Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down- Regulating EAAT2

Shannon R. Hinson, Shanu F. Roemer, Claudia F Lucchinetti, James P. Fryer, Thomas J. Kryzer, Jayne L. Chamberlain, Charles L Howe, Sean J Pittock, Vanda A Lennon

Research output: Contribution to journalArticle

220 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2473-2481
Number of pages9
JournalJournal of Experimental Medicine
Volume205
Issue number11
DOIs
StatePublished - Oct 27 2008

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ASJC Scopus subject areas

  • Immunology
  • Medicine(all)
  • Immunology and Allergy

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