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Affinity maturation

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https://www.readbyqxmd.com/read/29335468/aicda-drives-epigenetic-heterogeneity-and-accelerates-germinal-center-derived-lymphomagenesis
#1
Matt Teater, Pilar M Dominguez, David Redmond, Zhengming Chen, Daisuke Ennishi, David W Scott, Luisa Cimmino, Paola Ghione, Jayanta Chaudhuri, Randy D Gascoyne, Iannis Aifantis, Giorgio Inghirami, Olivier Elemento, Ari Melnick, Rita Shaknovich
Epigenetic heterogeneity is emerging as a feature of tumors. In diffuse large B-cell lymphoma (DLBCL), increased cytosine methylation heterogeneity is associated with poor clinical outcome, yet the underlying mechanisms remain unclear. Activation-induced cytidine deaminase (AICDA), an enzyme that mediates affinity maturation and facilitates DNA demethylation in germinal center (GC) B cells, is required for DLBCL pathogenesis and linked to inferior outcome. Here we show that AICDA overexpression causes more aggressive disease in BCL2-driven murine lymphomas...
January 15, 2018: Nature Communications
https://www.readbyqxmd.com/read/29324242/expression-profiling-of-the-dolichos-lablab-lectin-during-germination-and-development-of-the-seed
#2
Yashavanth L Vishweshwaraiah, Balaji Prakash, Lalitha R Gowda
The temporal expression of the field bean (Dolichos lablab) galactose specific lectin, DLL-II, during germination, post-germination and seed development was evaluated using Native-PAGE followed by activity staining, immunodetection and quantitative Real Time PCR (qPCR). A rapid and steep decline in the polyphenol oxidase (PPO) and hemagglutinating activity during the initial stages of germination, which did not correlate with the slow decline in total protein was observed. During post germination period, PPO and hemagglutination activities were negligible, whereas a rapid resorption of the protein was evident...
January 4, 2018: Plant Physiology and Biochemistry: PPB
https://www.readbyqxmd.com/read/29315477/enrichment-of-high-affinity-subclasses-and-glycoforms-from-serum-derived-igg-using-fc%C3%AE-rs-as-affinity-ligands
#3
Boesch Aw, Kappel Jh, Mahan Ae, Chu Th, Crowley Ar, Osei-Owusu Ny, Alter G, Ackerman Me
As antibodies continue to gain predominance in drug discovery and development pipelines, efforts to control and optimize their activity in vivo have matured to incorporate sophisticated abilities to manipulate engagement of specific Fc binding partners. Such efforts to promote diverse functional outcomes include modulating IgG-Fc affinity for FcγRs to alternatively potentiate or reduce effector functions, such as antibody-dependent cellular cytotoxicity and phagocytosis. While a number of natural and engineered Fc features capable of eliciting variable effector functions have been demonstrated in vitro and in vivo, elucidation of these important functional relationships has taken significant effort through use of diverse genetic, cellular and enzymatic techniques...
January 8, 2018: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/29300447/hsp70-inhibits-the-nucleation-and-elongation-of-tau-and-sequesters-tau-aggregates-with-high-affinity
#4
Franziska Kundel, Suman De, Patrick Flagmeier, Mathew H Horrocks, Magnus Kjaergaard, Sarah L Shammas, Sophie E Jackson, Christopher M Dobson, David Klenerman
As a key player of the protein quality control network of the cell, the molecular chaperone Hsp70 inhibits the aggregation of the amyloid protein tau. To date, the mechanism of this inhibition and the tau species targeted by Hsp70 remain unknown. This is partly due to the inherent difficulty of studying amyloid aggregates because of their heterogeneous and transient nature. Here, we used ensemble and single-molecule fluorescence measurements to dissect how Hsp70 counteracts the self-assembly process of K18 tau with the pathological deletion ∆K280...
January 4, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29298343/epcam-peptide-primed-dendritic-cell-vaccination-confers-significant-anti-tumor-immunity-in-hepatocellular-carcinoma-cells
#5
Yoo Jin Choi, Seong-Joon Park, You-Soo Park, Hee Sung Park, Kwang Mo Yang, Kyu Heo
Cancer stem-like cells (CSCs) may play a key role in tumor initiation, self-renewal, differentiation, and resistance to current treatments. Dendritic cells (DCs) play a vital role in host immune reactions as well as antigen presentation. In this study, we explored the suitability of using CSC peptides as antigen sources for DC vaccination against human breast cancer and hepatocellular carcinoma (HCC) with the aim of achieving CSC targeting and enhancing anti-tumor immunity. CD44 is used as a CSC marker for breast cancer and EpCAM is used as a CSC marker for HCC...
2018: PloS One
https://www.readbyqxmd.com/read/29296261/novel-recombinant-traceable-c-met-antagonist-avimer-antibody-mimetic-obtained-by-bacterial-expression-analysis
#6
Bahram Baghban Kohnehrouz, Afsaneh Talischian, Alireza Dehnad, Shahnoush Nayeri
Background: Avimers are originally types of artificial proteins with multiple binding sites for specific binding to certain antigens. Various radioisotopes and nanoparticles link these molecules, which are widely used in early detection in tissue imaging, treatment and study on carcinogenesis. Among these, c-Met antagonist avimer (C426 avimer), with ability to bind the c-Met receptor of tyrosine kinase (RTK) is an attractive candidate for targeted cancer therapy. In this study, a novel traceable C426 avimer gene was designed and introduced by adding the 12nt tracer binding site encoded four specific amino acid residues at the C-terminal region of C426 avimer coding sequence...
January 2018: Avicenna Journal of Medical Biotechnology
https://www.readbyqxmd.com/read/29284597/an-april-based-chimeric-antigen-receptor-for-dual-targeting-of-bcma-and-taci-in-multiple-myeloma
#7
Lydia Lee, Benjamin Draper, Neil Chaplin, Brian Philip, Melody Chin, Daria Galas-Filipowicz, Shimobi Onuoha, Simon Thomas, Vania Baldan, Reyisa Bughda, Paul Maciocia, Eva Kokalaki, Margarida P Neves, Dominic Patel, Manuel Rodriguez-Justo, James Francis, Kwee Yong, Martin Pule
B-cell maturation antigen (BCMA) is a promising therapeutic target for multiple myeloma (MM), but expression is variable, and early reports of BCMA targeting chimeric antigen receptors (CARs) suggest antigen down-regulation at relapse. Dual antigen targeting increases targetable tumour antigens and reduces the risk of antigen negative disease escape. 'A proliferation-inducing ligand' (APRIL) is a natural high affinity ligand for BCMA and transmembrane activator and CAML interactor (TACI). We quantified surface tumour expression of BCMA and TACI on primary MM cells (n=50)...
December 28, 2017: Blood
https://www.readbyqxmd.com/read/29283291/structural-insights-into-humanization-of-anti-tissue-factor-antibody-10h10
#8
Alexey Teplyakov, Galina Obmolova, Thomas J Malia, Gopalan Raghunathan, Christian Martinez, Johan Fransson, Wilson Edwards, Judith Connor, Matthew Husovsky, Heena Beck, Ellen Chi, Sandra Fenton, Hong Zhou, Juan Carlos Almagro, Gary L Gilliland
Murine antibody 10H10 raised against human tissue factor is unique in that it blocks the signaling pathway, and thus inhibits angiogenesis and tumor growth without interfering with coagulation. As a potential therapeutic, the antibody was humanized in a two-step procedure. Antigen-binding loops were grafted onto selected human frameworks and the resulting chimeric antibody was subjected to affinity maturation by using phage display libraries. The results of humanization were analyzed from the structural perspective through comparison of the structure of a humanized variant with the parental mouse antibody...
December 28, 2017: MAbs
https://www.readbyqxmd.com/read/29247988/interleukin-18-biological-properties-and-role-in-disease-pathogenesis
#9
REVIEW
Gilles Kaplanski
Initially described as an interferon (IFN)γ-inducing factor, interleukin (IL)-18 is indeed involved in Th1 and NK cell activation, but also in Th2, IL-17-producing γδ T cells and macrophage activation. IL-18, a member of the IL-1 family, is similar to IL-1β for being processed by caspase 1 to an 18 kDa-biologically active mature form. IL-18 binds to its specific receptor (IL-18Rα, also known as IL-1R7) forming a low affinity ligand chain. This is followed by recruitment of the IL-18Rβ chain. IL-18 then uses the same signaling pathway as IL-1 to activate NF-kB and induce inflammatory mediators such as adhesion molecules, chemokines and Fas ligand...
January 2018: Immunological Reviews
https://www.readbyqxmd.com/read/29247194/elucidating-the-16s-rrna-3-boundaries-and-defining-optimal-sd-asd-pairing-in-escherichia-coli-and-bacillus-subtilis-using-rna-seq-data
#10
Yulong Wei, Jordan R Silke, Xuhua Xia
Bacterial translation initiation is influenced by base pairing between the Shine-Dalgarno (SD) sequence in the 5' UTR of mRNA and the anti-SD (aSD) sequence at the free 3' end of the 16S rRNA (3' TAIL) due to: 1) the SD/aSD sequence binding location and 2) SD/aSD binding affinity. In order to understand what makes an SD/aSD interaction optimal, we must define: 1) terminus of the 3' TAIL and 2) extent of the core aSD sequence within the 3' TAIL. Our approach to characterize these components in Escherichia coli and Bacillus subtilis involves 1) mapping the 3' boundary of the mature 16S rRNA using high-throughput RNA sequencing (RNA-Seq), and 2) identifying the segment within the 3' TAIL that is strongly preferred in SD/aSD pairing...
December 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29247044/stochasticity-enables-bcr-independent-germinal-center-initiation-and-antibody-affinity-maturation
#11
Jared Silver, Teng Zuo, Neha Chaudhary, Rupa Kumari, Pei Tong, Sophie Giguere, Alessandra Granato, Rakesh Donthula, Colby Devereaux, Duane R Wesemann
Two immunoglobulin (Ig) diversification mechanisms collaborate to provide protective humoral immunity. Combinatorial assembly of IgH and IgL V region exons from gene segments generates preimmune Ig repertoires, expressed as B cell receptors (BCRs). Secondary diversification occurs when Ig V regions undergo somatic hypermutation (SHM) and affinity-based selection toward antigen in activated germinal center (GC) B cells. Secondary diversification is thought to only ripen the antigen-binding affinity of Igs that already exist (i...
December 15, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29246751/generation-and-characterization-of-an-anti-delta-like-ligand-4-nanobody-to-induce-non-productive-angiogenesis
#12
Rasoul Baharlou, Nader Tajik, Mahdi Behdani, Mohammad Ali Shokrgozar, Amir Hassan Zarnani, Fatemeh Shahhosseini, Mahdi Habibi-Anbouhi
Antibody-based targeting of angiogenesis is a key approach for cancer treatment. Delta-like ligand 4 (DLL4) plays a pivotal role in tumor neovascular development and angiogenesis during tumor progression. It forecasts the prognosis of human malignancies and blocking its signaling can help to inhibit neovascularization and tumor metastasis. Nanobodies are the smallest antigen-binding domains of heavy chain antibodies in camelidae. The aim of this study was to develop a Nanobody against DLL4 and apply binding and functional approaches to target it...
December 12, 2017: Analytical Biochemistry
https://www.readbyqxmd.com/read/29235109/-double-duty-conventional-dendritic-cells-in-the-amphibian-xenopus-as-the-prototype-for-antigen-presentation-to-b-cells
#13
Harold R Neely, Jacqueline Guo, Emily M Flowers, Michael F Criscitiello, Martin F Flajnik
Two populations of dendritic cells (DCs) are found in mammals, one derived from hematopoietic precursors (conventional/cDC), and another derived from mesenchymal precursors, the follicular DC (FDC); the latter is specialized for antigen presentation to B cells, and has only been definitively demonstrated in mammals. Both cDC and FDC are necessary for induction of germinal centers (GC) and GC-dependent class switch recombination (CSR) and somatic hypermutation (SHM). We demonstrate that in Xenopus, an amphibian in which immunoglobulin CSR and SHM occur without GC formation, a single type of DC has properties of both cDC and FDC, including high expression of MHC class II for the former and display of native antigen at the cell surface for the latter...
December 12, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/29234980/low-dose-interleukin-2-as-a-modulator-of-treg-homeostasis-after-hsct-current-understanding-and-future-perspectives
#14
REVIEW
Ken-Ichi Matsuoka
CD4+CD25+Foxp3+ Treg is a functionally distinct subset of mature T cells with broad suppressive activity and has been shown to play an important role in the establishment of immune tolerance after HSCT. Altered cytokine environment in post-HSCT lymphopenia with a relative functional deficiency of IL-2 could hamper the reconstitution of Treg, leading to refractory GVHD. Based on the theory of low-dose IL-2 in which Treg can be selectively stimulated through the high-affinity IL-2 receptor, clinical studies have been conducted and demonstrated that low-dose IL-2 administration can restore Treg homeostasis and promote the expansion of this subset on the polymorphic processes of Treg reconstitution after HSCT...
December 12, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/29230292/multiple-steroid-and-thyroid-hormones-detected-in-baleen-from-eight-whale-species
#15
Kathleen E Hunt, Nadine S Lysiak, Jooke Robbins, Michael J Moore, Rosemary E Seton, Leigh Torres, C Loren Buck
Recent studies have demonstrated that some hormones are present in baleen powder from bowhead (Balaena mysticetus) and North Atlantic right (Eubalaena glacialis) whales. To test the potential generalizability of this technique for studies of stress and reproduction in large whales, we sought to determine whether all major classes of steroid and thyroid hormones are detectable in baleen, and whether these hormones are detectable in other mysticetes. Powdered baleen samples were recovered from single specimens of North Atlantic right, bowhead, blue (Balaenoptera [B...
2017: Conservation Physiology
https://www.readbyqxmd.com/read/29229779/subtle-changes-at-the-variable-domain-interface-of-the-t-cell-receptor-can-strongly-increase-affinity
#16
Preeti Sharma, David M Kranz
Most affinity maturation campaigns for antibodies and T cell receptors (TCRs) operate on the residues at the binding site, located within the loops known as complementarity determining regions (CDRs). Accordingly, mutations in contact residues or so-called second shell residues that increase affinity are typically identified by directed evolution using combinatorial libraries. Here we used single codon libraries of both CDR and non-CDR residues to generate a deep mutational scan of a human TCR against the cancer antigen MART-1/HLA-A2...
December 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29221597/evolution-of-autoantibody-responses-in-individuals-at-risk-of-rheumatoid-arthritis
#17
REVIEW
Willem J J Falkenburg, Dirkjan van Schaardenburg
Autoantibodies such as rheumatoid factors (RFs), anti-citrullinated protein antibodies (ACPAs), and other anti-modified protein antibodies are important risk factors for the development of rheumatoid arthritis (RA) and probably play an important role in its pathogenesis. In the phase before clinical arthritis becomes apparent, different autoantibody responses can evolve because of increases in their level, isotype switching, affinity maturation, epitope spreading, and a changing glycosylation profile. This evolution may be crucial for the pathogenic properties of the autoantibody responses, and interfering with this process in individuals at risk may become a route to prevent RA...
February 2017: Best Practice & Research. Clinical Rheumatology
https://www.readbyqxmd.com/read/29218052/spoiling-for-a-fight-b-lymphocytes-as-initiator-and-effector-populations-within-tertiary-lymphoid-organs-in-autoimmunity-and-transplantation
#18
REVIEW
Jawaher Alsughayyir, Gavin J Pettigrew, Reza Motallebzadeh
Tertiary lymphoid organs (TLOs) develop at ectopic sites within chronically inflamed tissues, such as in autoimmunity and rejecting organ allografts. TLOs differ structurally from canonical secondary lymphoid organs (SLOs), in that they lack a mantle zone and are not encapsulated, suggesting that they may provide unique immune function. A notable feature of TLOs is the frequent presence of structures typical of germinal centers (GCs). However, little is known about the role of such GCs, and in particular, it is not clear if the B cell response within is autonomous, or whether it synergizes with concurrent responses in SLOs...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29212020/mechanotransmission-and-mechanosensing-of-human-alpha-actinin-1
#19
Shimin Le, Xian Hu, Mingxi Yao, Hu Chen, Miao Yu, Xiaochun Xu, Naotaka Nakazawa, Felix M Margadant, Michael P Sheetz, Jie Yan
α-Actinins, a family of critical cytoskeletal actin-binding proteins that usually exist as anti-parallel dimers, play crucial roles in organizing the framework of the cytoskeleton through crosslinking the actin filaments, as well as in focal adhesion maturation. However, the molecular mechanisms underlying its functions are unclear. Here, by mechanical manipulation of single human α-actinin 1 using magnetic tweezers, we determined the mechanical stability and kinetics of the functional domains in α-actinin 1...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29209315/gradual-increase-of-fc%C3%AE-riiia-cd16a-expression-and-shift-toward-ifn-%C3%AE-secretion-during-differentiation-of-cd56dim-natural-killer-cells
#20
Laurie Lajoie, Nicolas Congy-Jolivet, Armelle Bolzec, Gilles Thibault
Natural killer (NK) cell effector functions include cytotoxicity and secretion of cytokines such as interferon-γ (IFN-γ). The immature CD56bright subset of human NK cells lacks expression of FcγRIIIa/CD16a, one of the low-affinity immunoglobulin G receptors, or exhibits low-density expression (CD56brightCD16-/dim) and produces IFN-γ in response to cytokine stimulation, whereas the mature CD56dimCD16+ subset is the most cytotoxic one. A further differentiation/maturation of the latter subset according to the gradual loss of NKG2A and/or gain of KIR2DL (CD158a and CD158b) has been demonstrated and the ability to produce IFN-γ in response to activating receptor (AR) co-engagement is gradually acquired during terminal differentiation...
2017: Frontiers in Immunology
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