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

Marco Iannetta,Simona Pontecorvo,Claudia D’Agostino,Carla Prezioso,Antonio Cortese,Ada Francia,Marco Frontoni,Grazia Maria Liuzzi,Valeria Pietropaolo,Ilaria Pati,Maria Rosa Ciardi,Claudio Maria Mastroianni,Maria Antonella Zingaropoli,Tiziana Latronico,Vincenzo Vullo

doi:10.1038/s41598-018-36535-5

Marco Iannetta, Simona Pontecorvo + Show 13 more

Open Access

https://doi.org/10.1038/s41598-018-36535-5

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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.

Highlights

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal loss[1] and represents a prominent cause of neurological disability among young adults[2]
matrix metalloproteinase (MMP)-2 and MMP-9 plasma levels were measured by zymography on gelatin-copolymerized gels in 116 plasma samples from 34 RRMS patients stratified according to natalizumab infusion number
No variations were observed for plasma levels of MMP-2, which is constitutively expressed in body fluids and was used as an internal control of sample processing

Summary

Introduction

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal loss[1] and represents a prominent cause of neurological disability among young adults[2]. The elevated CSF and serum concentrations of MMP-9 were associated with magnetic resonance imaging (MRI) and clinical evidence of disease activity[13,14] and evolution[15] suggesting that MMP-9 represents a biomarker of disease activity[10] and a putative therapeutic target for MS16. In this respect, it has been demonstrated that IFN-β reduces T-lymphocyte transmigration by interfering with the production of MMP-917 and that the treatment of RRMS patients with IFN-β reduces serum MMP-9 concentrations and ameliorates the course of the disease[18]. The reduced T-cells migration across the BBB, is thought to be the reason for the increased risk of developing progressive multifocal leukoencephalopathy (PML), caused by John Cunningham Virus (JCV) reactivation[21]

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