Journal ArticleDOI
Mechanisms and consequences of Jak–STAT signaling in the immune system
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TLDR
Recent advances in Jak–STAT biology are reviewed, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent TFs.Abstract:
Kinases of the Jak ('Janus kinase') family and transcription factors (TFs) of the STAT ('signal transducer and activator of transcription') family constitute a rapid membrane-to-nucleus signaling module that affects every aspect of the mammalian immune system. Research on this paradigmatic pathway has experienced breakneck growth in the quarter century since its discovery and has yielded a stream of basic and clinical insights that have profoundly influenced modern understanding of human health and disease, exemplified by the bench-to-bedside success of Jak inhibitors ('jakinibs') and pathway-targeting drugs. Here we review recent advances in Jak-STAT biology, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent TFs.read more
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New and Emerging Therapies for Pediatric Atopic Dermatitis
TL;DR: New and emerging AD therapies will be discussed along with their mechanisms of action and their potential based on clinical study data.
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Immunostimulatory bacterial antigen-armed oncolytic measles virotherapy significantly increases the potency of anti-PD1 checkpoint therapy.
Eleni Panagioti,Eleni Panagioti,Cheyne Kurokawa,Kimberly Viker,Arun Ammayappan,S. Keith Anderson,Sotiris Sotiriou,Kyriakos Chatzopoulos,Katayoun Ayasoufi,Aaron J. Johnson,Ianko D. Iankov,Evanthia Galanis +11 more
TL;DR: In this paper, the authors used the Helicobacter pylori neutrophil-activating protein (NAP), a potent TLR2 agonist, as an immunostimulatory transgene expressed in an oncolytic measles virus (MV) platform, retargeted to allow viral entry through the urokinase-type plasminogen activator receptor (uPAR).
Journal ArticleDOI
Interferon signature in patients with STAT1 gain-of-function mutation is epigenetically determined.
Epp Kaleviste,Mario Saare,Timothy Ronan Leahy,Vincent Bondet,Darragh Duffy,Trine H. Mogensen,Trine H. Mogensen,Sofie E. Jørgensen,Helke Nurm,Winnie Ip,E. Graham Davies,Sascha Sauer,Sascha Sauer,Ann-Christine Syvänen,Lili Milani,Pärt Peterson,Kai Kisand +16 more
TL;DR: The results suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients and possibly predisposes for interferon‐related autoimmunity.
Journal ArticleDOI
Endothelial cell and T-cell crosstalk: targeting metabolism as a therapeutic approach in chronic inflammation
Michelangelo Certo,Hagar Elkafrawy,Valentina Pucino,Danilo Cucchi,Kenneth C. P. Cheung,Claudio Mauro +5 more
TL;DR: An overview of recent insights in the complex crosstalk between endothelial cells and T cells as well as their metabolic reprogramming following activation is discussed, highlighting key components of this metabolic switch that can lead to the development of new therapeutics against chronic inflammatory disorders.
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Engineered Tools to Study Intercellular Communication
TL;DR: In this article, a review discusses how salient engineered approaches and sequencing techniques can be applied to understand collective cell behavior and tissue functions, while resolving the molecular heterogeneity in "omic" layers that contribute to cell state and function.
References
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Journal ArticleDOI
Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.
TL;DR: The authors showed that CD4+CD25+ cells contribute to maintaining self-tolerance by downregulating immune response to self and non-self Ags in an Ag-nonspecific manner, presumably at the T cell activation stage.
Journal ArticleDOI
Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins
TL;DR: A previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that phosphorylate substrate proteins called STATs (signal transducers and activators of transcription).
Journal ArticleDOI
A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders
Robert Kralovics,Francesco Passamonti,Andreas Buser,Soon Siong Teo,Ralph Tiedt,Jakob Passweg,André Tichelli,Mario Cazzola,Radek C. Skoda +8 more
TL;DR: Genetic evidence and in vitro functional studies indicate that V617F gives hematopoietic precursors proliferative and survival advantages and a high proportion of patients with myeloproliferative disorders carry a dominant gain-of-function mutation of JAK2.
Journal ArticleDOI
Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.
E. Joanna Baxter,Linda M. Scott,Peter J. Campbell,Clare L. East,Nasios Fourouclas,Soheila Swanton,George S. Vassiliou,Anthony J. Bench,Elaine M. Boyd,Natasha Curtin,Michael A. Scott,Wendy N. Erber,Anthony R. Green,Anthony R. Green +13 more
TL;DR: A single acquired mutation of JAK2 was noted in more than half of patients with a myeloproliferative disorder and its presence in all erythropoietin-independent erythroid colonies demonstrates a link with growth factor hypersensitivity, a key biological feature of these disorders.
Journal ArticleDOI
A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera
Chloé James,Valérie Ugo,Jean-Pierre Le Couedic,Judith Staerk,François Delhommeau,Catherine Lacout,Loïc Garçon,Hana Raslova,Roland Berger,Annelise Bennaceur-Griscelli,Jean-Luc Villeval,Stefan N. Constantinescu,Nicole Casadevall,William Vainchenker +13 more
TL;DR: A clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model.