MAPK pathway and B cells overactivation in multiple sclerosis revealed by phosphoproteomics and genomic analysis
Kiani, Narsis A.
Alexopoulos, Leonidas G.
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Embargo End Date2019-10-19
Permanent link to this recordhttp://hdl.handle.net/10754/656425
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AbstractDysregulation 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.
CitationKotelnikova, E., Kiani, N. A., Messinis, D., Pertsovskaya, I., Pliaka, V., Bernardo-Faura, M., … Villoslada, P. (2019). MAPK pathway and B cells overactivation in multiple sclerosis revealed by phosphoproteomics and genomic analysis. Proceedings of the National Academy of Sciences, 201818347. doi:10.1073/pnas.1818347116
SponsorsWe 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.
PublisherNational Academy of Sciences
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