Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica

Neurology. 2007 Dec 11;69(24):2221-31. doi: 10.1212/01.WNL.0000289761.64862.ce. Epub 2007 Oct 10.


Background: Autoantibody specific for the aquaporin-4 astrocytic water channel is restricted to serum and CSF of patients with neuromyelitis optica (NMO) and related CNS inflammatory demyelinating disorders (relapsing optic neuritis and longitudinally extensive transverse myelitis). NMO-typical lesions are distinct from MS-typical lesions. Aquaporin-4 is lost selectively at vasculocentric sites of edema/inflammation coinciding with focal deposits of immunoglobulins (Ig) G, M, and terminal complement products, with and without myelin loss. Evidence for antigen-specific autoantibody pathogenicity is lacking.

Methods: We used confocal microscopy and flow cytometry to evaluate the selectivity and immunopathological consequences of Ig binding to surface epitopes of living target cells expressing aquaporin-4 fused at its cytoplasmic N-terminus with GFP. We tested serum, IgG-enriched and IgG-depleted serum fractions, and CSF from patients with NMO, neurologic control patients, and healthy subjects. We also analyzed aquaporin-4 immunoreactivity in myelinated adult mouse optic nerves and spinal cord, and plasma cell Ig isotypes in archived brain tissue from an NMO patient.

Results: Serum IgG from patients with NMO binds to the extracellular domain of aquaporin-4; it is predominantly IgG(1), and it initiates two potentially competing outcomes, aquaporin-4 endocytosis/degradation and complement activation. Serum and CSF lack aquaporin-4-specific IgM, and plasma cells in CNS lesions of NMO contain only IgG. Paranodal astrocytic endfeet highly express aquaporin-4.

Conclusions: NMO patients' serum IgG has a selective pathologic effect on cell membranes expressing aquaporin-4. IgG targeting astrocytic processes around nodes of Ranvier could initiate demyelination.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Aquaporin 4 / immunology
  • Aquaporin 4 / metabolism*
  • Binding Sites, Antibody*
  • Cell Line
  • Endocytosis / immunology
  • Extracellular Fluid / immunology
  • Extracellular Fluid / metabolism*
  • Humans
  • Immunoglobulin G / metabolism*
  • Mice
  • Neuromyelitis Optica / immunology*
  • Neuromyelitis Optica / metabolism*
  • Neuromyelitis Optica / pathology
  • Protein Binding / immunology


  • AQP4 protein, human
  • Aquaporin 4
  • Immunoglobulin G