title: Autocrine MMP-2/9 secretion increases the BBB permeability in neuromyelitis optica.
abstract: OBJECTIVE
  Pathological breakdown of the blood-brain barrier (BBB) is thought to constitute the beginning of the disease process in neuromyelitis optica (NMO). In the current study, we investigated possible molecular mechanisms responsible for the breakdown of BBB using NMO sera.
  
  
  METHODS
  We analysed the effects of sera obtained from anti-aquaporin 4 (AQP4) antibody-positive NMO spectrum disorder (NMOSD) patients, multiple sclerosis (MS) patients and control subjects on the production of claudin-5, matrix-metalloproteinases (MMPs)-2/9, and vascular cell adhesion protein-1 (VCAM-1) in human brain microvascular endothelial cells (BMECs). We also examined whether immunoglobulin G (IgG) purified from NMOSD sera influences the claudin-5 or VCAM-1 protein expression.
  
  
  RESULTS
  The disturbance of BBB properties in BMECs following exposure to NMOSD sera was restored after adding the MMP inhibitor, GM6001. The secretion of MMP-2/9 by BMECs significantly increased after applying the NMOSD sera. The sera from NMOSD patients also increased both the MMP-2/9 secretion and the VCAM-1 protein level by BMECs. The IgG purified from NMOSD sera did not influence the BBB properties or the amount of MMP-2/9 proteins, although it did increase the amount of VCAM-1 proteins in BMECs. Reduction in anti-AQP4 antibody titre was not correlated with a reduction in VCAM-1 expression.
  
  
  CONCLUSIONS
  The autocrine secretion of MMP-2/9 by BMECs induced by humoral factors, other than IgG, in sera obtained from NMOSD patients potentially increases BBB permeability. IgG obtained from NMOSD sera, apart from anti-AQP4 antibodies, affect the BBB by upregulating VCAM, thereby facilitating the entry of inflammatory cells into the central nervous system.
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, , Ube, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Tasaki
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Shimizu
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Sano
authors.forename: Miwako
authors.initials: M
authors.lastname: Fujisawa
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Hiroyo
authors.initials: H
authors.lastname: Haruki
authors.forename: Masaaki
authors.initials: M
authors.lastname: Abe
authors.forename: Michiaki
authors.initials: M
authors.lastname: Koga
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanda
mesh_terms: D000328:Adult; D051401:Aquaporin 4 / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D062507:Claudin-5 / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000503:physiopathology*; D009471:Neuromyelitis Optica / Q000097:blood / Q000503:physiopathology*; D010539:Permeability; D044967:Serum / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D051401:Aquaporin 4; D001323:Autoantibodies; C107466:CLDN5 protein, human; D062507:Claudin-5; D004151:Dipeptides; D007074:Immunoglobulin G; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D019010:Vascular Cell Adhesion Molecule-1; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Blood-Brain Barrier; Multiple Sclerosis