Type I interferon response gene expression in established rheumatoid arthritis is not associated with clinical parameters

Jong, Tamarah D. de; Blits, Marjolein; Ridder, Sander de; Vosslamber, Saskia; Wolbink, Gertjan; Nurmohamed, Michael T.; Verweij, Cornelis L.

doi:10.1186/s13075-016-1191-y

Cited by 19 publications

(24 citation statements)

References 20 publications

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“…Dysregulation of type-I INFs are often observed in autoimmunity and chronic inflammatory diseases [34][35][36][37]. In a study of at-risk individual for RA, IFN signalling genes were indicative of progression to the inflammatory stage [38][39][40]; however, IFN signatures were no longer reported predictive later in the disease course [35,41,42]. As supported by our data, this suggests that IFN signalling is associated with early pathogenesis, independently of whether this can be exploited clinically later in the disease.…”

Section: Discussionsupporting

confidence: 71%

Differential CpG DNA methylation in peripheral naïve CD4+ T-cells in early rheumatoid arthritis patients

et al. 2020

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Background: The genetic risk associated with rheumatoid arthritis (RA) includes genes regulating DNA methylation, one of the hallmarks of epigenetic re-programing, as well as many T-cell genes, with a strong MHC association, pointing to immunogenetic mechanisms as disease triggers leading to chronicity. The aim of our study was to explore DNA methylation in early, drug-naïve RA patients, towards a better understanding of early events in pathogenesis. Result: Monocytes, naïve and memory CD4 + T-cells were sorted from 6 healthy controls and 10 RA patients. DNA methylation was assessed using a genome-wide Illumina 450K CpG promoter array. Differential methylation was confirmed using bisulfite sequencing for a specific gene promoter, ELISA for several cytokines and flow cytometry for cell surface markers. Differentially methylated (DM) CpGs were observed in 1047 genes in naïve CD4 + T-cells, 913 in memory cells and was minimal in monocytes with only 177 genes. Naive CD4 + T-cells were further investigated as presenting differential methylation in the promoter of > 500 genes associated with several disease-relevant pathways, including many cytokines and their receptors. We confirmed hypomethylation of a region of the TNF-alpha gene in early RA and differential expression of 3 cytokines (IL21, IL34 and RANKL). Using a bioinformatics package (DMRcate) and an in-house analysis based on differences in β values, we established lists of DM genes between health and RA. Publicly available gene expression data were interrogated to confirm differential expression of over 70 DM genes. The lists of DM genes were further investigated based on a functional relationship database analysis, which pointed to an IL6/JAK1/STAT3 node, related to TNF-signalling and engagement in Th17 cell differentiation amongst many pathways. Five DM genes for cell surface markers (CD4, IL6R, IL2RA/CD25, CD62L, CXCR4) were investigated towards identifying subpopulations of CD4 + T-cells undergoing these modifications and pointed to a subset of naïve T-cells, with high levels of CD4, IL2R, and CXCR4, but reduction and loss of IL6R and CD62L, respectively. Conclusion: Our data provided novel conceptual advances in the understanding of early RA pathogenesis, with implications for early treatment and prevention.

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Section: Discussionsupporting

confidence: 71%

Differential CpG DNA methylation in peripheral naïve CD4+ T-cells in early rheumatoid arthritis patients

et al. 2020

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“…The Type I IFN pathway and the signature of genes that are involved in IFN responses have been shown to be elevated in patients with RA, though it appears that both the alpha and beta IFN subtypes are represented, while in other autoimmune conditions such as systemic lupus erythematosus (SLE), the alpha type predominates [30]. In general, the Type I IFN signature in patients with RA was found not to be suppressed by MTX [31]. Of interest is the previously reported finding that the ratio of serum activity of the Type I IFNs beta/alpha was predictive of reponse to anti-TNF therapeutics [32].…”

Section: Discussionmentioning

confidence: 99%

Peripheral Blood Gene Expression Signatures Identify Methotrexate Responders in Patients with Rheumatoid Arthritis

June

Feger

Nevin

et al. 2019

Preprint

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Background: Methotrexate (MTX) and biologic therapies have remarkably improved outcomes in patients with rheumatoid arthritis (RA). However, choices of therapeutic regimens in an individual patient remain empiric, resulting in a risk of delayed control of inflammation consequent joint damage. In previous studies we have shown that a large number of protein-coding genes are dysregulated in RA and that the expression levels of the majority of these dysregulated genes return to normal in patients who have control of disease after initiating MTX monotherapy. Furthermore, in vitro responses to MTX are rapid, suggesting that changes in expression could precede clinical outcome, and have prognostic value. The aim of the current study was to analyze whole blood gene expression for correlates of clinical responses to MTX, with the long-term objective of developing prognostic biomarkers.Methods: RA patients (N=32) and healthy controls (HC; N=8) were from the Investigation of Remission in Rheumatoid Arthritis (IRRA) cohort at Pennsylvania State M.S. Hershey Medical Center. The RA group included 16 patients with active disease and 16 with controlled disease; 8 patients in each group were currently being treated with MTX. Whole blood RNA profiling was carried out in the Penn State College of Medicine Genomics core laboratory. Transcript data were analyzed using clustering algorithms and pathways analysis software to determine relatedness of groups.Results: Patients with active RA showed patterns of gene dysregulation that were farther from HC values than RA patients with controlled disease, whether or not MTX was a current medication. Comparison of the four RA groups determined by activity levels and MTX use showed over-expression of genes in alpha/beta and gamma interferon pathways, especially in active RA patients not currently taking MTX, suggesting contributions to maintenance of active disease.Conclusion: Levels of genes that are expressed in peripheral blood of RA patients correlate with disease activity and also with MTX treatment status. Longitudinal studies to determine how early in the treatment course changes in gene expression levels are detectable will be of interest to determine the potential for development of prognostic biomarkers to guide therapeutic decisions.

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“…Baseline type I IFN activity (quantified as type I IFN protein and IFNGS expression) may predict clinical responders to TNF antagonists and non-responders to rituximab in patients with rheumatoid arthritis 81–83. However, the IFNGS may not reflect rheumatoid arthritis disease activity,84 and whether there is a causal relationship between IFNGS and rheumatoid arthritis pathogenesis is currently unclear. Indeed, recent evidence suggests that pDCs from drug-naïve patients with early rheumatoid arthritis differentially expressed genes suggestive of enhanced tolerogenic function 85…”

Section: Type I Ifns In Autoimmune Diseasesmentioning

confidence: 99%

Type I interferons in host defence and inflammatory diseases

Crow

Rönnblom

2019

Lupus Sci Med

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Type I interferons (IFN) can have dual and opposing roles in immunity, with effects that are beneficial or detrimental to the individual depending on whether IFN pathway activation is transient or sustained. Determinants of IFN production and its functional consequences include the nature of the microbial or nucleic acid stimulus, the type of nucleic acid sensor involved in inducing IFN, the predominant subtype of type I IFN produced and the immune ecology of the tissue at the time of IFN expression. When dysregulated, the type I IFN system drives many autoimmune and non-autoimmune inflammatory diseases, including SLE and the tissue inflammation associated with chronic infection. The type I IFN system may also contribute to outcomes for patients affected by solid cancers or myocardial infarction. Significantly more research is needed to discern the mechanisms of induction and response to type I IFNs across these diseases, and patient endophenotyping may help determine whether the cytokine is acting as ‘friend’ or ‘foe’, within a particular patient, and at the time of treatment. This review summarises key concepts and discussions from the second International Summit on Interferons in Inflammatory Diseases, during which expert clinicians and scientists evaluated the evidence for the role of type I IFNs in autoimmune and other inflammatory diseases.

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Type I interferon response gene expression in established rheumatoid arthritis is not associated with clinical parameters

Cited by 19 publications

References 20 publications

Differential CpG DNA methylation in peripheral naïve CD4+ T-cells in early rheumatoid arthritis patients

Differential CpG DNA methylation in peripheral naïve CD4+ T-cells in early rheumatoid arthritis patients

Peripheral Blood Gene Expression Signatures Identify Methotrexate Responders in Patients with Rheumatoid Arthritis

Type I interferons in host defence and inflammatory diseases

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