Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/13707
Title: Muscle-specific kinase myasthenia gravis IgG4 autoantibodies cause severe neuromuscular junction dysfunction in mice
Authors: Klooster, Rinse
Plomp, Jaap J.
Huijbers, Maartje G.
Niks, Erik H.
Straasheijm, Kirsten R.
Detmers, Frank J.
Hermans, Pim W.
Sleijpen, Kevin
Verrips, Aad
Losen, Mario
Martinez-Martinez, Pilar
DE BAETS, Marc 
van der Maarel, Silvere M.
Verschuuren, Jan J.
Issue Date: 2012
Publisher: OXFORD UNIV PRESS
Source: BRAIN, 135 (4), p. 1081-1101
Abstract: Myasthenia gravis is a paralytic disorder with autoantibodies against acetylcholine receptors at the neuromuscular junction. A proportion of patients instead has antibodies against muscle-specific kinase, a protein essential for acetylcholine receptor clustering. These are generally of the immunoglobulin-G4 subclass and correlate with disease severity, suggesting specific myasthenogenic activity. However, immunoglobulin-G4 subclass antibodies are generally considered to be 'benign' and direct proof for their pathogenicity in muscle-specific kinase myasthenia gravis (or other immunoglobulin-G4-associated disorders) is lacking. Furthermore, the exact electrophysiological synaptic defects caused at neuromuscular junctions by human anti-muscle-specific kinase autoantibodies are hitherto unknown. We show that purified immunoglobulin-G4, but not immunoglobulin-G1-3, from patients with muscle-specific kinase myasthenia gravis binds to mouse neuromuscular junctions in vitro, and that injection into immunodeficient mice causes paralysis. Injected immunoglobulin-G4 caused reduced density and fragmented area of neuromuscular junction acetylcholine receptors. Detailed electrophysiological synaptic analyses revealed severe reduction of postsynaptic acetylcholine sensitivity, and exaggerated depression of presynaptic acetylcholine release during high-rate activity, together causing the (fatigable) muscle weakness. Intriguingly, compensatory transmitter release upregulation, which is the normal homeostatic response in acetylcholine receptor myasthenia gravis, was absent. This conveys extra vulnerability to neurotransmission at muscle-specific kinase myasthenia gravis neuromuscular junctions. Thus, we demonstrate that patient anti-muscle-specific kinase immunoglobulin-G4 is myasthenogenic, independent of additional immune system components, and have elucidated the underlying electrophysiological neuromuscular junction abnormalities.
Notes: [Plomp, Jaap J.; Huijbers, Maartje G.; Niks, Erik H.; Verschuuren, Jan J.] Leiden Univ, Med Ctr, Dept Neurol, NL-2300 RC Leiden, Netherlands. [Klooster, Rinse; Straasheijm, Kirsten R.; van der Maarel, Silvere M.] Leiden Univ, Med Ctr, Ctr Med Genet, Dept Human Genet, NL-2300 RC Leiden, Netherlands. [Plomp, Jaap J.] Leiden Univ, Med Ctr, Dept MCB Neurophysiol, NL-2300 RC Leiden, Netherlands. [Huijbers, Maartje G.; Losen, Mario; Martinez-Martinez, Pilar; De Baets, Marc H.] Maastricht Univ, Fac Hlth Med & Life Sci, Dept Neurosci, Sch Mental Hlth & Neurosci, Maastricht, Netherlands. [Detmers, Frank J.; Hermans, Pim W.; Sleijpen, Kevin] BAC BV, Naarden, Netherlands. [Verrips, Aad] Canisius Wilhelmina Hosp, Dept Paediat Neurol, Nijmegen, Netherlands. [De Baets, Marc H.] Hasselt Univ, Biomed Res Inst BIOMED, Neuroimmunol Grp, Diepenbeek, Belgium. s.m.maarel@lumc.nl; j.j.g.m.verschuuren@lumc.nl
Keywords: Clinical Neurology; Neurosciences; muscle-specific kinase; myasthenia gravis; autoantibodies; neuromuscular junction; elektrophysiology;muscle-specific kinase; myasthenia gravis; autoantibodies; neuromuscular junction; electrophysiology
Document URI: http://hdl.handle.net/1942/13707
ISSN: 0006-8950
e-ISSN: 1460-2156
DOI: 10.1093/brain/aws025
ISI #: 000302948700016
Category: A1
Type: Journal Contribution
Validations: ecoom 2013
Appears in Collections:Research publications

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