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Visan, Ioana. "The interferon signature." Nature Immunology 18, no. 2 (February 2017): 151. http://dx.doi.org/10.1038/ni.3670.
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Suspitsin, E. N., R. K. Raupov, E. M. Kuchinskaya, and M. M. Kostik. "Analysis of interferon type I signature for differential diagnosis of diseases of the immune system ( review of literature)." Russian Clinical Laboratory Diagnostics 66, no. 5 (May 23, 2021): 279–84. http://dx.doi.org/10.51620/0869-2084-2021-66-5-279-284.
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Type 1 interferons (IFN1) are both key molecules of antiviral defense and potent inflammatory mediators. In 2003, increased expression of a variety of interferon 1-regulated genes was observed in a blood cells of patients with systemic lupus erythematosus (SLE). This phenomenon was called the type 1 interferon signature (IFN1-signature). Since then, expression patterns indicating the presence of an IFN1-signature were consistently detected in a range of monogenic and complex autoimmune and autoinflammatory conditions. A quantitative indicator reflecting the degree of hyperactivation of the IFN1 pathway is known as interferon score. This review discusses the possible causes of upregulated expression of interferon 1-induced genes, the laboratory approaches to the interferon score analysis, as well as the practical use of this indicator for the diagnosis of various conditions.
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Smith, Michael Alexander, Chia-Chien Chiang, Dominic Sinibaldi, Kamelia Zerrouki, Zerai Manna, Wendy I. White, Mariana J. Kaplan, et al. "Using the Circulating Proteome to Assess Type I Interferon Activity in Systemic Lupus Erythematosus." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 210.1. http://dx.doi.org/10.4049/jimmunol.198.supp.210.1.
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Abstract Type I interferon (IFN) signaling drives pathology in systemic lupus erythematosus (SLE) and can be tracked via IFN-inducible transcripts present in whole blood as described by several IFN gene signatures. As SLE is a complex disease affecting diverse organ systems, we examined whether measurement of circulating proteins, which can infiltrate the bloodstream from afflicted tissues, might also offer insight into global IFN activity. The presence of anti-DNA autoantibodies in patient serum has prevented effective use of SOMAmers for the evaluation of circulating proteins in SLE. Here, we adapted protocols to mitigate for those autoantibodies and report high reproducibility and accuracy with 100% QC pass rate and improved correlation with previously validated multi-analyte platform results. Using SOMAmers together with the IFN 21-gene signature1 (IFNGS), we derived an IFN protein signature that can approximate the IFNGS score. In a cohort of 82 SLE patients and 48 healthy donors, the protein signature was found elevated above healthy donors for most of IFNGS-high patients (49/55, 89%) and also for a subgroup of IFNGS-low patients (7/27, 26%). The protein signature correlated with global disease activity (median SLEDAI score of 4 for the cohort) in both lymphopenic and non-lymphopenic patients. Significant associations with skin involvement, low complement, anti DNA auto-antibodies, and thrombocytopenia were also observed. In sum, our results suggest blood derived protein measurements may complement validated gene signatures to monitor IFN activity.
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Rigolet, Muriel, Cyrielle Hou, Yasmine Baba Amer, Jessie Aouizerate, Baptiste Periou, Romain K. Gherardi, Peggy Lafuste, and François Jérôme Authier. "Distinct interferon signatures stratify inflammatory and dysimmune myopathies." RMD Open 5, no. 1 (February 2019): e000811. http://dx.doi.org/10.1136/rmdopen-2018-000811.
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ObjectiveThe role of interferons (IFN) in the pathophysiology of primary inflammatory and dysimmune myopathies (IDM) is increasingly investigated, notably because specific neutralisation approaches may constitute promising therapeutic tracks. In present work we analysed the muscular expression of specific IFNα/β and IFNγ-stimulated genes in patients with various types of IDM.Methods39 patients with IDM with inclusion body myositis (IBM, n=9), dermatomyositis (DM, n=10), necrotising autoimmune myopathies (NAM, n=10) and antisynthetase myositis (ASM, n=10), and 10 controls were included. Quantification of expression levels of IFNγ, ISG15, an IFNα/β-inducible gene and of six IFNγ-inducible genes (GBP2, HLA-DOB, HLA-DPB, CIITA, HLA-DRB and HLA-DMB) was performed on muscle biopsy samples.ResultsDM usually associated with strong type I IFNα/β signature, IBM and ASM with prominent type II IFNγ signature and NAM with neither type I nor type II IFN signature. Immunofluorescence study in ASM and IBM showed myofibre expression of major histocompatibility class 2 (MHC-2) and CIITA, confirming the induction of the IFNγ pathway. Furthermore, MHC-2-positive myofibres were observed in close proximity to CD8+ T cells which produce high levels of IFNγ.ConclusionDistinct IFN signatures allow a more distinct segregation of IDMs and myofibre MHC-2 expression is a reliable biomarker of type II IFN signature.
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Carrero, Javier, Boris Calderon, Stephen Ferris, and Emil Unanue. "Evaluation of the role of type I interferon to the development of type 1 diabetes. (BA3P.131)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 44.1. http://dx.doi.org/10.4049/jimmunol.192.supp.44.1.
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Abstract Our goal is to identify the earliest immunologically relevant events that trigger autoimmune diabetes. The first detectable inflammatory signature in the NOD mouse is the upregulation of type I interferons and an interferon-inducible gene signature. We reason that understanding the early interferon signature may provide targets for the prevention, treatment, or diagnosis of autoimmune diabetes. The two ubiquitous interferon receptors (IFNAR and IFNGR) upregulate hundreds genes, some shared and some unique to each receptor. We backcrossed the type I interferon receptor onto NOD background to determine the relative contribution of IFNAR-inducible transcripts in type I diabetes induction. In our specific pathogen-free colony, NOD.IFNAR-/- mice developed diabetes at a decreased rate and penetrance from littermate controls. This reduction in incidence was gender independent and NOD.IFNAR heterozygous mice developed diabetes normally. There was a reduction in the number of the immunological infiltrates in the islets of Langerhans of NOD.IFNAR-/- mice from 4-8 wks of age as detected by flow cytometry and immunofluorescence. Concomitantly, there was a reduction in inflammatory gene expression in NOD.IFNAR-/- when compared to controls. Additionally, analysis of the NOD.IFNGR-/- mice showed a decrease in penetrance and kinetics of type I diabetes. Based on this data, we hypothesize that IFNAR and IFNGR induce a common genetic signature that is required for type I diabetes to proceed.
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An, Yuanyuan, and Hua Duan. "The Comprehensive Analysis of Interferon-Related Prognostic Signature with regard to Immune Features in Ovarian Cancer." Disease Markers 2022 (June 20, 2022): 1–24. http://dx.doi.org/10.1155/2022/7900785.
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Interferon plays an important role in immune response of ovarian cancer. However, the expression pattern of interferon in ovarian cancer remains unclear. This study is aimed at exploring the expression profile of interferon-relate genes and constructing an interferon-based prognostic signature in ovarian cancer. The ovarian cancer samples collected from TCGA database were viewed as the training set, and ovarian cancer samples collected from GEO datasets were used as the independent validation sets. Univariate Cox regression analysis and multivariate Cox regression analysis were used to construct interferon-related signature, which worked as independent prognostic factor. Bioinformatics based on David software, GSEA, and R software were used to investigate the relationship between immune status and the signature in ovarian cancer. The signature showed close correlation with the status for ovarian cancer immune microenvironment, which might provide the possibility for clinical targeted therapy.
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Gallay, Laure, Guy Mouchiroud, and Bénédicte Chazaud. "Interferon-signature in idiopathic inflammatory myopathies." Current Opinion in Rheumatology 31, no. 6 (November 2019): 634–42. http://dx.doi.org/10.1097/bor.0000000000000653.
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Rönnblom, Lars, and Maija-Leena Eloranta. "The interferon signature in autoimmune diseases." Current Opinion in Rheumatology 25, no. 2 (March 2013): 248–53. http://dx.doi.org/10.1097/bor.0b013e32835c7e32.
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Vieira, Matheus, Paul Régnier, Anna Maciejewski-Duval, Alexandre Le Joncour, Guillaume Darasse-Jèze, Michelle Rosenzwajg, David Klatzmann, Patrice Cacoub, and David Saadoun. "Interferon signature in giant cell arteritis aortitis." Journal of Autoimmunity 127 (February 2022): 102796. http://dx.doi.org/10.1016/j.jaut.2022.102796.
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Gruber, Conor. "Impaired interferon signature in severe COVID-19." Nature Reviews Immunology 20, no. 6 (April 30, 2020): 353. http://dx.doi.org/10.1038/s41577-020-0335-0.
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Magro, R., C. Saliba, L. Camilleri, C. Scerri, and A. Borg. "THU0235 VITAMIN D AND INTERFERON SIGNATURE GENE EXPRESSION IN SYSTEMIC LUPUS ERYTHEMATOSUS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 344.3–345. http://dx.doi.org/10.1136/annrheumdis-2020-eular.934.
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Background:Vitamin D deficiency is more prevalent in patients with systemic lupus eythematosus (SLE) as a result of sun avoidance.1The potential negative impact of vitamin D deficiency on SLE disease activity has been shown in a number of studies.2The expression of the interferon signature genes in SLE correlates positively with disease activity, and these genes are thought to mediate the clinical manifestations of the disease.3Objectives:The aim of this study was to establish whether a relationship exists between serum 25-hydroxyvitamin D level and the interferon signature gene expression in whole blood of SLE patients.Methods:Informed consent was obtained from 92 SLE patients who were over the age of 18 and who fulfilled the SLICC classification criteria for SLE. The patients were interviewed and blood samples were taken. SLE disease activity was measured by SLE disease activity index-2K (SLEDAI-2K). RNA extraction was performed from whole blood. QuantiGene Plex technology was used to measure the expression of 12 interferon signature genes in the extracted RNA. The study was approved by the University Research Ethics Committee.Results:92.4% of the cohort studied were female. 58.7% were receiving vitamin D3 supplementation at a mean dose of 1031IU daily. 27.2% had vitamin D insufficiency (25-hydroxyvitamin D 21-29ng/ml) and 15.2% were vitamin D deficient (25-hydroxyvitamin D <20ng/ml). Mean serum 25-hydroxyvitamin D was 30.75ng/ml (standard deviation 9.53 ng/ml). Median SLEDAI-2K was 4 (range 0-12). Serum 25-hydroxyvitamin D had a significant negative correlation with body mass index (BMI) (R=-0.258, p=0.006) but there was no significant negative correlation with SLEDAI-2K or with the expression of the interferon signature genes. The expression of most interferon signatures genes measured (IFI35, OAS1, MX1, IFITM1, STAT2, IFIT3, IFIT1, STAT1, SOCS1) had a significant positive correlation with SLEDAI-2K.Conclusion:This study did not show a significant relationship between serum vitamin D level and disease activity. In keeping with this, there was no significant negative correlation between serum 25-hydroxyvitamin D and interferon signature gene expression. Further prospective studies and randomised controlled trials are required to study this relationship in greater depth.References:[1]Kamen DL, Cooper GS, Bouali H, Shaftman SR, Hollis BW, Gilkeson GS. Vitamin D deficiency in systemic lupus erythematosus. Autoimmun Rev. 2006; 5: 114-7.[2]Sahebari M, Nabavi N, Salehi M. Correlation between serum 25(OH)D values and lupus disease activity: an original article and a systematic review with meta-analysis focusing on serum VitD confounders.Lupus2014; 23: 1164-77.[3]Arasappan D, Tong W, Mummaneni P, Fang H, Amur S. Meta-analysis of microarray data using a pathway-based approach identifies a 37-gene expression signature for systemic lupus erythematosus in human peripheral blood mononuclear cells. BMC Med. 2011; 9: 65.Disclosure of Interests: :None declared
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Wigston, Z., A. Burska, A. Alase, K. Mahmoud, and E. Vital. "OP0091 A TWO-SCORE INTERFERON SIGNATURE AND MUSCULOSKELETAL IMAGING EXPLAIN THE ASSOCIATION BETWEEN INTERFERON AND ARTHRITIS IN SLE." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 60.2–60. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3564.
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Background:Interferon (IFN) signature is associated with disease activity and flare in SLE. We previously described two independent IFN gene expression scores; IFN Score A (the most commonly measured ISGs) and IFN Score B (less commonly measured ISGs which may also respond to IFN-II or other immune mediators)[1]. Many more clinical outcomes are associated with IFN Score B than with a “classic” interferon signature. These include progression of At-Risk individuals to SLE, response to rituximab, and differentiation of IFN signature in RA and SLE.In previous work, the relationship of IFN Signatures with arthritis was less clear than for other SLE features. This may be related to the local regulatory effects of IFN-beta in the synovium, contrasting with the pro-inflammatory effects of other interferons. Another reason may be the proven imprecision of clinical examination as a measure of MSK inflammation in SLE.USEFUL was a multicentre longitudinal study including serial ultrasound assessment of SLE patients with inflammatory MSK pain receiving treatment with glucocorticoids (GC).Objectives:To determine whether IFN scores A and B are associated with imaging-proven synovitis in SLE and measure the responsiveness of IFN scores to GC treatment.Methods:133 SLE patients were recruited into the USEFUL study if the referring physician deemed they had inflammatory pain warranting treatment. Participants received depomedrone 120mg IM then were assessed at 0, 2 and 6 weeks using clinical instruments and ultrasound (US). OMERACT US criteria were used to categorise patients as active (GS2 or PD1 in at least one joint or tendon), active in both joints and tendons, or non-active (no GS1 and PD0 or better in all joints).Expression of 26 interferon stimulated genes, normalised to PP1A was measured in whole blood collected in TEMPUS tubes using a custom Taqman array. IFN scores A and B were calculated as previously described[1]. Missing data was imputed using expectation-maximisation method. Parametric tests were applied with post hoc Tukey to compare scores between groups.Results:At baseline, there was no significant difference in IFN Score A between ultrasound groups (F = 1.045, p = 0.355). In contrast, IFN Score B differed significantly between ultrasound groups (F = 4.168, p = 0.018). The greatest difference was between active ultrasound for both joints and tendons (n=22) and non-active ultrasound (n=53) (difference = 0.75, 95% CI 0.13, 1.37, p=0.013).There was no significant change from baseline in IFN Score A at week 2 (mean difference 0.08, 95% -0.14, 0.31, p = 0.45) or week 6 (mean difference -0.03, 95% -0.25, 0.19, p = 0.79). Similarly, there was no significant change in IFN Score B at week 2 (mean difference -0.01, 95% -0.18, 0.17, p = 0.93) or week 6 (mean difference -0.07, 95% -0.21, 0.08, p = 0.36).Conclusion:Previous studies were unable to demonstrate an association between a typical interferon signature and arthritis in SLE. Our study includes a homogenous patient population and therapy, objective measure of synovitis, and a more detailed assessment of IFN Status. We found that imaging-proven synovitis is associated with increased expression of a specific subset of ISGs (IFN score B), but not a the more typical interferon signature genes (IFN Score A).This increases the body of evidence for the value of IFN score B in predicting clinical outcomes. GC treatment did not affect systemic IFN signature scores at follow up. Future analysis will explore the role of IFN Scores in predicting clinical responses to therapy in this study.References:[1]El-Sherbiny, Y.M., et al. Scientific Reports, 2018.8(1): p. 5793.Disclosure of Interests:Zoe Wigston: None declared, Agata Burska: None declared, Adewonuola Alase: None declared, Khaled Mahmoud: None declared, Edward Vital Grant/research support from: AstraZeneca, Roche/Genentech, and Sandoz, Consultant of: AstraZeneca, GSK, Roche/Genentech, and Sandoz, Speakers bureau: Becton Dickinson and GSK
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Wu, Kang, Hai Fang, Liang-Dong Lyu, Douglas B. Lowrie, Ka-Wing Wong, and Xiao-Yong Fan. "A Derived Network-Based Interferon-Related Signature of Human Macrophages Responding toMycobacterium tuberculosis." BioMed Research International 2014 (2014): 1–16. http://dx.doi.org/10.1155/2014/713071.
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Network analysis of transcriptional signature typically relies on direct interaction between two highly expressed genes. However, this approach misses indirect and biological relevant interactions through a third factor (hub). Here we determine whether a hub-based network analysis can select an improved signature subset that correlates with a biological change in a stronger manner than the original signature. We have previously reported an interferon-related transcriptional signature (THP1r2Mtb-induced) fromMycobacterium tuberculosis(M. tb)-infected THP-1 human macrophage. We selected hub-connected THP1r2Mtb-induced genes into the refined network signature TMtb-iNet and grouped the excluded genes into the excluded signature TMtb-iEx. TMtb-iNet retained the enrichment of binding sites of interferon-related transcription factors and contained relatively more interferon-related interacting genes when compared to THP1r2Mtb-induced signature. TMtb-iNet correlated as strongly as THP1r2Mtb-induced signature on a public transcriptional dataset of patients with pulmonary tuberculosis (PTB). TMtb-iNet correlated more strongly in CD4+and CD8+T cells from PTB patients than THP1r2Mtb-induced signature and TMtb-iEx. When TMtb-iNet was applied to data during clinical therapy of tuberculosis, it resulted in the most pronounced response and the weakest correlation. Correlation on dataset from patients with AIDS or malaria was stronger for TMtb-iNet, indicating an involvement of TMtb-iNet in these chronic human infections. Collectively, the significance of this work is twofold: (1) we disseminate a hub-based approach in generating a biologically meaningful and clinically useful signature; (2) using this approach we introduce a new network-based signature and demonstrate its promising applications in understanding host responses to infections.
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Templeton, Amanda K., N. Dominguez, R. Lu, G. Vidal, J. Levin, A. Sestak, J. Kelly, et al. "IRF5 Genetic Risk Haplotype Influences Host B Cell Gene Responses to Epstein-Barr Virus (EBV) (49.14)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 49.14. http://dx.doi.org/10.4049/jimmunol.182.supp.49.14.
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Abstract Both gene and environment interactions play keyroles in the development of systemic lupus erythematosus (SLE). We examined effects of the IRF5 lupus risk haplotype upon the host's B cell response to the binding or infection with EBV, a suspected environmental trigger for SLE. Whole genome microarray expression profile data was collected from cells exposed to EBV for 16 hours. Analysis of gene expression by gene set enrichment analysis revealed that key differences in expression between SLE patients and controls (or individuals carrying the IRF5 risk and non-risk haplotype) were in a subset of interferon response genes. Patients with the IRF5 risk haplotype have a heightened interferon signature under all experimental conditions; whereas, the patients with the IRF5 protective haplotype have a B cell interferon signature similar to that of unrelated, matched controls. Overexpression of interferon pathway genes in B cells following viral exposure in control individuals carrying the IRF5 risk haplotype suggests that the IRF5 risk alleles alone can modulate ones biological response to the environmental insult. Patients carrying either the IRF5 risk or non-risk alleles appear to already be predisposed to having a higher interferon signature even without exposure to virus, suggesting that other genetic factors are also influencing the interferon response, independent of virus. Support by NIH (AI007633 and AI31584).
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Sadanandam, Anguraj, Pawan Poudel, Elisa Fontana, and Chanthirika Ragulan. "Characterizing heterogeneity in KRAS mutant colorectal cancers (CRC) using cellular, mutation, and immune profiles." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 657. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.657.
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657 Background: Approximately 30%-50% of CRC patients have KRAS mutation, and they are associated with lack of treatment response to anti-EGFR therapy. KRAS mutant CRCs are heterogeneous that not all mutant tumors are dependent on its downstream signaling. At this era of the search for therapeutic targets related to mutant KRAS, it is essential to understand the underlying heterogeneity in KRAS mutant metastatic CRCs with a goal of identifying personalized therapeutic vulnerabilities. To understand KRAS mutation further, in this study we classified KRAS mutant CRCs based on individual cell types in the normal colon crypt and associated them with PIK3CA mutations and interferon-gamma responsive signature. Methods: Publicly available RNAseq gene expression data from KRAS mutant samples were used. Classification of CRC samples into CRCassigner subtypes, KRAS mutation dependents/independent groups, and interferon gamma-responsive status was performed using published signatures. Results: CRC samples (n>200) with KRAS mutant and wild-type statuses were classified into all the five CRCAssigner subtypes (goblet-like, enterocyte, transit-amplifying, stem-like and inflammatory) that represent individual cell types in the normal colon crypt. Interestingly, goblet-like subtype was found to be enriched for KRAS mutation. Among those KRAS mutant CRCs from all the subtypes (n=61), goblet-like samples showed significant enrichment (false discovery rate <0.05; hypergeometric test) for KRAS dependent signature, whereas stem-like subtype showed KRAS independent signature. KRAS independent stem-like CRCs showed increased PIK3CA mutation and expression of interferon-gamma responsive genes compared to dependent CRCs. Conclusions: Overall, KRAS mutant CRCs are heterogeneous with differentiated subtype highly dependent on the mutation and its signalling pathway, whereas less differentiated/stem-like subtype CRCs are independent of the mutation. Also, the enrichment of PIK3CA mutation and interferon-gamma responsive genes mainly in KRAS independent CRC subtype present a potential opportunity to target them using combination immunotherapeutics.
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Wigston, Z., A. Burska, M. Wittmann, and E. Vital. "POS0179 EXPLORING THE EFFECTS OF A TWO-SCORE INTERFERON SIGNATURE AND RESPONSES TO INTERFERON STIMULUS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 302.1–303. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1100.
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Background:IFN Scores are increasingly important as biomarkers to stratify RMDs and select patients for interferon targeted therapies. Several studies have previously demonstrated that different sets of interferon stimulated genes (ISGs) have different clinical associations. We validated a 2-score system of ISGs expression consisting of Score A (a set of ISGs included in most interferon signature assays) and Score B (a set of less commonly measured ISGs). Score B consistently demonstrated stronger clinical associations in studies of diagnosis, prediction of progression to SLE in At-Risk individuals, response to rituximab and imaging-proven synovitis. Previous literature suggested that subsets of ISGs were explained by different interferon subtypes.Objectives:To understand the determinants of IFN Score A and IFN Score B.Methods:PBMCs and whole blood Tempus from 4 different healthy doners were stimulated with various cytokines and IFNs at 6- and 24-hour time points. RNA from both sample types were extracted and the expression of 26 interferon stimulated genes were measured using TaqMan and normalised to house-keeping gene PPIA. IFN Scores A and B were calculated as previously described [1]. To compare relative increase in expression with each condition, we calculated delta Ct fold change relative to non-stimulated. To represent greater expression as numerically higher positive values, relative expression was calculated as (fold change*-100) +100. Independent T-test calculated the significant differences between each condition compared to IFN α stimulation.Results:Table 1 shows differences between each condition compared with IFN α at the 6-hour time point. In both sample types, all conditions excluding IFN β stimulation were shown to induce significantly lower expression of both scores compared to IFN α (p <0.01). At 6 and 24 hours, IFN α and IFN β showed a strong induction of IFN score A and B. At 6 hours, IFN γ, κ, and λ induced IFN score A and B but weaker than IFN α and β which was shown in both sample types. We did not observe a difference between the expression of these two scores according to interferon subtype. Other cytokines (TNF, IL-1 and IL-6) weakly induced expression of Score A and B. For IL-10 there was a possible discordant effect with increase in expression of Score B, but decreased expression of Score A, however these changes were small in magnitude.Table 1.ConditionIFN Score AIFN Score BMean relative expression vs. non-stimulatedP value(vs IFN α)Mean relative expression vs. non-stimulatedP value(vs IFN α)PBMCIFN α103.4-71.8-IFN β97.10.37364.70.352IFN γ37.5<0.00129.50.002IFN κ16.6<0.0013.1<0.001IFN λ24.8<0.00111.1<0.001IL-19.7<0.0014.4<0.001IL-64.5<0.0014.1<0.001IL-10-15.2<0.0018.0<0.001TNF α9.6<0.0011.2<0.001Whole BloodIFN α116.7-74.1-IFN β116.60.99773.20.894IFN κ23.00.0017.90.003IFN λ23.00.0017.6<0.001Conclusion:We found a difference in the induction of ISG expression between subtypes of Type I interferon, as well as other interferons and cytokines. However, the relative expression of IFN Score A and IFN Score B is not easily explained by the subtypes of interferon. We have also previously shown that these scores are both similarly expressed comparing different cell subsets. The explanation for the coordinated expression of these ISGs is therefore unclear and future work will explore the scores with a combination of conditions.References:[1]El-Sherbiny, Y.M., et al. Scientific Reports, 2018. 8(1): p. 5793.Disclosure of Interests:Zoe Wigston: None declared, Agata Burska: None declared, Miriam Wittmann Consultant of: Abbvie, Celgene, Janssen, L’Oreal, Novartis and Pfizer, Edward Vital Speakers bureau: Becton Dickinson and GSK, Consultant of: AstraZeneca, GSK, Roche/Genentech, and Sandoz, Grant/research support from: AstraZeneca, Roche/Genentech
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Komura, Kazuhiro, Yuki Ichimura, Naoko Okiyama, Kazuyoshi Watanabe, Hiroaki Muramoto, and Takashi Matsushita. "Interferon signature in cutaneous lesion of COVID toes." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 20.37. http://dx.doi.org/10.4049/jimmunol.206.supp.20.37.
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Abstract Increasing reports have showed several kinds of dermatological manifestation in Coronavirus disease 2019 (COVID-19). Some of them may occur as a direct implication of coronavirus infection. Within those, acral skin changes, recently called COVID toes, have a potential to provide a diagnostic value. We herein described a 49-year old Japanese man with COVID toes. The skin lesions appeared simultaneously with fever. The rash was similar for cold-induced erythema multiforme of the patients with familial Chilblain; hereditary type I interferonopathy. Histopathological staining indicated up-regulated expression of MxA, effected by local enhancement of type I interferon. These speculated that the specificity of COVID toes may depend on interferon up-regulated by specific mechanisms.
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Obermoser, G., and V. Pascual. "The interferon-α signature of systemic lupus erythematosus." Lupus 19, no. 9 (August 2010): 1012–19. http://dx.doi.org/10.1177/0961203310371161.
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Systemic lupus erythematosus (SLE) is a prototypic multisystem autoimmune disorder where interplay of environmental and genetic risk factors leads to progressive loss of tolerance to nuclear antigens over time, finally culminating in clinical disease. The heterogeneity of clinical manifestations and the disease’s unpredictable course characterized by flares and remissions are very likely a reflection of heterogeneity at the origin of disease, with a final common pathway leading to loss of tolerance to nuclear antigens. Impaired clearance of immune complexes and apoptotic material and production of autoantibodies have long been recognized as major pathogenic events in this disease. Over the past decade the type I interferon cytokine family has been postulated to play a central role in SLE pathogenesis, by promoting feedback loops progressively disrupting peripheral immune tolerance and driving disease activity. The identification of key molecules involved in the pathogenesis of SLE will not only improve our understanding of this complex disease, but also help to identify novel targets for biological intervention. Lupus (2010) 19, 1012—1019.
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Guthridge, Joel M., Daniel N. Clark, Amanda Templeton, Nicolas Dominguez, Rufei Lu, Gabriel S. Vidal, Jennifer A. Kelly, et al. "Effects of IRF5 Lupus Risk Haplotype on Pathways Predicted to Influence B Cell Functions." Journal of Biomedicine and Biotechnology 2012 (2012): 1–12. http://dx.doi.org/10.1155/2012/594056.
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Both genetic and environmental interactions affect systemic lupus erythematosus (SLE) development and pathogenesis. One known genetic factor associated with lupus is a haplotype of the interferon regulatory factor 5 (IRF5) gene. Analysis of global gene expression microarray data using gene set enrichment analysis identified multiple interferon- and inflammation-related gene sets significantly overrepresented in cells with the risk haplotype. Pathway analysis using expressed genes from the significant gene sets impacted by theIRF5risk haplotype confirmed significant correlation with the interferon pathway, Toll-like receptor pathway, and the B-cell receptor pathway. SLE patients with theIRF5risk haplotype have a heightened interferon signature, even in an unstimulated state (P=0.011), while patients with theIRF5protective haplotype have a B cell interferon signature similar to that of controls. These results identify multiple genes in functionally significant pathways which are affected by IRF5 genotype. They also establish the IRF5 risk haplotype as a key determinant of not only the interferon response, but also other B-cell pathways involved in SLE.
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Gallucci, Stefania, Heather Bennett, Debra Shivers, Yue Ning, Edward Behrens, Neelakshi Jog, Roberto Caricchio, and Uma Sriram. "Intrinsic Interferon Signature in Dendritic Cells in lupus-prone mice. (83.9)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 83.9. http://dx.doi.org/10.4049/jimmunol.184.supp.83.9.
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Abstract Type I Interferons (IFNs) are pathogenic in Systemic Lupus Erythematosus. PBMCs from lupus patients over-express Type I IFN responsive genes. The cause and cellular source of this "Interferon Signature" are still unclear. Since we found that dendritic cells (DCs) from lupus-prone mice express the IFN Signature, we asked whether this IFN Signature was intrinsic to the DCs. We found that bone marrow-derived dendritic cells (BMDCs) from young pre-diseased Sle1,2,3 lupus-prone mice constitutively over-express Type I IFN responsive genes, analyzed by real-time RT-PCR (IFN-a, IFN-b, STAT1, STAT2, Mx1, IL-6, IL-15, IRF-7), as compared to autoimmune C57BL/6 BMDCs, as well as ELISA and flow cytometry. We also found that STAT1 is constitutively phosphorylated, suggesting an ongoing response to Type I IFN in the Sle1,2,3 DCs. Treatment with ligands for TLR7 and TLR9 showed that lupus BMDCs are hyper-sensitive to nucleic acids. To determine the mechanism of the constitutive hyper-activation of the IFN response in lupus DCs, we treated Sle1,2,3 BMDCs with inhibitors of TLR7 and TLR9 and found a partial role for chronic exposure to nucleic acids. We are now testing other mechanisms to explain the IFN Signature in lupus DCs. We have reported earlier that IL-4 suppresses Type I IFN responses in DCs of normal mice. We have now found that IL-4 inhibits the IFN Signature in Sle1,2,3 BMDCs, suggesting IL-4 as a potential therapeutic strategy for lupus by suppressing the Type I IFN effects.
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Wu, Kang, Ka-Wing Wong, Wang-Long Deng, Hao Zhang, Jing Li, Douglas B. Lowrie, and Xiao-Yong Fan. "The Numerical Predominance and Large Transcriptome Differences of Neutrophils in Peripheral Blood Together Inevitably Account for a Reported Pulmonary Tuberculosis Signature." International Journal of Genomics 2017 (2017): 1–8. http://dx.doi.org/10.1155/2017/5830971.
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Previous transcriptomic analysis revealed a 393-transcript signature (PTBsig), which is dominated by interferon inducible genes, in whole blood of pulmonary tuberculosis (PTB) patients. Comparisons with a limited set of interferon-driven genes among separated monocytes, CD4+ T cells, CD8+ T cells, and neutrophils indicated that the signature is due to changes in neutrophils, the overwhelmingly predominant cell type. By extending the analysis to the entire 393 transcripts of PTBsig and by switching the cell proportions between separated monocytes, CD4+ T cells, CD8+ T cells, and neutrophils, we create putative PTBsig for whole blood (pPTBsig) in which CD4+ or CD8+ T cells or monocytes predominated or in which the cell proportions were unchanged. These putative signatures are then compared to the actual reported PTBsig. We show that, because of their predominance in peripheral blood and their larger transcriptional responses, neutrophils were indeed almost exclusively responsible for PTBsig. We caution that the functional significance of changes in other cell types might escape notice in transcriptome analysis that is based upon whole blood.
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Raupov, R., E. Suspitsin, R. Mulkidzhan, and M. Kostik. "POS1312 ANALYSIS OF INTERFERON TYPE I SIGNATURE IN JUVENILE DERMATOMYOSITIS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 993.3–994. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3292.
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Backgroundthe crucial role of hyperactivation IFN I signaling pathway has been proved in the pathogenesis of dermatomyositis. IFN I genes and chemokines activity vary according to subtype of inflammatory myopathies. IFN type 1 signature could be measured using different genes in the blood, skin and muscle tissue [1].Objectivesto evaluate IFN-score in children with dermatomyositis and compare with disease activityMethods15 patients (5 boys and 10 girls) were enrolled in the study. Clinical and laboratory parameters, disease activity (CMAS-childhood myositis assessment tool, aCAT- abbreviated cutaneous assessment tool) and treatment were assessed. Patients were compared accordingly to IFN-score elevation. IFN I-score was assessed by RT-PCR quantitation of 5 IFN I-regulated transcripts (IFI44L, IFI44, IFIT3, LY6E, MXA1); median relative expression of ≥ 2 was considered as a cut-off. IFN I-score was evaluated in dynamics in 9 patients.Resultsmedian age of patients was 6.2 (3.6; 7.6) years. Skin and muscle involvement were in all patients, arthritis in 5 (33%) patients, calcinosis in 3 (20%), lipodystrophy in 2 (13%) and lung involvement in 5 patients (33%), and 9 patients (60%) had positive myositis-related antibodies. Ten patients (67%) had an active disease, while elevated IFN-signature was detected in 12 (80%) patients.Cumulative IFN I-score and its’ five components were higher in active patients, compare to inactive (13.6 vs 1.4, p=0.006).Patients with increased IFN I-score had lower CMAS score and higher aCAT score compare to patients with normal levels of IFN I-score. IFN-I score correlated with aCAT, arthritis and lung involvement.ConclusionIFN-I score may be considered as disease activity biomarker in juvenile dermatomyositis with predominantly skin activity process.References[1]Rigolet M, Hou C, Baba Amer Y, Aouizerate J, Periou B, Gherardi RK et al. Distinct interferon signatures stratify inflammatory and dysimmune myopathies. RMD Open. 2019 Feb 26;5(1):e000811. doi: 10.1136/rmdopen-2018-000811. PMID: 30886734; PMCID: PMC6397431.AcknowledgementsThis work was supported by the RSF grant № 20-45-01005Disclosure of InterestsNone declared
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Genova, Elena, Maura Apollonio, Giuliana Decorti, Alessandra Tesser, Alberto Tommasini, and Gabriele Stocco. "In Vitro Effects of Sulforaphane on Interferon-Driven Inflammation and Exploratory Evaluation in Two Healthy Volunteers." Molecules 26, no. 12 (June 12, 2021): 3602. http://dx.doi.org/10.3390/molecules26123602.
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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.
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Edgar, Contessa, Deirdra Terrell, Sara Vesely, Igor Dozmorov, Jonathoan Wren, Mark Frank, Joan Merrill, et al. "Immune and ribosomal gene expression associate with relapse in ADAMTS13-deficient thrombotic thrombocytopenic purpura (P4086)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 51.9. http://dx.doi.org/10.4049/jimmunol.190.supp.51.9.
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Abstract 40% of patients who survive acute episodes of thrombotic thrombocytopenic purpura (TTP) associated with severe ADAMTS13 deficiency will relapse. Risk factors for relapse other than severe ADAMTS13 deficiency are unknown. ADAMTS13 autoantibodies, TTP episodes following infection or type I interferon treatment and reported ensuing systemic lupus erythematosus in some patients suggest immune dysregulation. This study asked whether ADAMTS13-deficient TTP patients in remission have peripheral blood transcriptional markers that associate with relapse history. Peripheral blood from 38 patients with acquired autoimmune ADAMTS13-deficient TTP in remission was examined for autoantibodies, type I interferon activity and global gene expression. A subset of patients (1.4-26.6 year follow-up; median 7.6 years) displayed a peripheral blood type I interferon gene signature that associated with elevated serum type I interferon activity and autoantibodies to RNA-binding proteins but not relapse. A second subset of patients (4.1-26.4 year follow-up; median 11.2 years) exhibited a peripheral blood gene signature composed of ribosomal transcripts that associated with relapse history. Patients who had relapsed also expressed higher natural killer cell, T lymphocyte and HLA transcript levels. The immune transcripts positively correlated with episode number but not with time since last episode. These data link a ribosomal/immune gene signature with relapse in acquired, ADAMTS13-deficient TTP.
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Shamitova, E. N., M. A. Dubinkina, and E. R. Khamidullova. "INTERFERON I SIGNATURE FOR DIFFERENTIAL DIAGNOSIS OF DISEASESOFTHE IMMUNESYSTEM." Научное обозрение. Биологические науки (Scientific Review. Biological Sciences), no. 2 2022 (2022): 48–53. http://dx.doi.org/10.17513/srbs.1272.
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Haupl, T., R. Biesen, B. Smiljanovic, J. R. Grun, J. Weix, B. Stuhlmuller, P. M. Villiger, G. R. Burmester, A. Radbruch, and A. Grutzkau. "The type 1 interferon signature: facts, fads and fallacies." Annals of the Rheumatic Diseases 70, Suppl 2 (February 22, 2011): A24. http://dx.doi.org/10.1136/ard.2010.148965.26.
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Farias Amorim, Camila, Fernanda O. Novais, Ba T. Nguyen, Mauricio T. Nascimento, Jamile Lago, Alexsandro S. Lago, Lucas P. Carvalho, Daniel P. Beiting, and Phillip Scott. "Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-γ signature." PLOS Neglected Tropical Diseases 15, no. 4 (April 1, 2021): e0009321. http://dx.doi.org/10.1371/journal.pntd.0009321.
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Cutaneous leishmaniasis is a localized infection controlled by CD4+ T cells that produce IFN-γ within lesions. Phagocytic cells recruited to lesions, such as monocytes, are then exposed to IFN-γ which triggers their ability to kill the intracellular parasites. Consistent with this, transcriptional analysis of patient lesions identified an interferon stimulated gene (ISG) signature. To determine whether localized L. braziliensis infection triggers a systemic immune response that may influence the disease, we performed RNA sequencing (RNA-seq) on the blood of L. braziliensis-infected patients and healthy controls. Functional enrichment analysis identified an ISG signature as the dominant transcriptional response in the blood of patients. This ISG signature was associated with an increase in monocyte- and macrophage-specific marker genes in the blood and elevated serum levels IFN-γ. A cytotoxicity signature, which is a dominant feature in the lesions, was also observed in the blood and correlated with an increased abundance of cytolytic cells. Thus, two transcriptional signatures present in lesions were found systemically, although with a substantially reduced number of differentially expressed genes (DEGs). Finally, we found that the number of DEGs and ISGs in leishmaniasis was similar to tuberculosis–another localized infection–but significantly less than observed in malaria. In contrast, the cytolytic signature and increased cytolytic cell abundance was not found in tuberculosis or malaria. Our results indicate that systemic signatures can reflect what is occurring in leishmanial lesions. Furthermore, the presence of an ISG signature in blood monocytes and macrophages suggests a mechanism to limit systemic spread of the parasite, as well as enhance parasite control by pre-activating cells prior to lesion entry.
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Heimes, Anne-Sophie, Franziska Härtner, Katrin Almstedt, Slavomir Krajnak, Antje Lebrecht, Marco J. Battista, Karolina Edlund, et al. "Prognostic Significance of Interferon-γ and Its Signaling Pathway in Early Breast Cancer Depends on the Molecular Subtypes." International Journal of Molecular Sciences 21, no. 19 (September 29, 2020): 7178. http://dx.doi.org/10.3390/ijms21197178.
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Interferons are crucial for adaptive immunity and play an important role in the immune landscape of breast cancer. Using microarray-based gene expression analysis, we examined the subtype-specific prognostic significance of interferon-γ (IFN-γ) as a single gene as well as an IFN-γ signature covering the signaling pathway in 461 breast cancer patients. Prognostic significance of IFN-γ, as well as the IFN-γ signature for metastasis-free survival (MFS), were examined using Kaplan–Meier as well as univariate and multivariate Cox regression analyses in the whole cohort and in different molecular subtypes. The independent prognostic significance of IFN-γ as a single gene was limited to basal-like breast cancer (hazard ratio (HR) 2.779, 95% confidence interval (95% CI) 1.117–6.919, p = 0.028). In contrast, the IFN-γ-associated gene signature was an independent prognostic factor in the whole cohort (HR 2.287, 95% CI 1.410–3.633, p < 0.001) as well as in the basal-like (HR 3.458, 95% CI 1.154–10.359, p = 0.027) and luminal B (HR 2.690, 95% CI 1.416–5.112, p = 0.003) molecular subtypes. These results underline the subtype-dependent prognostic influence of the immune system in early breast cancer.
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Kuo, Hung-Yang, Jhe-Cyuan Guo, Chia-Lang Hsu, Ta-Chen Huang, and Chih-Hung Hsu. "The immunogenomic difference between Asian and non-Asian esophageal squamous cell carcinoma (ESCC) patients: An analysis of the Cancer Genome Atlas (TCGA) cohort." Journal of Clinical Oncology 38, no. 5_suppl (February 10, 2020): 27. http://dx.doi.org/10.1200/jco.2020.38.5_suppl.27.
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27 Background: Recently reported global phase 3 trials of immune checkpoint inhibitor (ICI) versus second-line chemotherapy for esophageal cancer revealed that Asian population appear to obtain more benefit from ICI than non-Asian patients even in ESCC subgroups. Whether this observation could be explained by the immunogenomic difference between Asian and non-Asian ESCC remains uncertain. Methods: We retrieved the data of genetic alterations and gene expression profiling from ESCC patients of TCGA dataset, and compared the mutational profiles, immune subtypes, composition of immune cell infiltrates, and T cell-related signatures between Asian and Non-Asian patients with ESCC. Abundance of immune cell infiltrates were estimated by averaging expression values of the corresponding immune cells’ transcriptomic markers defined by Danaher et al. (J Immunother Cancer. 2017; 5:18.). The 6 immune subtypes were adopted from Thorsson et al (Immunity. 2018;48(4):812-830). The T-cell related signatures were determined by averaging the corresponding genes' expression values following previous reports. Results: We retrieved 93 patients with ESCC (Asian: non-Asian= 45: 48) from TCGA database. There is no statistical difference in overall survival between Asian and non-Asian ESCC patients. Higher mutation frequencies of TP53, NFE2L2, ZNF750, and lower mutation frequency of SMARCA4 were seen in Asian patients than in non-Asian patients. As for the immune contexture, we found that the composition of immune cell infiltrate, the distribution of immune subtypes, and a variety of T cell-related gene signatures including the 6-gene interferon-gamma signature, the 10-gene interferon-gamma signature defined by Merck or by Ribas et al, and the 13-gene inflammatory signature defined by Gajewski et al, were not significantly different between Asian and non-Asian groups. Conclusions: Our analysis failed to identify statistically significant difference in the immunogenomics of ESCC tumors between Asian and non-Asian patients in the TCGA cohort. Further immunogenomic studies focusing on patients from Asian countries with high ESCC prevalence are warranted.
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Wu, Zhicheng, Qiu Wang, Xiuqing Liu, Jiantong Zheng, Ling Ji, and Xiaofeng Li. "Identification and Validation of a Novel Multiomics Signature for Prognosis and Immunotherapy Response of Endometrial Carcinoma." Journal of Oncology 2022 (October 15, 2022): 1–13. http://dx.doi.org/10.1155/2022/8998493.
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Purpose. Cancer development and immune escape involve DNA methylation, copy number variation, and other molecular events. However, there are remarkably few studies integrating multiomics genetic profiles into endometrial cancer (EC). This study aimed to develop a multiomics signature for the prognosis and immunotherapy response of endometrial carcinoma. Methods. The gene expression, somatic mutation, copy number alteration, and DNA methylation data of EC were analyzed from the UCSC Xena database. Then, a multiomics signature was constructed by a machine learning model, with the ROC curve comparing its prognostic power with traditional clinical features. Two computational strategies were utilized to estimate the signature’s performance in predicting immunotherapy response in EC. Further validation focused on the most frequently mutant molecule, ARID1A, in the signature. The association of ARID1A with survival, MSI (Microsatellite-instability), immune checkpoints, TIL (tumor-infiltrating lymphocyte), and downstream immune pathways was explored. Results. The signature consisted of 22 multiomics molecules, showing excellent prognostic performance in predicting the overall survival of patients with EC (AUC = 0.788). After stratifying patients into a high and low-risk group according to the signature’s median value, low-risk patients displayed a greater possibility of respond to immunotherapy. Further validation on ARID1A suggested it could induce immune checkpoints upregulation, promote interferon response pathway, and interact with Treg (regulatory T cell) to facilitate immune activation in EC. Conclusion. A novel multiomics prognostic signature of EC was identified and validated in this study, which could guide clinical management of EC and benefit personalized immunotherapy.
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Kossenkov, Andrew V., Andrew Milcarek, Faiyaz Notta, Gun-Ho Jang, Julie M. Wilson, Steven Gallinger, Daniel Cui Zhou, et al. "Mitochondrial fitness and cancer risk." PLOS ONE 17, no. 10 (October 12, 2022): e0273520. http://dx.doi.org/10.1371/journal.pone.0273520.
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Changes in metabolism are a hallmark of cancer, but molecular signatures of altered bioenergetics to aid in clinical decision-making do not currently exist. We recently identified a group of human tumors with constitutively reduced expression of the mitochondrial structural protein, Mic60, also called mitofilin or inner membrane mitochondrial protein (IMMT). These Mic60-low tumors exhibit severe loss of mitochondrial fitness, paradoxically accompanied by increased metastatic propensity and upregulation of a unique transcriptome of Interferon (IFN) signaling and Senescence-Associated Secretory Phenotype (SASP). Here, we show that an optimized, 11-gene signature of Mic60-low tumors is differentially expressed in multiple malignancies, compared to normal tissues, and correlates with poor patient outcome. When analyzed in three independent patient cohorts of pancreatic ductal adenocarcinoma (PDAC), the Mic60-low gene signature was associated with aggressive disease variants, local inflammation, FOLFIRINOX failure and shortened survival, independently of age, gender, or stage. Therefore, the 11-gene Mic60-low signature may provide an easily accessible molecular tool to stratify patient risk in PDAC and potentially other malignancies.
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Kostik, M., R. Raupov, R. Mulkidzhan, A. Kosmin, and E. Suspitsin. "AB0001 INTERFERON SIGNATURE IN CHILDREN WITH CHRONIC NON-BACTERIAL OSTEOMYELITIS AND IT’S DYNAMIC AFTER BISPHOSPHONATES TREATMENT." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1036.2–1036. http://dx.doi.org/10.1136/annrheumdis-2021-eular.508.
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Background:Chronic non-bacterial osteomyelitis (CNO) is an immune-mediated chronic inflammatory bone disease which predominantly affects children and adolescents. The pathogenesis of CNO related to imbalance between pro-inflammatory and anti-inflammatory cytokines. Interferon-I mediated pathway is associated with pathogenesis of different pediatric rheumatic diseases, such as juvenile systemic lupus erythematosus (jSLE), juvenile dermatomyositis (JDM), systemic onset of juvenile idiopathic arthritis (soJIA), and, most of all, with macrophage activation syndrome. The data on interferon-I- regulated pathway in CNO is absent. NSAIDs, non-biologic and biologic anti-inflammatory drugs and bisphosphonates (BF) are treatment options for patients with CNO. The main adverse event of BF is a flu-like syndrome probably caused by the excessive cytokine release stimulated by BF.Objectives:The aim of our study was to evaluate activity of Interferon-I mediated pathway in CNO patients and it’s dynamics after BF treatment.Methods:This prospective study included children with CNO requiring BF treatment (n=9), patients with soJIA (n=8), JDM (n=11) and jSLE (n=40) and healthy controls (HC, n=21). The activity of Interferon-I mediated pathway was assessed using interferon I score (IFN1 score). The score represented the median expression of 5 IFN1-regulated genes (IFI44L, IFI44, IFIT3, LY6E, MX1) measured by quantitative real-time PCR. Patients with CNO were treated with standard 3-day regimen (1 mg/kg/day). We measured interferon score before pamidronate (Day 0, n=9) and after (Day 3, n=7).Results:Median interferon score was 1.09 (0.96; 1.67) in CNO patients, 1.95 (1.3; 5.75) in soJIA, 7.6 (1.78; 29.0) in JDM and 16.9 (2.55; 40.3) in jSLE and 0.95 (0.82; 1.17) in HC (p=0.00001). Where were no difference in the IFN1 score between CNO and HC (p=0.222). In 6/7 CNO patients interferon score increased after pamidronate (p=0.015). The median interferon score after pamidronate increased and became 3.06 (0.87; 4,9, p=0.043); this may possibly explain the development of BF-related flu-like symptoms (cytokine release syndrome).Conclusion:While interferon I-regulated pathway is not directly associated with CNO pathogenesis, BF likely activates interferon-I-regulated pathway and thus could be a possible cause of flu-like syndrome.This work supported by the Russian Foundation for Basic Research (grant № 18-515-57001).Disclosure of Interests:None declared
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Radke, Josefine, Randi Koll, Corinna Preuße, Debora Pehl, Kremena Todorova, Constanze Schönemann, Yves Allenbach, et al. "Architectural B-cell organization in skeletal muscle identifies subtypes of dermatomyositis." Neurology - Neuroimmunology Neuroinflammation 5, no. 3 (March 6, 2018): e451. http://dx.doi.org/10.1212/nxi.0000000000000451.
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ObjectiveTo study the B-cell content, organization, and existence of distinct B-cell subpopulations in relation to the expression of type 1 interferon signature related genes in dermatomyositis (DM).MethodsEvaluation of skeletal muscle biopsies from patients with adult DM (aDM) and juvenile DM (jDM) by histology, immunohistochemistry, electron microscopy, and quantitative reverse-transcription PCR.ResultsWe defined 3 aDM subgroups—classic (containing occasional B cells without clusters), B-cell–rich, and follicle-like aDM—further elucidating IM B-lymphocyte maturation and immunity. The quantity of B cells and formation of ectopic lymphoid structures in a subset of patients with aDM were associated with a specific profile of cytokines and chemokines involved in lymphoid neogenesis. Levels of type 1 interferon signature related gene expression paralleled B-cell content and architectural organization and link B-cell immunity to the interferon type I signature.ConclusionThese data corroborate the important role of B cells in DM, highlighting the direct link between humoral mechanisms as key players in B-cell immunity and the role of type I interferon–related immunity.
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Raupov, R., E. Suspitsin, E. Kalashnikova, N. Lybimova, E. Kuchinskaya, R. Mulkidzhan, A. Kosmin, and M. Kostik. "POS0078 CROSS-SECTIONAL ANALYSIS OF INTERFERON SIGNATURE IN PEDIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 246.1–247. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1956.
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Background:the role of interferon pathways in the pathogenesis of systemic lupus erythematosus (SLE) has been proven over the past years. Existing data suggest that interferon score (IFN I score) may serve as a useful marker of disease activity and patient clinical characteristics.Objectives:to compare characteristics of pediatric SLE patients with high and normal IFN I score.Methods:40 SLE patients (33 girls, 7 boys) under 18 years old were included in the cross-sectional study. In all cases the diagnosis was made using Systemic Lupus International Collaborating Clinics (SLICC) classification criteria. The data on clinical manifestations, disease activity by SLEDAI and ECLAM, laboratory findings in the onset of the disease and at the moment of interferon signature assessment were evaluated. Interferon signature was assessed by real-time PCR quantitation of 5 IFN I-regulated transcripts; median expression of ≥2 was considered as a threshold. The patients were divided into 2 groups depending on the level of interferon score: high (group1, n=31) and normal (group2, n=9).Results:The mean age of the disease onset was 12 (9.5; 14.0) years. The most common symptoms were skin lesions (85%), arthritis (67.5%), fever (55%), mucosa (45%), CNS (37.5%) and kidney (30%) involvement. Anemia, leukopenia and thrombocytopenia were observed in 62.5%, 27.5% and 50% of cases, while 87.5% and 70% of patients had ANA positivity and dsDNA antibodies at the onset. The comparison between the groups with increased and normal IFN I-signature is presented in Table 1.Table 1.ParametersGroup 1(High IFN-s)Group 2(Normal IFN-s)p-valueGirls, n (%)25 (80.7)8 (88.9)0.567The onset age, years12.0(10.0; 14.0)11.0 (9.0; 13.0)0.353Time to IFN-signature study, months from onset18.3 (7.0; 26.5)0.97 (0.87;1.73)0.987Skin involvement, n (%)12 (38.7)4 (44.4)0.837CNS involvement, n(%)8 (25.8)1 (11.1)0.353Arthritis, n(%)11 (35.5)2 (22.2)0.455Anemia, n(%)9 (29.0)2 (22.200.687Leucopenia, n(%)9 (29.0)1 (11.1)0.274ANA-positivity, n (%)27 (87.1)5 (55.6)0.037anti dsDNA antibodies, n(%)12 (38.7)2 (22.2)0.361Rheumatoid factor, n (%)11 (35.5)0 (0.0)0.036Hypocomplementemia, n (%)18/28 (64.3)2/6 (33.3)0.162Ferritin level, mkg/l112.0 (39.0; 271.0)21.0 (5.3; 23.7)0.0008Hematuria, n (%)10 (32.3)0 (0.0)0.049Proteinuria, n (%)11 (35.5)0 (0.0)0.036SELENA-SLEDAI, points9 (2;15)1 (0; 4)0.073ECLAM, points3.0 (1.0; 6.0)1.0 (0.0; 1.5)0.048Treatment with Rituximab or Cyclophosphamide, n (%)22 (71.0)3 (33.3)0.040GCS dose 0,2 mg/kg achievement for 6 months, n (%)9/21 (42.9)5/6 (83.3)0.080Conclusion:high IFN I-signature correlated with kidney involvement, ANA and RF-positivity, ferritinemia, proteinuria and hematuria. Patients with high IFN I-signature received more aggressive treatment and needed longer glucocorticosteroid (GCS) treatment. More meticulous dynamic evaluation of IFN-signature is needed to clarify its role as a predictive and prognostic marker.Acknowledgements:This work was supported by the RSF grant № 20-45-01005.Disclosure of Interests:None declared.
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Gallucci, Stefania, Linda Varghese, Heather Bennett, Neelakshi Jog, Debra Shivers, Yue Ning, Edward Behrens, Roberto Caricchio, and Uma Sriram. "Intrinsic interferon signature in myeloid dendritic cells from lupus-prone mice precedes disease onset (47.1)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 47.1. http://dx.doi.org/10.4049/jimmunol.186.supp.47.1.
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Abstract Systemic Lupus Erythematosus (SLE) patients over-express Type I Interferon (IFN) responsive genes but the cellular source of this IFN Signature is unclear. We found that ex vivo dendritic cells (DCs) from Sle1,2,3 lupus-prone mice express the IFN Signature. To test if the IFN Signature was intrinsic to DCs, we grew myeloid DCs in vitro from bone marrow in GM-CSF medium (BMDCs), and found that IFN responsive genes, analyzed by real-time RT-PCR, are constitutively over-expressed in Sle1,2,3 BMDCs as compared to non-autoimmune C57BL/6 BMDCs: expression of IFN-b, signaling molecules IRF-7, STAT1 and STAT2, and IFN responsive genes ISG-15, IL-15, Oas-3 and Mx1, was significantly higher in lupus BMDCs than in C57BL/6 BMDCs in absence of any stimulation. The IFN Signature was similar in BMDCs from mice negative for autoAbs and from mice with high autoAb titers, suggesting that the IFN Signature precedes disease onset and is not affected by the autoimmune process. Sle1,2,3 BMDCs were hyper-sensitive to nucleic acids CpGs and R848, confirming a role for TLR7 and TLR9 in lupus pathogenesis. However, treatment with oligonucleotide sequences inhibitory for TLR7/TLR9 did not suppress the constitutive over-expression of IFN responsive genes, indicating that DC IFN Signature is independent from chronic exposure to TLR7/9 ligands. We suggest that myeloid DCs are a source of IFN Signature in Sle1,2,3 mice and have an intrinsic dysregulation in the IFN signaling/response.
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Avdeeva, A. S., E. V. Tchetina, M. V. Cherkasova, G. A. Markova, A. S. Artyuhov, E. B. Dashinimaev, and E. L. Nasonov. "The expression of interferon-stimulated genes (interferon “signature”) in patients with rheumatoid arthritis (Preliminary results)." Rheumatology Science and Practice 58, no. 6 (January 14, 2021): 673–77. http://dx.doi.org/10.47360/1995-4484-2020-673-677.
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Khan, Sabbir, Rajasekaran Mahalingam, Shayak Sen, Kaitlin Gandy, Kristin Alfaro-Munoz, Nazanin Majd, Veerakumar Balasubramaniyan, and John DeGroot. "STEM-24. INTERFERON SIGNALING REGULATES THE PROLIFERATION AND MESENCHYMAL PHENOTYPE OF GLIOBLASTOMA STEM CELLS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi26. http://dx.doi.org/10.1093/neuonc/noab196.098.
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Abstract Interferon (IFN) signaling contributes to stemness, cell proliferation, cell death, and cytokine signaling in cancer and immune cells; however, the role of IFN signaling in glioblastoma (GBM) and GBM stem-like cells (GSCs) is unclear. This study aimed to investigate the cancer cell-intrinsic IFN signaling in tumorigenesis and malignant phenotype of GBM. We characterized cell-intrinsic IFN signaling in The Cancer Genome Atlas, patient-derived cohorts of GSCs, and published single-cell RNA sequencing datasets by in-silico analyses. The in-silico findings were further validated by evaluating the cytokine secretion and using pharmacological activators and blockers of IFN/transducer and activator of transcription 1 (STAT1) signaling. We found that GSCs and GBM tumors exhibited differential cell-intrinsic IFN signaling, and high IFN/STAT1 signaling is associated with mesenchymal phenotype and poor survival outcomes. Ruxolitinib, a pharmacological inhibitor of IFN/STAT1, abolished the IFN/STAT1 signaling in GSCs with intrinsically high IFN signaling. IFN-γ treatment for 1 week promotes the mesenchymal phenotype in GSCs with low IFN signature. In addition, chronic inhibition of IFN/STAT1 signaling with ruxolitinib decreased cell proliferation and mesenchymal signatures (CD44, YKL40, and TIMP1) in GSCs with intrinsically active IFN/STAT1 signaling. Publicly available human glioma single-cell RNA-seq (scRNA-seq) datasets analyses showed that both tumor and nontumor cells expressed IFN signaling genes, and the mesenchymal signature was highly expressed in the same cluster where IFN signaling genes were upregulated. We demonstrated that cell-intrinsic IFN signaling in GSCs and GBM tumors is associated with mesenchymal signatures and cell proliferation. Our study provides evidence for the possibility of targeting IFN signaling in a specific group of GBM patients.
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Gillezeau, Christina, Naimisha Movva, Maaike van Gerwen, Karma Rabon-Stith, Norah Shire, Philip Zachary Brohawn, Emanuela Taioli, and Jon Fryzek. "Interferon gamma expression and mortality in unselected cohorts of urothelial bladder cancer patients." PLOS ONE 17, no. 8 (August 30, 2022): e0271339. http://dx.doi.org/10.1371/journal.pone.0271339.
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Background The role of interferon gamma (IFN-γ) expression in long-term survival has not been studied in patients with urinary bladder cancer (UBC). IFN-γ expression was characterized among various UBC patient cohorts to assess if IFN-γ status is associated with overall survival (OS). Methods A tumor-based IFN-γ gene signature was evaluated among adult UBC patients newly diagnosed between 2004 and 2017 from two hospital systems in New York. Patient cohorts included metastatic (stage IV or progressing to stage IV [MBC]), muscle-invasive (stages T2a to T4a [MIBC]), and non–muscle-invasive (carcinoma in situ or stages 0a, 0is, and I [NMIBC]) disease. Descriptive analyses were conducted comparing IFN-γ signature in the highest tertile to those in the lowest two tertiles. Results 234 patients with bladder cancer were evaluated (56 MBC, 38 MIBC, and 140 NMIBC). Median OS was only reached in the MIBC cohort for those with an IFN-γ signature in the lowest two tertiles (15.03 months [95% CI, 8.50–50.60]). Those with an IFN-γ signature in the highest tertile had a decreased risk of mortality in all cohorts indicating better survival, but this was statistically significant in only the MIBC cohort (adjusted HR = 0.09 [95% CI, 0.01–0.73]). Conclusion IFN-γ signature status was associated with a decreased mortality risk in all cohorts, particularly MIBC, indicating that it may be a prognostic marker of survival in patients with UBC.
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Mattson, Lina, Antonio Lentini, Danuta R. Gawel, Tejaswi V. S. Badam, Mikael Benson, Torbjorn Ledin, Colm E. Nestor, et al. "Potential Involvement of Type I Interferon Signaling in Immunotherapy in Seasonal Allergic Rhinitis." Journal of Immunology Research 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/5153184.
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Specific immunotherapy (SIT) reverses the symptoms of seasonal allergic rhinitis (SAR) in most patients. Recent studies report type I interferons shifting the balance between type I T helper cell (Th1) and type II T helper cells (Th2) towards Th2 dominance by inhibiting the differentiation of naive T cells into Th1 cells. As SIT is thought to cause a shift towards Th1 dominance, we hypothesized that SIT would alter interferon type I signaling. To test this, allergen and diluent challenged CD4+ T cells from healthy controls and patients from different time points were analyzed. The initial experiments focused on signature genes of the pathway and found complex changes following immunotherapy, which were consistent with our hypothesis. As interferon signaling involves multiple genes, expression profiling studies were performed, showing altered expression of the pathway. These findings require validation in a larger group of patients in further studies.
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Tsao, Y. P., F. Y. Tseng, C. W. Chao, M. H. Chen, and S. T. Chen. "OP0045 NLRP12 INVOLVES IN THE LUPUS WITH POSITIVE INTERFERON SIGNATURE." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 23.2–24. http://dx.doi.org/10.1136/annrheumdis-2021-eular.4215.
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Background:Systemic lupus erythematous (SLE) is a systemic autoimmune disease with diverse etiological factors. It was recognized that interferon (IFN) signature involved in the progress of SLE. NLRP12 (NOD-like receptor family (NLR) pyrin domain containing 12) is a pyrin containing NLR protein that we had linked its new biological function to the cross-regulation of Toll like receptor (TLRs) and Rig-I like receptor (RIG-I) pathways. NLPR12 acts as an innate immune check-point in regulating type I IFNs expression during TLRs and RIG-I activation. The importance of NLRP12 in lupus disease activity remained to be elucidated.Objectives:To clarify the role of NLRP12 in regulating the interferon signature.Methods:Peripheral blood mononuclear cells (PBMCs) were collected from SLE patients and healthy donors for analysis of NLRP12 and IFN-α gene expression by RT-QPCR. PBMCs were applied for Chromatin immuneprecipitation (ChIP) assay and electrical mobility shift assay (EMSA) to determine the putative transcription factor that regulates NLRP12 expression. An involvement of epigenetic regulation of NLRP12 expression in SLE patients was also analyzed. Bone marrow derived dendritic cells (BMDCs) were collected from wild type mouse and Nlrp12 knocked-out mice. Another CD14+ monocytes were isolated from 10 cases of lupus patients and 8 cases of healthy control, following by stimulating different type of nucleic acids, and IFN-α and IL-6 were measured with ELISA assay. CD14+ monocytes in lupus patients were also pre-treated with IFNAR2 antibody for further nucleic acid stimulation. Two mice models were applied for evaluation the role of Nlrp12: intraperitoneal injection of TMPD (2,6,10,14-tetramethylpentadecane, or pristane) in C57BL/6 mice and Faslpr mice. Both models were conducted with and without Nlrp12 knockout.Results:NLRP12 expression was significantly lower in PBMC isolated from SLE patients compared to healthy donors. The inverse correlation was observed in NLRP12 and IFNA gene expression as well as NLRP12 expression and amount of double-stranded DNA autoantibody in SLE patients. NLRP12 expression showed negative correlations with IFN-α treatment, as well as herpes simplex virus-1 (HSV-1) infection. Results from ChIP and EMSA analysis indicated a potential transcription factor 1 (TF-1) regulating NLRP12 promoter activity. TF-1 lead to transcriptional suppression of NLRP12 in SLE PBMC, and it was gradually induced after IFN treatment. Recruitment of TF-1 to NLRP12 promoter in SLE PBMC compared to the healthy PBMC was detected, and increased when treating with IFN. Human CD14+ monocytes collected from lupus and healthy control stimulating with different type of nucleic acids revealing significant increasing level of IFN-α and IL-6 in lupus patients. Among animal models, both pristine induced mice and Faslpr mice revealed increasing autoantibodies production and severity of glomerulonephritis in Nlrp12-/- group in comparison with Nlrp12+/+ ones, indicating the role of NLRP12 in maintaining positive interferon signature as well as disease activity.Conclusion:Expression level of NLRP1.2 has been demonstrated to be a biomarker of disease activity in SLE patients. The NLRP12 was involved in the interferon signature, which was also negatively regulated by TF-1. Both clinical samples and animal models revealed NLRP12 in maintaining the positive interferon signature, indicating the possible role of exacerbating factor for lupus disease activity.Disclosure of Interests:None declared
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Tong, Run, Lin Feng, Lei Zhang, Jianzhi Zhang, Yousheng Mao, Kaitai Zhang, Yanning Gao, Guiqi Wang, and Shujun Cheng. "Decreased Interferon Alpha/Beta Signature Associated with Human Lung Tumorigenesis." Journal of Interferon & Cytokine Research 35, no. 12 (December 2015): 963–68. http://dx.doi.org/10.1089/jir.2015.0061.
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Bienkowska, Jadwiga, Norm Allaire, Alice Thai, Jaya Goyal, Tatiana Plavina, Ajay Nirula, Megan Weaver, et al. "Lymphotoxin-LIGHT Pathway Regulates the Interferon Signature in Rheumatoid Arthritis." PLoS ONE 9, no. 11 (November 18, 2014): e112545. http://dx.doi.org/10.1371/journal.pone.0112545.
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Uruha, A., Y. Allenbach, J. Charuel, L. Musset, A. Aussy, O. Boyer, K. Mariampillai, et al. "Type 1 interferon signature as a diagnostic marker of dermatomyositis." Neuromuscular Disorders 27 (October 2017): S152—S153. http://dx.doi.org/10.1016/j.nmd.2017.06.216.
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Uruha, A., Y. Allenbach, J. L. Charuel, L. Musset, A. Aussy, O. Boyer, K. Mariampillai, et al. "Type 1 interferon signature as a diagnostic marker of dermatomyositis." Journal of the Neurological Sciences 381 (October 2017): 1082. http://dx.doi.org/10.1016/j.jns.2017.08.3053.
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Kamiyama, Reikou, Ryusuke Yoshimi, Mitsuhiro Takeno, Yasuhiro Iribe, Toshinori Tsukahara, Daiga Kishimoto, Yosuke Kunishita, et al. "Dysfunction of TRIM21 in interferon signature of systemic lupus erythematosus." Modern Rheumatology 28, no. 6 (February 23, 2018): 993–1003. http://dx.doi.org/10.1080/14397595.2018.1436028.
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Nocturne, Gaetane, and Xavier Mariette. "Interferon signature in systemic autoimmune diseases: what does it mean?" RMD Open 8, no. 2 (December 2022): e002687. http://dx.doi.org/10.1136/rmdopen-2022-002687.
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Buie, Joy, and James Oates. "Interferon alpha deregulates endothelial nitric oxide synthase (P4085)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 127.14. http://dx.doi.org/10.4049/jimmunol.190.supp.127.14.
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Abstract Background: Recent in vitro studies suggest that Type I interferons promote endothelial progenitor cell dysfunction and apoptosis while others have shown that Type I interferon gene signature correlates with increased endothelial dysfunction in systemic lupus erythematosus patients. Although causes of ED are likely multifactorial, all pathways converge on the diminished activity of endothelial nitric oxide synthase. We examined the effects of IFN-alpha on eNOS gene expression, phosphorylation, and NO production. Methods: Changes in eNOS expression in response to IFN-a (100, 1000 IU) were quantified by real-time PCR. Functional changes in response to vascular endothelial growth factor were assessed by immunoblot. We also evaluated the effect of serum from patients that induce a type I IFN signature from 5 patients and 2 controls on eNOS expression and VEGF mediated function. Gene expression with PCR and phosphorylated serine 1177 eNOS expression with immunoblot were assessed . Type I IFN neutralization studies (IFN-a Ab, IFNAR Ab) were also performed and eNOS expression was assessed. Results: HUVECs treated with IFN-a at 100IU and 1000IU exhibited a significant reduction in eNOS gene expression, VEGF induced phosphorylation at the serine 1177 site after 24 hours, and NO production. SLE serum also caused a reduction in eNOS gene and phosphorylated eNOS protein expression. Moreover, addition of neutralizing antibodies partially reversed observed affects on eNOS gene changes.
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Haberman Ziv, Y., N. Loberman-Nachum, S. Katya, A. Di Segni, G. Efroni, T. Braun, M. BenShoshan, et al. "OP06 Comparison between Crohn and coeliac diseases small intestine transcriptomics and microbial data define similarities and divergent pathways linked to pathogenesis." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S006. http://dx.doi.org/10.1093/ecco-jcc/jjz203.005.
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Abstract Background Crohn disease and coeliac disease are two inflammatory conditions known to cause small intestine inflammation. Using high throughput transcriptomics, microbial, and bioinformatics approaches we aimed to capture differences and similarities linked to the pathogenesis and to future potential interventions for those chronic manifestations. Methods We performed high throughput transcriptomics and 16S microbial characterisation of 55 paediatric new-onset coeliac patients and controls using clinical pathology specimens, and compared those signatures to our previously reported 248 RISK Crohn’s disease newly diagnosed cohort. ToppGene/ToppCluster and ClueGO platforms were used for functional annotation enrichment analyses, and MaAsLin for microbial differential abundance. Results A substantial number (>90%) of genes passed the expression filtering criteria in both studies enabling the comparison. Of the 354 coeliac down-regulated genes, 59% (209/354) overlapped with the reduced Crohn signature. Shared reduced signatures and functions included a decrease in epithelial lipid metabolism, oxidoreductase activity, and brush border transport signatures. In contrast, a significantly smaller proportion [19% (97/427, Chi-squares p < 0.001] of the coeliac disease 524 up-regulated genes overlapped with the induced Crohn disease signature. We noted shared enriched signatures for adaptive immune-related pathways and interferon-γ in both coeliac and Crohn diseases. However, the Crohn disease signature exhibited more specific enrichments for signatures associated with innate immune pathways and with a strong signal for granulocytes, an extracellular matrix signature, and CXCR chemokines signalling, while the coeliac up-regulated signature showed unique enrichment for cell cycle and mitosis. As opposed to the robust dysbiosis previously characterised in Crohn disease, we were only able to identify significant enrichment for Bacteroidetes taxa in coeliac patients in comparison to controls. Conclusion We highlight important biologic differences between Crohn and coeliac diseases emphasising an intensified innate granulocytes activation signature in Crohn disease and a specific epithelial proliferative signal in coeliac disease. Unlike the robust dysbiosis linked to Crohn disease, the coeliac patient showed only modest enrichment for several Bacteroidetes taxa in comparison to controls. It is possible that microbial alteration in Crohn disease triggers granulocytes activation, and that this signal inhibits epithelial proliferation/renewal, eventually leading the epithelial damage seen in Crohn but not coeliac disease. Inhibiting innate immune activation or reverting Crohn dysbiosis may be a beneficial future therapy for Crohn disease.
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Huard, C., S. V. Gullà, D. V. Bennett, A. J. Coyle, R. A. Vleugels, and S. A. Greenberg. "Correlation of cutaneous disease activity with type 1 interferon gene signature and interferon β in dermatomyositis." British Journal of Dermatology 176, no. 5 (March 14, 2017): 1224–30. http://dx.doi.org/10.1111/bjd.15006.
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Avdeeva, A., E. Tchetina, G. Markova, and E. Nasonov. "POS0611 THE EFFECT OF RITUXIMAB BIOSIMILAR THERAPY ON THE EXPRESSION OF INTERFERON-STIMULATED GENES (“INTERFERON SIGNATURE”) IN PATIENTS WITH RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 542.2–542. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1551.
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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