Neuromyelitis optica (NMO) is currently the best-defined acquired inflammatory demyelinating disorder of the central nervous system (CNS) (1
). NMO attacks optic nerves and spinal cord selectively and repeatedly. The preferential distribution and severity of lesions in NMO is poorly understood. Clinical, histopathological, and immunobiological observations support a pathogenic role for an IgG autoantibody specific for the astrocytic water channel aquaporin-4 (AQP4), and the severity of acute NMO is ameliorated by antibody-depleting therapies (1
). In contrast to most inflammatory CNS demyelinating disorders, tissue destruction in NMO is profound. In addition to white matter lesions, NMO characteristically exhibits central necrosis of spinal cord gray matter (3
). Histopathological CNS lesions lack AQP4 (4
) and show deposition of IgM and IgG and products of complement activation in a vasculocentric pattern that coincides with the normal distribution of AQP4 (4
). Until recently, NMO was considered a rare and severe variant of multiple sclerosis (MS). However, the advent of serological testing for AQP4-IgG has revealed that NMO and its inaugural forms are more common than previously recognized. They tend to be misdiagnosed as MS, which lacks a specific biomarker (1
We recently demonstrated in vitro the pathogenicity of NMO-IgG for nonneural cells transgenically expressing AQP4, and that NMO serum IgM is not AQP4 specific. Binding of NMO-IgG to the extracellular domain of AQP4 reversibly down-regulates its plasma membrane expression (6
). In the presence of active complement, binding of NMO-IgG to surface AQP4 initiated robust complement activation and rapid loss of the target cell membrane's integrity. We concluded that the abundant IgM deposits in CNS lesions of NMO patients are plasma-derived and enter through the breached blood–brain barrier after initial focal activation of complement by AQP4-IgG (6
). Multisystem autoimmune diseases frequently accompany NMO (7
), and the elevated circulating IgM that is characteristic of multisystem autoimmunity has rheumatoid factor–like properties that could amplify the CNS inflammatory response in NMO (6
A recent report that astrocytes lacking AQP4 express a reduced level of the astrocytic Na+
-dependent excitatory amino acid transporter 2 (EAAT2; homologue of rodent GLT-1 [8
]) led us to hypothesize that if NMO-IgG altered the expression of EAAT2 in astrocyte membranes, this might impair glutamate homeostasis (6
). Resulting overstimulation of glutamate receptors in neurons and oligodendrocytes could contribute indirectly to the pathobiology of NMO. EAAT2 accounts for >90% of glutamate uptake in the CNS (9
), is critical for clearing glutamate from excitatory synapses, and is expressed selectively in astrocytes.
In this study, we demonstrate that: (a) when active complement is present, binding of NMO-IgG to AQP4 in astrocyte membranes causes membrane lesioning; (b) in the absence of complement, NMO-IgG causes antigen-specific removal of AQP4 from astrocytic membranes with reduction of Na+-dependent glutamate transport and loss of surface EAAT2; (c) transgenic expression of AQP4 in nonastrocytic cells, and physiological up-regulation of AQP4 in differentiating astrocytes, induces surface EAAT2 expression; (d) AQP4 and EAAT2 exist in astrocytic membranes as a macromolecular complex; and (e) regions of AQP4 loss in NMO spinal cord lesions are deficient in EAAT2.