TY - JOUR
T1 - Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down- Regulating EAAT2
AU - Hinson, Shannon R.
AU - Roemer, Shanu F.
AU - Lucchinetti, Claudia F.
AU - Fryer, James P.
AU - Kryzer, Thomas J.
AU - Chamberlain, Jayne L.
AU - Howe, Charles L.
AU - Pittock, Sean J.
AU - Lennon, Vanda A.
PY - 2008/10/27
Y1 - 2008/10/27
N2 - Neuromyelitis optica (NMO)-immunoglobulin G (IgG) is a clinically validated serum bio- marker that distinguishes relapsing central nervous system (CNS) inflammatory demyelinat- ing disorders related to NMO from multiple sclerosis. This autoantibody targets astrocytic aquaporin-4 (AQP4) water channels. Clinical, radiological, and immunopathological data suggest that NMO-IgG might be pathogenic. Characteristic CNS lesions exhibit selective depletion of AQP4, with and without associated myelin loss; focal vasculocentric deposits of IgG, IgM, and complement; prominent edema; and inflammation. The effect of NMO-IgG on astrocytes has not been studied. In this study, we demonstrate that exposure to NMO patient serum and active complement compromises the membrane integrity of CNS-derived astrocytes. Without complement, astrocytic membranes remain intact, but AQP4 is endocy- tosed with concomitant loss of Na +-dependent glutamate transport and loss of the excitatory amino acid transporter 2 (EAAT2). Our data suggest that EAAT2 and AQP4 exist in astrocytic membranes as a macromolecular complex. Transport-competent EAAT2 protein is up-regulated in differentiating astrocyte progenitors and in nonneural cells expressing AQP4 transgenically. Marked reduction of EAAT2 in AQP4-deficient regions of NMO patient spinal cord lesions supports our immunocytochemical and immunoprecipitation data. Thus, binding of NMO-IgG to astrocytic AQP4 initiates several potentially neuropathogenic mechanisms: complement activation, AQP4 and EAAT2 down-regulation, and disruption of glutamate homeostasis.
AB - Neuromyelitis optica (NMO)-immunoglobulin G (IgG) is a clinically validated serum bio- marker that distinguishes relapsing central nervous system (CNS) inflammatory demyelinat- ing disorders related to NMO from multiple sclerosis. This autoantibody targets astrocytic aquaporin-4 (AQP4) water channels. Clinical, radiological, and immunopathological data suggest that NMO-IgG might be pathogenic. Characteristic CNS lesions exhibit selective depletion of AQP4, with and without associated myelin loss; focal vasculocentric deposits of IgG, IgM, and complement; prominent edema; and inflammation. The effect of NMO-IgG on astrocytes has not been studied. In this study, we demonstrate that exposure to NMO patient serum and active complement compromises the membrane integrity of CNS-derived astrocytes. Without complement, astrocytic membranes remain intact, but AQP4 is endocy- tosed with concomitant loss of Na +-dependent glutamate transport and loss of the excitatory amino acid transporter 2 (EAAT2). Our data suggest that EAAT2 and AQP4 exist in astrocytic membranes as a macromolecular complex. Transport-competent EAAT2 protein is up-regulated in differentiating astrocyte progenitors and in nonneural cells expressing AQP4 transgenically. Marked reduction of EAAT2 in AQP4-deficient regions of NMO patient spinal cord lesions supports our immunocytochemical and immunoprecipitation data. Thus, binding of NMO-IgG to astrocytic AQP4 initiates several potentially neuropathogenic mechanisms: complement activation, AQP4 and EAAT2 down-regulation, and disruption of glutamate homeostasis.
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U2 - 10.1084/jem.20081241
DO - 10.1084/jem.20081241
M3 - Article
C2 - 18838545
AN - SCOPUS:58149171974
SN - 0022-1007
VL - 205
SP - 2473
EP - 2481
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 11
ER -