PMID- 18838545
OWN - NLM
STAT- MEDLINE
DCOM- 20081210
LR  - 20220316
IS  - 1540-9538 (Electronic)
IS  - 0022-1007 (Print)
IS  - 0022-1007 (Linking)
VI  - 205
IP  - 11
DP  - 2008 Oct 27
TI  - Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair 
      glutamate transport by down-regulating EAAT2.
PG  - 2473-81
LID - 10.1084/jem.20081241 [doi]
AB  - 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.
FAU - Hinson, Shannon R
AU  - Hinson SR
AD  - Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 
      Rochester, MN 55905, USA.
FAU - Roemer, Shanu F
AU  - Roemer SF
FAU - Lucchinetti, Claudia F
AU  - Lucchinetti CF
FAU - Fryer, James P
AU  - Fryer JP
FAU - Kryzer, Thomas J
AU  - Kryzer TJ
FAU - Chamberlain, Jayne L
AU  - Chamberlain JL
FAU - Howe, Charles L
AU  - Howe CL
FAU - Pittock, Sean J
AU  - Pittock SJ
FAU - Lennon, Vanda A
AU  - Lennon VA
LA  - eng
GR  - R01 NS049577/NS/NINDS NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20081006
PL  - United States
TA  - J Exp Med
JT  - The Journal of experimental medicine
JID - 2985109R
RN  - 0 (AQP4 protein, human)
RN  - 0 (Aquaporin 4)
RN  - 0 (Autoantibodies)
RN  - 0 (DNA Primers)
RN  - 0 (Excitatory Amino Acid Transporter 2)
RN  - 0 (Glutamate Plasma Membrane Transport Proteins)
RN  - 0 (Immunoglobulin G)
RN  - 0 (SLC1A2 protein, human)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - 9007-36-7 (Complement System Proteins)
SB  - IM
MH  - Aquaporin 4/*immunology/metabolism
MH  - Astrocytes/cytology/*metabolism
MH  - Autoantibodies/immunology/*metabolism
MH  - Biological Transport/immunology
MH  - Blotting, Western
MH  - Cell Membrane/drug effects
MH  - Complement System Proteins/toxicity
MH  - DNA Primers/genetics
MH  - Excitatory Amino Acid Transporter 2
MH  - Gene Expression Regulation/*immunology
MH  - Glutamate Plasma Membrane Transport Proteins/*metabolism
MH  - Glutamic Acid/*metabolism
MH  - Humans
MH  - Immunoglobulin G/metabolism
MH  - Immunoprecipitation
MH  - Neuromyelitis Optica/*immunology/pathology
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Spinal Cord/metabolism
PMC - PMC2571922
EDAT- 2008/10/08 09:00
MHDA- 2008/12/17 09:00
PMCR- 2009/04/27
CRDT- 2008/10/08 09:00
PHST- 2008/10/08 09:00 [pubmed]
PHST- 2008/12/17 09:00 [medline]
PHST- 2008/10/08 09:00 [entrez]
PHST- 2009/04/27 00:00 [pmc-release]
AID - jem.20081241 [pii]
AID - 20081241 [pii]
AID - 10.1084/jem.20081241 [doi]
PST - ppublish
SO  - J Exp Med. 2008 Oct 27;205(11):2473-81. doi: 10.1084/jem.20081241. Epub 2008 Oct 
      6.