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Kelly C G Manfrere, Marina P Torrealba, Denis R Miyashiro, Luanda M S Oliveira, Gabriel C de Carvalho, Josenilson F Lima, Anna Claudia C C Branco, Nátalli Z Pereira, Juliana Pereira, José A Sanches, Maria N Sato
Sézary syndrome (SS) carries a poor prognosis, and infections represent the most frequent cause of death in SS patients. Toll-like receptors (TLRs) are a family of innate immune receptors that induce protective immune responses against infections. We sought to evaluate the ability of TLR agonists to induce inflammatory cytokine, Th2 cytokine, and type I interferon (IFN-I) production by peripheral blood mononuclear cells (PBMC) of untreated SS patients. We detected impaired IL-6, IL-10 and IL-13 secretion by PBMC induced by the agonists for TLR5, TLR3, TLR7 and TLR9 in SS patients, while it was partially recovered by TLR2/TLR4 and TLR7/8 agonists TNF secretion was restored following stimulation with TLR2/TLR4 agonists...
October 21, 2016: Oncotarget
Soo Young Kim, Min Seok Hur, Byung Gon Choi, Min Jung Kim, Yang Won Lee, Yong Beom Choe, Kyu Joong Ahn
Psoriasis is a polygenic and multifactorial disease showing ethnic differences in terms of its severity and frequency. Therapies targeting interleukin 17A (IL-17A), interleukin 17 receptor (IL-17R), and Janus kinases (JAKs) are in clinical development for the treatment of psoriasis, and their success suggests the essential role of these molecules in psoriasis. To investigate the genetic susceptibility in T helper 17 (Th17) cell signal transduction pathways for promoting psoriasis, we performed candidate gene and linkage disequilibrium analysis...
October 24, 2016: Clinical and Experimental Immunology
Hélène Quach, Maxime Rotival, Julien Pothlichet, Yong-Hwee Eddie Loh, Michael Dannemann, Nora Zidane, Guillaume Laval, Etienne Patin, Christine Harmant, Marie Lopez, Matthieu Deschamps, Nadia Naffakh, Darragh Duffy, Anja Coen, Geert Leroux-Roels, Frederic Clément, Anne Boland, Jean-François Deleuze, Janet Kelso, Matthew L Albert, Lluis Quintana-Murci
Humans differ in the outcome that follows exposure to life-threatening pathogens, yet the extent of population differences in immune responses and their genetic and evolutionary determinants remain undefined. Here, we characterized, using RNA sequencing, the transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli-ligands activating Toll-like receptor pathways (TLR1/2, TLR4, and TLR7/8) and influenza virus-and mapped expression quantitative trait loci (eQTLs)...
October 20, 2016: Cell
Kazuhiko Maeda, Shizuo Akira
TLRs play central roles in host defense. In this issue of Immunity, Zhang et al. (2016) generate structures of TLR7 bound to multiple ligands and provide insight into the mechanism of TLR7 ligand recognition that highlights the differences in the features of the TLR subfamily.
October 18, 2016: Immunity
Alexander K Andrianov, Alexander Marin, Thomas R Fuerst
Two macromolecular immunoadjuvants - poly[di(carboxylatophenoxy)phosphazene], PCPP and poly[di(carboxylatoethylphenoxy)phosphazene], PCEP have been investigated for their molecular interactions with model and bio-pharmaceutically important proteins in solutions, as well as for their TLR stimulatory effects and pH-dependent membrane disruptive activity in cellular assays. Solution interactions between polyphosphazenes and proteins, including antigens and soluble immune receptor proteins, have been studied using Asymmetric Flow Field Flow Fractionation (AF4) and Dynamic Light Scattering (DLS) at near physiological conditions - phosphate buffered saline, pH 7...
October 17, 2016: Biomacromolecules
Naveen Surendran, Ted Nicolosi, Michael Pichichero
We recently identified a population of 10% of infants who respond with sub-protective antibody levels to most routine primary pediatric vaccinations due to altered innate and adaptive immune responses. We term these infants as low vaccine responders (LVRs). Here we report new data showing that TLR7/8 agonist - R848 stimulation of PBMCs of LVR infants elicit significantly lower IFN-α, IL-12p70 and IL-1β, while inducing higher levels of CCL5 (RANTES) compared to normal vaccine responder (NVR) infants.
October 13, 2016: Vaccine
Zhikuan Zhang, Umeharu Ohto, Takuma Shibata, Elena Krayukhina, Masato Taoka, Yoshio Yamauchi, Hiromi Tanji, Toshiaki Isobe, Susumu Uchiyama, Kensuke Miyake, Toshiyuki Shimizu
Toll-like receptor 7 (TLR7) is a single-stranded RNA (ssRNA) sensor in innate immunity and also responds to guanosine and chemical ligands, such as imidazoquinoline compounds. However, TLR7 activation mechanism by these ligands remain largely unknown. Here, we generated crystal structures of three TLR7 complexes, and found that all formed an activated m-shaped dimer with two ligand-binding sites. The first site conserved in TLR7 and TLR8 was used for small ligand-binding essential for its activation. The second site spatially distinct from that of TLR8 was used for a ssRNA-binding that enhanced the affinity of the first-site ligands...
October 5, 2016: Immunity
Mahalakshmi Ramadass, Jennifer Linda Johnson, Sergio D Catz
Neutrophil secretory proteins are mediators of systemic inflammation in infection, trauma, and cancer. In response to specific inflammatory mediators, neutrophil granules are mobilized and cargo proteins released to modulate the microenvironment of inflammatory sites and tumors. In particular, GM-CSF, a cytokine secreted by several immune, nonimmune, and tumor cells, regulates neutrophil priming and exocytosis. Whereas a comprehensive understanding of this process is necessary to design appropriate anti-inflammatory therapies, the molecular effectors regulating GM-CSF-dependent priming of neutrophil exocytosis are currently unknown...
October 12, 2016: Journal of Leukocyte Biology
Anna Pomerenke, Simon R Lea, Sarah Herrick, Mark A Lindsay, Dave Singh
PURPOSE: Viruses are a common cause of exacerbations in chronic obstructive pulmonary disease (COPD). They activate toll-like receptors (TLRs) 3, 7, and 8, leading to a pro-inflammatory response. We have characterized the responses of TLR3 and TLR7/8 in lung tissue explants from COPD patients and control smokers. METHODS: We prepared lung whole tissue explants (WTEs) from patients undergoing surgery for confirmed or suspected lung cancer. In order to mimic the conditions of viral infection, we used poly(I:C) for TLR3 stimulation and R848 for TLR7/8 stimulation...
2016: International Journal of Chronic Obstructive Pulmonary Disease
Yuangang Liu, Zhiping Wang, Rachel De La Torre, Ashley Barling, Takahiro Tsujikawa, Noah Hornick, Jon Hanifin, Eric Simpson, Yun Wang, Emily Swanzey, Aaron Wortham, Hao Ding, Lisa M Coussens, Molly Kulesz-Martin
Altered innate immunity is a feature of certain skin inflammatory diseases such as psoriasis and atopic dermatitis (AD). In this study, we provide evidence that deficiency in Trim32 (a tripartite motif (TRIM) protein with innate antiviral activity) contributes to a Th2 biased response and predisposes to features of AD in mice. Upon treatment with the TLR7 agonist imquimod (IMQ), Trim32 knockout (KO) mice displayed compromised psoriasiform phenotypes and defective Th17 response. Instead, IMQ treatment of Trim32 KO mice induced AD-like phenotypes with enhanced skin infiltration of eosinophils and mast cells, elevation of Th2 cytokines/chemokines expression, and reduced expression of filaggrin protein expression...
October 5, 2016: Journal of Investigative Dermatology
Diana M Giraldo, Juan C Hernandez, Silvio Urcuqui-Inchima
Neutrophils are key effector cells of the innate immune system and are involved in the host defense against invading pathogens such as viruses. Recently, it was reported that HIV-1-neutrophil interaction triggers neutrophil activation and promotes expression of Toll-like receptors (TLRs). Here, we assessed the role of single-stranded RNA40 (ssRNA40) derived from HIV-1 in neutrophil activation. We observed functional activation of neutrophils in response to HIV-1-derived ssRNA40 based on the expression of TLR7/8, RIG-I, and MDA5, induction of cytokines (IL-6 and TNF-α), and the production of reactive oxygen species (ROS)...
October 7, 2016: Immunologic Research
Qiongbo Hu, Wei Wu
RNA interference (RNAi) technology is considered as an alternative for control of pests. However, RNAi has not been used in field conditions yet, since delivering exogenous ds/siRNA to target pests is very difficult. The laboratory methods of introducing the ds/siRNA into insects through feeding, micro feeding / dripping and injecting cannot be used in fields. Transgenic crop is perhaps the most effective application of RNAi for pest control, but it needs long-time basic researches in order to reduce the cost and evaluate the safety...
August 10, 2016: Bioengineered
Shereen Oon, Huy Huynh, Tsin Yee Tai, Milica Ng, Katherine Monaghan, Mark Biondo, Gino Vairo, Eugene Maraskovsky, Andrew D Nash, Ian P Wicks, Nicholas J Wilson
To date, the major target of biologic therapeutics in systemic lupus erythematosus (SLE) has been the B cell, which produces pathogenic autoantibodies. Recently, targeting type I IFN, which is elaborated by plasmacytoid dendritic cells (pDCs) in response to endosomal TLR7 and TLR9 stimulation by SLE immune complexes, has shown promising results. pDCs express high levels of the IL-3Rα chain (CD123), suggesting an alternative potential targeting strategy. We have developed an anti-CD123 monoclonal antibody, CSL362, and show here that it affects key cell types and cytokines that contribute to SLE...
May 5, 2016: JCI Insight
Yan Wang, Jingxia Zhao, Tingting Di, Mingxing Wang, Zhitong Ruan, Lu Zhang, Xiangjiang Xie, Yujiao Meng, Yan Lin, Xin Liu, Ning Wang, Ping Li
β,β-dimethylacryloyl alkannin (DMA) is a key component of Lithospermum and possesses good efficacy for treating psoriasis. DMA inhibits activated dendritic cells (DCs), but the mechanism is unknown. Therefore, this study aimed to explore the modulation of the TLR7/8 pathway by DMA in psoriasis-activated DCs. Models of psoriasis-like skin lesions were established using BALB/c mice; 8 mice were treated with DMA (2.5mg/kg). Bone marrow cells were isolated and induced into DCs using R848, a TLR7/8 agonist. Splenic CD11c+ cells were detected by flow cytometry...
September 30, 2016: International Immunopharmacology
Frances T Hakim, Sarfraz Memon, Ping Jin, Matin M Imanguli, Huan Wang, Najibah Rehman, Xiao-Yi Yan, Jeremy Rose, Jacqueline W Mays, Susan Dhamala, Veena Kapoor, William Telford, John Dickinson, Sean Davis, David Halverson, Haley B Naik, Kristin Baird, Daniel Fowler, David Stroncek, Edward W Cowen, Steven Z Pavletic, Ronald E Gress
Although chronic graft-versus-host disease (CGVHD) is the primary nonrelapse complication of allogeneic transplantation, understanding of its pathogenesis is limited. To identify the main operant pathways across the spectrum of CGVHD, we analyzed gene expression in circulating monocytes, chosen as in situ systemic reporter cells. Microarrays identified two interrelated pathways: 1) IFN-inducible genes, and 2) innate receptors for cellular damage. Corroborating these with multiplex RNA quantitation, we found that multiple IFN-inducible genes (affecting lymphocyte trafficking, differentiation, and Ag presentation) were concurrently upregulated in CGVHD monocytes compared with normal subjects and non-CGVHD control patients...
September 30, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Christina J Groß, Ritu Mishra, Katharina S Schneider, Guillaume Médard, Jennifer Wettmarshausen, Daniela C Dittlein, Hexin Shi, Oliver Gorka, Paul-Albert Koenig, Stephan Fromm, Giovanni Magnani, Tamara Ćiković, Lara Hartjes, Joachim Smollich, Avril A B Robertson, Matthew A Cooper, Marc Schmidt-Supprian, Michael Schuster, Kate Schroder, Petr Broz, Claudia Traidl-Hoffmann, Bruce Beutler, Bernhard Kuster, Jürgen Ruland, Sabine Schneider, Fabiana Perocchi, Olaf Groß
Imiquimod is a small-molecule ligand of Toll-like receptor-7 (TLR7) that is licensed for the treatment of viral infections and cancers of the skin. Imiquimod has TLR7-independent activities that are mechanistically unexplained, including NLRP3 inflammasome activation in myeloid cells and apoptosis induction in cancer cells. We investigated the mechanism of inflammasome activation by imiquimod and the related molecule CL097 and determined that K(+) efflux was dispensable for NLRP3 activation by these compounds...
September 24, 2016: Immunity
Frédérique Larousserie, Laura Bsiri, Valérie Dumaine, Céline Dietrich, Anne Audebourg, Brigitte Radenen-Bussière, Philippe Anract, Marie-Cécile Vacher-Lavenu, Odile Devergne
IL-27 regulates immune responses as well as hematopoiesis and bone remodeling, but its cellular sources in the bone remain unknown. In this study, we investigated whether osteoclasts and osteoblasts-the 2 cell types orchestrating bone homeostasis-could be a source of IL-27 and identified stimuli that induce its expression in vitro. We observed that human monocyte-derived osteoclasts expressed a broader range of TLRs than did human primary osteoblasts and that both cell types exhibited a differential induction of IL-27 expression in response to TLR or cytokine stimulation...
September 27, 2016: Journal of Leukocyte Biology
Andriana I Papaioannou, Aris Spathis, Konstantinos Kostikas, Petros Karakitsos, Spyros Papiris, Christos Rossios
Asthma is a heterogeneous inflammatory disease caused by association of genetic and environmental factors and its incidence has significantly increased over the latest years. The clinical manifestations of asthma are the result of airway hyper-reactivity to a variety of triggers such as aeroallergens, viral and bacterial components. Toll-like receptors (TLRs) are pathogen associated molecular pattern receptors, which are also expressed in the lung tissue as well as in several cells of the innate and adaptive immune system...
September 24, 2016: European Journal of Pharmacology
Naomi I Maria, Eline C Steenwijk, Arne S IJpma, Cornelia G van Helden-Meeuwsen, Petra Vogelsang, Wouter Beumer, Zana Brkic, Paul L A van Daele, P Martin van Hagen, Peter J van der Spek, Hemmo A Drexhage, Marjan A Versnel
OBJECTIVE: The interferon (IFN) type I signature is present in over half of patients with primary Sjögren's syndrome (pSS) and associated with higher disease-activity and autoantibody presence. Plasmacytoid dendritic cells (pDCs) are considered as the main source of enhanced IFN type I expression. The objective of this study was to unravel the molecular pathways underlying IFN type I bioactivity in pDCs of patients with pSS. METHODS: Blood samples from 42 healthy controls (HC) and 115 patients with pSS were stratified according to their IFN type I signature...
September 26, 2016: Annals of the Rheumatic Diseases
A Głobińska, M Pawełczyk, A Piechota-Polańczyk, A Olszewska-Ziąber, S Moskwa, A Mikołajczyk, A Jabłońska, P Zakrzewski, M Brauncajs, M Jarzębska, S Taka, N G Papadopoulos, M L Kowalski
PURPOSE: The aim of the study was to assess the immune response to parainfluenza virus type 3 (PIV3), rhinovirus 1B (RV1B) and intracellular Toll-like receptors (TLR) agonists in nasal epithelial cells (NECs) from patients with allergic rhinitis and healthy controls. METHODS: NECs were obtained from 8 patients with allergic rhinitis (AR) and 11 non-atopic healthy controls (HC) by nasal scraping, grown to confluence and exposed to PIV3, RV1B infection or TLR3 and TLR7/8 agonists...
September 26, 2016: Clinical and Experimental Immunology
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