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


Kotelnikova, Ekaterina; Kiani, Narsis A; Messinis, Dimitris; Pertsovskaya, Inna; Pliaka, Vicky; Bernardo-Faura, Marti; Rinas, Melanie; Vila, Gemma; Zubizarreta, Irati; Pulido-Valdeolivas, Irene; Sakellaropoulos, Theodore; Faigle, Wolfgang; Silberberg, Gilad; Masso, Mar; Stridh, Pernilla; Behrens, Janina; Olsson, Tomas; Martin, Roland; Paul, Friedemann; Alexopoulos, Leonidas G; Saez-Rodriguez, Julio; Tegner, Jesper; Villoslada, Pablo (2019). MAPK pathway and B cells overactivation in multiple sclerosis revealed by phosphoproteomics and genomic analysis. Proceedings of the National Academy of Sciences of the United States of America, 116(19):9671-9676.

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<jats:sup>+</jats:sup> 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.

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<jats:sup>+</jats:sup> 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Multidisciplinary
Language:English
Date:19 April 2019
Deposited On:21 Aug 2019 11:37
Last Modified:17 Sep 2019 20:27
Publisher:National Academy of Sciences
ISSN:0027-8424
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1073/pnas.1818347116
PubMed ID:31004050
Project Information:
  • : FunderFP7
  • : Grant ID305397
  • : Project TitleCOMBIMS - A novel drug discovery method based on systems biology: combination therapy and biomarkers for Multiple Sclerosis

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