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https://www.readbyqxmd.com/read/28972092/ship-1-deficiency-in-aid-b-cells-leads-to-the-impaired-function-of-b10-cells-with-spontaneous-autoimmunity
#1
Yingjia Chen, Fanlei Hu, Xuejiao Dong, Meng Zhao, Jing Wang, Xiaolin Sun, Tae Jin Kim, Zhanguo Li, Wanli Liu
Unlike conventional B cells, regulatory B cells exhibit immunosuppressive functions to downregulate inflammation via IL-10 production. However, the molecular mechanism regulating the production of IL-10 is not fully understood. In this study, we report the finding that activation-induced cytidine deaminase (AID) is highly upregulated in the IL-10-competent B cell (B10) cell from Innp5d(fl/fl)Aicda(Cre/+) mice, whereas the 5' inositol phosphatase SHIP-1 is downregulated. Notably, SHIP-1 deficiency in AID(+) B cells leads to a reduction in cell count and impaired IL-10 production by B10 cells...
November 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28955333/accelerated-systemic-autoimmunity-in-the-absence-of-somatic-hypermutation-in-564igi-a-mouse-model-of-systemic-lupus-with-knocked-in-heavy-and-light-chain-genes
#2
Gabrielle McDonald, Carlos O Medina, Monika Pilichowska, John F Kearney, Reiko Shinkura, Erik Selsing, Henry H Wortis, Tasuku Honjo, Thereza Imanishi-Kari
564Igi mice have knocked-in immunoglobulin (Ig) heavy (H) and light (L) chain genes that encode an autoantibody recognizing RNA. Previously, we showed that these mice produce pathogenic IgG autoantibodies when activation-induced deaminase (AID) is expressed in pre-B and immature B cells but not when it is expressed only in mature B cells. AID has two functions; it is necessary for somatic hypermutation (SHM) and class switch recombination (CSR). To determine the role of each of these functions in the generation of pathogenic autoantibodies, we generated 564Igi mice that carry a mutant AID-encoding gene, Aicda (Aicda(G23S)), which is capable of promoting CSR but not SHM...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28676801/cd25-b-1a-cells-express-aicda
#3
Hiroaki Kaku, Nichol E Holodick, Joseph R Tumang, Thomas L Rothstein
B-1a cells are innate-like B-lymphocytes producing natural antibodies. Activation-induced cytidine deaminase (AID), a product of the Aicda gene, plays a central role in class-switch recombination and somatic hypermutation in B cells. Although a role for Aicda in B-1a cells has been suggested on the basis of experiments with knock out (KO) mice, whether B-1a cells express Aicda, and if so, which B-1a cell subpopulation expresses Aicda, remains unknown. Here, we demonstrate that B-1 cells express Aicda, but at a level below that expressed by germinal center (GC) B cells...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28589361/the-aid-cre-ert2-model-a-tool-for-monitoring-b-cell-immune-responses-and-generating-selective-hybridomas
#4
Simon Le Gallou, Takuya Nojima, Daisuke Kitamura, Jean-Claude Weill, Claude-Agnès Reynaud
Expression of activation-induced cytidine deaminase (AID) is the hallmark of B cells engaged in an immune response in germinal centers. We designed an inducible fate-mapping reporter mouse in which AID-expressing B cells could be timely and irreversibly marked, by knockin at the Aicda locus of a tamoxifen-inducible Cre recombinase. This mouse model allows notably for the long-term follow-up of memory B cells and plasma cells engaged in an immune response. We describe here a protocol to generate hybridomas from small memory subsets that can be easily traced and identified in this mouse line through Cre-activated fluorescent reporters...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28575114/early-derivation-of-igm-memory-cells-and-bone-marrow-plasmablasts
#5
Amber M Papillion, Kevin J Kenderes, Jennifer L Yates, Gary M Winslow
IgM memory cells are recognized as an important component of B cell memory in mice and humans. Our studies of B cells elicited in response to ehrlichial infection identified a population of CD11c-positive IgM memory cells, and an IgM bone marrow antibody-secreting cell population. The origin of these cells was unknown, although an early T-independent spleen CD11c- and T-bet-positive IgM plasmablast population precedes both, suggesting a linear relationship. A majority of the IgM memory cells detected after day 30 post-infection, also T-bet-positive, had undergone somatic hypermutation, indicating they expressed activation-induced cytidine deaminase (AID)...
2017: PloS One
https://www.readbyqxmd.com/read/28421278/an-efficient-method-to-enrich-for-knock-out-and-knock-in-cellular-clones-using-the-crispr-cas9-system
#6
Francesca Niccheri, Riccardo Pecori, Silvestro G Conticello
Clustered Regularly Interspaced Short Palindromic Repeats-associated protein 9 nuclease (CRISPR/Cas9) and Transcription Activator-Like Effector Nucleases (TALENs) are versatile tools for genome editing. Here we report a method to increase the frequency of Cas9-targeted cellular clones. Our method is based on a chimeric construct with a Blasticidin S Resistance gene (bsr) placed out-of-frame by a surrogate target sequence. End joining of the CRISPR/Cas9-induced double-strand break on the surrogate target can place the bsr in frame, thus providing temporary resistance to Blasticidin S: this is used to enrich for cells where Cas9 is active...
September 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28302172/transcriptome-analysis-of-bronchoalveolar-lavage-fluid-from-children-with-severe-mycoplasma-pneumoniae-pneumonia-reveals-novel-gene-expression-and-immunodeficiency
#7
Kuo Wang, Man Gao, Mingyue Yang, Fanzheng Meng, Deli Li, Ruihua Lu, Yan Wang, Huadong Zhuang, Mengyao Li, Genhong Cheng, Xiaosong Wang
BACKGROUND: A growing number of severe Mycoplasma pneumoniae pneumonia (MPP) cases have been reported recently. However, the pathogenesis of severe MPP is not clear. In the current study, transcriptome sequencing was used to identify gene expression and alternative splicing profiles to provide insights into the pathogenesis of severe MPP. METHODS: RNAs of bronchoalveolar lavage fluid (BALF) samples from three severe MPP children and three mild MPP children were analyzed respectively by deep sequencing followed by computational annotation and quantification...
March 16, 2017: Human Genomics
https://www.readbyqxmd.com/read/28247997/bcl2-mutations-do-not-confer-adverse-prognosis-in-follicular-lymphoma-patients-treated-with-rituximab
#8
Sarah Huet, Edith Szafer-Glusman, Bruno Tesson, Luc Xerri, Wayne J Fairbrother, Kiran Mukhyala, Chris Bolen, Elizabeth Punnoose, Laurie Tonon, Catherine Chassagne-Clément, Pierre Feugier, Alain Viari, Fabrice Jardin, Gilles Salles, Pierre Sujobert
BCL2 mutations have been suggested to confer an adverse prognosis to follicular lymphoma (FL) patients, but their prognostic value has not been assessed in patients treated with a rituximab-containing regimen. Here we evaluated the prognostic value of BCL2 mutations in a large prospective cohort of 252 patients with FL treated with immunochemotherapy in the PRIMA randomized trial. Using a DNA-targeted sequencing approach, we detected amino acid altering mutations in 135 patients (54%) and showed that these mutations were probably mediated by the over-activation of AICDA (activation-induced cytidine deaminase) in the context of the t(14;18) translocation...
June 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28143955/the-eph-related-tyrosine-kinase-ligand-ephrin-b1-marks-germinal-center-and-memory-precursor-b-cells
#9
Brian J Laidlaw, Timothy H Schmidt, Jesse A Green, Christopher D C Allen, Takaharu Okada, Jason G Cyster
Identification of germinal center (GC) B cells is typically reliant on the use of surface activation markers that exhibit a wide range of expression. Here, we identify Ephrin-B1, a ligand for Eph-related receptor tyrosine kinases, as a specific marker of mature GC B cells. The number of Ephrin-B1(+) GC B cells increases during the course of an immune response with Ephrin-B1(+) GC B cells displaying elevated levels of Bcl6, S1pr2, and Aicda relative to their Ephrin-B1(-) counterparts. We further identified a small proportion of recently dividing, somatically mutated Ephrin-B1(+) GC B cells that have begun to down-regulate Bcl6 and S1pr2 and express markers associated with memory B cells, such as CD38 and EBI2...
March 6, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28063995/activation-of-tnf-%C3%AE-aid-axis-and-co-inhibitory-signals-in-coordination-with-th1-type-immunity-in-a-mouse-model-recapitulating-hepatitis-b
#10
Tomonori Matsumoto, Ken Takahashi, Tadashi Inuzuka, Soo Ki Kim, Tomoaki Kurosaki, Shigeru Kawakami, Tsutomu Chiba, Hiroshi Seno, Hiroyuki Marusawa
Hepatitis B virus (HBV) infection evokes host immune responses that primarily determine the outcome of HBV infection and the clinical features of HBV-associated liver disease. The precise mechanisms by which host factors restrict HBV replication, however, are poorly understood due to the lack of useful animal models that recapitulate immune responses to HBV. Here, we performed comprehensive immunologic gene expression profiling of the liver of a mouse model recapitulating anti-HBV immune response using a high sensitivity direct digital counting system...
January 5, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28057924/tyrosine-kinase-c-abl-regulates-the-survival-of-plasma-cells
#11
Yan-Feng Li, Shengli Xu, Yuhan Huang, Xijun Ou, Kong-Peng Lam
Tyrosine kinase c-Abl plays an important role in early B cell development. Its deletion leads to reduced pro- and pre-B cell generation in mice. However, its function in B cell terminal differentiation remains unexplored. Here, we used c-Abl(f/f) Aicda(cre/+) mice, in which c-Abl is ablated only in antigen-activated B cells, to study the role of c-Abl in germinal center (GC) B and antibody-secreting plasma cell formation. Upon challenge with a model antigen, we found normal GC and memory B but reduced plasma cells and antigen-specific antibody response in the mutant mice...
January 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/27897229/global-gene-regulation-during-activation-of-immunoglobulin-class-switching-in-human-b-cells
#12
Youming Zhang, David J Fear, Saffron A G Willis-Owen, William O Cookson, Miriam F Moffatt
Immunoglobulin class switch recombination (CSR) to IgE is a tightly regulated process central to atopic disease. To profile the B-cell transcriptional responses underlying the activation of the germinal centre activities leading to the generation of IgE, naïve human B-cells were stimulated with IL-4 and anti-CD40. Gene expression and alternative splicing were profiled over 12 days using the Affymetrix Human Exon 1.0 ST Array. A total of 1,399 genes, forming 13 temporal profiles were differentially expressed...
November 29, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27793425/impact-of-tofacitinib-treatment-on-human-b-cells-in%C3%A2-vitro-and-in%C3%A2-vivo
#13
Marta Rizzi, Raquel Lorenzetti, Kathleen Fischer, Julian Staniek, Iga Janowska, Arianna Troilo, Valentina Strohmeier, Miriam Erlacher, Mirjam Kunze, Bettina Bannert, Diego Kyburz, Reinhard E Voll, Nils Venhoff, Jens Thiel
B-cells are pivotal to the pathogenesis of rheumatoid arthritis and tofacitinib, a JAK inhibitor, is effective and safe in its treatment. Tofacitinib interferes with signal transduction via cytokine receptors using the common γ-chain. Despite extensive data on T-lymphocytes, the impact of tofacitinib on B-lymphocytes is poorly understood. In this study we assessed the effect of tofacitinib on B-lymphocyte differentiation and function. Tofacitinib treatment strongly impaired in vitro plasmablast development, immunoglobulin secretion and induction of B-cell fate determining transcription factors, Blimp-1, Xbp-1, and IRF-4, in naïve B-cells...
February 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/27789066/novel-aicda-mutation-in-a-case-of-autosomal-recessive-hyper-igm-syndrome-growth-hormone-deficiency-and-autoimmunity
#14
A Fazel, S Kashef, S Aleyasin, S Harsini, Z Karamizadeh, S Zoghi, S K Flores, K Boztug, N Rezaei
BACKGROUND: The Hyper-immunoglobulin M syndromes (HIGM) are a heterogeneous group of genetic disorders, which have been rarely reported to be associated with growth hormone deficiency (GHD). METHODS AND RESULTS: A nine-year-old girl with recurrent urinary tract infections, diarrhoea, sinopulmonary infections, and failure to thrive since the age of six months had normal CD3+, CD4+, CD8+T lymphocytes, and CD19+B lymphocytes and natural killer (NK) cells, but extremely elevated IgM and significantly decreased IgG and IgA...
January 2017: Allergologia et Immunopathologia
https://www.readbyqxmd.com/read/27716525/activation-induced-cytidine-deaminase-mutant-aid-his130pro-from-hyper-igm-2-patient-retained-mutagenic-activity-on-shm-artificial-substrate
#15
Hanen Ouadani, Imen Ben-Mustapha, Meriem Ben-Ali, Beya Larguèche, Tihana Jovanic, Sylvie Garcia, Benoit Arcangioli, Houda Elloumi-Zghal, Dahmani Fathallah, Mongia Hachicha, Hatem Masmoudi, François Rougeon, Mohamed-Ridha Barbouche
Activation induced cytidine deaminase (AID) is an essential enzyme for class switch recombination (CSR) and somatic hypermutation (SHM) during secondary immune response. Mutations in the AICDA gene are responsible for Hyper IgM 2 syndrome where both CSR and SHM or only CSR are affected. Indeed, triggering either of the two mechanisms requires the DNA deamination activity of AID. Besides, different domains of AID may be differentially involved in CSR and SHM through their interaction with specific cofactors...
November 2016: Molecular Immunology
https://www.readbyqxmd.com/read/27701145/decreased-somatic-hypermutation-induces-an-impaired-peripheral-b-cell-tolerance-checkpoint
#16
Tineke Cantaert, Jean-Nicolas Schickel, Jason M Bannock, Yen-Shing Ng, Christopher Massad, Fabien R Delmotte, Natsuko Yamakawa, Salome Glauzy, Nicolas Chamberlain, Tuure Kinnunen, Laurence Menard, Aubert Lavoie, Jolan E Walter, Luigi D Notarangelo, Julie Bruneau, Waleed Al-Herz, Sara Sebnem Kilic, Hans D Ochs, Charlotte Cunningham-Rundles, Mirjam van der Burg, Taco W Kuijpers, Sven Kracker, Hideo Kaneko, Yujin Sekinaka, Shigeaki Nonoyama, Anne Durandy, Eric Meffre
Patients with mutations in AICDA, which encodes activation-induced cytidine deaminase (AID), display an impaired peripheral B cell tolerance. AID mediates class-switch recombination (CSR) and somatic hypermutation (SHM) in B cells, but the mechanism by which AID prevents the accumulation of autoreactive B cells in blood is unclear. Here, we analyzed B cell tolerance in AID-deficient patients, patients with autosomal dominant AID mutations (AD-AID), asymptomatic AICDA heterozygotes (AID+/-), and patients with uracil N-glycosylase (UNG) deficiency, which impairs CSR but not SHM...
November 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27504894/developmental-toxicity-of-zinc-oxide-nanoparticles-to-zebrafish-danio-rerio-a-transcriptomic-analysis
#17
Jin Soo Choi, Ryeo-Ok Kim, Seokjoo Yoon, Woo-Keun Kim
Zinc oxide nanoparticles (ZnO NPs) are being utilized in an increasing number of fields and commercial applications. While their general toxicity and associated oxidative stress have been extensively studied, the toxicological pathways that they induce in developmental stages are still largely unknown. In this study, the developmental toxicity of ZnO NPs to embryonic/larval zebrafish was investigated. The transcriptional expression profiles induced by ZnO NPs were also investigated to ascertain novel genomic responses related to their specific toxicity pathway...
2016: PloS One
https://www.readbyqxmd.com/read/27301862/transcriptome-sequencing-reveals-a-profile-that-corresponds-to-genomic-variants-in-waldenstr%C3%A3-m-macroglobulinemia
#18
Zachary R Hunter, Lian Xu, Guang Yang, Nicholas Tsakmaklis, Josephine M Vos, Xia Liu, Jie Chen, Robert J Manning, Jiaji G Chen, Philip Brodsky, Christopher J Patterson, Joshua Gustine, Toni Dubeau, Jorge J Castillo, Kenneth C Anderson, Nikhil M Munshi, Steven P Treon
Whole-genome sequencing has identified highly prevalent somatic mutations including MYD88, CXCR4, and ARID1A in Waldenström macroglobulinemia (WM). The impact of these and other somatic mutations on transcriptional regulation in WM remains to be clarified. We performed next-generation transcriptional profiling in 57 WM patients and compared findings to healthy donor B cells. Compared with healthy donors, WM patient samples showed greatly enhanced expression of the VDJ recombination genes DNTT, RAG1, and RAG2, but not AICDA Genes related to CXCR4 signaling were also upregulated and included CXCR4, CXCL12, and VCAM1 regardless of CXCR4 mutation status, indicating a potential role for CXCR4 signaling in all WM patients...
August 11, 2016: Blood
https://www.readbyqxmd.com/read/27297329/characterization-of-memory-b-cells-from-thymus-and-its-impact-for-dlbcl-classification
#19
Kim Steve Bergkvist, Martin Agge Nørgaard, Martin Bøgsted, Alexander Schmitz, Mette Nyegaard, Michael Gaihede, John Bæch, Marie-Louise Grønholdt, Frank Svendsen Jensen, Preben Johansen, Thomas Urup, Tarec C El-Galaly, Jakob Madsen, Julie Støve Bødker, Karen Dybkær, Hans Erik Johnsen
The rare memory B cells in thymus (Thy) are considered the cells of origin for primary mediastinal large B-cell lymphoma. The objectives of the present study were to characterize the normal memory B-cell compartment in Thy and to support its association with primary mediastinal B-cell lymphoma. Seven paired human tissue samples from Thy and sternum bone marrow (BM) were harvested during cardiac surgery. B-cell subsets were phenotyped by Euroflow standard and fluorescence-activated cell sorting for microarray analysis on the Human Exon 1...
October 2016: Experimental Hematology
https://www.readbyqxmd.com/read/27261530/molecular-functions-of-the-transcription-factors-e2a-and-e2-2-in-controlling-germinal-center-b-cell-and-plasma-cell-development
#20
Miriam Wöhner, Hiromi Tagoh, Ivan Bilic, Markus Jaritz, Daniela Kostanova Poliakova, Maria Fischer, Meinrad Busslinger
E2A is an essential regulator of early B cell development. Here, we have demonstrated that E2A together with E2-2 controlled germinal center (GC) B cell and plasma cell development. As shown by the identification of regulated E2A,E2-2 target genes in activated B cells, these E-proteins directly activated genes with important functions in GC B cells and plasma cells by inducing and maintaining DNase I hypersensitive sites. Through binding to multiple enhancers in the Igh 3' regulatory region and Aicda locus, E-proteins regulated class switch recombination by inducing both Igh germline transcription and AID expression...
June 27, 2016: Journal of Experimental Medicine
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