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Journal of Experimental Medicine

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https://www.readbyqxmd.com/read/28536241/correction-aav-mediated-expression-of-anti-tau-scfvs-decreases-tau-accumulation-in-a-mouse-model-of-tauopathy
#1
Christina Ising, Gilbert Gallardo, Cheryl E G Leyns, Connie H Wong, Hong Jiang, Floy Stewart, Lauren J Koscal, Joseph Roh, Grace O Robinson, Javier Remolina Serrano, David M Holtzman
No abstract text is available yet for this article.
May 23, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28536240/reply-to-tolerogenic-insulin-peptide-therapy-precipitates-type-1-diabetes
#2
Carolin Daniel, Benno Weigmann, Harald von Boehmer
In this issue of JEM, Bergman et al. (https://doi.org/10.1084/jem.20160471) challenge the data published in our previous JEM paper on the preventive effect of tolerogenic vaccination with a strong agonist insulin mimetope in type 1 diabetes. Here, we provide a response to these data and suggest that appropriate subimmunogenic conditions are required to induce Foxp3(+) regulatory T cell conversion.
May 23, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28536239/tolerogenic-insulin-peptide-therapy-precipitates-type-1-diabetes
#3
LETTER
Marie-Louise Bergman, Thiago Lopes-Carvalho, Ana-Catarina Martins, Fabio A Grieco, Décio L Eizirik, Jocelyne Demengeot
Daniel et al. (https://doi.org/10.1084/jem.20110574) have previously published in JEM a study on the preventive effect of tolerogenic vaccination with a strong agonist insulin mimetope in type 1 diabetes. Our study now challenges these results and shows that osmotic pump delivery of the modified insulin peptide R22E did not prevent hyperglycemia, accelerated disease onset, increased its incidence, and worsened insulitis.
May 23, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28533268/the-transcription-factor-gli3-promotes-b-cell-development-in-fetal-liver-through-repression-of-shh
#4
Anisha Solanki, Ching-In Lau, José Ignacio Saldaña, Susan Ross, Tessa Crompton
Before birth, B cells develop in the fetal liver (FL). In this study, we show that Gli3 activity in the FL stroma is required for B cell development. In the Gli3-deficient FL, B cell development was reduced at multiple stages, whereas the Sonic hedgehog (Hh [Shh])-deficient FL showed increased B cell development, and Gli3 functioned to repress Shh transcription. Use of a transgenic Hh-reporter mouse showed that Shh signals directly to developing B cells and that Hh pathway activation was increased in developing B cells from Gli3-deficient FLs...
May 22, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28526760/tissue-resident-t-cells-in-hepatitis-b-a-new-target-for-cure
#5
Fabian J Bolte, Barbara Rehermann
A hallmark of chronic hepatitis B virus (HBV) infection is the functional impairment and depletion of antiviral T cells. In this issue of JEM, Pallett et al. (https://doi.org/10.1084/jem.20162115) identify a reservoir of functional HBV-specific T cells among liver-resident T cells.
May 19, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28526759/il-2-high-tissue-resident-t-cells-in-the-human-liver-sentinels-for-hepatotropic-infection
#6
Laura J Pallett, Jessica Davies, Emily J Colbeck, Francis Robertson, Navjyot Hansi, Nicholas J W Easom, Alice R Burton, Kerstin A Stegmann, Anna Schurich, Leo Swadling, Upkar S Gill, Victoria Male, TuVinh Luong, Amir Gander, Brian R Davidson, Patrick T F Kennedy, Mala K Maini
The liver provides a tolerogenic immune niche exploited by several highly prevalent pathogens as well as by primary and metastatic tumors. We have sampled healthy and hepatitis B virus (HBV)-infected human livers to probe for a subset of T cells specialized to overcome local constraints and mediate immunity. We characterize a population of T-bet(lo)Eomes(lo)Blimp-1(hi)Hobit(lo) T cells found within the intrahepatic but not the circulating memory CD8 T cell pool expressing liver-homing/retention markers (CD69(+)CD103(+) CXCR6(+)CXCR3(+))...
May 19, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28522685/correction-self-reactive-vh4-34-expressing-igg-b-cells-recognize-commensal-bacteria
#7
Jean-Nicolas Schickel, Salomé Glauzy, Yen-Shing Ng, Nicolas Chamberlain, Christopher Massad, Isabelle Isnardi, Nathan Katz, Gulbu Uzel, Steven M Holland, Capucine Picard, Anne Puel, Jean-Laurent Casanova, Eric Meffre
No abstract text is available yet for this article.
May 18, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28515075/pigr-and-pecam-1-bind-to-pneumococcal-adhesins-rrga-and-pspc-mediating-bacterial-brain-invasion
#8
Federico Iovino, Joo-Yeon Engelen-Lee, Matthijs Brouwer, Diederik van de Beek, Arie van der Ende, Merche Valls Seron, Peter Mellroth, Sandra Muschiol, Jan Bergstrand, Jerker Widengren, Birgitta Henriques-Normark
Streptococcus pneumoniae is the main cause of bacterial meningitis, a life-threating disease with a high case fatality rate despite treatment with antibiotics. Pneumococci cause meningitis by invading the blood and penetrating the blood-brain barrier (BBB). Using stimulated emission depletion (STED) super-resolution microscopy of brain biopsies from patients who died of pneumococcal meningitis, we observe that pneumococci colocalize with the two BBB endothelial receptors: polymeric immunoglobulin receptor (pIgR) and platelet endothelial cell adhesion molecule (PECAM-1)...
May 17, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28515074/immune-checkpoints-on-innate-lymphoid-cells
#9
Laura Chiossone, Eric Vivier
In this issue of JEM, Taylor et al. (https://doi.org/10.1084/jem.20161653) describe PD-1 as a critical negative regulator of group 2 innate lymphoid cells (ILC-2s). PD-1 intrinsically controls proliferation and cytokine production of both mouse and human ILC-2s. PD-1 signaling inhibits STAT5 phosphorylation and the removal of this brake by knocking down PD-1 expression or by using anti-PD-1 blocking antibodies, translated in vivo into better clearance of helminth worm infection in mice.
May 17, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28512157/il-22bp-dictates-characteristics-of-peyer-s-patch-follicle-associated-epithelium-for-antigen-uptake
#10
Toshi Jinnohara, Takashi Kanaya, Koji Hase, Sayuri Sakakibara, Tamotsu Kato, Naoko Tachibana, Takaharu Sasaki, Yusuke Hashimoto, Toshiro Sato, Hiroshi Watarai, Jun Kunisawa, Naoko Shibata, Ifor R Williams, Hiroshi Kiyono, Hiroshi Ohno
Interleukin-22 (IL-22) acts protectively and harmfully on intestinal tissue depending on the situation; therefore, IL-22 signaling needs to be tightly regulated. IL-22 binding protein (IL-22BP) binds IL-22 to inhibit IL-22 signaling. It is expressed in intestinal and lymphoid tissues, although its precise distribution and roles have remained unclear. In this study, we show that IL-22BP is highly expressed by CD11b(+)CD8α(-) dendritic cells in the subepithelial dome region of Peyer's patches (PPs). We found that IL-22BP blocks IL-22 signaling in the follicle-associated epithelium (FAE) covering PPs, indicating that IL-22BP plays a role in regulating the characteristics of the FAE...
May 16, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28507062/interleukin-4-promotes-the-development-of-ex-foxp3-th2-cells-during-immunity-to-intestinal-helminths
#11
Victoria S Pelly, Stephanie M Coomes, Yashaswini Kannan, Manolis Gialitakis, Lewis J Entwistle, Jimena Perez-Lloret, Stephanie Czieso, Isobel S Okoye, Dominik Rückerl, Judith E Allen, Frank Brombacher, Mark S Wilson
Immunity to intestinal helminth infections requires the rapid activation of T helper 2 cells (Th2 cells). However, simultaneous expansion of CD4(+)Foxp3(+) regulatory T cells (T reg cells) impedes protective responses, resulting in chronic infections. The ratio between T reg and effector T cells can therefore determine the outcome of infection. The redifferentiation of T reg cells into Th cells has been identified in hyperinflammatory diseases. In this study, we asked whether ex-T reg Th2 cells develop and contribute to type-2 immunity...
May 15, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28507061/rnf8-mediates-histone-h3-ubiquitylation-and-promotes-glycolysis-and-tumorigenesis
#12
Yan Xia, Weiwei Yang, Ming Fa, Xinjian Li, Yugang Wang, Yuhui Jiang, Yanhua Zheng, Jong-Ho Lee, Jing Li, Zhimin Lu
Disassembly of nucleosomes in which genomic DNA is packaged with histone regulates gene expression. However, the mechanisms underlying nucleosome disassembly for gene expression remain elusive. We show here that epidermal growth factor receptor activation results in the binding of the RNF8 forkhead-associated domain to pyruvate kinase M2-phosphorylated histone H3-T11, leading to K48-linked polyubiquitylation of histone H3 at K4 and subsequent proteasome-dependent protein degradation. In addition, H3 polyubiquitylation induces histone dissociation from chromatin, nucleosome disassembly, and binding of RNA polymerase II to MYC and CCND1 promoter regions for transcription...
May 15, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28500047/self-reactive-vh4-34-expressing-igg-b-cells-recognize-commensal-bacteria
#13
Jean-Nicolas Schickel, Salomé Glauzy, Yen-Shing Ng, Nicolas Chamberlain, Christopher Massad, Isabelle Isnardi, Nathan Katz, Gulbu Uzel, Steven M Holland, Capucine Picard, Anne Puel, Jean-Laurent Casanova, Eric Meffre
The germline immunoglobulin (Ig) variable heavy chain 4-34 (VH4-34) gene segment encodes in humans intrinsically self-reactive antibodies that recognize I/i carbohydrates expressed by erythrocytes with a specific motif in their framework region 1 (FWR1). VH4-34-expressing clones are common in the naive B cell repertoire but are rarely found in IgG memory B cells from healthy individuals. In contrast, CD27(+)IgG(+) B cells from patients genetically deficient for IRAK4 or MYD88, which mediate the function of Toll-like receptors (TLRs) except TLR3, contained VH4-34-expressing clones and showed decreased somatic hypermutation frequencies...
May 12, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28490441/pd-1-regulates-klrg1-group-2-innate-lymphoid-cells
#14
Samuel Taylor, Yuefeng Huang, Grace Mallett, Chaido Stathopoulou, Tania C Felizardo, Ming-An Sun, Evelyn L Martin, Nathaniel Zhu, Emma L Woodward, Martina S Elias, Jonathan Scott, Nick J Reynolds, William E Paul, Daniel H Fowler, Shoba Amarnath
Group 2 innate lymphoid cells (ILC-2s) regulate immune responses to pathogens and maintain tissue homeostasis in response to cytokines. Positive regulation of ILC-2s through ICOS has been recently elucidated. We demonstrate here that PD-1 is an important negative regulator of KLRG1(+) ILC-2 function in both mice and humans. Increase in KLRG1(+) ILC-2 cell numbers was attributed to an intrinsic defect in PD-1 signaling, which resulted in enhanced STAT5 activation. During Nippostrongylus brasiliensis infection, a significant expansion of KLRG1(+) ILC-2 subsets occurred in Pdcd1(-/-) mice and, upon adoptive transfer, Pdcd1(-/-) KLRG1(+) ILC-2s significantly reduced worm burden...
May 10, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28490440/human-memory-cd8-t-cell-effector-potential-is-epigenetically-preserved-during-in-vivo-homeostasis
#15
Hossam A Abdelsamed, Ardiana Moustaki, Yiping Fan, Pranay Dogra, Hazem E Ghoneim, Caitlin C Zebley, Brandon M Triplett, Rafick-Pierre Sekaly, Ben Youngblood
Antigen-independent homeostasis of memory CD8 T cells is vital for sustaining long-lived T cell-mediated immunity. In this study, we report that maintenance of human memory CD8 T cell effector potential during in vitro and in vivo homeostatic proliferation is coupled to preservation of acquired DNA methylation programs. Whole-genome bisulfite sequencing of primary human naive, short-lived effector memory (TEM), and longer-lived central memory (TCM) and stem cell memory (TSCM) CD8 T cells identified effector molecules with demethylated promoters and poised for expression...
May 10, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28487311/egr2-and-3-control-adaptive-immune-responses-by-temporally-uncoupling-expansion-from-t-cell-differentiation
#16
Tizong Miao, Alistair L J Symonds, Randeep Singh, Janine D Symonds, Ane Ogbe, Becky Omodho, Bo Zhu, Suling Li, Ping Wang
Egr2 and 3 are important for maintaining immune homeostasis. Here we define a fundamental function of Egr2 and 3 operating as a checkpoint that controls the transition between clonal expansion and differentiation of effector T cells. Egr2 and 3 deficiency resulted in defective clonal expansion but hyperactivation and excessive differentiation of T cells in response to viral infection. Conversely, sustained Egr2 expression enhanced expansion but severely impaired effector differentiation. Egr2 bound to and controlled the expression of genes regulating proliferation (Myc and Myb) and differentiation repressors (Bcl6, Id3), while repressing transcription factors required for effector function (Zeb2, RORa, RORc, and Bhlhe40)...
May 9, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28487310/myeloid-derived-mir-223-regulates-intestinal-inflammation-via-repression-of-the-nlrp3-inflammasome
#17
Viola Neudecker, Moritz Haneklaus, Owen Jensen, Ludmila Khailova, Joanne C Masterson, Hazel Tye, Kathryn Biette, Paul Jedlicka, Kelley S Brodsky, Mark E Gerich, Matthias Mack, Avril A B Robertson, Matthew A Cooper, Glenn T Furuta, Charles A Dinarello, Luke A O'Neill, Holger K Eltzschig, Seth L Masters, Eóin N McNamee
MicroRNA (miRNA)-mediated RNA interference regulates many immune processes, but how miRNA circuits orchestrate aberrant intestinal inflammation during inflammatory bowel disease (IBD) is poorly defined. Here, we report that miR-223 limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223 was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. miR-223(-/y) mice presented with exacerbated myeloid-driven experimental colitis with heightened clinical, histopathological, and cytokine readouts...
May 9, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28484079/intrinsic-antiproliferative-activity-of-the-innate-sensor-sting-in-t-lymphocytes
#18
Silvia Cerboni, Nadia Jeremiah, Matteo Gentili, Ulf Gehrmann, Cécile Conrad, Marie-Claude Stolzenberg, Capucine Picard, Bénédicte Neven, Alain Fischer, Sébastian Amigorena, Frédéric Rieux-Laucat, Nicolas Manel
Activation of the cyclic dinucleotide sensor stimulator of interferon (IFN) genes (STING) is critical for IFN and inflammatory gene expression during innate immune responses. However, the role of STING in adaptive immunity is still unknown. In this study, we show that STING activation reduces the proliferation of T lymphocytes. This activity was independent of TBK1 and IRF3 recruitment and of type I IFN but required a distinct C-terminal domain of STING that activates NF-κB. Inhibition of cell proliferation by STING required its relocalization to the Golgi apparatus and caused mitotic errors...
May 8, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28484078/androgen-signaling-negatively-controls-group-2-innate-lymphoid-cells
#19
Sophie Laffont, Eve Blanquart, Magali Savignac, Claire Cénac, Gilles Laverny, Daniel Metzger, Jean-Philippe Girard, Gabrielle T Belz, Lucette Pelletier, Cyril Seillet, Jean-Charles Guéry
Prevalence of asthma is higher in women than in men, but the mechanisms underlying this sex bias are unknown. Group 2 innate lymphoid cells (ILC2s) are key regulators of type 2 inflammatory responses. Here, we show that ILC2 development is greatly influenced by male sex hormones. Male mice have reduced numbers of ILC2 progenitors (ILC2Ps) and mature ILC2s in peripheral tissues compared with females. In consequence, males exhibit reduced susceptibility to allergic airway inflammation in response to environmental allergens and less severe IL-33-driven lung inflammation, correlating with an impaired expansion of lung ILC2s...
May 8, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28476895/regression-of-apoptosis-resistant-colorectal-tumors-by-induction-of-necroptosis-in-mice
#20
Gui-Wei He, Claudia Günther, Veronika Thonn, Yu-Qiang Yu, Eva Martini, Barbara Buchen, Markus F Neurath, Michael Stürzl, Christoph Becker
Cancer cells often acquire capabilities to evade cell death induced by current chemotherapeutic treatment approaches. Caspase-8, a central initiator of death receptor-mediated apoptosis, for example, is frequently inactivated in human cancers via multiple mechanisms such as mutation. Here, we show an approach to overcome cell death resistance in caspase-8-deficient colorectal cancer (CRC) by induction of necroptosis. In both a hereditary and a xenograft mouse model of caspase-8-deficient CRC, second mitochondria-derived activator of caspase (SMAC) mimetic treatment induced massive cell death and led to regression of tumors...
May 5, 2017: Journal of Experimental Medicine
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