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Justus Mahnke, Valéa Schumacher, Stefanie Ahrens, Nadja Käding, Lea Marie Feldhoff, Magdalena Huber, Jan Rupp, Friederike Raczkowski, Hans-Willi Mittrücker
The transcription factor Interferon Regulatory Factor 4 (IRF4) is essential for TH2 and TH17 cell formation and controls peripheral CD8(+) T cell differentiation. We used Listeria monocytogenes infection to characterize the function of IRF4 in TH1 responses. IRF4(-/-) mice generated only marginal numbers of listeria-specific TH1 cells. After transfer into infected mice, IRF4(-/-) CD4(+) T cells failed to differentiate into TH1 cells as indicated by reduced T-bet and IFN-γ expression, and showed limited proliferation...
October 20, 2016: Scientific Reports
Stanley Ching-Cheng Huang, Amber M Smith, Bart Everts, Marco Colonna, Erika L Pearce, Joel D Schilling, Edward J Pearce
Macrophage activation status is intrinsically linked to metabolic remodeling. Macrophages stimulated by interleukin 4 (IL-4) to become alternatively (or, M2) activated increase fatty acid oxidation and oxidative phosphorylation; these metabolic changes are critical for M2 activation. Enhanced glucose utilization is also characteristic of the M2 metabolic signature. Here, we found that increased glucose utilization is essential for M2 activation. Increased glucose metabolism in IL-4-stimulated macrophages required the activation of the mTORC2 pathway, and loss of mTORC2 in macrophages suppressed tumor growth and decreased immunity to a parasitic nematode...
October 18, 2016: Immunity
Fahima Madouri, Pauline Chenuet, Chloé Beuraud, Louis Fauconnier, Tiffany Marchiol, Nathalie Rouxel, Aurélie Ledru, Margaux Gallerand, Vincent Lombardi, Laurent Mascarell, Quentin Marquant, Lionel Apetoh, François Erard, Marc Le Bert, Fabrice Trovero, Valérie F J Quesniaux, Bernhard Ryffel, Dieudonnée Togbe
BACKGROUND: Protein Kinase C theta (PKC-θ), a serine/threonine kinase is involved in T helper 2 (Th2) cell activation and proliferation. Innate lymphoid cells 2 (ILC2) resemble Th2 cells; produce the Th2 cytokines IL-5 and IL-13, but lack antigen specific receptors. The mechanism by which PKC-θ drives innate immune cells to instruct Th2 responses in allergic lung inflammation remains unknown. OBJECTIVES: We hypothesized that PKC-θ contributes to ILC2 activation and may be necessary for ILC2 to instruct Th2 response...
October 13, 2016: Journal of Allergy and Clinical Immunology
Ariunzaya Bat-Erdene, Hirokazu Miki, Asuko Oda, Shingen Nakamura, Jumpei Teramachi, Ryota Amachi, Hirofumi Tenshin, Masahiro Hiasa, Masami Iwasa, Takeshi Harada, Shiro Fujii, Kimiko Sogabe, Kumiko Kagawa, Sumiko Yoshida, Itsuro Endo, Kenichi Aihara, Masahiro Abe
Panobinostat, a pan-deacetylase inhibitor, synergistically elicits cytotoxic activity against myeloma (MM) cells in combination with the proteasome inhibitor bortezomib. Because precise mechanisms for panobinostat's anti-MM action still remain elusive, we aimed to clarify the mechanisms of anti-MM effects of panobinostat and its synergism with proteasome inhibitors. Although the transcription factor Sp1 was overexpressed in MM cells, the Sp1 inhibitor terameprocol induced MM cell death in parallel with reduction of IRF4 and cMyc...
October 12, 2016: Oncotarget
Nathalie Dehne, Bernhard Brüne
Hypoxia, by activating transcription factors induces transcription of some genes but it also reduces mRNA synthesis by mechanisms that are poorly defined. Activation of human macrophages with interleukin (IL)-4 showed that up-regulation of some IL-4 target genes was reduced when macrophages were incubated at 1% oxygen. Hypoxia impaired induction of chemokine (C-C motif) ligand 18 (CCL18), although IL-4-induced DNA binding of the transcription factor STAT6 remained intact. In contrast, induction of serine peptidase inhibitor, Kunitz type (SPINT)2, another IL-4/STAT6 target gene, was not affected by hypoxia...
October 11, 2016: Biochimica et Biophysica Acta
Li Jiang, Shuyu Yao, Su Huang, Jeffrey Wright, Thomas J Braciale, Jie Sun
Recent evidence has suggested that IL-10-producing effector CD8(+) T cells play an important role in regulating excessive inflammation during acute viral infections. However, the cellular and molecular cues regulating the development of IL-10-producing effector CD8(+) T cells are not completely defined. Here we show that type I interferons (IFNs) are required for the development of IL-10-producing effector CD8(+) T cells during influenza virus infection in mice. We find that type I IFNs can enhance IL-27 production by lung antigen presenting cells, thereby facilitating IL-10-producing CD8(+) T-cell development through a CD8(+) T cell non-autonomous way...
October 4, 2016: European Journal of Immunology
Mariateresa Mirarchi, Emilio De Raffele, Francesco Bacci, Dajana Cuicchi, Ferdinando Lecce, Bruno Cola
: Solitary extramedullary plasmacitomas (SEMP) of the liver are very rare. We report the case of an elderly woman with a huge symptomatic SEMP of the liver mimicking hepatocellular carcinoma (HCC). The patient was a 89-year-old woman who presented with severe abdominal pain and a huge solid mass in the right hypochondrium. The laboratory data on admission revealed normal liver function tests. A multiphasic computed tomography (CT) showed a huge solid mass of the left hemiliver, hypoattenuating on noncontrast images, dishomogeneously hyperenhancing in the late arterial phase, with washout in the portal venous and equilibrium phases...
2016: Annali Italiani di Chirurgia
Yasuhiro Kishi, Takaaki Kondo, Sheng Xiao, Nir Yosef, Jellert Gaublomme, Chuan Wu, Chao Wang, Norio Chihara, Aviv Regev, Nicole Joller, Vijay K Kuchroo
Th17 cells are key players in defense against pathogens and maintaining tissue homeostasis, but also act as critical drivers of autoimmune diseases. Based on single-cell RNA-seq profiling of pathogenic versus nonpathogenic Th17 cells, we identified protein C receptor (PROCR) as a cell surface molecule expressed in covariance with the regulatory module of Th17 cells. Although PROCR expression in T cells was controlled by the cooperative action of the Th17 lineage-specific transcription factors RORγt, IRF4, and STAT3, PROCR negatively regulated Th17 differentiation...
September 26, 2016: Journal of Experimental Medicine
Yeguang Hu, Zhihong Zhang, Mariko Kashiwagi, Toshimi Yoshida, Ila Joshi, Nilamani Jena, Rajesh Somasundaram, Akinola Olumide Emmanuel, Mikael Sigvardsson, Julien Fitamant, Nabeel El-Bardeesy, Fotini Gounari, Richard A Van Etten, Katia Georgopoulos
IKAROS is required for the differentiation of highly proliferative pre-B-cell precursors, and loss of IKAROS function indicates poor prognosis in precursor B-cell acute lymphoblastic leukemia (B-ALL). Here we show that IKAROS regulates this developmental stage by positive and negative regulation of superenhancers with distinct lineage affiliations. IKAROS defines superenhancers at pre-B-cell differentiation genes together with B-cell master regulators such as PAX5, EBF1, and IRF4 but is required for a highly permissive chromatin environment, a function that cannot be compensated for by the other transcription factors...
September 1, 2016: Genes & Development
Jianlin Qiao, Xiaoqian Li, Yulu Wu, Xiaoqing Wu, Feng Zhu, Na Liu, Kunming Qi, Hai Cheng, Depeng Li, Haiying Sun, Lingyu Zeng, Kailin Xu
Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disease, characterized by dysregulation of cellular immunity. Th9 cells were recently identified as a new subtype of Th cells, characterized by preferential production of IL-9. Given the pleiotropic function of IL-9, Th9 cells are demonstrated to be involved in various autoimmune diseases. However, whether Th9 cells are involved in the pathogenesis of ITP remains unclear. In this study, 49 active ITP patients, 39 ITP with remission and 20 healthy controls were included...
September 23, 2016: Platelets
Kaiyin Zhong, Joris A C Verkouteren, Leonie C Jacobs, Andre G Uitterlinden, A Hofman, Fan Liu, Tamar Nijsten, Manfred Kayser
Actinic keratosis (AK) is a skin disease frequently found in European elderly and represents the precursor of cutaneous squamous cell carcinoma (SCC). Our recent genome-wide association study (GWAS) highlighted DNA variants in two pigmentation genes, IRF4 and MC1R, to confer AK risk in Europeans. Here, we performed a genome-wide search for relaxed forms of compound heterozygosity (CH) in association with AK using our recently developed software CollapsABEL. In a discovery dataset of 3,193 Dutch Europeans, a total of 15 genetic loci showed genome-wide significant association with AK (P < 1...
September 16, 2016: Journal of Investigative Dermatology
Lei Chen, Lika'a Fasih Y Al-Kzayer, Tingting Liu, Norimoto Kobayashi, Yozo Nakazawa, Kenichi Koike
IRF4/MUM1-positive lymphoma is a new subgroup of germinal center-derived B-cell lymphoma, predominantly involving the Waldeyer ring (WR) in children. CD5 expression is rare in these lymphomas. We report a 7-year-old Chinese male with B-cell lymphoma. Evaluation of his specimen by morphology, immunohistochemistry, and FISH analysis demonstrated IRF4/MUM1-positive lymphoma with strong and extensive CD5 and CD10 positivity. Despite the lack of t(14;18)(q32;q21) rearrangement, BCL2 protein was expressed. Our report highlights the clinicopathologic features of IFR4/MUM1-positive lymphoma in WR with co-expression of CD5 and CD10, and thereby provides insight into this newly recognized disease entity...
September 12, 2016: Pediatric Blood & Cancer
Sorim Nam, Kyeongah Kang, Jae Seon Cha, Jung Woo Kim, Hee Gu Lee, Yonghwan Kim, Young Yang, Myeong-Sok Lee, Jong-Seok Lim
Myeloid-derived suppressor cells (MDSCs) are immature cells that do not differentiate into mature myeloid cells. Two major populations of PMN-MDSCs (Ly6G(high)Ly6C(low)Gr1(high)CD11b(+)) and MO-MDSCs (Ly6G(-)Ly6C(high)Gr-1(int)CD11b(+)) have an immune suppressive function. Interferon regulatory factor 4 (IRF4) has a role in the negative regulation of TLR signaling and is associated with lymphoid cell development. However, the roles of IRF4 in myeloid cell differentiation are unclear. In this study, we found that IRF4 expression was remarkably suppressed during the development of MDSCs in the tumor microenvironment...
September 6, 2016: Journal of Leukocyte Biology
Ming Zhao, Dingya Sun, Yangtai Guan, Zhihong Wang, Daoqian Sang, Mingdong Liu, Yingyan Pu, Xue Fang, Dan Wang, Aijun Huang, Xiaoying Bi, Li Cao, Cheng He
UNLABELLED: T-helper 17 (Th17) cells play an important role in the pathogenesis of multiple sclerosis (MS), an autoimmune demyelinating disease that affects the CNS. In the present study, MicroRNA sequencing (miRNA-seq) was performed in mouse Th0 and Th17 cells to determine the critical miRNAs that are related to Th17 differentiation. We found that miR-30a was significantly downregulated during mouse Th17 differentiation. In addition, the level of miR-30a in CD4(+) T cells from peripheral blood of MS patients and experimental autoimmune encephalomyelitis (EAE) animal models was also decreased and inversely correlated with the expression of interleukin 17a, the canonical cytokine of Th17 cells...
August 31, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Makoto Kuwahara, Wataru Ise, Mizuki Ochi, Junpei Suzuki, Kohei Kometani, Saho Maruyama, Maya Izumoto, Akira Matsumoto, Nobuaki Takemori, Ayako Takemori, Kenta Shinoda, Toshinori Nakayama, Osamu Ohara, Masaki Yasukawa, Tatsuya Sawasaki, Tomohiro Kurosaki, Masakatsu Yamashita
Although Bach2 has an important role in regulating the Th2-type immune response, the underlying molecular mechanisms remain unclear. We herein demonstrate that Bach2 associates with Batf and binds to the regulatory regions of the Th2 cytokine gene loci. The Bach2-Batf complex antagonizes the recruitment of the Batf-Irf4 complex to AP-1 motifs and suppresses Th2 cytokine production. Furthermore, we find that Bach2 regulates the Batf and Batf3 expressions via two distinct pathways. First, Bach2 suppresses the maintenance of the Batf and Batf3 expression through the inhibition of IL-4 production...
2016: Nature Communications
Kristina J H Kleinwort, Barbara Amann, Stefanie M Hauck, Regina Feederle, Walter Sekundo, Cornelia A Deeg
PURPOSE: Recently, formation of tertiary lymphoid structures was demonstrated and further characterized in the R161H mouse model of spontaneous autoimmune uveitis. In the horse model of spontaneous recurrent uveitis, intraocular lymphoid follicle formation is highly characteristic, and found in all stages and scores of disease, but in depth analyses of immunologic features of these structures are lacking to date. METHODS: Paraffin-embedded eye sections of cases with equine spontaneous recurrent uveitis (ERU) were characterized with immunohistochemistry to gain insight into the distribution, localization, and signaling of immune cells in intraocular tertiary lymphoid tissues...
August 1, 2016: Investigative Ophthalmology & Visual Science
Carmen B Lupiañez, María T Villaescusa, Agostinho Carvalho, Jan Springer, Michaela Lackner, José M Sánchez-Maldonado, Luz M Canet, Cristina Cunha, Juana Segura-Catena, Laura Alcazar-Fuoli, Carlos Solano, Luana Fianchi, Livio Pagano, Leonardo Potenza, José M Aguado, Mario Luppi, Manuel Cuenca-Estrella, Cornelia Lass-Flörl, Hermann Einsele, Lourdes Vázquez, Rafael Ríos-Tamayo, Jurgen Loeffler, Manuel Jurado, Juan Sainz
Invasive Aspergillosis (IA) is an opportunistic infection caused by Aspergillus, a ubiquitously present airborne pathogenic mold. A growing number of studies suggest a major host genetic component in disease susceptibility. Here, we evaluated whether 14 single-nucleotide polymorphisms within NFκB1, NFκB2, RelA, RelB, Rel, and IRF4 genes influence the risk of IA in a population of 834 high-risk patients (157 IA and 677 non-IA) recruited through a collaborative effort involving the aspBIOmics consortium and four European clinical institutions...
2016: Frontiers in Microbiology
Maryam M Asgari, Amanda E Toland, Sarah T Arron
No abstract text is available yet for this article.
August 24, 2016: Journal of Investigative Dermatology
Taishi Takahara, Keitaro Matsuo, Masao Seto, Shigeo Nakamura, Shinobu Tsuzuki
Diffuse large B cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma; it derives from germinal center (GC) B cells. Although DLBCL harbors many genetic alterations, synergistic roles between such alterations in the development of lymphoma are largely undefined. We previously established a mouse model of lymphoma by transplanting gene-transduced GC B cells into mice. Here, we chose one of the frequently mutated genes in DLBCL, Card11 mutant, to explore its possible synergy with other genes, employing our lymphoma model...
August 25, 2016: Cancer Science
Tomáš Bzdušek, QuanSheng Wu, Andreas Rüegg, Manfred Sigrist, Alexey A Soluyanov
The band theory of solids is arguably the most successful theory of condensed-matter physics, providing a description of the electronic energy levels in various materials. Electronic wavefunctions obtained from the band theory enable a topological characterization of metals for which the electronic spectrum may host robust, topologically protected, fermionic quasiparticles. Many of these quasiparticles are analogues of the elementary particles of the Standard Model, but others do not have a counterpart in relativistic high-energy theories...
August 24, 2016: Nature
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