Sera from remitting and secondary progressive multiple sclerosis patients disrupt the blood-brain barrier

PLoS One. 2014 Mar 31;9(3):e92872. doi: 10.1371/journal.pone.0092872. eCollection 2014.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantibodies / metabolism
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / pathology
  • Brain / metabolism
  • Brain / pathology
  • Cells, Cultured
  • Claudin-5 / metabolism
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Humans
  • Immunoglobulin G / metabolism
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Multiple Sclerosis, Chronic Progressive / blood*
  • Multiple Sclerosis, Chronic Progressive / metabolism
  • Multiple Sclerosis, Chronic Progressive / pathology
  • Multiple Sclerosis, Relapsing-Remitting / blood*
  • Multiple Sclerosis, Relapsing-Remitting / metabolism*
  • Multiple Sclerosis, Relapsing-Remitting / pathology
  • Serum / metabolism*
  • Vascular Cell Adhesion Molecule-1 / metabolism


  • Autoantibodies
  • Claudin-5
  • Immunoglobulin G
  • Vascular Cell Adhesion Molecule-1
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9

Grant support

This work was supported in part by research grants (Nos. 24790886, Nos. 22790821, and Nos. 23659457) from the Japan Society for the Promotion of Science, Tokyo, Japan, by a Health and Labor Sciences Research Grant for research on intractable diseases (Neuroimmunological Disease Research Committee) from the Ministry of Health, Labor and Welfare of Japan (K2002528) and also by a Translational Research Promotion Grant from Yamaguchi University Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.