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Type I Interferons (type + i_interferons)
Selected AbstractsNon-conventional signal transduction by type 1 interferons: The NF-,B pathwayJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2007Ziyun Du Abstract Type I interferons (IFNs) regulate diverse cellular functions by modulating the expression of IFN-stimulated genes (ISGs) through the activation of the well established signal transduction pathway of the Janus Kinase (JAK) and signal transducers and activators of transcription (STAT) proteins. Although the JAK,STAT signal transduction pathway is critical in mediating IFN's antiviral and antiproliferative activities, other signaling pathways are activated by IFNs and regulate cellular response to IFN. The NF-,B transcription factor regulates the expression of genes involved in cell survival and immune responses. We have identified a novel IFN mediated signal pathway that leads to NF-,B activation and demonstrate that a subset of ISGs that play key roles in cellular response to IFN is regulated by NF-,B. This review focuses on the IFN-induced NF-,B activation pathway and the role of NF-,B in ISG expression, antiviral activity and apoptosis, and the therapeutic application of IFN in cancer and infectious disease. J. Cell. Biochem. 102: 1087,1094, 2007. © 2007 Wiley-Liss, Inc. [source] Effects of Echinacea extracts on macrophage antiviral activitiesPHYTOTHERAPY RESEARCH, Issue 6 2010David S. Senchina Abstract Type I interferons are a class of cytokines synthesized by leukocytes such as macrophages that limit viral replication. We hypothesized that one mechanism whereby Echinacea spp. extracts may enhance immunity is through modulating interferon-associated macrophage pathways. We used herpes simplex viral infection in the murine macrophage cell line RAW264.7 and monitored virus-induced cell death, interferon secretion, and two intracellular proteins that indicate activation of interferon pathways. Cells were incubated with control media or extracts from four different species (E. angustifolia, E. purpurea, E. tennesseensis, E. pallida). Cells incubated with extracts prior to infection showed very modest enhancement of viability, and no increase in the secretion of interferons , or , as compared to control cells. Virus-infected macrophages treated with extracts from E. purpurea showed a small (<2-fold) induction of guanylate binding protein (GBP) production, but no effect of extracts from other species was observed. In virus-infected cells, all the extracts increased the amount of inducible nitric oxide synthase (iNOS) protein, and this effect varied by type of extraction preparation. Together, these results suggest that any potential antiviral activities of Echinacea spp. extracts are likely not mediated through large inductions of Type I interferon, but may involve iNOS. Copyright © 2009 John Wiley & Sons, Ltd. [source] Determination of the human type I interferon receptor binding site on human interferon-,2 by cross saturation and an NMR-based model of the complexPROTEIN SCIENCE, Issue 11 2006Sabine R. Quadt-Akabayov Abstract Type I interferons (IFNs) are a family of homologous helical cytokines that exhibit pleiotropic effects on a wide variety of cell types, including antiviral activity and antibacterial, antiprozoal, immunomodulatory, and cell growth regulatory functions. Consequently, IFNs are the human proteins most widely used in the treatment of several kinds of cancer, hepatitis C, and multiple sclerosis. All type I IFNs bind to a cell surface receptor consisting of two subunits, IFNAR1 and IFNAR2, associating upon binding of interferon. The structure of the extracellular domain of IFNAR2 (R2-EC) was solved recently. Here we study the complex and the binding interface of IFN,2 with R2-EC using multidimensional NMR techniques. NMR shows that IFN,2 does not undergo significant structural changes upon binding to its receptor, suggesting a lock-and-key mechanism for binding. Cross saturation experiments were used to determine the receptor binding site upon IFN,2. The NMR data and previously published mutagenesis data were used to derive a docking model of the complex with an RMSD of 1 Å, and its well-defined orientation between IFN,2 and R2-EC and the structural quality greatly improve upon previously suggested models. The relative ligand,receptor orientation is believed to be important for interferon signaling and possibly one of the parameters that distinguish the different IFN I subtypes. This structural information provides important insight into interferon signaling processes and may allow improvement in the development of therapeutically used IFNs and IFN-like molecules. [source] Type I Interferons Are Not Critical for Skin Allograft Rejection or the Generation of Donor-Specific CD8+ Memory T CellsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2010M. H. Oberbarnscheidt Type I interferons (IFN-I) link innate to adaptive immunity in microbial infection, autoimmune disease and tumor immunity. It is not known whether IFN-I have an equally central role in alloimmunity. Here we tested this possibility by studying skin allograft survival and donor-specific CD8+ T-cell responses in mice that lack the IFN-I receptor (IFN-IR,/,). We found that IFN-IR,/, mice reject fully allogeneic wild-type skin grafts at the same rate as wild-type recipients. Similarly, allograft rejection was not delayed if IFN-IR,/, male skin was transplanted to syngeneic IFN-IR,/, female mice. Quantitation of the male (H-Y)-specific CD8+ T-cell response in these mice revealed normal generation of donor-specific CD8+ effector T cells but fourfold reduction in CD8+ memory T cells. Memory CD8+ T cells generated in the absence of IFN-IR had normal phenotype and recall function, assessed by ex vivo cytokine production and the ability of IFN-IR,/, mice to mount second set rejection. Finally, these memory T cells were maintained at a constant number despite their inability to respond to IFN-1. Our findings indicate that IFN-I cytokines are not critical for acute allograft rejection or for the expansion and differentiation of donor-specific CD8+ T cells into long-lived, functional memory T cells. [source] Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, function as inhibitors of cellular and molecular components involved in type I interferon productionARTHRITIS & RHEUMATISM, Issue 7 2010Hideki Amuro Objective Statins, which are used as cholesterol-lowering agents, have pleiotropic immunomodulatory properties. Although beneficial effects of statins have been reported in autoimmune diseases, the mechanisms of these immunomodulatory effects are still poorly understood. Type I interferons (IFNs) and plasmacytoid dendritic cells (PDCs) represent key molecular and cellular pathogenic components in autoimmune diseases such as systemic lupus erythematosus (SLE). Therefore, PDCs may be a specific target of statins in therapeutic strategies against SLE. This study was undertaken to investigate the immunomodulatory mechanisms of statins that target the IFN response in PDCs. Methods We isolated human blood PDCs by flow cytometry and examined the effects of simvastatin and pitavastatin on PDC activation, IFN, production, and intracellular signaling. Results Statins inhibited IFN, production profoundly and tumor necrosis factor , production modestly in human PDCs in response to Toll-like receptor ligands. The inhibitory effect on IFN, production was reversed by geranylgeranyl pyrophosphate and was mimicked by either geranylgeranyl transferase inhibitor or Rho kinase inhibitor, suggesting that statins exert their inhibitory actions through geranylgeranylated Rho inactivation. Statins inhibited the expression of phosphorylated p38 MAPK and Akt, and the inhibitory effect on the IFN response was through the prevention of nuclear translocation of IFN regulatory factor 7. In addition, statins had an inhibitory effect on both IFN, production by PDCs from SLE patients and SLE serum,induced IFN, production. Conclusion Our findings suggest a specific role of statins in controlling type I IFN production and a therapeutic potential in IFN-related autoimmune diseases such as SLE. [source] Neutralization of interferon-,/,,inducible genes and downstream effect in a phase I trial of an anti,interferon-, monoclonal antibody in systemic lupus erythematosus,ARTHRITIS & RHEUMATISM, Issue 6 2009Yihong Yao Objective Type I interferons (IFNs) play an important role in the pathogenesis of systemic lupus erythematosus (SLE). This phase Ia trial was undertaken to evaluate the safety, pharmacokinetics, and immunogenicity of anti-IFN, monoclonal antibody (mAb) therapy in SLE. During the trial, we also examined whether overexpression of an IFN,/,-inducible gene signature in whole blood could serve as a pharmacodynamic biomarker to evaluate IFN, neutralization and investigated downstream effects of neutralizing IFN, on BAFF and other key signaling pathways, i.e., granulocyte,macrophage colony-stimulating factor (GM-CSF), interleukin-10 (IL-10), tumor necrosis factor , (TNF,), and IL-1,, in SLE. Methods Affymetrix Human Genome U133 Plus 2.0 microarrays were used to profile whole blood and lesional skin of patients receiving standard therapy for mild to moderate SLE. Selected IFN,/,-inducible proteins were analyzed by immunohistochemistry. Results With the study treatment, we observed anti-IFN, mAb,specific and dose-dependent inhibition of overexpression of IFN,/,-inducible genes in whole blood and skin lesions from SLE patients, at both the transcript and the protein levels. In SLE patients with overexpression of messenger RNA for BAFF, TNF,, IL-10, IL-1,, GM-CSF, and their respective inducible gene signatures in whole blood and/or skin lesions, we observed a general trend toward suppression of the expression of these genes and/or gene signatures upon treatment with anti-IFN, mAb. Conclusion IFN,/,-inducible gene signatures in whole blood are effective pharmacodynamic biomarkers to evaluate anti-IFN, mAb therapy in SLE. Anti-IFN, mAb can neutralize overexpression of IFN,/,-inducible genes in whole blood and lesional skin from SLE patients and has profound effects on signaling pathways that may be downstream of IFN, in SLE. [source] Induction of type I interferons by bacteriaCELLULAR MICROBIOLOGY, Issue 7 2010Kathryn M. Monroe Summary Type I interferons (IFNs) are secreted cytokines that orchestrate diverse immune responses to infection. Although typically considered to be most important in the response to viruses, type I IFNs are also induced by most, if not all, bacterial pathogens. Although diverse mechanisms have been described, bacterial induction of type I IFNs occurs upon stimulation of two main pathways: (i) Toll-like receptor (TLR) recognition of bacterial molecules such as lipopolysaccharide (LPS); (ii) TLR-independent recognition of molecules delivered to the host cell cytosol. Cytosolic responses can be activated by two general mechanisms. First, viable bacteria can secrete stimulatory ligands into the cytosol via specialized bacterial secretion systems. Second, ligands can be released from bacteria that lyse or are degraded. The bacterial ligands that induce the cytosolic pathways remain uncertain in many cases, but appear to include various nucleic acids. In this review, we discuss recent advances in our understanding of how bacteria induce type I interferons and the roles type I IFNs play in host immunity. [source] Breastfeeding is associated with the production of type I interferon in infants infected with influenza virusACTA PAEDIATRICA, Issue 10 2010Guillermina A Melendi Abstract Background:, Breast milk-mediated protection against respiratory viruses is well established. However, protective mechanisms are unclear. Type I interferons (IFN) mediate host defence against respiratory viruses, particularly influenza virus. The relationship among type I IFN, respiratory viral infections and breastfeeding has not been explored. Methods:, Type I IFN responses were studied by ELISA and real time PCR in nasal secretions of infants experiencing their first respiratory infection. Modulation of IFN by breastfeeding and other variables affecting severity during viral infection was explored. Results:, One hundred and twenty infants were positive by RT-PCR for influenza virus (n = 24), human metapneumovirus (hMPV) (n = 30) or respiratory syncytial virus (RSV) (n = 66). Type I IFNs were detected more frequently in infants infected with influenza virus than in those infected with RSV or hMPV. Breastfeeding promoted higher rates and levels of type I IFN only in infants infected with influenza virus. No effect on IFN production was observed for age, gender or smoking. Conclusion:, Our study confirms that type I IFN production is detected more frequently in infants infected with influenza virus. Importantly, higher rates and levels of type I IFN in these infants are associated with breastfeeding. These observations suggest that breast milk can protect against respiratory viruses by activating innate antiviral mechanisms in the host. [source] Interferon-,2a is sufficient for promoting dendritic cell immunogenicityCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2005A. Tamir Summary Type I interferons (IFNs) are widely used therapeutically. IFN-,2a in particular is used as an antiviral agent, but its immunomodulatory properties are poorly understood. Dendritic cells (DCs) are the only antigen-presenting cells able to prime naive T cells and therefore play a crucial role in initiating the adaptive phase of the immune response. We studied the effects of IFN-,2a on DC maturation and its role in determining Th1/Th2 equilibrium. We found that IFN-,2a induced phenotypic maturation of DCs and increased their allostimulatory capacity. When dendritic cells were stimulated simultaneously by CD40 ligation and IFN-,2a, the production of interleukin (IL)-10 and IL-12 was increased. In contrast, lipopolysaccharide (LPS) stimulation in the presence of IFN-,2a mainly induced IL-10 release. The production of IFN-, and IL-5 by the responder naive T cells was also amplified in response to IFN-,2a-treated DCs. Furthermore, IL-12 production by IFN-,2a-treated DCs was enhanced further in the presence of anti-IL-10 antibody. Different results were obtained when DCs were treated simultaneously with IFN-,2a and other maturation factors, in particular LPS, and then stimulated by CD40 ligation 36 h later. Under these circumstances, IFN-,2a did not modify the DC phenotype, and the production of IL-10/IL-12 and IFN-,/IL-5 by DCs and by DC-stimulated naive T cells, respectively, was inhibited compared to the effects on DCs treated with maturation factors alone. Altogether, this work suggests that IFN-,2a in isolation is sufficient to promote DC activation, however, other concomitant events, such as exposure to LPS during a bacterial infection, can inhibit its effects. These results clarify some of the in vivo findings obtained with IFN-,2a and have direct implications for the design of IFN-,-based vaccines for immunotherapy. [source] Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2005Ingrid Abstract Dendritic cells (DC) are key components of innate and adaptive immune responses. Plasmacytoid DC (PDC) are a specialized DC subset that produce high amounts of type I interferons in response to microbes. High mobility group box 1 protein (HMGB1) is an abundant nuclear protein, which acts as a potent pro-inflammatory factor when released extracellularly. We show that HMGB1 leaves the nucleus of maturing PDC following TLR9 activation, and that PDC express on the plasma membrane the best-characterized receptor for HMGB1, RAGE. Maturation and type I IFN secretion of PDC is hindered when the HMGB1/RAGE pathway is disrupted. These results reveal HMGB1 and RAGE as the first known autocrine loop modulating the maturation of PDC, and suggest that antagonists of HMGB1/RAGE might have therapeutic potential for the treatment of systemic human diseases. [source] Distinct roles of protein kinase R and toll-like receptor 3 in the activation of astrocytes by viral stimuliGLIA, Issue 3 2007Pamela A. Carpentier Abstract Impaired immune surveillance and constitutive immunosuppressive properties make the central nervous system (CNS) a particular challenge to immune defense, and require that CNS-resident cells be capable of rapidly recognizing and responding to infection. We have previously shown that astrocytes respond to treatment with a TLR3 ligand, poly I:C, with the upregulation of innate immune functions. In the current study, we examine the activation of innate immune functions of astrocytes by Theiler's murine encephalomyelitis virus (TMEV), a picornavirus, which establishes a persistent infection in the CNS of susceptible strains of mice and leads to the development of an autoimmune demyelinating disease that resembles human multiple sclerosis. Astrocytes infected with TMEV are activated to produce type I interferons, the cytokine IL-6, and chemokines CCL2 and CXCL10. We further examined the mechanisms that are responsible for the activation of astrocytes in response to direct viral infection and treatment with poly I:C. We found that the cytoplasmic dsRNA-activated kinase PKR is important for innate immune responses to TMEV infection, but has no role in their induction by poly I:C delivered extracellularly. In contrast, we found that TLR3 has only a minor role in responses to TMEV infection, but is important for responses to poly I:C. These results highlight the differences between responses induced by direct, nonlytic virus infection and extracellular poly I:C. The activation of astrocytes through these different pathways has implications for the initiation and progression of viral encephalitis and demyelinating diseases such as multiple sclerosis. © 2006 Wiley-Liss, Inc. [source] The role of type I interferons in non-viral infectionsIMMUNOLOGICAL REVIEWS, Issue 1 2004Christian Bogdan Summary:, For a long time, the family of type I interferons (IFN-,/,) has received little attention outside the fields of virology and tumor immunology. In recent years, IFN-,/, regained the interest of immunologists, due to the phenotypic and functional characterization of IFN-,/,-producing cells, the definition of novel immunomodulatory functions and signaling pathways of IFN-,/,, and the observation that IFN-,/, not only exerts antiviral effects but is also relevant for the pathogenesis or control of certain bacterial and protozoan infections. This review summarizes the current knowledge on the production and function of IFN-,/, during non-viral infections in vitro and in vivo. [source] Interleukin-12 family members and type I interferons in Th17-mediated inflammatory disordersALLERGY, Issue 5 2009S. Goriely Cytokines produced by antigen-presenting cells govern the fate of helper T-cell responses. Herein, we review the impact of interleukin (IL)-23 and IL-27 on the outcome of T-helper (Th) 17 cell responses and discuss their impact in the pathogenesis of T-cell-mediated inflammatory disorders of autoimmune or allergic origin. We then discuss how type I interferons might influence the course of autoimmune diseases by tipping the balance between IL-12 family members. [source] Immunopathogenesis of juvenile dermatomyositisMUSCLE AND NERVE, Issue 5 2010Sahil Khanna MBBS Abstract There is increasing evidence for involvement of the mechanisms of the innate immune system in the pathogenesis of idiopathic inflammatory myopathies (IIMs), especially in the adult and juvenile forms of dermatomyositis. Juvenile dermatomyositis (JDM) is the most common form of childhood IIM, and this review focuses on recent advances in understanding the actions of the innate immune system in this condition. Over the last few years, great strides have been made in understanding immune dysregulation in IIM, including JDM. Novel autoantibodies have been identified, and new genetic contributions have been described. Among the most striking findings is type I interferon activity in JDM tissue and peripheral blood. This is in conjunction with the description of dysregulation of the major histocompatibility complex (MHC) class I gene and identification of plasmacytoid dendritic infiltrates as the possible cellular source of type I interferons. These findings also point toward the potential prognostic value of muscle biopsies and have helped expand our understanding of the etiopathogenesis of IIM. Muscle Nerve 41: 581,592, 2010 [source] Interferon-, treatment of female (NZW × BXSB)F1 mice mimics some but not all features associated with the Yaa mutationARTHRITIS & RHEUMATISM, Issue 4 2009Meera Ramanujam Objective Male (NZW × BXSB)F1 mice develop antiphospholipid syndrome (APS) and proliferative glomerulonephritis that is markedly accelerated by the Yaa locus encoding an extra copy of Tlr7. Female (NZW × BXSB)F1 mice with only 1 active copy of Tlr7 develop late-onset glomerulonephritis but not APS. Because a major function of Toll-like receptor 7 is to induce type I interferons (IFNs), our goal was to determine whether IFN, can induce or accelerate the manifestations of systemic lupus erythematosus (SLE) in female (NZW × BXSB)F1 mice. Methods Eight-week-old female (NZW × BXSB)F1 mice were injected with a single dose of adenovirus expressing IFN,. Mice were monitored for the development of thrombocytopenia and proteinuria. Sera were tested for anticardiolipin and anti-Sm/RNP antibodies. Mice were killed at 17 or 22 weeks of age, and their kidneys and hearts were examined histologically and by immunohistochemistry. Spleen cells were phenotyped, and enzyme-linked immunospot assays for autoantibody-producing B cells were performed. Results IFN, markedly accelerated nephritis and death in female (NZW × BXSB)F1 mice. A significant increase in spleen cell numbers associated with a striking increase in the number of activated B and T cells was observed. Marginal-zone B cells were retained. IFN,-induced increased titers of autoantibodies were observed, but thrombocytopenia was not observed. Cardiac damage was milder than that in male mice. Conclusion IFN, accelerates the development of renal inflammatory disease in female (NZW × BXSB)F1 mice but induces only mild APS and does not induce thrombocytopenia. The effect of IFN, on SLE disease manifestations is strain dependent. These findings are relevant to our understanding of the physiologic significance of the IFN signature. [source] Lupus-like disease and high interferon levels corresponding to trisomy of the type I interferon cluster on chromosome 9pARTHRITIS & RHEUMATISM, Issue 5 2006Haoyang Zhuang Objective Systemic lupus erythematosus (SLE) is associated with type I interferons (IFNs) and can be induced by IFN, treatment. This study looked for evidence of autoimmunity in a pedigree consisting of 4 family members with a balanced translocation 9;21 and 2 members with an unbalanced translocation resulting in trisomy of the short (p) arm and part of the long (q) arm of chromosome 9. These latter 2 subjects had 3 copies of the IFN gene cluster. Methods Subjects were evaluated clinically and serologically for autoimmune disease. Expression levels of IFN,4, IFN,, the type I IFN,inducible gene Mx1, the type I IFN receptor, interleukin-6, and tumor necrosis factor , were determined by real-time polymerase chain reaction. Circulating plasmacytoid dendritic cells, the main IFN-producing cells, were quantified by flow cytometry. Results Both subjects with trisomy of chromosome 9p had a lupus-like syndrome with joint manifestations and antinuclear antibodies: one had anti-RNP and antiphospholipid autoantibodies, and the other had anti,Ro 60. The 3 family members with a balanced translocation 9;21 had no clinical or serologic evidence of autoimmunity, similar to that in relatives who were unaffected by the chromosomal translocation. In the 2 subjects with trisomy of 9p, high levels of IFN,/, (comparable with those found in patients with SLE), increased signaling through the IFN receptor (as indicated by high Mx1 expression), and low levels of circulating plasmacytoid dendritic cells (as observed in patients with SLE) were evident. These abnormalities were not seen in individuals with a balanced translocation. Conclusion Trisomy of the type I IFN cluster of chromosome 9p was associated with lupus-like autoimmunity and increased IFN,/, and IFN receptor signaling. The data support the idea that abnormal regulation of type I IFN production is involved in the pathogenesis of SLE. [source] Crystallization and preliminary crystallographic studies of human RIG-I in complex with double-stranded RNAACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 6 2009Hyunjin Moon Retinoic acid inducible gene-I (RIG-I) is an essential component of the innate immune system that is responsible for the detection and elimination of invading viruses. RIG-I recognizes viral RNAs inside the cell and then initiates downstream signalling to activate the IRF-3 and NF-,B genes, which results in the production of type I interferons. RIG-I is composed of an N-terminal CARD domain for signalling and C-terminal helicase and repressor domains for RNA recognition. A RIG-I,RNA binding assay was performed to investigate the in vitro RIG-I,RNA binding properties. Selenomethionine-incorporated RIG-I was expressed using Escherichia coli and purified for crystallization. X-ray data were collected from RIG-I,dsRNA complex crystals to 2.8,Å resolution using synchrotron radiation. [source] Detection of myxovirus resistance protein A in lichen planus lesions and its relationship to hepatitis C virusBRITISH JOURNAL OF DERMATOLOGY, Issue 5 2009O.G. Shaker Summary Background, Lichen planus (LP) is an inflammatory disease of the skin and oral mucosa. Studies suggested that type I interferons (IFNs) could play an important role in the cytotoxic inflammation in LP. Type I IFNs stimulate the production of several IFN-induced proteins including myxovirus resistance protein A (MxA protein). The association of LP and chronic hepatitis C is well established, with variable prevalence rates among different populations. Many authors have considered hepatitis C virus (HCV) as a possible antigen for inducing cytotoxic immune response in LP. Objectives, To investigate the role of type I IFNs in LP through the detection of MxA protein, and to compare the expression of MxA protein between HCV-positive and HCV-negative patients with LP in an attempt to clarify the role of HCV in the pathogenesis of LP. Methods, The study included 33 skin biopsies from patients with LP and 10 control biopsies. MxA mRNA was detected by reverse transcription-polymerase chain reaction. HCV-specific antibodies were detected in patient sera by enzyme-linked immunosorbent assay. Results, Our analysis revealed a significantly higher level of MxA protein in all the LP skin biopsies compared with controls. The expression was significantly higher in HCV-positive patients than in HCV-negative patients. Conclusions, Type I IFNs play a role in the pathogenesis of LP, and HCV could induce LP through increasing the production of type I IFNs. [source] The expression pattern of interferon-inducible proteins reflects the characteristic histological distribution of infiltrating immune cells in different cutaneous lupus erythematosus subsetsBRITISH JOURNAL OF DERMATOLOGY, Issue 4 2007J. Wenzel Summary Background, Plasmacytoid dendritic cells and type I interferons (IFNs) are supposed to play a central proinflammatory role in the pathogenesis of cutaneous lupus erythematosus (LE). The IFN-inducible chemokines CXCL9 and CXCL10 are involved in recruiting CXCR3+ effector lymphocytes from the peripheral blood into skin lesions of LE. We hypothesized that the expression pattern of IFN-inducible proteins reflects the characteristic distribution of the inflammatory infiltrate in different subsets of cutaneous LE. Objectives, To test this hypothesis in patients with LE. Methods, Lesional skin biopsies taken from patients with different subsets of LE [chronic discoid LE (CDLE), n = 12; subacute cutaneous LE (SCLE), n = 5; LE tumidus (LET), n = 4; LE profundus (LEP), n = 6] were investigated by immunohistochemistry using monoclonal antibodies to the lymphocyte surface markers CD3, CD4, CD8, CD20 and CD68, the cytotoxic proteins Tia1 and granzyme B, the chemokine receptor CXCR3, the specifically type I IFN-inducible protein myxovirus protein A (MxA) and the chemokines CXCL9 and CXCL10. Results, The expression pattern of MxA followed the distribution of the inflammatory infiltrate typically seen in the investigated cutaneous LE subsets. In CDLE and SCLE, expression was focused in the epidermis and upper dermis, while in LET a perivascular and in LEP a subcutaneous pattern was found. Similar findings were obtained for CXCL9 and CXCL10. Conclusions, Our results demonstrate a close morphological association between the expression pattern of IFN-inducible proteins and the distribution of CXCR3+ CD3+ lymphocytes in all investigated subsets of cutaneous LE. This supports the importance of an IFN-driven inflammation in this condition. Infiltrating lymphocytes carrying CXCL10 in their granules might amplify the lesional inflammation and be responsible for the chronic course of this disease. [source] Evidence for a role of type I interferons in the pathogenesis of dermatomyositis: reply from authorsBRITISH JOURNAL OF DERMATOLOGY, Issue 2 2005M. Caproni No abstract is available for this article. [source] Induction of type I interferons by bacteriaCELLULAR MICROBIOLOGY, Issue 7 2010Kathryn M. Monroe Summary Type I interferons (IFNs) are secreted cytokines that orchestrate diverse immune responses to infection. Although typically considered to be most important in the response to viruses, type I IFNs are also induced by most, if not all, bacterial pathogens. Although diverse mechanisms have been described, bacterial induction of type I IFNs occurs upon stimulation of two main pathways: (i) Toll-like receptor (TLR) recognition of bacterial molecules such as lipopolysaccharide (LPS); (ii) TLR-independent recognition of molecules delivered to the host cell cytosol. Cytosolic responses can be activated by two general mechanisms. First, viable bacteria can secrete stimulatory ligands into the cytosol via specialized bacterial secretion systems. Second, ligands can be released from bacteria that lyse or are degraded. The bacterial ligands that induce the cytosolic pathways remain uncertain in many cases, but appear to include various nucleic acids. In this review, we discuss recent advances in our understanding of how bacteria induce type I interferons and the roles type I IFNs play in host immunity. [source] Non-invasive imaging of mouse hepatitis coronavirus infection reveals determinants of viral replication and spread in vivoCELLULAR MICROBIOLOGY, Issue 5 2009Matthijs Raaben Summary Bioluminescence imaging (BLI) is a powerful new method to study virus dissemination in the live animal. Here we used this method to monitor the spatial and temporal progression of mouse hepatitis coronavirus (MHV) infection in mice using luciferase-expressing viruses. Upon intranasal inoculation, virus replication could initially be observed in the nasal cavity and the cervical lymph nodes, after which the infection spread to the brain and frequently to the eyes. The kinetics of virus spread to and clearance from the brain appeared to depend on the inoculation dose. After intraperitoneal inoculation, virus replication was predominantly observed in the liver and occasionally in the intestines, but interestingly also in the tail and paws. BLI thus elucidated new anatomic locations of virus replication. Furthermore, MHV dissemination was shown to be critically depended on the viral spike protein, but also on the mouse strain used. Widespread dissemination was observed in mice lacking a functional type I interferon response. The importance of the type I interferon system in limiting viral spread was also demonstrated by the administration of type I interferons to mice. Our results provide new insights in coronavirus pathogenesis and demonstrate the potential of BLI to study coronavirus,host interactions in vivo. [source] Innate immunity to respiratory virusesCELLULAR MICROBIOLOGY, Issue 7 2007Jennifer P. Wang Summary Pattern recognition receptors are critically involved in the development of innate and adaptive antiviral immunity. Innate immune activation by viruses may occur via cell surface, intracellular and cytosolic pattern recognition receptors. These receptors sense viral components and may activate unique downstream pathways to generate antiviral immunity. In this article, we summarize the pattern recognition receptors that recognize major human respiratory viral pathogens, including influenza virus, respiratory syncytial virus and adenovirus. We also provide an overview of the current knowledge of regulation of type I interferons and inflammatory cytokines in viral infection. [source] Brucella requires a functional Type IV secretion system to elicit innate immune responses in miceCELLULAR MICROBIOLOGY, Issue 7 2007Christelle M. Roux Summary The virB operon, encoding a Type IV secretion system (T4SS), is essential for intracellular survival and persistent infection by Brucella spp. To better understand the role of the T4SS in evading host defence mechanisms and establishing chronic infection, we compared transcriptional profiles of the host response to infection with wild-type and virB mutant Brucella strains. Analysis of gene expression profiles in murine splenocytes 3 days after inoculation with wild-type Brucella strains revealed an inflammatory response, with a prominent upregulation of genes induced by both type I and type II interferons. Real-time RT-PCR showed that a group of genes from these pathways were induced by day 3 post infection and declined to baseline levels by day 7. In contrast, neither of the two virB mutant strains elicited a proinflammatory gene expression profile, demonstrating that the T4SS was required to trigger this response. Infection studies using type I interferon receptor knockout mice showed that a lack of type I interferon signalling did not affect Brucella replication during the first 4 weeks of infection. Thus, induction of type I interferons does not appear to be an essential mechanism by which the T4SS promotes persistent infection by Brucella. [source] Novel sequence variation of AIRE and detection of interferon-, antibodies in early infancyCLINICAL ENDOCRINOLOGY, Issue 5 2010Beáta Tóth Summary Objective, Autoimmune polyendocrine syndrome type I (APS I) is a rare primary immunodeficiency disorder characterized by chronic mucocutaneous candidiasis, multi-organ autoimmunity and ectodermal dysplasia. Autoantibodies to parathyroid and adrenal glands and type I interferons (IFN) are hallmarks of APS I, which results from mutations in the autoimmune regulator (AIRE) gene. We wished to study clinical, immunological and genetic features of APS I in Hungarian patients, and to correlate anti-IFN-, serum concentration with APS I and other multi-organ autoimmune diseases. Design, Detailed analysis of patients with APS I and multi-organ autoimmune diseases. Patients, Seven patients with APS I and 11 patients with multi-organ autoimmune diseases were studied. Measurements, Mutational analysis was performed by bidirectional sequencing of AIRE. Antibodies against IFN-, and endocrine organ-specific autoantigens were studied with radioimmunoassay. RFLP was performed by digestion of DNA with Hin6I restriction enzyme. Results, AIRE sequence analysis revealed homozygous c.769C>T mutations in three patients and compound heterozygous sequence variants (c.769C>T/c.44_66dup26bp; c.769C>T/c.965_977del13bp; c.769C>T/c.1344delC) in four patients with APS I. All the six live patients tested had markedly elevated IFN-, antibodies, which were not found in heterozygous siblings or parents. One of the identified patients was negative for antibodies against IFN-, at 6 weeks of age, but became positive at 7 months. At age 1, he is still without symptoms of the disease. In contrast to patients with APS I, no AIRE mutation or elevation of IFN-, antibodies were detected in patients with multi-organ autoimmune diseases. Conclusion, This is the first overview of patients diagnosed with APS I in Hungary. A novel c.1344delC mutation in AIRE was detected. Anti-IFN-, antibodies seem to appear very early in life and are helpful to differentiate APS I from other multi-organ autoimmune diseases. [source] | ||||||||||||||||