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

SR Hinson, SJ Pittock, CF Lucchinetti, SF Roemer… - Neurology, 2007 - AAN Enterprises
SR Hinson, SJ Pittock, CF Lucchinetti, SF Roemer, JP Fryer, TJ Kryzer, VA Lennon
Neurology, 2007AAN Enterprises
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 …
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 IgG1, 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.
American Academy of Neurology