Neurological autoimmunity targeting aquaporin-4

Neuromyelitis optica (NMO) is the first inflammatory autoimmune demyelinating disease of the CNS for which a specific tissue target molecule has been identified--the astrocytic water channel aquaporin-4 (AQP4). Immunological insights have propelled significant advances in understanding the clinical, radiologic and immunopathologic characteristics of the disease in the last 5 years. In this review, we describe features distinguishing CNS AQP4 autoimmunity from classical multiple sclerosis (MS). In NMO, disease attacks preferentially involve the optic nerves and spinal cord (hence the name), but neurological signs in the initial attack of AQP4 autoimmunity in children commonly involve the brain. A clinically validated serum biomarker, NMO-IgG, distinguishes relapsing CNS inflammatory demyelinating disorders related to NMO from MS. The NMO-IgG autoantibody is AQP4-specific. Clinical, radiological and immunopathological data support its role in the pathogenesis of NMO spectrum disorders. Lesions characteristic of NMO are distinct from MS: AQP4 and its coupled glutamate transporter, excitatory amino acid transporter 2 (EAAT2), are lost, with and without associated myelin loss, IgG, IgM and complement are deposited in a vasculocentric pattern, edema and inflammation are prominent. In vitro studies demonstrate that binding of NMO-IgG to astrocytic AQP4 initiates multiple potentially neuropathogenic mechanisms: complement activation, AQP4 and EAAT2 downregulation with disruption of water and glutamate homeostasis, enhanced blood-brain barrier permeability, plasma protein and granulocyte influx, and antibody-dependent cell-mediated cytotoxicity. Development of effective, and potentially curative, therapies requires validated models of the disease, in animals and cell culture systems.