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Shabman, Reed Solomon Heise Mark T. "Alphavirus evasion of type I interferons." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,1879.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2008.<br>Title from electronic title page (viewed Dec. 11, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Microbiology and Immunology." Discipline: Microbiology and Immunology; Department/School: Medicine.
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Ching, Yee-Man. "Regulation of type 2 inflammation by type I interferons." Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/43755.
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Rhinovirus-induced asthma exacerbations are a major cause of morbidity and mortality in patients. Experimental clinical infection studies indicate rhinovirus augments type 2 inflammation in asthma. Additionally, asthmatic lung cells have impaired type I interferon production in response to rhinovirus stimulation. Evidence suggests co-regulation of type I interferon signalling and type 2 immunity exists; therefore, we hypothesised that type I interferon deficiency in asthma leads to the reduced regulation of type 2 immunity, resulting in exacerbation of allergen-induced type 2 inflammation during rhinovirus infection. To investigate the role of type I interferon signalling, type I interferon receptor (IFNAR1) knockout mice, an anti-IFNAR1 blocking antibody and recombinant interferon-β therapy were used in mouse models of rhinovirus-induced airways disease. Impaired IFNAR1 signalling resulted in enhanced eosinophilic inflammation in response to allergen challenge and rhinovirus infection, which was associated with increased CCL24 and Th2 chemokines CCL17 and CCL22. Recombinant interferon-β treatment had limited effects on responses to the combination of allergen and rhinovirus, but suppressed allergen-induced CCL17. In THP1-derived macrophages, interferon-β co-treatment and pre-treatment suppressed IL-4 and TNFα-induced Th2 chemokine production. Microarray analysis was performed on these cells to help identify the regulatory mechanism of type I interferon on Th2 chemokine expression. Interferon-β pre-treatment significantly upregulated PTPN6 (encoding SHP1, a phosphatase that regulates STAT6 activity) expression compared with IL-4 and TNFα-stimulated cells. Western blot analysis did not identify differences in STAT6 phosphorylation following interferon-β treatment, or differences in SHP1 protein levels. These findings support a role for type I interferon in the negative regulation of type 2 inflammation in both the presence and absence of rhinovirus; however, this mechanism has yet to be identified. Impaired interferon responses in asthma may contribute to enhanced type 2 immunity that is considered pathological in allergic airways inflammation and virus-induced asthma exacerbations.
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Platis, Dimitris. "Structure/function analysis of Type I interferons." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.397783.
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Cooles, Faye Anisa Hogarth. "Type 1 interferons in early rheumatoid arthritis." Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3733.
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Rheumatoid arthritis (RA) is a heterogeneous autoimmune disease predominantly causing synovial inflammation. Early and established RA exhibit both overlapping and distinct pathological processes. Early treatment improves clinical outcomes and delineating early disease pathology can inform novel therapeutic pathways. Type 1 interferons have diverse effects on immune function and relative exposure can be recorded using an interferon gene signature (IGS). The IGS is positive in 20-30% of established RA patients where it does not associate with disease activity but can predict response to some biological therapies. However, glucocorticoids and potentially other immunomodulatory therapies can modify the IGS. I therefore examined the IGS in early, drug naïve RA focusing on prevalence, association with clinical phenotype, and impact on disease progression. I additionally attempted to identify the source of type 1 interferons and triggers for their production. I demonstrated the IGS is increased in early RA, falls with treatment/time and appears to predict clinical response to initial therapies. In this latter capacity it out-performed baseline CRP, ESR and DAS-28. The IGS also positively associated with disease activity and IgM rheumatoid factor titres. The latter association was supported by an analysis of the B cell transcriptome of IGS+ early RA patients, where there was increased gene expression in pathways related to B cell activation; increased plasma cell differentiation; and propensity to produce IgM. Genes were also upregulated that are usually expressed in B cell malignancies, further emphasising a potentially pathologically activated state. Retroelements (SINE, LINE-1 and ERV), are putative triggers of type 1 interferons in autoimmunity. However early RA whole blood LINE-1 activity was comparable to healthy controls and was actually reduced in IGS+ patients. Furthermore pDCs showed uniformly reduced retroelement activity in early RA compared with healthy controls. Indeed there was differential retroelement expression across lymphocyte subsets in early RA; expression was highest in B and T cells and comparatively lower in DCs and monocytes. Finally despite being a major source of type 1 interferons, pDCs in IGS+ early RA patients had comparable interferon-α expression to other lymphocytes. In conclusion I demonstrate that type 1 interferons may play a pathogenic role in early RA and disease progression - although their source and triggers remain unclear. Nonetheless I hypothesise that therapies that target type 1 interferons could have clinical benefit in early RA.
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Hidmark, Åsa. "Induction of type I interferons and viral immunity /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-227-9/.
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Wahlund, Casper. "Detection And Quantification Of Equine Type I Interferons." Thesis, Uppsala universitet, Medicinska fakulteten, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-159198.
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Type I interferons (IFNs), perhaps the most important of cytokines in fighting viral infections, have been target for detailed research only the past few decades and much is yet to be investigated. Hidden in the mysteries of IFNs might be powerful anti-viral and anti-tumor therapies, alongside greatly increased understanding of vertebrate immunology. This project aims at investigating IFN expression of in vitro stimulated equine cell lines and studies of IFN expression in horses, both healthy and a number of horses diagnosed with inflammatory bowel disease (IBD). Amongst equine diseases, IBD is of increasing concern and scientific progressions within the project are, in several aspects, also applicable for human medicine.
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SPOSITO, BENEDETTA. "Type III Interferons: Running Interference with Mucosal Repair." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2023. https://hdl.handle.net/10281/402377.
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Gli interferoni (IFN) sono mediatori e regolatori fondamentali della risposta immunitaria dell'ospite a virus e ad altri agenti microbici. Gli IFN di tipo I e di tipo III (o IFN-λ) sono tra le prime citochine ad essere indotte in seguito a infezioni virali. Il legame tra gli IFN e i rispettivi recettori attiva vie di trasduzione del segnale simili tra loro che inducono l'espressione di geni stimolati dagli IFN (ISG) con funzioni antivirali. La caratteristica principale che rende ciascuna di queste famiglie di IFN unica e non ridondante è l'esistenza di recettori distinti che fanno sì che gli IFN-I attivino una risposta ubiquitaria e che gli IFN-III agiscano esclusivamente sulle cellule epiteliali e su un sottoinsieme di cellule immunitarie. Ulteriori distinzioni riguardano la natura meno infiammatoria degli IFN-III e la loro induzione solitamente anticipata rispetto a quella degli IFN-I. Pertanto gli IFN-III sono considerati i difensori di prima linea delle mucose con la capacità di attivare una risposta antivirale precoce senza causare danno tissutale. Se la loro azione risulta insufficiente a contenere l’infezione, il sistema passa all’induzione degli IFN-I, i quali generano una risposta antivirale e infiammatoria più potente e a livello sistemico, che tuttavia può portare ad immunopatologia. Nel corso della mia tesi ho verificato l'ipotesi secondo cui anche gli IFN-III possano causare immunopatologia, in particolare durante infezioni virali delle vie respiratorie e in contesti di danno all’epitelio gastrointestinale in malattie infiammatorie croniche intestinali e lesioni da radiazioni.
In primo luogo, io e i miei colleghi abbiamo dimostrato che in un polmone in cui è stata indotta una risposta antivirale, gli IFN-III prodotti dalle cellule dendritiche inibiscono la proliferazione delle cellule epiteliali portando ad una compromissione del rigenerazione della barriera e ad un aumento della suscettibilità ad infezioni batteriche. In seguito abbiamo analizzato la produzione di IFN lungo il tratto respiratorio di pazienti affetti da COVID-19. Abbiamo trovato che, nelle alte vie aeree, l'espressione di IFN-I/III correla con la carica virale e che negli anziani, che presentano un maggiore rischio di sviluppare una patologia severa, questa correlazione è più debole o assente. Una forte espressione di IFN-λ1, IFN-λ3 e ISG caratterizza le alte vie aeree di pazienti con sintomatologia lieve, mentre risultano fortemente espressi gli IFN-I, IFN-λ2 e un insieme di geni antiproliferativi e proapoptotici lungo tutto il tratto respiratorio di pazienti ospedalizzati, suggerendo che possano ostacolare il processo di riparazione dell’epitelio. Infine, abbiamo dimostrato che gli IFN-III ritardano la rigenerazione dell'intestino tenue e del colon in seguito a danno da radiazioni o da colite indotta da destrano sodio solfato, poiché contribuiscono a indurre la morte cellulare delle cellule epiteliali tramite la formazione di un complesso proteico costituito da Z-DNA binding protein (ZBP1) e gasdermin C (GSDMC).
I nostri risultati mettono in discussione il ruolo degli IFN-III come protettori delle mucose poiché indicano che quando non propriamente regolati possono causare immunopatologia. Queste evidenze portano alla necessità di progettare l’uso clinico degli IFN di tipo III in modo da evitare le loro funzioni dannose per i tessuti e massimizzarne gli effetti benefici.<br>Interferons (IFNs) are fundamental mediators and regulators of the host immune response to viruses and other microbial agents. Type I and type III IFNs (also known as IFN-λ) are some of the first cytokines to be induced upon detection of viral infections. Signaling through their specific receptors leads to the activation of a similar signaling cascade that triggers the expression of a common set of IFN-stimulated genes (ISGs) with antiviral effector functions. The main feature that makes each of these families of IFNs unique and nonredundant is the existence of distinct receptors that differentiate them in their ability to act on virtually every cell type (type I IFNs) or exclusively on epithelial cells and a subset of immune cells (type III IFNs). Despite inducing a widely overlapping set of genes, IFN-I can mount a stronger proinflammatory response compared to IFN-III. This, coupled with the earlier induction of IFN-III upon infection, has led to the classification of IFN-III as front-line defenders of mucosal surfaces with the ability to initiate an early antiviral response with minimal tissue-damaging effects. If their response is insufficient the system shifts to the more potent and broader-acting antiviral and inflammatory IFN-I response that can cause immunopathology. In the course of my thesis, I have tested the hypothesis that also IFN-III contribute to immunopathology at barrier sites such as the respiratory and gastrointestinal epithelia during viral infections and inflammatory bowel disease/radiation-induced injury respectively.
First, my colleagues and I found that in a mouse model where we mimicked the induction of antiviral responses in the respiratory tract, IFN-III produced by lung dendritic cells inhibited the proliferation of lung epithelial cells leading to an impairment in barrier restoration and an increase in susceptibility to bacterial infections. Then we measured IFN responses along the respiratory tract of COVID-19 patients. We uncovered that in the upper airways expression of IFN-I/III correlated with viral load and elderly patients, that have a higher risk of developing severe COVID-19, had a dysregulation in the IFN response. A strong expression of IFN-λ1, IFN-λ3 and ISGs characterized the upper airways of mild patients. IFN-I and IFN-λ2 together with antiproliferative and proapoptotic genes were upregulated along all the respiratory tract of severe COVID-19 patients, suggesting that they might contribute to the impairment of epithelium restitution. Finally, we demonstrated that IFN-III delayed colon and small intestine repair after dextran sulfate sodium-induced colitis and radiation-induced injury by triggering cell death of epithelial cells via the formation of a novel protein complex that includes Z-DNA binding protein (ZBP1) and gasdermin C (GSDMC).
Our findings challenge the role of IFN-III as protectors of mucosal barriers as they indicate that a dysregulated IFN-III response holds the potential to contribute to immunopathology. Therefore, the clinical use of type III IFNs should be designed in such a way that their tissue-damaging functions are avoided and their beneficial effects are maximized.
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Goritzka, Michelle. "Regulation of virus induced inflammation by type I interferons." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/49786.
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Type I interferons (IFNs) are the first line of defence against viral pathogens. They play a crucial role in activating antiviral responses to limit viral replication and viral spread. Human respiratory syncytial virus (RSV) can cause severe lung inflammation and this has been associated with polymorphisms in several innate immune response genes, including many that control the IFN system. In order to elucidate the importance of type I IFNs in regulating local inflammatory responses in the lung, their role in pulmonary immune responses to RSV infection was assessed in mice lacking the type I IFN receptor (Ifnar1-/-). Levels of proinflammatory cytokines and chemokines were markedly reduced during RSV infection. Similar results were obtained when in Ifnar1-/- mice were challenged with non-infectious innate stimuli such as Toll-like receptor agonists. It was further shown that the administration of recombinant IFN-α together with innate stimuli was sufficient to potentiate the proinflammatory cytokine production. Exploiting a reporter mouse strain expressing GFP under the control of the Ifna6 promoter, alveolar macrophages (AMs) were identified as the predominant source of type I IFNs during RSV infection. This type I IFN production solely relied on signalling through the cytosolic RIG-I-like receptors (RLRs), as AMs lacking MAVS, the adaptor downstream of RLRs, were unable to produce type I IFNs. Furthermore, Mavs-/- mice showed compromised production of proinflammatory cytokines and chemokines, and as a consequence had an increased viral burden and RSV-induced pathology. Interestingly, Mavs-/- mice had a marked deficiency in the production of monocyte chemoattractants and recruitment of inflammatory monocytes (infMo). The administration of recombinant CCL2 during RSV infection permitted monocyte recruitment into the lung of Mavs-/- mice and mediated an unexpected antiviral activity and reduced disease severity. This work emphasises a role for type I IFNs in antiviral immune responses by driving early proinflammatory cytokine responses and recruitment of antiviral monocytes, a yet underappreciated novel cell type responsible for dampening RSV-disease burden in vivo.
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Wang, Ling, and Shunbin Ning. ""Toll-Free" Pathways for Production of Type I Interferons." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/6540.
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Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) are recognized by different cellular pathogen recognition receptors (PRRs), which are expressed on cell membrane or in the cytoplasm of cells of the innate immune system. Nucleic acids derived from pathogens or from certain cellular conditions represent a large category of PAMPs/DAMPs that trigger production of type I interferons (IFN-I) in addition to pro-inflammatory cytokines, by specifically binding to intracellular Toll-like receptors or cytosolic receptors. These cytosolic receptors, which are not related to TLRs and we call them "Toll-free" receptors, include the RNA-sensing RIG-I like receptors (RLRs), the DNA-sensing HIN200 family, and cGAS, amongst others. Viruses have evolved myriad strategies to evoke both host cellular and viral factors to evade IFN-I-mediated innate immune responses, to facilitate their infection, replication, and establishment of latency. This review outlines these "Toll-free" innate immune pathways and recent updates on their regulation, with focus on cellular and viral factors with enzyme activities.
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Koppe, Uwe Moritz Eberhard. "Role of type I interferons in Streptococcus pneumoniae pneumonia." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2012. http://dx.doi.org/10.18452/16532.
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Streptococcus pneumoniae ist die häufigste Ursache für ambulant erworbene Pneumonien weltweit. Daher müssen die Wirts-Pathogen-Interaktionen erforscht werden, um neue Therapiestrategien zu entwickeln. In dieser Studie habe ich 1. den Typ I Interferon (IFN)-stimulierenden Signalweg des angeborenen Immunsystems in Pneumokokken-infizierten Wirtszellen sowie 2. dessen Bedeutung in der Pneumokokkenpneumonie untersucht. Humane und murine Makrophagen, aber nicht alveolare Epithelzellen, produzierten Typ I IFNs nach Infektion mit S. pneumoniae. Dieses war abhängig vom Virulenzfaktor Pneumolysin und erforderte sowohl die Phagozytose der Bakterien als auch die Ansäuerung der Endosomen. Die Induktion der Typ I IFNs wird durch einen zytosolischen Signalweg vermittelt, welcher wahrscheinlich DNA erkennt und sowohl das Adapterprotein STING als auch den Transkriptionsfaktor IRF3 aktiviert. Typ I IFNs, welche von infizierten Makrophagen gebildet wurden, regulierten die Expression von IFN-stimulierten Genen (ISGs) und Chemokinen in Makrophagen und co-kultivierten alveolaren Epithelzellen in vitro und in Mauslungen in vivo. In einem murinen Pneumoniemodell hatten die Typ I IFNs jedoch einen negativen Effekt für den Wirt. Mäuse mit einem Defekt im Typ I IFN-Rezeptor oder mit einem Knockout im Typ I und Typ II IFN-Rezeptor hatten eine signifikant geringere Bakterienlast in der Lunge und eine verminderte Reduktion der Körpertemperatur und des Körpergewichtes als wild-typ Mäuse. Diese Effekte waren nicht durch Änderungen in der Zellrekrutierung oder durch Änderungen der Zytokin-/Chemokinexpression erklärbar. Zusammenfassend lässt sich feststellen, dass Typ I IFNs durch Pneumokokken induziert werden, aber dass sie trotz einiger positiver Effekte auf die Expression von ISGs einen negativen Gesamteffekt in einem murinen Pneumoniemodell aufweisen. Ein detailliertes Verständnis der Typ I IFN-Antwort während der Pneumokokkeninfektion kann die Entwicklung neuer Therapiestrategien unterstützen.<br>Streptococcus pneumoniae is the leading cause of community-acquired pneumonia world-wide. A detailed understanding of the host-pathogen interactions is required in order to foster the development of new therapeutic strategies. Here, I (I) characterized an innate immune recognition pathway that senses pneumococcal infection and triggers the production of type I interferons (IFNs), and (II) examined the role of type I IFNs in pneumococcal pneumonia in mice. Human and murine macrophages, but not alveolar epithelial cells, produced type I IFNs after infection with S. pneumoniae. This induction was dependent on the virulence factor pneumolysin, the phagocytosis of the bacteria, and the acidification of the endosome. Moreover, it appeared to be mediated by a cytosolic DNA-sensing pathway involving the adaptor molecule STING and the transcription factor IRF3. Type I IFNs produced by S. pneumoniae-infected macrophages positively regulated the expression of IFN-stimulated genes (ISGs) and chemokines in macrophages and co-cultured alveolar epithelial cells in vitro and in mouse lungs in vivo. However, in a murine model of pneumococcal pneumonia, type I IFN signaling was detrimental to the host defense. Mice deficient in the type I IFN signaling or double deficient in type I and type II IFN signaling had a significantly reduced bacterial load in the lung and a diminished reduction of body temperature and body weight compared to wild-type mice. The decreased susceptibility of the knockout mice was unlikely to be attributable to alterations in cell recruitment or cytokine/chemokine production. In conclusion, type I IFNs are induced during pneumococcal infection. However, despite their positive effects on the expression of some ISGs and chemokines, they negatively affect the outcome of pneumococcal pneumonia in an in vivo mouse model. Targeting the type I IFN system could potentially be an effective way in enhancing the immune response in patients with S. pneumoniae pneumonia.
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Xu, Jun. "Regulation of type I interferons in murine dendritic cells." Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/308946.
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Microbiology and Immunology<br>Ph.D.<br>Conventional Dendritic cells (cDCs), a specialized group of immunological sentinels with tree-like or dendritic shapes, are critical for recognition of danger signals, presentation of antigens and control of a spectrum of innate and adaptive immune responses. Type I interferons (IFNs), as important danger signals, activate cDCs through the canonical type I IFN receptor signaling. Type I IFNs are the first line of host defense against viral infection by up-regulating IFN-stimulated genes (ISGs). However, there are circumstances in which the silencing of excessive type I IFNs could be beneficial to the host, such as IFN-dependent autoimmune diseases, gene therapy that uses viral vectors and transplantation. The role of type I IFNs in DC development, activation and antigen presentation function remains to be completely investigated. In this dissertation, we studied the regulation of Type I IFNs in murine DCs, both cDCs and plasmacytoid DCs (pDCs), and specifically we investigated the role of two molecules, Signal Transducer and Activator of Transcription 2 (STAT2) and Three prime Repair EXonuclease 1 (Trex1), in DC biology. Our research furthers our understanding of DC development, activation and function, and provides important data for the therapeutic application of modified DCs to induce immunological tolerance in gene therapy, IFN-dependent autoimmune diseases and transplantation. STAT2 is a nuclear transcription factor downstream of type I IFN receptor-mediated signaling, the role of which has been mostly explored in antiviral responses mediated by type I IFNs. However, the involvement of STAT2 in cDC activation and function such as cross-presentation remains hitherto unclear. We report that STAT2 is essential for murine cDC activation upon TLR3, -4, -7 and -9 stimulation. In the absence of STAT2, cDCs displayed impaired up-regulation of type I IFN response (costimulatory molecules and type I IFN-stimulated genes), and reduced inflammatory cytokine production when stimulated with TLR ligands. STAT2 was required in all of the DC responses to exogenous IFNα, suggesting that the canonical STAT1-STAT2 heterodimers are the major signaling transducers downstream of type I IFNs in DCs. Of interest, LPS-induced TNFα and IL6 production were reduced in STAT2-/- DCs but not in IFNAR1-/- DCs, suggesting a novel STAT2-dependent pathway mediated by LPS, bypassing type I IFN-receptor signaling. STAT2-deficient cDCs showed impaired cross-presentation leading to decreased CD8+ T cell response both in vitro and CTL killing in vivo, indicating that STAT2 is essential for TLR-induced cross-presentation. These results demonstrate that STAT2 is critical in the regulation of TLR-induced DC activation and cross-presentation, suggesting an essential role for STAT2 in anti-viral and anti-tumor immune responses. We also propose a novel regulatory function of STAT2 in the LPS response independent of type I IFN receptor signaling. Trex1 mutations are associated with a spectrum of type I IFN-dependent autoimmune diseases such as Aicardi-Goutières syndrome and systemic lupus erythematosus. Trex1 plays an essential role in preventing accumulation of excessive cytoplasmic DNA, avoiding cell-intrinsic innate DNA sensor activation and suppressing activation of both type I IFN-stimulated and IFN-independent antiviral genes. Trex1 also helps HIV escape cytoplasmic detection by DNA sensors. However, regulation of Trex1 in DC biology is lacking. We report that murine cDCs have high constitutive expression of Trex1 in vitro and in vivo in the spleen. In resting bone marrow-derived cDCs, type I IFNs up-regulate Trex1 expression via the canonical IFN receptor signaling pathway (STAT1-, STAT2-dependent). DC activation induced by TLR3, -4, -7 and -9 ligands also augments Trex1 expression through autocrine IFNß production and triggering of the IFN signaling pathway, while TLR4 ligand LPS also stimulates an early expression of Trex1 through an IFN-independent NFΚB-dependent signaling pathway. Furthermore, retroviral infection also induces Trex1 up-regulation in cDCs, as we found that a gene therapy HIV-1-based lentiviral vector induces significant Trex1 expression, suggesting that Trex1 may affect local and systemic administration of gene therapy vehicles. Our data indicate that Trex1 is induced in cDCs during activation upon IFN- and TLR- stimulation through the canonical IFN signaling pathway, and suggest that Trex1 may play a role in cDC activation during infection and autoimmunity. Finally, these results suggest that HIV-like viruses may up-regulate Trex1 to increase their ability to escape immunosurveillance. In order to dissect the role of Trex1 in DC functions, we compared DCs from Trex1-/- and wild-type mice. We report that Trex1 deficiency reduces absolute number of pDCs in BM but not in spleen of male over female mice. Furthermore, Trex1 deficiency preferentially represses Flt3L-induced DC development both in vitro and in vivo but not GM-CSF-dependent DC development, suggesting that Trex1 plays an indispensable role in Flt3L-induced DC development and GM-CSF may compensate the effect of Trex1 deficiency. This defect is only limited to male Trex1-/- DCs, and mimics the effect of mTOR inhibition. Furthermore, although Flt3L-induced Trex1-/- DCs expressed a type I IFN signature, they also exhibited decreased pDC development markers, indicating Trex1 regulates pDC development at the transcriptional level. Thus, we propose a novel and essential role of Trex1 in Flt3L-induced DC development, and the effect of Trex1 regulation is gender-dependent. Together, these findings enhance our understanding of regulatory roles of Type I IFNs in DC development, activation and function, supporting the beneficial role of STAT2/type I IFN axis in TLR-induced DC activation and cross-presentation. Our study in Trex1 reveals Trex1 induction by viral infection, type I IFNs and TLRs in DCs, and a new role of Trex1 in early development of Flt3L-induced DCs in a gender-dependent manner, whereby a balance between type I IFNs and Trex1 is important for DC activation and hemostasis.<br>Temple University--Theses
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Rothfuchs, Antonio Carlos Gigliotti (Tony). "Interferons in immunity to chlamydia pneumoniae/." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-830-0/.
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Mulligan, Rebecca. "The role of type-1 interferons during Salmonella typhimurium infection." Thesis, University of Ottawa (Canada), 2010. http://hdl.handle.net/10393/28658.
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Type-I interferons (IFN-I) play a key protective role during viral infections, however, their role during bacterial infections remains unclear. We evaluated the influence of IFN-I signalling during infection of mice with the facultative intracellular bacterium, Salmonella typhimurium (ST). Wild-type (WT) C57BL/6J mice succumbed to infection by day 7 and death was accelerated in mice deficient in key innate immune mediators (IFN-gamma, TNF-alpha, iNOS-2). Surprisingly, IFN-I receptor-deficient (IFN-I R-/-) mice survived ST infection up to 35 days. Despite enhanced inflammation, WT mice displayed uncontrolled ST burden and lower macrophage numbers in the spleen, compared with IFN-I R-/- mice. In vitro, IFN-I-deficient macrophages expressed reduced levels of TNF-alpha and NO2- in response to ST and displayed prolonged survival in comparison with WT macrophages. Since macrophages play key protective roles during intracellular bacterial infections, our results indicate that IFN-I signalling during ST infection promotes the elimination of macrophages resulting in poor pathogen control.
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Psarras, Antonios. "Regulation of type I interferons in health and autoimmune disease." Thesis, University of Leeds, 2018. http://etheses.whiterose.ac.uk/22934/.
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Type I interferons (IFN) have a crucial role in the pathogenesis of a range of autoimmune diseases including systemic lupus erythematosus (SLE). Increased IFN activity is observed at preclinical stages and associated with disease progression, but the cause of this dysregulation remains unclear. Plasmacytoid dendritic cells (pDCs) produce large amounts of IFNs in viral infection, however their precise role in autoimmunity is still elusive. Peripheral blood and skin biopsies from different patient groups were used for gene expression assays, immunophenotyping, in vitro functional assays, transcriptomics and other assays to investigate the dysregulated IFN axis and the role of pDCs in preclinical autoimmunity and SLE. In preclinical autoimmunity and SLE, pDCs were found to exhibit an exhausted phenotype with: (i) loss of TLR-mediated IFN-α production; (ii) failure to induce T cell activation; (iii) transcriptional profile of cellular senescence; (iv) increased telomere erosion. In contrast, diffuse expression of type I IFNs was observed in the epidermis but not in leucocyte-infiltrating areas of patients with SLE as well as in non-lesional skin of individuals with preclinical autoimmunity. Additionally, keratinocytes isolated from non-lesional skin of patients with SLE and individuals with preclinical autoimmunity showed a significantly enhanced type I IFN expression in response to UV light and nucleic acids. Lastly, TNF-α regulates the function of pDCs by suppressing IFN-α production but enhancing a functional drift to antigen presentation and T cell activation. These findings revise our understanding of immune regulation in human autoimmunity. Non-haematopoietic tissue cells can perpetuate IFN responses; meanwhile the professional IFN-producing pDCs have lost their immunogenic properties. In patients with SLE, these insights may indicate potential therapeutic targets outside the conventional immune system, while knowledge of how IFN dysregulation initiates could allow disease prevention.
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Kole, Abhisake. "The role of type I interferons in regulating intestinal inflammation." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:eb8860d1-9ab9-49b9-81b4-b74b4442f2d5.
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Intestinal homeostasis is a delicate balance between suppression of immune responses against innocuous antigens and stimulation of immune responses against pathogens. Type I interferon (IFN-1) cytokines have both immunostimulatory and immunomodulatory effects. Colon mononuclear phagocytes (MP) constitutively produced IFN-1 in a TRIFdependent manner. We explored the function of endogenous IFN-1 in the colon using the T cell adoptive transfer model of colitis. Transfer of CD4<sup>+</sup>CD45RB<sup>hi</sup> naïve T cells from wild type (WT) or IFNAR subunit 1 knockout (IFNAR1<sup>-/-</sup>) mice into RAG<sup>-/-</sup> hosts resulted in similar onset and severity of colitis. In contrast, RAG<sup>-/-</sup> x IFNAR1<sup>-/-</sup> double knockout (DKO) mice developed accelerated severe colitis compared to RAG<sup>-/-</sup> hosts when transferred WT CD4<sup>+</sup>CD45RB<sup>hi</sup> T cells. Although WT or IFNAR1<sup>-/-</sup> regulatory T (Treg) cells equally prevented disease caused by CD45RB<sup>hi</sup> naïve T cells, WT Treg cells co-transferred with naïve CD4<sup>+</sup> T cells into DKO recipients failed to expand or maintain Foxp3 expression and gained effector functions in the colon. IFNAR signaling on host hematopoietic cells inhibited T cell-mediated colitis, but not innate colitis. MPs isolated from the colon lamina propria (cLP) required IFNAR signaling for the production of the anti-inflammatory cytokines, IL-10, IL-27, and IL-1RA, but not for the production of classic pro-inflammatory cytokines. IFN-1-dependent secretion of IL-1RA was particularly important in inhibiting the migration of inflammatory DCs with potent T cell proliferative capacity from the cLP to the mesenteric lymph nodes. Finally, preliminary results suggested that IFN-1 may shape the commensal microbiota, but is not essential for controlling specific colitis-inducing bacteria.
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Germain, Conrad Andrew. "Production and function of type 1 interferons in the immune response." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417038.
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Liu, Qinfang. "Interaction of type I interferons and mTOR signaling underlying PRRSV infection." Thesis, Kansas State University, 2016. http://hdl.handle.net/2097/32860.
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Master of Science in Biomedical Sciences<br>Department of Anatomy and Physiology<br>Yongming Sang<br>Animal metabolic and immune systems integrate and inter-regulate to exert effective immune responses to distinct pathogens. The signaling pathway mediated by mechanistic target of rapamycin (mTOR) is critical in cellular metabolism and implicated in host antiviral responses. Recent studies highlight the significance of the mTOR signaling pathway in the interferon (IFN) response. Type I IFNs mediate host defense, particularly, against viral infections, and have myriad roles in antiviral innate and adaptive immunity. In addition to their well-known antiviral properties, type I IFNs also affect host metabolism. However, little is known about how animal type I IFN signaling coordinates immunometabolic reactions during antiviral defense. Therefore, understanding the interaction of mTOR signaling and the type I IFN system becomes increasingly important in potentiating antiviral immunity.
Tissue macrophages (MФs) are a primary IFN producer during viral infection, and their polarization to different activation statuses is critical for regulation of immune and metabolic homeostasis. Using porcine reproductive and respiratory syndrome virus (PRRSV) as a model, we found that genes in the mTOR signaling pathway were regulated differently in PRRSV-infected porcine alveolar MФs at different activation statuses. Therefore we hypothesize that: 1) the mTOR signaling pathway involves host anti-PRRSV regulation; 2) mTOR signaling interacts with IFN signaling to modulate the antiviral response; and 3) different type I IFN subtypes (such as IFN-α1 and IFN-β) regulate mTOR signaling differently. We show that modulation of mTOR signaling regulated PRRSV infection in MARC-145 cells and porcine primary cells, in part, through regulating production and signaling of type I IFNs. In addition, expression and phosphorylation of two key components in the mTOR signaling pathway, AKT and p70 S6 kinase, were regulated by type I IFNs and PRRSV infection.
Taken together, we determined that the mTOR signaling pathway, a key pathway in regulation of cell metabolism, also mediates the type I IFN response, a key immune response in PRRSV infection. Our findings reveal that the mTOR signaling pathway potentially has a bi-directional loop with the type I IFN system and implies that some components in the mTOR signaling pathway can serve as targets for augmentation of antiviral immunity and therapeutic designs.
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Mouchel-Vielh, Emmanuèle. "Etude genetique et fonctionnelle du recepteur des interferons de type i." Paris 6, 1994. http://www.theses.fr/1994PA066201.
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Le recepteur des interferons alpha et beta est un complexe multiproteique dont un composant transmembranaire, la proteine ifnar, a ete clone. L'analyse de la sequence de la proteine ifnar ainsi que le clonage de son gene et la determination de la structure de celui-ci mettent en evidence l'appartenance de cette proteine a la famille des recepteurs des cytokines. De plus, l'etude fonctionnelle du recepteur bovin des interferons alpha et beta confirme qu'au moins deux autres composants, une proteine transmembranaire et une proteine tyrosine kinase cytoplasmique, sont impliques dans la formation d'un recepteur fonctionnel
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Shahangian, Arash. "Influenza-induced type I interferons sensitize hosts to secondary pneumococcal pneumonia." Diss., Restricted to subscribing institutions, 2008. http://proquest.umi.com/pqdweb?did=1621828411&sid=2&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Rice-Hills, Ann A. "Signal transduction mechanisms of the type I interferons in the human endometrium." Thesis, Middlesex University, 2006. http://eprints.mdx.ac.uk/13394/.
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Unlike humans, the primary signal for maternal recognition ofpregnancy in ruminants is the Type I interferon (IFN) IFN-t. IFN1: is produced by the conceptus and acts upon the endometrium where it inhibits the production ofprostaglandin F2a and subsequent luteolysis ofthe corpus luteum. It is difficult to establish what precise role interferonlike signalling might play in human reproduction due to ethical barriers. However, indirect investigations are possible by in vitro investigation . of human endometrial . response to Type I IFN stimulation. Type I IFNs (a, P and 1:) activate a common tyrosine kinase signalling pathway' involving the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) proteins. However, the Type I IFNs elicit different cellular responses. The aim of this thesis is to establish that, whilst it is known that the Type I IFNs trigger~e JAKISTAT activation pathway, there is a simultaneous activation of different phospholipase pathways which determines the specificity of the response. This hypothesis was investigated using human endometrial tissue which is known to respond to Type I IFNs. Long-term primary human endometrial cell cultures were established from tissue taken from the proliferative and secretory phases of the menstrual cycle. Cell function and viability were determined by measuring placental proteins and cytokines. 33p labelled endometrial cells exposed to IFNs a and 1: showed hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) with corresponding production of diacylglycerol (DAG). IFNa and IFN1: also stimulated hydrolysis of phosphatidylinositol-4- phosphate (pIP). These IFNs did not demonstrate activation of any other phospholipase. There was no phospholipid turnover via any phospholipase in response to IFN~. Using imrnunoprecipitation, SDS-PAGE and Western blotting it was possible to show the presence of phosphorylated STATl a in unstimulated endometrial cells. In response to stimulation by IFN a and ~ there was an increase in phosphorylated STATla, STATI and Tyk2 (a member ofthe Janus kinase family). In contrast, IFN1: activated the phosphorylation of Tyk2 but not STATla or STATI. There was no stimulation of JAKl phosphorylation by any of the IFNs. In summary, Type I IFNs u, ~ and 1: each elicit a different pattern of signal transduction response in cultured human endometrial cells, not only via the JAKISTAT pathway but also via phospholipase activation. The ability of IFN't to stimulate a signalling pathway, distinct from that of IFNu and ~ is sufficient circumstantial evidence to suggest that at least a residual signalling pathway for IFN't exists in the human endometrium and further investigation is warranted.
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Walker, Josef Arthur. "An investigation into the effects of type 1 interferons on human dendritic cells." Thesis, University College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405933.
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Metidji, Amina. "Type I interferons and T regulatory cells : effects on development, homeostasis and function." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066058/document.
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L'interféron de type I (IFN) est une famille de cytokine avec des propriétés antivirales et immunomodulatrices. Alors que les effets antiviraux de l'IFN sont bien caractérisés, leurs propriétés immunomodulatrices le sont moins. Nous avons examiné en profondeur les effets de l'IFN de type I sur le développement, l'homéostasie, et la fonction des cellules Treg. Nous avons utilisé des souris chimériques reconstituées avec une mixture de moelle osseuse de souris normale (WT) et de souris sans le récepteur de l'IFN(IFNAR)KO, et des souris femelles hétérozygotes exprimant une délétion d'IFNAR spécifiquement sur les Treg. Dans ces deux modèles, la signalisation d'IFNAR favorise le développement de la lignée Treg dans le thymus et leur survie dans la périphérie. Nous avons également généré des souris chimériques en utilisant le foie f¿tal de souris scurfy, les Treg dérivés de IFNAR KO ont été incapables de contrôler l'activation des cellules T effectrices et l'inflammation des tissus. Nous avons aussi examiné les effets pendant l'infection avec le virus chorioméningite lymphocytaire chronique (LCMV). Nous avons démontré que le pourcentage de V?5+ Treg était significativement réduit chez les souris IFNAR KO. Nous avons également examiné l'effet pendant Encéphalomyélite auto-immune expérimentale (EAE). Suite à l'induction de l'EAE, les souris chimériques WT/IFNAR KO développent une maladie plus sévère que les souris WT/WT. Nous montrons aussi que les souris avec une délétion conditionnelle de IFNAR dans les Tregs développent une forme très grave de l'EAE. Ces résultats démontrent que la signalisation via IFNAR est nécessaire pour la fonction de suppressive des Treg dans l'EAE<br>Type I Interferons (IFNs) are a family of cytokines with antiviral and immunomodulatory properties. While the antiviral effects of IFNs are well characterized, their immunomodulatory properties are less clear. We examined the effects of type I IFN on development, homeostasis, and function of Treg cells. We used mixed bone marrow (BM) chimeras between WT and IFNαβ receptor (IFNAR) KO mice, and heterozygous female mice expressing a Treg-specific deletion of the IFNAR. IFNAR signaling promoted the development of the Treg lineage in the thymus and their survival in the periphery. IFNAR KO Treg from chimeric mice displayed a more naïve phenotype. In mixed chimeras with Scurfy fetal liver, Treg derived from IFNAR KO BM were unable to control T effector cell activation and tissue inflammation. We also examined the potential effects during Chronic Lymphocytic Choriomeningitis Virus infection. We demonstrated that the percentage of Vβ5+ Treg was significantly reduced in IFNAR KO mice, and that the IFNAR functions in a Treg cell intrinsic manner. We also studied the effect during Experimental autoimmune encephalomyelitis (EAE). Following induction of EAE, WT / IFNAR KO chimeras develop more severe disease than the WT/WT chimeras. Mice with a conditional deletion of the IFNAR in Treg rapidly developed a very severe form of EAE. These results demonstrate that signaling via the IFNAR is required for Treg suppressor function in EAE. Collectively, these studies demonstrate that under certain condition including stress, chronic infection, and autoimmune disease, IFNAR signaling is essential to maintain Treg development, homeostasis, and function
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CAPPELLETTI, CRISTINA. "Type I interferons and toll-like receptors are linked to pathological alterations of idiopathic inflammatory myopathiens." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2009. http://hdl.handle.net/10281/9235.
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Objective: The triggering factor of inflammation in idiopathic inflammatory myopathies (IIMs) is
still unknown and an involvement of viruses or bacteria has been put forward. We sought to
investigate the expression of type I interferons (IFNα/β) and of endosomal Toll-like receptors
(TLRs) in IIM muscles.
Methods: Ten IIM and 5 control muscle biopsies were assessed by microarray analysis for the
expression of approximately 16,000 genes; 37 additional samples from IIM and controls were
studied for IFNα/β-dependent genes and intracellular TLR expression using
immunohistochemistry, confocal miscroscopy, real-time quantitative and qualitative PCR.
Results: IFNα/β-dependent gene transcripts were up-regulated in all IIM muscle specimens
compared to controls. In juvenile dermatomyositis (JDM) ISG15 (408-fold), IFIT3 (261-fold), MX1
(99-fold), IRF7 (37-fold) were those most expressed. TLR3, TLR7 and TLR9 were differentially
expressed in IIM muscles: TLR3 was highly up-regulated in JDM, localized on vascular endothelial
cells, muscle infiltrating cells and regenerating myofibers; TLR7 and TLR9 were frequently
detected in polymyositis (PM), mainly on cell infiltrates (particularly plasma cells), and on some
injured myofibers.
Conclusion: Transcriptome analysis indicated that IFNα/β-induced molecules play a key role in the
pathogenesis of IIMs, particularly in JDM. Endosomal TLRs represent important effector molecules
that link innate and adaptive immune responses in affected muscles, showing their potential as new
therapeutic targets for the IIM treatment.
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Adatia, Femina. "A role for type I interferons in the resistance of chronic lymphocytic leukemia to vesicular stomatitis virus." Thesis, University of Ottawa (Canada), 2005. http://hdl.handle.net/10393/26833.
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Vesicular Stomatitis Virus (VSV) is a naturally oncolytic agent that is exquisitely sensitive to the antiviral effects of Type I Interferons (IFN). Although 81% of human cancer cell lines in the NCI-60 panel are sensitive to VSV, Chronic Lymphocytic Leukemia (CLL), the most common adult leukemia in the West, is resistant. It is hypothesized that this resistance is due to an intact IFN pathway in CLL cells. A quantitative PCR based approach was taken to examine the IFN gene expression profile of CLL cells. It was discovered that CLL cells constitutively express IFNbeta and IFNalphaR1 transcripts which may contribute to an inherent antiviral state in these cells. However, upon activation of CLL cells, IFN transcript levels decrease and susceptibility to VSV infection is increased. As complete sensitivity to VSV is not achieved, the contribution of other antiviral mechanisms cannot be excluded. Understanding the mechanisms of viral resistance in CLL and uncovering novel approaches of manipulating them will have future implications for VSV therapy of CLL.
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Sang, Wenjing. "Differential expression of type I interferons in fetal tissues and the maternal-fetal interface in response to PRRSV infection." Thesis, Kansas State University, 2012. http://hdl.handle.net/2097/14183.
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Master of Science<br>Department of Diagnostic Medicine/Pathobiology<br>Raymond R. R. Rowland<br>Interferons (IFNs) comprise a group of antiviral cytokines; however, their expression at the porcine maternal-fetal interface and in fetal tissues has not previously been investigated. The purpose of this study was to analyze the expression of type I IFNs and their receptors in maternal and fetal tissues from sows infected with PRRSV. The approach was to use real-time RT-PCR to identify the expression of different subtypes of type I IFN genes. The results show that the constitutive gene expression of some subtypes including IFN-[alpha] and IFN-[alpha][omega] were detected in fetal lymphoid nodes (IFN-[alpha][omega]), placenta (several IFN-[alpha] subtypes and IFN-[omega]5) and particularly, thymus (multiple IFN-[alpha], IFN-[delta] and IFN-[omega]5). The results demonstrate that porcine type I IFNs are differentially expressed at the maternal-fetal interface and in fetal tissues in response to PRRSV infection.
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Cessford, Erin Lauren. "Mechanistic Insights into Necroptosis of Macrophages." Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31771.
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Cell death is an imperative mechanism for the development, homeostasis and survival of an organism. Various forms of cell death have been documented and recent reports indicate that the mode of cell death elicited can have a profound influence on the development and perpetuation of inflammation. Apoptosis is the predominant, programmed pathway of cell death, which ensures physiological elimination of unwanted cells. On the other hand, another cell death pathway described as programmed necrosis (necroptosis), has recently been revealed. The induction of necroptosis and its impact in host biology is not clear. Herein I have evaluated the mechanisms of necroptosis in macrophages, an important cell type of the immune system. My experiments indicate that type I interferon (IFN-I) signaling through transcription factors STAT1, STAT2 and IRF9, collectively described as the ISGF3 complex, is indispensable for necroptosis of macrophages. Furthermore, my results indicate that IFN-I signaling promotes the sustained phosphorylation of receptor interacting protein kinase 3 (Rip3), a key protein required for the execution of necroptosis. My findings also reveal that dynamin-dependent endocytosis following IFNβ stimulation and caspase inhibition is necessary for the induction of necroptosis. The results presented in this thesis provide new insights into the molecular mechanisms of necroptosis and therefore contribute to a deeper understanding of multiple inflammatory pathologies.
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DEREUDDRE, BOSQUET NATHALIE. "Physiopathologie et approches therapeutiques experimentales des infections lentivirales : role de l'interleukine-10 et des interferons de type 1." Paris, Institut national d'agronomie de Paris Grignon, 1999. http://www.theses.fr/1999INAP0041.
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Le reseau des cytokines est etroitement implique dans la physiopathologie de l'infection par le vih. Les macrophages sont infectables par le vih in vivo et in vitro. L'il-10 est une cytokine immunosuppressive, impliquee dans la mise en place du deficit immunitaire lors de l'infection par le vih et produite par les macrophages. Lors d'un stress inflammatoire, elle est produite par les macrophages pour reguler la production des cytokines pro-inflammatoires. Pour determiner si le vih pouvait induire la production de l'il-10 par les macrophages, nous avons infecte in vitro des macrophages humains obtenus a partir de monocytes du sang peripherique de donneurs sains. Dans nos conditions experimentales, l'infection par le vih et sa replication ne modifient pas la production de l'il-10, ni de l'il-1beta, de l'il-6 et du tnf-alpha par les macrophages. La replication du vih est regulee par les cytokines. Pour evaluer une approche therapeutique basee sur l'utilisation de cytokines anti-inflammatoires et antivirales, nous avons mesure les effets de l'il-10 et d'un nouvel ifn de type 1, l'ifn-tau, sur la replication du vih. L'il-10 et l'ifn-tau inhibent la replication du vih ; toutefois, l'efficacite de l'il-10 depend du micro-environnement cellulaire, car, dans un contexte inflammatoire, l'il-10 perd son efficacite. L'il-10 presenterait donc peu d'interet en tant que cytokine anti-vih. L'ifn-tau affecte la replication du vih preferentiellement avant l'integration du provirus. L'il-6, synthetisee par les macrophages traites par l'ifn-tau, participe a ses effets antiviraux. Les effets des cytokines sur la replication du vih sont complexes. Ils dependent en effet de la nature des cellules, de leur niveau d'activation et du micro-environnement
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Li, Wen. "Investigation of Type I Interferon Signaling in the Cellular Response and Host Defense." Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/10615.
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Type I interferons (IFN-I) mediate the antiviral host response through activation of interferon-stimulated gene factor 3 (ISGF3) complex consisting of STAT1, STAT2 and IRF9. However, IFN-I can activate a number of non-canonical signaling pathways, which may contribute to neurological diseases in transgenic mice with CNS-production of IFN-α. It remained largely unknown how and to what extent non-canonical signaling pathways mediate the functional effects of IFN-I. Thus, the role of IFN-α-stimulated ISGF3-independent gene regulation was investigated in murine primary mixed glial cells (MGCs) in the absence or presence of STAT1, STAT2 or IRF9 using global gene expression profiling. This study revealed for the first time the existence of non-ISGF3 dependent IFN-I signaling pathways, primarily dependent on STAT1 and STAT2. Several possible target genes (e.g. IRF7) were identified to be involved in mediating the adverse effects of IFN-I in the CNS. IRF7 is a key regulator of IFN-I production. STAT1 KO mice following lymphocytic choriomeningitis virus (LCMV) infection develop a unique lethal disease associated with excessive serum IFN-I production. The STAT1-independent induction of IRF7 following LCMV infection has been reported previously. Thus, we investigated whether IRF7-induced IFN-I production is involved in the lethal host response to LCMV in STAT1 KO mice. This study demonstrated that IRF7 is required for the early innate control of LCMV infection, likely through the regulation of the appropriate IFN-I response, and is not required for the antiviral CD8+ T-cell-dependent clearance of LCMV. Furthermore, these studies indicated that the lethal immune-mediated disease resulting from LCMV infection in STAT1 KO mice is dependent on IRF7-induced IFN-I production, and is driven by non-canonical IFN-I signaling via STAT2 and IRF9. These studies highlight how IFN-I mediates cellular response via non-canonical IFN-I signaling in CNS and in host defense against LCMV infection.
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Riding, Rebecca L. "The Role of Type I Interferon in Vitiligo Pathogenesis and Melanoma Immunotherapy." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1065.
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Vitiligo is an autoimmune skin disease in which the pigment producing cells of the epidermis, melanocytes, are targeted for destruction by CD8+ T cells specific for melanocyte/melanoma-shared antigens. Previous work has identified IFNg as the central cytokine driving disease pathogenesis in both human patients and in our mouse model of vitiligo. IFNg signaling induces production of the chemokines CXCL9 and CXCL10, which trigger autoreactive T cell migration into the epidermis where effector T cells can target and destroy melanocytes. However, both IFNg and type I IFN signaling through activation of STAT1 proteins can induce transcription of the chemokines CXCL9 and CXCL10. Therefore, it seems reasonable that type I IFN signaling may also contribute to disease pathogenesis.
The role of type I IFN in vitiligo is still unclear. Genome wide association studies identified multiple genes within the type I IFN pathway including TICAM1 and IFIH1 as susceptibility loci in vitiligo. One additional study reported increased epidermal staining of CD123, a marker expressed by pDCs, and the type I IFN induced gene MX1 in vitiligo patient skin. However, this study did not show any functional data to support the role of type I IFN signaling in vitiligo pathogenesis. Since the role of type I IFN in vitiligo is ill-defined, we used two different mouse models of vitiligo to functionally determine the role of type I IFN in disease by inducing vitiligo in hosts which lack the type I IFN receptor (IFNaR).
In the first model, we induced vitiligo by adoptive transfer of melanocyte-specific CD8 T cells, which are activated in vivo by infection with recombinant vaccinia virus (VACV) expressing their cognate antigen. Vitiligo induction in IFNaR-deficient mice led to the development of severe disease compared to wild type mice. Acceleration and severity of disease was characterized by increased early recruitment of melanocyte-specific CD8 T cells to the skin, increased production of effector cytokines TNFa and IFNg, and reduced PD-1 expression. Increased production of IFNg by CD8 T cells in the skin of IFNaR-deficient mice led to increased expression of the chemokines CXCL9 and CXCL10 driving disease progression. IFNaR-deficient mice also displayed significantly increased VACV titters compared to wild type hosts. This data reveals a role of type I IFN in the clearance of recombinant VACV. This data also suggests that persistent VACV infection and prolonged antigen exposure in IFNaR deficient hosts is likely driving enhanced activation of melanocyte specific CD8 T cells and the subsequent development of severe vitiligo.
Since melanocytes and melanoma cells express shared antigens that can be recognized by CD8 T cells, and because the development of vitiligo after melanoma immunotherapy is a positive prognostic factor for patients, we asked whether VACV vaccine therapy in IFNaR deficient mice would enhance the anti-tumor response to melanoma. B16-F10 inoculated wild type and IFNaR-deficient mice received adoptive transfer of melanocyte-specific CD8 T cells in combination with vaccinia virus expressing their cognate antigen to activate the cells in vivo. Treatment of adoptive T cell transfer and infection with VACV in IFNaR-deficient mice revealed significantly reduced tumor burden compared to wild type mice. Improved tumor regression in IFNaR-deficient hosts was characterized by increased infiltrating cytotoxic T lymphocytes and reduced PD-1 expression. These results further demonstrate that in the absence of type I IFN, hosts mount a robust cytotoxic CD8 T cell response against melanocyte/melanoma antigens and this is likely a result of persistent VACV that leads to prolonged CD8 T cell priming. As a result, IFNaR deficient hosts kill tumor cells more efficiently.
To determine whether type I IFN regulates disease pathogenesis in the absence of virus infection, we generated a model of vitiligo in which bone marrow derived dendritic cells (BMDCs) pulsed with the cognate antigen were used to prime melanocyte-specific T cells in place of the viral vector. Induction of vitiligo in IFNaR-deficient hosts using BMDCs revealed no significant differences in disease score compared to wild type hosts. This data clearly demonstrates that type I IFN, in contrast to IFNg, is not required during the effector stage of vitiligo pathogenesis in mice.
However, since we intentionally activate transferred melanocyte-specific CD8 T cells with VACV or BMDCs expressing their cognate antigen, our mouse models may circumvent the role of type I IFNs in initiating activation of autoreactive cells and driving autoimmunity. Type I IFN is critical for providing innate immune signals that drive the priming of autoreactive T cells through maturation of DCs by inducing antigen presentation, co-stimulatory molecule expression, and migration to the lymph nodes to encounter naïve T cells. Our mouse models of vitiligo may not capture this process. We have addressed this question by using a TLR ligand to activate BMDCs before transfer into hosts. In fact, activation of BMDCs before transfer leads to significantly enhanced vitiligo in mice and this is partially a result of type I IFN signaling on host cells. Thus, we provide evidence that type I IFNs can enhance the activation of melanocyte-specific CD8 T cells and drive autoimmunity.
Collectively, our results show that type I IFN signaling has disparate effects on autoreactive T cell priming in a context dependent manner. We reveal that although type I IFN is not required for the effector phase of vitiligo in mice, maturation of DCs and subsequent type I IFN production can enhance the priming of autoreactive T cells and enhance vitiligo severity. Our studies also reveal that type I IFN is required to clear recombinant attenuated VACV infection and vaccine administration in IFNaR deficient hosts led to a robust autoreactive and anti-tumor response. These insights describing the role of type I IFN in autoimmunity and tumor immunology could have important implications for T cell dependent tumor immunotherapy.
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McFarlane, Amanda Jayne. "Effects of the strictly enteric helminth, Heligmosomoides polygyrus, on respiratory syncytial virus (RSV) infection." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/17625.
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RSV is the most common cause of infant bronchiolitis, leading to morbidity and mortality in both infants and the elderly. The relationship between RSV and asthma development further highlights the need to fully understand the immune responses involved in order to develop effective vaccines and therapeutics to aid prevention and treatment of RSV infection respectively. Helminths have long been studied both as a major pathogen of humans, infecting approximately 3 billion people worldwide, and also their ability to modulate the host immune response to allow survival and chronic infection to ensue. Specifically, helminth infections are thought to modulate the host immune response through regulatory mechanisms which are not fully understood. This not only confers protection and survival of the parasites themselves, but also modulates the immune response to unrelated antigens and pathogens. In this thesis, the potential role of a strictly enteric helminth infection, with Heligmosomoides polygyrus, in the modulation of respiratory syncytial virus (RSV) infection was investigated and the associated immune mechanisms were investigated. Firstly, the effects of prior H. polygyrus infection on RSV infection and immune responses in the lung were analysed. H. polygyrus significantly reduced the number of natural killer cells, CD8+ T cells, B cells and conventional dendritic cells in the lung following RSV infection. Co-infection also reduced the production of pro-inflammatory cytokines IL-6 and TNF-α in the lungs. All of these reductions were associated with significantly lower viral titres on day 4 of RSV infection. Interestingly, this attenuation of immune responses and viral titres, correlated with reduced severity of clinical disease, as assessed by weight loss and lung function. H. polygyrus excretory secretory product (HES) was not found to be the immune-modulatory factor in this system, as HES failed to suppress viral titres and reduce immune cell responses to RSV infection. However, irradiated larvae with stunted maturation to adult worms, revealed that larval stages were sufficient to suppress viral titres. Next, the role of type 2 signalling for H. polygyrus effects on RSV infection were examined, using IL-4Rα-/- mice. H. polygyrus infection maintained the ability to attenuate RSV infection and subsequent immune responses in IL-4Rα-/- mice. Furthermore, the presence of the adaptive immune response was not required for H. polygyrus-induced attenuation of RSV infection, as demonstrated in recombinase-activating gene (RAG-/-) deficient mice. H. polygyrus induces innate type 2 immune responses indicating the release of the innate alarmin, IL-33, in the lung and consequently an accumulation of group 2 innate lymphoid cells (ILC2). Their contribution to H. polygyrus effects remain to be fully elucidated. Finally, the role of antiviral responses was explored in H. polygyrus and RSV co-infection. H. polygyrus infection alone induced expression of antiviral genes, IFN-β, OAS1A, Viperin and the antimicrobial peptide CRAMP, in both the duodenum and the lung. Expression of these genes was still higher in the lung 1 hour after RSV in H. polygyrus co-infected mice compared to controls without co-infection. The importance of type I IFN signalling pathway was demonstrated using mice deficient in the type I IFN receptor in H. polygyrus co-infection, which failed to suppress RSV titres and subsequent lung immune cell infiltration. These data highlight the ability of the strictly enteric helminth H. polygyrus to attenuate RSV infection and subsequent immune responses in the lung through the potentiation of type I IFN signalling and consequent upregulation of antiviral immune responses in the lung.
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Yue, Chanyu. "STAT2 in the regulation of tumor growth and antitumor effects of type I interferons in a mouse model of melanoma." Diss., Temple University Libraries, 2013. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/233175.
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Biochemistry<br>Ph.D.<br>Signal Transducer and Activator of Transcription (STAT) 2 is one of seven members of the STAT family of transcription factors with dual roles in signal transduction and gene activation. STAT2 is a central transcription factor that regulates the antiviral, apoptotic and cell growth inhibitory effects of type I interferons (IFN-α/β), a small family of secreted glycoproteins induced by the host after sensing the presence of tumor cells and pathogens. The creation of Stat2-/- mice established the pivotal role of STAT2 in type I IFN signaling and in antiviral immunity. In vitro studies conducted in STAT2 deficient tumor cell lines suggested a role in suppressing tumor cell growth in response to IFN treatment. Based on these properties STAT2 is presumed to have tumor suppressor functions but data to support this notion in animal models of cancer are limited. To address the role of STAT2 in cancer, I used the murine B16-F1 tumor transplantation model of human melanoma. The B16-F1 melanoma cell line was established from a spontaneous tumor that arose in mice. I discovered that tumor cells transplanted subcutaneously in Stat2-/- mice grew more aggressively than in the counterpart wild type mice. Closer examination of B16-F1 tumors harvested from wild type and Stat2-/- mice revealed an unexpected dramatic similar reduction of STAT2 and STAT1 proteins. Yet soluble factors secreted by B16-F1 tumors established in Stat2-/- mice alone were sufficient to enhance proliferation of B16-F1 tumor cells. I further showed that tumor-bearing wild type mice treated with IFN-β developed smaller tumors compared to Stat2-/- mice, whose tumors continued to grow and hence were unresponsive to IFN intervention. Lastly, to elucidate a mechanism that leads to enhanced tumor growth in Stat2-/- mice, I questioned the involvement of the host immune response in restricting tumor growth. I found that tumor specific T cell priming by Stat2-/- dendritic cells (DCs) was defective since generated cytotoxic T cells (CD8+ T lymphocytes) produced low levels of IFN-γ and IL-2 and adoptive transfer of these B16-F1 tumor specific CD8+ T cells in B16-F1 bearing Stat2-/- mice did not cause tumor regression with IFN-β intervention. Collectively, my findings reveal that host STAT2 restricts the establishment of melanoma tumors. More importantly, type I IFN/STAT2 signaling on DCs plays a pivotal role in tumor antigen cross-presentation to CD8+ T cells and in the development of a protective antitumor response resulting in tumor rejection. To now address whether STAT2 expression in cancer cells could influence tumor establishment and the antitumor effects of type I IFNs, STAT2 expression was silenced in B16-F1 tumor cells. Contrary to my expectation, silencing STAT2 augmented the growth inhibitory effects of IFN-β both in vitro and in vivo. However, loss of STAT2 expression in the tumor did not cause B16-F1 tumor cells to grow more aggressively compared to control B16-F1 cells. Furthermore, compared to B16-F1 control cells, STAT2-silenced B16-F1 cells showed an initial delay but later persistent STAT activation and formation of the ISGF3 transcriptional complex (consisting of STAT1, STAT2 and IRF9). This observation paralleled with an initial delay and then later an increase in the expression of IFN regulated genes. In addition, reduced activation of STAT5 induced by IFN-β was observed in STAT2-silenced B16-F1 cells. This may partially explain the enhanced growth inhibitory effects of type I IFNs. Together these results shed light on the unexpected role of tumor STAT2 expression in diminishing the efficacy of type I IFN treatment of melanoma.<br>Temple University--Theses
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Koppe, Uwe Moritz Eberhard [Verfasser], Arturo [Akademischer Betreuer] Zychlinsky, Bastian [Akademischer Betreuer] Opitz, and Ralf [Akademischer Betreuer] Schumann. "Role of type I interferons in Streptococcus pneumoniae pneumonia / Uwe Moritz Eberhard Koppe. Gutachter: Arturo Zychlinsky ; Bastian Opitz ; Ralf Schumann." Berlin : Humboldt Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2012. http://d-nb.info/1023931613/34.
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Cordeil, Stéphanie. "Etude de la différence de susceptibilité des lentivirus de primates aux interférons de type I." Thesis, Lyon, École normale supérieure, 2012. http://www.theses.fr/2012ENSL0781.
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Les IFN-I (interférons de type I), principalement IFN et , constituent un mécanisme de défense primordial de l’hôte contre les pathogènes. Pourtant, dans le cas du VIH-1 (virus de l’immunodéficience humaine), la relation entre les IFN-I et la réplication virale apparaît plus complexe. En effet, si les IFN-I inhibent la réplication du VIH-1 ex vivo, un état d’hyperactivation permanent de la réponse IFN-I a été récemment associé à la progression vers le SIDA ainsi qu’à une forte virémie chez les patients infectés par le VIH-1. De même, la dérégulation de la réponse IFN-I est un critère déterminant dans l’issue pathogénique de certains modèles d’infection virale chez le singe. Si l’hypothèse du rôle pathogénique des IFN-I s’avère correcte, le VIH-1 pourrait avoir évolué afin de se répliquer même en présence d’une telle réponse, qui semble être au final, plus délétère pour l’hôte que pour le virus. L’objectif de ce travail a été d’évaluer la résistance du VIH-1 aux IFN. Dans ce contexte, le VIH-1 a été comparé au VIH-2 et au SIVmac (virus de l’immunodéficience simienne), virus phylogénétiquement proches mais peu ou pas pathogènes pour l’homme, lors de l’infection de plusieurs types cellulaires tels que des lymphocytes, des macrophages et des cellules dendritiques. En accord avec l’hypothèse initiale de travail, les expériences réalisées ont montré que le VIH-1 est capable de se répliquer dans les cellules primaires prétraitées avec des doses d’IFN comparables à celles mesurées in vivo, alors que la réplication des virus VIH-2/SIVmac est complètement bloquée, même à des concentrations très faibles d’IFN. Ce travail a permis de démontrer que le blocage induit par l’IFN s’exerce au niveau des phases précoces de l’infection et plus précisément à l’étape de la transcription inverse. En effet, les données obtenues suggèrent que l’IFN induit l’expression d’un effecteur cellulaire qui affecte différentiellement la stabilité des complexes viraux, ce qui se traduit par un défaut d’accumulation de l’ADN viral plus important pour le VIH-2 et le SIVmac, que pour le VIH-1. La différence de susceptibilité des lentivirus de primates aux IFN-I pourrait ainsi expliquer en partie, les différents niveaux de réplication de ces virus, associés à leurs degrés de pathogénicité in vivo<br>Type I Interferons (IFN-α/β, herein IFNs) provide an important mechanism of defense against pathogens and regulate in a paracrine and autocrine manner both intrinsic and adaptive immune responses. In the case of HIV-1 however, the relationship between IFNs and viral replication appears more complex. Indeed, if IFNs have been described to interfere with HIV-1 at basically all phases of its life cycle ex vivo, an IFN-induced state is linked to AIDS progression and to high viral loads in HIV-1 infected individuals. Similarly, a deregulated and prolonged IFN production/state seems one of the main distinguishing features between pathogenic and non-pathogenic SIV infection in primate animal models, suggesting that a deregulated IFN-state may be more detrimental to the host than to the virus itself in vivo.If this hypothesis is correct and if HIV-1 plays an active role in the perpetration of this antiviral state, it is possible that HIV-1 may have overall evolved to cope with this environment, remaining able to replicate despite it.To determine whether HIV-1 was better armed to replicate in the presence of an IFN-state environment than other primate lentiviruses, we compared HIV-1 to SIVmac and more importantly to HIV-2 that albeit capable of inducing AIDS in humans does so in a much less aggressive manner. In agreement with the initial hypothesis, our results indicate that HIV-1 is better fit to replicate in primary cells in the presence of amounts of IFN comparable to the ones measured in vivo, while the replication of HIV-2/SIVmac viruses is completely blocked even in the presence of low levels of IFN. By decorticating the effects of IFNs on the early and late phases of the viral life cycle in primary macrophages, we show here that the main target of the differential action of IFNs are the early phases of infection. More specifically, with time kinetics that we determine herein, IFNs induce cellular factor/s that differentially affect the stability of pre-reverse transcription complexes of HIV-2, but not of HIV-1. Our results could underlie a different evolutionary adaptation of primate lentiviruses to interferons that might be responsible for their different pathogenicity in vivo
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SEVERA, MARTINA. "Toll-like receptor-mediated induction of type I interferons promotes functional modifications and changing in the gene expression profile along dendritic cell maturation." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2009. http://hdl.handle.net/2108/979.
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Le cellule dendritiche (DC) sono considerate le principali cellule presentanti l`antigene per la loro straordinaria capacità di modulare sia la risposta innata che quella adattativa. Il riconoscimento dei patogeni da parte dei Toll-like Receptors (TLR) induce la maturazione delle DC e la successiva produzione di citochine necessarie per la regolazione della risposta immunitaria. Tra le citochine prodotte, gli Interferoni di tipo I (IFN) svolgono un ruolo chiave nella regolazione della risposta immunitaria in quanto, oltre a regolare la proliferazione, differenziamento e maturazione di diverse popolazioni leucocitarie, sono in grado di modulare diverse funzioni delle DC agendo in maniera autocrina e paracrina.
Sulla base di queste evidenze gli obiettivi principali di questa tesi sono stati la caratterizzazione del profilo di espressione dei vari sottotipi degli IFN di tipo I indotti nelle DC in seguito ad infezione virale o attivazione dei TLR e l’analisi delle modificazioni funzionali e dei cambiamenti nel trascrittoma IFN-mediati durante la maturazione delle DC.
I risultati ottenuti dimostrano:
- che sia l`infezione delle DC con il virus dell`Influenza di tipo A (Flu) o con il virus Sendai (SV) che la stimolazione del TLR3 e TLR4 con i rispettivi agonisti, l`acido polinosinic-poliacitidilico [poly(I:C)] e il lipopolisaccaride (LPS), inducono un`espressione selettiva dei vari sottotipi degli IFN di tipo I. In particolare, mentre tutti gli IFN di tipo I analizzati vengono indotti in seguito ad infezione virale, l`attivazione del TLR3 e TLR4 promuove soprattutto l`espressione dell` IFN-beta suggerendo la possibilità che questa citochina abbia un ruolo cruciale nel processo di maturazione delle DC;
- l’esistenza di uno specifico set di geni, coinvolti nelle risposte immuni anti-virali o anti-batteriche, specificamente indotto dalla produzione di IFN-beta durante la maturazione delle DC indotta dal trattamento con LPS;
- che fra i geni IFN-regolati è presente Viperin (virus inhibitory protein, endoplasmic reticulum-associated, interferon-beta inducible), una molecola che possiede un’attività antivirale il cui ruolo non è stato completamente chiarito. La stimolazione del TLR3 e del TLR4 induce alti livelli di espressione di Viperin tramite il pathway intracellulare che coinvolge TRIF, TBK1 e il recettore per il type I IFN (IFNalfa/betaR), mentre l`espressione di Viperin indotta dall`infezione con SV è TLR-independente e coinvolge l`RNA elicasi Retinoic acid-inducible gene (RIG-I). Abbiamo inoltre identificato come fattore trascrizionale chiave per l`induzione di Viperin il complesso IFN-stimulated gene factor (ISGF)-3, la cui azione viene bloccata dal repressore trascrizionale positive regulatory domain I-binding factor 1 (PRDI-BF1, anche chiamato BLIMP1) in grado di competere con ISGF-3 per i siti IFN stimulatory and regulatory element (ISRE) presenti all`interno della regione promotrice del gene Viperin.
- il gene codificante per il TLR7 è indotto in maniera IFN-dipendente durante la maturazione delle DC mediata da LPS. Sono stati esaminati i meccanismi responsabili dell`espressione del TLR7 identificando nel fattore trascrizionale IRF-1, i cui siti di legame sono presenti nel promotore del TLR7, il principale attivatore. Inoltre, abbiamo dimostrato che il “priming” con IFN- esogeno delle DC immature, che esprimono solo il TLR8, induce un TLR7 funzionalmente attivo. Infatti, l’utilizzo di un agonista specifico per il TLR7 (3M-001) induce la maturazione delle DC caratterizzata dall`espressione di molecole costimolatorie e dalla produzione di citochine pro-infiammatorie e regolatorie.
L’insieme dei nostri dati suggerisce che il rilascio di IFN di tipo I, indotto dalla stimolazione del TLR4, induce nelle DC uno specifico programma trascrizionale in grado di amplificare l`espressione di “sensori” intracellulari per differenti patogeni e rispondere in questo modo correttamente e combinatoriamente sia alle infezioni virali che a quelle batteriche.
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COLIN, MICOUIN ANNE. "P95 v a v et la signalisation par les interferons de type i dans les lignees megacaryocytaires ; implications dans un syndrome myeloproliferatif humain : la splenomegalie myeloide." Paris 7, 2000. http://www.theses.fr/2000PA077044.
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Le proto oncogene restreint aux lignees hematopoietiques, p95 v a v, possede des domaines structuraux lui conferant a la fois les caracteristiques d'un facteur de transcription et d'une molecule transductrice du signal. Nous avons montre, dans des lignees megacaryocytaires (dami et ut7), l'association constitutive de p95 v a v aux chaines ifnar1 et ifnar2 du recepteur des ifns de type i. La stimulation par les ifns / induit la phosphorylation rapide et transitoire de p95 v a v ainsi que l'augmentation de son association avec ifnar1 et ifnar2. Comme le laissait prevoir sa structure, p95 v a v presente une localisation aussi bien cytoplasmique que nucleaire ou il est associe a la proteine nucleaire ku-70. La stimulation par les ifn/ induit l'accumulation de p95 v a v phosphorylee au noyau et l'augmentation de son association a ku-70. Par l'utilisation d'oligonucleotides antisens de vav, nous avons montre l'implication de p95 v a v dans l'effet antiproliferatif des ifns de type i. Dans un deuxieme temps, nous avons etudie l'expression et la fonctionnalite de ce proto oncogene dans un syndrome myeloproliferatif : la myelofibrose primitive. La population megacaryocytaire semble jouer un role preponderant dans cette pathologie. Un essai de phase ii multicentrique utilisant l'inf- a ete ouvert. Nous avons montre que dans les cellules mononuclees du sang peripherique de malades p95 v a v est hyperphosphorylee en absence de tout traitement. La stimulation de ces cellules par l'ifn- n'induit pas d'augmentation de la phosphorylation constitutive.
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Fujita, Tomoko. "Type 1 interferons attenuate T cell activating functions of human mast cells by decreasing TNF-α production and OX40 ligand expression while increasing IL-10 production". Kyoto University, 2007. http://hdl.handle.net/2433/135668.
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Govender, Umeshree. "Study of transcription factors involved in the upregulation of IL-10 expression in human CD4 T cells costimulated by T cell receptor and type I interferon." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066076.
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L'objectif de cette thèse a été d'étudier le mécanisme de la coopération entre les voies de signalisation du TCR et de l'interféron de type I qui est responsable de l'augmentation d'expression de la cytokine anti-inflammatoire IL-10 dans les lymphocytes T CD45RA+CD4+ humains. En utilisant une approche transcriptomique et d'interférence d'ARNm, j'ai observé que les voies IFN et TCR contrôlent différemment l'expression des STATs et que les BATFs sont induits par l'IFN et augmentés par la costimulation TCR/IFN. STAT3 a été identifié comme régulateur majeur de l'IL-10 et il est recruté à proximité d'un site de liaison pour BATF au locus IL-10. Sur la base d'essais de co-silencing des trois BATFs, nous avons proposé que les BATFs contrôlent l'amplitude de la réponse IFN en agissant comme facteurs de transcription " pionniers ". D'autres résultats obtenus par une étude transcriptomique d'environ 200 gènes, montrent des contributions uniques et combinées des voies TCR et de l'IFN dans le programme d'expression de gènes des lymphocytes CD45RA+CD4+ activés et indiquent que d'autres facteurs de transcription pourraient réguler l'IL-10. Cette étude est susceptible d'apporter une connaissance plus large de mécanismes impliqués dans la régulation croisée entre les voies TCR et IFN<br>In CD4 T cells several transcription factors (TFs) regulate expression of the anti-inflammatory cytokine IL-10. I investigated how type I interferon (IFN) cytokines and T cell receptor (TCR) pathways cooperate toward early upregulation of IL-10 in human CD45RA+ CD4+ T cells. I interrogated the role of the STAT and BATF family by transciptomics and RNAi-mediated gene-silencing. IFN and TCR induced STAT2 and STAT3 expression, respectively, while the BATFs were induced early by IFN and further enhanced by TCR/IFN together. STAT3 was the major regulator of TCR- and TCR/IFN-mediated IL-10 while STAT2 contributed to the latter. STAT3 was recruited adjacent to a BATF-binding site at the IL-10 locus early in response to TCR/IFN. Co-silencing of the three BATFs led to a marked decrease in TCR- and TCR/IFN-mediated IL-10. We propose that the BATFs control the magnitude of the IFN response as pioneer factors. Additional results of transcriptional profiling of ± 200 genes, including TFs downstream of TCR and IFN and TFs involved in IL-10 regulation, revealed that TCR and IFN provide unique and combined contributions to the early CD45RA+CD4+ T cell gene activation program and identified other potential TFs involved in TCR/IFN-mediated IL-10 transcription. This study may provide broad mechanistic bases for crosstalk between the TCR- and IFN-pathways
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Dunuwille, Saranajith Wangisa. "MODULATION OF INFLAMMATORY CYTOKINE, CHEMOKINE, AND TOLL-LIKE RECEPTOR GENES AND TRANSCRIPTOME ANALYSIS OF EQUINE ENDOTHELIAL CELLS FOLLOWING INFECTION WITH EQUID HERPESVIRUS-1, AND EQUINE ARTERITIS VIRUS." UKnowledge, 2019. https://uknowledge.uky.edu/gluck_etds/44.
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EHV-1 is a double-stranded DNA virus whereas EAV is a positive sense, single-stranded RNA virus. Therefore, genetically, they are very different from one another. However, both these viruses are endotheliotropic and thus, infect and replicates in equine endothelial cells resulting in vasculitis. Vasculitis is central to the pathogenesis of these two viruses. Thus, the main objective of this thesis was to investigate the inflammatory and innate immune responses of EECs that contribute towards the development of vasculitis following infection with EHV-1 and EAV in-vitro. Since proinflammatory cytokines and chemokines produced by endothelial cells play a significant role in the development of vasculitis, we investigated their gene expression as well as secretion. Results from this study showed that the proinflammatory response of EECs induced by EAV is relatively less when compared with the corresponding results from EHV-1 infected EECs. Furthermore, EAV elicits a lower type I interferon response in EECs when compared with EHV-1. Further investigations revealed an active role played by TLR 3 in inducing the proinflammatory response in EHV-1 infected EECs during the first 6 hours of infection but not in EAV infected EECs. Analyzing the whole transcriptome of EHV-1 and EAV infected EECs revealed a complex pattern of gene regulation and cellular pathways related to cellular immune, inflammatory and apoptotic responses. Finally, we investigated host genetic factors associated with EHV-1 induced myeloencephalopathy but found no evidence for a recessive allele influencing the development of EHM following EHV-1 infection for any genetic locus was identified. However, more complex host-pathogen interactions are possible.
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Isaksson, Magnus. "Initiation of Autoimmunity in Experimental Autoimmune Encephalomyelitis." Doctoral thesis, Uppsala universitet, Molekylär medicin, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-173427.
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The events that trigger an autoimmune disease remain largely unknown. To study these events animal models are necessary because symptoms of autoimmune diseases are preceded by a long asymptomatic period in humans. Experimental autoimmune encephalomyelitis (EAE) is the best characterized model for cell mediated autoimmunity and an animal model for the human disease multiple sclerosis. EAE is induced in rodents by immunization with myelin antigens (Ags) together with adjuvants. After immunization, T cells are primed in the periphery by Ag presenting cells and subsequently invade the central nervous system where they mediate parenchymal inflammation, resulting in demyelination and clinical symptoms of an ascending paralysis. It is now generally recognised that the main cell type mediating EAE is the T helper type 17 (Th17) cell. Tolerance to EAE can be attained by DNA vaccination, but how the immune response against the myelin Ags is abrogated after DNA vaccination is not known. By employing short interfering RNA technology, induction of the innate immune signalling molecule interferon (IFN) -β was found to be necessary for the protective effect of DNA vaccination in EAE. In addition, DNA vaccination inhibited subsequent autoimmune Th17 cell responses. The Toll-like receptors (TLRs) of the innate immune system have evolved to recognise conserved molecular structures on microbes and signalling through them almost exclusively converge on the molecule MyD88. Signalling via MyD88 was found to be required for induction of EAE since mice deficient in this molecule did not develop disease. Upstream signalling via TLR4 and TLR9 had tolerogenic properties. In studies of Ag presentation in EAE, two major subtypes of dendritic cells (DCs) were examined. Plasmacytoid DCs were found to have a promoting role in the induction of EAE, partly via type 1 IFNs. Myeloid DCs had a redundant role in the induction phase of EAE, neither disease severity nor encephalitogenic Th17 responses were affected by their absence during priming. These studies further demonstrate that the cells and molecules of the innate immune system exhibit a crucial role in controlling the adaptive immune system which mediates tissue damage in autoimmune diseases.
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Mattiuz, Raphaël. "Rôle des cellules dendritiques conventionnelles de type 1 dans l'immunosurveillance des cancers." Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0437.
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Nous avons généré les souris Xcr1-DTA, Karma et Xcr1-hDTR pour éliminer les cellules dendritiques conventionnelles de type 1 (cDC1) de manière constitutive ou conditionnelle, et les souris Xcr1Cre et KarmaCre pour inactiver de manière sélective des gènes candidats dans ces cellules (Mattiuz et al., Front Immunol 2018). Nous avons utilisé ces modèles pour comprendre le rôle des cDC1 dans l'immunité naturelle contre le cancer. Nous avons utilisé un modèle d'adénocarcinome du sein (NOP23) spontanément rejeté après implantation orthotopique chez des souris femelles C57BL/6.Nous avons montré que les cDC1, les interférons, les lymphocytes T CD4+ conventionnels et CD8+, et plus tard les lymphocytes NK/NKT, sont cruciaux pour l'immunosurveillance du cancer du sein. Cependant, ni la réponse intrinsèque des cDC1 aux interférons de type I ni les molécules CXCL9, IL-12, IL-15 et XCR1 n'étaient nécessaires au rejet des tumeurs. Les voies de signalisation IFN-γ et STAT1 intrinsèques aux cDC1 jouent néanmoins un rôle déterminant dans l'immunosurveillance du cancer du sein. Nous avons établi que les cDC1 interagissent dans le stroma tumoral de manière simultanée avec les lymphocytes T CD8+ et CD4+ spécifiques de la tumeur. Ainsi, les cDC1 et les interférons façonnent la composition immunitaire tumorale et favorisent l’acquisition des phénotypes effecteurs des lymphocytes T CD4+ et CD8+, leur différentiation terminale et leurs fonctions. Conformément à nos résultats chez la souris, une forte expression intratumorale des gènes des cDC1, des CTLs, des T auxiliaires et de réponses aux interférons est associée à un bon pronostic chez les patientes atteintes d'un cancer du sein<br>We have generated and validated unique and specific mouse models to study the type 1 conventional dendritic cells (cDC1), including the Xcr1-DTA, Karma and Xcr1-hDTR mice to eliminate cDC1 constitutively or conditionally, and the Xcr1Cre and KarmaCre mice to selectively inactivate candidate genes in these cells (Mattiuz et al., Frontiers in Immunology 2018). We took advantage of these different models to better understand the role of cDC1 in natural immunity to cancer. To do this, we used a model of breast adenocarcinoma (NOP23), which is spontaneously rejected after orthotopic implantation in syngeneic C57BL/6 female mice.We have shown that cDC1, interferons, conventional CD4+ and CD8+ T cells and later NK/NKT cells are instrumental in breast cancer immunosurveillance. However, surprisingly, neither cDC1 cell-intrinsic response to type I interferons nor CXCL9, IL-12, IL-15 and XCR1 were necessary for tumor rejection. cDC1-intrinsic IFN-γ and STAT1 signaling pathways were nevertheless instrumental in breast cancer immunosurveillance. We have established that cDC1 interact with tumor-specific CD8+ T cells and CD4+ T cells together in the tumor stroma. Accordingly, cDC1 and interferons shape the tumor immune landscape and notably promote CD4+ and CD8+ T cell effector phenotypes, terminal differentiation and functions. In accordance with our experimental results in mice, high expression in the tumor microenvironment of genes specific to cDC1, cytotoxic T lymphocytes (CTL), helper T cells or interferon responses (ISGs) are associated with a better prognosis in human breast cancer patients
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Fries, Anissa. "Etude de la différenciation et des fonctions des monocytes classiques au cours de l'infection par le cytomégalovirus murin." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4047.
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Les monocytes classiques (cMo) sont des phagocytes mononucléés circulant dans le sang et capables de migrer vers les tissus enflammés pour s’y différencier en monocytes inflammatoires, cellules dendritiques dérivées de monocytes (MoDC), macrophages (MoM) ou cellules myéloïdes suppressives. Selon le contexte physiopathologique, les cellules dérivées de cMo peuvent être bénéfiques ou néfastes. Dans l’infection par le cytomégalovirus murin (MCMV) leur rôle est controversé. Les divergences apparentes dans la littérature pourraient s’expliquer par l’utilisation de souches distinctes de souris ou de virus, l’étude d’organes différents, et la confusion existante sur l’identité et la plasticité de différents sous-types de cellules dérivées de cMo. Par des analyses transcriptionnelles, morphologiques et fonctionnelles, mon travail de thèse montre que, dans la rate de souris infectées par MCMV, les cMo se différencient simultanément en monocytes inflammatoires, MoDC et MoM. Cette différenciation est abrogée lorsque les cMo sont incapables de répondre aux interférons de type I (IFN-I), massivement produits dans les infections virales, qui boostent l’immunité intrinsèque antivirale et promeuvent l’activation des cellules immunitaires innées et adaptatives. La déplétion des cMo compromet le contrôle de l’infection et les réponses des cellules Natural Killer et des lymphocytes T CD8+. Mon travail montre que, dans les souris infectées par MCMV, les cMo se différencient, de manière dépendante de l’IFN-I, en trois sous-types cellulaires distincts qui contribuent à la fois au contrôle de la réplication virale et à la promotion de réponses immunitaires innées et adaptatives protectrices<br>Classical monocytes (cMo) are mononuclear phagocytes mainly localized in the blood at steady state. Upon inflammation cMo migrate into inflamed tissues where they can differentiate in inflammatory monocytes, monocyte-derived dendritic cells (MoDC), monocyte-derived macrophages (MoM) or myeloid derived suppressor cells (MDSC). Depending on the physiopathological context, cMo-derived cells can be beneficial or detrimental. There are major discrepancies between published reports on the role of cMo during MCMV infection. This may be due to the use of distinct strains of mice or of virus, to the study of different organs, or to the confusion existing in the field regarding the identity and the plasticity of the different types of cMo-derived cells. During my PhD, by combining gene expression profiling, morphological, phenotypical and functional studies, I have shown that splenic cMo in MCMV-infected mice encompass cells that had simultaneously differentiated in vivo into either inflammatory monocytes, MoDC or MoM. This cMo differentiation is abrogated in the absence of responsiveness to type I interferons (IFN-I), which are highly produced during viral infections and boosting cell-intrinsic anti-viral immunity as well as promoting the activation of innate and adaptive immune responses. cMo depletion compromises the control of MCMV replication and the antiviral responses of Natural Killer cells and CD8+ T lymphocytes. My PhD work demonstrates that, in MCMV-infected mice, cMo differentiate, via an IFN-I-dependent pathway, into three distinct cell subtypes that are involved both in the control of MCMV replication and in the induction of protective innate and adaptive immunity
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Plaçais, Léo. "Modulation de l’expression des molécules point de contrôle inhibitrices par la voie des interférons / JAK-STAT dans l’infection chronique par le VIH-1." Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASQ023.
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Les personnes vivant avec le VIH-1 (PVVIH) présentent un risque plus élevé de comorbidité, associé à un état d'inflammation chronique et de dysfonction du système immunitaire. Cette dysfonction immunitaire se compose d'un état d'activation immunitaire et d'exhaustion, défini par l'expression de molécules points de contrôle inhibitrices (PCI) à la surface des cellules (PD-1, PD-L1). L'infection par le VIH-1 non traitée est responsable d'une augmentation de la signalisation interféron de type 1 (IFN-1), qui est réduite sous traitement antirétroviral. Nous avons donc souhaité évaluer le rôle de la signalisation IFN dans l'expression des PCI dans les cellules immunitaires de PVVIH sous traitement antirétroviral. Nos résultats démontrent la persistance d'une signalisation IFN élevée chez les PVVIH en dépit du traitement antirétroviral, associée à l'expression de pd-l1. L'exposition aux IFN-1 in vitro entraînait l'expression de PD-L1 dans les cellules myéloïdes, qui était plus marquée chez les PVVIH - ainsi que sur les lymphocytes T CD4 et CD8. Les effets d'activation de l'IFN-1 sur les lymphocytes T CD4 nécessitaient la présence de monocytes, et le degré d'expression de PD-L1 monocytaire en réponse à l'IFN-1 corrélait avec l'activation CD4 induite. Le profil d'expression de gènes de l'inflammation ex-vivo et les réponses transcriptionnelles à l'IFN-1 différaient entre monocytes de PVVIH et d'individus non-infectés. Les effets des IFN était abrogés en présence d'inhibiteur de JAK-1/2 ou de TYK-2. Ces résultats suggèrent l'existence d'une réponse IFN-1 monocytaire augmentée chez les PVVIH, médiant l'activation lymphocytaire T et modulable par des inhibiteurs de JAK<br>People living with HIV-1 (PLH) experience an increased risk of comorbidities, associated with signs of chronic inflammation and immune system dysfunction. Immune cells from PLH show signs of activation and exhaustion, with increased expression of checkpoint inhibitor molecules (CPI, PD-1/PD-L1). An increased type 1 interferon (IFN-1) signaling is paramount of the untreated HIV-infection and only partially reduced upon antiretroviral therapy. We therefore aimed to investigate the role of IFN-1 on the expression of CPI in immunes cells from PLH under antiretroviral therapy. We report an increased IFN-1 signaling in PLH primary cells, correlated with the expression of pd-l1. In vitro exposure to IFN-1 induced PD-L1 and HLA-DR expression on myeloid cells, at a higher extent in PLH cells than uninfected individuals (UIs). IFN-1 potentiated T cell activation and increased their expression of activation markers and of PD-L1, again at a higher extent in PLH than UIs. Importantly, IFN-1 potentialisation of CD4 T cell activation required CD14+ monocytes, and a transfer of IFN-1-exposed CD14+ monocytes increased T cell activation. CD14+ cells from PLH expressed a distinct pattern of inflammation-related genes than UIs, and IFN-1 induced differential gene expression between PLH and UIs. IFN-1 mediated effets on monocytes, dendritic cells and T lymphocytes were abrogated in the presence of a JAK-1/2 inhibitor or a TYK-2 inhibitor. Overall, our results identify heightened IFN-1 responses in monocytes from PLH as a driver of T cell activation and PD-L1 expression, and pave the way for JAK-inhibition strategies to reduce immune activation and inflammation in PLH
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Bruel, Timothée. "Étude des mécanismes de la réponse interféron de type I précoce et du contrôle à long terme de la virémie dans le modèle d’infection du macaque cynomolgus par le SIV : implications dans la physiopathologie du VIH." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA114819.
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L’infection par le VIH induit une activation immunitaire chronique qui est suspectée d’être un des moteurs de la pathogénèse du SIDA. L’identification des mécanismes de contrôle de cette activation immunitaire, ainsi qu’une meilleure compréhension du contrôle spontané de l’infection chez certains patients, sont des étapes essentielles vers la conception de thérapies innovantes. Nous avons utilisé le modèle d’infection du macaque cynomolgus (Macaca fascicularis) par le virus de l’immunodéficience simienne (SIV) pour étudier ces deux points fondamentaux de la physiopathologie de l’infection.Il est proposé que l’induction précoce de l’activation immunitaire chronique soit une conséquence de la surexpression des gènes induits par les interférons (ISG) en réponse aux interférons de type I (IFN-I). Ces IFN-I ( et ) sont notamment produits par les cellules dendritiques plasmacytoïdes (pDC) en réponse aux virus. Notre premier objectif a été d’étudier la dynamique de production des IFN-I et celle des pDC durant l’infection, en parallèle de celle de l’activation immunitaire chronique et de la virémie. Nos résultats montrent que les pDC sont activées dans les tissus et qu’elles sont responsables de la production d’IFN-I observée transitoirement au cours de la primo-infection. La dynamique des pDC (apoptose, activation, renouvellement) entraîne un épuisement de la capacité des pDC à produire de l’IFN-I, qui pourrait rendre compte à la fois de l’altération fonctionnelle des pDC et de l’arrêt de la production d’IFN-I. De manière surprenante, ce contrôle de la production d’IFN-I n’est pas suivi d’un contrôle de la surexpression des ISG, ce qui suggère l’existence d’autres mécanismes inducteurs des ISG et souligne l’origine multifactorielle de l’activation immunitaire chronique.Dans une seconde étude, nous avons analysé l’impact d’une déplétion in vivo des lymphocytes exprimant le CD8 chez des animaux contrôlant spontanément la réplication virale sur le long terme. Quatre des cinq animaux de l’étude n’expriment pas de complexe majeur d’histocompatibilité (CMH) précédemment associé au contrôle, et aucun d’entre eux ne présente de forte réponse LT CD8. La déplétion transitoire des cellules CD8 entraîne chez quatre des contrôleurs une augmentation transitoire de la virémie qui se stabilise ensuite à des valeurs similaires aux niveaux pré-déplétion lors du retour des cellules CD8+. Un de ces animaux contrôle sa virémie avant la restauration des LT CD8. Chez le cinquième animal, la déplétion des CD8 n’a pas été accompagnée d’une élévation de virémie. Globalement, le contrôle de la virémie après l’élévation transitoire n’a pas été accompagné d’une augmentation de leur fonction antivirale. En revanche, une expansion et une activation des LT CD4 consécutive à la déplétion des CD8 ont été remarquées et corrélées positivement avec la virémie plasmatique. Ces résultats suggèrent que les réponses LT CD8 ne sont pas les principales responsables du contrôle à long terme de la virémie chez ces animaux. Dans notre modèle, d’autres mécanismes, tels qu’un réservoir de virus limité ou un meilleur contrôle de l’activation immunitaire, semblent participer à ce phénotype de contrôle.En conclusion, ces résultats éclairent la contribution des pDC, des IFN-I et des LT CD8 dans la physiopathologie du VIH, et permettent de proposer un nouveau modèle d’étude des mécanismes immunologiques précoces mis en place chez les patients contrôleurs de la virémie à long terme<br>HIV infection induces a chronic immune activation, which is suspected to be a driving force in the pathogenesis of AIDS. Identifying control mechanisms of this immune activation, and a better understanding of the spontaneous control observed in some patients, are essential steps towards the development of innovative therapies. We used the model of cynomolgus macaques (Macaca fascicularis) infected by the simian immunodeficiency virus (SIV) to study these two fundamental fields of HIV pathogenesis.It is proposed that early induction of chronic immune activation is a consequence of an interferon-induced genes (ISG) overexpression in response to type I interferons (IFN-I). These I IFN (α and β) are preferentially produced by plasmacytoid dendritic cells (pDC) in response to the virus. Our first objective was to study the dynamics of pDC and IFN-I production during infection, together with chronic immune activation and viremia analysis. Our results indicate that pDCs are activated in tissues and are responsible for the transient IFN-I production observed during primary infection. The dynamics of pDCs (apoptosis, activation, renewal) induces an impaired IFN-I production by pDC, which could account both the functional defect of pDCs and the arrest of IFN-I production. Surprisingly, control of IFN-I production is not followed by down-regulation of ISG, which suggests the existence of other mechanisms that induce ISG and emphasizes the multifactorial origin of chronic immune activation.In a second study, we analyzed the impact of a in vivo CD8 T cells depletion in animals which spontaneously control viral replication in the long term. Importantly, four of the five animals in the study do not express major histocompatibility complex (MHC) previously associated with control, and none of them display strong CD8 response. The transient depletion of CD8 cells results in four controllers in a transient increase in viremia, which then stabilizes at values similar to pre-depletion levels when CD8+ cells come back. One of these animals controls their viremia before the restoration of CD8. In the fifth animal, CD8 depletion was not followed by a rise in viremia. Overall, the control of viremia after the transient increase was not associated to an increase of the antiviral function of CD8 T cells. In contrast, CD4 T cells expansion and activation were noticed and positively correlated to plasma viremia. These results suggest that CD8 responses are not the main cause of long-term control of viremia in these animals. In our model, other mechanisms, such as smaller reservoir or better control of immune activation, seem to be involved in this controller phenotype.In conclusion, these results shed light on the contribution of pDCs, IFN-I and CD8 T cells in the pathogenesis of HIV, and allow us to propose a new model for studying early immunological mechanisms in HIV controllers
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Ogor, Thomas. "Ciblage cellulaire spécifique de l'interféron α pour le contrôle des défenses immunitaires antitumorales". Thesis, Université de Montpellier (2022-….), 2022. http://www.theses.fr/2022UMONT001.
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Il est largement admis qu'un cancer se développe lorsque les cellules cancéreuses échappent au contrôle du système immunitaire et que l'exploitation des défenses immunitaires afin de réactiver les cellules T endogènes anti-tumorales pourrait être une option thérapeutique pour obtenir des réponses complètes et durables.L'interféron de type I est connu pour sa puissante activité antitumorale dans les tumeurs expérimentales de la souris. En outre, il s'est avéré être une cytokine clé nécessaire à l'efficacité de nombreux agents anticancéreux ciblant non seulement les cellules cancéreuses (radiations ionisantes, produits chimiques cytostatiques, AcM...) mais aussi le système immunitaire (vaccination, cellules CAR-T...). Cependant, son utilisation n'est plus envisagée par le clinicien en raison des effets secondaires subis par les patients. Pour répondre à cette préoccupation, une technologie très prometteuse permettant la conception de molécules d'interféron ciblées et spécifiques aux cellules a été développée et l'objectif de notre travail actuel est de générer et d'évaluer pré-cliniquement des composés principaux. Pour cela, il faut s'attaquer à un certain nombre de frontières de la recherche, notamment répondre aux questions fondamentales "où" et "quand" l'interféron doit agir pour exercer son activité antitumorale, seul ou en combinaison avec les stratégies thérapeutiques susmentionnées.La question "quand" est importante car on soupçonne fortement que le moment relatif de l'action de l'interféron et de la stimulation du TCR détermine si l'effet de l'interféron est immunostimulant ou immunosuppresseur. La question "où" est évidente car elle détermine le choix de la partie ciblée des interférons modifiés. Nous savons que l'action de l'interféron sur les cellules dendritiques est nécessaire à son activité antitumorale, mais est-elle suffisante ? Une action sur les cellules T est-elle également obligatoire ? L'action de l'interféron sur les cellules tumorales ou les cellules du stroma est-elle nécessaire pour attirer les cellules immunitaires effectrices ?<br>It is widely accepted that a cancer develops when cancer cells escape from the control of the immune system and that harnessing the immune defences in order to reactivate endogenous anti-tumor T cells could be a therapeutic option for full and durable responses.Type I interferon is known for its potent antitumor activity in experimental mouse tumors. Furthermore, it has been shown to be a key cytokine necessary for the efficacy of many anticancer agents targeting not only cancer cells (ionising radiations, cytostatic chemicals, mAbs…) but also the immune system (vaccination, CAR-T cells…). However, its use is no longer considered by the clinician owing to the side effects experienced by the patients. To address this concern, a highly promising technology allowing the design of cell-specific targeted interferon molecules has been developed and the objective of our present work is to generate and pre-clinically evaluate lead compounds. For this, a number of research frontiers must be tackled, these include to answer to the fundamental questions 'where' and 'when' interferon must act in order to exert its antitumor activity either alone or in combination with the above-mentioned therapeutic strategies.The question 'when' is important because it is highly suspected that the relative timing of interferon action and TCR stimulation determines whether the effect of interferon is immunostimulant or immunosuppressive. The question 'where' is evident since it determines the choice of the targeting moiety of the engineered interferons. We know that the action of interferon on dendritic cells is necessary for its antitumor activity but is it sufficient? Is an action on T cells also mandatory? Is an interferon action on tumor cells or stroma cells necessary for attracting effector immune cells?
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Ghislain, Julien Johannes. "Type I interferon signal transduction." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0015/NQ27652.pdf.
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Orvain, Cindy. "Implication des cellules souches du follicule pileux dans la physiopathologie de l'hidradénite suppurée." Electronic Thesis or Diss., Paris Est, 2019. http://www.theses.fr/2019PESC0038.
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L’hidradénite suppurée (HS) est une dermatose inflammatoire chronique affectant 1% de la population française. Les lésions se présentent sous forme d’abcès et de fistules très douloureux dans les zones riches en poils notamment les aisselles et la zone périnéale. L’HS est la maladie dermatologique avec la plus faible qualité de vie. En effet, les patients HS présentent une souffrance psychologique importante se traduisant par une honte vis-à-vis de leurs lésions, une isolation sociale et le développement d’états dépressifs. De nos jours, les traitements proposés ne permettent pas la guérison mais seulement une amélioration des symptômes. L’HS est communément décrite comme une maladie atteignant le follicule pileux. En effet, l’occlusion du follicule entraînerait sa rupture et la dissémination de bactéries et de kératine dans le derme initiant une inflammation qui deviendrait chronique. Notre équipe s’intéresse aux cellules de la gaine externe du follicule pileux que l’on nomme ORS pour Outer Root Sheath cells. Nous avons montré que les ORS isolées à partir de patients HS (ORS-HS) présentaient un phénotype pro-inflammatoire se traduisant par la sécrétion spontanée de deux chimiokines, CXCL10 et CCL5. Le but de ma thèse était d’identifier les mécanismes moléculaires et cellulaires à l’origine du phénotype pro-inflammatoire des ORS-HS. Nous avons posé l’hypothèse qu’une dérégulation du cycle cellulaire des ORS entraînerait un stress réplicatif et une accumulation d’ADN cytoplasmique qui induirait la production d’IFN de type I via STING. L’analyse transcriptomique des ORS-HS a mis en évidence une signature IFN de type I et une dérégulation des gènes du cycle cellulaire. L’étude clonotypique des ORS-HS confirme une augmentation du potentiel de prolifération des ORS-HS. De plus, l’analyse par cytométrie de flux des populations des cellules du follicule pileux a révélé l’absence de la population cellules souches quiescentes CD200+ CD34- CD49f+ CytoK15high en faveur des cellules progénitrices prolifératives CD200+ CD34- CD49f+ CytoK15lowchez les patients HS. La capacité augmentée de prolifération des ORS-HS nous a conduit à analyser leur cycle cellulaire. Nous avons montré une accumulation d’ORS-HS en phase S. Afin de déterminer si cette accumulation était lié à un stress réplicatif, nous avons étudié la vitesse de la fourche de réplication de l’ADN. Nous avons observé une altération de la vitesse de la fourche de réplication de l’ADN et une activation spontanée de la voie ATR-CHK1, voie activée lors des dommages à l’ADN, dans les ORS-HS. Des études récentes ont montré que les dommages à l’ADN menaient à la formation de micronuclei qui en se dissociant libéraient l’ADN dans le cytosol et activaient le senseur STING. Les ORS-HS présentaient plus de micronuclei et une accumulation d’ADN cytosolique comparés aux ORS-HD. L’étude des ORS-HS transfectées par des siRNA dirigés contre STING et IFI16, montre une diminution des transcrits de l’IFNb. Ces résultats suggèrent l’implication de la voie IFI16/STING dans la signature IFN de type I des ORS-HS. Nos résultats révèlent qu’un défaut de l’homéostasie des HFSC serait le primum movens de la maladie et initierait une boucle inflammatoire. Le stress réplicatif des ORS-HS, les dommages à l’ADN ainsi que la voie STING seraient impliqués dans ce mécanisme. L’inflammation pourrait également contribuer à la perturbation de l’homéostasie des HF-SC ce qui créerait un cercle vicieux inflammatoire. Durant notre étude, nous avons remarqué l’existence de deux groupes de patients : un groupe présentait un stress réplicatif et une activation des voies de dommages à l’ADN élevé alors que l’autre groupe était plus faible pour ces deux paramètres. Il serait intéressant de définir de nouveaux biomarqueurs permettant de distinguer ces deux groupes de patients afin de proposer des thérapies ciblées<br>Role of hair follicle stem cells in hidradenitis suppurativa physiopathologyHidradenitis suppurativa (HS) is a chronic inflammatory dermatosis which affects 1% of the French population. Lesions are painful and characterized by abcesses, fistulaes and malodorous discharges. They appear in hair rich skin areas like the armpits, the pubis and the buttock. HS causes a high extent of emotional and physical distress, as well as social embarrassment, isolation and depression, making it the common dermatosis which leads to the most severe impairment of quality of life. As most treatments have been unsatisfactory, and as there are many recurrences, HS remains difficult to cure.HS appears to be a primary abnormality in the pilosebaceous-apocrine unit, which leads to follicular occlusion, perifollicular cyst development which traps commensal microbes, and rupture into the dermis. Our team focused on hair follicle cells and especially Outer Root Sheath Cells (ORS). We previously showed that ORS isolated from hair follicle of HS patients (HS-ORS) spontaneously secrete IP10 (CXCL10) and RANTES (CCL5). The aim of my thesis is to characterize molecular and cellular mechanisms involved in this pro-inflammatory phenotype of HS-ORS. We hypothesized that cell cycle deregulation in the ORS leads to replication stress and accumulation of cytoplasmic ssDNA, inducing IFN synthesis involved in the establishment of chronic inflammation.First, we performed a transcriptomic analysis of HS-ORS, which revealed an interferon signature and an alteration of cell cycle pathways. Colony-forming efficiency assay of ORS showed a much higher colony-forming ability of HS-ORS compared to healthy donor (HD)-ORS. We highlighted the loss of quiescent hair follicle stem cell population described as CD200+ CD34- CD49f+ CytoK15high cells and an increased number of proliferating cells in HS patients. The increased number of proliferating ORS cells in HS patients led us to analyse their cell-cycle distribution. The percentage of ORS in S phase was increased in HS patients. We next asked whether this was due to increased replication stress, which is defined as a global perturbation of the DNA replication program altering the speed of replication forks and activating the ATR-CHK1 pathway. We observed that the progression of replication fork was severely altered in HS-ORS. Moreover, the ATR-CHK1 pathway was spontaneously activated in HS-ORS cells. Recent evidence indicates that micronuclei formation is increased upon DNA damage and their rupture exposes DNA to cytosolic nucleases and activates the STING pathway. We observed an accumulation of ssDNA and micronuclei in the cytoplasm of HS-ORS. Thus we analyzed STING pathway. In HS patients, ORS lacking STING expressed reduced levels of IFN-β transcripts compared to ORS transfected with a scramble siRNA. Lastly, we revealed that STING activation was mediated by the DNA binding protein IFI16.We report the first mechanistic analysis of the etiology of HS in the hair follicle stem cells (HF-SC) compartment. Our results suggested that modifications of HF-SC homeostasis are the primum movens to initiate an inflammatory loop. Replicative stress leads to genomic DNA damage triggering inflammatory response through IFI16-STING pathway. Inflammation could also contribute to the perturbation of HF-SC homeostasis which perpetuates the inflammatory circle. Future work will focus on mechanisms which lead to quiescence loss of HF-SC. During our study, we noticed two groups of HS patients: one with high replicative stress and DNA damage activation and another with moderate replicative stress and DNA damage activation. It would be of interest to define new biomarkers to distinguish these two groups of patients in order to propose personalized treatment
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Fenner, Jennifer Eve. "Regulation of Type I interferon responses." Monash University, Centre for Functional Genomics and Human Disease, 2003. http://arrow.monash.edu.au/hdl/1959.1/9437.
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Kamphuis, Elisabeth. "Type I interferon stimulation of lymphocytes." Giessen : VVB Laufersweiler, 2007. http://geb.uni-giessen.de/geb/volltexte/2007/4791/index.html.
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Kamphuis, Elisabeth. "Type I interferon stimulation of lymphocytes." Giessen VVB Laufersweiler, 2006. http://d-nb.info/988717891/34.
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Walker, Angela Marie Roberts R. M. "The type I IFN of Bos taurus." Diss., Columbia, Mo. : University of Missouri-Columbia, 2008. http://hdl.handle.net/10355/6864.
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The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on April 1, 2010). Vita. Thesis advisor: R. Michaels Roberts. "May 2008" Includes bibliographical references