scholarly journals An internal deletion of ADAR rescued by MAVS deficiency leads to a minute phenotype

2020 ◽  
Vol 48 (6) ◽  
pp. 3286-3303 ◽  
Author(s):  
Prajakta Bajad ◽  
Florian Ebner ◽  
Fabian Amman ◽  
Brigitta Szabó ◽  
Utkarsh Kapoor ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Innate Immunity ◽  
Expression Profiling ◽  
Growth Defect ◽  
Internal Deletion ◽  
Multiple Functions ◽  
Independent Functions ◽  
Immunity Genes ◽  
Mouse Genetic

Abstract The RNA-editing protein ADAR is essential for early development in the mouse. Genetic evidence suggests that A to I editing marks endogenous RNAs as ‘self’. Today, different Adar knockout alleles have been generated that show a common phenotype of apoptosis, liver disintegration, elevated immune response and lethality at E12.5. All the Adar knockout alleles can be rescued by a concomitant deletion of the innate immunity genes Mavs or Ifih1 (MDA5), albeit to different extents. This suggests multiple functions of ADAR. We analyze AdarΔ7-9 mice that show a unique growth defect phenotype when rescued by Mavs. We show that AdarΔ7-9 can form a truncated, unstable, editing deficient protein that is mislocalized. Histological and hematologic analysis of these mice indicate multiple tissue- and hematopoietic defects. Gene expression profiling shows dysregulation of Rps3a1 and Rps3a3 in rescued AdarΔ7-9. Consistently, a distortion in 40S and 60S ribosome ratios is observed in liver cells. This dysregulation is also seen in AdarΔ2-13; Mavs−/− but not in AdarE861A/E861A; Ifih1−/− mice, suggesting editing-independent functions of ADAR in regulating expression levels of Rps3a1 and Rps3a3. In conclusion, our study demonstrates the importance of ADAR in post-natal development which cannot be compensated by ADARB1.

TLR2-mediated innate immune priming boosts lung anti-viral immunity

2020 ◽  
pp. 2001584
Author(s):  
Jason Girkin ◽  
Su-Ling Loo ◽  
Camille Esneau ◽  
Steven Maltby ◽  
Francesca Mercuri ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Innate Immunity ◽  
Viral Load ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Immune Cell ◽  
Innate Immune ◽  
Immune Priming ◽  
Tlr2 Activation

Research questionAssessment of whether TLR2 activation boosts the innate immune response to rhinovirus infection, as a treatment strategy for virus-induced respiratory diseases.MethodsWe employed treatment with a novel TLR2 agonist (INNA-X) prior to rhinovirus infection in mice, and INNA-X treatment in differentiated human bronchial epithelial cells derived from asthmatic-donors. We assessed viral load, immune cell recruitment, cytokines, type I and III IFN production, as well as the lung tissue and epithelial cell immune transcriptome.ResultsWe show in vivo, that a single INNA-X treatment induced innate immune priming characterised by low-level IFN-λ, Fas ligand, chemokine expression and airway lymphocyte recruitment. Treatment 7-days before infection significantly reduced lung viral load, increased IFN-β/λ expression and inhibited neutrophilic inflammation. Corticosteroid treatment enhanced the anti-inflammatory effects of INNA-X. Treatment 1-day before infection increased expression of 190 lung tissue immune genes. This tissue gene expression signature was absent with INNA-X treatment 7-days before infection, suggesting an alternate mechanism, potentially via establishment of immune cell-mediated mucosal innate immunity. In vitro, INNA-X treatment induced a priming response defined by upregulated IFN-λ, chemokine and anti-microbial gene expression that preceded an accelerated response to infection enriched for NF-κB-regulated genes and reduced viral loads, even in epithelial cells derived from asthmatic donors with intrinsic delayed anti-viral immune response.ConclusionAirway epithelial cell TLR2 activation induces prolonged innate immune priming, defined by early NF-κB activation, IFN-λ expression and lymphocyte recruitment. This response enhanced anti-viral innate immunity and reduced virus-induced airway inflammation.

Gene Expression Profiling within the Context of JAK Inhibitor Therapy for Myelofibrosis: Correlation with Treatment Effect and Anemia Response

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1751-1751
Author(s):  
Animesh Pardanani ◽  
Rebecca R. Laborde ◽  
Terra L Lasho ◽  
Christy Finke ◽  
Alexey A. Leontovich ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Trial ◽  
Immune Response ◽  
Gene Expression Profiling ◽  
Pathway Analysis ◽  
Treatment Effect ◽  
Expression Profiling ◽  
Phase 1 ◽  
Hemoglobin Level ◽  
Jak Inhibitors

Abstract Abstract 1751 Background: JAK inhibitors have significant palliative benefit in myelofibrosis (MF), mainly in the form of improved constitutional symptoms and reduced splenomegaly. Preliminary data suggests that CYT387, a JAK-1/2 inhibitor, also has the ability to produce anemia responses (ASH Annual Meeting, 2011). In general, the mechanism(s) underlying treatment effects of JAK inhibitors remain unclear but likely represent a drug-specific balance between anti-clonal activity and modulation of immuno cellular-cytokine pathways. We conducted a gene expression profiling (GEP) study using primary cells from MF patients undergoing therapy with CYT387 followed by correlation with clinical data. Methods: Study subjects were enrolled in the Phase-1/2 study of CYT387 treatment in patients with primary (PMF), post-polycythemia vera (PPMF) or post-essential thrombocythemia (PTMF) myelofibrosis. Paired research samples were collected; the time points were pre-study and 12 weeks after commencing study treatment. PBMCs were purified from whole blood by Ficoll separation; RNA was isolated from this cell fraction for GEP analysis. Gene expression profiles were generated using Illumnia Human HT-12 v4 microarray. Pair wise analysis was conducted using the Wilcoxon signed-rank test with a p-value cutoff of 0.05 to generate lists of differentially expressed genes between assigned groups. Pathway analysis was conducted to identify relevant pathways enriched for differentially expressed genes. Comprehensive plasma cytokine profiling was performed using Multiplex Bead-Based Luminex technology (Invitrogen, Carlsbad, CA). Results: Seventeen patients were studied based on sample availability; 11 (65%) mere male with median age of 66 years (range 53–85). Twelve (71%) were JAK2V617F mutation positive and the DIPSS-plus risk categorization was 10 (59%) high and 7 (41%) intermediate-2. All patients were evaluable for anemia response; 14 (82%) were red cell transfusion dependent at study start. Nine (53%) patients achieved anemia response by IWG-MRT criteria; of these, 8 patients achieved transfusion independence (minimum non-transfused hemoglobin level of 8 g/dL maintained for at least 12 weeks) and 1 had a sustained >2 g/dL increase in hemoglobin level above baseline. The initial pair wise analysis to identify differential patterns of gene expression compared pre- and post-treatment groups (Figure 1A). This revealed a cluster of significantly (p <0.05) down-regulated genes (minimum 2-fold; median 17-fold) following treatment (displayed in green; upper left quadrant). Pathway enrichment analysis revealed significant associations of these genes with cytokine regulation of immune response, cell proliferation, chemotaxis and cytoskeleton remodeling. We then conducted a pair wise analysis of anemia responders versus non-responders; this revealed a predominance of over expressed gene targets (median 35-fold) in the anemia responder group (Figure 1B) (displayed in red; upper right quadrant). Similar pathway analysis identified enrichment for genes involved in immune system function in this cluster. Conclusions: The current preliminary analysis suggests that genes relevant to immune response-cytokine pathways are significantly over expressed in patients who achieve anemia response following CYT387 therapy. This further suggests a dominant immune component that underpins ineffective hematopoiesis in responding patients. On the basis of broad treatment-related changes in gene expression we suggest that an important component of CYT387's treatment effect is down regulation of these dysregulated pathways. Ongoing studies include validation of select gene targets which will be tested prospectively in future treatment protocols, as well as correlation of gene expression with circulating cytokine-chemokine levels. Disclosures: Pardanani: Bristol-Myers Squibb: Clinical trial support, Clinical trial support Other; YM BioSciences: Clinical trial support, Clinical trial support Other; Sanofi-Aventis: Clinical trial support Other. Off Label Use: Data from Phase −1/2 study of CYT387 use in myelofibrosis is mentioned.

scholarly journals Innate immunity-related Gene Expression Profiling Reveals Two Distinct Endotypes in PFAPA Syndrome

2018 ◽  
Vol 141 (2) ◽  
pp. AB118
Author(s):  
Mariko Hara ◽  
Noriko Morimoto ◽  
Kae Fujii ◽  
Sota Yamaguchi ◽  
Mayumi Tsunoda ◽  
...  
Keyword(s):  
Gene Expression ◽  
Innate Immunity ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Related Gene ◽  
Pfapa Syndrome

scholarly journals Specificity and Complexity of the Caenorhabditis elegans Innate Immune Response

2007 ◽  
Vol 27 (15) ◽  
pp. 5544-5553 ◽  
Author(s):  
Scott Alper ◽  
Sandra J. McBride ◽  
Brad Lackford ◽  
Jonathan H. Freedman ◽  
David A. Schwartz
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Caenorhabditis Elegans ◽  
Signaling Pathways ◽  
Large Set ◽  
Immune Signaling ◽  
C Elegans ◽  
Immunity Genes ◽  
Simple Model System ◽  
Overlapping Sets

ABSTRACT In response to infection, Caenorhabditis elegans produces an array of antimicrobial proteins. To understand the C. elegans immune response, we have investigated the regulation of a large, representative sample of candidate antimicrobial genes. We found that all these putative antimicrobial genes are expressed in tissues exposed to the environment, a position from which they can ward off infection. Using RNA interference to inhibit the function of immune signaling pathways in C. elegans, we found that different immune response pathways regulate expression of distinct but overlapping sets of antimicrobial genes. We also show that different bacterial pathogens regulate distinct but overlapping sets of antimicrobial genes. The patterns of genes induced by pathogens do not coincide with any single immune signaling pathway. Thus, even in this simple model system for innate immunity, striking specificity and complexity exist in the immune response. The unique patterns of antimicrobial gene expression observed when C. elegans is exposed to different pathogens or when different immune signaling pathways are perturbed suggest that a large set of yet to be identified pathogen recognition receptors (PRRs) exist in the nematode. These PRRs must interact in a complicated fashion to induce a unique set of antimicrobial genes. We also propose the existence of an “antimicrobial fingerprint,” which will aid in assigning newly identified C. elegans innate immunity genes to known immune signaling pathways.

Epigenetic Silencing of BCL2, ETS1, IL27RA and DICER1 in Low-Risk MDS Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1704-1704
Author(s):  
Mónica del Rey ◽  
Kathleen O'Hagan ◽  
Margaret Dellett ◽  
Sara Aibar ◽  
Hilary A. A. Colyer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Transcription Factor ◽  
Expression Profiling ◽  
Target Genes ◽  
Integrative Analysis ◽  
Low Risk ◽  
Control Group ◽  
Down Regulation ◽  
Interleukin Receptors

Abstract Abstract 1704 Gene expression profiling studies have been performed in MDS to better characterize these diseases. However, the molecular pathogenesis of low-risk MDS is not yet fully understood. Furthermore, the transcriptional activity is dependent on many factors including epigenetic modifications. Therefore the integration of genome-wide epigenetic regulatory marks along with gene expression levels would provide additional information regarding the biological characteristics of low-risk MDS. A total of 83 low-risk MDS patients and 36 age-matched controls were included in the study. A cohort of 18 patients with low-risk MDS and seven controls were included in a simultaneous integrative study of methylation and expression, while the whole series was used as a control group of expression data. Both the RNA and the DNA were isolated from BM mononucleate cells and hybridised with the Human Genome Expression Array (U133 Plus) from Affymetrix and MCAM Array from University Health Network (Canada), respectively. For analysis and interpretation of the hybridisation results, the R/Bioconductor program, DAVID bioinformatic resource, the web-delivered bioinformatics tool set Ingenuity Pathway Analysis and Metacore Analytical Suite were used. The results generated by expression and methylation microarrays were confirmed using Q- PCR and pyrosequencing, respectively. A total of 817 differentially methylated genes were identified as being present in low-risk MDS (p< 0.10); hyper-methylated genes (n=457) were more frequent than hypo-methylated genes (n=360). In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hyper-methylated genes were under-expressed in low-risk MDS cases. The most represented categories were regulation of apoptosis, gene expression, immune response and RNA process. BCL2, ETS1, IL27RA and DICER1, all of them hyper-methylated and down-expressed, were the most significant genes related to these functions. 1. Regarding apoptosis and BCL2, an over-expression of BCL2L11 and MYC were found in low-risk MDS. In contrast, BAX and CUX1 were under-expressed with respect to the control group. In addition, SYK gene was also hyper-methylated and under-expressed. 2. Promoter region analysis demonstrated that ETS1 transcription factor was involved in the regulation of 83 target genes included in the down-regulation signature of the low-risk MDS patients. The most significant functions of these target genes revealed that the cell-to-cell signaling and interaction pathway were prominently affected. In addition, apoptosis was identified as the function with the most number of down-regulated target genes. Therefore, the overall apoptosis pathway could be affected in low-risk MDS patients in two ways: methylation and decreased expression of BCL2 with the deregulation of related genes, as well as methylation and decreased expression of the ETS1 transcription factor with the deregulation of the apoptosis-related targets. 3. Regarding immune response, the study showed that besides IL27RA, another nine interleukins and interleukin receptors were under-expressed in the same cohort of patients: IL16, IL32, IL1RAP, IL2RB, IL6R, IL7R, IL10RA, IL10RB and IL13RA1. Three of them (IL16, IL1RAP and IL10RB) had direct genetic interactions with IL27RA. 4. Finally, the identification of DICER1 as a gene significantly altered by methylation and expression in low-risk MDS prompted us to measure the 183 miRNAs expression. A general down-regulation of miRNAs was observed in low-risk MDS cases respect to the control group (p=0.039). Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could play a central role in these diseases. Furthermore, we highlight candidate DNA methylation changes associated with low-risk MDS patients. Disclosures: No relevant conflicts of interest to declare.

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