Dynamic changes of MMP-9 plasma levels correlate with JCV reactivation and immune activation in natalizumab-treated multiple sclerosis patients

Abstract

The aim of the study was to investigate the changes of matrix metalloproteinase (MMP)-2 and MMP-9 plasma levels during natalizumab treatment and their correlation with JC virus (JCV) reactivation and T-lymphocyte phenotypic modifications in peripheral blood samples from 34 relapsing-remitting multiple sclerosis (RRMS) patients. MMP-9 levels were assessed by zymography in plasma samples. JCV-DNA was detected through quantitative real time PCR in plasma samples. T-lymphocyte phenotype was assessed with flow cytometry. MMP-9 plasma levels resulted increased from 12 to 24 natalizumab infusions. Stratifying plasma samples according to JCV-DNA detection, MMP-9 plasma levels were significantly increased in JCV-DNA positive than JCV-DNA negative samples. MMP-9 plasma levels resulted positively correlated with JCV viral load. CD4 immune senescence, CD8 immune activation and CD8 effector percentages were positively correlated to MMP-9 plasma levels, whereas a negative correlation between CD8 naïve percentages and MMP-9 plasma levels was found. Our data indicate an increase of MMP-9 plasma levels between 12 and 24 natalizumab infusions and a correlation with JCV-DNA detection in plasma, T-lymphocyte immune activation and senescence. These findings could contribute to understand PML pathogenesis under natalizumab treatment, suggesting a potential role of MMP-9 as a predictive marker of PML in RRMS patients.

JCPyV NCCR analysis in PML patients with different risk factors: exploring common rearrangements as essential changes for neuropathogenesis

“…The emergence of PML in MS patients under immunosuppressive therapies and DMTs, such as natalizumab, motivated a search for biological factors contributing to the risk of this serious brain infection [21], such as T-lymphocytes changes [22,23] and matrix metalloproteinase-9 enzymatic activity [24]. The CNS immune surveillance impairment, the reactivation of latent JCPyV and the blood-brain barrier damage can explain the increased risk of PML development in natalizumab-treated MS patients.…”

Increasing Oxygen Partial Pressures Induce a Distinct Transcriptional Response in Human PBMC: A Pilot Study on the “Normobaric Oxygen Paradox”

“…Plasma levels of MMP-2 and MMP-9 were detected by zymography as reported by [ 53 ]. Briefly, 3 µl of plasma were solubilized with 10 µL of non-reducing sodium dodecyl sulfate (SDS)-sample buffer and loaded on a 7.5% polyacrylamide gel copolymerized with 0.1% ( w / v ) gelatin.…”

Metalloproteinases and Their Inhibitors: Potential for the Development of New Therapeutics

“…Various studies have established the link between MS and MMP activities i.e., high levels of MMP-1, -2, -3, -7, and -12 have been detected in MS patients [134]. The irregular activities of MMPs, specifically MMP-2 and MMP-9, allow the excessive migration of immune cells into the CNS during MS, which are considered undesirable as MS is considered an autoimmune disease [135]. Remarkably, under conditions where the immune system is fragile or compromised, MS is a result of progressive multifocal encephalopathy (PML) disease, caused by John Cunningham (JC) virus or JCV [136].…”

“…Remarkably, under conditions where the immune system is fragile or compromised, MS is a result of progressive multifocal encephalopathy (PML) disease, caused by John Cunningham (JC) virus or JCV [136]. The correlation between high levels of MMP-9 and the JCV reactivation in relapsing-remitting MS patients was another indicator for the role of MMP-9 in progressive MS [135]. Furthermore, the abundance of MMP-7 and MMP-9 in experimental autoimmune encephalomyelitis, such as MS, suggests the key contribution of specific MMPs in neuroinflammation disorder [137].…”