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Activation induced cytidine deaminase

Christine Grundström, Anjani Kumar, Anshu Priya, Neema Negi, Thomas Grundström
B lymphocytes optimize antibody responses by class switch recombination (CSR), which changes the expressed constant region exon of the immunoglobulin heavy chain (IgH), and by somatic hypermutation (SH) that introduces point mutations in the variable regions of the antibody genes. Activation-induced cytidine deaminase (AID) is the key mutagenic enzyme that initiates both these antibody diversification processes by deaminating cytosine to uracil. Here we asked the question if transcription factors can mediate the specific targeting of the antibody diversification by recruiting AID...
August 8, 2018: European Journal of Immunology
Hyeseon Cho, Henrique Jaime, Rafael Pires de Oliveira, Byunghyun Kang, Rosanne Spolski, Tina Vaziri, Timothy G Myers, Vishal Thovarai, Zeli Shen, James G Fox, Warren J Leonard, Brian L Kelsall
Despite studies indicating the effects of IL-21 signaling in intestinal inflammation, its roles in intestinal homeostasis and infection are not yet clear. Here, we report potent effects of commensal microbiota on the phenotypic manifestations of IL-21 receptor deficiency. IL-21 is produced highly in the small intestine and appears to be critical for mounting an IgA response against atypical commensals such as segmented filamentous bacteria and Helicobacter, but not to the majority of commensals. In the presence of these atypical commensals, IL-21R-deficient mice exhibit reduced numbers of germinal center and IgA+ B cells and expression of activation-induced cytidine deaminase in Peyer's patches as well as a significant decrease in small intestine IgA+ plasmablasts and plasma cells, leading to higher bacterial burdens and subsequent expansion of Th17 and Treg cells...
August 7, 2018: Mucosal Immunology
Timothy Recaldin, Philip S Hobson, Elizabeth H Mann, Faruk Ramadani, David J Cousins, Paul Lavender, David J Fear
Class-switch recombination (CSR) is an essential B cell process that alters the isotype of antibody produced by the B cell, tailoring the immune response to the nature of the invading pathogen. CSR requires the activity of the mutagenic enzyme AID (encoded by AICDA) to generate chromosomal lesions within the immunoglobulin genes that initiate the class switching recombination event. These AID-mediated mutations also participate in somatic-hypermutation of the immunoglobulin variable region, driving affinity maturation...
August 3, 2018: Molecular Immunology
Hiroki Sasaguri, Kenichi Nagata, Misaki Sekiguchi, Ryo Fujioka, Yukio Matsuba, Shoko Hashimoto, Kaori Sato, Deepika Kurup, Takanori Yokota, Takaomi C Saido
Base Editor (BE) and Target-AID (activation-induced cytidine deaminase) are engineered genome-editing proteins composed of Cas9 and cytidine deaminases. These base-editing tools convert C:G base pairs to T:A at target sites. Here, we inject either BE or Target-AID mRNA together with identical single-guide RNAs (sgRNAs) into mouse zygotes, and compare the base-editing efficiencies of the two distinct tools in vivo. BE consistently show higher base-editing efficiency (10.0-62.8%) compared to that of Target-AID (3...
July 24, 2018: Nature Communications
Yoav Binenbaum, Eran Fridman, Zvi Yaari, Neta Milman, Avi Schroeder, Gil Ben David, Tomer Shlomi, Ziv Gil
Pancreatic ductal adenocarcinoma (PDAC) is known for its resistance to gemcitabine, which acts to inhibit cell growth by termination of DNA replication. Tumor-associated macrophages (TAM) were recently shown to contribute to gemcitabine resistance; however, the exact mechanism of this process is still unclear. Using a genetic mouse model of PDAC and electron microscopy analysis, we show that TAM communicate with the tumor microenvironment via secretion of ~90nm vesicles, which are selectively internalized by cancer cells...
July 24, 2018: Cancer Research
Danielle T Avery, Alisa Kane, Tina Nguyen, Anthony Lau, Akira Nguyen, Helen Lenthall, Kathryn Payne, Wei Shi, Henry Brigden, Elise French, Julia Bier, Jana R Hermes, David Zahra, William A Sewell, Danyal Butt, Michael Elliott, Kaan Boztug, Isabelle Meyts, Sharon Choo, Peter Hsu, Melanie Wong, Lucinda J Berglund, Paul Gray, Michael O'Sullivan, Theresa Cole, Steven M Holland, Cindy S Ma, Christoph Burkhart, Lynn M Corcoran, Tri Giang Phan, Robert Brink, Gulbu Uzel, Elissa K Deenick, Stuart G Tangye
Gain-of-function (GOF) mutations in PIK3CD , encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery...
August 6, 2018: Journal of Experimental Medicine
Victoria K Tesch, Hanna IJspeert, Andrea Raicht, Daniel Rueda, Nerea Dominguez-Pinilla, Luis M Allende, Chrystelle Colas, Thorsten Rosenbaum, Denisa Ilencikova, Hagit N Baris, Michaela H M Nathrath, Manon Suerink, Danuta Januszkiewicz-Lewandowska, Iman Ragab, Amedeo A Azizi, Soeren S Wenzel, Johannes Zschocke, Wolfgang Schwinger, Matthias Kloor, Claudia Blattmann, Laurence Brugieres, Mirjam van der Burg, Katharina Wimmer, Markus G Seidel
Immunoglobulin class-switch recombination (CSR) and somatic hypermutations (SHMs) are prerequisites for antibody and immunoglobulin receptor maturation and adaptive immune diversity. The mismatch repair (MMR) machinery, consisting of homologs of MutSα, MutLα, and MutSβ (MSH2/MSH6, MLH1/PMS2, and MSH2/MSH3, respectively) and other proteins, is involved in CSR, primarily acting as a backup for nonhomologous end-joining repair of activation-induced cytidine deaminase-induced DNA mismatches and, furthermore, in addition to error-prone polymerases, in the repair of SHM-induced DNA breaks...
2018: Frontiers in Immunology
Xiao-Fang Wei, You-Fan Feng, Qiao-Lin Chen, Qi-Ke Zhang
Background: As a disease of hematopoietic stem cell, chronic myeloid leukemia (CML) possesses unique biological and clinical features. However, the biologic mechanism underlying its development remains poorly understood. Thus, the objective of the present study is to discuss the effect of cytidine deaminase (CDA) gene silencing on the apoptosis and proliferation of CML K562 cells. Methods: CDA mRNA expression was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and enzymatic activity of CDA was measured by a nuclide liquid scintillation method...
2018: Cancer Cell International
Georgina Galicia, Dennis S W Lee, Valeria Ramaglia, Lesley A Ward, Jennifer Y Yam, Leslie Y T Leung, Rui Li, Marcus Handy, Junxian Zhang, Paulina C Drohomyrecky, Eric Lancaster, Amit Bar-Or, Alberto Martin, Jennifer L Gommerman
B cell-depleting therapies have been shown to ameliorate symptoms in multiple sclerosis (MS) patients; however, the mechanism of action remains unclear. Following priming with Ag, B cells undergo secondary diversification of their BCR, including BCR class-switch recombination (CSR) and somatic hypermutation (SHM), with both processes requiring the enzyme activation-induced (cytidine) deaminase. We previously reported that activation-induced (cytidine) deaminase is required for full clinical manifestation of disease in an animal model of MS (experimental autoimmune encephalomyelitis; EAE) provoked by immunization with the extracellular domain of recombinant human myelin oligodendrocyte glycoprotein (hMOG)...
July 6, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Rajib Ghosh, Debamitra Das, Sonia Franco
In response to DNA double strand breaks (DSB), mammalian cells activate the DNA Damage Response (DDR), a network of factors that coordinate their detection, signaling and repair. Central to this network is the ATM kinase and its substrates at chromatin surrounding DSBs H2AX, MDC1 and 53BP1. In humans, germline inactivation of ATM causes Ataxia Telangiectasia (A-T), an autosomal recessive syndrome of increased proneness to hematological malignancies driven by clonal chromosomal translocations. Studies of cancers arising in A-T patients and in genetically engineered mouse models (GEMM) deficient for ATM and its substrates have revealed complex, multilayered roles for ATM in translocation suppression and identified functional redundancies between ATM and its substrates in this context...
2018: Advances in Experimental Medicine and Biology
Tom S Weber
Adaptation of antibody-mediated immunity occurs in germinal centers (GC). It is where affinity maturation, class switching, memory and plasma cell differentiation synergize to generate specific high-affinity antibodies that aid both to clear and protect against reinfection of invading pathogens. Within GCs, light and dark zone are two compartments instrumental in regulating this process, by segregating T cell-dependent selection and differentiation from generation of GC B cells bearing hypermutated antigen receptors...
2018: Frontiers in Immunology
Atanu Maiti, Wazo Myint, Tapan Kanai, Krista Delviks-Frankenberry, Christina Sierra Rodriguez, Vinay K Pathak, Celia A Schiffer, Hiroshi Matsuo
The human APOBEC3G protein is a cytidine deaminase that generates cytidine to deoxy-uridine mutations in single-stranded DNA (ssDNA), and capable of restricting replication of HIV-1 by generating mutations in viral genome. The mechanism by which APOBEC3G specifically deaminates 5'-CC motifs has remained elusive since structural studies have been hampered due to apparently weak ssDNA binding of the catalytic domain of APOBEC3G. We overcame the problem by generating a highly active variant with higher ssDNA affinity...
June 25, 2018: Nature Communications
Talal Salem Al-Qaisi, Yu-Cheng Su, Steve R Roffler
Activation induced cytidine deaminase (AID) in germinal center B cells introduces somatic DNA mutations in transcribed immunoglobulin genes to increase antibody diversity. Ectopic expression of AID coupled with selection has been successfully employed to develop proteins with desirable properties. However, this process is laborious and time consuming because many rounds of selection are typically required to isolate the target proteins. AID expression can also adversely affect cell viability due to off target mutagenesis...
June 20, 2018: Scientific Reports
Jeremy K Haakenson, Ruiqi Huang, Vaughn V Smider
Typical antibodies found in humans and mice usually have short CDR H3s and generally flat binding surfaces. However, cows possess a subset of antibodies with ultralong CDR H3s that can range up to 70 amino acids and form a unique "stalk and knob" structure, with the knob protruding far out of the antibody surface, where it has the potential to bind antigens with concave epitopes. Activation-induced cytidine deaminase (AID) has a proven role in diversifying antibody repertoires in humoral immunity, and it has been found to induce somatic hypermutation in bovine immunoglobulin genes both before and after contact with antigen...
2018: Frontiers in Immunology
Ophélie Alyssa Martin, Armand Garot, Sandrine Le Noir, Jean-Claude Aldigier, Michel Cogné, Eric Pinaud, François Boyer
In B-lineage cells, the cytidine deaminase AID not only generates somatic mutations to variable regions of Ig genes but also inflicts, at a lower frequency, mutations to several non-Ig genes named AID off-targets, which include proto-oncogenes. High-throughput sequencing should be in principle the method of choice to detect and document these rare nucleotide substitutions. So far, high-throughput sequencing-based methods are impaired by a global sequencing error rate that usually covers the real mutation rate of AID off-target genes in activated B cells...
August 1, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Hiroshi Kimura
Epstein-Barr virus (EBV), which is associated with B-cell proliferative disorders, also transforms T- or natural killer (NK)-lineage cells and has been connected with various T- or NK (T/NK)-cell malignancies, such as extranodal NK/T-cell lymphoma-nasal type and aggressive NK-cell leukemia. Chronic active EBV (CAEBV) disease , which occurs most often in children and young adults in East Asia, is an EBV-associated T-/NK-cell lymphoproliferative disease. Patients with CAEBV often progress to overt lymphoma or leukemia over a long-term clinical course...
2018: Advances in Experimental Medicine and Biology
Sumaira Bilal, Kai Kristoffer Lie, Øystein Sæle, Ivar Hordvik
Previously, somatic hypermutation (SHM) was considered to be exclusively associated with affinity maturation of antibodies, although it also occurred in T cells under certain conditions. More recently, it has been shown that SHM generates diversity in the variable domain of T cell receptor (TCR) in camel and shark. Here, we report somatic mutations in TCR alpha chain genes of the teleost fish, Ballan wrasse ( Labrus bergylta ), and show that this mechanism adds extra diversity to the polymorphic constant (C) region as well...
2018: Frontiers in Immunology
Kevin Wiehe, Todd Bradley, R Ryan Meyerhoff, Connor Hart, Wilton B Williams, David Easterhoff, William J Faison, Thomas B Kepler, Kevin O Saunders, S Munir Alam, Mattia Bonsignori, Barton F Haynes
HIV-1 broadly neutralizing antibodies (bnAbs) require high levels of activation-induced cytidine deaminase (AID)-catalyzed somatic mutations for optimal neutralization potency. Probable mutations occur at sites of frequent AID activity, while improbable mutations occur where AID activity is infrequent. One bottleneck for induction of bnAbs is the evolution of viral envelopes (Envs) that can select bnAb B cell receptors (BCR) with improbable mutations. Here we define the probability of bnAb mutations and demonstrate the functional significance of key improbable mutations in three bnAb B cell lineages...
June 13, 2018: Cell Host & Microbe
Mel Greaves
In this Review, I present evidence supporting a multifactorial causation of childhood acute lymphoblastic leukaemia (ALL), a major subtype of paediatric cancer. ALL evolves in two discrete steps. First, in utero initiation by fusion gene formation or hyperdiploidy generates a covert, pre-leukaemic clone. Second, in a small fraction of these cases, the postnatal acquisition of secondary genetic changes (primarily V(D)J recombination-activating protein (RAG) and activation-induced cytidine deaminase (AID)-driven copy number alterations in the case of ETS translocation variant 6 (ETV6)-runt-related transcription factor 1 (RUNX1)+ ALL) drives conversion to overt leukaemia...
August 2018: Nature Reviews. Cancer
Zenpei Shimatani, Ushio Fujikura, Hisaki Ishii, Yusuke Matsui, Minoru Suzuki, Yuki Ueke, Ken-Ichiro Taoka, Rie Terada, Keiji Nishida, Akihiko Kondo
The CRISPR/Cas9 system is a revolutionary genome-editing tool for directed gene editing in various organisms. Cas9 variants can be applied as molecular homing devices when combined with various functional effectors such as transcriptional activators or DNA modification enzymes. Target-AID is a synthetic complex of nuclease deficient Cas9 fused to an activation-induced cytidine deaminase (AID) that enables targeted nucleotide substitution (C to T or G to A). We previously demonstrated that the introduction of desired point mutations into target genes by Target-AID confers herbicide tolerance to rice callus...
April 25, 2018: Plant Physiology and Biochemistry: PPB
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