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https://www.readbyqxmd.com/read/28273354/mtorc2-controls-th9-polarization-and-allergic-airway-inflammation
#1
Hui Chen, Lianjun Zhang, Peng Wang, Huiting Su, Wei Wang, Zhulang Chu, Lianfeng Zhang, Xiaodong Zhang, Yong Zhao
BACKGROUND: T helper type 9 (Th9) cells, a subpopulation of CD4(+) T cells, play a critical role in the pathogenesis of allergic airway inflammation. However, it remains unknown whether mTORC2 regulates Th9 differentiation or function during allergic inflammation. METHODS: T cell-specific Rictor-deficient mice, a mouse model of allergic airway inflammation induced by OVA sensitization and a mouse model of adoptive transfer of induced Th9 cells were used to address the roles of mTORC2 in the pathogenesis of allergic airway inflammation...
March 8, 2017: Allergy
https://www.readbyqxmd.com/read/28272467/meta-analysis-identifies-novel-risk-loci-and-yields-systematic-insights-into-the-biology-of-male-pattern-baldness
#2
Stefanie Heilmann-Heimbach, Christine Herold, Lara M Hochfeld, Axel M Hillmer, Dale R Nyholt, Julian Hecker, Asif Javed, Elaine G Y Chew, Sonali Pechlivanis, Dmitriy Drichel, Xiu Ting Heng, Ricardo C-H Del Rosario, Heide L Fier, Ralf Paus, Rico Rueedi, Tessel E Galesloot, Susanne Moebus, Thomas Anhalt, Shyam Prabhakar, Rui Li, Stavroula Kanoni, George Papanikolaou, Zoltán Kutalik, Panos Deloukas, Michael P Philpott, Gérard Waeber, Tim D Spector, Peter Vollenweider, Lambertus A L M Kiemeney, George Dedoussis, J Brent Richards, Michael Nothnagel, Nicholas G Martin, Tim Becker, David A Hinds, Markus M Nöthen
Male-pattern baldness (MPB) is a common and highly heritable trait characterized by androgen-dependent, progressive hair loss from the scalp. Here, we carry out the largest GWAS meta-analysis of MPB to date, comprising 10,846 early-onset cases and 11,672 controls from eight independent cohorts. We identify 63 MPB-associated loci (P<5 × 10(-8), METAL) of which 23 have not been reported previously. The 63 loci explain ∼39% of the phenotypic variance in MPB and highlight several plausible candidate genes (FGF5, IRF4, DKK2) and pathways (melatonin signalling, adipogenesis) that are likely to be implicated in the key-pathophysiological features of MPB and may represent promising targets for the development of novel therapeutic options...
March 8, 2017: Nature Communications
https://www.readbyqxmd.com/read/28264055/enhancement-of-pomalidomide-anti-tumor-response-with-acy-241-a-selective-hdac6-inhibitor
#3
Brian J North, Ingrid Almeciga-Pinto, David Tamang, Min Yang, Simon S Jones, Steven N Quayle
Thalidomide-based Immunomodulatory Drugs (IMiDs®), including lenalidomide and pomalidomide, are effective therapeutics for multiple myeloma. These agents have been approved with, or are under clinical development with, other targeted therapies including proteasome inhibitors, αCD38 monoclonal antibodies, as well as histone deacetylase (HDAC) inhibitors for combination therapy. HDAC inhibitors broadly targeting Class I and IIb HDACs have shown potent preclinical efficacy but have frequently demonstrated an undesirable safety profile in combination therapy approaches in clinical studies...
2017: PloS One
https://www.readbyqxmd.com/read/28263097/transcriptional-and-epigenetic-regulation-of-follicular-t-helper-cells-and-their-role-in-autoimmunity
#4
Hong Qiu, Haijing Wu, Vera Chan, Chak-Sing Lau, Qianjin Lu
T-follicular helper (Tfh) cells are a specialized subset of T cells that provide help to B cells and promote the formation of germinal centers (GCs). Tfh cells transmit important signals to B cells that drive class switch recombination, somatic hyper-mutation, the generation of high-affinity antibodies, immunological memory and their differentiation into plasma cells or memory B cells in the GCs. Tfh-cell differentiation is regulated by the coordinated functions of distinct cytokines, including interleukin (IL)-6, IL-21, IL-12, IL-23, IL-2, IL-7 and transforming growth factor-β (TGF-β), as well as transcription factors, including B-cell lymphoma 6 protein (Bcl-6), Signal transducers and activators of transcription (STAT)1, STAT3, STAT4, B-cell activating transcription factor (Batf), interferon regulatory factor 4 (IRF4), v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (C-Maf), T-cell-specific transcription factor 1 (TCF-1) and Achaete-scute homolog 2 (Acl2), which have been shown to form a complex transcriptional network...
March 2017: Autoimmunity
https://www.readbyqxmd.com/read/28262505/distinct-roles-of-brd2-and-brd4-in-potentiating-the-transcriptional-program-for-th17-cell-differentiation
#5
Ka Lung Cheung, Fan Zhang, Anbalagan Jaganathan, Rajal Sharma, Qiang Zhang, Tsuyoshi Konuma, Tong Shen, June-Yong Lee, Chunyan Ren, Chih-Hung Chen, Geming Lu, Matthew R Olson, Weijia Zhang, Mark H Kaplan, Dan R Littman, Martin J Walsh, Huabao Xiong, Lei Zeng, Ming-Ming Zhou
The BET proteins are major transcriptional regulators and have emerged as new drug targets, but their functional distinction has remained elusive. In this study, we report that the BET family members Brd2 and Brd4 exert distinct genomic functions at genes whose transcription they co-regulate during mouse T helper 17 (Th17) cell differentiation. Brd2 is associated with the chromatin insulator CTCF and the cohesin complex to support cis-regulatory enhancer assembly for gene transcriptional activation. In this context, Brd2 binds the transcription factor Stat3 in an acetylation-sensitive manner and facilitates Stat3 recruitment to active enhancers occupied with transcription factors Irf4 and Batf...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28251349/prognostic-significance-of-interferon-regulating-factor-4-irf4-in-node-negative-breast-cancer
#6
Anne-Sophie Heimes, K Madjar, K Edlund, M J Battista, K Almstedt, S Gebhard, S Foersch, J Rahnenführer, W Brenner, A Hasenburg, J G Hengstler, M Schmidt
PURPOSE: The transcription factor IRF4 regulates immunoglobulin class switch recombination as well as plasma cell differentiation. We examined the prognostic significance of IRF4 expression in node-negative breast cancer (BC). METHODS: IRF4 expression was evaluated by immunostaining in a cohort of 197 node-negative BC patients not treated in adjuvant setting, referred to as Mainz cohort. The prognostic significance of immunohistochemically determined IRF4 expression for metastasis-free survival (MFS) was examined by Kaplan-Meier survival analysis as well as univariate and multivariate Cox analysis adjusted for age, pT stage, histological grade, ER, and HER2 status...
March 1, 2017: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/28245601/distinct-antigen-delivery-systems-induce-dendritic-cells-divergent-transcriptional-response-new-insights-from-a-comparative-and-reproducible-computational-analysis
#7
Valerio Costa, Dario Righelli, Francesco Russo, Piergiuseppe De Berardinis, Claudia Angelini, Luciana D'Apice
Vaccination is the most successful and cost-effective method to prevent infectious diseases. However, many vaccine antigens have poor in vivo immunogenic potential and need adjuvants to enhance immune response. The application of systems biology to immunity and vaccinology has yielded crucial insights about how vaccines and adjuvants work. We have previously characterized two safe and powerful delivery systems derived from non-pathogenic prokaryotic organisms: E2 and fd filamentous bacteriophage systems. They elicit an in vivo immune response inducing CD8+ T-cell responses, even in absence of adjuvants or stimuli for dendritic cells' maturation...
February 25, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28245413/-research-progress-in-transgenic-animal-models-of-chronic-lymphocytic-leukemia-review
#8
Fang-Tian Wu, Wei Xu, Jian-Yong Li
Transgenic mouse models of chronic lymphocytic leukemia (CLL) are crucially required for the elucidation of the underlying pathogenic mechanisms and for finding new therapies. So far, several mouse models have been established, mimicking either genetic aberrations or dysregulated gene expression in CLL. Among all the models, TCL1 transgenic model is the most commonly used one. Additionally, there are also other models, such as 13q14-deletion model. In this review, the major genetically engineered mouse models of CLL in current use are summarized, the main problems include TCL-1 transgenic mice, miR15a/16-1 gene knockdown mice and miR29 transgeneic mice, BAFF and APRIL transgeneic mice, BCL-2:Traf2DN double transgeneic mice, IRF4(-/-)Vh11 transgeneic mice and so on...
February 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28241741/differential-correlation-analysis-of-glioblastoma-reveals-immune-cerna-interactions-predictive-of-patient-survival
#9
Yu-Chiao Chiu, Li-Ju Wang, Tzu-Pin Lu, Tzu-Hung Hsiao, Eric Y Chuang, Yidong Chen
BACKGROUND: Recent studies illuminated a novel role of microRNA (miRNA) in the competing endogenous RNA (ceRNA) interaction: two genes (ceRNAs) can achieve coexpression by competing for a pool of common targeting miRNAs. Individual biological investigations implied ceRNA interaction performs crucial oncogenic/tumor suppressive functions in glioblastoma multiforme (GBM). Yet, a systematic analysis has not been conducted to explore the functional landscape and prognostic significance of ceRNA interaction...
February 28, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28240301/pplase-of-dermatophagoides-farinae-promotes-ovalbumin-induced-airway-allergy-by-modulating-the-functions-of-dendritic-cells-in-a-mouse-model
#10
Hui Wang, Lihua Mo, Xiaojun Xiao, Shu An, Xiaoyu Liu, Jinge Ba, Weifang Wu, Pixin Ran, Pingchang Yang, Zhigang Liu
Our previous studies revealed that many proteins in addition to the known allergens of D. farinae have not been fully characterized. We observed that Pplase did not respond to serum collected from patients sensitized to D. farinae. In a mouse model, Pplase significantly enhanced airway hyperresponsiveness (AHR) and Th2 responses induced by ovalbumin (OVA) compared with mice treated with OVA alone. Moreover, exposure to Pplase significantly increased the expression of IRF4, CD80, CD83, MHCII and TNF-α in DC2...
February 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28228760/perturbed-microrna-expression-by-mycobacterium-tuberculosis-promotes-macrophage-polarization-leading-to-pro-survival-foam-cell
#11
Pankaj Kumar Ahluwalia, Rajan Kumar Pandey, Prabodh Kumar Sehajpal, Vijay Kumar Prajapati
Tuberculosis (TB) is one of the prevalent causes of death worldwide, with 95% of these deaths occurring in developing countries, like India. The causative agent, Mycobacterium tuberculosis (MTb) has the tenacious ability to circumvent the host's immune system for its own advantage. Macrophages are one of the phagocytic cells that are central to immunity against MTb. These are highly plastic cells dependent on the milieu and can showcase M1/M2 polarization. M1 macrophages are bactericidal in action, but M2 macrophages are anti-inflammatory in their immune response...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28187441/neutralization-of-interleukin-9-ameliorates-symptoms-of-allergic-rhinitis-by-reducing-th2-th9-and-th17-responses-and-increasing-the-treg-response-in-a-murine-model
#12
Zhao Wei Gu, Yun Xiu Wang, Zhi Wei Cao
A novel independent Th-cell subset, characterized by high expression of interleukin (IL)-9, has been recognized as the "Th9" subset. Although Th9 cells are important in many diseases, their contribution to allergic rhinitis (AR) remains unclear. We therefore first determined whether Th9 cells were present in a mouse model of AR. We then investigated the their involvement in the distribution of CD4+ T-cell subsets and the symptoms of AR by treating mice with anti-IL-9 antibodies (Abs). Anti-IL-9 Abs were administered intranasally during rechallenge of ovalbumin (OVA)-induced AR in BALB/c mice...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28164410/hypoxia-inducible-microrna-210-regulates-the-dimt1-irf4-oncogenic-axis-in-multiple-myeloma
#13
Sho Ikeda, Akihiro Kitadate, Fumito Abe, Saitoh Hirobumi, Yoshihiro Michishita, Yoshiaki Hatano, Yoshinari Kawabata, Atsushi Kitabayashi, Kazuaki Teshima, Masaaki Kume, Naoto Takahashi, Hiroyuki Tagawa
Multiple myeloma (MM) is characterized by the accumulation of a population of malignant plasma cells within the bone marrow and its microenvironment. A hypoxic niche is located within the microenvironment, which causes myeloma cells to become quiescent, anti-apoptotic, glycolytic, and immature. Cell heterogeneity may be related to distinct gene expression profiles under hypoxic and normoxic conditions. During hypoxia, myeloma cells acquire these phenotypes by downregulating interferon regulatory factor 4 (IRF4), an essential transcription factor in myeloma oncogenesis...
February 6, 2017: Cancer Science
https://www.readbyqxmd.com/read/28137851/a-mechanism-for-the-induction-of-type-2-immune-responses-by-a-protease-allergen-in-the-genital-tract
#14
Ji Eun Oh, Dong Sun Oh, Hi Eun Jung, Heung Kyu Lee
The genital mucosa is a barrier that is constantly exposed to a variety of pathogens, allergens, and external stimuli. Although both allergen exposure and parasite infections frequently occur in the genital area, the mechanism by which immune responses-particularly type 2 immunity-are induced has rarely been studied in the genital mucosa. Here, we demonstrate the induction of T helper type 2 (Th2) immunity in the genital mucosa in response to a model allergen, the protease papain. Intravaginal papain immunization induced type 2 immunity in a manner that was dependent on protease activity and the estrous phase of the mice...
February 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28132936/rhs6-mediated-chromosomal-looping-and-nuclear-substructure-binding-is-required-for-th2-cytokine-gene-expression
#15
Soo Seok Hwang, Sung Woong Jang, Gap Ryol Lee
Subset-specific gene expression is a critical feature of CD4 T cell differentiation. Th2 cells express Th2 cytokine genes including Il4, Il5, and Il13 and mediate the immune response against helminths. The expression of Th2 cytokine genes is regulated by Rad50 hypersensitive site 6 (RHS6) in the Th2 locus control region; however, the molecular mechanisms of RHS6 action at the chromatin level are poorly understood. Here, we demonstrate that RHS6 is crucial for chromosomal interactions and nuclear substructure binding of the Th2 cytokine locus...
March 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28130292/transcriptional-determinants-of-tolerogenic-and-immunogenic-states-during-dendritic-cell-maturation
#16
Bryan Vander Lugt, Jeremy Riddell, Aly A Khan, Jason A Hackney, Justin Lesch, Jason DeVoss, Matthew T Weirauch, Harinder Singh, Ira Mellman
Dendritic cells (DCs) promote either tolerogenic or immunogenic T cell responses, the latter upon sensing microbes. Using an in vitro system, we analyzed transcriptional determinants that enable mature DCs to direct these opposing T cell outcomes. In the absence of microbial products, the transcription factor interferon regulatory factor 4 (IRF4) promotes regulatory T cell (Treg) generation by enhancing expression of genes required for antigen presentation along with those for T cell tolerance. IRF4-deficient DCs were impaired for Treg generation in vivo...
March 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28129744/vitiligo-blood-transcriptomics-provides-new-insights-into-disease-mechanisms-and-identifies-potential-novel-therapeutic-targets
#17
Rama Dey-Rao, Animesh A Sinha
BACKGROUND: Significant gaps remain regarding the pathomechanisms underlying the autoimmune response in vitiligo (VL), where the loss of self-tolerance leads to the targeted killing of melanocytes. Specifically, there is incomplete information regarding alterations in the systemic environment that are relevant to the disease state. METHODS: We undertook a genome-wide profiling approach to examine gene expression in the peripheral blood of VL patients and healthy controls in the context of our previously published VL-skin gene expression profile...
January 28, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28108985/the-th2-gene-cluster-unraveled-role-of-rhs6
#18
EDITORIAL
Cameron H Flayer, Angela Haczku
Although the transcription factors that regulate T helper (Th) type 2 cytokine production (IL-4, IL-5, and IL-13) are possible novel therapeutic targets, we lack a detailed understanding of the mechanisms that regulate the transcription of these cytokines. In this issue of Allergy, Hwang et al. studied the role of a specific DNA region (a cis-acting element called Rad50 hypersensitive site 6) RHS6, in the development of allergic airway inflammation. RHS6 is found in the Th2 cytokine "locus control region" but its role in activation of the IL-4, IL-5, and IL-13 genes was unknown...
January 20, 2017: Allergy
https://www.readbyqxmd.com/read/28108558/irf4-expression-in-thymic-epithelium-is-critical-for-thymic-regulatory-t-cell-homeostasis
#19
Uku Haljasorg, James Dooley, Martti Laan, Kai Kisand, Rudolf Bichele, Adrian Liston, Pärt Peterson
The thymus is a primary lymphoid organ required for the induction and maintenance of central tolerance. The main function of the thymus is to generate an immunocompetent set of T cells not reactive to self. During negative selection in the thymus, thymocytes with autoreactive potential are either deleted or differentiated into regulatory T cells (Tregs). The molecular basis by which the thymus allows high-efficiency Treg induction remains largely unknown. In this study, we report that IFN regulatory factor 4 (Irf4) is highly expressed in murine thymic epithelium and is required to prime thymic epithelial cells (TEC) for effective Treg induction...
January 20, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28105134/increased-circulating-il-9-producing-cd8-t-cells-are-associated-with-eosinophilia-and-high-feno-in-allergic-asthmatics
#20
Wei Wang, Zhen-Shun Cheng, Yi-Fei Chen, Yu-Hui Lin
Allergic asthma is a chronic airway disorder mediated by Th2 cells. It has been shown that IL-9-producing CD8(+) cytotoxic T (Tc9) cells promote the subsequent onset of allergic airway inflammation in mice mediated by abnormal Th2 immunity. Whether Tc9 cells are associated with the immunopathogenesis of asthmatic patients remains unknown. In the present study, peripheral blood mononuclear cells (PBMCs) were separated by Ficoll-Hypaque gradient centrifugation from all subjects. The frequency of Tc9 cells was measured by flow cytometry...
December 2016: Experimental and Therapeutic Medicine
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