Anti-MuSK patient antibodies disrupt the mouse neuromuscular junction

• Published in: Annals of neurology 2008-06, Vol.63 (6), p.782-789
• Main Authors: Cole, Rebecca N., Reddel, Stephen W., Gervásio, Othon L., Phillips, William D.
• Format: Article
• Language: English
• Subjects: Acetylcholine - metabolism; Animals; Autoantibodies - immunology; Autoantibodies - toxicity; Biological and medical sciences; Humans; Immunoglobulin G - immunology; Immunoglobulin G - toxicity; Medical sciences; Mice; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Muscle Weakness - chemically induced; Muscle Weakness - immunology; Muscle Weakness - physiopathology; Myasthenia Gravis - immunology; Myasthenia Gravis - physiopathology; Myasthenia Gravis, Autoimmune, Experimental - chemically induced; Myasthenia Gravis, Autoimmune, Experimental - immunology; Myasthenia Gravis, Autoimmune, Experimental - physiopathology; Neurology; Neuromuscular Junction - drug effects; Neuromuscular Junction - immunology; Neuromuscular Junction - physiopathology; Receptor Protein-Tyrosine Kinases - immunology; Receptors, Cholinergic - immunology; Synaptic Membranes - drug effects; Synaptic Membranes - immunology; Synaptic Membranes - pathology; Synaptic Transmission - drug effects; Synaptic Transmission - immunology
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.21371

Objective A subset of myasthenia gravis patients that are seronegative for anti‐acetylcholine receptor (anti‐AChR) antibodies are instead seropositive for antibodies against the muscle‐specific kinase (anti‐MuSK–positive). Here, we test whether transfer of IgG from anti‐MuSK–positive patients to mice confers impairment of the neuromuscular junction and muscle weakness. Methods IgG from anti‐MuSK–positive myasthenia gravis patients or control IgG (seronegative for AChR and MuSK) was injected intraperitoneally (45mg daily for 14 days) into 6‐week‐old female FVB/NJ and C57BL/6J mice. Changes at neuromuscular junctions in the tibialis anterior and diaphragm muscles were assessed by confocal fluorescent imaging of AChRs stained with fluorescent‐α‐bungarotoxin. Loss of function was assessed by electromyography. Results In experimental mice injected with anti‐MuSK–positive patient IgG, postsynaptic AChR staining was reduced to as little as 22% of that seen in control mice. Experimental mice showed reduced apposition of the nerve terminal (labeled with antibodies against synaptophysin and neurofilament) and the postsynaptic AChR cluster (labeled with fluorescent‐α‐bungarotoxin). Mice injected with IgG from two of three anti‐MuSK–positive patients lost weight and developed muscle weakness associated with a decremental electromyographic trace on repetitive nerve stimulation. Interpretation IgG from anti‐MuSK–positive patients can cause myasthenia gravis when injected into mice. This may be explained by a progressive reduction in the density of postsynaptic AChR combined with changes in the nerve terminal and its relation to the postsynaptic structure. Ann Neurol 2008