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Matrix metalloproteinase 9 is decreased in natalizumab‐treated multiple sclerosis patients at risk for progressive multifocal leukoencephalopathy
Author(s) -
Fissolo Nicolas,
Pignolet Béatrice,
MatuteBlanch Clara,
Triviño Juan Carlos,
Miró Berta,
Mota Miriam,
PerezHoyos Santiago,
Sanchez Alex,
Vermersch Patrick,
Ruet Aurélie,
Sèze Jérôme,
Labauge Pierre,
Vukusic Sandra,
Papeix Caroline,
Almoyna Laurent,
Tourbah Ayman,
Clavelou Pierre,
Moreau Thibault,
Pelletier Jean,
LebrunFrenay Christine,
Montalban Xavier,
Brassat David,
Comabella Manuel
Publication year - 2017
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24987
Subject(s) - natalizumab , progressive multifocal leukoencephalopathy , medicine , mmp9 , immunology , biomarker , multiple sclerosis , chemokine , peripheral blood mononuclear cell , biology , inflammation , gene , biochemistry , downregulation and upregulation , in vitro
Objective To identify biomarkers associated with the development of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients treated with natalizumab (NTZ). Methods Relapsing–remitting MS patients who developed PML under NTZ therapy (pre‐PML) and non‐PML NTZ‐treated patients (NTZ‐ctr) were included in the study. Cryopreserved peripheral blood mononuclear cells and serum samples collected at baseline, at 1‐ and 2‐year treated time points, and during PML were analyzed for gene expression by RNA sequencing and for serum protein levels by Luminex and enzyme‐linked immunosorbent assays, respectively. Results Among top differentially expressed genes in the RNA sequencing between pre‐PML and NTZ‐ctr patients, pathway analysis revealed a high representation of genes belonging to the following categories: proangiogenic factors ( MMP9 , VEGFA ), chemokines ( CXCL1 , CXCL5 , IL8 , CCL2 ), cytokines ( IL1B , IFNG ), and plasminogen‐ and coagulation‐related molecules ( SERPINB2 , PLAU , PLAUR , TFPI , THBD ). Serum protein levels for these candidates were measured in a 2‐step manner in a screening cohort and a validation cohort of pre‐PML and NTZ‐ctr patients. Only matrix metalloproteinase 9 (MMP9) was validated; in pre‐PML patients, MMP9 protein levels were significantly reduced at baseline compared with NTZ‐ctr patients, and levels remained lower at later time points during NTZ treatment. Interpretation The results from this study suggest that the proangiogenic factor MMP9 may play a role as a biomarker associated with the development of PML in MS patients treated with NTZ. Ann Neurol 2017;82:186–195.