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https://www.readbyqxmd.com/read/28346226/a-tlr9-dependent-checkpoint-governs-b-cell-responses-to-dna-containing-antigens
#1
Vishal J Sindhava, Michael A Oropallo, Krishna Moody, Martin Naradikian, Lauren E Higdon, Lin Zhou, Arpita Myles, Nathaniel Green, Kerstin Nündel, William Stohl, Amanda M Schmidt, Wei Cao, Stephanie Dorta-Estremera, Taku Kambayashi, Ann Marshak-Rothstein, Michael P Cancro
Mature B cell pools retain a substantial proportion of polyreactive and self-reactive clonotypes, suggesting that activation checkpoints exist to reduce the initiation of autoreactive B cell responses. Here, we have described a relationship among the B cell receptor (BCR), TLR9, and cytokine signals that regulate B cell responses to DNA-containing antigens. In both mouse and human B cells, BCR ligands that deliver a TLR9 agonist induce an initial proliferative burst that is followed by apoptotic death. The latter mechanism involves p38-dependent G1 cell-cycle arrest and subsequent intrinsic mitochondrial apoptosis and is shared by all preimmune murine B cell subsets and CD27- human B cells...
March 27, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28343701/toll-like-receptor-8-agonist-nanoparticles-mimic-immunomodulating-effects-of-the-live-bcg-vaccine-and-enhance-neonatal-innate-and-adaptive-immune-responses
#2
David J Dowling, Evan A Scott, Annette Scheid, Ilana Bergelson, Sweta Joshi, Carlo Pietrasanta, Spencer Brightman, Guzman Sanchez-Schmitz, Simon D Van Haren, Jana Ninković, Dina Kats, Cristiana Guiducci, Alexandre de Titta, Daniel K Bonner, Sachiko Hirosue, Melody A Swartz, Jeffrey A Hubbell, Ofer Levy
BACKGROUND: Newborns display distinct immune responses, leaving them vulnerable to infections and impairing immunization. Targeting newborn dendritic cells (DCs), which integrate vaccine signals into adaptive immune responses, might enable development of age-specific vaccine formulations to overcome suboptimal immunization. OBJECTIVE: Small-molecule imidazoquinoline Toll-like receptor (TLR) 8 agonists robustly activate newborn DCs but can result in reactogenicity when delivered in soluble form...
March 14, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28342266/increased-number-of-mast-cells-in-the-dermis-in-actinic-keratosis-lesions-effectively-treated-with-imiquimod
#3
Satomi Oyama, Yoko Funasaka, Shin-Ichi Tsuchiya, Seiji Kawana, Hidehisa Saeki
Actinic keratosis (AK) is a cutaneous cancer in situ which develops as a result of excessive exposure to ultraviolet (UV). Toll-like receptor (TLR)7 agonist imiquimod is a topical immune response modifier and is effective for the treatment of non-melanoma skin cancers. Recently, the diagnostic role of the dermatoscope has been reported in the course of treatment of AK. In addition, mast cells are now considered to contribute to both the innate and adaptive immune systems in topical imiquimod therapy. We assessed the effect of imiquimod treatment by dermatoscopic and immunohistochemical findings in 14 patients with a total of 21 AK lesions...
March 24, 2017: Journal of Dermatology
https://www.readbyqxmd.com/read/28341741/endogenous-prostaglandin-e2-amplifies-il-33-production-by-macrophages-through-an-e-prostanoid-ep-2-ep4-cyclic-camp-epac-dependent-pathway
#4
Sachin K Samuchiwal, Barbara Balestrieri, Hannah Raff, Joshua A Boyce
When activated through toll-like receptors (TLRs), macrophages generate interleukin-33 (IL-33), an IL-1 family member that induces innate immune responses through ST2 signaling. Lipopolysaccharide (LPS), a TLR4 ligand, induces macrophages to generate prostaglandin E2 (PGE2) through inducible cyclooxygenase (COX)-2 and microsomal PGE2 synthase-1 (mPGES-1) (1). We demonstrate that IL-33 production by bone marrow derived murine macrophages (bmMFs) requires the generation of endogenous PGE2 and the intrinsic expression of EP2 receptors to amplify NF-κB-dependent LPS-induced IL-33 expression via Exchange Protein Activated by cAMP (EPAC)...
March 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28341671/lipopolysaccharide-elicited-tslpr-expression-enriches-a-functionally-discrete-subset-of-human-cd14-cd1c-monocytes
#5
Francesco Borriello, Raffaella Iannone, Sarah Di Somma, Viviana Vastolo, Giuseppe Petrosino, Feliciano Visconte, Maddalena Raia, Giulia Scalia, Stefania Loffredo, Gilda Varricchi, Maria Rosaria Galdiero, Francescopaolo Granata, Luigi Del Vecchio, Giuseppe Portella, Gianni Marone
Thymic stromal lymphopoietin (TSLP) is a cytokine produced mainly by epithelial cells in response to inflammatory or microbial stimuli and binds to the TSLP receptor (TSLPR) complex, a heterodimer composed of TSLPR and IL-7 receptor α (CD127). TSLP activates multiple immune cell subsets expressing the TSLPR complex and plays a role in several models of disease. Although human monocytes express TSLPR and CD127 mRNAs in response to the TLR4 agonist LPS, their responsiveness to TSLP is poorly defined. We demonstrate that TSLP enhances human CD14(+) monocyte CCL17 production in response to LPS and IL-4...
March 24, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28337144/generation-and-characterization-of-specific-antibodies-to-the-murine-and-human-ectonucleotidase-ntpdase8
#6
Julie Pelletier, Mabrouka Salem, Joanna Lecka, Michel Fausther, François Bigonnesse, Jean Sévigny
The ectonucleotidase nucleoside triphosphate diphosphohydrolase-8 (NTPDase8) is the last member of the Ecto-NTPDase family to be discovered and characterized. It is a transmembrane protein which regulates the concentration of the agonists of P1 and P2 receptors at the cell surface. The functions of the enzyme are still not known partly due to the lack of specific tools such as antibodies. In this work, guinea pig polyclonal antibodies against mouse NTPDase8 and mouse monoclonal antibodies against human NTPDase8 have been generated and characterized...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28336292/structural-elucidation-and-physiologic-functions-of-specialized-pro-resolving-mediators-and-their-receptors
#7
REVIEW
Nan Chiang, Charles N Serhan
The acute inflammatory response is host protective to contain foreign invaders. Many of today's pharmacopeia that block pro-inflammatory chemical mediators can cause serious unwanted side effects such as immune suppression. Uncontrolled inflammation is now considered a pathophysiologic basis associated with, many widely occurring diseases such as cardiovascular disease, neurodegenerative diseases, diabetes, obesity and asthma, as well as the classic inflammatory diseases, e.g. arthritis, periodontal diseases...
March 20, 2017: Molecular Aspects of Medicine
https://www.readbyqxmd.com/read/28336214/indoleamine-2-3-dioxygenase-1-ido1-inhibitors-activate-the-aryl-hydrocarbon-receptor
#8
Benjamin J Moyer, Itzel Y Rojas, Iain A Murray, Seokwon Lee, Haley F Hazlett, Gary H Perdew, Craig R Tomlinson
Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in the immune system by regulating tryptophan levels and T cell differentiation. Several tumor types overexpress IDO1 to avoid immune surveillance making IDO1 of interest as a target for therapeutic intervention. As a result, several IDO1 inhibitors are currently being tested in clinical trials for cancer treatment as well as several other diseases. Many of the IDO1 inhibitors in clinical trials naturally bear structural similarities to the IDO1 substrate tryptophan, as such, they fulfill many of the structural and functional criteria as potential AHR ligands...
March 20, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28335888/second-and-third-generation-drugs-for-immuno-oncology-treatment-the-more-the-better
#9
REVIEW
Wolfram C M Dempke, Klaus Fenchel, Peter Uciechowski, Stephen P Dale
Recent success in cancer immunotherapy (anti-CTLA-4, anti-PD1/PD-L1) has confirmed the hypothesis that the immune system can control many cancers across various histologies, in some cases producing durable responses in a way not seen with many small-molecule drugs. However, only less than 25% of all patients do respond to immuno-oncology drugs and several resistance mechanisms have been identified (e.g. T-cell exhaustion, overexpression of caspase-8 and β-catenin, PD-1/PD-L1 gene amplification, MHC-I/II mutations)...
March 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28330868/protein-arginine-methyltransferase-1-modulates-innate-immune-responses-through-regulation-of-peroxisome-proliferator-activated-receptor-gamma-dependent-macrophage-differentiation
#10
Irina Tikhanovich, Jie Zhao, Jody Olson, Abby Adams, Ryan Taylor, Brian Bridges, Laurie Marshall, Benjamin Roberts, Steven A Weinman
Arginine methylation is a common posttranslational modification that has been shown to regulate both gene expression and extranuclear signaling events. We recently reported defects in Protein Arginine Methyltransferase 1 (PRMT1) activity and arginine methylation in the livers of cirrhosis patients with a history of recurrent infections. To examine the role of PRMT1 in innate immune responses in vivo, we created a cell type specific knockout mouse model. We showed that myeloid specific PRMT1 knockout mice demonstrate higher proinflammatory cytokine production and a lower survival rate after cecal ligation and puncture...
March 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28329286/short-course-tlr9-agonist-treatment-impacts-innate-immunity-and-plasma-viremia-in-individuals-with-hiv-infection
#11
Line Vibholm, Mariane H Schleimann, Jesper F Højen, Thomas Benfield, Rasmus Offersen, Katrine Rasmussen, Rikke Olesen, Anders Dige, Jørgen Agnholt, Judith Grau, Maria Buzon, Burghardt Wittig, Mathias Lichterfeld, Andreas Munk Petersen, Xutao Deng, Mohammed Abdel-Mohsen, Satish K Pillai, Sofie Rutsaert, Wim Trypsteen, Ward De Spiegelaere, Linos Vandekerchove, Lars Østergaard, Thomas A Rasmussen, Paul W Denton, Martin Tolstrup, Ole S Søgaard
Background: Treatment with latency reversing agents (LRA) enhances HIV-1 transcription in vivo but only leads to modest reductions in the size of the reservoir, possibly due to insufficient immune-mediated elimination of infected cells. We hypothesized that a single drug molecule - a novel toll-like receptor 9 (TLR9) agonist, MGN1703 - could function as an enhancer of innate immunity and an LRA in vivo. Methods: We conducted a single-arm, open-label study, where 15 virologically suppressed HIV-1 infected individuals on antiretroviral therapy received 60 mg MGN1703 s...
March 9, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/28327944/a-phase-2-randomized-double-blind-placebo-%C3%A2-controlled-study-of-chemo-immunotherapy-combination-using-motolimod-with-pegylated-liposomal-doxorubicin-in-recurrent-or-persistent-ovarian-cancer-a-gynecologic-oncology-group-partners-study
#12
B J Monk, M F Brady, C Aghajanian, H A Lankes, T Rizack, J Leach, J M Fowler, R Higgins, P Hanjani, M Morgan, R Edwards, W Bradley, T Kolevska, P Foukas, E Swisher, K S Anderson, R Gottardo, J K Bryan, M Newkirk, K L Manjarrez, R S Mannel, R M Hershberg, G Coukos
Background: A phase 2, randomized, placebo-controlled trial was conducted in women with recurrent epithelial ovarian carcinoma to evaluate the efficacy and safety of motolimod-a Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses-combined with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death. Patients and methods: Women with ovarian, fallopian tube, or primary peritoneal carcinoma were randomized 1 : 1 to receive PLD in combination with blinded motolimod or placebo...
February 21, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28326085/dectin-1-compromises-innate-responses-and-host-resistance-against-neospora-caninum-infection
#13
Murilo Vieira da Silva, Flávia Batista Ferreira França, Caroline Martins Mota, Arlindo Gomes de Macedo Júnior, Eliézer Lucas Pires Ramos, Fernanda Maria Santiago, José Roberto Mineo, Tiago Wilson Patriarca Mineo
Neospora caninum is an intracellular protozoan parasite that has drawn increasing interest due to its association with worldwide repetitive bovine abortions, which cause billionaire losses to the meat and dairy industries annually. Innate immunity plays an important role in infection control, and N. caninum activates the production of inflammatory mediators through toll-like receptors, NOD-like receptors, and mitogen-activated protein kinase signaling pathways. Advances in the knowledge of initial host-parasite interactions are desirable for the design of control measures against the infection, obliterating its pathogenesis...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28325871/progression-of-type-1-diabetes-from-the-prediabetic-stage-is-controlled-by-interferon-%C3%AE-signaling
#14
Brett S Marro, Brian C Ware, Jaroslav Zak, Juan Carlos de la Torre, Hugh Rosen, Michael B A Oldstone
Blockade of IFN-α but not IFN-β signaling using either an antibody or a selective S1PR1 agonist, CYM-5442, prevented type 1 diabetes (T1D) in the mouse Rip-LCMV T1D model. First, treatment with antibody or CYM-5442 limited the migration of autoimmune "antiself" T cells to the external boundaries around the islets and prevented their entry into the islets so they could not be positioned to engage, kill, and thus remove insulin-producing β cells. Second, CYM-5442 induced an exhaustion signature in antiself T cells by up-regulating the negative immune regulator receptor genes Pdcd1, Lag3, Ctla4, Tigit, and Btla, thereby limiting their killing ability...
March 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28325863/pharmacological-targeting-of-plasmin-prevents-lethality-in-a-murine-model-of-macrophage-activation-syndrome
#15
Hiroshi Shimazu, Shinya Munakata, Yoshihiko Tashiro, Yousef Salama, Douaa Dhahri, Salita Eiamboonsert, Yasunori Ota, Haruo Onoda, Yuko Tsuda, Yoshio Okada, Hiromitsu Nakauchi, Beate Heissig, Koichi Hattori
Macrophage activation syndrome (MAS) is a life-threatening disorder characterized by a cytokine storm and multiorgan dysfunction due to excessive immune activation. Although abnormalities of coagulation and fibrinolysis are major components of MAS, the role of the fibrinolytic system and its key player, plasmin, in the development of MAS remains to be solved. We established a murine model of fulminant MAS by repeated injections of Toll-like receptor-9 (TLR-9) agonist and D-galactosamine (DG) in immunocompetent mice...
March 21, 2017: Blood
https://www.readbyqxmd.com/read/28325822/structural-basis-for-chemokine-recognition-by-a-g-protein-coupled-receptor-and-implications-for-receptor-activation
#16
Joshua J Ziarek, Andrew B Kleist, Nir London, Barak Raveh, Nicolas Montpas, Julien Bonneterre, Geneviève St-Onge, Crystal J DiCosmo-Ponticello, Chad A Koplinski, Ishan Roy, Bryan Stephens, Sylvia Thelen, Christopher T Veldkamp, Frederick D Coffman, Marion C Cohen, Michael B Dwinell, Marcus Thelen, Francis C Peterson, Nikolaus Heveker, Brian F Volkman
Chemokines orchestrate cell migration for development, immune surveillance, and disease by binding to cell surface heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). The array of interactions between the nearly 50 chemokines and their 20 GPCR targets generates an extensive signaling network to which promiscuity and biased agonism add further complexity. The receptor CXCR4 recognizes both monomeric and dimeric forms of the chemokine CXCL12, which is a distinct example of ligand bias in the chemokine family...
March 21, 2017: Science Signaling
https://www.readbyqxmd.com/read/28325295/aptamers-for-cd-antigens-from-cell-profiling-to-activity-modulation
#17
REVIEW
Amin Nozari, Maxim V Berezovski
Nucleic acid-based aptamers are considered to be a promising alternative to antibodies because of their strong and specific binding to diverse targets, fast and inexpensive chemical synthesis, and easy labeling with a fluorescent dye or therapeutic agent. Cluster of differentiation (CD) proteins are among the most popular antigens for aptamers on the cell surface. These anti-CD aptamers could be used in cell biology and biomedicine, from simple cell phenotyping by flow cytometry or fluorescent microscopy to diagnosis and treatment of HIV/AIDS to cancer and immune therapies...
March 17, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28324760/trpv1-agonism-inhibits-endothelial-cell-inflammation-via-activation-of-enos-no-pathway
#18
Youping Wang, Lin Cui, Hui Xu, Suxiao Liu, Feiyun Zhu, Fengna Yan, Si Shen, Mingjun Zhu
BACKGROUND AND AIMS: Transient receptor potential vanilloid type 1 channel (TRPV1) is found to be expressed in endothelial cells (ECs) and activate endothelial nitric oxide synthase (eNOS). Recent studies implicate TRPV1 in attenuating inflammatory responses. However, the mechanisms underlying the beneficial effects remain unclear. In this study, we investigated whether TRPV1 suppresses inflammatory responses of ECs via eNOS/NO pathway. METHODS: Human umbilical vein endothelial cells (HUVECs) and renal microvascular endothelial cells (MVECs) isolated from deoxycorticosterone (DOCA)-salt hypertensive mice were cultured in the presence of capsaicin (CAP, a specific TRPV1 agonist) with or without the specific inhibitor of TRPV1, NOS, or Ca(2+)-dependent phosphatidylinositol 3-kinase (PI3K)/Akt pathway, before lipopolysaccharide (LPS) stimulation...
March 10, 2017: Atherosclerosis
https://www.readbyqxmd.com/read/28322156/recent-findings-on-the-application-of-toll-like-receptors-agonists-in-cancer-therapy
#19
Martina Mikulandra, Jasminka Pavelic, Tanja Matijevic Glavan
The immune system's first line of defense is innate immunity, largely based on a large family of pattern recognition receptors (PRRs) that recognize evolutionary conserved molecular motifs on pathogens called pathogen-associated molecular patterns (PAMPs). The most extensively studied family of PRRs are Toll-like receptors (TLRs), which can trigger various cellular pathways after ligand stimulation. Their role in cancer is still unresolved as there are many different studies showing contradictory results. TLRs have been associated with both tumor progression and immunosuppression as well as with apoptosis and immune system activation...
March 20, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28315343/inhibition-of-agonist-induced-smooth-muscle-contraction-by-picotamide-in-the-male-human-lower-urinary-tract-outflow-region
#20
Martin Hennenberg, Alexander Tamalunas, Yiming Wang, Patrick Keller, Melanie Schott, Frank Strittmatter, Annika Herlemann, Qingfeng Yu, Beata Rutz, Anna Ciotkowska, Christian G Stief, Christian Gratzke
Male lower urinary tract symptoms (LUTS) due to bladder outlet obstruction are characterized by abnormal smooth muscle contractions in the lower urinary tract. Alpha1-adrenoceptor antagonists may induce smooth muscle relaxation in the outflow region and represent the current goldstandard of medical treatment. However, results may be unsatisfactory or inadequate. Apart from α1-adrenoceptor agonists, smooth muscle contraction in the outflow region may be induced by thromboxane A2 (TXA2), endothelins, or muscarinic receptor agonists...
March 14, 2017: European Journal of Pharmacology
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