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https://www.readbyqxmd.com/read/28319730/deconstructing-the-germinal-center-one-cell-at-a-time
#1
REVIEW
Chad R Dufaud, Louise J McHeyzer-Williams, Michael G McHeyzer-Williams
Successful vaccination relies on driving the immune response towards high specificity, affinity and longevity. Germinal centers facilitate the evolution of antigen-specific B cells by iterative rounds of diversification, selection, and differentiation to memory and plasma cells. Experimental evidence points to B cell receptor affinity and amount of antigen presented to follicular helper T cells as main drivers of clonal evolution. Concurrent studies suggest that modifiers of cognate contact, temporal mechanisms, and stochastic factors can also shape diversity and influence differentiation to memory and plasma cells, but molecular pathways driving these selection decisions are unresolved...
March 17, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28303891/il-21-restricts-t-follicular-regulatory-t-cell-proliferation-through-bcl-6-mediated-inhibition-of-responsiveness-to-il-2
#2
Christoph Jandl, Sue M Liu, Pablo F Cañete, Joanna Warren, William E Hughes, Alexis Vogelzang, Kylie Webster, Maria E Craig, Gulbu Uzel, Alexander Dent, Polina Stepensky, Bärbel Keller, Klaus Warnatz, Jonathan Sprent, Cecile King
T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3(+) regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization...
March 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28303660/brazilin-inhibits-prostatic-acidic-phosphatase-fibrillogenesis-and-reduces-its-cytotoxicity
#3
Ming Li, Xiaoyan Dong, Yang Liu, Yan Sun
The 39-amino acid peptide fragment derived from prostatic acidic phosphatase (PAP), PAP248-286, is secreted in large amount into human semen and form amyloid fibrils. The fibrils can capture HIV virions and increase the attachment of virions to target cells, so they are called semen-derived enhancer of virus infection (SEVI). Therefore, it is of significance to inhibit the formation of PAP248-286 amyloid fibrils. Herein, we have demonstrated that brazilin could effectively inhibit PAP248-286 aggregation. The inhibition effect increased with increasing brazilin concentration...
March 16, 2017: Chemistry, An Asian Journal
https://www.readbyqxmd.com/read/28302091/development-of-a-test-that-measures-real-time-her2-signaling-function-in-live-breast-cancer-cell-lines-and-primary-cells
#4
Yao Huang, David J Burns, Benjamin E Rich, Ian A MacNeil, Abhijit Dandapat, Sajjad M Soltani, Samantha Myhre, Brian F Sullivan, Carol A Lange, Leo T Furcht, Lance G Laing
BACKGROUND: Approximately 18-20% of all human breast cancers have overexpressed human epidermal growth factor receptor 2 (HER2). Standard clinical practice is to treat only overexpressed HER2 (HER2+) cancers with targeted anti-HER2 therapies. However, recent analyses of clinical trial data have found evidence that HER2-targeted therapies may benefit a sub-group of breast cancer patients with non-overexpressed HER2. This suggests that measurement of other biological factors associated with HER2 cancer, such as HER2 signaling pathway activity, should be considered as an alternative means of identifying patients eligible for HER2 therapies...
March 16, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28298421/mimicry-of-an-hiv-broadly-neutralizing-antibody-epitope-with-a-synthetic-glycopeptide
#5
S Munir Alam, Baptiste Aussedat, Yusuf Vohra, R Ryan Meyerhoff, Evan M Cale, William E Walkowicz, Nathan A Radakovich, Kara Anasti, Lawrence Armand, Robert Parks, Laura Sutherland, Richard Scearce, M Gordon Joyce, Marie Pancera, Aliaksandr Druz, Ivelin S Georgiev, Tarra Von Holle, Amanda Eaton, Christopher Fox, Steven G Reed, Mark Louder, Robert T Bailer, Lynn Morris, Salim S Abdool-Karim, Myron Cohen, Hua-Xin Liao, David C Montefiori, Peter K Park, Alberto Fernández-Tejada, Kevin Wiehe, Sampa Santra, Thomas B Kepler, Kevin O Saunders, Joseph Sodroski, Peter D Kwong, John R Mascola, Mattia Bonsignori, M Anthony Moody, Samuel Danishefsky, Barton F Haynes
A goal for an HIV-1 vaccine is to overcome virus variability by inducing broadly neutralizing antibodies (bnAbs). One key target of bnAbs is the glycan-polypeptide at the base of the envelope (Env) third variable loop (V3). We have designed and synthesized a homogeneous minimal immunogen with high-mannose glycans reflective of a native Env V3-glycan bnAb epitope (Man9-V3). V3-glycan bnAbs bound to Man9-V3 glycopeptide and native-like gp140 trimers with similar affinities. Fluorophore-labeled Man9-V3 glycopeptides bound to bnAb memory B cells and were able to be used to isolate a V3-glycan bnAb from an HIV-1-infected individual...
March 15, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28298420/staged-induction-of-hiv-1-glycan-dependent-broadly-neutralizing-antibodies
#6
Mattia Bonsignori, Edward F Kreider, Daniela Fera, R Ryan Meyerhoff, Todd Bradley, Kevin Wiehe, S Munir Alam, Baptiste Aussedat, William E Walkowicz, Kwan-Ki Hwang, Kevin O Saunders, Ruijun Zhang, Morgan A Gladden, Anthony Monroe, Amit Kumar, Shi-Mao Xia, Melissa Cooper, Mark K Louder, Krisha McKee, Robert T Bailer, Brendan W Pier, Claudia A Jette, Garnett Kelsoe, Wilton B Williams, Lynn Morris, John Kappes, Kshitij Wagh, Gift Kamanga, Myron S Cohen, Peter T Hraber, David C Montefiori, Ashley Trama, Hua-Xin Liao, Thomas B Kepler, M Anthony Moody, Feng Gao, Samuel J Danishefsky, John R Mascola, George M Shaw, Beatrice H Hahn, Stephen C Harrison, Bette T Korber, Barton F Haynes
A preventive HIV-1 vaccine should induce HIV-1-specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site adjacent to the third variable loop (V3) of the HIV-1 envelope protein require limited SHM, the V3-glycan epitope is an attractive vaccine target. By studying the cooperation among multiple V3-glycan B cell lineages and their coevolution with autologous virus throughout 5 years of infection, we identify key events in the ontogeny of a V3-glycan bnAb...
March 15, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28297712/cd32a-is-a-marker-of-a-cd4-t-cell-hiv-reservoir-harbouring-replication-competent-proviruses
#7
Benjamin Descours, Gaël Petitjean, José-Luis López-Zaragoza, Timothée Bruel, Raoul Raffel, Christina Psomas, Jacques Reynes, Christine Lacabaratz, Yves Levy, Olivier Schwartz, Jean Daniel Lelievre, Monsef Benkirane
The persistence of the HIV reservoir in infected individuals is a major obstacle to the development of a cure for HIV. Here, using an in vitro model of HIV-infected quiescent CD4 T cells, we reveal a gene expression signature of 103 upregulated genes that are specific for latently infected cells, including genes for 16 transmembrane proteins. In vitro screening for surface expression in HIV-infected quiescent CD4 T cells shows that the low-affinity receptor for the immunoglobulin G Fc fragment, CD32a, is the most highly induced, with no detectable expression in bystander cells...
March 15, 2017: Nature
https://www.readbyqxmd.com/read/28297661/t-follicular-helper-cells-promote-a-beneficial-gut-ecosystem-for-host-metabolic-homeostasis-by-sensing-microbiota-derived-extracellular-atp
#8
Lisa Perruzza, Giorgio Gargari, Michele Proietti, Bruno Fosso, Anna Maria D'Erchia, Caterina Elisa Faliti, Tanja Rezzonico-Jost, Daniela Scribano, Laura Mauri, Diego Colombo, Giovanni Pellegrini, Annalisa Moregola, Catherine Mooser, Graziano Pesole, Mauro Nicoletti, Giuseppe Danilo Norata, Markus B Geuking, Kathy D McCoy, Simone Guglielmetti, Fabio Grassi
The ATP-gated ionotropic P2X7 receptor regulates T follicular helper (Tfh) cell abundance in the Peyer's patches (PPs) of the small intestine; deletion of P2rx7, encoding for P2X7, in Tfh cells results in enhanced IgA secretion and binding to commensal bacteria. Here, we show that Tfh cell activity is important for generating a diverse bacterial community in the gut and that sensing of microbiota-derived extracellular ATP via P2X7 promotes the generation of a proficient gut ecosystem for metabolic homeostasis...
March 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/28293238/role-of-memory-t-cells-in-allograft-rejection-and-tolerance
#9
REVIEW
Gilles Benichou, Bruno Gonzalez, Jose Marino, Katayoun Ayasoufi, Anna Valujskikh
Memory T cells are characterized by their low activation threshold, robust effector functions, and resistance to conventional immunosuppression and costimulation blockade. Unlike their naïve counterparts, memory T cells reside in and recirculate through peripheral non-lymphoid tissues. Alloreactive memory T cells are subdivided into different categories based on their origins, phenotypes, and functions. Recipients whose immune systems have been directly exposed to allogeneic major histocompatibility complex (MHC) molecules display high affinity alloreactive memory T cells...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28293236/interferon-lambda-modulating-immunity-in-infectious-diseases
#10
REVIEW
Mohammedyaseen Syedbasha, Adrian Egli
Interferon lambdas (IFN-λs; IFNL1-4) modulate immunity in the context of infections and autoimmune diseases, through a network of induced genes. IFN-λs act by binding to the heterodimeric IFN-λ receptor (IFNLR), activating a STAT phosphorylation-dependent signaling cascade. Thereby hundreds of IFN-stimulated genes are induced, which modulate various immune functions via complex forward and feedback loops. When compared to the well-characterized IFN-α signaling cascade, three important differences have been discovered...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28293233/the-soil-bacterium-methylococcus-capsulatus-bath-interacts-with-human-dendritic-cells-to-modulate-immune-function
#11
Stine Indrelid, Charlotte Kleiveland, René Holst, Morten Jacobsen, Tor Lea
The prevalence of inflammatory bowel disease (IBD) has increased in Western countries during the course of the twentieth century, and is evolving to be a global disease. Recently we showed that a bacterial meal of a non-commensal, non-pathogenic methanotrophic soil bacterium, Methylococcus capsulatus Bath prevents experimentally induced colitis in a murine model of IBD. The mechanism behind the effect has this far not been identified. Here, for the first time we show that M. capsulatus, a soil bacterium adheres specifically to human dendritic cells, influencing DC maturation, cytokine production, and subsequent T cell activation, proliferation and differentiation...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28290809/-role-of-autoantibodies-against-1-adrenergic-receptor-in-cardiovascular-disease
#12
M V Kostyukevich, K A Zykov, N A Mironova, O Y Agapova, A Y Shevelev, E E Efremov, T N Vlasik, S P Golitsyn
According to current knowledge, autoantibodies against 1-adrenergic receptors may be involved in pathogenesis of different cardiovascular diseases and are mostly studied in patients with Chagas disease, dilated cardiomyopathy and heart rhythm disorders. They may play an important role in cardiomyocyte apoptosis, alteration of their chrono- and inotropic effects and electrophysiological characteristics. Their effects are transduced via 1-adrenergic receptors and depend on multiple factors as ligand properties, durability of its coupling with the receptor, amount of receptors on the cell surface, their affinity and conformation...
December 2016: Kardiologiia
https://www.readbyqxmd.com/read/28289210/phosphorylation-induced-conformational-dynamics-in-an-intrinsically-disordered-protein-and-potential-role-in-phenotypic-heterogeneity
#13
Prakash Kulkarni, Mohit Kumar Jolly, Dongya Jia, Steven M Mooney, Ajay Bhargava, Luciane T Kagohara, Yihong Chen, Pengyu Hao, Yanan He, Robert W Veltri, Alexander Grishaev, Keith Weninger, Herbert Levine, John Orban
Intrinsically disordered proteins (IDPs) that lack a unique 3D structure and comprise a large fraction of the human proteome play important roles in numerous cellular functions. Prostate-Associated Gene 4 (PAGE4) is an IDP that acts as a potentiator of the Activator Protein-1 (AP-1) transcription factor. Homeodomain-Interacting Protein Kinase 1 (HIPK1) phosphorylates PAGE4 at S9 and T51, but only T51 is critical for its activity. Here, we identify a second kinase, CDC-Like Kinase 2 (CLK2), which acts on PAGE4 and hyperphosphorylates it at multiple S/T residues, including S9 and T51...
March 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28287730/discovery-of-n-3r-4r-4-fluoro-1-6-3-methoxy-1-methyl-1h-pyrazol-4-yl-amino-9-methyl-9h-purin-2-yl-pyrrolidine-3-yl-acrylamide-pf-06747775-through-structure-based-drug-design-a-high-affinity-irreversible-inhibitor-targeting-oncogenic-egfr-mutants-with-selectivity
#14
Simon Planken, Douglas Carl Behenna, Sajiv K Nair, Theodore Otto Johnson, Asako Nagata, Chau Almaden, Simon Bailey, T Eric Ballard, Louise Bernier, Hengmiao Cheng, Sujin Cho-Schultz, Deepak Dalvie, Judith G Deal, Dac M Dinh, Martin P Edwards, Rose Ann Ferre, Ketan S Gajiwala, Michelle D Hemkens, Robert S Kania, John C Kath, Jean Matthews, Brion W Murray, Sherry Niessen, Suvi T M Orr, Mason Pairish, Neal W Sach, Hong Shen, Manli Shi, James Solowiej, Khanh Tran, Elaine Tseng, Paolo Vicini, Yuli Wang, Scott L Weinrich, Ru Zhou, Michael Zientek, Longqing Liu, Yiqin Luo, Shuibo Xin, Chengyi Zhang, Jennifer Anne Lafontaine
Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR-mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants was recently disclosed1...
March 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28287715/a-dual-recognition-fret-based-platform-for-one-step-sensitive-detection-of-pathogenic-bacteria-using-fluorescent-vancomycin-gold-nanoclusters-and-aptamer-gold-nanoparticles
#15
Mengqun Yu, Hong Wang, Fei Fu, Linyao Li, Jing Li, Gan Li, Yang Song, Mark T Swihart, Erqun Song
The effective monitoring, identification, and quantification of pathogenic bacteria is essential for addressing serious public health issues. In this study, we present a universal and facile one-step strategy for sensitive and selective detection of pathogenic bacteria using a dual molecular affinity-based Förster (fluorescence) resonance energy transfer (FRET) platform based on the recognition of bacterial cell walls by antibiotic and aptamer molecules, respectively. As a proof of concept, Vancomycin (Van), and a nucleic acid aptamer were employed in a model dual recognition scheme for detecting Staphylococcus aureus (S...
March 13, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28287405/t-cells-control-the-generation-of-nanomolar-affinity-anti-glycan-antibodies
#16
Zinaida Polonskaya, Shenglou Deng, Anita Sarkar, Lisa Kain, Marta Comellas-Aragones, Craig S McKay, Katarzyna Kaczanowska, Marie Holt, Ryan McBride, Valle Palomo, Kevin M Self, Seth Taylor, Adriana Irimia, Sanjay R Mehta, Jennifer M Dan, Matthew Brigger, Shane Crotty, Stephen P Schoenberger, James C Paulson, Ian A Wilson, Paul B Savage, M G Finn, Luc Teyton
Vaccines targeting glycan structures at the surface of pathogenic microbes must overcome the inherent T cell-independent nature of immune responses against glycans. Carbohydrate conjugate vaccines achieve this by coupling bacterial polysaccharides to a carrier protein that recruits heterologous CD4 T cells to help B cell maturation. Yet they most often produce low- to medium-affinity immune responses of limited duration in immunologically fit individuals and disappointing results in the elderly and immunocompromised patients...
March 13, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28284714/strain-specificities-in-cellular-and-molecular-immunopathogenic-mechanisms-underlying-development-of-experimental-autoimmune-encephalomyelitis-in-aged-rats
#17
Mirjana Nacka-Aleksić, Zorica Stojić-Vukanić, Ivan Pilipović, Ivana Vujnović, Biljana Bufan, Mirjana Dimitrijević, Gordana Leposavić
To understand strain-specificities of immune system in aged rats and their immunopathological implications, CD4+ T lymphocyte-mediated neuroinflammation in experimental autoimmune encephalomyelitis (EAE) was studied in two strains. Upon immunization for EAE, 22-24-month-old Albino Oxford (AO) rats developed milder neurological deficit of prolonged duration compared with their Dark Agouti (DA) counterparts. Consistently, they exhibited: (i) diminished neuroantigen-specific CD4+ T lymphocyte generation in draining lymph nodes (reflecting lower density of high-affinity IL-2 receptor complex on their surface and higher CD4+FoxP3+CD25+ regulatory cell frequency); (ii) less favorable spinal cord expression of CXCL12 and CCL2, and consequently diminished infiltration of neuroantigen-specific CD4+ T lymphocytes, including highly pathogenic IL-17+IFN-γ+ ones, and inflammatory monocytes into the spinal cord and (iii) subsequently impaired CD4+ T lymphocyte reactivation/survival and differentiation into highly pathogenic IL-17+ cells (reflecting downregulated expression of IL-1β, IL-6 and IL-23/p19)...
March 8, 2017: Mechanisms of Ageing and Development
https://www.readbyqxmd.com/read/28283061/functional-selectivity-in-cytokine-signaling-revealed-through-a-pathogenic-epo-mutation
#18
Ah Ram Kim, Jacob C Ulirsch, Stephan Wilmes, Ekrem Unal, Ignacio Moraga, Musa Karakukcu, Daniel Yuan, Shideh Kazerounian, Nour J Abdulhay, David S King, Namrata Gupta, Stacey B Gabriel, Eric S Lander, Turkan Patiroglu, Alper Ozcan, Mehmet Akif Ozdemir, K Christopher Garcia, Jacob Piehler, Hanna T Gazda, Daryl E Klein, Vijay G Sankaran
Cytokines are classically thought to stimulate downstream signaling pathways through monotonic activation of receptors. We describe a severe anemia resulting from a homozygous mutation (R150Q) in the cytokine erythropoietin (EPO). Surprisingly, the EPO R150Q mutant shows only a mild reduction in affinity for its receptor but has altered binding kinetics. The EPO mutant is less effective at stimulating erythroid cell proliferation and differentiation, even at maximally potent concentrations. While the EPO mutant can stimulate effectors such as STAT5 to a similar extent as the wild-type ligand, there is reduced JAK2-mediated phosphorylation of select downstream targets...
March 9, 2017: Cell
https://www.readbyqxmd.com/read/28278297/directed-evolution-of-a-soluble-human-dr3-receptor-for-the-inhibition-of-tl1a-induced-cytokine-secretion
#19
Itay Levin, Marianna Zaretsky, Amir Aharoni
TNF-like 1A (TL1A) is a cytokine belonging to the TNF superfamily that promotes inflammation in autoimmune diseases. Inhibiting the interaction of TL1A with the endogenous death-domain receptor 3 (DR3) offers a therapeutic approach for treating TL1A-induced autoimmune diseases. Here, we generated improved DR3 variants showing increased TL1A binding affinity and stability using a directed evolution approach. Given the high cysteine content and post-translational modification of DR3, we employed yeast surface display and expression in mammalian cell lines for screening, expression and characterization of improved DR3 variants...
2017: PloS One
https://www.readbyqxmd.com/read/28275173/tropism-and-innate-host-responses-of-influenza-a-h5n6-virus-an-analysis-of-ex%C3%A2-vivo-and-in-vitro-cultures-of-the-human-respiratory-tract
#20
Kenrie P Y Hui, Louisa L Y Chan, Denise I T Kuok, Chris K P Mok, Zi-Feng Yang, Run-Feng Li, Geraldine S M Luk, Elaine F Lee, Jimmy C C Lai, Hui-Ling Yen, Huachen Zhu, Yi Guan, John M Nicholls, J S Malik Peiris, Michael C W Chan
Since their first isolation in 2013, influenza A/H5N6 viruses have spread amongst poultry across multiple provinces in China and to Laos, Vietnam and Myanmar. So far, there have been 14 human H5N6 infections with 10 fatalities.We investigated the tropism, replication competence and cytokine induction of one human and two avian H5N6 isolates in ex vivo and in vitro cultures derived from the human respiratory tract. Virus tropism and replication were studied in ex vivo cultures of human nasopharynx, bronchus and lung...
March 2017: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
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