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Journal of Experimental Medicine

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https://www.readbyqxmd.com/read/28432200/tissue-adaptation-implications-for-gut-immunity-and-tolerance
#1
REVIEW
Ana M C Faria, Bernardo S Reis, Daniel Mucida
Tissue adaptation is an intrinsic component of immune cell development, influencing both resistance to pathogens and tolerance. Chronically stimulated surfaces of the body, in particular the gut mucosa, are the major sites where immune cells traffic and reside. Their adaptation to these environments requires constant discrimination between natural stimulation coming from harmless microbiota and food, and pathogens that need to be cleared. This review will focus on the adaptation of lymphocytes to the gut mucosa, a highly specialized environment that can help us understand the plasticity of leukocytes arriving at various tissue sites and how tissue-related factors operate to shape immune cell fate and function...
April 21, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28432199/phagocytosis-imprints-heterogeneity-in-tissue-resident-macrophages
#2
Noelia A-Gonzalez, Juan A Quintana, Susana García-Silva, Marina Mazariegos, Arturo González de la Aleja, José A Nicolás-Ávila, Wencke Walter, Jose M Adrover, Georgiana Crainiciuc, Vijay K Kuchroo, Carla V Rothlin, Héctor Peinado, Antonio Castrillo, Mercedes Ricote, Andrés Hidalgo
Tissue-resident macrophages display varying phenotypic and functional properties that are largely specified by their local environment. One of these functions, phagocytosis, mediates the natural disposal of billions of cells, but its mechanisms and consequences within living tissues are poorly defined. Using a parabiosis-based strategy, we identified and isolated macrophages from multiple tissues as they phagocytosed blood-borne cellular material. Phagocytosis was circadianally regulated and mediated by distinct repertoires of receptors, opsonins, and transcription factors in macrophages from each tissue...
April 21, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28428203/tslp-activated-dendritic-cells-induce-human-t-follicular-helper-cell-differentiation-through-ox40-ligand
#3
Lucia Pattarini, Coline Trichot, Sofia Bogiatzi, Maximilien Grandclaudon, Stephan Meller, Zela Keuylian, Melanie Durand, Elisabetta Volpe, Stefania Madonna, Andrea Cavani, Andrea Chiricozzi, Marco Romanelli, Toshiyuki Hori, Alain Hovnanian, Bernhard Homey, Vassili Soumelis
T follicular helper cells (Tfh) are important regulators of humoral responses. Human Tfh polarization pathways have been thus far associated with Th1 and Th17 polarization pathways. How human Tfh cells differentiate in Th2-skewed environments is unknown. We show that thymic stromal lymphopoietin (TSLP)-activated dendritic cells (DCs) promote human Tfh differentiation from naive CD4 T cells. We identified a novel population, distinct from Th2 cells, expressing IL-21 and TNF, suggestive of inflammatory cells...
April 20, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28424248/splenic-ly6g-high-mature-and-ly6g-int-immature-neutrophils-contribute-to-eradication-of-s-pneumoniae
#4
Justin F Deniset, Bas G Surewaard, Woo-Yong Lee, Paul Kubes
The spleen plays an integral protective role against encapsulated bacterial infections. Our understanding of the associated mechanisms is limited to thymus-independent (TI) antibody production by the marginal zone (MZ) B cells, leaving the contribution of other splenic compartments such as the red pulp (RP) largely unexplored despite asplenic patients succumbing to the infection in the first 24 h, suggesting important antibody-independent mechanisms. In this study, using time-lapse intravital imaging of the spleen, we identify a tropism for Streptococcus pneumoniae in this organ mediated by tissue-resident MZ and RP macrophages and a protective role for two distinct splenic neutrophil populations (Ly6G(hi) and Ly6G(intermediate)) residing in the splenic RP...
April 19, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28424247/location-in-the-spleen-dictates-the-function-of-murine-neutrophils
#5
Patrizia Scapini, Marco A Cassatella
In this issue of JEM, Deniset et al. (https://doi.org/10.1084/jem.20161621) provide new data that extend our knowledge on the mechanisms whereby Streptococcus pneumoniae is cleared by the spleen. The authors identify novel populations of murine splenic neutrophils that localize in the red pulp and the marginal zone. During the acute phases of S. pneumoniae infection, these populations of splenic neutrophils act in concert with specialized macrophage and B cell populations to provide very rapid innate immune protection...
April 19, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28424246/enteropathy-associated-t-cell-lymphoma-subtypes-are-characterized-by-loss-of-function-of-setd2
#6
Andrea B Moffitt, Sarah L Ondrejka, Matthew McKinney, Rachel E Rempel, John R Goodlad, Chun Huat Teh, Sirpa Leppa, Susanna Mannisto, Panu E Kovanen, Eric Tse, Rex K H Au-Yeung, Yok-Lam Kwong, Gopesh Srivastava, Javeed Iqbal, Jiayu Yu, Kikkeri Naresh, Diego Villa, Randy D Gascoyne, Jonathan Said, Magdalena B Czader, Amy Chadburn, Kristy L Richards, Deepthi Rajagopalan, Nicholas S Davis, Eileen C Smith, Brooke C Palus, Tiffany J Tzeng, Jane A Healy, Patricia L Lugar, Jyotishka Datta, Cassandra Love, Shawn Levy, David B Dunson, Yuan Zhuang, Eric D Hsi, Sandeep S Dave
Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1, JAK3, STAT3, and SOCS1 We also identified mutations in KRAS, TP53, and TERT Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis...
April 19, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28420735/correction-the-soluble-pattern-recognition-receptor-ptx3-links-humoral-innate-and-adaptive-immune-responses-by-helping-marginal-zone-b-cells
#7
Alejo Chorny, Sandra Casas-Recasens, Jordi Sintes, Meimei Shan, Nadia Polentarutti, Ramón García-Escudero, A Cooper Walland, John R Yeiser, Linda Cassis, Jorge Carrillo, Irene Puga, Cristina Cunha, Hélder Bastos, Fernando Rodrigues, João F Lacerda, António Morais, Rebeca Dieguez-Gonzalez, Peter S Heeger, Giovanni Salvatori, Agostinho Carvalho, Adolfo Garcia-Sastre, J Magarian Blander, Alberto Mantovani, Cecilia Garlanda, Andrea Cerutti
No abstract text is available yet for this article.
April 18, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28420734/mink1-the-missing-link-between-ros-and-its-inhibition-of-th17-cells
#8
Gustavo J Martinez
In this issue of JEM, Fu et al. (https://doi.org/10.1084/jem.20161120) identified the kinase Mink1 as a novel negative regulator of Th17 cell generation. Mink1, activated by reactive oxygen species (ROS), prevents TGF-β activation of Smad2, therefore limiting Th17 cell differentiation.
April 18, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28420733/detection-of-interferon-alpha-protein-reveals-differential-levels-and-cellular-sources-in-disease
#9
Mathieu P Rodero, Jérémie Decalf, Vincent Bondet, David Hunt, Gillian I Rice, Scott Werneke, Sarah L McGlasson, Marie-Alexandra Alyanakian, Brigitte Bader-Meunier, Christine Barnerias, Nathalia Bellon, Alexandre Belot, Christine Bodemer, Tracy A Briggs, Isabelle Desguerre, Marie-Louise Frémond, Marie Hully, Arn M J M van den Maagdenberg, Isabelle Melki, Isabelle Meyts, Lucile Musset, Nadine Pelzer, Pierre Quartier, Gisela M Terwindt, Joanna Wardlaw, Stewart Wiseman, Frédéric Rieux-Laucat, Yoann Rose, Bénédicte Neven, Christina Hertel, Adrian Hayday, Matthew L Albert, Flore Rozenberg, Yanick J Crow, Darragh Duffy
Type I interferons (IFNs) are essential mediators of antiviral responses. These cytokines have been implicated in the pathogenesis of autoimmunity, most notably systemic lupus erythematosus (SLE), diabetes mellitus, and dermatomyositis, as well as monogenic type I interferonopathies. Despite a fundamental role in health and disease, the direct quantification of type I IFNs has been challenging. Using single-molecule array (Simoa) digital ELISA technology, we recorded attomolar concentrations of IFNα in healthy donors, viral infection, and complex and monogenic interferonopathies...
April 18, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28416651/aav-mediated-expression-of-anti-tau-scfvs-decreases-tau-accumulation-in-a-mouse-model-of-tauopathy
#10
Christina Ising, Gilbert Gallardo, Cheryl E G Leyns, Connie H Wong, Floy Stewart, Lauren J Koscal, Joseph Roh, Grace O Robinson, Javier Remolina Serrano, David M Holtzman
Tauopathies are characterized by the progressive accumulation of hyperphosphorylated, aggregated forms of tau. Our laboratory has previously demonstrated that passive immunization with an anti-tau antibody, HJ8.5, decreased accumulation of pathological tau in a human P301S tau-expressing transgenic (P301S-tg) mouse model of frontotemporal dementia/tauopathy. To investigate whether the Fc domain of HJ8.5 is required for the therapeutic effect, we engineered single-chain variable fragments (scFvs) derived from HJ8...
April 17, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28416650/epigenetic-regulator-cxxc5-recruits-dna-demethylase-tet2-to-regulate-tlr7-9-elicited-ifn-response-in-pdcs
#11
Shixin Ma, Xiaoling Wan, Zihou Deng, Lei Shi, Congfang Hao, Zhenyuan Zhou, Chun Zhou, Yiyuan Fang, Jinghua Liu, Jing Yang, Xia Chen, Tiantian Li, Aiping Zang, Shigang Yin, Bin Li, Joel Plumas, Laurence Chaperot, Xiaoming Zhang, Guoliang Xu, Lubin Jiang, Nan Shen, Sidong Xiong, Xiaoming Gao, Yan Zhang, Hui Xiao
TLR7/9 signals are capable of mounting massive interferon (IFN) response in plasmacytoid dendritic cells (pDCs) immediately after viral infection, yet the involvement of epigenetic regulation in this process has not been documented. Here, we report that zinc finger CXXC family epigenetic regulator CXXC5 is highly expressed in pDCs, where it plays a crucial role in TLR7/9- and virus-induced IFN response. Notably, genetic ablation of CXXC5 resulted in aberrant methylation of the CpG-containing island (CGI) within the Irf7 gene and impaired IRF7 expression in steady-state pDCs...
April 17, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28416649/optic-nerve-astrocyte-reactivity-protects-function-in-experimental-glaucoma-and-other-nerve-injuries
#12
Daniel Sun, Sara Moore, Tatjana C Jakobs
Reactive remodeling of optic nerve head astrocytes is consistently observed in glaucoma and other optic nerve injuries. However, it is unknown whether this reactivity is beneficial or harmful for visual function. In this study, we used the Cre recombinase (Cre)-loxP system under regulation of the mouse glial fibrillary acidic protein promoter to knock out the transcription factor signal transducer and activator of transcription 3 (STAT3) from astrocytes and test the effect this has on reactive remodeling, ganglion cell survival, and visual function after experimental glaucoma and nerve crush...
April 17, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28408410/decreased-cohesin-in-the-brain-leads-to-defective-synapse-development-and-anxiety-related-behavior
#13
Yuki Fujita, Koji Masuda, Masashige Bando, Ryuichiro Nakato, Yuki Katou, Takashi Tanaka, Masahiro Nakayama, Keizo Takao, Tsuyoshi Miyakawa, Tatsunori Tanaka, Yukio Ago, Hitoshi Hashimoto, Katsuhiko Shirahige, Toshihide Yamashita
Abnormal epigenetic regulation can cause the nervous system to develop abnormally. Here, we sought to understand the mechanism by which this occurs by investigating the protein complex cohesin, which is considered to regulate gene expression and, when defective, is associated with higher-level brain dysfunction and the developmental disorder Cornelia de Lange syndrome (CdLS). We generated conditional Smc3-knockout mice and observed greater dendritic complexity and larger numbers of immature synapses in the cerebral cortex of Smc3(+/-) mice...
April 13, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28404595/nlr-members-nlrc4-and-nlrp3-mediate-sterile-inflammasome-activation-in-microglia-and-astrocytes
#14
Leslie Freeman, Haitao Guo, Clément N David, W June Brickey, Sushmita Jha, Jenny P-Y Ting
Inflammation in the brain accompanies several high-impact neurological diseases including multiple sclerosis (MS), stroke, and Alzheimer's disease. Neuroinflammation is sterile, as damage-associated molecular patterns rather than microbial pathogens elicit the response. The inflammasome, which leads to caspase-1 activation, is implicated in neuroinflammation. In this study, we reveal that lysophosphatidylcholine (LPC), a molecule associated with neurodegeneration and demyelination, elicits NLRP3 and NLRC4 inflammasome activation in microglia and astrocytes, which are central players in neuroinflammation...
April 12, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28400474/suppression-of-th17-cell-differentiation-by-misshapen-nik-related-kinase-mink1
#15
Guotong Fu, Qin Xu, Yuanjun Qiu, Xuexiao Jin, Ting Xu, Shunli Dong, Jianli Wang, Yuehai Ke, Hu Hu, Xuetao Cao, Di Wang, Harvey Cantor, Xiang Gao, Linrong Lu
T helper type 17 cells (Th17 cells) are major contributors to many autoimmune diseases. In this study, we demonstrate that the germinal center kinase family member MINK1 (misshapen/NIK-related kinase 1) negatively regulates Th17 cell differentiation. The suppressive effect of MINK1 on induction of Th17 cells is mediated by the inhibition of SMAD2 activation through direct phosphorylation of SMAD2 at the T324 residue. The importance of MINK1 to Th17 cell differentiation was strengthened in the animal model of experimental autoimmune encephalomyelitis (EAE)...
April 11, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28400473/tlr-sensing-of-bacterial-spore-associated-rna-triggers-host-immune-responses-with-detrimental-effects
#16
Min-Kyung Choo, Yasuyo Sano, Changhoon Kim, Kei Yasuda, Xiao-Dong Li, Xin Lin, Mary Stenzel-Poore, Lena Alexopoulou, Sankar Ghosh, Eicke Latz, Ian R Rifkin, Zhijian J Chen, George C Stewart, Hyonyong Chong, Jin Mo Park
The spores of pathogenic bacteria are involved in host entry and the initial encounter with the host immune system. How bacterial spores interact with host immunity, however, remains poorly understood. Here, we show that the spores of Bacillus anthracis (BA), the etiologic agent of anthrax, possess an intrinsic ability to induce host immune responses. This immunostimulatory activity is attributable to high amounts of RNA present in the spore surface layer. RNA-sensing TLRs, TLR7, and TLR13 in mice and their human counterparts, are responsible for detecting and triggering the host cell response to BA spores, whereas TLR2 mediates the sensing of vegetative BA...
April 11, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28396461/in-vivo-evasion-of-mxa-by-avian-influenza-viruses-requires-human-signature-in-the-viral-nucleoprotein
#17
Christoph M Deeg, Ebrahim Hassan, Pascal Mutz, Lara Rheinemann, Veronika Götz, Linda Magar, Mirjam Schilling, Carsten Kallfass, Cindy Nürnberger, Sébastien Soubies, Georg Kochs, Otto Haller, Martin Schwemmle, Peter Staeheli
Zoonotic transmission of influenza A viruses can give rise to devastating pandemics, but currently it is impossible to predict the pandemic potential of circulating avian influenza viruses. Here, we describe a new mouse model suitable for such risk assessment, based on the observation that the innate restriction factor MxA represents an effective species barrier that must be overcome by zoonotic viruses. Our mouse lacks functional endogenous Mx genes but instead carries the human MX1 locus as a transgene. Such transgenic mice were largely resistant to highly pathogenic avian H5 and H7 influenza A viruses, but were almost as susceptible to infection with influenza viruses of human origin as nontransgenic littermates...
April 10, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28389502/dc-subset-specific-induction-of-t-cell-responses-upon-antigen-uptake-via-fc%C3%AE-receptors-in-vivo
#18
Christian H K Lehmann, Anna Baranska, Gordon F Heidkamp, Lukas Heger, Kirsten Neubert, Jennifer J Lühr, Alana Hoffmann, Katharina C Reimer, Christin Brückner, Simone Beck, Michaela Seeling, Melissa Kießling, Didier Soulat, Anne B Krug, Jeffrey V Ravetch, Jeanette H W Leusen, Falk Nimmerjahn, Diana Dudziak
Dendritic cells (DCs) are efficient antigen-presenting cells equipped with various cell surface receptors for the direct or indirect recognition of pathogenic microorganisms. Interestingly, not much is known about the specific expression pattern and function of the individual activating and inhibitory Fcγ receptors (FcγRs) on splenic DC subsets in vivo and how they contribute to the initiation of T cell responses. By targeting antigens to select activating and the inhibitory FcγR in vivo, we show that antigen uptake under steady-state conditions results in a short-term expansion of antigen-specific T cells, whereas under inflammatory conditions especially, the activating FcγRIV is able to induce superior CD4(+) and CD8(+) T cell responses...
April 7, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28385925/neutrophil-myeloperoxidase-diminishes-the-toxic-effects-and-mortality-induced-by-lipopolysaccharide
#19
Laurent L Reber, Caitlin M Gillis, Philipp Starkl, Friederike Jönsson, Riccardo Sibilano, Thomas Marichal, Nicolas Gaudenzio, Marion Bérard, Stephan Rogalla, Christopher H Contag, Pierre Bruhns, Stephen J Galli
Neutrophils have crucial antimicrobial functions but are also thought to contribute to tissue injury upon exposure to bacterial products, such as lipopolysaccharide (LPS). To study the role of neutrophils in LPS-induced endotoxemia, we developed a new mouse model, PMN(DTR) mice, in which injection of diphtheria toxin induces selective neutrophil ablation. Using this model, we found, surprisingly, that neutrophils serve to protect the host from LPS-induced lethal inflammation. This protective role was observed in conventional and germ-free animal facilities, indicating that it does not depend on a particular microbiological environment...
April 6, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28363897/differentiation-of-germinal-center-b-cells-into-plasma-cells-is-initiated-by-high-affinity-antigen-and-completed-by-tfh-cells
#20
Nike J Kräutler, Dan Suan, Danyal Butt, Katherine Bourne, Jana R Hermes, Tyani D Chan, Christopher Sundling, Warren Kaplan, Peter Schofield, Jennifer Jackson, Antony Basten, Daniel Christ, Robert Brink
Plasma cells (PCs) derived from germinal centers (GCs) secrete the high-affinity antibodies required for long-term serological immunity. Nevertheless, the process whereby GC B cells differentiate into PCs is uncharacterized, and the mechanism underlying the selective PC differentiation of only high-affinity GC B cells remains unknown. In this study, we show that differentiation into PCs is induced among a discrete subset of high-affinity B cells residing within the light zone of the GC. Initiation of differentiation required signals delivered upon engagement with intact antigen...
March 31, 2017: Journal of Experimental Medicine
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