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Activation induced cytidine deaminase

Chiara Farroni, Emiliano Marasco, Valentina Marcellini, Ezio Giorda, Diletta Valentini, Stefania Petrini, Valentina D'Oria, Marco Pezzullo, Simona Cascioli, Marco Scarsella, Alberto G Ugazio, Giovanni C De Vincentiis, Ola Grimsholm, Rita Carsetti
Children with Down Syndrome (DS) suffer from immune deficiency with a severe reduction in switched memory B cells (MBCs) and poor response to vaccination. Chromosome 21 (HSA21) encodes two microRNAs (miRs), miR-125b, and miR-155, that regulate B-cell responses. We studied B- and T- cell subpopulations in tonsils of DS and age-matched healthy donors (HD) and found that the germinal center (GC) reaction was impaired in DS. GC size, numbers of GC B cells and Follicular Helper T cells (TFH ) expressing BCL6 cells were severely reduced...
2018: Frontiers in Immunology
Tadashi Yoshino, Katsuyoshi Takata, Takehiro Tanaka, Yasuharu Sato, Akira Tari, Hiroyuki Okada
The incidence of lymphoma has rapidly increased over the last 40 years in Japan, following a trend that is very similar to that of breast cancer. In particular, the relative frequency of follicular lymphoma (FL) has reached that in Western countries. Given its indolence, a "watch-and-wait" approach is often applied to FL patients. We have shown that FL is often detected in the second portion of the duodenum and has a distinct follicular dendritic cell distribution and heavy chain variable usage similar to mucosa-associated lymphoid tissue (MALT) lymphoma...
November 20, 2018: Pathology International
Cai Zong, Yusuke Kimura, Kazuo Kinoshita, Shigetada Takasu, Xiao Zhang, Toshihiro Sakurai, Yoshitaka Sekido, Sahoko Ichihara, Ginji Endo, Gaku Ichihara
Background: 1,2-dichloropropane (1,2-DCP) was reclassified recently by IARC as a Group 1 carcinogen based on epidemiological studies on an outbreak of cholangiocarcinoma in offset-printing workers exposed to 1,2-DCP in Japan. However, the underlying mechanism of 1,2-DCP-induced cholangiocarcinoma remains obscure. A previous whole-genome mutation analysis of cholangiocarcinoma of four cases exposed to 1,2-DCP suggested the involvement of activation-induced cytidine deaminase (AID), based on specific signatures of mutation patterns...
November 19, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
Nazanin Mohammadzadeh, Tyson B Follack, Robin P Love, Kris Stewart, Stephen Sanche, Linda Chelico
The APOBEC3 enzyme family are host restriction factors that induce mutagenesis of HIV-1 proviral genomes through the deamination of cytosine to form uracil in nascent single-stranded (-)DNA. HIV-1 suppresses APOBEC3 activity through the HIV-1 protein Vif that induces APOBEC3 degradation. Here we compared two common polymorphisms of APOBEC3F. We found that although both polymorphisms have HIV-1 restriction activity, APOBEC3F 108 A/231V can restrict HIV-1 ΔVif up to 4-fold more than APOBEC3F 108 S/231I and is partially protected from Vif-mediated degradation...
November 15, 2018: Virology
Kristina Zaprazna, Kamila Reblova, Veronika Svobodova, Lenka Radova, Vojtech Bystry, Jiri Baloun, Kristina Durechova, Nikola Tom, Tomas Loja, Martina Buresova, Kamila Stranska, Alexandra Oltova, Michael Doubek, Michael L Atchison, Martin Trbusek, Jitka Malcikova, Sarka Pospisilova
Activation-induced cytidine deaminase (AID) is a mutator enzyme essential for somatic hypermutation (SHM) and class switch recombination (CSR) during effective adaptive immune responses. Its aberrant expression and activity have been detected in lymphomas, leukemias, and solid tumors. In chronic lymphocytic leukemia (CLL) increased expression of alternatively spliced AID variants has been documented. We used real-time RT-PCR to quantify the expression of AID and its alternatively spliced transcripts (AIDΔE4a, AIDΔE4, AIDivs3, and AIDΔE3E4) in 149 CLL patients and correlated this expression to prognostic markers including recurrent chromosomal aberrations, the presence of complex karyotype, mutation status of the immunoglobulin heavy chain variable gene, and recurrent mutations...
October 27, 2018: Annals of Hematology
J Jiao, Y Jin, M Zheng, H Zhang, M Yuan, Z Lv, W Odhiambo, X Yu, P Zhang, C Li, Y Ma, Y Ji
Diffuse large B cell lymphoma (DLBCL) is traced to a mature B malignance carrying abnormal activation-induced cytidine deaminase (AID) expression. AID activity initially focuses on deamination of cytidine to uracil to generate somatic hypermutation and class-switch recombination of the immunoglobulin (Ig), but recently it has been implicated in DNA demethylation of genes required for B cell development and proliferation in the germinal centre (GC). However, whether AID activity on mutation or demethylation of genes involves oncogenesis of DLBCL has not been well characterized...
October 25, 2018: Clinical and Experimental Immunology
Masamichi Muramatsu, Kazuo Kinoshita, Sidonia Fagarasan, Shuichi Yamada, Yoichi Shinkai, Tasuku Honjo
No abstract text is available yet for this article.
November 1, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Rachel A Woolaver, Xiaoguang Wang, Yonatan Dollin, Ping Xie, Jing H Wang, Zhangguo Chen
Effective humoral immunity requires class switch recombination (CSR) catalyzed by activation-induced cytidine deaminase (AID). In response to T cell-dependent (TD) Ags, CSR can be induced by CD40 signaling in B cells. TNFR-associated factors 2 and 3 (TRAF2/TRAF3) function as adaptors of the CD40 signaling pathway. B cell-intrinsic TRAF2 or TRAF3 (B-TRAF2 or B-TRAF3) knockout mice were previously reported to have indistinguishable phenotypes in gene expression, B cell survival and development, and enlarged peripheral lymphoid organs...
December 1, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Jeffrey R Atkinson, Mihyun Hwang, Angel Reyes-Rodriguez, Cornelia C Bergmann
Humoral responses within the central nervous system (CNS) are common to many neurotropic viral infections, with antibody (Ab) secreting cells (ASC) contributing to local protection. However, a role for virus-specific memory B cells (Bmem) within the CNS is poorly explored due to lack of robust phenotypic or functional identification in mice. This study takes advantage of mice expressing tamoxifen-inducible Cre recombinase (Cre-ERT2) under the Aicda promoter crossed with Rosa26-loxP-tdTomato reporter mice (AIDCre -Rosa26tdTomato ) to monitor B cells having undergone activation-induced cytidine deaminase (AID)-mediated somatic hypermutation (SHM) following neurotropic coronavirus infection...
October 17, 2018: Journal of Virology
Najwa El Kadi, Luo Wang, April Davis, Hasan Korkaya, Alexander Cooke, Varun Vadnala, Noah A Brown, Bryan L Betz, Marilia Cascalho, Gregory P Kalemkerian, Khaled A Hassan
Almost all patients with EGFR-driven lung cancer who are treated with EGFR tyrosine kinase inhibitors (TKI) develop resistance to treatment. A single base (c.2369C>T) transition mutation, EGFR T790M, is the most frequent resistance event after first-generation exposure to EGFR TKIs. Whether T790M mutation is acquired or is selected from a preexisting clone has been a matter of significant debate. In this study, we show that treatment with EGFR TKIs leads to activation of the NFκB pathway, which in turn induces expression of activation-induced cytidine deaminase (AICDA)...
October 17, 2018: Cancer Research
Verónica Delgado-Benito, Daniel B Rosen, Qiao Wang, Anna Gazumyan, Joy A Pai, Thiago Y Oliveira, Devakumar Sundaravinayagam, Wenzhu Zhang, Matteo Andreani, Lisa Keller, Kyong-Rim Kieffer-Kwon, Aleksandra Pękowska, Seolkyoung Jung, Madlen Driesner, Roman I Subbotin, Rafael Casellas, Brian T Chait, Michel C Nussenzweig, Michela Di Virgilio
Class switch recombination (CSR) is a DNA recombination reaction that diversifies the effector component of antibody responses. CSR is initiated by activation-induced cytidine deaminase (AID), which targets transcriptionally active immunoglobulin heavy chain (Igh) switch donor and acceptor DNA. The 3' Igh super-enhancer, 3' regulatory region (3'RR), is essential for acceptor region transcription, but how this function is regulated is unknown. Here, we identify the chromatin reader ZMYND8 as an essential regulator of the 3'RR...
November 15, 2018: Molecular Cell
Juanjuan Yuan, Yunqing Ma, Tao Huang, Yanhao Chen, Yuanzheng Peng, Bing Li, Jia Li, Yuchen Zhang, Bing Song, Xiaofang Sun, Qiurong Ding, Yan Song, Xing Chang
RNA splicing is a critical mechanism by which to modify transcriptome, and its dysregulation is the underlying cause of many human diseases. It remains challenging, however, to genetically modulate a splicing event in its native context. Here, we demonstrate that a CRISPR-guided cytidine deaminase (i.e., targeted-AID mediated mutagenesis [TAM]) can efficiently modulate various forms of mRNA splicing. By converting invariant guanines to adenines at either 5' or 3' splice sites (SS), TAM induces exon skipping, activation of alternative SS, switching between mutually exclusive exons, or targeted intron retention...
October 18, 2018: Molecular Cell
Simar Pal Singh, Marjolein J W de Bruijn, Mariana P de Almeida, Ruud W J Meijers, Lars Nitschke, Anton W Langerak, Saravanan Y Pillai, Ralph Stadhouders, Rudi W Hendriks
Chronic lymphocytic leukemia (CLL) can be divided into prognostically distinct subsets with stereotyped or non-stereotyped, mutated or unmutated B cell receptors (BCRs). Individual subsets vary in antigen specificity and origin, but the impact of antigenic pressure on the CLL BCR repertoire remains unknown. Here, we employed IgH.TE μ mice that spontaneously develop CLL, expressing mostly unmutated BCRs of which ~35% harbor VH 11-2/Vκ14-126 and recognize phosphatidylcholine. Proportions of VH 11/Vκ14-expressing CLL were increased in the absence of functional germinal centers in IgH...
2018: Frontiers in Immunology
Yunxiang Mu, Kevin M McBride
The mutations induced by activation-induced cytidine deaminase (AID) trigger antibody diversification but can cause genome instability. We find that AID phosphorylation is an important determinant of "off-target" mutagenesis and identify a drug that increases this activity. These studies demonstrate how dysregulating AID phosphorylation can promote oncogenesis.
2018: Molecular & Cellular Oncology
Shengcai Yang, Dawei Zhang, Na Shen, Guanyi Wang, Zhaohui Tang, Xuesi Chen
Ovarian cancer is the major cause of death in women gynecological malignancy and gemcitabine (GEM) is commonly used in related chemotherapy. However, more than 90% GEM is catalyzed into an inactive metabolite 2'-deoxy-2',2'-difluorouridine by stromal and cellular cytidine deaminase (CDA). Dihydroartemisinin (DHA), which possesses an intramolecular endoperoxide bridge, could be activated by heme or ferrous iron to produce reactive oxygen species (ROS). The excess ROS generation will excite expression of heme oxygenase-1 and suppress CDA expression...
January 2019: Journal of Cellular Biochemistry
Masayuki Kuraoka, Eric Meffre, Garnett Kelsoe
Activation-induced cytidine deaminase (AID) expression in the germinal center response drives the immunoglobulin class-switch recombination and V(D)J hypermutation necessary for efficacious, high-affinity antibody responses. That AID is expressed in developing lymphocytes is less well known, but represents an evolutionarily conserved pattern of lymphocyte development that is represented in all vertebrate species. Here we review the role of early, developmentally regulated AID expression in mice and humans and its role in establishing the first B-cell tolerance checkpoint...
2018: Advances in Immunology
David H Phillips
Reporter gene assays, in which a single mutation from each experiment can contribute to the assembly of a mutation spectrum for an agent, have provided the basis for understanding the mutational processes induced by mutagenic agents and for providing clues to the origins of mutations in human tumours. More recently exome and whole genome sequencing of human tumours has revealed distinct patterns of mutation that could provide additional clues for the causative origins of cancer. This can be tested by examining the mutational signatures induced in experimental systems by putative cancer-causing agents...
August 24, 2018: DNA Repair
Lindsay K Nicholson, Harsh Pratap, Elisabeth Bowers, Elise Gunzburger, Srinivasa R Bandi, Edward M Gardner, Brent E Palmer, Timothy Wright, John Kittelson, Edward N Janoff
Identifying HIV-1-associated B cell defects and responses to activation may direct interventions to circumvent their impaired antibody responses to infection and vaccines. Among 34 viremic HIV-1-infected and 20 seronegative control adults, we measured baseline frequencies and activation of B and T cell subsets, expression of activation-induced cytidine deaminase (AID), potential determinants of B cell activation in vivo and B and T cell responses in vitro. At baseline, HIV-1 infection was associated with increased IgM memory and decreased anergic cell frequencies, as well as increased activation in all 10 B cell subsets compared with controls...
December 2018: Immunobiology
Peter M Bowers, William J Boyle, Robert Damoiseaux
The engineering of antibodies and antibody fragments for affinity maturation, stability, and other biophysical characteristics is a common aspect of therapeutic development. Maturation of antibodies in B cells during the adaptive immune response is the result of a process called somatic hypermutation (SHM), in which the activation-induced cytidine deaminase (AID) acts to introduce mutations into immunoglobulin (Ig) genes. Iterative selection and clonal expansion of B cells containing affinity-enhancing mutations drive an increase in the overall affinity of antibodies...
2018: Methods in Molecular Biology
John J Wilson, Kin-Hoe Chow, Nathan J Labrie, Jane A Branca, Thomas J Sproule, Bryant R A Perkins, Elise E Wolf, Mauro Costa, Grace Stafford, Christine Rosales, Kevin D Mills, Derry C Roopenian, Muneer G Hasham
Targeting the early steps of the glycolysis pathway in cancers is a well-established therapeutic strategy; however, the doses required to elicit a therapeutic effect on the cancer can be toxic to the patient. Consequently, numerous preclinical and clinical studies have combined glycolytic blockade with other therapies. However, most of these other therapies do not specifically target cancer cells, and thus adversely affect normal tissue. Here we first show that a diverse number of cancer models - spontaneous, patient-derived xenografted tumor samples, and xenografted human cancer cells - can be efficiently targeted by 2-deoxy-D-Glucose (2DG), a well-known glycolytic inhibitor...
September 5, 2018: Cancer Biology & Therapy
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