Neuromyelitis Optica Immunoglobulin G present in sera from neuromyelitis optica patients affects aquaporin-4 expression and water permeability of the astrocyte plasma membrane

J Neurosci Res. 2012 Jun;90(6):1240-8. doi: 10.1002/jnr.22822. Epub 2012 Feb 22.

Abstract

NMO-IgG autoantibody selectively binds to aquaporin-4 (AQP4), the most abundant water channel in the central nervous system and is now considered a useful serum biomarker of neuromyelitis optica (NMO). A series of clinical and pathological observations suggests that NMO-IgG may play a central role in NMO physiopathology. The current study evaluated, in well-differentiated astrocytes cultures, the consequences of NMO-IgG binding on the expression pattern of AQP4 and on plasma membrane water permeability. To avoid or to facilitate AQP4 down-regulation, cells were exposed to inactivated sera in two different situations (1 hr at 4°C or 12 hr at 37°C). AQP4 expression was detected by immunofluorescence studies using a polyclonal anti-AQP4 or a human anti-IgG antibody, and the water permeability coefficient was evaluated by a videomicroscopy technique. Our results showed that, at low temperatures, cell exposure to either control or NMO-IgG sera does not affect either AQP4 expression or plasma membrane water permeability, indicating that the simple binding of NMO-IgG does not affect the water channel's activity. However, at 37°C, long-term exposure to NMO-IgG induced a loss of human IgG signal from the plasma membrane along with M1-AQP4 isoform removal and a significant reduction of water permeability. These results suggest that binding of NMO-IgG to cell membranes expressing AQP4 is a specific mechanism that may account for at least part of the pathogenic process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Animals, Newborn
  • Antigens, Neoplasm / metabolism
  • Aquaporin 4 / metabolism*
  • Astrocytes / drug effects*
  • Astrocytes / physiology
  • Biotinylation
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Female
  • Glial Fibrillary Acidic Protein / metabolism
  • Humans
  • Immunoglobulin G / blood
  • Immunoglobulin G / pharmacology*
  • Membrane Glycoproteins / metabolism
  • Middle Aged
  • Neuromyelitis Optica / immunology*
  • Neuromyelitis Optica / pathology
  • Permeability / drug effects
  • Protein Transport / drug effects
  • Protein Transport / physiology
  • Rats
  • Water / metabolism*
  • Young Adult

Substances

  • Antigens, Neoplasm
  • Aquaporin 4
  • Glial Fibrillary Acidic Protein
  • Immunoglobulin G
  • Membrane Glycoproteins
  • glycoprotein 40 antigen, human
  • Water