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Interferon alpha-2 is a protein that in humans is encoded by the IFNA2 gene. Human interferon alpha-2 (IFNα2) is a cytokine belonging to the family of type I IFNs. IFNα2 is a protein secreted by cells infected by a virus and acting on other cells to inhibit viral infection. The first description of IFNs as a cellular agent interfering with viral replication was made by Alick Isaacs and Jean Lindenmann in 1957. The history of this finding was recently reviewed. There are 3 types of IFNs: Interferon type I, Interferon type II and Interferon type III. The type II IFN, also called IFNγ, is produced by specific cells of the immune system. Unlike type I and type III IFNs, IFNγ has only a modest role in directly restricting viral infections. Type I and type III IFNs act similarly. However, the action of type III IFNs, also known as IFNλ, is limited to epithelial cells while type I IFNs act on all bodys cells. Type I IFNs form a family of several proteins: in humans, there are 13 α subtypes, 1 β ...
Our study is the first to simultaneously assess protein levels of MxA, CD64, CD169 and BAFF as biomarkers for IFN type I detection. Herein, MxA was distinguished as the best functional biomarker for systemic IFN type I activity in pSS.. MxA protein is considered as an important mediator of early innate immune defence and its expression has been used as a marker for IFN bioactivity in experimental as well as clinical settings.19 ,27 The MxA gene, in contrast to other IFIGs, is not directly induced by viruses and strictly depends on IFN signalling.27 Furthermore, the stability of MxA protein in cells was observed to be higher than the corresponding mRNA levels.26 We assessed intracellular MxA protein using an EIA method on whole blood and flow cytometric analyses on circulating CD14 monocytes. In our patients, flow cytometric detection of MxA in monocytes showed a slightly better distinction between IFNpos and IFNneg patients within this pSS group, relative to the EIA in whole blood. Nevertheless, ...
Our study is the first to simultaneously assess protein levels of MxA, CD64, CD169 and BAFF as biomarkers for IFN type I detection. Herein, MxA was distinguished as the best functional biomarker for systemic IFN type I activity in pSS.. MxA protein is considered as an important mediator of early innate immune defence and its expression has been used as a marker for IFN bioactivity in experimental as well as clinical settings.19 ,27 The MxA gene, in contrast to other IFIGs, is not directly induced by viruses and strictly depends on IFN signalling.27 Furthermore, the stability of MxA protein in cells was observed to be higher than the corresponding mRNA levels.26 We assessed intracellular MxA protein using an EIA method on whole blood and flow cytometric analyses on circulating CD14 monocytes. In our patients, flow cytometric detection of MxA in monocytes showed a slightly better distinction between IFNpos and IFNneg patients within this pSS group, relative to the EIA in whole blood. Nevertheless, ...
The transcription factor interferon regulatory factor 1 (IRF-1) binds tightly to the interferon (IFN)-beta promoter and has been implicated in the induction of type I IFNs. We generated mice devoid of functional IRF-1 by targeted gene disruption. As reported by others, IRF-1-deficient mice showed a discrete phenotype: the CD4/CD8 ratio was increased and IFN-gamma-induced levels of macrophage iNO synthase mRNA were strongly diminished. However, type I IFN induction in vivo by virus or double-stranded RNA was unimpaired, as evidenced by serum IFN titers and IFN mRNA levels in spleen, liver and lung. There was also no impairment in the response of type I IFN-inducible genes. Therefore, IRF-1 is not essential for these processes in vivo. Reis, L. F.; Ruffner, H.; Stark, G.; Aguet, M.; Weissmann, C.
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Background/Purpose: The deficiency of adenosindeaminase 2 (DADA2) is a recently described autosomal recessive autoinflammatory disease, caused by mutations of CECR1 and characterized by early onset vasculopathy with livedoid skin associated to systemic inflammation. In some patients, the disease is mild and skin-limited, in others is severe, with multi-organ involvement including ischemic or hemorrhagic strokes. In some DADA2 patients a mild immunodeficiency was detected involving adaptive immunity. TNF inhibitors are very efficacious. Recently, an upregulation of type I interferon-stimulated gene transcripts, so called interferon signature, was described also in two DADA2 patients. We describe the clinical course of a 4 patients with CECR1 mutations and we assess the role of interferon type I signature as marker of diseases activity Methods: Molecular analysis of CECR1 was performed using next generation sequencing and confirmed by sanger sequencing. Blood was collected into PAXgene tubes and ...
In the treatment of renal cell carcinoma both complete (CRs) and partial remissions (PRs) have been obtained using recombinant (r) interferon alpha (IFN-alpha), with response rates ranging from 0 to 31% (mean 16%). rIFN-gamma is a potent immunostimulating agent, but the clinical experience of its use is limited and results are conflicting. In a phase II study with the combination of rIFN-alpha(2c) (Boehringer Ingelheim) and rIFN-gamma (Genentech, supplied by Boehringer Ingelheim) in 31 eligible patients, a response rate of 25% was recorded. Based on this observation a randomised phase III study was initiated to investigate the possible advantage of the addition rIFN-gamma to rIFN-alpha(2c) treatment. Treatment consisted of rIFN-alpha(2c) 30 pg m(-2) = 10 x 10(6) IU m(-2) s.c. twice weekly in arm A and the same dose of rIFN-alpha combined with rIFN-gamma 100 mu g m(-2) = 2 x 10(6) IU m(-2) in arm B. Eligibility criteria included documented progression of disease; patients with bone lesions only ...
Specific immunotherapy (SIT) reverses the symptoms of seasonal allergic rhinitis (SAR) in most patients. Recent studies report type I interferons shifting the balance between type I T helper cell (Th1) and type II T helper cells (Th2) towards Th2 dominance by inhibiting the differentiation of naive Tcells into Th1 cells. As SIT is thought to cause a shift towardsTh1 dominance, we hypothesized that SIT would alter interferon type I signaling. To test this, allergen and diluent challenged CD4(+) T cells from healthy controls and patients from different time points were analyzed. The initial experiments focused on signature genes of the pathway and found complex changes following immunotherapy, which were consistent with our hypothesis. As interferon signaling involves multiple genes, expression profiling studies were performed, showing altered expression of the pathway. These findings require validation in a larger group of patients in further studies.. ...
Abortive infection of macrophages serves as a "dead end" for most seasonal influenza A virus (IAV) strains, and it is likely to contribute to effective host defence. Interferon (IFN)-induced transmembrane protein 3 (IFITM3) restricts the early stages of IAV replication in epithelial cells, but IFITM3 restriction of IAV replication in macrophages has not been previously investigated. Herein, macrophages isolated from IFITM3-deficient mice were more susceptible to initial IAV infection, but late-stage viral replication was still controlled through abortive infection. Strikingly, IFNα/β receptor (IFNAR)-deficient macrophages infected with IAV were not only more susceptible to initial infection, but these cells also supported productive viral replication. Significantly, we have established that abortive IAV infection in macrophages is controlled through a type I IFN-dependent mechanism, where late-stage IAV replication can proceed in the absence of type I IFN responses. These findings provide ...
Clone REA521 recognizes the human interferon regulatory factor 7 (IRF-7) antigen, regardless of phosphorylation status. IRF-7 is a member of the IRF family of transcription factors and a key player in the innate immune response against viral infections. Constitutive expression of IRF-7 is limited to peripheral blood lymphocytes and dendritic cells while in most cell types its expression can be induced by type I interferon. IRF-7 is sequestered in the cytoplasm of uninfected cells and following viral infection, double-stranded RNA, or toll-like receptor signaling, it becomes phosphorylated by TBK and IKK-i kinases. Phosphorylated IRF-7 migrates in the nucleus where it can activate interferon type I genes and other interferon-stimulated genes. Additional information: Clone REA521 displays negligible binding to Fc receptors. - Great Britain
Clone REA310 recognizes the interferon regulatory factor 7 (IRF-7) phosphorylated at serines 477 and 479 (pS477/pS479). IRF-7 is a member of the IRF family of transcription factors and a key player in the innate immune response against viral infections. Constitutive expression of IRF-7 is limited to peripheral blood lymphocytes and dendritic cells while in most cell types its expression can be induced by type I interferon. IRF-7 is sequestered in the cytoplasm of uninfected cells and following viral infection, double-stranded RNA, or toll-like receptor signaling, it becomes phosphorylated by TBK and IKK-i kinases. Phosphorylated IRF-7 migrates in the nucleus where it can activate interferon type I genes and other interferon-stimulated genes. Additional information: Clone REA310 displays negligible binding to Fc receptors. - Lëtzebuerg
Precise control of interferons (IFNs) is crucial to maintain immune homeostasis. Here, we demonstrated that homeodomain-interacting protein kinase 2 (HIPK2) was required for the production of type I IFNs in response to RNA virus infection. HIPK2 deficiency markedly impaired IFN production in macrophages after vesicular stomatitis virus (VSV) infection, and HIPK2-deficient mice were more susceptible to lethal VSV disease than were wild-type mice. After VSV infection, HIPK2 was cleaved by active caspases, which released a hyperactive, N-terminal fragment that translocated to the nucleus and further augmented antiviral responses. In part, HIPK2 interacted with ELF4 and promoted its phosphorylation at Ser369, which enabled Ifn-b transcription. In addition, HIPK2 production was stimulated by type I IFNs to further enhance antiviral immunity. These data suggest that the kinase activity and nuclear localization of HIPK2 are essential for the production of type I IFNs. ...
BACKGROUND: Childhood-onset systemic lupus erythematosus (cSLE) is an incurable multi-systemic autoimmune disease. Interferon type I (IFN-I) plays a pivotal role in the pathogenesis of SLE. The objective of this study was to assess the prevalence of the IFN-I signature and the contribution of cytosolic nucleic acid receptors to IFN-I activation in a cohort of primarily white cSLE patients. METHODS: The IFN-I score (positive or negative), as a measure of IFN-I activation, was assessed using real-time quantitative PCR (RT-PCR) expression values of IFN-I signature genes (IFI44, IFI44L, IFIT1, Ly6e, MxA, IFITM1) in CD14+ monocytes of cSLE patients and healthy controls (HCs ...
Type I interferon (IFN) is an important host defense cytokine against intracellular pathogens, mainly viruses. In assessing IFN production in response to group B streptococcus (GBS), we find that IFN-beta was produced by macrophages upon stimulation with both heat-killed and live GBS. Exposure of macrophages to heat-killed GBS activated a Toll-like receptor (TLR)-dependent pathway, whereas live GBS activated a TLR/NOD/RIG-like receptor (RLR)-independent pathway. This latter pathway required bacterial phagocytosis, proteolytic bacterial degradation, and phagolysosomal membrane destruction by GBS pore-forming toxins, leading to the release of bacterial DNA into the cytosol. GBS DNA in the cytosol induced IFN-beta production via a pathway dependent on the activation of the serine-threonine kinase TBK1 and phosphorylation of the transcription factor IRF3. Thus, activation of IFN-alpha/-beta production during infection with GBS, commonly considered an extracellular pathogen, appears to result from the
The microbiota is known to modulate the host response to influenza infection through as-yet-unclear mechanisms. We hypothesized that components of the microbiota exert effects through type I interferon (IFN), a hypothesis supported by analysis of influenza in a gain-of-function genetic mouse model. Here we show that a microbially associated metabolite, desaminotyrosine (DAT), protects from influenza through augmentation of type I IFN signaling and diminution of lung immunopathology. A specific human-associated gut microbe, Clostridium orbiscindens, produced DAT and rescued antibiotic-treated influenza-infected mice. DAT protected the host by priming the amplification loop of type I IFN signaling. These findings show that specific components of the enteric microbiota have distal effects on responses to lethal infections through modulation of type I IFN. ...
Cai, Baowei; Wu, Jian; Yu, Xiao; Su, Xin-zhuan; Wang, Rong-Fu (2017). FOSL1 Inhibits Type I Interferon Responses to Malaria and Viral Infections by Blocking TBK1 and TRAF3/TRIF Interactions. MBio. Available electronically from http : / /hdl .handle .net /1969 .1 /180911. ...
TY - JOUR. T1 - Type i interferon responses in rhesus macaques prevent SIV infection and slow disease progression. AU - Sandler, Netanya G.. AU - Bosinger, Steven E.. AU - Estes, Jacob D.. AU - Zhu, Richard T R. AU - Tharp, Gregory K.. AU - Boritz, Eli. AU - Levin, Doron. AU - Wijeyesinghe, Sathi. AU - Makamdop, Krystelle Nganou. AU - Del Prete, Gregory Q.. AU - Hill, Brenna J.. AU - Timmer, J. Katherina. AU - Reiss, Emma. AU - Yarden, Ganit. AU - Darko, Samuel. AU - Contijoch, Eduardo. AU - Todd, John Paul. AU - Silvestri, Guido. AU - Nason, Martha. AU - Norgren, Robert B.. AU - Keele, Brandon F.. AU - Rao, Srinivas. AU - Langer, Jerome A.. AU - Lifson, Jeffrey D.. AU - Schreiber, Gideon. AU - Douek, Daniel C.. PY - 2014. Y1 - 2014. N2 - Inflammation in HIV infection is predictive of non-AIDS morbidity and death, higher set point plasma virus load2 and virus acquisition; thus, therapeutic agents are in development to reduce its causes and consequences. However, inflammation may simultaneously ...
TY - JOUR. T1 - Type i interferon responses in rhesus macaques prevent SIV infection and slow disease progression. AU - Sandler, Netanya G.. AU - Bosinger, Steven E.. AU - Estes, Jacob D.. AU - Zhu, Richard T.R.. AU - Tharp, Gregory K.. AU - Boritz, Eli. AU - Levin, Doron. AU - Wijeyesinghe, Sathi. AU - Makamdop, Krystelle Nganou. AU - Del Prete, Gregory Q.. AU - Hill, Brenna J.. AU - Timmer, J. Katherina. AU - Reiss, Emma. AU - Yarden, Ganit. AU - Darko, Samuel. AU - Contijoch, Eduardo. AU - Todd, John Paul. AU - Silvestri, Guido. AU - Nason, Martha. AU - Norgren, Robert B.. AU - Keele, Brandon F.. AU - Rao, Srinivas. AU - Langer, Jerome A.. AU - Lifson, Jeffrey D.. AU - Schreiber, Gideon. AU - Douek, Daniel C.. PY - 2014/1/1. Y1 - 2014/1/1. N2 - Inflammation in HIV infection is predictive of non-AIDS morbidity and death, higher set point plasma virus load2 and virus acquisition; thus, therapeutic agents are in development to reduce its causes and consequences. However, inflammation may ...
Type I IFNs can be produced by many cell types in response to virus encounter. They act through the IFNAR to induce a large number of genes encoding inhibitors of viral replication and virus assembly that together mediate cell-intrinsic resistance to virus infection and protect from viral spread. Genetic association studies have implicated a role for the type I IFN system in severe lung inflammation induced by RSV infection in some individuals. However, the cellular origin of those type I IFNs and the physiological role of type I IFN-induced inflammation remains unclear. Here, we show that AMs are responsible for production of type I IFNs during lower respiratory tract RSV infection and use the RLR-MAVS pathway for RSV detection. Notably, loss of type I IFN production by AMs results in increased viral replication and exacerbated disease. However, this is not fully attributable to loss of cell-intrinsic viral control but, rather, is associated with lack of recruitment of monocyte-derived ...
A novel gammaretrovirus named xenotropic MuLV-related retrovirus (XMRV) has been recently identified with 40 % prevalence in prostate tumor samples from US American patients carrying a homozygous R462Q mutation in the RNASEL gene. This mutation impairs the function of the innate antiviral type I interferon pathway and is a known susceptibility factor for prostate cancer. In subsequent studies, analyzing small European cohorts of prostate cancer patients a less significant prevalence and correlation of the QQ-phenotype with XMRV has been found or even a complete absence of viral traces was reported. A second independent report from the US found XMRV DNA in 6% and XMRV protein expression in 23% of prostate cancers. Contrary to the initial report the XMRV infection was not associated with this common variant of RNASEL and predominantly observed in malignant epithelial cells.. We aimed to determine the prevalence of XMRV in prostate cancer patients who had undergone radical prostatectomy at the ...
Interferons are cytokines that are very important in regulating both innate and adaptive immune response. Of the two different types of interferons, Type I interferons are potent mediators of the innate immune response against viruses and cancer. Type II interferons, mainly IFN-y enhances T cell polarization in the lymph nodes that result in their expansion. This book discusses the characterization, mechanisms of action and clinical applications of interferons. Topics include interferon-gamma, oligodendrocyte injury and inflammatory demyelination; the role of IFN-y in esophageal squamous cell carcinoma; interferons in multiple sclerosis; the effect of interferons on NK cell activity in HIV infection and tumor cell development; and understanding the mechanisms of interaction between serine proteases, serine protease receptors and interferons. (Imprint: Nova Biomedical ). ...
PubMed Central Canada (PMC Canada) provides free access to a stable and permanent online digital archive of full-text, peer-reviewed health and life sciences research publications. It builds on PubMed Central (PMC), the U.S. National Institutes of Health (NIH) free digital archive of biomedical and life sciences journal literature and is a member of the broader PMC International (PMCI) network of e-repositories.
The efficacy of recombinant leukocyte A interferon (rIFN-alpha A [Roferon-A, Hoffman-La Roche, Nutley, NJ]) treatment of Kaposis sarcoma in patients with acquired immunodeficiency syndrome was evaluated in sequential trials using high doses (36 X 10(6) units) and low doses (3 X 10(6) units) of interferon. A major response was seen in 38% of patients treated at the high dose, with a median response duration of 18 months. At the low dose, the major response rate was 3%; dose escalation to 36 X 10(6) units resulted in an additional major response rate of 17% in low-dose nonresponders, with a median response duration of 10 months. Four of 11 patients who achieved a complete response remain free of disease, whereas all partial responders have shown disease progression. Unacceptable toxicity occurred in 27% of patients initially treated at the high dose and only in 10% of those who had progressive dose escalation up to 36 X 10(6) units. Prior opportunistic infections correlated negatively with ...
Type-I interferons (IFN-I) play an important role in the innate immune response to several retroviruses. They seem to be effective in controlling the in vivo infection, though many of the clinical signs of retroviral infection may be due to their continual presence which over-stimulates the immune system and activates apoptosis. IFN-I not only affect the immune system, but also operate directly on virus replication. Most data suggest that the in vitro treatment with IFN-I of retrovirus infected cells inhibits the final stages of virogenesis, avoiding the correct assembly of viral particles and their budding, even though the mechanism is not well understood. However, in some retroviruses IFN-I may also act at a previous stage as some retroviral LTRs posses sequences homologous to the IFNstimulated response element (ISRE). When stimulated, ISREs control viral transcription. HIV-1 displays several mechanisms for evading IFN-I, such as through Tat and Nef. Besides IFN-α and IFN-β, some other type I IFN,
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Deciphering a Different Kind of Code. You may have great genes, but if the genes are tightly wrapped up in the proteins that organize DNA into chromosomes, those genes can t be accessed and turned on. Now a regulatory code that controls if an enveloped gene will be active or silent has been deciphered for the first time by P&S researchers.. Cells can get access to genes by pushing the chromosomal proteins, called histones, away from the gene s DNA. But first the cell must decipher a code, which consists of a chemical modification of the histones. Understanding the histone code could lead to therapies that shut down or turn on genes in diseases, such as cancer, that have aberrant patterns of gene expression.. Dr. Dimitris Thanos, associate professor of biochemistry and molecular biophysics, and his postdoctoral researcher, Dr. Theodora Agalioti, cracked the histone code that controls the human beta-interferon gene. The research was published in the Nov. 1, 2002, issue of Cell. Rare Disorders May ...
|strong|Mouse anti Human interferon alpha antibody, clone C10F5|/strong| recognizes an epitope common to IFN-alpha subtypes A, F, D, I1 and P. Strongest reaction in ELISA is with subtypes alpha F and…
Stimulator of interferon genes (STING), also known as transmembrane protein 173 (TMEM173) and MPYS/MITA/ERIS is a protein that in humans is encoded by the TMEM173 gene. STING plays an important role in innate immunity. STING induces type I interferon production when cells are infected with intracellular pathogens, such as viruses, mycobacteria and intracellular parasites. Type I interferon, mediated by STING, protects infected cells and nearby cells from local infection by binding to the same cell that secretes it (autocrine signaling) and nearby cells (paracrine signaling.) STING is encoded by the TMEM173 gene. It works as both a direct cytosolic DNA sensor (CDS) and an adaptor protein in Type I interferon signaling through different molecular mechanisms. It has been shown to activate downstream transcription factors STAT6 and IRF3 through TBK1, which are responsible for antiviral response and innate immune response against intracellular pathogen. Amino acids 1-379 of human STING include the 4 ...
Type I interferons are critical in antiviral immune responses, but increased type I interferons have also been associated with autoimmune diseases, including type I diabetes and systemic lupus erythematosus (SLE). The RNA sensing molecule interferon induced with helicase C domain 1 (IFIH1) is a cytosolic receptor that recognizes single and double-stranded RNAs (dsRNAs) and confers protection in the context of RNA virus infection. When activated by its RNA ligands, IFIH1 induces production of type I interferons and interferon-stimulated genes. Activating mutations in IFIH1 have been documented in early onset auto-inflammatory disorders, whereas loss-of-function variants of IFIH1 have been associated with decreased susceptibility to autoimmunity. Gorman et al. focused their studies on the rs1990760, a risk allele of IFIH1 associated with multiple autoimmune disorders that has a frequency of ~57% in European populations. The variant causes a single amino acid change, A946T, in the C-terminal ...
Balanced induction of proinflammatory and type I IFN responses upon activation of Toll-like receptors (TLRs) determines the outcome of microbial infections and the pathogenesis of autoimmune and other inflammatory diseases. Mast cells, key components of the innate immune system, are known for their debilitating role in allergy and autoimmunity. However, their role in antimicrobial host defenses is being acknowledged increasingly. How mast cells interact with microbes and the nature of responses triggered thereby is not well characterized. Here we show that in response to TLR activation by Gram-positive and -negative bacteria or their components, mast cells elicit proinflammatory but not type I IFN responses. We demonstrate that in mast cells, bound bacteria and TLR ligands remain trapped at the cell surface and do not undergo internalization, a prerequisite for type I IFN induction. Such cells, however, can elicit type I IFNs in response to vesicular stomatitis virus which accesses the cytosolic ...
The Basic Protocol in this unit describes measurement of murine interferon (IFN)α/β by intracellular staining for these cytokines and detection by flow cytometry
article{e4d203bb-f377-4f98-a74e-49b35da750f2, abstract = {,p,Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that affects many different organ systems, with excessive production of type I interferons (IFNs) and autoantibodies against nucleic acids as hallmarks. Activation of the type I IFN system in SLE is due to continuous stimulation of plasmacytoid dendritic cells by endogenous nucleic acids, leading to sustained type I IFN production. This is reflected by an overexpression of type I IFN-regulated genes or an IFN signature. Type I IFNs have effects on both the innate and adaptive immune systems, which contribute to both loss of tolerance and the autoimmune disease process. In this review, we discuss the current understanding of IFNs in SLE, focusing on their regulation, the influence of genetic background, and environmental factors and therapies that are under development aiming to inhibit the type I IFN system in SLE.,/p,}, author = {Bengtsson, Anders A. and ...
Innate immunity is crucial in the early stages of resistance to novel viral infection. The family of cytokines known as the interferons (IFNs) forms an essential component of this system: they are responsible for signalling that an infection is underway and for promoting an antiviral response in susceptible cells. We construct a spatial stochastic model, parameterized by experimental data and informed by analytic approximation, to capture the dynamics of virus-IFN interaction during in vitro infection of Madin-Darby bovine kidney cell monolayers by Herpes simplex virus 1. The dose dependence of infection progression, subsequent monolayer destruction and IFN-β production are investigated. Implications for in vivo infections, in particular the priming of susceptible cells by IFN-β during infection, are considered. ...
Key transcriptional regulator of type I interferon (IFN)-dependent immune responses and plays a critical role in the innate immune response against DNA and RNA viruses. Regulates the transcription of type I IFN genes (IFN-alpha and IFN-beta) and IFN-stimulated genes (ISG) by binding to an interferon-stimulated response element (ISRE) in their promoters. Can efficiently activate both the IFN-beta (IFNB) and the IFN-alpha (IFNA) genes and mediate their induction via both the virus-activated, MyD88-independent pathway and the TLR-activated, MyD88-dependent pathway. Required during both the early and late phases of the IFN gene induction but is more critical for the late than for the early phase. Exists in an inactive form in the cytoplasm of uninfected cells and following viral infection, double-stranded RNA (dsRNA), or toll-like receptor (TLR) signaling, becomes phosphorylated by IKBKE and TBK1 kinases. This induces a conformational change, leading to its dimerization and nuclear localization where along
Our study identifies a new physiological function of pDCs. We show that pDCs, which are normally absent from healthy skin, rapidly infiltrate common skin wounds with a surprisingly rapid kinetics, paralleling the infiltration of neutrophils. We also find that these pDCs become activated to produce IFN-α/β through endosomal TLR7 and TLR9, suggesting that they recognize nucleic acids released in the skin wounds. Finally, we demonstrate that these pDCs and their activation to produce IFN-α/β play an important role in inducing early inflammatory responses and reepithelization of skin wounds. Although pDCs have been classically considered a specialized immune cell type in sensing viral infection and initiating antiviral immunity, our study now identifies an additional important physiological function of these cells in sensing tissue damage and initiating tissue repair at epithelial surfaces.. The ability of pDCs to sense host-derived nucleic acids has been recently uncovered in psoriasis (Lande ...
Susanne Wegmann, Bahareh Eftekharzadeh, Katharina Tepper, Katarzyna M Zoltowska, Rachel E Bennett, Simon Dujardin, Pawel R Laskowski, Danny MacKenzie, Tarun Kamath, Caitlin Commins, Charles Vanderburg, Allyson D Roe, Zhanyun Fan, Amandine M Molliex, Amayra Hernandez‐Vega, Daniel Muller, Anthony A Hyman, Eckhard Mandelkow, J Paul Taylor, Bradley T Hyman ...
Our findings show the involvement of type I IFN signaling in response to sterile injury in the CNS. Type I IFN signaling in the CNS is normally associated with antiviral immune responses (10, 30). Type I IFNs exert a wide range of effects on inflammatory processes in the CNS during infection and in EAE, in both of which pathogen-associated signals may play a role. The functional significance of type I IFN in sterile injury-induced response in the CNS is therefore of interest. Similar to findings in viral infection models (10, 30), the expression of IRF7 and IRF9 gene increased following axonal lesion, and this increase was IFNAR dependent (10). Other studies have shown a role for type I IFN in regulating leukocyte infiltration to the CNS in EAE models (11, 12, 31), and we have shown a similar effect in response to sterile injury. Our results support an innate signaling role for type I IFN in the CNS.. IRF7 and IRF9 belong to a family of transcription factors with diverse functions including host ...
Sixteen patients with advanced cancer were treated with recombinant-DNA-produced pure leukocyte A interferon (IFLrA) intramuscularly in doses ranging from 3 to 198 X 106 units, with interval periods of 72 to 96 hours between doses. At the two lowest doses of 3 and 9 million units, there was a cross-over evaluation between IFLrA and partially pure leukocyte interferon (IFN-C) produced from human cells. The maximum observed serum concentration of IFLrA measured by enzyme immunoassay and bioassay increased with increasing doses. The mean serum concentrations of IFLrA and IFN-C were similar. Clinical effects produced by IFLrA and IFN-C were similar, including fever, chills, myalgias, headache, fatigue, and reversible leukopenia and granulocytopenia. Eight patients had transient and mild numbness of the hands or feet, or both. Three patients developed low titers of antibody to IFLrA. Seven of 16 patients showed objective evidence of tumor regression during the study. ...
It has been nearly two decades since type I IFNs were developed as a cancer therapeutic (1). Clinical evaluation ultimately led to the Food and Drug Administration approval of systemically administered IFN-α2b as a postsurgical adjuvant treatment for patients with melanoma (2). We have recently uncovered a critical role for endogenous type I IFN production in the innate immune recognition of tumors, which serves as a bridge to a spontaneous adaptive T cell response (3, 4). Mechanistic experiments revealed that endogenous IFN-β is produced by CD11c+ dendritic cells (DCs) in response to tumor presence, which in turn acts on the CD8α+ DC lineage to promote cross-priming of tumor Ag-specific CD8+ T cells in vivo (5). This type I IFN-dependent innate tumor recognition pathway appears crucial for directing the initial adaptive immune response against several murine tumors but is not always sufficient to enable tumor regression, largely because of the upregulation of immune inhibitory mechanisms ...
IFN-omega1 (Interferon omega) exhibits antiproliferative effects and stimulates Natural Killer cell activity. It is 75% homologous to IFN-alpha.
Type I IFNs have been proposed to play an important role in the pathogenesis of SARD through a potential feed-forward mechanism in which elevated levels of nuclear antigen-containing immune complexes lead to enhanced production of type I IFNs, which in turn further disturbs B- and T-cell tolerance mechanisms promoting production of ANAs [24]. Consequently, it has been hypothesized that elevated levels of type I IFNs may accompany and drive the conversion from pre-clinical to symptomatic autoimmunity in SARD [24]. In support of this concept, administration of type I IFNs to patients with hepatitis or malignancy leads to development of SARD in a small subset of patients, which abates once treatment is discontinued [25, 26]. In addition, the majority of patients with SARD have blood changes consistent with elevation of type I IFNs [11-16], and a number of SARD genetic risk variants have been shown to enhance the production of and/or the response to these IFNs [27]. Although there is some data ...
Successful containment of an infection is dependent on both innate and adaptive immune response. Cytokines are essential effectors of both of these systems. In particular, type I interferons (IFN-I) are important components of early innate immunity against an infection. However, the production of IFN-I could serve as a double edge sword, either containing an infection or enhancing susceptibility. For example, IFN-I, which is essential for early containment of viral infections, has been shown to be detrimental to the host during bacterial infections. In fact, recent significant reports have shown that influenza virus induced IFN-I responses can enhance the host susceptibility to secondary bacterial infections. These recent reports highlight the expanding immunoregulatory role of IFN-I in the host immunity. With these recent findings in mind, the aim of this research topic is to welcome novel data, opinion and literature reviews on the newly identified dual functions of IFN-I. This research topic will
[175 Pages Report] Expression Vectors Market report categorizes the global market by Application (Research, Industrial & Therapeutic), Host Type (Mammalian/CHO, Bacterial/E.Coli, Insect/Baculovirus and Yeast), End User (Biotechnology, Pharmaceutical, CROs & CMOs, and Academic Research) & Geography
Plays an essential role in transcription initiation and cap-stealing mechanism, in which cellular capped pre-mRNAs are used to generate primers for viral transcription. Recognizes and binds the 7-methylguanosine-containing cap of the target pre-RNA which is subsequently cleaved after 10-13 nucleotides by the viral protein PA. Plays a role in the initiation of the viral genome replication and modulates the activity of the ribonucleoprotein (RNP) complex. In addition, participates in the inhibition of type I interferon induction through interaction with and inhibition of the host mitochondrial antiviral signaling protein MAVS.
Humanized BLT mice. Humanized mice were constructed as described previously (15, 30). In short, CD34+ cells were purified via magnetic cell sorting with CD34 microbeads (Miltenyi Biotec) from freshly obtained fetal liver tissues. NOD-SCID-common γ chain knockout (cγ-/-) mice (NSG mice) mice were sublethally irradiated (2.7 Gy) before the surgery and implanted with fetal liver and thymus derived from the same donor as the CD34+ cells. Afterward, mice were injected with 0.5 million to 1 million CD34+ cells. After 8-10 weeks, each mouse was bled retro-orbitally to check human immune cell engraftment. Each donor tissue can be used to construct 15-25 mice. Mice that had more than 50% human lymphocytes in the peripheral blood mononuclear cells were used for HIV infection and further experiments. A standard healthy uninfected humanized BLT mouse contains 0.5 million to 2 million human lymphocytes per milliliter in the blood and 10 million to 30 million human lymphocytes per milliliter in the ...
There is a growing need for novel vaccine adjuvants that can provide safe and potent T-helper type 1 (Th1) activity. RNA-like immune response modifiers (IRMs) are candidate T-cell adjuvants that skew acquired immune responses towards a Th1 phenotype. We set out to delineate the essential signaling pathways by which the RNA-like IRMs, resiquimod (R-848) and polyinosinic:polycytidylic acid (poly I:C), augment CD4+ T-helper 1 (Th1) responses. Highly purified murine conventional dendritic cells (cDCs) and conventional CD4+ T-cells were co-cultured in allogeneic and MHC congenic mixed leukocyte reactions. The activation of CD4+ Th1 cells was examined utilizing cells from mice deficient in specific RNA-sensing pattern recognition receptors and signaling mediators. R-848 and poly I:C stimulation of Type I interferon production and signaling in cDCs was essential but not sufficient for driving CD4+ Th1 responses. The early and rapid production of IL-1alpha and IL-1beta was equally critical for the optimal
Investigators: Gurol Suel, Roy Wollman. Understanding the emergent properties of tissue-level organization is a fundamental problem in biology. These properties emerge from the many different interactions of individual cells within a tissue. Yet, there are no methods that use the spatial distribution of cells and their signaling state to build a computational model that can make specific, testable predictions on tissue-level phenotypes. In this project we will use the maps-to-models paradigm to study two models of biological tissue organization: (1) antibiotic resistance of a biofilm of Bacillus subtilis; and (2) induction of viral protection through type I interferon response in lung epithelial cells during influenza infection. Through the use of two separate model systems we will demonstrate the utility of our approach and show how it could be further adapted to the analysis of tissue-level biological organization.. A key benefit of the Maps-to-Models paradigm is the generation of two ...
Certain pathogens, including HIV and hepatitis viruses, that lead to persistent infections are often associated with suboptimal antibody responses. Using LCMV infection in mice, Fallet et al., Moseman et al., and Sammicheli et al. report that up-regulation of type I interferon (IFN-I) in the early phase of infection is a key contributor to premature deletion of virus-specific B cells. Blockade of IFN-I prevents B cell deletion. Although the studies agree that IFN-I does not act directly on B cells, they found that distinct immune cells mediate IFN-I-dependent deletion of B cells, depending on the system examined. Targeting of the IFN-I pathway could be used to restore B cell responses during persistent viral infections in humans. ...
By Kevin E. Noonan -- Today the Federal Circuit reversed a priority determination in an interference over claims to human beta-interferon, in an opinion teeming with irony, déjà vu, anachronism, and the peculiar effects on outcome caused by the form of interference counts. Two interferences, Nos. 105,334 and 105,337 between Junior Party David Goeddel and Robert Crea and Senior Party Haruo Sugano, Masami Muramatsu, and Tadatsigi Tanaguchi, were directed towards claims to isolated human DNA encoding beta-interferon (also termed human fibroblast interferon or hFIF in the opinion) as well as the isolated interferon protein itself. The DNA Interference was declared...