Mouse Models of Myasthenia Gravis

Abstract

Myasthenia gravis is a muscle weakness disease characterized by autoantibodies that target components of the neuromuscular junction, impairing synaptic transmission. The most common form of myasthenia gravis involves antibodies that bind the nicotinic acetylcholine receptors in the postsynaptic membrane. Many of the remaining cases are due to antibodies against muscle specific tyrosine kinase (MuSK). Recently, autoantibodies against LRP4 (another component of the MuSK signaling complex in the postsynaptic membrane) were identified as the likely cause of myasthenia gravis in some patients. Fatiguing weakness is the common symptom in all forms of myasthenia gravis, but muscles of the body are differentially affected, for reasons that are not fully understood. Much of what we have learnt about the immunological and neurobiological aspects of the pathogenesis derives from mouse models. The most widely used mouse models involve either passive transfer of autoantibodies, or active immunization of the mouse with acetylcholine receptors or MuSK protein. These models can provide a robust replication of many of the features of the human disease. Depending upon the protocol, acute fatiguing weakness develops 2 - 14 days after the start of autoantibody injections (passive transfer) or might require repeated immunizations over several weeks (active models). Here we review mouse models of myasthenia gravis, including what they have contributed to current understanding of the pathogenic mechanisms and their current application to the testing of therapeutics.

Animal models of myasthenia gravis: utility and limitations

“… 45 Experimental animals actively immunized with MuSK (active MuSK EAMG) develop MuSK auto-Abs and muscle weakness, which are accompanied by reduced postsynaptic AChR numbers, decremented amplitudes of endplate potentials, and failure of neuromuscular transmission. 46 – 48 Although MuSK immunization stimulates the production of all antibody isotypes, noncomplement-fixing IgG1, the mouse analog of human IgG4, is the dominant anti-MuSK Ig isotype in both sera and NMJs. 47 Moreover, MuSK-immunized mice sera and supernatants of cultured lymph node cells show high levels of interleukin (IL)-4 and IL-10, suggesting a role for Th2-type cells in the activation of anti-MuSK IgG1.…”

Forced expression of muscle specific kinase slows postsynaptic acetylcholine receptor loss in a mouse model of MuSK myasthenia gravis

“…The major pathogenic mechanisms involve bivalent AChR autoantibodies cross‐linking adjacent AChR to cause accelerated AChR degradation (antigenic modulation) and complement‐mediated damage to the postsynaptic membrane (Baggi et al. ; Tüzün and Christadoss ; Ban and Phillips ). However, a proportion of MG patients instead express autoantibodies that target the extracellular domains of muscle‐specific (tyrosine) kinase (MuSK; Hoch et al.…”

“…Most cases of myasthenia gravis (MG) are caused by autoantibodies that target the nicotinic acetylcholine receptor (AChR) in the postsynaptic membrane of the neuromuscular junction (NMJ; Berrih-Aknin et al 2014). The major pathogenic mechanisms involve bivalent AChR autoantibodies cross-linking adjacent AChR to cause accelerated AChR degradation (antigenic modulation) and complement-mediated damage to the postsynaptic membrane (Baggi et al 2012;T€ uz€ un and Christadoss 2013;Ban and Phillips 2015). However, a proportion of MG patients instead express autoantibodies that target the extracellular domains of muscle-specific (tyrosine) kinase (MuSK; Hoch et al 2001;McConville et al 2004;Reddel et al 2014) or its co-receptor, low-density lipoprotein receptor-related protein 4 (LRP4; Higuchi et al 2011;Pevzner et al 2012;Zhang et al 2012;Zisimopoulou et al 2014).…”

Forelimb unloading impairs glenohumeral muscle development in growing rats

“…For each muscle, 9 muscle fibers were extracted, 3 each from the proximal, middle, and distal regions of the muscle. Sarcomere lengths were measured via a 5.0-mW HeNe laser with a wavelength of 633 nm (Thorlabs, Newton, NJ) using an established laser diffraction method 26 . All muscle lengths and distances between each diffraction band were measured using digital calipers (resolution of 0.01 mm).…”

“…Unloading models have traditionally focused on the hindlimbs 15 , resulting in limited understanding of the specific contributions of forelimb unloading to changes in muscle of glenohumeral joint, particularly during development. With a combined incidence of more than 5 per 1,000 live births 16–19 , pathologies affecting the developing muscles surrounding the glenohumeral joint (e.g., brachial plexus birth injury 20–22 , congenital muscular dystrophy 23–25 , cerebral palsy 26–28 , and congenital myasthenia gravis 29–31 ) have substantial implications for the effects of altered forelimb loading during development. However, isolating the role that altered loading plays in these conditions is challenging, since, for example, nerve injury also directly contributes to detrimental muscle 12,13 changes.…”