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Acta Neuropathologica

, Volume 126, Issue 5, pp 699–709 | Cite as

Involvement of antibody-dependent cell-mediated cytotoxicity in inflammatory demyelination in a mouse model of neuromyelitis optica

  • Julien Ratelade
  • Nithi Asavapanumas
  • Alanna M. Ritchie
  • Scott Wemlinger
  • Jeffrey L. Bennett
  • A. S. VerkmanEmail author
Original Paper

Abstract

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system that can cause paralysis and blindness. The pathogenesis of NMO involves binding of immunoglobulin G autoantibodies to aquaporin-4 (AQP4) on astrocytes, which is thought to cause complement-dependent cytotoxicity (CDC) and a secondary inflammatory response leading to oligodendrocyte and neuronal damage. Here, we investigate in vivo the role of antibody-dependent cell-mediated cytotoxicity (ADCC) triggered by AQP4 autoantibodies (AQP4-IgG) in the development of NMO pathology. A high-affinity, human recombinant monoclonal AQP4-IgG was mutated in its Fc region to produce ‘NMO superantibodies’ with enhanced CDC and/or ADCC effector functions, without altered AQP4 binding. Pathological effects of these antibodies were studied in a mouse model of NMO produced by intracerebral injection of AQP4-IgG and human complement. The original (non-mutated) antibody produced large NMO lesions in this model, with loss of AQP4 and GFAP immunoreactivity, inflammation and demyelination, as did a mutated antibody with enhanced CDC and ADCC effector functions. As anticipated, a mutated AQP4-IgG lacking CDC, but having tenfold enhanced ADCC, produced little pathology. However, unexpectedly, a mutated antibody with ninefold enhanced CDC, but lacking ADCC, produced much less pathology than the original AQP4-IgG. Also, pathology was greatly reduced following administration of AQP4-IgG and complement to mice lacking the FcγIII receptor involved in effector cell activation during ADCC, and to normal mice injected with an Fcγ receptor blocking antibody. Our results provide evidence for the central involvement of ADCC in NMO pathology and suggest ADCC as a new therapeutic target in NMO.

Keywords

NMO Aquaporin CDC ADCC Fcγ receptor Astrocyte 

Notes

Acknowledgments

This work was supported by grants from the Guthy-Jackson Charitable Foundation (ASV, JLB) and grants EY13574, EB00415, DK35124, HL73856, DK86125 and DK72517 (ASV) and EY022936 (JLB) from the National Institutes of Health.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Julien Ratelade
    • 1
  • Nithi Asavapanumas
    • 1
  • Alanna M. Ritchie
    • 2
  • Scott Wemlinger
    • 2
  • Jeffrey L. Bennett
    • 2
  • A. S. Verkman
    • 1
    • 3
    Email author
  1. 1.Departments of Medicine and PhysiologyUniversity of CaliforniaSan FranciscoUSA
  2. 2.Departments of Neurology and OphthalmologyUniversity of Colorado DenverAuroraUSA
  3. 3.University of CaliforniaSan FranciscoUSA

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