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      Effects of neuromyelitis optica–IgG at the blood–brain barrier in vitro

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          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.


          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.


          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.


          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.

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          Most cited references 26

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          Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment.

          IL-6-/- mice showed impaired leukocyte accumulation in subcutaneous air pouches. Defective leukocyte accumulation was not due to a reduced migratory capacity of IL-6-/- leukocytes and was associated with a reduced in situ production of chemokines. These observations led to a reexamination of the interaction of IL-6 with endothelial cells (EC). EC express only the gp130 signal transducing chain and not the subunit-specific IL-6R and are therefore unresponsive to IL-6. However, EC are responsive to a combination of IL-6 and soluble IL-6R as measured by the activation of STAT3, chemokine expression, and augmentation of ICAM-1. Activation by IL-6-IL-6R complexes was inhibited by an IL-6 receptor antagonist and potentiated by a superagonist. Hence, in vivo and in vitro evidence supports the concept that the IL-6 system plays an unexpected positive role in local inflammatory reactions by amplifying leukocyte recruitment.
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            Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6.

            Postnatal neurogenesis can be modulated after brain injury, but the role of the attendant expression of inflammatory mediators in such responses remains to be determined. Here we report that transgenically directed production of interleukin-6 (IL-6) by astroglia decreased overall neurogenesis by 63% in the hippocampal dentate gyrus of young adult transgenic mice. The proliferation, survival, and differentiation of neural progenitor cells labeled with the thymidine analog bromodeoxyuridine were all reduced in the granule cell layer of these mice, whereas their distribution and gliogenesis appeared normal. These effects were not a consequence of general toxicity of the IL-6 transgene, because they were manifested in the absence of neuronal death and of major changes in glial cell number and morphology. These findings suggest that long-term exposure of the brain to proinflammatory mediators such as IL-6, as is seen in certain degenerative disorders and infections, can interfere with adult neurogenesis.
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              Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica.

              Autoantibody specific for the aquaporin-4 astrocytic water channel is restricted to serum and CSF of patients with neuromyelitis optica (NMO) and related CNS inflammatory demyelinating disorders (relapsing optic neuritis and longitudinally extensive transverse myelitis). NMO-typical lesions are distinct from MS-typical lesions. Aquaporin-4 is lost selectively at vasculocentric sites of edema/inflammation coinciding with focal deposits of immunoglobulins (Ig) G, M, and terminal complement products, with and without myelin loss. Evidence for antigen-specific autoantibody pathogenicity is lacking. We used confocal microscopy and flow cytometry to evaluate the selectivity and immunopathological consequences of Ig binding to surface epitopes of living target cells expressing aquaporin-4 fused at its cytoplasmic N-terminus with GFP. We tested serum, IgG-enriched and IgG-depleted serum fractions, and CSF from patients with NMO, neurologic control patients, and healthy subjects. We also analyzed aquaporin-4 immunoreactivity in myelinated adult mouse optic nerves and spinal cord, and plasma cell Ig isotypes in archived brain tissue from an NMO patient. Serum IgG from patients with NMO binds to the extracellular domain of aquaporin-4; it is predominantly IgG(1), and it initiates two potentially competing outcomes, aquaporin-4 endocytosis/degradation and complement activation. Serum and CSF lack aquaporin-4-specific IgM, and plasma cells in CNS lesions of NMO contain only IgG. Paranodal astrocytic endfeet highly express aquaporin-4. NMO patients' serum IgG has a selective pathologic effect on cell membranes expressing aquaporin-4. IgG targeting astrocytic processes around nodes of Ranvier could initiate demyelination.

                Author and article information

                Neurol Neuroimmunol Neuroinflamm
                Neurol Neuroimmunol Neuroinflamm
                Neurology® Neuroimmunology & Neuroinflammation
                Lippincott Williams & Wilkins (Hagerstown, MD )
                19 December 2016
                January 2017
                19 December 2016
                : 4
                : 1
                From the 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.
                Author notes
                Correspondence to Dr. Ransohoff: richard.ransohoff@

                Funding information and disclosures are provided at the end of the article. Go to for full disclosure forms. The Article Processing Charge was paid by the authors.

                Copyright © 2016 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

                Funded by: NIH
                Award ID: K24NS51400, R21NS78420, and P50NS38667
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