Aberrant cell signalling in PBMCs upon IFN‐α stimulation in primary Sjögren's syndrome patients associates with type I interferon signature. Issue 7 (26th April 2018)

• Record Type: Journal Article
• Authors: Davies, Richard; Hammenfors, Daniel; Bergum, Brith; Vogelsang, Petra; Gavasso, Sonia; Brun, Johan G.; Jonsson, Roland; Appel, Silke
• Is Part Of: European journal of immunology. Volume 48:Issue 7(2018)
• Page Start: 1217
• Page End: 1227
• Publication Date: 2018-04-26
• Subjects: Autoantibodies -- Extraglandular manifestations -- Phosphoflow -- Sjögren's syndrome -- Type I interferon; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201747213
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: Primary Sjögren's syndrome (pSS) is a complex systemic autoimmune disease with heterogeneous disease manifestations. Genetic predisposition, hormonal and environmental factors are all thought to contribute to disease etiology and pathogenesis. A better understanding of the disease pathogenesis is required in order to establish new targeted therapies. We analysed MAPK/ERK and JAK/STAT signalling networks in peripheral blood mononuclear cells (PBMCs) upon stimulation with interferon alpha 2b (IFN‐α2b) by flow cytometry to define potentially dysfunctional intracellular signalling pathways involved in disease pathogenesis. Cells derived from pSS patients displayed small but significant increases in basal phosphorylation levels of numerous signalling proteins compared to cells from healthy donors. The phosphorylation profiles following stimulation with IFNα2b differed significantly between pSS patients and healthy donors, especially regarding STAT1 Y701. PCA further grouped patients according to clinical characteristics. Type I IFN induced gene expression was found to negatively correlate with the IFN‐α2b induced phosphorylation of STAT3 S727 in T cells and positively with pSTAT1 Y701 in B cells. Increases in pSTAT1 Y701 were associated with the presence of autoantibodies. Our results indicate involvement of both STAT3 S727 and STAT1 Y701 pathways in pSS patients. Therapies targeting these pathways might therefore be beneficial for certain subgroups of patients. Abstract : Altered responses to signals modulating type I interferon gene expression may drive an up‐regulation of IFN induced genes and the production of SSA autoantibodies, common features of primary Sjögren's syndrome. Measurements of phospho‐epitopes in PBMCs over a 4‐h time course following IFN‐α stimulation display dysregulation compared to healthy donors.