PMID- 32505442 OWN - NLM STAT- MEDLINE DCOM- 20211012 LR - 20211012 IS - 1095-9157 (Electronic) IS - 0896-8411 (Linking) VI - 112 DP - 2020 Aug TI - MuSK antibodies, lessons learned from poly- and monoclonality. PG - 102488 LID - S0896-8411(20)30106-2 [pii] LID - 10.1016/j.jaut.2020.102488 [doi] AB - 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. CI - Copyright (c) 2020 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Vergoossen, Dana L E AU - Vergoossen DLE AD - Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, the Netherlands. FAU - Augustinus, Roy AU - Augustinus R AD - Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, the Netherlands. FAU - Huijbers, Maartje G AU - Huijbers MG AD - 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: M.G.M.Huijbers@lumc.nl. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20200604 PL - England TA - J Autoimmun JT - Journal of autoimmunity JID - 8812164 RN - 0 (Autoantibodies) RN - 0 (Autoantigens) RN - 0 (Epitopes) RN - 0 (Receptors, Cholinergic) RN - EC 2.7.10.1 (MUSK protein, human) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) SB - IM MH - Animals MH - Autoantibodies/blood/*immunology/metabolism MH - Autoantigens/*immunology/metabolism MH - Disease Models, Animal MH - Epitopes/immunology MH - Humans MH - Myasthenia Gravis/blood/*immunology/pathology MH - Neuromuscular Junction/immunology/*pathology MH - Receptor Protein-Tyrosine Kinases/*immunology/metabolism MH - Receptors, Cholinergic/*immunology/metabolism OTO - NOTNLM OT - Antibodies OT - Autoimmunity OT - Fab-arm exchange OT - IgG4 OT - MuSK OT - Neuromuscular junction COIS- Declaration of competing interest LUMC/MGH receives royalties from licensed patent applications on MuSK-related research. All other authors report no interests. EDAT- 2020/06/09 06:00 MHDA- 2021/10/13 06:00 CRDT- 2020/06/08 06:00 PHST- 2020/03/03 00:00 [received] PHST- 2020/04/28 00:00 [revised] PHST- 2020/05/06 00:00 [accepted] PHST- 2020/06/09 06:00 [pubmed] PHST- 2021/10/13 06:00 [medline] PHST- 2020/06/08 06:00 [entrez] AID - S0896-8411(20)30106-2 [pii] AID - 10.1016/j.jaut.2020.102488 [doi] PST - ppublish SO - J Autoimmun. 2020 Aug;112:102488. doi: 10.1016/j.jaut.2020.102488. Epub 2020 Jun 4.