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Type: Journal article
Title: Characterization of immune cell subsets during the active phase of multiple sclerosis reveals disease and c-Jun N-terminal kinase pathway biomarkers
Author: Ferrandi, C.
Richard, F.
Tavano, P.
Hauben, E.
Barbie, V.
Gotteland, J.
Greco, B.
Fortunato, M.
Mariani, M.
Furlan, R.
Comi, G.
Martino, G.
Zaratin, P.
Citation: Multiple Sclerosis, 2011; 17(1):43-56
Publisher: Nature Publishing Group
Issue Date: 2011
ISSN: 1352-4585
1477-0970
Statement of
Responsibility: 
Chiara Ferrandi, Fabien Richard, Patrizia Tavano, Ehud Hauben, Valerie Barbie, Jean-Pierre Gotteland, Beatrice Greco, Mara Fortunato, Maurizio F Mariani, Roberto Furlan, Giancarlo Comi, Gianvito Martino and Paola F Zaratin
Abstract: <h4>Background</h4>Autoimmune activation and deregulated apoptosis of T lymphocytes are involved in multiple sclerosis (MS). c-Jun N-terminal kinase (JNK) plays a role in T-cell survival and apoptosis.<h4>Objectives</h4>The aim of this work was to investigate the role of the JNK-dependent apoptosis pathway in relapsing-remitting MS (RRMS).<h4>Methods</h4>The immunomodulatory effect of AS602801, a JNK inhibitor, was firstly evaluated on activated peripheral blood mononuclear cells (PBMCs) from healthy volunteers (HVs) and secondly in unstimulated purified CD4+, CD8+ and CD11b+ cells from RRMS patients and HVs. Moreover JNK/inflammation/apoptosis related genes were investigated in RRMS and HV samples.<h4>Results</h4>In activated PBMCs from HVs, we showed that AS602801 blocked T-lymphocyte proliferation and induced apoptosis. In RRMS CD4+ and CD8+ cells, AS602801 induced apoptosis genes and expression of surface markers, while in RRMS CD11b+ cells it induced expression of innate immunity receptors and co-stimulatory molecules. Untreated cells from RRMS active-phase patients significantly released interleukin-23 (IL-23) and interferon-gamma (IFN-γ) and expressed less apoptosis markers compared to the cells of HVs. Moreover, gene expression was significantly different in cells from RRMS active-phase patients vs. HVs. By comparing RRMS PBMCs in the active and stable phases, a specific genomic signature for RRMS was indentified. Additionally, CASP8AP2, CD36, ITGAL, NUMB, OLR1, PIAS-1, RNASEL, RTN4RL2 and THBS1 were identified for the first time as being associated to the active phase of RRMS.<h4>Conclusions</h4>The analysis of the JNK-dependent apoptosis pathway can provide biomarkers for activated lymphocytes in the active phase of RRMS and a gene expression signature for disease status. The reported results might be useful to stratify patients, thereby supporting the development of novel therapies.
Keywords: Multiple sclerosis; JNK/Inflammation/Apoptosis; biomarkers; protein kinase inhibitor
Rights: © The Author(s) 2011
RMID: 0020114729
DOI: 10.1177/1352458510381258
Appears in Collections:Surgery publications

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