MuSK cysteine-rich domain antibodies are pathogenic in a mouse model of autoimmune myasthenia gravis
Marius Halliez, Steve Cottin, Axel You, Céline Buon, Antony Grondin, Léa S. Lippens, Mégane Lemaitre, Jérome Ezan, Charlotte Isch, Yann Rufin, Mireille Montcouquiol, Nathalie Sans, Bertrand Fontaine, Julien Messéant, Rozen Le Panse, Laure Strochlic
Marius Halliez, Steve Cottin, Axel You, Céline Buon, Antony Grondin, Léa S. Lippens, Mégane Lemaitre, Jérome Ezan, Charlotte Isch, Yann Rufin, Mireille Montcouquiol, Nathalie Sans, Bertrand Fontaine, Julien Messéant, Rozen Le Panse, Laure Strochlic
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Research Article Immunology Muscle biology Neuroscience

MuSK cysteine-rich domain antibodies are pathogenic in a mouse model of autoimmune myasthenia gravis

Abstract

The neuromuscular junction (NMJ), a synapse between the motor neuron terminal and a skeletal muscle fiber, is crucial throughout life in maintaining the reliable neurotransmission required for functional motricity. Disruption of this system leads to neuromuscular disorders, such as autoimmune myasthenia gravis (MG), the most common form of NMJ disease. MG is caused by autoantibodies directed mostly against the acetylcholine receptor (AChR) or the muscle-specific kinase MuSK. Several studies report immunoreactivity to the Frizzled-like cysteine-rich Wnt-binding domain of MuSK (CRD) in patients, although the pathogenicity of the antibodies involved remains unknown. We showed here that the immunoreactivity to MuSK CRD induced by the passive transfer of anti-MuSKCRD antibodies in mice led to typical MG symptoms, characterized by a loss of body weight and a locomotor deficit. The functional and morphological integrity of the NMJ was compromised with a progressive decay of neurotransmission and disruption of the structure of presynaptic and postsynaptic compartments. We found that anti-MuSKCRD antibodies completely abolished Agrin-mediated AChR clustering by decreasing the Lrp4-MuSK interaction. These results demonstrate the role of the MuSK CRD in MG pathogenesis and improve our understanding of the underlying pathophysiological mechanisms.

Authors

Marius Halliez, Steve Cottin, Axel You, Céline Buon, Antony Grondin, Léa S. Lippens, Mégane Lemaitre, Jérome Ezan, Charlotte Isch, Yann Rufin, Mireille Montcouquiol, Nathalie Sans, Bertrand Fontaine, Julien Messéant, Rozen Le Panse, Laure Strochlic

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Figure 3

NMJ structural defects in the TA muscles of CRD mice.

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NMJ structural defects in the TA muscles of CRD mice. (A) Representative...
(A) Representative confocal images of isolated TA muscle fibers from control PBS, IgG, and CRD mice at the end of the passive immunization protocol. Muscles were stained with α-bungarotoxin for detection of the acetylcholine receptor (AChR, green) and antibodies directed against neurofilament and synaptic vesicle protein 2A (NF/SV2, red) for the labeling of nerve terminals. Scale bar: 10 μm in the merged images. (B–H) Quantitative analysis of the endplate area (B), AChR labeling area (C), NMJ compactness corresponding to the ratio of C to B (D), number of isolated AChR fragments per NMJ (E), distribution of NMJ by fragment number (F), area of contact between the nerve terminal and the area labeled for AChR (G), and the percentage of presynaptic and postsynaptic overlap corresponding to the ratio of G to C (H). The data are shown as mean ± SEM. PBS, n = 5; IgG, n = 3; CRD, n = 4. At least 20 NMJs were analyzed for each muscle. White-filled large symbols represent the mean of all NMJs for each biological replicate; ns, not significant; *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; 1-way ANOVA with Tukey’s post hoc test (B–E, G, and H), 2-way ANOVA with Tukey’s post hoc test (F).