Cytokine-induced STAT1 activation is increased in patients with primary Sjögren's syndrome

Pertovaara, Marja; Silvennoinen, Olli; Isomäki, Pia

doi:10.1016/j.clim.2016.03.010

Cited by 35 publications

(25 citation statements)

References 41 publications

(76 reference statements)

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“…Potentiated phosphorylation of STAT1 Y701 in monocytes, B cells and CD4 + T cells from pSS patients has been described previously in response to IFN‐γ and/or IL‐6 . In addition to receptor expression, signal transduction pathways leading to phosphorylation of STAT are mediated through activation of Janus kinases and are negatively regulated by several mechanisms, including suppressor of cytokine signaling (SOCS) family members, ubiquitin carboxy‐terminal hydrolase 18 and various microRNA .…”

Section: Discussionmentioning

confidence: 84%

“…Previous studies have described upregulations of STAT1 and STAT3 mRNA in PBMCs from pSS patients , while no differences were found regarding STAT3 protein expression in CD3 + and CD19 + cells . Increased expression of SOCS1 and ‐3 mRNA have been found in PBMCs from pSS patients , and dysregulation of microRNA expression patterns have been recently observed in B and T cells from pSS patients .…”

Section: Discussionmentioning

confidence: 91%

“…Gene expression may in addition be altered through changes in responsiveness to a given stimulus. Previous studies of peripheral blood cells from SS patients have found alterations of basal phosphorylation levels of STAT3 and STAT5 , as well as increased phosphorylation of STAT1 Y701 upon stimulation with IFN‐α, IFN‐γ and IL‐6 .…”

Section: Introductionmentioning

confidence: 92%

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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

et al. 2018

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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.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 91%

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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

et al. 2018

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“…Furthermore, NFκB activation is promoted by reduced IκBα expression in Sjögren monocytes ( 106 ). Increased STAT1 is seen in SS monocytes ( 107 ), similar to constitutive STAT5 activation ( 108 ).…”

Section: Sjögren’s Syndrome (Ss)mentioning

confidence: 91%

The Potential Role of Trained Immunity in Autoimmune and Autoinflammatory Disorders

2018

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During induction of trained immunity, monocytes and macrophages undergo a functional and transcriptional reprogramming toward increased activation. Important rewiring of cellular metabolism of the myeloid cells takes place during induction of trained immunity, including a shift toward glycolysis induced through the mTOR pathway, as well as glutaminolysis and cholesterol synthesis. Subsequently, this leads to modulation of the function of epigenetic enzymes, resulting in important changes in chromatin architecture that enables increased gene transcription. However, in addition to the beneficial effects of trained immunity as a host defense mechanism, we hypothesize that trained immunity also plays a deleterious role in the induction and/or maintenance of autoimmune and autoinflammatory diseases if inappropriately activated.

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“…IL-6 levels are increased in the serum, tears, and salivary gland epithelial cells of patients with pSS. Interestingly, co-cultures of salivary gland epithelial cells with T cells induce Tfh cell differentiation ( 3 , 232 ) suggesting a critical role for epithelial cell-derived IL-6 in Tfh cell differentiation in pSS. There are several treatment options for patients with pSS that target Tfh cell functions and therefore the humoral response.…”

Section: The Role Of Tfh Cells In Diseasesmentioning

confidence: 99%

Insights Into the Molecular Mechanisms of T Follicular Helper-Mediated Immunity and Pathology

et al. 2018

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T follicular helper (Tfh) cells play key role in providing help to B cells during germinal center (GC) reactions. Generation of protective antibodies against various infections is an important aspect of Tfh-mediated immune responses and the dysregulation of Tfh cell responses has been implicated in various autoimmune disorders, inflammation, and malignancy. Thus, their differentiation and maintenance must be closely regulated to ensure appropriate help to B cells. The generation and function of Tfh cells is regulated by multiple checkpoints including their early priming stage in T zones and throughout the effector stage of differentiation in GCs. Signaling pathways activated downstream of cytokine and costimulatory receptors as well as consequent activation of subset-specific transcriptional factors are essential steps for Tfh cell generation. Thus, understanding the mechanisms underlying Tfh cell-mediated immunity and pathology will bring into spotlight potential targets for novel therapies. In this review, we discuss the recent findings related to the molecular mechanisms of Tfh cell differentiation and their role in normal immune responses and antibody-mediated diseases.

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Cytokine-induced STAT1 activation is increased in patients with primary Sjögren's syndrome

Cited by 35 publications

References 41 publications

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

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

The Potential Role of Trained Immunity in Autoimmune and Autoinflammatory Disorders

Insights Into the Molecular Mechanisms of T Follicular Helper-Mediated Immunity and Pathology

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