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Longitudinally extensive NMO spinal cord pathology produced by passive transfer of NMO-IgG in mice lacking complement inhibitor CD59.

ABSTRACT: Spinal cord pathology with inflammatory, demyelinating lesions spanning three or more vertebral segments is a characteristic feature of neuromyelitis optica (NMO). NMO pathogenesis is thought to involve binding of immunoglobulin G anti-aquaporin-4 autoantibodies (NMO-IgG) to astrocytes, causing complement-dependent cytotoxicity (CDC) and secondary inflammation, demyelination and neuron loss. We investigated the involvement of CD59, a glycophosphoinositol (GPI)-anchored membrane protein on astrocytes that inhibits formation of the terminal C5b-9 membrane attack complex. CD59 inhibition by a neutralizing monoclonal antibody greatly increased NMO-IgG-dependent CDC in murine astrocyte cultures and ex vivo spinal cord slice cultures. Greatly increased NMO pathology was also found in spinal cord slice cultures from CD59 knockout mice, and in vivo following intracerebral injection of NMO-IgG and human complement. Intrathecal injection (at L5-L6) of small amounts of NMO-IgG and human complement in CD59-deficient mice produced robust, longitudinally extensive white matter lesions in lumbar spinal cord. Pathology was most severe at day 2 after injection, showing loss of AQP4 and GFAP, C5b-9 deposition, microglial activation, granulocyte infiltration, and demyelination. Hind limb motor function was remarkably impaired as well. There was partial remyelination and recovery of motor function by day 5. Our results implicate CD59 as an important modulator of the immune response in NMO, and provide a novel animal model of NMO that closely recapitulates human NMO pathology. Up-regulation of CD59 on astrocytes may have therapeutic benefit in NMO.

SUBMITTER: Zhang H

PROVIDER: S-EPMC4162764 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Longitudinally extensive NMO spinal cord pathology produced by passive transfer of NMO-IgG in mice lacking complement inhibitor CD59.

Zhang Hua H Verkman A S AS

Journal of autoimmunity 20140331

Spinal cord pathology with inflammatory, demyelinating lesions spanning three or more vertebral segments is a characteristic feature of neuromyelitis optica (NMO). NMO pathogenesis is thought to involve binding of immunoglobulin G anti-aquaporin-4 autoantibodies (NMO-IgG) to astrocytes, causing complement-dependent cytotoxicity (CDC) and secondary inflammation, demyelination and neuron loss. We investigated the involvement of CD59, a glycophosphoinositol (GPI)-anchored membrane protein on astroc ...[more]

PMID: 24698947

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Project description:Several enveloped viruses including human immunodeficiency virus type 1 (HIV-1), cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1), Ebola virus, vaccinia virus, and influenza virus have been found to incorporate host regulators of complement activation (RCA) into their viral envelopes and, as a result, escape antibody-dependent complement-mediated lysis (ADCML). Hepatitis C virus (HCV) is an enveloped virus of the family Flaviviridae and incorporates more than 10 host lipoproteins. Patients chronically infected with HCV develop high-titer and crossreactive neutralizing antibodies (nAbs), yet fail to clear the virus, raising the possibility that HCV may also use the similar strategy of RCA incorporation to escape ADCML. The current study was therefore undertaken to determine whether HCV virions incorporate biologically functional CD59, a key member of RCA. Our experiments provided several lines of evidence demonstrating that CD59 was associated with the external membrane of HCV particles derived from either Huh7.5.1 cells or plasma samples from HCV-infected patients. First, HCV particles were captured by CD59-specific Abs. Second, CD59 was detected in purified HCV particles by immunoblot analysis and in the cell-free supernatant from HCV-infected Huh7.5.1 cells, but not from uninfected or adenovirus serotype 5 (Ad5) (a nonenveloped cytolytic virus)-infected Huh7.5.1 cells by enzyme-linked immunosorbent assay. Last, abrogation of CD59 function with its blockers increased the sensitivity of HCV virions to ADCML, resulting in a significant reduction of HCV infectivity. Additionally, direct addition of CD59 blockers into plasma samples from HCV-infected patients increased autologous virolysis.Our study, for the first time, demonstrates that CD59 is incorporated into both cell line-derived and plasma primary HCV virions at levels that protect against ADCML. This is also the first report to show that direct addition of RCA blockers into plasma from HCV-infected patients renders endogenous plasma virions sensitive to ADCML.

Dataset Information

Longitudinally extensive NMO spinal cord pathology produced by passive transfer of NMO-IgG in mice lacking complement inhibitor CD59.

Publications

Longitudinally extensive NMO spinal cord pathology produced by passive transfer of NMO-IgG in mice lacking complement inhibitor CD59.

Similar Datasets

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