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Magdalena Janina Laskaj, Anne Troldborg, Ellen-Margrethe Hauge, Shervin Bahrami, Kristian Stengaard-Pedersen
OBJECTIVES: Human Endogenous Retroviruses (HERVs) are remnants of past retroviral infections in the human genome and have been implicated in different aspects of human biology. The aim of this study was to identify HERVs which are associated with the pathogenesis of Rheumatoid diseases represented by Systemic Lupus Erythematosus (SLE). METHODS: The study subjects included 45 female patients with SLE and 50 geographically and age matched healthy. Real-time RT-PCR analysis was used to examine the transcription levels of 11 genes with coding capacity for complete envelope protein in these individuals...
October 1, 2016: Arthritis & Rheumatology
Nancy Gupta, Satish Vedi, Dennis Y Kunimoto, Babita Agrawal, Rakesh Kumar
Mycobacterium tuberculosis (Mtb), the bacterial cause of tuberculosis, is a leading infectious agent worldwide. The development of a new vaccine against Mtb is essential to control global spread of tuberculosis, since the current vaccine BCG is not very effective and antibiotic resistance is a serious, burgeoning problem. ESAT-6 is a secreted protein of Mtb, which is absent in BCG but has been implicated in inducing protective immunity against Mtb. Peptide based subunit vaccines are attractive due to their safety and high specificity in eliciting immune responses, but small synthetic peptides are usually not very immunogenic...
September 29, 2016: Vaccine
Lydia Dyck, Mieszko M Wilk, Mathilde Raverdeau, Alicja Misiak, Louis Boon, Kingston H G Mills
The co-inhibitory molecule PD-1 suppresses T cell responses and has been targeted in the treatment of cancer. Here, we examined the role of PD-1 in regulating the balance between regulatory and effector T cells and whether blocking PD-1 could enhance tumour vaccine-induced protective immunity. A significantly higher proportion of tumour-resident T cells expressed PD-1 and Foxp3 compared with T cells in the tumour circulation or draining lymph nodes, and this correlated with a lower frequency of IFN-γ- and TNF-secreting CD8 T cells...
September 28, 2016: Cancer Immunology, Immunotherapy: CII
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
Tae Whan Kim, Seunghee Hong, Yin Lin, Elise Murat, HyeMee Joo, Taeil Kim, Virginia Pascual, Yong-Jun Liu
Type I IFNs are crucial mediators of human innate and adaptive immunity and are massively produced from plasmacytoid dendritic cells (pDCs). IFN regulatory factor (IRF)7 is a critical regulator of type I IFN production when pathogens are detected by TLR 7/9 in pDC. However, hyperactivation of pDC can cause life-threatening autoimmune diseases. To avoid the deleterious effects of aberrant pDC activation, tight regulation of IRF7 is required. Nonetheless, the detailed mechanisms of how IRF7 transcription is regulated in pDC are still elusive...
September 14, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Robert A Mitchell, Rita Altszuler, Ute Frevert, Elizabeth H Nardin
Malaria eradication will require a combination of vector control, chemotherapy and an easily administered vaccine. Sterile immunity can be elicited in humans by immunization with sporozoites, the infective stage injected by bite of the mosquito vector, however, whole parasite vaccines present formidable logistical challenges for production, storage and administration. The "gold standard" for infectious disease eradiation, the Smallpox Eradication Programme, utilized mass immunization using the skin scarification (SS) route...
2016: Scientific Reports
Yazhong Tao, Xin Zhang, Silva Markovic-Plese
We report that B cells from patients with RRMS have decreased endogenous IFN-β secretion and deficient IFN receptor (IFNAR)1/2 and TLR7 gene expression in comparison to healthy controls (HCs), which may contribute to disregulation of cytokine secretion by B cells. We propose that TLR7 and TLR9 stimulation with loxorubin (LOX) and CpG, in combination with exogenous IFN-β may effectively reconstitute endogenous IFN-β production deficit and induce the secretion of immunoregulatory cytokines by B cells. Both LOX/IFN-β and CpG/IFN-β in-vitro treatments of B cells from RRMS patients induced higher endogenous IFN-β gene expression in comparison to the exogenous IFN-β alone...
September 15, 2016: Journal of Neuroimmunology
Funda Orhan, Maria Bhat, Kristian Sandberg, Sara Ståhl, Fredrik Piehl, Camilla Svensson, Sophie Erhardt, Lilly Schwieler
Tryptophan degradation along the kynurenine pathway is of central importance for the immune function. Toll-like receptors (TLRs), representing the first line of immune defense against pathogens, are expressed in various cell types. The most abundant expression is found on monocytes, macrophages and dendritic cells. The aim of the present study is to investigate if stimulation with different TLR ligands induces the kynurenine pathway in human peripheral monocytes. Cell supernatants were analyzed using a liquid chromatography/mass spectrometry to measure kynurenine, kynurenic acid (KYNA), quinolinic acid (QUIN) and tryptophan...
September 8, 2016: Scandinavian Journal of Immunology
Joseph R Francica, Geoffrey M Lynn, Richard Laga, Michael Gordon Joyce, Tracy J Ruckwardt, Kaitlyn M Moribito, Man Chen, Rajoshi Chaudhuri, Baoshan Zhang, Mallika Sastry, Kiyoon Ko, Misook Choe, Michal Pechar, Ivelin S Georgiev, Lisa A Kueltzo, Leonard W Seymour, John R Mascola, Peter D Kwong, Barney S Graham, Robert A Seder
Structure-based vaccine design has been used to develop immunogens that display conserved neutralization sites on pathogens such as HIV-1, respiratory syncytial virus (RSV) and influenza. Improving the immunogenicity of these designed immunogens with adjuvants will require formulations that do not alter protein antigenicity. Here we show that nanoparticle-forming thermo-responsive polymers (TRP) allow for co-delivery of RSV fusion (F) protein trimers with Toll-like receptor 7 and 8 agonists (TLR-7/8a) to enhance protective immunity...
September 1, 2016: Bioconjugate Chemistry
Benjamin Krämer, Claudia Finnemann, Beatriz Sastre, Philipp Lutz, Andreas Glässner, Franziska Wolter, Felix Goeser, Pavlos Kokordelis, Dominik Kaczmarek, Hans-Dieter Nischalke, Christian P Strassburg, Ulrich Spengler, Jacob Nattermann
BACKGROUND: Immuno-genetic studies suggest a functional link between NK cells and λ-IFNs. We recently showed that NK cells are negative for the IFN-λ receptor IFN-λR1 and do not respond to IFN-λ, suggesting a rather indirect association between IL-28B genotype and NK cell activity. METHODS: A total of 75 HCV(+) patients and 67 healthy controls were enrolled into this study. IL-28B (rs12979860) and IFNL-4 (rs368234815) genotypes were determined by rtPCR. Total PBMC, monocytes, and NK cells were stimulated with IL-29, the TLR-7/8 agonist R848, or a combination of both...
2016: PloS One
Naihan Chen, Michael A Collier, Matthew D Gallovic, Graham C Collins, Carla C Sanchez, Elizabeth Q Fernandes, Eric M Bachelder, Kristy M Ainslie
Microparticles (MPs) derived from acid-sensitive biopolymers enable rapid degradation and cargo release under acidic conditions, such as at tumor microenvironments, within lysosomal/phagosomal compartments inside phagocytic cells, or at sites of inflammation. One such acid-sensitive biopolymer, acetalated dextran (Ace-DEX), has tunable degradation rates and pH-neutral degradation byproducts consisting of dextran, acetone, and ethanol. By studying the degradation profiles of Ace-DEX MPs with varying cyclic acetal coverage (CAC) and dextran molecular weight (MW), we concluded that MPs composed of low CAC or high MW polymer degraded the fastest at both pH 7...
October 15, 2016: International Journal of Pharmaceutics
David McGowan, Florence Herschke, Frederik Pauwels, Bart Stoops, Stefaan Last, Serge Pieters, Annick Scholliers, Tine Thoné, Bertrand Van Schoubroeck, Dorien De Pooter, Wendy Mostmans, Mourad Daoubi Khamlichi, Werner Embrechts, Deborah Dhuyvetter, Ilham Smyej, Eric Arnoult, Samuël Demin, Herman Borghys, Gregory Fanning, Jaromir Vlach, Pierre Raboisson
Toll-like receptor (TLR) 7 and 8 agonists can potentially be used in the treatment of viral infections and are particularly promising for chronic hepatitis B virus (HBV) infection. An internal screening effort identified a pyrimidine Toll-like receptor 7 and 8 dual agonist. This provided a novel alternative over the previously reported adenine and pteridone type of agonists. Structure-activity relationship, lead optimization, in silico docking, pharmacokinetics, and demonstration of ex vivo and in vivo cytokine production of the lead compound are presented...
September 8, 2016: Journal of Medicinal Chemistry
Xavier S Revelo, Magar Ghazarian, Melissa Hui Yen Chng, Helen Luck, Justin H Kim, Kejing Zeng, Sally Y Shi, Sue Tsai, Helena Lei, Justin Kenkel, Chih Long Liu, Stephanie Tangsombatvisit, Hubert Tsui, Corneliu Sima, Changting Xiao, Lei Shen, Xiaoying Li, Tianru Jin, Gary F Lewis, Minna Woo, Paul J Utz, Michael Glogauer, Edgar Engleman, Shawn Winer, Daniel A Winer
Obesity-related inflammation of metabolic tissues, including visceral adipose tissue (VAT) and liver, are key factors in the development of insulin resistance (IR), though many of the contributing mechanisms remain unclear. We show that nucleic-acid-targeting pathways downstream of extracellular trap (ET) formation, unmethylated CpG DNA, or ribonucleic acids drive inflammation in IR. High-fat diet (HFD)-fed mice show increased release of ETs in VAT, decreased systemic clearance of ETs, and increased autoantibodies against conserved nuclear antigens...
July 19, 2016: Cell Reports
Beth C Holbrook, Jong R Kim, Lance K Blevins, Matthew J Jorgensen, Nancy D Kock, Ralph B D'Agostino, S Tyler Aycock, Mallinath B Hadimani, S Bruce King, Griffith D Parks, Martha A Alexander-Miller
Influenza virus infection of neonates poses a major health concern, often resulting in severe disease and hospitalization. At present, vaccines for this at-risk population are lacking. Thus, development of an effective vaccine is an urgent need. In this study, we have used an innovative nonhuman primate neonate challenge model to test the efficacy of a novel TLR 7/8 agonist R848-conjugated influenza virus vaccine. The use of the intact virus represents a step forward in conjugate vaccine design because it provides multiple antigenic targets allowing for elicitation of a broad immune response...
July 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Besma Aouar, Denisa Kovarova, Sebastien Letard, Albert Font-Haro, Jonathan Florentin, Jan Weber, David Durantel, Laurence Chaperot, Joel Plumas, Katerina Trejbalova, Jiri Hejnar, Jacques A Nunès, Daniel Olive, Patrice Dubreuil, Ivan Hirsch, Ruzena Stranska
Crosslinking of regulatory immunoreceptors (RR), such as BDCA-2 (CD303) or ILT7 (CD85g), of plasmacytoid dendritic cells (pDCs) efficiently suppresses production of type-I interferon (IFN)-α/β and other cytokines in response to Toll-like receptor (TLR) 7/9 ligands. This cytokine-inhibitory pathway is mediated by spleen tyrosine kinase (Syk) associated with the ITAM-containing adapter of RR. Here we demonstrate by pharmacological targeting of Syk that in addition to the negative regulation of TLR7/9 signaling via RR, Syk also positively regulates the TLR7/9 pathway in human pDCs...
2016: PloS One
Simon J Dovedi, Grazyna Lipowska-Bhalla, Stephen A Beers, Eleanor J Cheadle, Lijun Mu, Martin J Glennie, Timothy M Illidge, Jamie Honeychurch
Tumor cells dying after cytotoxic therapy are a potential source of antigen for T-cell priming. Antigen-presenting cells (APC) can cross-present MHC I-restricted peptides after the uptake of dying cells. Depending on the nature of the surrounding environmental signals, APCs then orchestrate a spectrum of responses ranging from immune activation to inhibition. Previously, we had demonstrated that combining radiation with either agonistic monoclonal antibody (mAb) to CD40 or a systemically administered TLR7 agonist could enhance CD8 T-cell-dependent protection against syngeneic murine lymphoma models...
July 2016: Cancer Immunology Research
Dana Saadeh, Mazen Kurban, Ossama Abbas
Plasmacytoid dendritic cells (pDCs) correspond to a specialized dendritic cell population that exhibit plasma cell morphology, express CD4, CD123, HLA-DR, blood-derived dendritic cell antigen-2 (BDCA-2), and Toll-like receptor (TLR)7 and TLR9 within endosomal compartments. Through their production of type I interferons (IFNs) and other pro-inflammatory cytokines, pDCs provide anti-viral resistance and link the innate and adaptive immunity by controlling the function of myeloid DCs, lymphocytes, and natural killer (NK) cells...
July 2016: Journal of Dermatological Science
Dong Gao, Juan Zeng, Xiaodong Wang, Yu Liu, Wang Li, Yunlong Hu, Ningning Gao, Yuwen Diao, Zhulin Wang, Wenqi Jiang, Jinhua Chen, Guangyi Jin
To study the structure-activity relationship (SAR) of Toll-like receptor 7 (TLR-7) agonists based on 8-oxoadenines, a novel subset of C9-substituted 8-hydroxy-2-(2-methoxyethoxy)-adenines and their antigen conjugates were synthesized. In vitro, the ability of cytokines (IL-12p70 and IFN-γ) induction of ligands with alkyl acid at C9-position were very weak compared with benzoic acid counter parts. Unexpectedly, its antigen conjugates that conjugated with proteins or peptides with weak immunogenicity, showed enhanced activity of cytokines induction...
September 14, 2016: European Journal of Medicinal Chemistry
I C Ballweg, K Frölich, E Fandrey, H Kliem, M W Pfaffl
The competences of the immune systems of the ancient pig breed Turopolje (T×T), German Landrace × Turopolje (L×T) and 'modern' pig breed German Landrace × Pietrain (L×P) were compared in this study. All pigs were immunized with a modified live vaccine against 'Porcine Reproductive and Respiratory Syndrome' (PRRS) virus (Ingelvac PRRS MLV(®)) to simulate an infection. Antibody production against PRRS MLV was evaluated in serum. Elimination of the viral infectious fragments during the experimental period was monitored in serum, leukocytes and tonsils by RT-qPCR...
June 2016: Veterinary Immunology and Immunopathology
Olivia J Larsson, Martijn L Manson, Magnus Starkhammar, Barbara Fuchs, Mikael Adner, Susanna Kumlien Georén, Lars-Olaf Cardell
Toll-like receptor (TLR) 7 agonists are known to reduce allergic airway inflammation. Their recently reported ability to rapidly relax airways has further increased their interest in the treatment of pulmonary disease. However, the mechanisms behind this effect are not fully understood. The present study, therefore, aimed to determine whether airway smooth muscle (ASM)-dependent mechanisms could be identified. TLR7 agonists were added to guinea pig airways following precontraction with carbachol in vitro or histamine in vivo...
June 1, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
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