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Affinity maturation

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https://www.readbyqxmd.com/read/28636966/the-torc-that-gets-the-gc-cycling
#1
Elissa K Deenick, Stuart G Tangye
The signaling pathways regulating positive selection in germinal centers (GCs) are incompletely understood. Ersching et al. (2017) identify a critical but temporal role for the action of the kinase mechanistic target of rapamycin complex (mTORC1), which promotes key changes in GC B cells and thereby facilitates affinity maturation.
June 20, 2017: Immunity
https://www.readbyqxmd.com/read/28636954/germinal-center-selection-and-affinity-maturation-require-dynamic-regulation-of-mtorc1-kinase
#2
Jonatan Ersching, Alejo Efeyan, Luka Mesin, Johanne T Jacobsen, Giulia Pasqual, Brian C Grabiner, David Dominguez-Sola, David M Sabatini, Gabriel D Victora
During antibody affinity maturation, germinal center (GC) B cells cycle between affinity-driven selection in the light zone (LZ) and proliferation and somatic hypermutation in the dark zone (DZ). Although selection of GC B cells is triggered by antigen-dependent signals delivered in the LZ, DZ proliferation occurs in the absence of such signals. We show that positive selection triggered by T cell help activates the mechanistic target of rapamycin complex 1 (mTORC1), which promotes the anabolic program that supports DZ proliferation...
June 20, 2017: Immunity
https://www.readbyqxmd.com/read/28630428/nuclear-accumulation-of-symplekin-promotes-cellular-proliferation-and-dedifferentiation-in-an-erk1-2-dependent-manner
#3
Chen Zhang, Hai-Lei Mao, Yi Cao
Symplekin is a multifunctional protein that localizes to both tight junctions and the nucleus in polarized epithelial cells, with confirmed roles in mRNA maturation, transcriptional modulation and tight-junction assembly. However, the mechanisms governing its subcellular distribution and related functions remain unclear. In this study, we found that symplekin primarily localizes to the nuclei of cultured dedifferentiated colorectal cancer cells, and nuclear symplekin showed higher phosphorylation and binding affinity with YBX3 than its membrane fraction...
June 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28630079/what-are-the-primary-limitations-in-b-cell-affinity-maturation-and-how-much-affinity-maturation-can-we-drive-with-vaccination-lessons-from-the-antibody-response-to-hiv-1
#4
Gabriel D Victora, Hugo Mouquet
Most broadly neutralizing antibodies to HIV-1 have in common an extreme degree of somatic hypermutation (SHM), which correlates with their ability to neutralize multiple viral strains. However, achieving such extreme SHM by immunization remains a challenge. Here, we discuss how antigenic variation during HIV-1 infection may work to exacerbate SHM by permitting multiple iterative cycles of affinity maturation in germinal centers, and speculate on how this could be recapitulated through vaccination.
June 19, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/28630078/what-are-the-primary-limitations-in-b-cell-affinity-maturation-and-how-much-affinity-maturation-can-we-drive-with-vaccination-a-role-for-antibody-feedback
#5
Kai-Michael Toellner, Daniel M-Y Sze, Yang Zhang
We discuss the impact of antibody feedback on affinity maturation of B cells. Competition from epitope-specific antibodies produced earlier during the immune response leads to immune complex formation, which is essential for transport and deposition of antigen onto follicular dendritic cells (FDCs). It also reduces the concentration of free epitopes into the μm to nm range, which is essential for B-cell receptors (BCRs) to sense affinity-dependent changes in binding capacity. Antibody feedback may also induce epitope spreading, leading to a broader selection of epitopes recognized by newly emerging B-cell clones...
June 19, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/28630077/what-are-the-primary-limitations-in-b-cell-affinity-maturation-and-how-much-affinity-maturation-can-we-drive-with-vaccination-breaking-through-immunity-s-glass-ceiling
#6
Garnett Kelsoe, Barton F Haynes
A key goal of HIV-1 vaccine development is the induction of broadly neutralizing antibodies (bnAbs) targeted to the vulnerable regions of the HIV envelope. BnAbs develop over time in ∼50% of HIV-1-infected individuals. However, to date, no vaccines have induced bnAbs and few or none of these vaccine-elicited HIV-1 antibodies carry the high frequencies of V(D)J mutations characteristic of bnAbs. Do the high frequencies of mutations characteristic of naturally induced bnAbs represent a fundamental barrier to the induction of bnAbs by vaccines? Recent studies suggest that high frequencies of V(D)J mutations can be achieved by serial vaccination strategies...
June 19, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/28630076/what-are-the-primary-limitations-in-b-cell-affinity-maturation-and-how-much-affinity-maturation-can-we-drive-with-vaccination-is-affinity-maturation-a-self-defeating-process-for-eliciting-broad-protection
#7
Christopher T Stamper, Patrick C Wilson
Vaccinations are one of the greatest success stories of modern medicine, saving millions of lives since their widespread adoption. However, several diseases continue to elude highly effective vaccination strategies. Chief among these are human immunodeficiency virus (HIV) and influenza (flu), both of which will require vaccines that can guide the creation of highly mutated, broadly neutralizing antibodies (bnAbs). The generation of bnAbs is hindered by our inability to effectively drive the high levels of affinity maturation required to achieve them in a large number of cells...
June 19, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/28625790/preprotein-conformational-dynamics-drive-bivalent-translocase-docking-and-secretion
#8
Marios Frantzeskos Sardis, Alexandra Tsirigotaki, Katerina Elias Chatzi, Athina George Portaliou, Giorgos Gouridis, Spyridoula Karamanou, Anastassios Economou
Most bacterial secretory proteins destined beyond the plasma membrane are secreted post-translationally by the Sec translocase. In the first step of translocation, preproteins are targeted for binding to their 2-site receptor SecA, the peripheral ATPase subunit of the translocase. We now reveal that secretory preproteins use a dual-key mechanism to bridge the signal peptide and mature domain receptor sites and cooperatively enhance their affinities. Docking of targeting-competent mature domains requires that their extensive disorder is finely tuned...
June 5, 2017: Structure
https://www.readbyqxmd.com/read/28619678/april-taci-axis-is-dispensable-for-the-immune-response-to-rabies-vaccination
#9
Shannon L Haley, Evgeni P Tzvetkov, Andrew G Lytle, Kishore R Alugupalli, Joseph R Plummer, James P McGettigan
There is significant need to develop a single-dose rabies vaccine to replace the current multi-dose rabies vaccine regimen and eliminate the requirement for rabies immune globulin in post-exposure settings. To accomplish this goal, rabies virus (RABV)-based vaccines must rapidly activate B cells to secrete antibodies which neutralize pathogenic RABV before it enters the CNS. Increased understanding of how B cells effectively respond to RABV-based vaccines may improve efforts to simplify post-exposure prophylaxis (PEP) regimens...
June 12, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28619052/heterologous-expression-of-an-%C3%AE-amylase-inhibitor-from-common-bean-phaseolus-vulgaris-in-kluyveromyces-lactis-and-saccharomyces-cerevisiae
#10
Stephanie Brain-Isasi, Alejandro Álvarez-Lueje, Thomas Joseph V Higgins
BACKGROUND: Phaseolamin or α-amylase inhibitor 1 (αAI) is a glycoprotein from common beans (Phaseolus vulgaris L.) that inhibits some insect and mammalian α-amylases. Several clinical studies support the beneficial use of bean αAI for control of diabetes and obesity. Commercial extracts of P. vulgaris are available but their efficacy is still under question, mainly because some of these extracts contain antinutritional impurities naturally present in bean seeds and also exhibit a lower specific activity αAI...
June 15, 2017: Microbial Cell Factories
https://www.readbyqxmd.com/read/28617936/t-follicular-regulatory-cells-in-mice-and-men
#11
REVIEW
Ana Raquel Maceiras, Valter R Fonseca, Ana Agua-Doce, Luis Graca
It has long been known that CD4 T cells are necessary to provide help to B cells, triggering a germinal center (GC) reaction where affinity maturation and isotype switching occurs. However, the nature of the dedicated CD4 helper T cells, known as T follicular helper (Tfh), was only recently described. Here, we review the biology and function of the recently described T follicular regulatory (Tfr) cells, another CD4 T cell population also found within GCs but with regulatory function and characteristics. Tfr cells have been identified in mice and humans as simultaneously, presenting simultaneously characteristics of T follicular cells (namely CXCR5 expression) and regulatory T cells (including Foxp3 expression)...
June 15, 2017: Immunology
https://www.readbyqxmd.com/read/28616170/variation-in-species-level-plant-functional-traits-over-wetland-indicator-status-categories
#12
Miles E McCoy-Sulentic, Thomas E Kolb, David M Merritt, Emily C Palmquist, Barbara E Ralston, Daniel A Sarr
Wetland indicator status (WIS) describes the habitat affinity of plant species and is used in wetland delineations and resource inventories. Understanding how species-level functional traits vary across WIS categories may improve designations, elucidate mechanisms of adaptation, and explain habitat optima and niche. We investigated differences in species-level traits of riparian flora across WIS categories, extending their application to indicate hydrologic habitat. We measured or compiled data on specific leaf area (SLA), stem specific gravity (SSG), seed mass, and mature height of 110 plant species that occur along the Colorado River in Grand Canyon, Arizona...
June 2017: Ecology and Evolution
https://www.readbyqxmd.com/read/28612854/fragile-x-mental-retardation-protein-recognizes-a-g-quadruplex-structure-within-the-survival-motor-neuron-domain-containing-1-mrna-5-utr
#13
Damian S McAninch, Ashley M Heinaman, Cara N Lang, Kathryn R Moss, Gary J Bassell, Mihaela Rita Mihailescu, Timothy L Evans
G quadruplex structures have been predicted by bioinformatics to form in the 5'- and 3'-untranslated regions (UTRs) of several thousand mature mRNAs and are believed to play a role in translation regulation. Elucidation of these roles has primarily been focused on the 3'-UTR, with limited focus on characterizing the G quadruplex structures and functions in the 5'-UTR. Investigation of the affinity and specificity of RNA binding proteins for 5'-UTR G quadruplexes and the resulting regulatory effects have also been limited...
June 14, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28611475/murine-lrba-deficiency-causes-ctla-4-deficiency-in-tregs-without-progression-to-immune-dysregulation
#14
Deborah Burnett, Ian Parish, Etienne Masle-Farquhar, Robert Brink, Christopher Goodnow
Inherited mutations in Lipopolysaccharide Responsive Beige-like Anchor (LRBA) cause a recessive human immune dysregulation syndrome with memory B cell and antibody deficiency (common variable immunodeficiency, CVID), inflammatory bowel disease, enlarged spleen and lymph nodes, accumulation of activated T cells, and multiple autoimmune diseases. To understand the pathogenesis of the syndrome, C57BL/6 mice carrying a homozygous truncating mutation in Lrba were produced using CRISPR/Cas9-mediated gene targeting...
June 14, 2017: Immunology and Cell Biology
https://www.readbyqxmd.com/read/28606479/therapeutic-potential-of-ranibizumab-in-corneal-neovascularization
#15
Marianne L Shahsuvaryan
Ranibizumab is a humanized, affinity-matured vascular endothelial growth factor (VEGF) antibody fragment that neutralizes all isoforms of VEGF and is FDA approved for use in ophthalmology. Recently it was suggested that ranibizumab may be useful in the treatment of corneal neovascularization, but in reality this therapy is not yet evidence based.
June 9, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28604797/a-human-inferred-germline-antibody-binds-to-an-immunodominant-epitope-and-neutralizes-zika-virus
#16
Diogo M Magnani, Cassia G T Silveira, Brandon C Rosen, Michael J Ricciardi, Núria Pedreño-Lopez, Martin J Gutman, Varian K Bailey, Helen S Maxwell, Aline Domingues, Lucas Gonzalez-Nieto, Vivian I Avelino-Silva, Mateus Trindade, Juliana Nogueira, Consuelo S Oliveira, Alvino Maestri, Alvina Clara Felix, José Eduardo Levi, Mauricio L Nogueira, Mauricio A Martins, José M Martinez-Navio, Sebastian P Fuchs, Stephen S Whitehead, Dennis R Burton, Ronald C Desrosiers, Esper G Kallas, David I Watkins
The isolation of neutralizing monoclonal antibodies (nmAbs) against the Zika virus (ZIKV) might lead to novel preventative strategies for infections in at-risk individuals, primarily pregnant women. Here we describe the characterization of human mAbs from the plasmablasts of an acutely infected patient. One of the 18 mAbs had the unusual feature of binding to and neutralizing ZIKV despite not appearing to have been diversified by affinity maturation. This mAb neutralized ZIKV (Neut50 ~ 2 μg/ml) but did not react with any of the four dengue virus serotypes...
June 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28596941/highly-specific-and-effective-targeting-of-egfrviii-positive-tumors-with-tandab-antibodies
#17
Kristina Ellwanger, Uwe Reusch, Ivica Fucek, Stefan Knackmuss, Michael Weichel, Thorsten Gantke, Vera Molkenthin, Eugene A Zhukovsky, Michael Tesar, Martin Treder
To harness the cytotoxic capacity of immune cells for the treatment of solid tumors, we developed tetravalent, bispecific tandem diabody (TandAb) antibodies that recognize EGFRvIII, the deletion variant III of the epidermal growth factor receptor (EGFR), and CD3 on T-cells, thereby directing immune cells to eliminate EGFRvIII-positive tumor cells. Using phage display, we identified scFv antibodies selectively binding to EGFRvIII. These highly EGFRvIII-specific, fully human scFv were substantially improved by affinity maturation, achieving KDs in the picomolar range, and were used to construct a set of bispecific EGFRvIII-targeting TandAbs with a broad range of binding and cytotoxic properties...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28595551/nmr-based-drug-development-and-improvement-against-malignant-melanoma-implications-for-the-mia-protein-family
#18
Oliver Arnolds, Xueyin Zhong, King Tuo Yip, Miriam Schöpel, Bastian Kohl, Stefanie Pütz, Raid Abdel-Jalil, Raphael Stoll
The Melanoma Inhibitory Activity (MIA) protein is strongly expressed and secreted by malignant melanoma cells and was shown to promote melanoma development and invasion. The MIA protein was the first extracellular protein shown to adopt a Src homology 3 (SH3) domain-like fold in solution that can bind to fibronectin type III domains. Together with MIA, the homologous proteins OTOR (or FDP), MIA-2, and TANGO (or MIA-3) constitute a protein family of non-cytoplasmic and - except for full-length TANGO and TANGO1-like (TALI) - extracellular SH3-domain containing proteins...
June 8, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28591728/generation-and-evaluation-of-antibody-agents-for-molecular-imaging-of-cd44v6-expressing-cancers
#19
Anna-Karin Haylock, Johan Nilvebrant, Anja Mortensen, Irina Velikyan, Marika Nestor, Ronny Falk
AIM: The aim of this study was to generate and characterize scFv antibodies directed to human CD44v6, as well as to radiolabel and evaluate top candidates in vitro and in vivo for their potential use in CD44v6-targeted molecular imaging in cancer patients. MATERIALS AND METHODS: Phage display selections were used to isolate CD44v6-specific scFvs. A chain shuffling strategy was employed for affinity maturation based on a set of CD44v6-specific first-generation clones...
May 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28589908/activation-of-trka-receptor-elicits-mastocytosis-in-mice-and-is-involved-in-the-development-of-resistance-to-kit-targeted-therapy
#20
Min Yang, Zengkai Pan, Kezhi Huang, Guntram Büsche, Friedrich Feuerhake, Anuhar Chaturvedi, Danian Nie, Michael Heuser, Felicitas Thol, Nils von Neuhoff, Arnold Ganser, Zhixiong Li
The neurotrophins (NTs) play a key role in neuronal survival and maintenance. The TRK (tropomyosin-related kinase) tyrosine kinase receptors (TRKA, TRKB, TRKC) are high affinity receptors for NTs. There is increasing data demonstrating an important role of the TRK family in cancer initiation and progression. NTs have been known for many years to promote chemotaxis, maturation, and survival of mast cells. However, the role of NT signaling in the pathogenesis of mastocytosis is not well understood. In this study, we demonstrate that activation of TRKA by its ligand nerve growth factor (NGF) is potent to trigger a disease in mice with striking similarities to human systemic mastocytosis (SM)...
May 19, 2017: Oncotarget
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