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

Item Type:Article
Title:MAPK pathway and B cells overactivation in multiple sclerosis revealed by phosphoproteomics and genomic analysis
Creators Name:Kotelnikova, E. and Kiani, N.A. and Messinis, D. and Pertsovskaya, I. and Pliaka, V. and Bernardo-Faura, M. and Rinas, M. and Vila, G. and Zubizarreta, I. and Pulido-Valdeolivas, I. and Sakellaropoulos, T. and Faigle, W. and Silberberg, G. and Masso, M. and Stridh, P. and Behrens, J. and Olsson, T. and Martin, R. and Paul, F. and Alexopoulos, L.G. and Saez-Rodriguez, J. and Tegner, J. and Villoslada, P.
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.
Keywords:Multiple Sclerosis, Phosphoproteomics, Signaling Pathways, B Cells, Autoimmunity
Source:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
Page Range:9671-9676
Date:7 May 2019
Official Publication:https://doi.org/10.1073/pnas.1818347116
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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