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Acta Neuropathologica

, Volume 123, Issue 6, pp 861–872 | Cite as

Neuromyelitis optica IgG and natural killer cells produce NMO lesions in mice without myelin loss

  • Julien Ratelade
  • Hua Zhang
  • Samira Saadoun
  • Jeffrey L. Bennett
  • Marios C. Papadopoulos
  • A. S. VerkmanEmail author
Original Paper

Abstract

The pathogenesis of neuromyelitis optica (NMO) involves targeting of NMO-immunoglobulin G (NMO-IgG) to aquaporin-4 (AQP4) on astrocytes in the central nervous system. Prior work provided evidence for complement-dependent cytotoxicity (CDC) in NMO lesion development. Here, we show that antibody-dependent cellular cytotoxicity (ADCC), in the absence of complement, can also produce NMO-like lesions. Antibody-dependent cellular cytotoxicity was produced in vitro by incubation of mouse astrocyte cultures with human recombinant monoclonal NMO-IgG and human natural killer cells (NK-cells). Injection of NMO-IgG and NK-cells in mouse brain caused loss of AQP4 and GFAP, two characteristic features of NMO lesions, but little myelin loss. Lesions were minimal or absent following injection of: (1) control (non-NMO) IgG with NK-cells; (2) NMO-IgG and NK-cells in AQP4-deficient mice; or (3) NMO-IgG and NK-cells in wild-type mice together with an excess of mutated NMO-IgG lacking ADCC effector function. NK-cells greatly exacerbated NMO lesions produced by NMO-IgG and complement in an ex vivo spinal cord slice model of NMO, causing marked myelin loss. NMO-IgG can thus produce astrocyte injury by ADCC in a complement-independent and dependent manner, suggesting the potential involvement of ADCC in NMO pathogenesis.

Keywords

NMO Aquaporin Natural killer cell Astrocyte Demyelination 

Notes

Acknowledgments

This work was supported by grants from the Guthy-Jackson Charitable Foundation (ASV, MCP, JLB), Grants EY13574, EB00415, DK35124, HL73856, DK86125 and DK72517 from the National Institutes of Health (ASV) and grant RG4320 from the National Multiple Sclerosis Society (JLB).

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Julien Ratelade
    • 1
    • 2
  • Hua Zhang
    • 1
    • 2
  • Samira Saadoun
    • 3
  • Jeffrey L. Bennett
    • 4
    • 5
  • Marios C. Papadopoulos
    • 3
  • A. S. Verkman
    • 1
    • 2
    Email author
  1. 1.Department of MedicineUniversity of California, San FranciscoSan FranciscoUSA
  2. 2.Department of PhysiologyUniversity of California, San FranciscoSan FranciscoUSA
  3. 3.Academic Neurosurgery UnitSt. George’s University of LondonLondonUK
  4. 4.Department of NeurologyUniversity of Colorado DenverAuroraUSA
  5. 5.Department of OphthalmologyUniversity of Colorado DenverAuroraUSA

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