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Human immunoglobulin G reduces the pathogenicity of aquaporin-4 autoantibodies in neuromyelitis optica.

Abstract
Neuromyelitis optica (NMO) pathogenesis involves binding of anti-aquaporin-4 (AQP4) autoantibodies (NMO-IgG) present in serum to AQP4 on astrocytes, which causes complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Human immunoglobulin G (hIgG) is effective for treatment of humorally mediated neurological autoimmune diseases and has been reported to improve disease outcome in a limited number of NMO patients. Here, we investigated hIgG actions on NMO-IgG pathogenicity using an in vivo rat model of NMO and in vitro assays. In rats administered NMO-IgG by intracerebral injection, the size of neuroinflammatory demyelinating lesions was reduced by ~50% when hIgG was administered by intraperitoneal injection to reach levels of 10-25mg/mL in rat serum, comparable with human therapeutic levels. In vitro, hIgG at 10mg/mL reduced by 90% NMO-IgG-mediated CDC following addition of NMO-IgG and human complement to AQP4-expressing cells. The hIgG effect was mainly on the classical complement pathway. hIgG at 10mg/mL also reduced by up to 90% NMO-IgG-mediated ADCC as assayed with human natural killer cells as effector cells. However, hIgG at up to 40mg/mL did not affect AQP4 cell surface expression or its supramolecular assembly in orthogonal arrays of particles, nor did it affect NMO-IgG binding to AQP4. We conclude that hIgG reduces NMO-IgG pathogenicity by inhibition of CDC and ADCC, providing a mechanistic basis to support further clinical evaluation of its therapeutic efficacy in NMO.
AuthorsJulien Ratelade, Alex J Smith, A S Verkman
JournalExperimental neurology (Exp Neurol) Vol. 255 Pg. 145-53 (May 2014) ISSN: 1090-2430 [Electronic] United States
PMID24636863 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Inc. All rights reserved.
Chemical References
  • Aquaporin 4
  • Autoantibodies
  • Immunoglobulin G
Topics
  • Animals
  • Aquaporin 4 (immunology, metabolism)
  • Astrocytes (drug effects, metabolism)
  • Autoantibodies (metabolism)
  • CHO Cells
  • Cricetulus
  • Disease Models, Animal
  • Female
  • Immunoglobulin G (pharmacology, therapeutic use)
  • Neuromyelitis Optica (drug therapy, immunology, pathology)
  • Rats
  • Rats, Inbred Lew

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