title: Aquaporin-4 autoantibodies cause asymptomatic aquaporin-4 loss and activate astrocytes in mouse.
abstract: BACKGROUND
  Neuromyelitis optica (NMO) is a central nervous system inflammatory demyelinating disorder. Up to 90% of patients are seropositive for aquaporin-4 autoantibodies (AQP4 Ab). The pathogenetic mechanisms underlying clinical onset and relapse of NMO are uncertain.
  
  
  OBJECTIVE
  Study the pathogenicity of AQP4 Ab in the absence of complement activation.
  
  
  METHODS
  Female C57BL/6N mice (human IgG cannot activate mouse complements) pretreated with complete Freund's adjuvant (CFA, day 0) and pertussis toxin (PTx, day 0 and day 2) were transferred with IgG isolated from serum of healthy subjects or NMO patients (AQP4 Ab-positive or negative) intraperitoneally (day 7-9). Mice were observed for signs of experimental autoimmune encephalomyelitis (EAE) by standard 6-grade EAE scores. Spinal cord was obtained at day 11 for immunohistochemistry.
  
  
  RESULTS
  None of the mice had clinical signs of encephalomyelitis, inflammatory cells infiltration or demyelination of spinal cord. CFA and PTx induce BBB breakdown evidenced by leakage of human IgG into cord parenchyma. Patchy areas of AQP4 loss were observed in spinal cord of mice transferred with IgG from AQP4 Ab-positive NMO patients but not in mice transferred with IgG from AQP4 Ab-negative NMO patients or healthy subjects; but there was no loss of glial fibrillary acidic protein immunoreactivity in all mice. Markedly increased proliferation of astrocytic processes suggestive of astrocytic activation was observed in mice transferred with IgG from AQP4 Ab-positive patients.
  
  
  CONCLUSIONS
  AQP4 Ab cause asymptomatic AQP4 loss and astrocytic activation but not myelitis, demyelination or astrocytic cytotoxicity in spinal cord of mouse in the absence of complement activation.
authors.affiliation: University Department of Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong. koonho@hkucc.hku.hk
authors.forename: K H
authors.initials: KH
authors.lastname: Chan
authors.forename: R
authors.initials: R
authors.lastname: Zhang
authors.forename: J S C
authors.initials: JS
authors.lastname: Kwan
authors.forename: V Y
authors.initials: VY
authors.lastname: Guo
authors.forename: P W L
authors.initials: PW
authors.lastname: Ho
authors.forename: J W M
authors.initials: JW
authors.lastname: Ho
authors.forename: A C Y
authors.initials: AC
authors.lastname: Chu
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D001323:Autoantibodies / Q000633:toxicity*; D003167:Complement Activation / Q000276:immunology; D003711:Demyelinating Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009471:Neuromyelitis Optica / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
chemical_list: C496030:AQP4 protein, human; C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D001323:Autoantibodies