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

Exp Neurol. 2014 May;255:145-53. doi: 10.1016/j.expneurol.2014.03.004. Epub 2014 Mar 14.

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.

Keywords: AQP4; Astrocyte; Complement; Human immunoglobulin; NMO; Neuroinflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aquaporin 4 / immunology*
  • Aquaporin 4 / metabolism
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Autoantibodies / metabolism*
  • CHO Cells
  • Cricetulus
  • Disease Models, Animal
  • Female
  • Immunoglobulin G / pharmacology
  • Immunoglobulin G / therapeutic use*
  • Neuromyelitis Optica / drug therapy
  • Neuromyelitis Optica / immunology*
  • Neuromyelitis Optica / pathology
  • Rats
  • Rats, Inbred Lew

Substances

  • Aquaporin 4
  • Autoantibodies
  • Immunoglobulin G