title: Sera from remitting and secondary progressive multiple sclerosis patients disrupt the blood-brain barrier.
abstract: BACKGROUND
  Pathological destruction of blood-brain barrier (BBB) has been thought to be the initial key event in the process of developing multiple sclerosis (MS). The purpose of the present study was to clarify the possible molecular mechanisms responsible for the malfunction of BBB by sera from relapse-remitting MS (RRMS) and secondary progressive MS (SPMS) patients.
  
  
  METHODS
  We evaluated the effects of sera from the patients in the relapse phase of RRMS (RRMS-R), stable phase of RRMS (RRMS-S) and SPMS on the expression of tight junction proteins and vascular cell adhesion protein-1 (VCAM-1), and on the transendothelial electrical resistance (TEER) in human brain microvascular endothelial cells (BMECs).
  
  
  RESULTS
  Sera from the RRMS-R or SPMS patients decreased the claudin-5 protein expression and the TEER in BMECs. In RRMS-R, this effect was restored after adding an MMP inhibitor, and the MMP-2/9 secretion by BMECs was significantly increased after the application of patients' sera. In SPMS, the immunoglobulin G (IgG) purified from patients' sera also decreased the claudin-5 protein expression and the TEER in BMECs. The sera and purified IgG from all MS patients increased the VCAM-1 protein expression in BMECs.
  
  
  CONCLUSIONS
  The up-regulation of autocrine MMP-2/9 by BMECs after exposure to sera from RRMS-R patients or the autoantibodies against BMECs from SPMS patients can compromise the BBB. Both RRMS-S and SPMS sera increased the VCAM-1 expression in the BBB, thus indicating that targeting the VCAM-1 in the BBB could represent a possible therapeutic strategy for even the stable phase of MS and SPMS.
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Shimizu
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.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Sano
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Mihua
authors.initials: M
authors.lastname: Ju
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nishihara
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Oishi
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Koga
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Motoharu
authors.initials: M
authors.lastname: Kawai
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanda
mesh_terms: D001323:Autoantibodies / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D062507:Claudin-5 / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020528:Multiple Sclerosis, Chronic Progressive / Q000097:blood* / Q000378:metabolism / Q000473:pathology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood* / Q000378:metabolism* / Q000473:pathology; D044967:Serum / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D062507:Claudin-5; D007074:Immunoglobulin G; D019010:Vascular Cell Adhesion Molecule-1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9