase, is expressed at the neuromuscular junctions (NMJs) from the earliest stages of synaptogenesis and plays a crucial role in the development and maintenance of the NMJ. MuSK-MG patients are more severely affected and more refractory to treatments currently used for MG. Most patients require long-term immunosuppression, stressing the need for improved treatments. Ideally, preferred treatments should specifically delete the antigen-specific autoimmune response, without affecting the entire immune system. Mucosal tolerance, induced by oral or nasal administration of an auto-antigen through the mucosal system, resulting in an antigen-specific immunological systemic hyporesponsiveness, might be considered as a treatment of choice for MuSK-MG. In the present study we have characterized several immunological parameters of murine MuSK-EAMG and have employed induction of oral tolerance in mouse MuSK-EAMG, by feeding with a recombinant MuSK protein one week before disease induction. Such a treatment has been shown to attenuate MuSK-EAMG. Both induction and progression of disease were ameliorated following oral treatment with the recombinant MuSK fragment, as indicated by lower clinical scores and lower anti-MuSK antibody titers.
Highlights
Myasthenia gravis (MG) is an autoimmune disease characterized by skeletal muscle weakness as a result of an immunological attack at the neuromuscular junction (NMJ)
muscle-specific receptor tyrosine kinase (MuSK)-experimental autoimmune myasthenia gravis (EAMG), an experimental model of MuSK-MG, has been established in our lab in FVB/N female mice, according to Mori et al [14], which observed that these mice are highly susceptible to MuSK-EAMG induction. 8 weeks old female FVB/N mice were immunized with recombinant MuSK protein (20 or 40 μg/mouse, as indicated) in CFA on day 0 and boosted 14 days later, with a similar dose of antigen, in incomplete Freund’s adjuvant (IFA)
At the end of the experiment (35 days after disease induction) the CFA control group had a clinical score of 0, the MuSK 20 μg had a clinical score of 3 ± 0.6 (SD), and the MuSK 40 μg had a clinical score of 2.5 ± 1 (SD) (Figure 1A)
Summary
Myasthenia gravis (MG) is an autoimmune disease characterized by skeletal muscle weakness as a result of an immunological attack at the neuromuscular junction (NMJ). In 5–8% of MG patients the autoantibodies present in the sera are against the muscle-specific receptor tyrosine kinase (MuSK) classifying these patients as a distinct MG sub-group called MuSK-MG [1]. MuSK is a tyrosine kinase receptor expressed from early stages of synaptogenesis at the NMJ and has been shown to play a critical role in NMJ development and maintenance [2]. Agrin binding results in dimerization of MuSK and LRP4 followed by activation of MuSK [3]. It is still unknown how these molecules regulate NMJ formation [4]
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