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 journalArticlepeer-review

232 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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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