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

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 dist...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Neurology Jg. 69; H. 24; S. 2221
Hauptverfasser: Hinson, S R, Pittock, S J, Lucchinetti, C F, Roemer, S F, Fryer, J P, Kryzer, T J, Lennon, V A
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 11.12.2007
Schlagworte:
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
ISSN:1526-632X, 1526-632X
Online-Zugang:Weitere Angaben
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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. 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. 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. 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.
Bibliographie:ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Feature-1
content type line 23
ISSN:1526-632X
1526-632X
DOI:10.1212/01.wnl.0000289761.64862.ce