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MuSK antibodies, lessons learned from poly- and monoclonality.
Metadata
Journaljournal of autoimmunity6.658Date
2020 Jun 04
4 months ago
Type
Review
Journal Article
Volume
2020-Aug / 112 : 102488
Author
Vergoossen DLE 1, Augustinus R 1, Huijbers MG 2
Affiliation
  • 2. Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, the Netherlands; Department of Neurology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands. Electronic address: [email protected]
Doi
PMIDMESH
Abstract
Muscle-specific kinase (MuSK) plays a critical role in establishing and maintaining neuromuscular synapses. Antibodies derived from immunizing animals with MuSK were important tools to help detect MuSK and its activity. The role of antibodies in MuSK-related research got an extra dimension when autoantibodies to MuSK were found to cause myasthenia gravis (MG) in 2001. Active immunization with MuSK or passive transfer of polyclonal purified IgG(4) fractions from patients reproduced myasthenic muscle weakness in a range of animal models. Polyclonal patient-purified autoantibodies were furthermore found to block agrin-Lrp4-MuSK signaling, explaining the synaptic disassembly, failure of neuromuscular transmission and ultimately muscle fatigue observed in vivo. MuSK autoantibodies are predominantly of the IgG4 subclass. Low levels of other subclass MuSK antibodies coexist, but their role in the pathogenesis is unclear. Patient-derived monoclonal antibodies revealed that MuSK antibody subclass and valency alters their functional effects and possibly their pathogenicity. Interestingly, recombinant functional bivalent MuSK antibodies might even have therapeutic potential for a variety of neuromuscular disorders, due to their agonistic nature on the MuSK signaling cascade. Thus, MuSK antibodies have proven to be helpful tools to study neuromuscular junction physiology, contributed to our understanding of the pathophysiology of MuSK MG and might be used to treat neuromuscular disorders. The source of MuSK antibodies and consequently their (mixed) polyclonal or monoclonal nature were important confounding factors in these experiments. Here we review the variety of MuSK antibodies described thus far, the insights they have given us and their potential for the future.
Keywords: Antibodies Autoimmunity Fab-arm exchange IgG4 MuSK Neuromuscular junction
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6.7
J Autoimmunjournal of autoimmunity
Metadata
LocationEngland
FromACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD

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