Abstract
BackgroundPathological 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.MethodsWe 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).ResultsSera 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.ConclusionsThe 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.
Highlights
Multiple sclerosis (MS) is defined as a chronic inflammatory demyelinating disease of the central nervous system, which is pathologically characterized by the presence of focal demyelinated plaques within the white matter [1]
The amount of claudin-5 in TY09 was significantly decreased after exposure to sera from patients with relapse-remitting MS (RRMS)-R or secondary progressive MS (SPMS), whereas it was not affected by the sera from RRMS patients in the stable phase (RRMS-S) patients or from healthy controls, as determined by a Western blot analysis (Figs. 1A–F)
The amount of occludin protein in TY09 was significantly decreased after exposure to the sera from SPMS patients, it was not changed after exposure to sera from RRMS-R or RRMS-S patients, or from healthy controls (Figs. 1A–F)
Summary
Multiple sclerosis (MS) is defined as a chronic inflammatory demyelinating disease of the central nervous system, which is pathologically characterized by the presence of focal demyelinated plaques within the white matter [1]. In RRMS, the pathological alterations in the brain are clearly associated with the inflammatory process, because newly formed lesions within the central nervous system (CNS) can be visualized by the contrast gadolinium (Gd)enhancement of the brain parenchyma during magnetic resonance imaging (MRI), and anti-inflammatory therapies and immunomodulation exert a beneficial effect at this stage of the disease [3,4]. SPMS appears to be less driven by the inflammatory process than RRMS: Gd-enhancing lesions are rare, but progressive loss of brain volume is observed in MRI and, most importantly, the current immunomodulatory or anti-inflammatory treatments have little beneficial effect in SPMS [4,5,6,7,8]. 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
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