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Yanming Meng, Heng Xu, Shouyue Zhang, Junlong Zhang, Lu Wang, Honghu Tang, Yongkang Wu
OBJECTIVE: Interleukin-21 (IL-21) contributes to expansion, differentiation, and modulation of various immunocompetent cells. Deregulated production of IL-21 plays a role of cardinal significance in the pathogenesis of systemic lupus erythematosus (SLE). We aimed to determine whether single nucleotide polymorphisms (SNP) near the IL-21 gene have significant association with SLE susceptibility and the T helper-related inflammatory cytokine profile of SLE patients. METHODS: We enrolled 460 SLE patients and 460 healthy controls...
February 18, 2019: Lupus
Ulrike Kaufmann, Sascha Kahlfuss, Jun Yang, Elitza Ivanova, Sergei B Koralov, Stefan Feske
Pathogenic Th17 cells play important roles in many autoimmune and inflammatory diseases. Their function depends on T cell receptor (TCR) signaling and cytokines that activate signal transducer and activator of transcription 3 (STAT3). TCR engagement activates stromal interaction molecule 1 (STIM1) and calcium (Ca2+ ) influx through Ca2+ -release-activated Ca2+ (CRAC) channels. Here, we show that abolishing STIM1 and Ca2+ influx in T cells expressing a hyperactive form of STAT3 (STAT3C) attenuates pathogenic Th17 cell function and inflammation associated with STAT3C expression...
February 12, 2019: Cell Metabolism
Dayasagar Das, Shamima Akhtar, Santosh Kurra, Somesh Gupta, Alpana Sharma
Autoimmune skin diseases are a group of disorders that arise due to a deregulated immune system resulting in skin tissue destruction. In the majority of these conditions, either autoreactive immune cells or the autoantibodies are generated against self-antigens of the skin. Although the etiology of these diseases remains elusive, biochemical, genetic, and environmental factors such as infectious agents, toxins damage the skin tissue leading to self-antigen generation, autoantibody attack and finally results in autoimmunity of skin...
February 8, 2019: Cytokine & Growth Factor Reviews
Di Long, Yongjian Chen, Haijing Wu, Ming Zhao, Qianjin Lu
Interleukin-21 (IL-21), an autocrine cytokine predominantly produced by follicular helper T (Tfh) and T helper 17 (Th17) cells, has been proven to play an important role in the immune system, for example, by promoting proliferation and the development of Tfh and Th17 cells, balancing helper T cell subsets, inducing B cell generation and differentiation into plasma cells, and enhancing the production of immunoglobulin. These effects are mainly mediated by activation of the JAK/STAT, MAPK and PI3K pathways...
February 14, 2019: Journal of Autoimmunity
Asa B Gudmundsdottir, Asa Brynjolfsdottir, Elin Soffia Olafsdottir, Ingibjorg Hardardottir, Jona Freysdottir
Regular bathing in the Blue Lagoon has beneficial effects on psoriasis. Previously, we showed that exopolysaccharides (EPS-Ca) secreted by Cyanobacterium aponinum, a dominating organism in the Blue Lagoon, increased IL-10 secretion by human dendritic cells (DCs). In addition, co-culturing allogeneic CD4+ T cells with DCs matured in the presence of EPS-Ca increased differentiation of T cells into T regulatory cells at the cost of the disease inducing Th17 cells. In the present study, EPS-Ca increased the proportion of DCs expressing CD141, a surface molecule linked to regulatory DCs, and the CD141+ cells secreted more IL-10 than the CD141- cells...
February 14, 2019: International Immunopharmacology
Fangming Xiu, Zubair Sabz Ali, Nades Palaniyar, Neil Sweezey
New procedures are required to optimize the use of blood samples to study different cell types. The purification of neutrophils and T cells from the same blood sample is not commonly described. We have previously used PolymorphPrep™ (P) or LymphoPrep™ (L) for purifying neutrophils or T cells, respectively. In this study, we describe a new method for purifying both of these cells using P and L from the same sample, and methodological considerations required to obtain consistent Th17 differentiation results...
February 13, 2019: Journal of Immunological Methods
Siyan Liu, Yuxuan Li, Liping Xia, Hui Shen, Jing Lu
OBJECTIVES: Angiogenesis in bone and osteogenesis appear to be closely linked, suggesting the existence of molecular crosstalk between pro-angiogenic molecules and osteoblasts. The pro-angiogenic molecules vascular endothelial growth factor (VEGF) with its receptors Flt-1, Flk-1 and fibroblast growth factor (FGF)-2 play a crucial role in born formation, an early and critical event in the pathogenesis of rheumatoid arthritis (RA). Interleukin (IL)-35 is demonstrated to be an anti-inflammatory cytokine in RA...
February 11, 2019: Clinical and Experimental Rheumatology
Daniela A B Cervilha, Juliana T Ito, Juliana D Lourenço, Clarice R Olivo, Beatriz M Saraiva-Romanholo, Rildo A Volpini, Manoel C Oliveira-Junior, Thais Mauad, Milton A Martins, Iolanda F L C Tibério, Rodolfo P Vieira, Fernanda D T Q S Lopes
We proposed an experimental model to verify the Th17/Treg cytokine imbalance in COPD exacerbation. Forty C57BL/6 mice were exposed to room air or cigarette smoke (CS) (12 ± 1 cigarettes, twice a day, 30 min/exposure and 5 days/week) and received saline (50 µl) or lipopolysaccharide (LPS) (1 mg/kg in 50 µl of saline) intratracheal instillations. We analyzed the mean linear intercept, epithelial thickness and inflammatory profiles of the bronchoalveolar lavage fluid and lungs. We evaluated macrophages, neutrophils, CD4+ and CD8+ T cells, Treg cells, and IL-10+ and IL-17+ cells, as well as STAT-3, STAT-5, phospho-STAT3 and phospho-STAT5 levels using immunohistochemistry and IL-17, IL-6, IL-10, INF-γ, CXCL1 and CXCL2 levels using ELISA...
February 13, 2019: Scientific Reports
Kai Wang, Zhuo-Lun Song, Bin Wu, Chun-Lei Zhou, Wei Liu, Wei Gao
Th17 and imbalance of Treg/Th17 might be one of the mechanisms of acute rejection. We aim to explore the role of Th17s in the balance of Treg/Th17 in acute rejection after LT in children diagnosed with BA. The ratios of Treg and Th17 in peripheral blood were detected by flow cytometry pre-LT, post-LT, and when rejection occurred. Treg proportion was higher before transplantation than at 2 weeks and 1 month after transplantation, with no statistical difference between 2 weeks and 1 month. However, Treg proportions were lower in pediatric recipients than healthy controls...
February 12, 2019: Pediatric Transplantation
Alex B Blair, Jennifer Kleponis, Dwayne L Thomas Ii, Stephen T Muth, Adrian G Murphy, Victoria Kim, Lei Zheng
Pancreatic ductal adenocarcinoma (PDAC) represents an immune quiescent tumor that is resistant to immune checkpoint inhibitors. Previously, our group has shown that a GM-CSF secreting allogenic pancreatic tumor cell vaccine (GVAX), may prime the tumor microenvironment by inducing intratumoral T-cell infiltration. Here, we show that untreated PDACs express minimal indoleamine-2, 3-dioxygenase (IDO1); however, GVAX therapy induced IDO1 expression on tumor epithelia as well as vaccine-induced tertiary lymphoid aggregates...
February 12, 2019: Journal of Clinical Investigation
Jinlong Tian, Nannan Sun, Mingcheng Yu, Xianfeng Gu, Qiong Xie, Liming Shao, Jin Liu, Li Liu, Yonghui Wang
The retinoic acid receptor-related orphan receptor-gamma-t (RORγt) is a promising therapeutic target for treatment of Th17 cell-mediated autoimmune diseases. Based on a scaffold hopping/conformational restriction strategy, a series of N-indanyl benzamides as novel RORγt inverse agonists was discovered. Exploration of structure-activity relationship on the piperazine ring, benzoyl moiety and cyclopentyl moiety of N-indanyl benzamides 2a and 2d led to identification of potent RORγt inverse agonists. Compound 5c with (S)-enantiomer was found having an IC50 of 153...
February 4, 2019: European Journal of Medicinal Chemistry
Jian Deng, Xiao-Qiang Yu, Pei-Hui Wang
Immune sensing of exogenous molecules from microbes (e.g., pathogen-associated molecular patterns) and nonmicrobial molecules (e.g., asbestos, alum, and silica), as well as endogenous damage-associated molecular patterns (e.g., ATP, uric acid crystals, and amyloid A) activates innate immunity by inducing immune-related genes, including proinflammatory cytokines, which further facilitate the development of adaptive immunity. The roles of transcriptional responses downstream of immune sensing have been widely characterized in informing adaptive immunity; however, few studies focus on the effect of post-translational responses on the modulation of adaptive immune responses...
February 7, 2019: Molecular Immunology
Marco Antonio Pires-Lapa, Marianna Mainardi Koga, Ildefonso Alves da Silva-, Luciano Ribeiro Filgueiras, Sonia Jancar
Dendritic cells (DCs) link innate and adaptive immunity. The microenvironment generated during the innate immunity affects DCs and the type of adaptive immunity generated. Lipid mediators are released early in inflammation and could modify the functional state of DCs. Leukotriene B4 (LTB4 ) has a wide range of effects on macrophages and in the present study we investigated if it also affects DCs. Murine bone marrow-derived DCs were employed and it was found that stimulation of DCs with LTB4 (10 nM) increased the gene expression of the high affinity receptor BLT-1 but not of BLT-2...
February 7, 2019: Prostaglandins & Other Lipid Mediators
Emma Guttman-Yassky, Ana B Pavel, Lisa Zhou, Yeriel D Estrada, Ning Zhang, Hui Xu, Xiangyu Peng, Huei-Chi Wen, Panayiota Govas, Girish Gudi, C A Vinu, Hui Fang, Yacine Salhi, Jonathan Back, Venkateshwar Reddy, Robert Bissonnette, Catherine Maari, Fred Grossman, Gerhard Wolff
BACKGROUND: GBR 830 is a humanized, monoclonal antibody against OX40, a co-stimulatory receptor on activated T-cells. OX40 inhibition may have a therapeutic role in T-cell-mediated diseases, including atopic dermatitis (AD). OBJECTIVE: This exploratory phase 2a study investigated safety, efficacy, and tissue effects of GBR 830 in AD. METHODS: Moderate-to-severe AD subjects (affected body-surface area ≥10%, Eczema Area and Severity Index [EASI] ≥12, inadequate response to topical treatments) were randomized 3:1 to intravenous GBR 830 10 mg/kg or placebo on Day 1/baseline and Day 29...
February 6, 2019: Journal of Allergy and Clinical Immunology
Shahnawaz Imam, R Prathibha, Pervaiz Dar, Khalil Almotah, Ahmed Al-Khudhair, Syed Abdul-Moiz Hasan, Nancy Salim, Talha Naser Jilani, Raghavendra G Mirmira, Juan Carlos Jaume
We have developed a transgenic mouse model of Type 1 Diabetes (T1D) in which human GAD65 is expressed in pancreatic β-cells, and human MHC-II is expressed on antigen presenting cells. Induced GAD65 antigen presentation activates T-cells, which initiates the downstream events leading to diabetes. In our humanized mice, we have shown downregulation of eukaryotic translation initiation factor 5 A (elF5A), expressed only in actively dividing mammalian cells. In-vivo inhibition of elF5A hypusination by deoxyhypusine synthase (DHS) inhibitor "GC7" was studied; DHS inhibitor alters the pathophysiology in our mouse model by catalyzing the crucial hypusination and the rate-limiting step of elF5A activation...
February 7, 2019: Scientific Reports
Qian Yi, Jinxia Wang, Yaxin Song, Zhenzhen Guo, Shan Lei, Xue Yang, Liangping Li, Caiping Gao, Zhou Zhou
Inflammatory bowel disease (IBD) has been well-documented as a chronic gastrointestinal autoimmune disease, but its etiology remains to be elusive. Ascl2 (achaete-scute complex homologue 2), identified as a homologue of the Drosophila achaete-scute gene, has been shown to play an essential for the pathogenesis of autoimmune diseases and cancers. However, whether it is associated with the pathogenesis of IBD remains unclear. Here, we demonstrated that Ascl2 was greatly down-regulated in human IBD and experimental colitis...
February 2, 2019: Biochemical and Biophysical Research Communications
Kareem L Graham, Bonnie J Werner, Kimberly M Moyer, Alycia K Patton, Charles R Krois, Hong Sik Yoo, Maria Tverskoy, Melissa LaJevic, Joseph L Napoli, Raymond A Sobel, Brian A Zabel, Eugene C Butcher
The balance of effector versus regulatory T cells (Tregs) controls inflammation in numerous settings, including multiple sclerosis (MS). Here we show that memory phenotype CD4+ T cells infiltrating the central nervous system during experimental autoimmune encephalomyelitis (EAE), a widely studied animal model of MS, expressed high levels of mRNA for Dgat1 encoding diacylglycerol-O-acyltransferase-1 (DGAT1), an enzyme that catalyzes triglyceride synthesis and retinyl ester formation. DGAT1 inhibition or deficiency attenuated EAE, with associated enhanced Treg frequency; and encephalitogenic, DGAT1-/- in vitro-polarized Th17 cells were poor inducers of EAE in adoptive recipients...
February 4, 2019: Proceedings of the National Academy of Sciences of the United States of America
Emmanouil Antalis, Aris Spathis, Christine Kottaridi, Athanasios Kossyvakis, Kalliopi Pastellas, Konstantinos Tsakalos, Andreas Mentis, Christos Kroupis, Sotirios Tsiodras
BACKGROUND: Th17 cytokines are associated with modulation of inflammation and may be beneficial in clearing influenza infection in experimental models. The Th17 cytokine profile was evaluated in a pilot study of respiratory virus infections. METHODS: Consecutive patients with symptoms of respiratory tract infection visiting the emergency department of a tertiary care hospital during the winter influenza season of 2014 to 2015 were evaluated. CLART PneumoVir kit, (GENOMICA, Madrid, Spain) was used for viral detection of all known respiratory viruses...
February 4, 2019: Journal of Medical Virology
S Bishu, M El Zaatari, A Hayashi, G Hou, N Bowers, J Kinnucan, B Manoogian, M M Muza-Moons, M Zhang, H Grasberger, C Bourque, W Zou, P D R Higgins, J R Spence, R W Stidham, N Kamada, J Y Kao
Background and Aims: Tumor necrosis factor (TNF)α and IL-17A producing T-cells are implicated in Crohn's disease (CD). Tissue-resident memory T (TRM) cells are tissue-restricted T-cells that are regulated by PR zinc finger domain 1 (PRDM1), which has been implicated in pathogenic Th17 cell responses. TRM cells provide host defense but their role in CD is unknown. We thus examined CD4+ TRM cells in CD. Methods: Colon samples were prospectively collected at endoscopy or surgery in CD and control subjects...
February 4, 2019: Journal of Crohn's & Colitis
Charlotte M Mousset, Willemijn Hobo, Rob Woestenenk, Frank Preijers, Harry Dolstra, Anniek B van der Waart
The T cell compartment can form a powerful defense against extrinsic (e.g., pathogens) and intrinsic danger (e.g., malignant cells). At the same time, specific subsets of T cells control this process to keep the immune system in check and prevent autoimmunity. A wide variety in T cell functionalities exists, which is dependent on the differentiation and maturation state of the T cells. In this review, we report an overview for the identification of CD4+ T-αβ cells (T-helper (Th)1, Th2, Th9, Th17, Th22, and CD4+ regulatory T cells), CD8+ T-αβ cells (cytotoxic T lymphocyte (Tc)1, Tc2, Tc9, Tc17, and CD8+ regulatory T cells), and their additional effector memory status (naïve, stem cell memory, central memory, effector memory, and effector) using flow cytometry...
February 4, 2019: Cytometry. Part A: the Journal of the International Society for Analytical Cytology
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