Characterization of immune cell subsets during the active phase of multiple sclerosis reveals disease and c-Jun N-terminal kinase pathway biomarkers

Chiara Ferrandi, Fabien Richard, Patrizia Tavano, Ehud Hauben, Valerie Barbié, Jean Pierre Gotteland, Beatrice Greco, Mara Fortunato, Maurizio F. Mariani, Roberto Furlan, Giancarlo Comi, Gianvito Martino, Paola F. Zaratin

Research output: Contribution to journalArticle

Abstract

Background: 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. Objectives: The aim of this work was to investigate the role of the JNK-dependent apoptosis pathway in relapsing- remitting MS (RRMS). Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)43-56
Number of pages14
JournalMultiple Sclerosis Journal
Volume17
Issue number1
DOIs
Publication statusPublished - 2011

Keywords

  • biomarkers
  • JNK/Inflammation/Apoptosis
  • Multiple sclerosis
  • protein kinase inhibitor

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

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    Ferrandi, C., Richard, F., Tavano, P., Hauben, E., Barbié, V., Gotteland, J. P., Greco, B., Fortunato, M., Mariani, M. F., Furlan, R., Comi, G., Martino, G., & Zaratin, P. F. (2011). Characterization of immune cell subsets during the active phase of multiple sclerosis reveals disease and c-Jun N-terminal kinase pathway biomarkers. Multiple Sclerosis Journal, 17(1), 43-56. https://doi.org/10.1177/1352458510381258