Aberrant cell signalling in PBMCs upon IFN‐α stimulation in primary Sjögren's syndrome patients associates with type I interferon signature

Davies, Richard A.; Hammenfors, Daniel; Bergum, Brith; Vogelsang, Petra; Gavasso, Sonia; Brun, Johan G.; Jönsson, Roland; Appel, Silke

doi:10.1002/eji.201747213

Cited by 19 publications

(22 citation statements)

References 37 publications

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“…Continuous activation and dysregulation of TLR and type I IFN signaling have been speculated to play a part in this signature and pathogenesis of autoimmune disease (29), and IFN signature positive pSS patients have been shown to have increased expression of TLR7 in certain cell types (30). In addition, we have previously shown that PBMC of pSS patients have an altered response to IFN-α stimulation (10). Hence we investigated cell signaling profiles in PBMC of pSS patients upon stimulation via TLR7 and −9, determined the gene expression profile of several IFN inducible genes and correlated these findings to plasma cytokine levels.…”

Section: Discussionmentioning

confidence: 99%

“…Total RNA was isolated from PBMC of 20 pSS patients and 17 healthy controls and transcribed into cDNA as described previously (10). The following Taqman gene expression assays were utilized: Hs00895608_m1 ( MxA ); Hs00973637_m1 ( OAS1 ); Hs00951349_m1 ( IFI44 ); Hs00977005_m1 ( GBP1 ); Hs00894837_m1 ( GBP2 ); Hs03928990_g1 (18S rRNA) (all Thermo Fisher Scientific, Waltham, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Dysfunctional intracellular signaling mechanisms may influence the immunological response of a cell to a given stimulus, affecting transduction of a given signal and resulting in aberrant gene expression. We have previously shown that patients with pSS have an altered response of PBMC to IFN stimulation (10). Interestingly, several genetic variants associated with SS function in downstream signaling from TLRs or their regulation, including IRF5 (11, 12), IL-10 (13), I κ B α (14), TNFAIP3 interacting protein 1 ( TNIP1 ) (12), and OAS1 (15).…”

Section: Introductionmentioning

confidence: 99%

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Single Cell Based Phosphorylation Profiling Identifies Alterations in Toll-Like Receptor 7 and 9 Signaling in Patients With Primary Sjögren's Syndrome

et al. 2019

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Primary Sjögren's syndrome (pSS) is associated with polymorphisms and mRNA expression profiles that are indicative of an exaggerated innate and type I IFN immune response. Excessive activation potential of signaling pathways may play a role in this profile, but the intracellular signaling profile of the disease is not well characterized. To gain insights into potentially dysfunctional intracellular signaling profiles of pSS patients we conducted an exploratory analysis of MAPK/ERK and JAK/STAT signaling networks in peripheral blood mononuclear cells (PBMC) from 25 female pSS patients and 25 female age-matched healthy donors using phospho-specific flow cytometry. We analyzed unstimulated samples, as well as samples during a 4 h time period following activation of Toll-like receptor (TLR) 7 and 9. Expression levels of MxA, IFI44, OAS1, GBP1 , and GBP2 in PBMC were analyzed by real-time PCR. Cytokine levels in plasma were determined using a 25-plex Luminex-assay. Principal component analysis (PCA) showed that basal phosphorylation profiles could be used to differentiate pSS patients from healthy donor samples by stronger intracellular signaling pathway activation in NK and T cells relative to B cells. Stimulation of PBMC with TLR7 and −9 ligands showed significant differences in the phosphorylation profiles between samples from pSS patients and healthy donors. Including clinical parameters such as extraglandular manifestations (EGM), we observed stronger responses of NF-κB and STAT3 S727 in B cells from EGM-negative patients compared to EGM-positive patients and healthy controls. Plasma cytokine levels were correlated to the basal phosphorylation levels in these patients. In addition, 70% of the patients had a positive IFN score. These patients differed from the IFN score negative patients regarding their phosphorylation profiles and their plasma cytokine levels. In conclusion, we here report increased signaling potentials in peripheral B cells of pSS patients in response to TLR7 and −9 stimulation through STAT3 S727 and NF-κB that correlate with a type I IFN signature. Induction of these pathways could contribute to the generation of a type I IFN signature in pSS. Patients displaying elevated potentiation of STAT3 S727 and NF-κB signaling could therefore benefit from therapies targeting these pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Single Cell Based Phosphorylation Profiling Identifies Alterations in Toll-Like Receptor 7 and 9 Signaling in Patients With Primary Sjögren's Syndrome

et al. 2019

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“…Sjögren's syndrome is an autoimmune disease with glandular lymphocyte infiltration leading to symptoms of dry mouth and eyes, where approximately 50% of patients have a type I IFN signature (45,46). Given that this IFN signature is not present in all patients, one study analyzed the effects of IFN-a2b treatment of peripheral blood mononuclear cells (PBMCs) from patients with Sjögren's compared with PBMCs from healthy donors, including type I IFN signature-positive and negative patients (45). Baseline effector protein phosphorylation levels differed predominantly in T cells in Sjögren's patients compared with healthy individuals, with higher p-p38 and p-STAT1 (Y701, S727).…”

Section: Canonical and Non-canonical Signaling In Autoimmune Diseasesmentioning

confidence: 99%

Type I Interferon (IFN)-Regulated Activation of Canonical and Non-Canonical Signaling Pathways

et al. 2020

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For several decades there has been accumulating evidence implicating type I interferons (IFNs) as key elements of the immune response. Therapeutic approaches incorporating different recombinant type I IFN proteins have been successfully employed to treat a diverse group of diseases with significant and positive outcomes. The biological activities of type I IFNs are consequences of signaling events occurring in the cytoplasm and nucleus of cells. Biochemical events involving JAK/STAT proteins that control transcriptional activation of IFN-stimulated genes (ISGs) were the first to be identified and are referred to as “canonical” signaling. Subsequent identification of JAK/STAT-independent signaling pathways, critical for ISG transcription and/or mRNA translation, are denoted as “non-canonical” or “non-classical” pathways. In this review, we summarize these signaling cascades and discuss recent developments in the field, specifically as they relate to the biological and clinical implications of engagement of both canonical and non-canonical pathways.

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“…Targeting STAT1 may contribute to the treatment of patients with SS. 25 A JAK-1 inhibitor was thought to inhibit IFN-induced transcription genes and B lymphocyte stimulator (BLyS) dominating B-cell differentiation, homeostasis in human salivary glands, as well as regulate IFNα- and IFNγ-induced pSTAT-1 in human salivary gland epithelial cells (SGECs). 26…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis for Identification of Key Genes in Salivary Gland and the Potential of a Combination of Biomarkers for the Diagnosis of SS

Chen¹,

Lu²,

Yu³

et al. 2021

JIR

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Purpose Sjögren’s syndrome (SS) is a systemic autoimmune disease mainly characterized by dysfunction of exocrine glands. Studies on diagnosis models specific for SS patients are very limited. We aimed to use gene expression datasets from salivary glands to identify aberrant differentially expressed genes (DEGs) and pathways by bioinformatics and validate candidate genes by clinical minor labial gland biopsy (MSGB) samples, and finally build a combined gene quantitative diagnosis model of SS. Patients and Methods Original datasets GSE23117, GSE7451, and GSE127952 were obtained from the Gene Expression Omnibus database (GEO) and integrated and analyzed for differentially expressed genes in SS salivary glands. ClueGO and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of upregulated and downregulated DEGs were performed, and protein–protein interaction (PPI) networks were constructed using the STRING and Cytoscape database. H&E staining and immunohistochemistry were used to validate the expression levels of four hub genes in salivary glands. Finally, a receiver operating characteristic (ROC) curve of the combined diagnosis of four hub genes was analyzed in SS patients and non-SS patients in order to explore the diagnostic efficacy of these genes compared with conventional FS in SS. Results Fifty-three upregulated genes and fifteen downregulated genes were identified. We analyzed the expression and function of four hub genes via H&E, immunohistochemistry, and ROC analysis. We then evaluated and verified the diagnosis value of four hub genes, STAT1, MNDA, IL10RA , and CCR1 in MSGB of SS and non-SS. A combined diagnosis model of four indicators was established to identify patients’ discrete data on the foci size (AUC=0.915). Conclusion The expression of STAT1, MNDA , and IL10RA may be potential biological indicators for SS diagnosis. Compared with FS, a combined diagnosis model of quantitative gene expression could potentially contribute to improving the sensitivity and specificity of MSGB of SS.

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Aberrant cell signalling in PBMCs upon IFN‐α stimulation in primary Sjögren's syndrome patients associates with type I interferon signature

Cited by 19 publications

References 37 publications

Single Cell Based Phosphorylation Profiling Identifies Alterations in Toll-Like Receptor 7 and 9 Signaling in Patients With Primary Sjögren's Syndrome

Single Cell Based Phosphorylation Profiling Identifies Alterations in Toll-Like Receptor 7 and 9 Signaling in Patients With Primary Sjögren's Syndrome

Type I Interferon (IFN)-Regulated Activation of Canonical and Non-Canonical Signaling Pathways

Bioinformatics Analysis for Identification of Key Genes in Salivary Gland and the Potential of a Combination of Biomarkers for the Diagnosis of SS

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