title: Effects of neuromyelitis optica-IgG at the blood-brain barrier in vitro.
abstract: OBJECTIVE
  To address the hypothesis that physiologic interactions between astrocytes and endothelial cells (EC) at the blood-brain barrier (BBB) are afflicted by pathogenic inflammatory signaling when astrocytes are exposed to aquaporin-4 (AQP4) antibodies present in the immunoglobulin G (IgG) fraction of serum from patients with neuromyelitis optica (NMO), referred to as NMO-IgG.
  
  
  METHODS
  We established static and flow-based in vitro BBB models incorporating co-cultures of conditionally immortalized human brain microvascular endothelial cells and human astrocyte cell lines with or without AQP4 expression.
  
  
  RESULTS
  In astrocyte-EC co-cultures, exposure of astrocytes to NMO-IgG decreased barrier function, induced CCL2 and CXCL8 expression by EC, and promoted leukocyte migration under flow, contingent on astrocyte expression of AQP4. NMO-IgG selectively induced interleukin (IL)-6 production by AQP4-positive astrocytes. When EC were exposed to IL-6, we observed decreased barrier function, increased CCL2 and CXCL8 expression, and enhanced leukocyte transmigration under flow. These effects were reversed after application of IL-6 neutralizing antibody.
  
  
  CONCLUSIONS
  Our results indicate that NMO-IgG induces IL-6 production by AQP4-positive astrocytes and that IL-6 signaling to EC decreases barrier function, increases chemokine production, and enhances leukocyte transmigration under flow.
authors.affiliation: Neuroinflammation Research Center (Y.T., B.O., A.C.C., S.F.S., F.S., E.Y., R.M.R.), Lerner Research Institute, Cleveland Clinic, OH; Department of Neurology and Clinical Neuroscience (Y.S., T.K.), Yamaguchi University Graduate School of Medicine, Japan; and Department of Laboratory Medicine and Pathology (T.J.K., V.A.L.), Mayo Clinic, Rochester, MN. Y.T. and F.S. are currently affiliated with the Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan. B.O., A.C.C., and R.M.R. are currently affiliated with Neuroimmunology Research, Biogen, Cambridge, MA. S.F.S. is currently affiliated with the Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Italy.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Takeshita
authors.affiliation: Neuroinflammation Research Center (Y.T., B.O., A.C.C., S.F.S., F.S., E.Y., R.M.R.), Lerner Research Institute, Cleveland Clinic, OH; Department of Neurology and Clinical Neuroscience (Y.S., T.K.), Yamaguchi University Graduate School of Medicine, Japan; and Department of Laboratory Medicine and Pathology (T.J.K., V.A.L.), Mayo Clinic, Rochester, MN. Y.T. and F.S. are currently affiliated with the Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan. B.O., A.C.C., and R.M.R. are currently affiliated with Neuroimmunology Research, Biogen, Cambridge, MA. S.F.S. is currently affiliated with the Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Italy.
authors.forename: Birgit
authors.initials: B
authors.lastname: Obermeier
authors.affiliation: Neuroinflammation Research Center (Y.T., B.O., A.C.C., S.F.S., F.S., E.Y., R.M.R.), Lerner Research Institute, Cleveland Clinic, OH; Department of Neurology and Clinical Neuroscience (Y.S., T.K.), Yamaguchi University Graduate School of Medicine, Japan; and Department of Laboratory Medicine and Pathology (T.J.K., V.A.L.), Mayo Clinic, Rochester, MN. Y.T. and F.S. are currently affiliated with the Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan. B.O., A.C.C., and R.M.R. are currently affiliated with Neuroimmunology Research, Biogen, Cambridge, MA. S.F.S. is currently affiliated with the Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Italy.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Cotleur
authors.affiliation: Neuroinflammation Research Center (Y.T., B.O., A.C.C., S.F.S., F.S., E.Y., R.M.R.), Lerner Research Institute, Cleveland Clinic, OH; Department of Neurology and Clinical Neuroscience (Y.S., T.K.), Yamaguchi University Graduate School of Medicine, Japan; and Department of Laboratory Medicine and Pathology (T.J.K., V.A.L.), Mayo Clinic, Rochester, MN. Y.T. and F.S. are currently affiliated with the Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan. B.O., A.C.C., and R.M.R. are currently affiliated with Neuroimmunology Research, Biogen, Cambridge, MA. S.F.S. is currently affiliated with the Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Italy.
authors.forename: Simona F
authors.initials: SF
authors.lastname: Spampinato
authors.affiliation: Neuroinflammation Research Center (Y.T., B.O., A.C.C., S.F.S., F.S., E.Y., R.M.R.), Lerner Research Institute, Cleveland Clinic, OH; Department of Neurology and Clinical Neuroscience (Y.S., T.K.), Yamaguchi University Graduate School of Medicine, Japan; and Department of Laboratory Medicine and Pathology (T.J.K., V.A.L.), Mayo Clinic, Rochester, MN. Y.T. and F.S. are currently affiliated with the Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan. B.O., A.C.C., and R.M.R. are currently affiliated with Neuroimmunology Research, Biogen, Cambridge, MA. S.F.S. is currently affiliated with the Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Italy.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Shimizu
authors.affiliation: Neuroinflammation Research Center (Y.T., B.O., A.C.C., S.F.S., F.S., E.Y., R.M.R.), Lerner Research Institute, Cleveland Clinic, OH; Department of Neurology and Clinical Neuroscience (Y.S., T.K.), Yamaguchi University Graduate School of Medicine, Japan; and Department of Laboratory Medicine and Pathology (T.J.K., V.A.L.), Mayo Clinic, Rochester, MN. Y.T. and F.S. are currently affiliated with the Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan. B.O., A.C.C., and R.M.R. are currently affiliated with Neuroimmunology Research, Biogen, Cambridge, MA. S.F.S. is currently affiliated with the Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Italy.
authors.forename: Erin
authors.initials: E
authors.lastname: Yamamoto
authors.affiliation: Neuroinflammation Research Center (Y.T., B.O., A.C.C., S.F.S., F.S., E.Y., R.M.R.), Lerner Research Institute, Cleveland Clinic, OH; Department of Neurology and Clinical Neuroscience (Y.S., T.K.), Yamaguchi University Graduate School of Medicine, Japan; and Department of Laboratory Medicine and Pathology (T.J.K., V.A.L.), Mayo Clinic, Rochester, MN. Y.T. and F.S. are currently affiliated with the Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan. B.O., A.C.C., and R.M.R. are currently affiliated with Neuroimmunology Research, Biogen, Cambridge, MA. S.F.S. is currently affiliated with the Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Italy.
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Sano
authors.affiliation: Neuroinflammation Research Center (Y.T., B.O., A.C.C., S.F.S., F.S., E.Y., R.M.R.), Lerner Research Institute, Cleveland Clinic, OH; Department of Neurology and Clinical Neuroscience (Y.S., T.K.), Yamaguchi University Graduate School of Medicine, Japan; and Department of Laboratory Medicine and Pathology (T.J.K., V.A.L.), Mayo Clinic, Rochester, MN. Y.T. and F.S. are currently affiliated with the Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan. B.O., A.C.C., and R.M.R. are currently affiliated with Neuroimmunology Research, Biogen, Cambridge, MA. S.F.S. is currently affiliated with the Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Italy.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kryzer
authors.affiliation: Neuroinflammation Research Center (Y.T., B.O., A.C.C., S.F.S., F.S., E.Y., R.M.R.), Lerner Research Institute, Cleveland Clinic, OH; Department of Neurology and Clinical Neuroscience (Y.S., T.K.), Yamaguchi University Graduate School of Medicine, Japan; and Department of Laboratory Medicine and Pathology (T.J.K., V.A.L.), Mayo Clinic, Rochester, MN. Y.T. and F.S. are currently affiliated with the Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan. B.O., A.C.C., and R.M.R. are currently affiliated with Neuroimmunology Research, Biogen, Cambridge, MA. S.F.S. is currently affiliated with the Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Italy.
authors.forename: Vanda A
authors.initials: VA
authors.lastname: Lennon
authors.affiliation: Neuroinflammation Research Center (Y.T., B.O., A.C.C., S.F.S., F.S., E.Y., R.M.R.), Lerner Research Institute, Cleveland Clinic, OH; Department of Neurology and Clinical Neuroscience (Y.S., T.K.), Yamaguchi University Graduate School of Medicine, Japan; and Department of Laboratory Medicine and Pathology (T.J.K., V.A.L.), Mayo Clinic, Rochester, MN. Y.T. and F.S. are currently affiliated with the Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan. B.O., A.C.C., and R.M.R. are currently affiliated with Neuroimmunology Research, Biogen, Cambridge, MA. S.F.S. is currently affiliated with the Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Italy.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanda
authors.affiliation: Neuroinflammation Research Center (Y.T., B.O., A.C.C., S.F.S., F.S., E.Y., R.M.R.), Lerner Research Institute, Cleveland Clinic, OH; Department of Neurology and Clinical Neuroscience (Y.S., T.K.), Yamaguchi University Graduate School of Medicine, Japan; and Department of Laboratory Medicine and Pathology (T.J.K., V.A.L.), Mayo Clinic, Rochester, MN. Y.T. and F.S. are currently affiliated with the Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan. B.O., A.C.C., and R.M.R. are currently affiliated with Neuroimmunology Research, Biogen, Cambridge, MA. S.F.S. is currently affiliated with the Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Italy.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff