Ricerc@Sapienza

During the last two decades, an association between progressive multifocal leukoencephalopathy (PML) and diseases modifying therapies (DMT) for multiple sclerosis (MS) has come into light. PML is a demyelinating disease of the central nervous system (CNS) associated with JC virus (JCV) infection in the oligodendrocytes. Several cases of PML associated with natalizumab, a monoclonal antibody (anti-CD49d), have been reported. An increased PML risk in MS patients treated with other DMT was reported. Recently, a new monoclonal antibody was licensed for MS treatment: ocrelizumab (anti-CD20) and some cases of PML during this treatment were reported. Monoclonal antibodies such as natalizumab and ocrelizumab are likely to generate immunological impairments leading to JCV reactivation and PML development. During MS, matrix metalloproteinase (MMP)-9 plays a role in the breakdown of the blood-brain barrier (BBB), thus facilitating the entry of inflammatory cells into the central nervous system (CNS). A reduction in the levels of molecules involved in BBB disruption, such as MMP-9, could interfere with CD8+ T-lymphocyte immune surveillance mechanisms in the CNS, predisposing MS patients to JCV reactivation and PML development. MMP-9 plasma activity and mRNA expression in peripheral blood mononuclear cells (PBMC), JCV-DNA and T-lymphocyte phenotypic modifications will be evaluated in multiple sclerosis (MS) patients starting or already under natalizumab or ocrelizumab treatment. MMP-9 activity will be assessed by zymography in plasma samples while MMP-9 mRNA expression will be evaluated through quantitative real time PCR (qPCR) in PBMC. JCV-DNA will be detected through qPCR in urine and plasma samples and PBMC. B and T-lymphocyte phenotype will be assessed by flow cytometry. These findings could contribute to understand PML pathogenesis under DMT, defining the role of MMP-9 in this setting.