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European Journal of Immunology

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https://www.readbyqxmd.com/read/30242842/metformin-inhibits-ige-and-aryl-hydrocarbon-receptor-mediated-mast-cell-activation-in-vitro-and-in-vivo
#1
Hsueh-Chun Wang, Shau-Ku Huang
Metformin, an anti-diabetic drug, possesses anti-inflammatory property beyond its glucose-lowering activity, but its regulatory effect on mast cells and allergic responses remains unknown, wherein the aryl hydrocarbon receptor (AhR)-ligand axis is critical in controlling mast cell activation. Herein, we provide evidence supporting the role of metformin in modulating mast cell activation by FcεR1-, AhR-mediated signaling or their combination. Metformin at relatively low doses was shown to suppress FcεR1-mediated degranulation, IL-13, TNF-α and sphingosine-1-phosphate (S1P) secretion in murine bone marrow-derived mast cells (BMMCs)...
September 22, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30242834/the-tyrosine-kinase-inhibitor-dasatinib-reduces-the-growth-of-intracellular-mycobacterium-tuberculosis-despite-impairing-t-cell-function
#2
Stephanie Wehrstedt, Jan Kubis, Andreas Zimmermann, Heiko Bruns, Daniel Mayer, Mark Grieshober, Steffen Stenger
Tyrosine kinases are checkpoints for multiple cellular pathways and dysregulation induces malignancies, most notably chronic myeloid leukemia (CML). Inhibition of Abl-tyrosine kinases has evolved as a new concept for the treatment of CML and other malignant diseases. Due to the multiple immune-modulatory pathways controlled by tyrosine kinases, treatment with tyrosine kinase inhibitors (TKIs) will not only affect the biology of malignant cells but also modulate physiological immune functions. To understand the effects of TKIs on host defense against intracellular bacteria, we investigated the immunological impact of the dual Abl/Src TKI dasatinib on the cellular immune response to Mycobacterium tuberculosis (Mtb)...
September 22, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30218581/a-hyperactive-mutant-of-interferon-regulatory-factor-4
#3
LETTER
Chol Ho Kang, Enno Hartmann, Lisa Menke, Daniel Staudenraus, El-Fadil Abass, Hartmann Raifer, Alekya Porapu, Bärbel Camara, Anne Brüstle, Olaf Pinkenburg, Maria Bieringer, Michael Lohoff
IRFs are a family of transcription factors with pleiotropic functions in immune cells, including in generation of subsets of DCs and macrophages and B cell maturation [1]. IRF1 deficiency results in strongly diminished Th1 responses [2] and an inability to counteract pro-asthmatic Th9 responses [3].
September 15, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30218573/tmp778-a-selective-inhibitor-of-ror%C3%AE-t-suppresses-experimental-autoimmune-uveitis-development-but-affects-both-th17-and-th1-cell-populations
#4
Cancan Lyu, So Jin Bing, Wambui S Wandu, Biying Xu, Guangpu Shi, Samuel J Hinshaw, Mercedes Lobera, Rachel R Caspi, Lin Lu, Jianfei Yang, Igal Gery
EAU, an animal model for severe intraocular inflammatory eye diseases, is mediated by both Th1 and Th17 cells. Here, we examined the capacity of TMP778, a selective inhibitor of RORγt, to inhibit the development of EAU, as well as the related immune responses. EAU was induced in B10.A mice by immunization with interphotoreceptor retinoid-binding protein (IRBP). Treatment with TMP778 significantly inhibited the development of EAU, determined by histological examination. In addition, the treatment suppressed the cellular immune response to IRBP, determined by reduced production of IL-17 and IFN-γ, as well as lower percentages of lymphocytes expressing these cytokines, as compared to vehicle-treated controls...
September 15, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30216414/prophylactic-treatment-against-gm-csf-but-not-il-17-abolishes-relapses-in-a-chronic-murine-model-of-multiple-sclerosis
#5
Catherine Uyttenhove, Mélanie Gaignage, Dominique Donckers, Zakia Nasr, Pamela Cheou, Jacques van Snick, Ludovic D'Auria, Vincent van Pesch
The pathogenic role of IL-17 and GM-CSF has been unravelled in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). However, in most models, EAE is characterised by a monophasic attack which is not representative of the relapsing nature nor the chronicity displayed in MS. Here, we used proteolipid protein peptide (PLP139-151 ) to trigger EAE-relapses (EAE-II) in SJL mice that had recovered from a primary-EAE episode (EAE-I). This procedure resulted in severe and irreversible disease that, unlike EAE-I, was not abolished by anti-IL-17-mAb...
September 14, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30207595/proteomic-analysis-of-human-t-cell-derived-exosomes-reveals-differential-ras-mapk-signaling
#6
LETTER
Inbar Azoulay-Alfaguter, Adam Mor
Exosomes are cell derived vesicles that have been implicated in the pathogenesis of many inflammatory diseases. More specifically, it has been shown that T cell-derived exosomes can induce immunological responses; however, little is known about the mechanism and the molecular content of these vesicles. Here, we used a proteomic approach to characterize human T cell-derived exosomes. We found that specific proteins of the RAS signaling pathway were enriched in exosomes derived from activated T cells, and that these vesicles induced ERK phosphorylation in recipient immune cells...
September 12, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30184256/airway-epithelial-tslp-production-of-tlr2-drives-type-2-immunity-in-allergic-airway-inflammation
#7
Jiajia Lv, Qianying Yu, Jie Lv, Caixia Di, Xiaoliang Lin, Wen Su, Min Wu, Zhenwei Xia
Epithelial cells (ECs)-derived cytokines are induced by different stimuli through pattern recognition receptors (PRRs) to mount a type-2-cell-mediated immune response; however, the underlying mechanisms are poorly characterized. Here, we demonstrated asthmatic features in both primary bronchial epithelial cells (pBECs) and mouse model using several allergens including ovalbumin (OVA), house dust mite (HDM), or Alternaria alternate. We found that toll-like receptor 2 (TLR2) was highly induced in ECs but not dendritic cells (DCs) by various allergens, leading to recruitment of circulating basophils into the lung via C-C chemokine ligand-2 (CCL2)...
September 5, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30184252/fc-gamma-receptor-iia-suppresses-type-i-and-iii-interferon-production-by-human-myeloid-immune-cells
#8
Melissa Newling, Willianne Hoepel, Lisa T C Vogelpoel, Marieke H Heineke, Johan A van Burgsteden, Esther W M Taanman-Kueter, Dirk Eggink, Taco W Kuijpers, Tim Beaumont, Marjolein van Egmond, Martien L Kapsenberg, Dominique L P Baeten, Jeroen den Dunnen, Esther C de Jong
Type I and type III interferons (IFNs) are fundamental for antiviral immunity, but prolonged expression is also detrimental to the host. Therefore, upon viral infection high levels of type I and III IFNs are followed by a strong and rapid decline. However, the mechanisms responsible for this suppression are still largely unknown. Here, we show that IgG opsonization of model viruses influenza and respiratory syncytial virus (RSV) strongly and selectively suppressed type I and III IFN production by various human antigen-presenting cells...
September 5, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30183074/murine-eosinophil-development-and-allergic-lung-eosinophilia-are-largely-dependent-on-the-signaling-adaptor-grb2
#9
Ralf Willebrand, Axel Dietschmann, Lars Nitschke, Sven Krappmann, David Voehringer
Eosinophils are innate effector cells associated with allergic inflammation. Their development and survival is largely dependent on IL-5 and the common beta chain (βc ) of the IL-5 receptor that serves as docking site for several proteins that mediate down-stream signaling cascades including JAK/STAT, PI3 kinase, NFκB, and RAS-MAP kinase pathways. The relative contribution of these signaling pathways for eosinophil development and homeostasis in vivo are poorly understood. Here, we investigated the role of GRB2, an adaptor protein that binds to βc and other proteins and elicits the RAS-MAP kinase pathway...
September 5, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30183071/nlrp2-negatively-regulates-antiviral-immunity-by-interacting-with-tbk1
#10
Yanqing Yang, Xueting Lang, Song Sun, Chun Gao, Jianguo Hu, Shuqin Ding, Jing Li, Yuyun Li, Fengchao Wang, Tao Gong
Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are intracellular pattern recognition receptors (PRRs) that regulate a variety of inflammatory and host defense responses. Unlike the well-established NLRs, the roles of NLRP2 are controversial and poorly defined. Here, we report that NLRP2 acts as a negative regulator of TANK-binding kinase 1 (TBK1)-mediated type I interferon (IFN) signaling. Mechanistically, NLRP2 interacted directly with TBK1, and this binding disrupted the interaction of TBK1 and interferon regulatory factor 3 (IRF3), which interfered with TBK1-induced IRF3 phosphorylation...
September 5, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30169894/fkbp51-modulates-steroid-sensitivity-and-nf%C3%AE%C2%BAb-signalling-a-novel-anti-inflammatory-drug-target
#11
Marc Kästle, Barbara Kistler, Thorsten Lamla, Tom Bretschneider, David Lamb, Paul Nicklin, David Wyatt
Steroid refractory inflammation is an unmet medical need in the management of inflammatory diseases. Thus, mechanisms, improving steroid sensitivity and simultaneously decreasing inflammation have potential therapeutic utility. The FK506-binding protein 51 (FKBP51) is reported to influence steroid sensitivity in mental disorders. Moreover, biochemical data highlight a connection between FKBP51 and the IKK complex. The aim of this study was to elucidate whether FKBP51 inhibition had utility in modulating steroid resistant inflammation by increasing the sensitivity of the glucocorticoid receptor (GR) signalling and simultaneously inhibiting NFκB-driven inflammation...
August 31, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30160778/the-macrophage-migration-inhibitory-factor-pathway-in-human-b-cells-is-tightly-controlled-and-dysregulated-in-multiple-sclerosis
#12
Liza Rijvers, Marie-José Melief, Roos M van der Vuurst de Vries, Maeva Stéphant, Jamie van Langelaar, Annet F Wierenga-Wolf, Jeanet M Hogervorst, Anneke J Geurts-Moespot, Fred C G J Sweep, Rogier Q Hintzen, Marvin M van Luijn
In multiple sclerosis (MS), B cells survive peripheral tolerance checkpoints to mediate local inflammation, but the underlying molecular mechanisms are relatively underexplored. In mice, the macrophage migration inhibitory factor (MIF) pathway controls B-cell development and the induction of experimental autoimmune encephalomyelitis. Here, we found that MIF and MIF receptor CD74 are downregulated, while MIF receptor CXCR4 is upregulated in B cells from early onset MS patients. B cells were identified as the main immune subset in blood expressing MIF...
August 30, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30160302/pathogen-interactions-with-endothelial-cells-and-the-induction-of-innate-and-adaptive-immunity
#13
REVIEW
Christoph Konradt, Christopher A Hunter
There are over 10 trillion endothelial cells (EC) that line the vasculature of the human body. These cells not only have specialized functions in the maintenance of homeostasis within the circulation and various tissues but they also have a major role in immune function. EC also represent an important replicative niche for a subset of viral, bacterial, and parasitic organisms that are present in the blood or lymph; however, there are major gaps in our knowledge regarding how pathogens interact with EC and how this influences disease outcome...
August 30, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30144039/tumor-shed-antigen-ca125-blocks-complement-mediated-killing-via-suppression-of-c1q-antibody-binding
#14
J Brad Kline, Shawn Fernando, Erin N Ross, Luigi Grasso, Nicholas C Nicolaides
C1q-engagement with IgG and IgM type antibodies is the initiating step of classical complement-mediated immunity. The tumor shed antigen CA125 has been reported to have immunosuppressive effects on host tumor responses as well as commercially approved and experimental monoclonal antibody (mAb)-based therapeutic agents. To better understand this effect, molecular and cellular studies were carried out testing the ability of CA125 to perturb the classical complement pathway. Here we show that patient-derived CA125 inhibits IgG1, IgG3, and IgM-mediated complement dependent cytotoxicity (CDC) by perturbing antibody-Fc interaction with the C1q complement-initiating protein only in those mAbs that are directly bound by CA125...
August 24, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30144030/eomes-controls-the-development-of-th17-derived-non-classic-th1-cells-during-chronic-inflammation
#15
Alessio Mazzoni, Laura Maggi, Francesco Siracusa, Matteo Ramazzotti, Maria Caterina Rossi, Veronica Santarlasci, Gianni Montaini, Manuela Capone, Beatrice Rossettini, Raffaele De Palma, Andrey Kruglov, Hyun-Dong Chang, Rolando Cimaz, Enrico Maggi, Sergio Romagnani, Francesco Liotta, Lorenzo Cosmi, Francesco Annunziato
It is well accepted that Th17 cells are a highly plastic cell subset that can be easily directed towards the Th1 phenotype in vitro and also in vivo during inflammation. However, there is an ongoing debate regarding the reverse plasticity (conversion from Th1 to Th17). We show here that ectopic ROR-γt expression can restore or initiate IL-17 expression by non-classic or classic Th1 cells, respectively, while common pro-Th17 cytokine cocktails are ineffective. This stability of the Th1 phenotype is at least partially due to the presence of a molecular machinery governed by the transcription factor Eomes, which promotes IFN-γ secretion while inhibiting the expression of ROR-γt and IL-17...
August 24, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30138536/relt-negatively-regulates-the-early-phase-of-the-t-cell-response-in-mice
#16
Beom K Choi, Seon-Hee Kim, Young H Kim, Don G Lee, Ho S Oh, Chungyong Han, Yu I Kim, Yoon Jeon, Ho Lee, Byoung S Kwon
RELT (tumor necrosis factor receptor superfamily member 19-like, TNFRSF19L) is a TNFR superfamily member that is primarily expressed in immune cells and lymphoid tissues, but whose immunological function is not well-defined. Here, we show that RELT is expressed by naive T cells and DCs, and their activation or maturation decreases RELT expression. Using RELT knockout (RELT-/- ) mice, we demonstrate that RELT deficiency selectively promotes the homeostatic proliferation of CD4+ T cells but not CD8+ T cells, and enhances anti-tumor CD8+ T-cell responses...
August 23, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30118145/intestinal-epithelial-cells-and-t-cells-differentially-recognize-and-respond-to-candida-albicans-yeast-and-hypha
#17
Anja Schirbel, Dror S Shouval, Betty Hebecker, Bernhard Hube, Andreas Sturm, Lael Werner
Inflammatory bowel diseases (IBD) is a multifactorial disorder. Our understanding of the role of bacteria in the pathogenesis of IBD has increased substantially; however, only scarce data exist regarding the role of commensal fungi in maintaining intestinal homeostasis and triggering IBD. Candida albicans (C. albicans) is a member of the intestinal mycobiome and proposed to contribute to IBD pathogenesis. We aimed to investigate the influence of the two morphologies of C. albicans, yeast and hypha, on epithelial cells and T cells from IBD patients vs...
August 17, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30098001/the-selective-rock2-inhibitor-kd025-reduces-il-17-secretion-in-human-peripheral-blood-mononuclear-cells-independent-of-il-1-and-il-6
#18
Isak W Tengesdal, David Kitzenberg, Suzhao Li, Melanie S Nyuydzefe, Wei Chen, Jonathan M Weiss, Jingya Zhang, Samuel D Waksal, Alexandra Zanin-Zhorov, Charles A Dinarello
Reducing the activities of the pro-inflammatory cytokine IL-17 is an effective treatment strategy for several chronic autoimmune disorders. Rho-associated coiled-coil containing kinase 2 (ROCK2) is a member of the serine-threonine protein kinase family that regulates IL-17 secretion in T cells via signal transducer and activator of transcription 3 (STAT3)-dependent mechanism. We reported here that the selective ROCK2 inhibitor KD025 significantly reduced in vitro production of IL-17 in unfractionated human peripheral blood mononuclear cells (PBMCs) stimulated with the dectin-1 agonist Candida albicans (C...
August 11, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30089192/ets1-and-pax5-transcription-factors-recruit-aid-to-igh-dna
#19
Christine Grundström, Anjani Kumar, Anshu Priya, Neema Negi, Thomas Grundström
B lymphocytes optimize antibody responses by class switch recombination (CSR), which changes the expressed constant region exon of the immunoglobulin heavy chain (IgH), and by somatic hypermutation (SH) that introduces point mutations in the variable regions of the antibody genes. Activation-induced cytidine deaminase (AID) is the key mutagenic enzyme that initiates both these antibody diversification processes by deaminating cytosine to uracil. Here we asked the question if transcription factors can mediate the specific targeting of the antibody diversification by recruiting AID...
August 8, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30063799/nk-cell-mediated-anti-leukemia-cytotoxicity-is-enhanced-using-a-nkg2d-ligand-mica-and-anti-cd20-scfv-chimeric-protein
#20
Yizhou Zou, Weiguang Luo, Jing Guo, Qizhi Luo, Mi Deng, Zhigang Lu, Yi Fang, Cheng Cheng Zhang
NK cells are important innate cytotoxic lymphocytes that have potential in treatment of leukemia. Engagement of NKG2D receptor on NK cells enhances the target cytotoxicity. Here, we produced a fusion protein consisting of the extracellular domain of the NKG2D ligand MICA and the anti-CD20 single-chain variable fragment (scfv). This recombinant protein is capable of binding both NK cells and CD20+ tumor cells. Using a human NKG2D reporter cell system we developed, we showed that this fusion protein could decorate CD20+ tumor cells with MICA extracellular domain and activate NK through NKG2D...
July 31, 2018: European Journal of Immunology
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