title: Autoantibody pathogenicity in a multifocal motor neuropathy induced pluripotent stem cell-derived model.
abstract: We investigated the pathogenicity of immunoglobulin M (IgM) anti-GM1 antibodies in serum from patients with multifocal motor neuropathy (MMN) using human induced pluripotent stem cell (iPSC)-derived motor neurons (MNs).
  
  
  
  iPSCs were generated from fibroblasts and differentiated into MNs. We studied the binding of IgM to MNs, their complement-activating properties, and effects on structural integrity using fluorescence and electron microscopy. Live cell imaging was used to study effects of antibody binding on MNs in the presence and absence of complement.
  
  
  
  IgM antibody binding to MNs was detected using sera from MMN patients with and without detectable anti-GM1 IgM antibody titers in enzyme-linked immunosorbent assay, but not with sera from (disease) controls. Competition and depletion experiments showed that antibodies specifically bound to GM1 on iPSC-derived MNs. Binding of these antibodies disrupted calcium homeostasis by both complement-dependent and complement-independent pathways. MNs showed marked axonal damage after complement activation, and reduced antibody pathogenicity following treatment with immunoglobulin preparations.
  
  
  
  Our data provide evidence for the pathogenicity of anti-GM1 IgM antibodies in MMN patients and link their presence to the clinical characteristics of axonal damage and immunoglobulin responsiveness. This iPSC-derived disease model will facilitate diagnosis, studies on autoantibody pathogenicity, drug development, and screening in immune-mediated neuropathies. Ann Neurol 2016;80:71-88.
authors.affiliation: Department of Neurology and Neurosurgery, University Medical Center Utrecht, Brain Center Rudolf Magnus, Utrecht, the Netherlands.|Department of Translational Neuroscience, University Medical Center Utrecht, Brain Center Rudolf Magnus, Utrecht, the Netherlands.
authors.forename: Oliver
authors.identifier: 0000-0001-6496-881X
authors.initials: O
authors.lastname: Harschnitz
authors.affiliation: Department of Neurology and Neurosurgery, University Medical Center Utrecht, Brain Center Rudolf Magnus, Utrecht, the Netherlands.
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.affiliation: Department of Translational Neuroscience, University Medical Center Utrecht, Brain Center Rudolf Magnus, Utrecht, the Netherlands.
authors.forename: Lill Eva
authors.initials: LE
authors.lastname: Johansen
authors.affiliation: Department of Neurology and Neurosurgery, University Medical Center Utrecht, Brain Center Rudolf Magnus, Utrecht, the Netherlands.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Jansen
authors.affiliation: Department of Neurology and Neurosurgery, University Medical Center Utrecht, Brain Center Rudolf Magnus, Utrecht, the Netherlands.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kling
authors.affiliation: Department of Translational Neuroscience, University Medical Center Utrecht, Brain Center Rudolf Magnus, Utrecht, the Netherlands.
authors.forename: Renata
authors.initials: R
authors.lastname: Vieira de Sá
authors.affiliation: Department of Translational Neuroscience, University Medical Center Utrecht, Brain Center Rudolf Magnus, Utrecht, the Netherlands.
authors.forename: Lotte
authors.initials: L
authors.lastname: Vlam
authors.affiliation: Department of Neurology and Neurosurgery, University Medical Center Utrecht, Brain Center Rudolf Magnus, Utrecht, the Netherlands.|Department of Translational Neuroscience, University Medical Center Utrecht, Brain Center Rudolf Magnus, Utrecht, the Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: van Rheenen
authors.affiliation: Department of Translational Neuroscience, University Medical Center Utrecht, Brain Center Rudolf Magnus, Utrecht, the Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: Karst
authors.affiliation: Division of Cell Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
authors.forename: Corette J
authors.initials: CJ
authors.lastname: Wierenga
authors.affiliation: Department of Translational Neuroscience, University Medical Center Utrecht, Brain Center Rudolf Magnus, Utrecht, the Netherlands.
authors.forename: R Jeroen
authors.initials: RJ
authors.lastname: Pasterkamp
authors.affiliation: Department of Neurology and Neurosurgery, University Medical Center Utrecht, Brain Center Rudolf Magnus, Utrecht, the Netherlands.
authors.forename: W Ludo
authors.initials: WL
authors.lastname: van der Pol
mesh_terms: D000328:Adult; D001323:Autoantibodies / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D018920:Coculture Techniques; D005260:Female; D005677:G(M1) Ganglioside / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology* / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D016501:Neurites / Q000473:pathology; D011115:Polyneuropathies / Q000097:blood / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000276:immunology
chemical_list: D001323:Autoantibodies; D007075:Immunoglobulin M; D005677:G(M1) Ganglioside; D002118:Calcium