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TLR9

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https://www.readbyqxmd.com/read/29157732/rnase-7-strongly-promotes-tlr9-mediated-dna-sensing-by-human-plasmacytoid-dendritic-cells
#1
V Kopfnagel, S Wagenknecht, J Harder, K Hofmann, M Kleine, A Buch, B Sodeik, T Werfel
Plasmacytoid dendritic cells (pDCs) were described to accumulate in the skin of patients with psoriasis and to be recruited into the dermis upon allergen challenge in atopic dermatitis. Importantly, activation of pDCs in the skin has been identified as important initiator of psoriasis development. RNase 7 is one of the major antimicrobial peptides (AMP) secreted by keratinocytes and is expressed in significantly higher amounts in lesional skin of patients with atopic dermatitis or psoriasis than in healthy individuals...
November 17, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29156818/a-plasmid-containing-cpg-odn-as-vaccine-adjuvant-against-grass-carp-reovirus-in-grass-carp-ctenopharyngodon-idella
#2
Hang Su, Zhiwei Liao, Gailing Yuan, Jianguo Su
CpG oligodeoxynucleotides (ODNs) are proved to have strong immune stimulatory activity. Plasmids containing CpG ODNs could be conveniently and low-costly used as vaccine adjuvant. However, they are different among various plasmids, motif repeats, species, etc. In the present study, plasmid pcDNA3.1 (+) containing five repetitions of CpG ODN 1670A named pcDNA3.1-1670A*5 with strong immunostimulation was screened out from twelve recombinant plasmids and three empty vectors by cell proliferation activity, interferon promoter activities and immune related gene expressions in CIK cells...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29155428/small-molecule-inhibition-of-tlr8-through-stabilization-of-its-resting-state
#3
Shuting Zhang, Zhenyi Hu, Hiromi Tanji, Shuangshuang Jiang, Nabanita Das, Jing Li, Kentaro Sakaniwa, Jin Jin, Yanyan Bian, Umeharu Ohto, Toshiyuki Shimizu, Hang Yin
Endosomal Toll-like receptors (TLR3, TLR7, TLR8, and TLR9) are highly analogous sensors for various viral or bacterial RNA and DNA molecular patterns. Nonetheless, few small molecules can selectively modulate these TLRs. In this manuscript, we identified the first human TLR8-specific small-molecule antagonists via a novel inhibition mechanism. Crystal structures of two distinct TLR8-ligand complexes validated a unique binding site on the protein-protein interface of the TLR8 homodimer. Upon binding to this new site, the small-molecule ligands stabilize the preformed TLR8 dimer in its resting state, preventing activation...
November 20, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29150564/essential-role-of-card14-in-murine-experimental-psoriasis
#4
Mayuri Tanaka, Kouji Kobiyama, Tetsuya Honda, Kozue Uchio-Yamada, Yayoi Natsume-Kitatani, Kenji Mizuguchi, Kenji Kabashima, Ken J Ishii
Caspase recruitment domain family member 14 (CARD14) was recently identified as a psoriasis-susceptibility gene, but its immunological role in the pathogenesis of psoriasis in vivo remains unclear. In this study, we examined the role of CARD14 in murine experimental models of psoriasis induced by either imiquimod (IMQ) cream or recombinant IL-23 injection. In all models tested, the psoriasiform skin inflammation was abrogated in Card14(-/-) mice. Comparison of the early gene signature of the skin between IMQ-cream-treated Card14(-/-) mice and Tlr7(-/-)Tlr9(-/-) mice revealed not only their similarity, but also distinct gene sets targeted by IL-23...
November 17, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29150239/tissue-resident-macrophages-are-locally-programmed-for-silent-clearance-of-apoptotic-cells
#5
Allison W Roberts, Bettina L Lee, Jacques Deguine, Shinu John, Mark J Shlomchik, Gregory M Barton
Although apoptotic cells (ACs) contain nucleic acids that can be recognized by Toll-like receptors (TLRs), engulfment of ACs does not initiate inflammation in healthy organisms. Here we identified macrophage populations that continually engulf ACs in distinct tissues and found that these macrophages share characteristics compatible with immunologically silent clearance of ACs; such characteristics include high expression of AC recognition receptors, low expression of TLR9, and reduced TLR responsiveness to nucleic acids...
November 21, 2017: Immunity
https://www.readbyqxmd.com/read/29147913/expression-of-tlr7-tlr9-jak2-and-stat3-genes-in-peripheral-blood-mononuclear-cells-from-patients-with-systemic-sclerosis
#6
Miša Vreća, Ana Zeković, Nemanja Damjanov, Marina Andjelković, Milena Ugrin, Sonja Pavlović, Vesna Spasovski
Systemic sclerosis (SSc) is a rare, chronic, multisystem autoimmune disease clinically characterized by progressive fibrosis of the skin and internal organs. The basic mechanism appears to involve endothelial cell injury, overproduction of extracellular matrix proteins, and aberrant immune activation. So far, there have been a few attempts to find genetic biomarkers for monitoring disease activity or for correlation with certain symptoms. In order to reveal reliable biomarkers, we analyzed the expression of four genes representing three important signaling pathways, TLR7, TLR9, and JAK2-STAT3...
November 16, 2017: Journal of Applied Genetics
https://www.readbyqxmd.com/read/29147012/piperidylmethyloxychalcone-improves-immune-mediated-acute-liver-failure-via-inhibiting-tak1-activity
#7
Sun Hong Park, Jeong-Ah Kwak, Sang-Hun Jung, Byeongwoo Ahn, Won-Jea Cho, Cheong-Yong Yun, Chang Seon Na, Bang Yeon Hwang, Jin Tae Hong, Sang-Bae Han, Youngsoo Kim
Mice deficient in the toll-like receptor (TLR) or the myeloid differentiation factor 88 (MyD88) are resistant to acute liver failure (ALF) with sudden death of hepatocytes. Chalcone derivatives from medicinal plants protect from hepatic damages including ALF, but their mechanisms remain to be clarified. Here, we focused on molecular basis of piperidylmethyloxychalcone (PMOC) in the treatment of TLR/MyD88-associated ALF. C57BL/6J mice were sensitized with D-galactosamine (GalN) and challenged with Escherichia coli lipopolysaccharide (LPS, TLR4 agonist) or oligodeoxynucleotide containing unmethylated CpG motif (CpG ODN, TLR9 agonist) for induction of ALF...
November 17, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29146546/signaling-via-toll-like-receptor-4-and-cd40-in-b-cells-plays-a-regulatory-role-in-the-pathogenesis-of-multiple-sclerosis-through-interleukin-10-production
#8
Yoichiro Okada, Hirofumi Ochi, Chihiro Fujii, Yuichiro Hashi, Mio Hamatani, Shinji Ashida, Kazuyuki Kawamura, Hirofumi Kusaka, Sadayuki Matsumoto, Masanori Nakagawa, Toshiki Mizuno, Ryosuke Takahashi, Takayuki Kondo
BACKGROUND: B cells play an important role in the development of multiple sclerosis (MS), but can also exhibit regulatory functions through IL-10 production. Toll-like receptors (TLR) and CD40 signaling are likely to be involved in this process. OBJECTIVE: To investigate the ability of MS B cells to produce IL-10 in response to TLR stimulation in the presence or absence of CD40 co-stimulation. METHODS: Peripheral blood mononuclear cells obtained from 34 MS patients and 24 matched healthy participants (HS) were stimulated through either TLR4 or TLR9 alone, or together with CD40...
November 13, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/29142307/genetic-polymorphism-related-to-monocyte-macrophage-function-is-associated-with-graft-versus-host-disease
#9
Kati Hyvärinen, Jarmo Ritari, Satu Koskela, Riitta Niittyvuopio, Anne Nihtinen, Liisa Volin, David Gallardo, Jukka Partanen
Despite detailed human leukocyte antigen (HLA) matching and modern immunosuppressive therapy, severe graft-versus-host disease (GvHD) remains a major hurdle for successful allogeneic hematopoietic stem cell transplantation (HSCT). As the genetic diversity in GvHD complicates the systematic discovery of associated variants across populations, we studied 122 GvHD-associated single nucleotide polymorphisms (SNPs) in 492 HLA-matched sibling HSCT donor-recipient pairs from Finland and Spain. The association between these candidate SNPs and grade III-IV acute GvHD and extensive chronic GvHD was assessed...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29141862/the-activation-of-human-dermal-microvascular-cells-by-poly-i-c-lipopolysaccharide-imiquimod-and-odn2395-is-mediated-by-the-fli1-foxo3a-pathway
#10
Lukasz Stawski, Grace Marden, Maria Trojanowska
Endothelial cell (EC) dysfunction has been associated with inflammatory and autoimmune diseases; however, the factors contributing to this dysfunction have not been fully explored. Because activation of TLRs has been implicated in autoimmune diseases, the goal of this study was to determine the effects of TLR ligands on EC function. Human dermal microvascular ECs (HDMECs) treated with TLR3 [Poly(I:C)], TLR4 (LPS), and TLR7 (imiquimod) agonists showed decreased proliferation and a reduced total number of branching tubules in three-dimensional human dermal organoid ex vivo culture...
November 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29134633/first-in-human-study-with-the-inhaled-tlr9-oligonucleotide-agonist-azd1419-results-in-interferon-responses-in-the-lung-and-is-safe-and-well-tolerated
#11
Sam Jackson, Albert F Candia, Stephen Delaney, Simone Floettmann, Clifford Wong, John D Campbell, Sariah Kell, Jeremy Lum, Edith Hessel, Paula Traquina, Mark McHale, Ian Robinson, John Bell, Rainard Fuhr, David Keeling, Robert L Coffman
Current asthma treatments address symptoms rather than the underlying disease pathophysiology, a better understanding of which has led to the identification of the Th2 high endotype. The activation of Toll-like receptors to induce Type I interferons directly in the lungs represents a novel therapeutic approach to reset this underlying Th2 pathophysiology with the potential to provide long-term disease modification. We present the nonclinical data and phase 1 clinical profile of an inhaled TLR9 agonist, AZD1419, a C-type CpG designed to induce interferon in the lung...
November 14, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29132311/weighted-gene-co-expression-network-analysis-of-expression-data-of-monozygotic-twins-identifies-specific-modules-and-hub-genes-related-to-bmi
#12
Weijing Wang, Wenjie Jiang, Lin Hou, Haiping Duan, Yili Wu, Chunsheng Xu, Qihua Tan, Shuxia Li, Dongfeng Zhang
BACKGROUND: The therapeutic management of obesity is challenging, hence further elucidating the underlying mechanisms of obesity development and identifying new diagnostic biomarkers and therapeutic targets are urgent and necessary. Here, we performed differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) to identify significant genes and specific modules related to BMI based on gene expression profile data of 7 discordant monozygotic twins. RESULTS: In the differential gene expression analysis, it appeared that 32 differentially expressed genes (DEGs) were with a trend of up-regulation in twins with higher BMI when compared to their siblings...
November 13, 2017: BMC Genomics
https://www.readbyqxmd.com/read/29130391/the-vici-syndrome-protein-epg5-regulates-intracellular-nucleic-acid-trafficking-linking-autophagy-to-innate-and-adaptive-immunity
#13
E Piano Mortari, V Folgiero, V Marcellini, P Romania, E Bellacchio, V D'Alicandro, C Bocci, R Carrozzo, D Martinelli, S Petrini, E Axiotis, C Farroni, F Locatelli, U Schara, D Pilz, H Jungbluth, C Dionisi-Vici, R Carsetti
Vici syndrome is a human inherited multi-system disorder caused by recessive mutations in EPG5, encoding the EPG5 protein that mediates the fusion of autophagosomes with lysosomes. Immunodeficiency characterized by lack of memory B cells and increased susceptibility to infection is an integral part of the condition, but the role of EPG5 in the immune system remains unknown. Here we show that EPG5 is indispensable for the transport of the TLR9 ligand CpG to the late endosomal-lysosomal compartment, and for TLR9-initiated signaling, a step essential for the survival of human memory B cells and their ultimate differentiation into plasma cells...
November 13, 2017: Autophagy
https://www.readbyqxmd.com/read/29128901/fgl2-knockdown-improves-heart-function-through-regulation-of-tlr9-signaling-in-the-experimental-autoimmune-myocarditis-rats
#14
Zhenzhong Zheng, Longhui Yu, Yujing Wu, Hao Wu
Fibrinogen-like protein 2 (FGL2) is an important immune regulator of both innate and adaptive response. It is present on the surface of macrophages and endothelial cells, and can be constitutively secreted by CD4(+)CD8(+) T cells. Previous studies showed that FGL2 is a potential target for the treatment of experimental autoimmune myocarditis. However, the molecular mechanism of the roles of FGL2 in experimental autoimmune myocarditis is poorly understood. Here, we silenced FGL2 gene by using FGL2-RNAi lentivirus to reveal the heart function in experimental autoimmune myocarditis rats...
November 11, 2017: Immunologic Research
https://www.readbyqxmd.com/read/29123526/toll-like-receptor-ligands-and-interferon-%C3%AE-synergize-for-induction-of-antitumor-m1-macrophages
#15
Elisabeth Müller, Panagiotis F Christopoulos, Sanjib Halder, Anna Lunde, Kahsai Beraki, Martin Speth, Inger Øynebråten, Alexandre Corthay
Tumor-associated macrophages may either promote or suppress tumor growth depending on their activation status. Interferon-γ (IFN-γ) has been identified as a key factor for inducing tumoricidal M1 phenotype in macrophages. However, it remains unclear whether IFN-γ is sufficient or if additional stimuli are required. Here, we tested IFN-γ and a panel of toll-like receptor (TLR) agonists for the ability to activate murine macrophages toward a tumoricidal M1 phenotype. The following TLR ligands were used: TLR1/TLR2 agonist Pam3CSK4, TLR2/TLR6 agonist lipotechoic acid, TLR3 agonist poly(I:C), TLR4 agonist lipopolysaccharide (LPS), TLR5 agonist flagellin, TLR7 agonist CL264, and TLR9 agonist CpG...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29118245/mer-receptor-tyrosine-kinase-signaling-prevents-self-ligand-sensing-and-aberrant-selection-in-germinal-centers
#16
Stephanie L Schell, Chetna Soni, Melinda J Fasnacht, Phillip P Domeier, Timothy K Cooper, Ziaur S M Rahman
Mer tyrosine kinase (Mer) signaling maintains immune tolerance by clearing apoptotic cells (ACs) and inducing immunoregulatory signals. We previously showed that Mer-deficient mice (Mer(-/-)) have increased germinal center (GC) responses, T cell activation, and AC accumulation within GCs. Accumulated ACs in GCs can undergo necrosis and release self-ligands, which may influence the outcome of a GC response and selection. In this study, we generated Mer(-/-) mice with a global MyD88, TLR7, or TLR9 deficiency and cell type-specific MyD88 deficiency to study the functional correlation between Mer and TLRs in the development of GC responses and autoimmunity...
November 8, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29116594/elevated-expression-of-ebv-and-tlrs-in-the-brain-is-associated-with-rasmussen-s-encephalitis
#17
Xin Wang, Yisong Wang, Dong Liu, Peigang Wang, Dongying Fan, Yuguang Guan, Tianfu Li, Guoming Luan, Jing An
Rasmussen's encephalitis (RE) is a rare pediatric neurological disorder, the etiology of which remains unclear. It has been speculated that the immunopathogenesis of RE involves damage to neurons, which eventually leads to the occurrence of RE. Viral infection may be a critical factor in triggering RE immunopathogenesis. In this study, we analyzed the expression of Epstein-Barr virus (EBV) antigens as well as of Toll-like receptor 3 (TLR3), TLR9, and downstream adapter TIRdomain-containing adapter-inducing interferon-β (TRIF) in the brain tissues of 26 patients with RE and 16 control individuals using immunohistochemistry (IHC)...
October 2017: Virologica Sinica
https://www.readbyqxmd.com/read/29112074/toll-like-receptor-tlr-9-polymorphism-is-associated-with-increased-epstein-barr-virus-and-cytomegalovirus-acquisition-in-hiv-exposed-infants
#18
Kristin Beima-Sofie, Dalton Wamalwa, Elizabeth Maleche-Obimbo, Jairam R Lingappa, Romel Mackelprang, Soren Gantt, Grace John-Stewart, Corey Casper, Jennifer A Slyker
Polymorphisms in the Toll-Like Receptor (TLR9) 1635 locus have been associated with HIV-1 acquisition and progression. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) acquisition were compared between Kenyan HIV-exposed infants by 1635 genotype. Having 1 or more copies of the 1635A allele was associated with increased CMV acquisition in HIV-infected infants (42% vs 11%, p = 0.03) and increased risk of EBV acquisition in HIV-exposed uninfected infants (HR = 4.2, p = 0.02) compared to 1635GG. Additionally, 1635A was associated with 0...
November 2, 2017: AIDS
https://www.readbyqxmd.com/read/29112067/memory-b-cell-dysregulation-in-hiv-1-infected-individuals
#19
Jorge Carrillo, Eugenia Negredo, Jordi Puig, Luis Manuel Molinos-Albert, Maria Luisa Rodríguez de la Concepción, Marta Curriu, Marta Massanella, Jordi Navarro, Manel Crespo, Ester Viñets, Fuensanta Millá, Bonaventura Clotet, Julià Blanco
OBJECTIVE: To characterize the effect of the HIV-1 infection and antiretroviral treatment (ART) in the human memory B (MEB) cell compartment. DESIGN: A cross-sectional study was designed to analyze MEB cells of HIV-1+ ART-treated and ART-naïve subjects, and uninfected individuals. METHODS: Frequency and absolute counts of MEB cell subsets in blood were determined by multicolor flow cytometry. Spontaneous cell death and B cell proliferative capacity was evaluated in vitro by cell culture and flow cytometry...
November 2, 2017: AIDS
https://www.readbyqxmd.com/read/29104574/fcrl4-expression-identifies-a-pro-inflammatory-b-cell-subset-in-viremic-hiv-infected-subjects
#20
Basile Siewe, Allison J Nipper, Haewon Sohn, Jack T Stapleton, Alan Landay
In autoimmune diseases, toll-like receptor (TLR)-stimulated pro-inflammatory IL-6-secreting B cells exert pathogenic roles. Similarly, B cell Fc receptor-like 4 (FcRL4) expression amplifies TLR stimulation, and in rheumatoid arthritis patients, FcRL4 expression identifies a pro-inflammatory B cell subset. B cells from HIV-infected subjects also express heightened levels of FcRL4 and secrete high levels of IL-6: a critical mediator of HIV disease progression. In this study, we sought to determine if FcRL4 identifies a pro-inflammatory B cell subset in HIV-infected subjects and further elucidate the mechanisms underlying FcRL4 amplification of TLR stimulation...
2017: Frontiers in Immunology
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