PMID- 28461494
OWN - NLM
STAT- MEDLINE
DCOM- 20180514
LR  - 20181202
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 114
IP  - 21
DP  - 2017 May 23
TI  - Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 
      glutamate transporter requires astrocytic Fc receptor.
PG  - 5491-5496
LID - 10.1073/pnas.1701960114 [doi]
AB  - Aquaporin-4 (AQP4) water channel-specific IgG distinguishes neuromyelitis optica 
      (NMO) from multiple sclerosis and causes characteristic immunopathology in which 
      central nervous system (CNS) demyelination is secondary. Early events initiating 
      the pathophysiological outcomes of IgG binding to astrocytic AQP4 are poorly 
      understood. CNS lesions reflect events documented in vitro following IgG 
      interaction with AQP4: AQP4 internalization, attenuated glutamate uptake, 
      intramyelinic edema, interleukin-6 release, complement activation, inflammatory 
      cell recruitment, and demyelination. Here, we demonstrate that AQP4 
      internalization requires AQP4-bound IgG to engage an astrocytic Fcgamma receptor 
      (FcgammaR). IgG-lacking Fc redistributes AQP4 within the plasma membrane and induces 
      interleukin-6 release. However, AQP4 endocytosis requires an activating FcgammaR's 
      gamma subunit and involves astrocytic membrane loss of an inhibitory FcgammaR, CD32B. 
      Interaction of the IgG-AQP4 complex with FcgammaRs triggers coendocytosis of the 
      excitatory amino acid transporter 2 (EAAT2). Requirement of FcgammaR engagement for 
      internalization of two astrocytic membrane proteins critical to CNS homeostasis 
      identifies a complement-independent, upstream target for potential early 
      therapeutic intervention in NMO.
FAU - Hinson, Shannon R
AU  - Hinson SR
AD  - Neuroimmunology Laboratory, Department of Laboratory Medicine and Pathology, 
      College of Medicine, Mayo Clinic, Rochester, MN 55905.
FAU - Clift, Ian C
AU  - Clift IC
AD  - Neuroimmunology Laboratory, Department of Laboratory Medicine and Pathology, 
      College of Medicine, Mayo Clinic, Rochester, MN 55905.
FAU - Luo, Ningling
AU  - Luo N
AD  - Neuroimmunology Laboratory, Department of Laboratory Medicine and Pathology, 
      College of Medicine, Mayo Clinic, Rochester, MN 55905.
FAU - Kryzer, Thomas J
AU  - Kryzer TJ
AD  - Neuroimmunology Laboratory, Department of Laboratory Medicine and Pathology, 
      College of Medicine, Mayo Clinic, Rochester, MN 55905.
FAU - Lennon, Vanda A
AU  - Lennon VA
AD  - Neuroimmunology Laboratory, Department of Laboratory Medicine and Pathology, 
      College of Medicine, Mayo Clinic, Rochester, MN 55905; lennon.vanda@mayo.edu.
AD  - Department of Neurology, College of Medicine, Mayo Clinic, Rochester, MN 55905.
AD  - Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN 55905.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170501
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Aquaporin 4)
RN  - 0 (Excitatory Amino Acid Transporter 2)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Interleukin-6)
RN  - 0 (Receptors, IgG)
SB  - IM
MH  - Animals
MH  - Aquaporin 4/immunology/*metabolism
MH  - Astrocytes/*metabolism
MH  - Case-Control Studies
MH  - Excitatory Amino Acid Transporter 2/*metabolism
MH  - Female
MH  - Humans
MH  - Immunoglobulin G/metabolism
MH  - Interleukin-6/metabolism
MH  - Mice, Inbred C57BL
MH  - Neuromyelitis Optica/*immunology
MH  - Pregnancy
MH  - Primary Cell Culture
MH  - Rats, Inbred Lew
MH  - Rats, Sprague-Dawley
MH  - Receptors, IgG/*metabolism
PMC - PMC5448211
OTO - NOTNLM
OT  - CD32
OT  - CD64
OT  - autoimmune astrocytopathy
OT  - neuromyelitis optica
OT  - pathogenic IgG
COIS- Conflict of interest statement: V.A.L. and T.J.K. are named inventors on a patent 
      relating to AQP4 as NMO antigen, but receive no royalties from service tests 
      performed by Mayo Medical Laboratories. Earnings from technology licensing have 
      exceeded the federal threshold for significant interest. V.A.L. and S.R.H. are 
      named inventors on two patent applications filed by Mayo Foundation relating to 
      functional clinical assays for detecting AQP4-IgG.
EDAT- 2017/05/04 06:00
MHDA- 2018/05/15 06:00
PMCR- 2017/05/01
CRDT- 2017/05/03 06:00
PHST- 2017/05/04 06:00 [pubmed]
PHST- 2018/05/15 06:00 [medline]
PHST- 2017/05/03 06:00 [entrez]
PHST- 2017/05/01 00:00 [pmc-release]
AID - 1701960114 [pii]
AID - 201701960 [pii]
AID - 10.1073/pnas.1701960114 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2017 May 23;114(21):5491-5496. doi: 
      10.1073/pnas.1701960114. Epub 2017 May 1.