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https://www.readbyqxmd.com/read/28108985/the-th2-gene-cluster-unraveled-role-of-rhs6
#1
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
#2
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
#3
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
https://www.readbyqxmd.com/read/28103633/irf4-rs12203592-functional-variant-and-melanoma-survival
#4
Miriam Potrony, Aida Rebollo-Morell, Pol Giménez-Xavier, Lisa Zimmer, Joan Anton Puig-Butille, Gemma Tell-Marti, Antje Sucker, Celia Badenas, Cristina Carrera, Josep Malvehy, Dirk Schadendorf, Susana Puig
Inherited genetic factors may modulate clinical outcome in melanoma. Some low to medium risk genes in melanoma susceptibility play a role in melanoma outcome. Our aim was to assess the role of the functional IRF4 SNP rs12203592 in melanoma prognosis in two independent sets (Barcelona N=493 and Essen N=438). Genotype association analyses showed that the IRF4 rs12203592 T allele increased the risk of dying from melanoma in both sets (Barcelona: Odds Ratio [OR]=6.53, 95%CI 1.38 to 30.87, Adj P=0.032; Essen: OR=1...
January 19, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28079574/prognostic-impact-of-mum1-irf4-expression-in-burkitt-lymphoma-bl-a-reappraisal-of-88-bl-patients-in-japan
#5
Akira Satou, Naoko Asano, Seiichi Kato, Ahmed A Elsayed, Naoya Nakamura, Hiroaki Miyoshi, Koichi Ohshima, Shigeo Nakamura
MUM1/IRF4 expression is detected in 18% to 41% of Burkitt lymphoma (BL). However, only a few studies of MUM1-positive (MUM1) BL have been reported, and its characteristics still remain controversial. To highlight the features of MUM1 BL, we compared the clinicopathologic characteristics of 37 cases of MUM1 and 51 cases of MUM1-negative (MUM1) BL in Japan. Compared with MUM1 BL, patients with MUM1 BL showed significantly younger onset (P=0.0062) and a higher ratio of females (P=0.013). We have also revealed the difference in the involved sites...
January 10, 2017: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28052520/ikaros-expression-in-distinct-bone-marrow-cell-populations-as-a-candidate-biomarker-for-outcome-with-lenalidomide-dexamethasone-therapy-in-multiple-myeloma
#6
Arnold Bolomsky, Wolfgang Hübl, Stefano Spada, Ercan Müldür, Karin Schlangen, Daniel Heintel, Alberto Rocci, Adalbert Weißmann, Veronique Fritz, Martin Willheim, Niklas Zojer, Antonio Palumbo, Heinz Ludwig
Immunomodulatory drugs (IMiDs) are a cornerstone in the treatment of multiple myeloma (MM), but specific markers to predict outcome are still missing. Recent work pointed to a prognostic role for IMiD target genes (e.g. CRBN). Moreover, indirect activity of IMiDs on immune cells correlated with outcome, raising the possibility that cell populations in the bone marrow (BM) microenvironment could serve as biomarkers. We therefore analysed gene expression levels of six IMiD target genes in whole BM samples of 44 myeloma patients treated with lenalidomide-dexamethasone...
January 4, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28052118/tgf-%C3%AE-3-inhibits-antibody-production-by-human-b-cells
#7
Yumi Tsuchida, Shuji Sumitomo, Kazuyoshi Ishigaki, Akari Suzuki, Yuta Kochi, Haruka Tsuchiya, Mineto Ota, Toshihiko Komai, Mariko Inoue, Kaoru Morita, Tomohisa Okamura, Kazuhiko Yamamoto, Keishi Fujio
TGF-β is a pleotropic cytokine involved in various biological processes. Of the three isoforms of TGF-β, TGF-β1 has long been recognized as an important inhibitory cytokine in the immune system and has been reported to inhibit B cell function in both mice and humans. Recently, it has been suggested that TGF-β3 may play an important role in the regulation of immune system in mice. Murine CD4+CD25-LAG3+ regulatory T cells suppress B cell function through the production of TGF-β3, and it has been reported that TGF-β3 is therapeutic in a mouse model of systemic lupus erythematosus...
2017: PloS One
https://www.readbyqxmd.com/read/28025584/genome-wide-association-study-of-immunoglobulin-light-chain-amyloidosis-in-three-patient-cohorts-comparison-to-myeloma
#8
M I da Silva Filho, A Försti, N Weinhold, I Mezian, C Campo, S Huhn, J Nickel, P Hoffmann, M M Nöthen, K-H Jöckel, S Landi, J S Mitchell, D Johnson, G J Morgan, R Houlston, H Goldschmidt, A Jauch, P Milani, G Merlini, D Rowcieno, P Hawkins, U Hegenbart, G Palladini, A Wechalekar, S O Schönland, K Hemminki
Immunoglobulin light chain (AL) amyloidosis is characterized by tissue deposition of amyloid fibers derived from immunoglobulin light chain. AL amyloidosis and multiple myeloma (MM) originate from monoclonal gammopathy of undetermined significance. We wanted to characterize germline susceptibility to AL amyloidosis using a genome-wide association study (GWAS) on 1229 AL amyloidosis patients from Germany, UK and Italy, and 7526 healthy local controls. For comparison with MM, recent GWAS data on 3790 cases were used...
December 27, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28009285/anabolism-associated-mitochondrial-stasis-driving-lymphocyte-differentiation-over-self-renewal
#9
William C Adams, Yen-Hua Chen, Radomir Kratchmarov, Bonnie Yen, Simone A Nish, Wen-Hsuan W Lin, Nyanza J Rothman, Larry L Luchsinger, Ulf Klein, Meinrad Busslinger, Jeffrey C Rathmell, Hans-Willem Snoeck, Steven L Reiner
Regeneration requires related cells to diverge in fate. We show that activated lymphocytes yield sibling cells with unequal elimination of aged mitochondria. Disparate mitochondrial clearance impacts cell fate and reflects larger constellations of opposing metabolic states. Differentiation driven by an anabolic constellation of PI3K/mTOR activation, aerobic glycolysis, inhibited autophagy, mitochondrial stasis, and ROS production is balanced with self-renewal maintained by a catabolic constellation of AMPK activation, mitochondrial elimination, oxidative metabolism, and maintenance of FoxO1 activity...
December 20, 2016: Cell Reports
https://www.readbyqxmd.com/read/27983717/evaluation-of-methylation-biomarkers-for-detection-of-circulating-tumor-dna-and-application-to-colorectal-cancer
#10
Susan M Mitchell, Thu Ho, Glenn S Brown, Rohan T Baker, Melissa L Thomas, Aidan McEvoy, Zheng-Zhou Xu, Jason P Ross, Trevor J Lockett, Graeme P Young, Lawrence C LaPointe, Susanne K Pedersen, Peter L Molloy
Solid tumors shed DNA into circulation, and there is growing evidence that the detection of circulating tumor DNA (ctDNA) has broad clinical utility, including monitoring of disease, prognosis, response to chemotherapy and tracking tumor heterogeneity. The appearance of ctDNA in the circulating cell-free DNA (ccfDNA) isolated from plasma or serum is commonly detected by identifying tumor-specific features such as insertions, deletions, mutations and/or aberrant methylation. Methylation is a normal cell regulatory event, and since the majority of ccfDNA is derived from white blood cells (WBC), it is important that tumour-specific DNA methylation markers show rare to no methylation events in WBC DNA...
December 15, 2016: Genes
https://www.readbyqxmd.com/read/27965670/activated-il-1ri-signaling-pathway-induces-th17-cell-differentiation-via-interferon-regulatory-factor-4-signaling-in-patients-with-relapsing-remitting-multiple-sclerosis
#11
Yonggang Sha, Silva Markovic-Plese
IL-1β plays a crucial role in the differentiation of human Th17 cells. We report here that IL-1RI expression is significantly increased in both naive and memory CD4(+) T cells derived from relapsing-remitting multiple sclerosis (RR MS) patients in comparison to healthy controls. Interleukin 1 receptor (IL-1R)I expression is upregulated in the in vitro-differentiated Th17 cells from RR MS patients in comparison to the Th1 and Th2 cell subsets, indicating the role of IL-1R signaling in the Th17 cell differentiation in RR MS...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27941786/transcriptional-programs-that-control-expression-of-the-autoimmune-regulator-gene-aire
#12
Yonatan Herzig, Shir Nevo, Chamutal Bornstein, Miriam R Brezis, Sharon Ben-Hur, Aya Shkedy, Michal Eisenberg-Bord, Ben Levi, Michael Delacher, Yael Goldfarb, Eyal David, Leehee Weinberger, Sergey Viukov, Shifra Ben-Dor, Matthieu Giraud, Jacob H Hanna, Achim Breiling, Frank Lyko, Ido Amit, Markus Feuerer, Jakub Abramson
Aire is a transcriptional regulator that induces promiscuous expression of thousands of genes encoding tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs). While the target genes of Aire are well characterized, the transcriptional programs that regulate its own expression have remained elusive. Here we comprehensively analyzed both cis-acting and trans-acting regulatory mechanisms and found that the Aire locus was insulated by the global chromatin organizer CTCF and was hypermethylated in cells and tissues that did not express Aire...
February 2017: Nature Immunology
https://www.readbyqxmd.com/read/27939672/dynamic-changes-in-chromatin-accessibility-occur-in-cd8-t-cells-responding-to-viral-infection
#13
James P Scott-Browne, Isaac F López-Moyado, Sara Trifari, Victor Wong, Lukas Chavez, Anjana Rao, Renata M Pereira
In response to acute infection, naive CD8(+) T cells expand, differentiate into effector cells, and then contract to a long-lived pool of memory cells after pathogen clearance. During chronic infections or in tumors, CD8(+) T cells acquire an "exhausted" phenotype. Here we present genome-wide comparisons of chromatin accessibility and gene expression from endogenous CD8(+) T cells responding to acute and chronic viral infection using ATAC-seq and RNA-seq techniques. Acquisition of effector, memory, or exhausted phenotypes was associated with stable changes in chromatin accessibility away from the naive T cell state...
December 20, 2016: Immunity
https://www.readbyqxmd.com/read/27935477/regulation-of-b-cell-fate-by-chronic-activity-of-the-ige-b-cell-receptor
#14
Zhiyong Yang, Marcus J Robinson, Xiangjun Chen, Geoffrey A Smith, Jack Taunton, Wanli Liu, Christopher D C Allen
IgE can trigger potent allergic responses, yet the mechanisms regulating IgE production are poorly understood. Here we reveal that IgE(+) B cells are constrained by chronic activity of the IgE B cell receptor (BCR). In the absence of cognate antigen, the IgE BCR promoted terminal differentiation of B cells into plasma cells (PCs) under cell culture conditions mimicking T cell help. This antigen-independent PC differentiation involved multiple IgE domains and Syk, CD19, BLNK, Btk, and IRF4. Disruption of BCR signaling in mice led to consistently exaggerated IgE(+) germinal center (GC) B cell but variably increased PC responses...
December 9, 2016: ELife
https://www.readbyqxmd.com/read/27928009/influence-of-plasma-cell-niche-factors-on-the-recruitment-and-maintenance-of-irf4hi-plasma-cells-and-plasmablasts-in-vaccinated-siv-infected-rhesus-macaques-with-low-and-high-viremia
#15
Julia M Shaw, Leia K Miller-Novak, Venkatramanan Mohanram, Katherine McKinnon, Thorsten Demberg, Diego A Vargas-Inchaustegui, David Venzon, Marjorie Robert-Guroff
: In a recent study, we found protection following SIV exposure correlated with rectal plasma cell frequency in vaccinated female rhesus macaques. We sought to determine if these same macaques maintained high mucosal plasma cell frequencies post-infection and if this translated to reduced viremia. Although delayed SIV acquisition did not predict subsequent viral control, alterations existed in the distribution of plasma cells and plasmablasts between macaques that exhibited high or low viremia...
December 7, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27910098/gata-3-specific-dnazyme-a-novel-approach-for-stratified-asthma-therapy
#16
REVIEW
Holger Garn, Harald Renz
It is now well established that type-2 immune mechanisms drive the inflammation in about 50% of asthma patients. The major cellular and molecular players regulating this important network have been identified. In terms of therapeutic intervention, cytokine and cytokine-receptor pathways have been given major attention, since these molecules are relatively easily accessible for a blockade through monoclonal antibodies, and a number of positive clinical results support this concept. However, targeting events controlling the type-2 immunity network upstream of selective cytokine pathways would be equally attractive...
December 2, 2016: European Journal of Immunology
https://www.readbyqxmd.com/read/27903272/inhibition-of-bromodomain-and-extra-terminal-bet-proteins-increases-nkg2d-ligand-mica-expression-and-sensitivity-to-nk-cell-mediated-cytotoxicity-in-multiple-myeloma-cells-role-of-cmyc-irf4-mir-125b-interplay
#17
Maria Pia Abruzzese, Maria Teresa Bilotta, Cinzia Fionda, Alessandra Zingoni, Alessandra Soriani, Elisabetta Vulpis, Cristiana Borrelli, Beatrice Zitti, Maria Teresa Petrucci, Maria Rosaria Ricciardi, Rosa Molfetta, Rossella Paolini, Angela Santoni, Marco Cippitelli
BACKGROUND: Anti-cancer immune responses may contribute to the control of tumors after conventional chemotherapy, and different observations have indicated that chemotherapeutic agents can induce immune responses resulting in cancer cell death and immune-stimulatory side effects. Increasing experimental and clinical evidence highlight the importance of natural killer (NK) cells in immune responses toward multiple myeloma (MM), and combination therapies able to enhance the activity of NK cells against MM are showing promise in treating this hematologic cancer...
December 1, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27897229/global-gene-regulation-during-activation-of-immunoglobulin-class-switching-in-human-b-cells
#18
Youming Zhang, David J Fear, Saffron A G Willis-Owen, William O Cookson, Miriam F Moffatt
Immunoglobulin class switch recombination (CSR) to IgE is a tightly regulated process central to atopic disease. To profile the B-cell transcriptional responses underlying the activation of the germinal centre activities leading to the generation of IgE, naïve human B-cells were stimulated with IL-4 and anti-CD40. Gene expression and alternative splicing were profiled over 12 days using the Affymetrix Human Exon 1.0 ST Array. A total of 1,399 genes, forming 13 temporal profiles were differentially expressed...
November 29, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27897162/batf3-selectively-determines-acquisition-of-cd8-dendritic-cell-phenotype-and-function
#19
Janin Chandra, Paula T Y Kuo, Anne M Hahn, Gabrielle T Belz, Ian H Frazer
Batf3 is a transcription factor that impacts the development of CD103(+) tissue-resident dendritic cells (DCs). However, whether Batf3 is absolutely required for the development of CD8(+) DCs remains controversial. Id2 is required for CD8(+) DC development. Here we show that bone marrow chimeric mice with a deletion of Id2 in the CD11c compartment lose the ability to reject a skin graft expressing a non-self protein antigen or mount a delayed hypersensitivity response. In contrast, Batf3((-/-)) mice remained competent for skin graft rejection and delayed hypersensitivity, and retained a CD8(+) DC population with markers characteristic of the CD11b(+) DC lineage, including CD11b, CD4 and CD172α, as well as the key regulator transcription factor IRF4, but lacked IRF8 expression...
November 29, 2016: Immunology and Cell Biology
https://www.readbyqxmd.com/read/27890933/preclinical-activity-of-cpi-0610-a-novel-small-molecule-bromodomain-and-extra-terminal-protein-inhibitor-in-the-therapy-of-multiple-myeloma
#20
K T Siu, J Ramachandran, A J Yee, H Eda, L Santo, C Panaroni, J A Mertz, R J Sims Iii, M R Cooper, N Raje
Inhibition of the bromodomain and extra-terminal (BET) proteins is a promising therapeutic strategy for various hematologic cancers. Previous studies suggest that BET inhibitors constrain tumor cell proliferation and survival mainly through the suppression of MYC transcription and activity. However, suppression of the transcription of additional genes also contributes to the antitumor activity of BET inhibitors but is less well understood. Here we examined the therapeutic potential of CPI-0610, a potent BET inhibitor currently undergoing phase I clinical testing, in multiple myeloma (MM)...
January 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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