TY - JOUR
T1 - MAPK pathway and B cells overactivation in multiple sclerosis revealed by phosphoproteomics and genomic analysis
AU - Kotelnikova, Ekaterina
AU - Kiani, Narsis A.
AU - Messinis, Dimitris
AU - Pertsovskaya, Inna
AU - Pliaka, Vicky
AU - Bernardo-Faura, Marti
AU - Rinas, Melanie
AU - Vila, Gemma
AU - Zubizarreta, Irati
AU - Pulido-Valdeolivas, Irene
AU - Sakellaropoulos, Theodore
AU - Faigle, Wolfgang
AU - Silberberg, Gilad
AU - Masso, Mar
AU - Stridh, Pernilla
AU - Behrens, Janina
AU - Olsson, Tomas
AU - Martin, Roland
AU - Paul, Friedemann
AU - Alexopoulos, Leonidas G.
AU - Saez-Rodriguez, Julio
AU - Tegner, Jesper
AU - Villoslada, Pablo
N1 - KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: We thank Mark Sefton for editorial assistance. This study was supported by the European Commission (CombiMS project) under Grant Agreement 305397 (FP7/2007-2013); Sys4MS project (Horizon2020: Eracosysmed: ID-43); the Instituto de Salud Carlos III (Fondo Europeo de Desarrollo Regional funds “Otra forma de hacer Europa” Grant AC15-00052); and Centres de Recerca de Catalunya Programme/Generalitat de Catalunya.
PY - 2019/4/19
Y1 - 2019/4/19
N2 - Dysregulation of signaling pathways in multiple sclerosis (MS) can be analyzed by phosphoproteomics in peripheral blood mono-nuclear cells (PBMCs). We performed in vitro kinetic assays on PBMCs in 195 MS patients and 60 matched controls and quantified the phosphorylation of 17 kinases using xMAP assays. Phosphopro-tein levels were tested for association with genetic susceptibility by typing 112 single-nucleotide polymorphisms (SNPs) associated with MS susceptibility. We found increased phosphorylation of MP2K1 in MS patients relative to the controls. Moreover, we identified one SNP located in the PHDGH gene and another on IRF8 gene that were associated with MP2K1 phosphorylation levels, providing a first clue on how this MS risk gene may act. The analyses in patients treated with disease-modifying drugs identified the phosphorylation of each receptor’s downstream kinases. Finally, using flow cytometry, we detected in MS patients increased STAT1, STAT3, TF65, and HSPB1 phosphorylation in CD19+ cells. These findings indicate the activation of cell survival and proliferation (MAPK), and proinflammatory (STAT) pathways in the immune cells of MS patients, primarily in B cells. The changes in the activation of these kinases suggest that these pathways may represent therapeutic targets for modulation by kinase inhibitors.
AB - Dysregulation of signaling pathways in multiple sclerosis (MS) can be analyzed by phosphoproteomics in peripheral blood mono-nuclear cells (PBMCs). We performed in vitro kinetic assays on PBMCs in 195 MS patients and 60 matched controls and quantified the phosphorylation of 17 kinases using xMAP assays. Phosphopro-tein levels were tested for association with genetic susceptibility by typing 112 single-nucleotide polymorphisms (SNPs) associated with MS susceptibility. We found increased phosphorylation of MP2K1 in MS patients relative to the controls. Moreover, we identified one SNP located in the PHDGH gene and another on IRF8 gene that were associated with MP2K1 phosphorylation levels, providing a first clue on how this MS risk gene may act. The analyses in patients treated with disease-modifying drugs identified the phosphorylation of each receptor’s downstream kinases. Finally, using flow cytometry, we detected in MS patients increased STAT1, STAT3, TF65, and HSPB1 phosphorylation in CD19+ cells. These findings indicate the activation of cell survival and proliferation (MAPK), and proinflammatory (STAT) pathways in the immune cells of MS patients, primarily in B cells. The changes in the activation of these kinases suggest that these pathways may represent therapeutic targets for modulation by kinase inhibitors.
UR - http://hdl.handle.net/10754/656425
UR - http://www.pnas.org/lookup/doi/10.1073/pnas.1818347116
UR - http://www.scopus.com/inward/record.url?scp=85065654813&partnerID=8YFLogxK
U2 - 10.1073/pnas.1818347116
DO - 10.1073/pnas.1818347116
M3 - Article
C2 - 31004050
SN - 0027-8424
VL - 116
SP - 9671
EP - 9676
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 19
ER -