Inflammatory demyelinating diseases of the central nervous system (CNS) are recognized to be immune-mediated, but no disease-specific microbial antigen or autoantigen has been identified to date. Neuromyelitis optica (NMO; formerly known as Devic's disease) accounts for approximately one third of the cases of multiple sclerosis (MS) that are encountered in Asia, where it is known as optic-spinal MS (1
). The characteristic immunopathology of NMO is restricted to spinal cord and optic nerves, and affects gray and white matter. IgG, IgM, and products of complement activation are deposited in a vasculocentric pattern, which suggests a pathogenic role for autoantibody (2
). Blood vessels within demyelinating lesions are distinctively thickened and hyalinized, disproportionate to the patient's age (3
). Active lesions exhibit swelling, infiltrating macrophages, activated microglia, demyelination, axonal loss, prominent necrosis, and variable perivascular inflammation, with evidence of eosinophils and products of their exocytosis (2
). Chronic lesions are characterized by gliosis, cystic degeneration, cavitation, and atrophy.
Typically, NMO has a worse outcome than MS, with frequent and early relapses (4
). Vision and ambulation are impaired within 5 yr of its onset in 50% of patients, and 20% succumb to respiratory failure from cervical myelitis (5
). Plasmapheresis has been reported to improve the neurologic outcome for patients who have NMO with severe longitudinally extensive myelitis of recent onset (6
). This observation further supports an autoantibody-mediated pathogenesis for NMO. We recently described an IgG specific for NMO in the serum of 73% of patients who had NMO, and in 58% of patients who had the Asian optic-spinal form of MS. Patients who had classical (western) MS—for which no biomarker is recognized—were uniformly seronegative (7
). Thus, seropositivity for NMO-IgG allows early diagnostic distinction between patients who have NMO and those who have MS. This distinction is important prognostically and therapeutically because optimal treatments differ for NMO (immunosuppression; reference 8
) and MS (immunomodulation with β-IFN or glatiramer acetate; reference 9
). NMO-IgG binds to the abluminal face of microvessels, pia, subpia, and Virchow-Robin sheath in sections of normal mouse CNS tissues. Its partial colocalization with laminin (7
) is consistent with the autoantigen being a component of the glia limitans at the blood–brain barrier (BBB; reference 10
). In this report we show that NMO-IgG binds to the aquaporin-4 (AQP4) water channel.