title: Neuromyelitis optica study model based on chronic infusion of autoantibodies in rat cerebrospinal fluid.
abstract: Devic's neuromyelitis optica (NMO) is an autoimmune astrocytopathy, associated with central nervous system inflammation, demyelination, and neuronal injury. Several studies confirmed that autoantibodies directed against aquaporin-4 (AQP4-IgG) are relevant in the pathogenesis of NMO, mainly through complement-dependent toxicity leading to astrocyte death. However, the effect of the autoantibody per se and the exact role of intrathecal AQP4-IgG are still controversial.
  
  
  
  To explore the intrinsic effect of intrathecal AQP4-IgG, independent from additional inflammatory effector mechanisms, and to evaluate its clinical impact, we developed a new animal model, based on a prolonged infusion of purified immunoglobulins from NMO patient (IgG(AQP4+), NMO-rat) and healthy individual as control (Control-rat) in the cerebrospinal fluid (CSF) of live rats.
  
  
  
  We showed that CSF infusion of purified immunoglobulins led to diffusion in the brain, spinal cord, and optic nerves, the targeted structures in NMO. This was associated with astrocyte alteration in NMO-rats characterized by loss of aquaporin-4 expression in the spinal cord and the optic nerves compared to the Control-rats (p = 0.001 and p = 0.02, respectively). In addition, glutamate uptake tested on vigil rats was dramatically reduced in NMO-rats (p = 0.001) suggesting that astrocytopathy occurred in response to AQP4-IgG diffusion. In parallel, myelin was altered, as shown by the decrease of myelin basic protein staining by up to 46 and 22 % in the gray and white matter of the NMO-rats spinal cord, respectively (p = 0.03). Loss of neurofilament positive axons in NMO-rats (p = 0.003) revealed alteration of axonal integrity. Then, we investigated the clinical consequences of such alterations on the motor behavior of the NMO-rats. In a rotarod test, NMO-rats performance was lower compared to the controls (p = 0.0182). AQP4 expression, and myelin and axonal integrity were preserved in AQP4-IgG-depleted condition. We did not find a major immune cell infiltration and microglial activation nor complement deposition in the central nervous system, in our model.
  
  
  
  We establish a link between motor-deficit, NMO-like lesions and astrocytopathy mediated by intrathecal AQP4-IgG. Our study validates the concept of the intrinsic effect of autoantibody against surface antigens and offers a model for testing antibody and astrocyte-targeted therapies in NMO.
authors.affiliation: INSERM U1028, CNRS UMR 5292, Center for Research in Neuroscience of Lyon, Lyon, France. romain.marignier@chu-lyon.fr.|Université Lyon 1, Université de Lyon, Lyon, France. romain.marignier@chu-lyon.fr.|Service de Neurologie A, Eugène Devic EDMUS Foundation Against Multiple Sclerosis, Observatoire Français de la Sclérose en Plaques, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, 59 Boulevard Pinel, 69677, Lyon-Bron cedex, France. romain.marignier@chu-lyon.fr.
authors.forename: R
authors.initials: R
authors.lastname: Marignier
authors.affiliation: INSERM U1028, CNRS UMR 5292, Center for Research in Neuroscience of Lyon, Lyon, France.|Université Lyon 1, Université de Lyon, Lyon, France.
authors.forename: A
authors.initials: A
authors.lastname: Ruiz
authors.affiliation: INSERM U1028, CNRS UMR 5292, Center for Research in Neuroscience of Lyon, Lyon, France.|Université Lyon 1, Université de Lyon, Lyon, France.
authors.forename: S
authors.initials: S
authors.lastname: Cavagna
authors.affiliation: INSERM U1028, CNRS UMR 5292, Center for Research in Neuroscience of Lyon, Lyon, France.
authors.forename: A
authors.initials: A
authors.lastname: Nicole
authors.affiliation: INSERM U1028, CNRS UMR 5292, Center for Research in Neuroscience of Lyon, Lyon, France.|Université Lyon 1, Université de Lyon, Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Watrin
authors.affiliation: INSERM U1028, CNRS UMR 5292, Center for Research in Neuroscience of Lyon, Lyon, France.|Université Lyon 1, Université de Lyon, Lyon, France.
authors.forename: M
authors.initials: M
authors.lastname: Touret
authors.affiliation: INSERM U1028, CNRS UMR 5292, Center for Research in Neuroscience of Lyon, Lyon, France.|Université Lyon 1, Université de Lyon, Lyon, France.
authors.forename: S
authors.initials: S
authors.lastname: Parrot
authors.affiliation: INSERM U1028, CNRS UMR 5292, Center for Research in Neuroscience of Lyon, Lyon, France.|Université Lyon 1, Université de Lyon, Lyon, France.
authors.forename: G
authors.initials: G
authors.lastname: Malleret
authors.affiliation: INSERM U1028, CNRS UMR 5292, Center for Research in Neuroscience of Lyon, Lyon, France.|Université Lyon 1, Université de Lyon, Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Peyron
authors.affiliation: INSERM U1028, CNRS UMR 5292, Center for Research in Neuroscience of Lyon, Lyon, France.|Université Lyon 1, Université de Lyon, Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Benetollo
authors.affiliation: INSERM U1028, CNRS UMR 5292, Center for Research in Neuroscience of Lyon, Lyon, France.|Université Lyon 1, Université de Lyon, Lyon, France.
authors.forename: N
authors.initials: N
authors.lastname: Auvergnon
authors.affiliation: INSERM U1028, CNRS UMR 5292, Center for Research in Neuroscience of Lyon, Lyon, France.|Université Lyon 1, Université de Lyon, Lyon, France.|Service de Neurologie A, Eugène Devic EDMUS Foundation Against Multiple Sclerosis, Observatoire Français de la Sclérose en Plaques, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, 59 Boulevard Pinel, 69677, Lyon-Bron cedex, France.
authors.forename: S
authors.initials: S
authors.lastname: Vukusic
authors.affiliation: INSERM U1028, CNRS UMR 5292, Center for Research in Neuroscience of Lyon, Lyon, France.|Université Lyon 1, Université de Lyon, Lyon, France.
authors.forename: P
authors.initials: P
authors.lastname: Giraudon
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051401:Aquaporin 4 / Q000276:immunology* / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects* / Q000648:ultrastructure; D001369:Axons / Q000473:pathology / Q000648:ultrastructure; D002478:Cells, Cultured; D002555:Cerebrospinal Fluid / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage*; D009069:Movement Disorders / Q000150:complications; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D009471:Neuromyelitis Optica / Q000134:cerebrospinal fluid* / Q000150:complications / Q000209:etiology* / Q000473:pathology; D009900:Optic Nerve / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D013116:Spinal Cord / Q000473:pathology / Q000648:ultrastructure
chemical_list: C496030:AQP4 protein, human; D051401:Aquaporin 4; D005904:Glial Fibrillary Acidic Protein; D007074:Immunoglobulin G; D004676:Myelin Basic Protein; D018698:Glutamic Acid
keywords: Animal model; Aquaporin-4; Astrocyte; Autoantibodies; Autoimmune diseases; Glutamate; Neuromyelitis optica