scholarly journals An Easy and Reliable Strategy for Making Type I Interferon Signature Analysis Comparable among Research Centers

Diagnostics ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 113 ◽  
Author(s):  
Alessia Pin ◽  
Lorenzo Monasta ◽  
Andrea Taddio ◽  
Elisa Piscianz ◽  
Alberto Tommasini ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Diagnostic Value ◽  
Type I ◽  
Data Normalization ◽  
Signature Analysis ◽  
Interferon Signature ◽  
Interferon Stimulated Genes ◽  
Targeted Treatments ◽  
To Receive

Interferon-stimulated genes (ISGs) are a set of genes whose transcription is induced by interferon (IFN). The measure of the expression of ISGs enables calculating an IFN score, which gives an indirect estimate of the exposition of cells to IFN-mediated inflammation. The measure of the IFN score is proposed for the screening of monogenic interferonopathies, like the Aicardi-Goutières syndrome, or to stratify subjects with systemic lupus erythematosus to receive IFN-targeted treatments. Apart from these scenarios, there is no agreement on the diagnostic value of the score in distinguishing IFN-related disorders from diseases dominated by other types of cytokines. Since the IFN score is currently measured in several research hospitals, merging experiences could help define the potential of scoring IFN inflammation in clinical practice. However, the IFN score calculated at different laboratories may be hardly comparable due to the distinct sets of IFN-stimulated genes assessed and to different controls used for data normalization. We developed a reliable approach to minimize the inter-laboratory variability, thereby providing shared strategies for the IFN signature analysis and allowing different centers to compare data and merge their experiences.

scholarly journals Functionally impaired plasmacytoid dendritic cells and non-haematopoietic sources of type I interferon characterize human autoimmunity

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Antonios Psarras ◽  
Adewonuola Alase ◽  
Agne Antanaviciute ◽  
Ian M. Carr ◽  
Md Yuzaiful Md Yusof ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell Activation ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Type I Interferon ◽  
Connective Tissue Diseases ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Interferon Production ◽  
Interferon Signature

AbstractAutoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons have a crucial role in the progression to established autoimmune diseases. The cellular source and regulation in disease initiation of these cytokines is not clear, but plasmacytoid dendritic cells have been thought to contribute to excessive type I interferon production. Here, we show that in preclinical autoimmunity and established systemic lupus erythematosus, plasmacytoid dendritic cells are not effector cells, have lost capacity for Toll-like-receptor-mediated cytokine production and do not induce T cell activation, independent of disease activity and the blood interferon signature. In addition, plasmacytoid dendritic cells have a transcriptional signature indicative of cellular stress and senescence accompanied by increased telomere erosion. In preclinical autoimmunity, we show a marked enrichment of an interferon signature in the skin without infiltrating immune cells, but with interferon-κ production by keratinocytes. In conclusion, non-hematopoietic cellular sources, rather than plasmacytoid dendritic cells, are responsible for interferon production prior to clinical autoimmunity.

scholarly journals Positive natural selection in primate genes of the type I interferon response

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Elena N. Judd ◽  
Alison R. Gilchrist ◽  
Nicholas R. Meyerson ◽  
Sara L. Sawyer
Keyword(s):  
Natural Selection ◽  
Positive Selection ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Sequence Alignments ◽  
Multiple Sequence ◽  
Multiple Sequence Alignments ◽  
Interferon Stimulated Genes ◽  
Interferon Induction

Abstract Background The Type I interferon response is an important first-line defense against viruses. In turn, viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. Thus, hosts and viruses are locked in an evolutionary arms race for dominance of the Type I interferon pathway. As a result, many genes in interferon pathways have experienced positive natural selection in favor of new allelic forms that can better recognize viruses or escape viral antagonists. Here, we performed a holistic analysis of selective pressures acting on genes in the Type I interferon family. We initially hypothesized that the genes responsible for inducing the production of interferon would be antagonized more heavily by viruses than genes that are turned on as a result of interferon. Our logic was that viruses would have greater effect if they worked upstream of the production of interferon molecules because, once interferon is produced, hundreds of interferon-stimulated proteins would activate and the virus would need to counteract them one-by-one. Results We curated multiple sequence alignments of primate orthologs for 131 genes active in interferon production and signaling (herein, “induction” genes), 100 interferon-stimulated genes, and 100 randomly chosen genes. We analyzed each multiple sequence alignment for the signatures of recurrent positive selection. Counter to our hypothesis, we found the interferon-stimulated genes, and not interferon induction genes, are evolving significantly more rapidly than a random set of genes. Interferon induction genes evolve in a way that is indistinguishable from a matched set of random genes (22% and 18% of genes bear signatures of positive selection, respectively). In contrast, interferon-stimulated genes evolve differently, with 33% of genes evolving under positive selection and containing a significantly higher fraction of codons that have experienced selection for recurrent replacement of the encoded amino acid. Conclusion Viruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.

scholarly journals POS0611 THE EFFECT OF RITUXIMAB BIOSIMILAR THERAPY ON THE EXPRESSION OF INTERFERON-STIMULATED GENES (“INTERFERON SIGNATURE”) IN PATIENTS WITH RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 542.2-542
Author(s):  
A. Avdeeva ◽  
E. Tchetina ◽  
G. Markova ◽  
E. Nasonov
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Signature ◽  
Response To Therapy ◽  
Type I Interferons ◽  
Control Group ◽  
Type I ◽  
Acute Phase Reactants ◽  
Interferon Signature ◽  
Interferon Stimulated Genes ◽  
Healthy Donors

Background:Type I interferons (IFN-Is) are a group of molecules with pleiotropic effects on the immune system forming a crucial link between innate and adaptive immune responses. The type I interferon pathway has been implicated in the pathogenesis of a number of rheumatic diseases, including rheumatoid arthritis. IFN activity is usually quantified using expression of interferon-stimulated genes (ISGs) referred to as an IFN signature. Acellbia (BIOCAD) is the first Russian rituximab (RTX) biosimilar which was approved for medical use in rheumatoid arthritis (RA) patients in Russia and some CIS countries.Objectives:To evaluate the changes in expression of ISGs in patients (pts) with RA during RTX biosimilar therapyMethods:20 RA pts (18 woman, Me;IQR age 61.5(54-66.5) years, disease duration 39.5(20-84) months, mean DAS 28 5.6(4.9-6.8)) received two intravenous RTX biosimilar infusions (600 mg №2) in combination with DMARDs and glucocorticoids. Laboratory biomarkers were assessed at baseline and 24 weeks after the first infusion of RTX. 5 genes (IFI44L, MX1, IFIT 1, RSAD2, EPSTI1) were selected for evaluation of the “interferon signature” (Type I IFN gene signature – IFNGS). IFI44L and IFIT1 expression was undetectable, therefore the remaining three genes (MSX1, EPSTI1, RSAD2) were included into further analysis. IFNGS was calculated as the average expression values of the three selected genes. The control group included 20 age and gender matching healthy donors.Results:The baseline expression levels of MX1-11.48 (5.45-19.38), EPSTI1-12.83 (5.62-19.64), RSAD2-5.16 (2.73-10.4), and IFNGS-10.3 (5.18-17.12) in RA patients were significantly higher compared to healthy donors– 1,26 (0,73-1,6); 1,06 (0,81-1,48); 0,93 (0,72-1,19); 1,09 (0,92-1,42), (p<0.05, respectively). IFNGS was detected in 15 (75%) patients, and was not found in 5 (15%) patients. RTX induced reduction in disease activity, and the level of acute phase reactants (ESR, CRP) after 12 and 24 weeks of therapy, p<0.05 (fig.1). Increased RSAD 2 expression (p<0.05) and a trend to increasing IFNGS levels (p=0.06) were documented in the whole group, and also in patients with moderate treatment effects by week 24. Among patients with a good EULAR response to therapy, changes in expression were not significant (p> 0.05) (fig.1)Figure 1.Conclusion:Expression of IFN-stimulated genes was increased in RA patients compared to healthy donors. Increased RSAD2 and IFNGS expression was documented in patients with moderate effect of RTX therapy, therefore, these findings have important clinical relevance as predictors of RA clinical course which necessitates personified approach to treatment.Disclosure of Interests:None declared

scholarly journals In Vitro Effects of Sulforaphane on Interferon-Driven Inflammation and Exploratory Evaluation in Two Healthy Volunteers

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3602
Author(s):  
Elena Genova ◽  
Maura Apollonio ◽  
Giuliana Decorti ◽  
Alessandra Tesser ◽  
Alberto Tommasini ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Supportive Therapy ◽  
P Value ◽  
Type I ◽  
Interferon Signature ◽  
Interferon Stimulated Genes ◽  
Immune System Activation ◽  
In Vitro Effects

Interferonopathies are rare genetic conditions defined by systemic inflammatory episodes caused by innate immune system activation in the absence of pathogens. Currently, no targeted drugs are authorized for clinical use in these diseases. In this work, we studied the contribution of sulforaphane (SFN), a cruciferous-derived bioactive molecule, in the modulation of interferon-driven inflammation in an immortalized human hepatocytes (IHH) line and in two healthy volunteers, focusing on STING, a key-component player in interferon pathway, interferon signature modulation, and GSTM1 expression and genotype, which contributes to SFN metabolism and excretion. In vitro, SFN exposure reduced STING expression as well as interferon signature in the presence of the pro-inflammatory stimulus cGAMP (cGAMP 3 h vs. SFN+cGAMP 3 h p value < 0.0001; cGAMP 6 h vs. SFN+cGAMP 6 h p < 0.001, one way ANOVA), restoring STING expression to the level of unstimulated cells. In preliminary experiments on healthy volunteers, no appreciable variations in interferon signature were identified after SFN assumption, while only in one of them, presenting the GSTM1 wild type genotype related to reduced SFN excretion, could a downregulation of STING be recorded. This study confirmed that SFN inhibits STING-mediated inflammation and interferon-stimulated genes expression in vitro. However, only a trend towards the downregulation of STING could be reproduced in vivo. Results obtained have to be confirmed in a larger group of healthy individuals and in patients with type I interferonopathies to define if the assumption of SFN could be useful as supportive therapy.

Modulation of cardiometabolic disease markers by type I interferon inhibition in systemic lupus erythematosus

2020 ◽  
Author(s):  
Kerry A Casey ◽  
Michael A Smith ◽  
Dominic Sinibaldi ◽  
Nickie L Seto ◽  
Martin P Playford ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Cardiometabolic Disease ◽  
Type I ◽  
Systemic Lupus ◽  
Disease Markers
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