MuSK myasthenia gravis IgG4 disrupts the interaction of LRP4 with MuSK but both IgG4 and IgG1-3 can disperse preformed agrin-independent AChR clusters

PloS One
Inga KonecznyAngela Vincent

Abstract

A variable proportion of patients with generalized myasthenia gravis (MG) have autoantibodies to muscle specific tyrosine kinase (MuSK). During development agrin, released from the motor nerve, interacts with low density lipoprotein receptor-related protein-4 (LRP4), which then binds to MuSK; MuSK interaction with the intracellular protein Dok7 results in clustering of the acetylcholine receptors (AChRs) on the postsynaptic membrane. In mature muscle, MuSK helps maintain the high density of AChRs at the neuromuscular junction. MuSK antibodies are mainly IgG4 subclass, which does not activate complement and can be monovalent, thus it is not clear how the antibodies cause disruption of AChR numbers or function to cause MG. We hypothesised that MuSK antibodies either reduce surface MuSK expression and/or inhibit the interaction with LRP4. We prepared MuSK IgG, monovalent Fab fragments, IgG1-3 and IgG4 fractions from MuSK-MG plasmas. We asked whether the antibodies caused endocytosis of MuSK in MuSK-transfected cells or if they inhibited binding of LRP4 to MuSK in co-immunoprecipitation experiments. In parallel, we investigated their ability to reduce AChR clusters in C2C12 myotubes induced by a) agrin, reflecting neuromuscular dev...Continue Reading

References

Jan 1, 1990·Cold Spring Harbor Symposia on Quantitative Biology·U J McMahan
Jan 1, 1987·Annals of the New York Academy of Sciences·A VincentJohn Newsom-Davis
Jan 1, 1988·Annual Review of Immunology·R A Margni, R A Binaghi
Nov 16, 1984·Journal of Immunological Methods·P AucouturierJ L Preud'homme
Oct 1, 1995·International Archives of Allergy and Immunology·V PuigneróJ Queralt
Jan 5, 2000·The EMBO Journal·R Herbst, Steven J Burden
Mar 30, 2004·Annals of Neurology·John McConvilleAngela Vincent
Mar 25, 2006·The Journal of Clinical Investigation·Kazuhiro ShigemotoSeiji Matsuda
Jun 24, 2006·Science·Kumiko OkadaYuji Yamanashi
Aug 9, 2006·Neurology·E BartoccioniA Evoli
Aug 19, 2006·Science·David BeesonYuji Yamanashi
Mar 6, 2007·Journal of Neuroimmunology·Maria Elena FarrugiaAngela Vincent
Apr 4, 2008·Annals of Neurology·R N ColeWilliam D Phillips
Apr 4, 2008·Journal of Neuroimmunology·Erik H NiksJan J Verschuuren
Jun 3, 2008·Brain : a Journal of Neurology·Maria Isabel LeiteAngela Vincent
Oct 14, 2008·Cell·Natalie KimSteven J Burden
Oct 30, 2008·Neuron·Bin ZhangLin Mei
Feb 19, 2009·Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology·R C AalberseT Rispens
Feb 27, 2009·Science Signaling·Akane InoueYuji Yamanashi
Sep 12, 2009·The American Journal of Pathology·W Pascale ter BeekPeter C Molenaar
Oct 27, 2010·The International Journal of Biochemistry & Cell Biology·Nazanin GhazanfariWilliam D Phillips
Dec 3, 2010·Current Opinion in Rheumatology·Ajay NirulaFrederick R Taylora
Jan 25, 2011·The European Journal of Neuroscience·Anna Rostedt PungaMarkus A Ruegg
Mar 10, 2011·Annals of Neurology·Osamu HiguchiYuji Yamanashi
Oct 12, 2011·Medical Principles and Practice : International Journal of the Kuwait University, Health Science Centre·Erdem TüzünGüher Saruhan-Direskeneli
Jan 6, 2012·Neurology·J Díaz-ManeraI Illa
Feb 10, 2012·Development·Laura R GordonMichael Granato
Mar 1, 2012·Current Opinion in Pharmacology·Anna Rostedt Punga, Markus A Ruegg
Mar 21, 2012·Immunology and Cell Biology·Kerstin KieferAnn Marshak-Rothstein
Sep 25, 2012·Journal of Neuroimmunology·Masaharu TakamoriMasakatsu Motomura
Nov 3, 2012·Seminars in Neurology·Nicholas J Silvestri, Gil I Wolfe
Dec 1, 2012·Rinshō shinkeigaku = Clinical neurology·Kinji Ohno
Dec 25, 2012·BMJ : British Medical Journal·J SpillaneD M Kullmann
Jan 3, 2013·Annals of the New York Academy of Sciences·Judith CossinsDavid Beeson
Mar 6, 2013·Journal of Anatomy·Inga KonecznyAngela Vincent
May 3, 2013·Cold Spring Harbor Perspectives in Biology·Steven J BurdenWei Zhang
Jun 14, 2013·Journal of Neurology, Neurosurgery, and Psychiatry·Benison KeungRichard J Nowak
Jul 23, 2013·PloS One·Dongsheng XuLuwen Zhang

Citations

Aug 28, 2014·Current Opinion in Neurology·Stephen W ReddelWilliam D Phillips
Jun 22, 2014·Brain : a Journal of Neurology·Alexander Carvajal-GonzálezAngela Vincent
Mar 6, 2016·Journal of Neuroimmunology·Tanel PungaAnna Rostedt Punga
Feb 10, 2016·Journal of Neuroimmunology·Maartje G HuijbersJan J Verschuuren
Dec 26, 2015·Journal of Neurology·Sophie BinksJacqueline Palace
Jun 13, 2015·Scientific Reports·Guang ZhaoJianming Jiang
Sep 14, 2015·Drugs & Aging·Nuha M Alkhawajah, Joel Oger
Jun 3, 2015·European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies·Maartje G HuijbersJan J Verschuuren
May 29, 2016·Journal of Neuroimmunology·Melike KüçükerdenP Christadoss
May 31, 2015·Journal of Neuroimmunology·A I TsonisSocrates Tzartos
Mar 19, 2015·Experimental Neurology·P M Rodriguez CruzAngela Vincent
Dec 30, 2014·Experimental Neurology·William D PhillipsAngela Vincent
Apr 23, 2016·Nature Reviews. Neurology·N E GilhusSocrates Tzartos
Dec 22, 2017·Journal of Biomedical Materials Research. Part a·Erfan SolimanHua Ye
May 8, 2018·Acta Neurologica Scandinavica·Y HongN E Gilhus
Jan 15, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jason A Vander HeidenKevin C O'Connor
Sep 24, 2017·Muscle & Nerve·John S YiKevin C O'Connor
Aug 30, 2018·Current Opinion in Neurology·Renato MantegazzaPaola Cavalcante
Jul 14, 2016·F1000Research·William D Phillips, Angela Vincent
Mar 3, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Panos StathopoulosKevin C O'Connor
Jan 26, 2016·Nature Reviews. Neuroscience·Sarah J CrispAngela Vincent
Aug 22, 2017·Expert Opinion on Therapeutic Targets·Kinji OhnoMikako Ito
Jan 30, 2018·Annals of the New York Academy of Sciences·Angela VincentDavid Beeson
Jun 20, 2017·Neurology. Neuroimmunology and Neuroinflammation·Saif HudaAngela Vincent
Mar 19, 2019·Neurology. Neuroimmunology and Neuroinflammation·Maartje G HuijbersJan J Verschuuren
Dec 14, 2019·Neurology. Neuroimmunology and Neuroinflammation·Saif HudaAngela Vincent
Dec 14, 2019·Neurology. Neuroimmunology and Neuroinflammation·Maartje G Huijbers, Jan J Verschuuren
Jan 23, 2018·Annals of the New York Academy of Sciences·Jan J VerschuurenMaartje G Huijbers
Feb 9, 2018·International Journal of Molecular Sciences·Steven J BurdenLeonor Remedio
Jan 30, 2018·Annals of the New York Academy of Sciences·Maartje G HuijbersJan J Verschuuren
Jan 31, 2020·Frontiers in Molecular Biosciences·Salvatore R GuarinoFederico Forneris
Jul 31, 2020·Cellular & Molecular Immunology·Alicia ZouFabienne Brilot
Feb 7, 2018·Annals of the New York Academy of Sciences·Claire Legay
Nov 11, 2017·Annals of the New York Academy of Sciences·Nazanin GhazanfariWilliam D Phillips
Feb 28, 2018·Frontiers in Immunology·Inga Koneczny
May 28, 2020·Frontiers in Immunology·Lucia S Borges, David P Richman
Aug 23, 2016·Annals of Clinical and Translational Neurology·Jae-Yun LeeKevin C O'Connor
Nov 11, 2017·Annals of the New York Academy of Sciences·Anna Rostedt Punga, Tanel Punga
Mar 3, 2020·Frontiers in Immunology·Konstantinos Lazaridis, Socrates Tzartos
Jan 31, 2018·Annals of the New York Academy of Sciences·Panos StathopoulosKevin C O'Connor
Dec 22, 2020·Frontiers in Molecular Neuroscience·Pedro M Rodríguez CruzAngela Vincent
Dec 18, 2020·Frontiers in Neurology·Konstantinos Lazaridis, Socrates Tzartos
Mar 23, 2021·Proceedings of the National Academy of Sciences of the United States of America·Dana L E VergoossenMaartje G Huijbers
May 11, 2021·Expert Review of Molecular Diagnostics·M GastaldiD Franciotta

Methods Mentioned

BETA
electrophoresis
immunoprecipitation
flow cytometry
confocal microscopy
co-immunoprecipitation
immunoprecipitations
co-IP

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