{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:08:13Z","timestamp":1791472093857,"version":"4.3.4"},"reference-count":29,"publisher":"Rockefeller University Press","issue":"11","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,10,27]]},"abstract":"<jats:p>Neuromyelitis optica (NMO)-immunoglobulin G (IgG) is a clinically validated serum biomarker that distinguishes relapsing central nervous system (CNS) inflammatory demyelinating 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 endocytosed 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.<\/jats:p>","DOI":"10.1084\/jem.20081241","type":"journal-article","created":{"date-parts":[[2008,10,6]],"date-time":"2008-10-06T20:45:09Z","timestamp":1223325909000},"page":"2473-2481","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":330,"title":["Aquaporin-4\u2013binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2"],"prefix":"10.1084","volume":"205","author":[{"given":"Shannon R.","family":"Hinson","sequence":"first","affiliation":[{"name":"1Laboratory Medicine and Pathology"},{"name":"Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanu F.","family":"Roemer","sequence":"additional","affiliation":[{"name":"2Neurology,"},{"name":"Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia F.","family":"Lucchinetti","sequence":"additional","affiliation":[{"name":"2Neurology,"},{"name":"Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"Fryer","sequence":"additional","affiliation":[{"name":"1Laboratory Medicine and Pathology"},{"name":"Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Kryzer","sequence":"additional","affiliation":[{"name":"1Laboratory Medicine and Pathology"},{"name":"Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayne L.","family":"Chamberlain","sequence":"additional","affiliation":[{"name":"3Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905"},{"name":"Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles L.","family":"Howe","sequence":"additional","affiliation":[{"name":"2Neurology,"},{"name":"Departments of"},{"name":"3Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905"},{"name":"Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean J.","family":"Pittock","sequence":"additional","affiliation":[{"name":"1Laboratory Medicine and Pathology"},{"name":"Departments of"},{"name":"2Neurology,"},{"name":"Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanda A.","family":"Lennon","sequence":"additional","affiliation":[{"name":"1Laboratory Medicine and Pathology"},{"name":"Departments of"},{"name":"2Neurology,"},{"name":"Departments of"},{"name":"3Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905"},{"name":"Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2008,10,6]]},"reference":[{"key":"2023072516125114100_BIB1","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/S1474-4422(07)70216-8","volume":"6","year":"2007","journal-title":"Lancet Neurol."},{"key":"2023072516125114100_BIB2","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1084\/jem.20050304","volume":"202","year":"2005","journal-title":"J. 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