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MAPK pathway and B cells overactivation in multiple sclerosis revealed by phosphoproteomics and genomic analysis

Authors :
Wolfgang Faigle
Irene Pulido-Valdeolivas
Narsis A. Kiani
Mar Masso
Leonidas G. Alexopoulos
Tomas Olsson
Ekaterina Kotelnikova
Melanie Rinas
Dimitris E Messinis
Theodore Sakellaropoulos
Julio Saez-Rodriguez
Pablo Villoslada
Janina Behrens
Pernilla Stridh
Inna Pertsovskaya
Irati Zubizarreta
Roland Martin
Gemma Vila
Gilad Silberberg
Friedemann Paul
Marti Bernardo-Faura
Vicky Pliaka
Jesper Tegnér
University of Zurich
Villoslada, Pablo
Publication Year :
2019
Publisher :
National Academy of Sciences, 2019.

Abstract

Dysregulation of signaling pathways in multiple sclerosis (MS) can be analyzed by phosphoproteomics in peripheral blood mononuclear 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. Phosphoprotein 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.

Details

Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....185f36e00d4d57e8cdf512da41a69f05
Full Text :
https://doi.org/10.5167/uzh-172331