PMID- 25542977 OWN - NLM STAT- MEDLINE DCOM- 20150428 LR - 20220331 IS - 1090-2430 (Electronic) IS - 0014-4886 (Print) IS - 0014-4886 (Linking) VI - 265 DP - 2015 Mar TI - The intrinsic pathogenic role of autoantibodies to aquaporin 4 mediating spinal cord disease in a rat passive-transfer model. PG - 8-21 LID - S0014-4886(14)00400-2 [pii] LID - 10.1016/j.expneurol.2014.12.015 [doi] AB - 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. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Geis, Christian AU - Geis C AD - Department of Neurology and Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Wurzburg, 97080 Wurzburg, 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. FAU - Ritter, Christian AU - Ritter C AD - Department of Neurology and Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Wurzburg, 97080 Wurzburg, Germany. FAU - Ruschil, Christoph AU - Ruschil C AD - Department of Neurology and Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Wurzburg, 97080 Wurzburg, Germany. FAU - Weishaupt, Andreas AU - Weishaupt A AD - Department of Neurology and Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Wurzburg, 97080 Wurzburg, Germany. FAU - Grunewald, Benedikt AU - Grunewald B AD - Department of Neurology and Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Wurzburg, 97080 Wurzburg, 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. FAU - Stoll, Guido AU - Stoll G AD - Department of Neurology and Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Wurzburg, 97080 Wurzburg, Germany. FAU - Holmoy, Trygve AU - Holmoy T AD - Department of Neurology, Akershus University Hospital and Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway. FAU - Misu, Tatsuro AU - Misu T AD - Department of Multiple Sclerosis Therapeutics and Neurology, Tohoku University Graduate School of Medicine, Sendai, 980-8577 Japan. FAU - Fujihara, Kazuo AU - Fujihara K AD - Department of Multiple Sclerosis Therapeutics and Neurology, Tohoku University Graduate School of Medicine, Sendai, 980-8577 Japan. FAU - Hemmer, Bernhard AU - Hemmer B AD - Klinikum rechts der Isar, Technische Universitat, 81675 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 81675 Munich, Germany. FAU - Stadelmann, Christine AU - Stadelmann C AD - Institute of Neuropathology, University Medical Center Gottingen, 37099 Gottingen, Germany. FAU - Bennett, Jeffrey L AU - Bennett JL AD - Departments of Neurology and Ophthalmology, University of Colorado Denver, Aurora, CO 80045, USA. FAU - Sommer, Claudia AU - Sommer C AD - Department of Neurology and Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Wurzburg, 97080 Wurzburg, Germany. FAU - Toyka, Klaus V AU - Toyka KV AD - Department of Neurology and Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Wurzburg, 97080 Wurzburg, Germany. LA - eng GR - R01 EY022936/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20141224 PL - United States TA - Exp Neurol JT - Experimental neurology JID - 0370712 RN - 0 (Aqp4 protein, rat) RN - 0 (Aquaporin 4) RN - 0 (Autoantibodies) SB - IM MH - Animals MH - Aquaporin 4/administration & dosage/*immunology MH - Autoantibodies/administration & dosage/*immunology MH - *Disease Models, Animal MH - Female MH - Humans MH - Immunization, Passive/*methods MH - Injections, Spinal MH - Neuromyelitis Optica/etiology/*immunology/pathology MH - Rats MH - Rats, Inbred Lew MH - Spinal Cord Diseases/etiology/immunology/pathology PMC - PMC4382207 MID - NIHMS661852 OTO - NOTNLM OT - Aquaporin 4 OT - Astrocyte OT - EAAT2 OT - Intrathecal passive transfer OT - NMDA receptor OT - Neuromyelitis optica EDAT- 2014/12/30 06:00 MHDA- 2015/04/29 06:00 PMCR- 2015/04/01 CRDT- 2014/12/28 06:00 PHST- 2014/10/28 00:00 [received] PHST- 2014/12/15 00:00 [revised] PHST- 2014/12/17 00:00 [accepted] PHST- 2014/12/28 06:00 [entrez] PHST- 2014/12/30 06:00 [pubmed] PHST- 2015/04/29 06:00 [medline] PHST- 2015/04/01 00:00 [pmc-release] AID - S0014-4886(14)00400-2 [pii] AID - 10.1016/j.expneurol.2014.12.015 [doi] PST - ppublish SO - Exp Neurol. 2015 Mar;265:8-21. doi: 10.1016/j.expneurol.2014.12.015. Epub 2014 Dec 24.