title: The intrinsic pathogenic role of autoantibodies to aquaporin 4 mediating spinal cord disease in a rat passive-transfer model.
abstract: Neuromyelitis optica (NMO) is causally linked to autoantibodies (ABs) against aquaporin 4 (AQP4). Here, we focused on the pathogenic effects exclusively mediated by human ABs to AQP4 in vivo. We performed cell-free intrathecal (i.th.) passive transfer experiments in Lewis rats using purified patient NMO immunoglobulin G (IgG) and various recombinant human anti-AQP4 IgG-ABs via implanted i.th. catheters. Repetitive application of patient NMO IgG fractions and of recombinant human anti-AQP4 ABs induced signs of spinal cord disease. Magnetic resonance imaging (MRI) revealed longitudinal spinal cord lesions at the site of application of anti-AQP4 IgG. Somatosensory evoked potential amplitudes were reduced in symptomatic animals corroborating the observed functional impairment. Spinal cord histology showed specific IgG deposition in the grey and white matter in the affected areas. We did not find inflammatory cell infiltration nor activation of complement in spinal cord areas of immunoglobulin deposition. Moreover, destructive lesions showing axon or myelin damage and loss of astrocytes and oligodendrocytes were all absent. Immunoreactivity to AQP4 and to the excitatory amino acid transporter 2 (EAAT2) was markedly reduced whereas immunoreactivity to the astrocytic marker glial fibrillary acid protein (GFAP) was preserved. The expression of the NMDA-receptor NR1 subunit was downregulated in areas of IgG deposition possibly induced by sustained glutamatergic overexcitation. Disease signs and histopathology were reversible within weeks after stopping injections. We conclude that in vivo application of ABs directed at AQP 4 can induce a reversible spinal cord disease in recipient rats by inducing distinct histopathological abnormalities. These findings may be the experimental correlate of "penumbra-like" lesions recently reported in NMO patients adjacent to effector-mediated tissue damage.
authors.affiliation: Department of Neurology and Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Würzburg, 97080 Würzburg, Germany; Hans Berger Department of Neurology, Jena University Hospital, 07747 Jena, Germany; The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, 07747 Jena, Germany. Electronic address: christian.geis@med.uni-jena.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Geis
authors.affiliation: Department of Neurology and Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Ritter
authors.affiliation: Department of Neurology and Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Ruschil
authors.affiliation: Department of Neurology and Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Weishaupt
authors.affiliation: Department of Neurology and Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Würzburg, 97080 Würzburg, Germany; Hans Berger Department of Neurology, Jena University Hospital, 07747 Jena, Germany; The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, 07747 Jena, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Grünewald
authors.affiliation: Department of Neurology and Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Stoll
authors.affiliation: Department of Neurology, Akershus University Hospital and Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway.
authors.forename: Trygve
authors.initials: T
authors.lastname: Holmoy
authors.affiliation: Department of Multiple Sclerosis Therapeutics and Neurology, Tohoku University Graduate School of Medicine, Sendai, 980-8577 Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Misu
authors.affiliation: Department of Multiple Sclerosis Therapeutics and Neurology, Tohoku University Graduate School of Medicine, Sendai, 980-8577 Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Fujihara
authors.affiliation: Klinikum rechts der Isar, Technische Universität, 81675 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 81675 Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hemmer
authors.affiliation: Institute of Neuropathology, University Medical Center Göttingen, 37099 Göttingen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann
authors.affiliation: Departments of Neurology and Ophthalmology, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Bennett
authors.affiliation: Department of Neurology and Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommer
authors.affiliation: Department of Neurology and Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Klaus V
authors.initials: KV
authors.lastname: Toyka
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000008:administration & dosage / Q000276:immunology*; D001323:Autoantibodies / Q000008:administration & dosage / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D007278:Injections, Spinal; D009471:Neuromyelitis Optica / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D013118:Spinal Cord Diseases / Q000209:etiology / Q000276:immunology / Q000473:pathology
chemical_list: C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D001323:Autoantibodies
keywords: Aquaporin 4; Astrocyte; EAAT2; Intrathecal passive transfer; NMDA receptor; Neuromyelitis optica