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


OBJECTIVE
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.
Ferrandi
Chiara
C
Merck Serono Research/RBM S.p.A., I-10010, Turin, Italy. chiara.ferrandi@procelltech.net
Richard
Fabien
F
Tavano
Patrizia
P
Hauben
Ehud
E
Barbié
Valerie
V
Gotteland
Jean-Pierre
JP
Greco
Beatrice
B
Fortunato
Mara
M
Mariani
Maurizio F
MF
Furlan
Roberto
R
Comi
Giancarlo
G
Martino
Gianvito
G
Zaratin
Paola F
PF
D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D055815:Young Adult
D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases