title: Guidelines for pre-clinical animal and cellular models of MuSK-myasthenia gravis.
abstract: Muscle-specific tyrosine kinase (MuSK) autoantibodies are the hallmark of a form of myasthenia gravis (MG) that can challenge the neurologist and the experimentalist. The clinical disease can be difficult to treat effectively. MuSK autoantibodies affect the neuromuscular junction in several ways. When added to muscle cells in culture, MuSK antibodies disperse acetylcholine receptor clusters. Experimental animals actively immunized with MuSK develop MuSK autoantibodies and muscle weakness. Weakness is associated with reduced postsynaptic acetylcholine receptor numbers, reduced amplitudes of miniature endplate potentials and endplate potentials, and failure of neuromuscular transmission. Similar impairments have been found in mice injected with IgG from MG patients positive for MuSK autoantibody (MuSK-MG). The active and passive models have begun to reveal the mechanisms by which MuSK antibodies disrupt synaptic function at the neuromuscular junction, and should be valuable in developing therapies for MuSK-MG. However, translation into new and improved treatments for patients requires procedures that are not too cumbersome but suitable for examining different aspects of MuSK function and the effects of potential therapies. Study design, conduct and analysis should be carefully considered and transparently reported. Here we review what has been learnt from animal and culture models of MuSK-MG, and offer guidelines for experimental design and conduct of studies, including sample size determination, randomization, outcome parameters and precautions for objective data analysis. These principles may also be relevant to the increasing number of other antibody-mediated diseases that are now recognized.
authors.affiliation: School of Medical Sciences (Physiology) and Bosch Institute, Anderson Stuart Bldg (F13), University of Sydney, NSW 2006, Australia. Electronic address: william.phillips@sydney.edu.au.
authors.forename: W D
authors.initials: WD
authors.lastname: Phillips
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address: pchrista@utmb.edu.
authors.forename: P
authors.initials: P
authors.lastname: Christadoss
authors.affiliation: Department of Neuroscience, School of Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands. Electronic address: m.losen@maastrichtuniversity.nl.
authors.forename: M
authors.initials: M
authors.lastname: Losen
authors.affiliation: Institute of Neuroscience, Department of Clinical Neurophysiology, Uppsala University, Uppsala, Sweden. Electronic address: anna.rostedt.punga@neuro.uu.se.
authors.forename: A R
authors.initials: AR
authors.lastname: Punga
authors.affiliation: Department of Geriatric Medicine, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan. Electronic address: kazshige@tmig.or.jp.
authors.forename: K
authors.initials: K
authors.lastname: Shigemoto
authors.affiliation: Department of Neurology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands. Electronic address: J.J.G.M.Verschuuren@lumc.nl.
authors.forename: J
authors.initials: J
authors.lastname: Verschuuren
authors.affiliation: Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Electronic address: angela.vincent@ndcn.ox.ac.uk.
authors.forename: A
authors.initials: A
authors.lastname: Vincent
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D017408:Guidelines as Topic; D006801:Humans; D009157:Myasthenia Gravis; D020720:Myasthenia Gravis, Autoimmune, Experimental; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology; D011950:Receptors, Cholinergic / Q000276:immunology; D012107:Research Design / Q000592:standards*
chemical_list: D001323:Autoantibodies; D011950:Receptors, Cholinergic; D020794:Receptor Protein-Tyrosine Kinases
keywords: Antibody-mediated; Autoantibodies; Consensus protocol; Experimental design; Muscle specific kinase; Myasthenia gravis; Neuromuscular junction; Preclinical; Rodent models