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V(d)J recombination

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https://www.readbyqxmd.com/read/29659703/b-cell-receptor-reconstruction-from-single-cell-rna-seq-with-vdjpuzzle
#1
Simone Rizzetto, David N P Koppstein, Jerome Samir, Mandeep Singh, Joanne H Reed, Curtis H Cai, Andrew R Lloyd, Auda A Eltahla, Christopher C Goodnow, Fabio Luciani
Motivation: The B-cell receptor (BCR) performs essential functions for the adaptive immune system including recognition of pathogen-derived antigens. The vast repertoire and adaptive variation of BCR sequences due to V(D)J recombination and somatic hypermutation (SHM) necessitates single-cell characterization of BCR sequences. Single-cell RNA sequencing (scRNA-seq) presents the opportunity for simultaneous capture of paired BCR heavy and light chains and the transcriptomic signature. Results: We developed VDJPuzzle, a novel bioinformatic tool that reconstructs productive, full-length B-cell receptor sequences of both heavy and light chains and extract somatic mutations on the VDJ region...
April 5, 2018: Bioinformatics
https://www.readbyqxmd.com/read/29659614/kshv-induces-immunoglobulin-rearrangements-in-mature-b-lymphocytes
#2
Jennifer Totonchy, Jessica M Osborn, Amy Chadburn, Ramina Nabiee, Lissenya Argueta, Geoffrey Mikita, Ethel Cesarman
Kaposi Sarcoma Herpesvirus (KSHV/HHV-8) is a B cell tropic human pathogen, which is present in vivo in monotypic immunoglobulin λ (Igλ) light chain but polyclonal B cells. In the current study, we use cell sorting to infect specific B cell lineages from human tonsil specimens in order to examine the immunophenotypic alterations associated with KSHV infection. We describe IL-6 dependent maturation of naïve B lymphocytes in response to KSHV infection and determine that the Igλ monotypic bias of KSHV infection in vivo is due to viral induction of BCR revision...
April 16, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29656238/terminal-deoxynucleotidyltransferase-the-story-of-an-untemplated-dna-polymerase-capable-of-dna-bridging-and-templated-synthesis-across-strands
#3
REVIEW
Jérôme Loc'h, Marc Delarue
Terminal deoxynucleotidyltransferase (TdT) is a member of the polX family which is involved in DNA repair. It has been known for years as an untemplated DNA polymerase used during V(D)J recombination to generate diversity at the CDR3 region of immunoglobulins and T-cell receptors. Recently, however, TdT was crystallized in the presence of a complete DNA synapsis made of two double-stranded DNA (dsDNA), each with a 3' protruding end, and overlapping with only one micro-homology base-pair, thus giving structural insight for the first time into DNA synthesis across strands...
April 12, 2018: Current Opinion in Structural Biology
https://www.readbyqxmd.com/read/29651132/compositional-characteristics-of-human-peripheral-trbv-pseudogene-rearrangements
#4
Bin Shi, Long Ma, Xiaoyan He, Peipei Wu, Peng Wang, Xiaomei Wang, Rui Ma, Xinsheng Yao
The diversity of the T cell receptor (TCR) complementarity determining region 3 (CDR3) repertoire is the result of random combinations, insertions and deletions during recombination of the germline V, D and J gene fragments. During evolution, some human TCR beta chain variable (TRBV) pseudogenes have been retained. Many previous studies have focused on functional TRBV genes, while little attention has been given to TRBV pseudogenes. To describe the compositional characteristics of TRBV pseudogene rearrangements, we compared and analysed TRBV pseudogenes, TRBV open reading frames (ORFs) and functional TRBV genes via high-throughput sequencing of DNA obtained from the peripheral blood of 4 healthy volunteers and 4 patients...
April 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29628308/cracking-the-dna-code-for-v-d-j-recombination
#5
Min-Sung Kim, Watchalee Chuenchor, Xuemin Chen, Yanxiang Cui, Xing Zhang, Z Hong Zhou, Martin Gellert, Wei Yang
To initiate V(D)J recombination for generating the adaptive immune response of vertebrates, RAG1/2 recombinase cleaves DNA at a pair of recombination signal sequences, the 12- and 23-RSS. We have determined crystal and cryo-EM structures of RAG1/2 with DNA in the pre-reaction and hairpin-forming complexes up to 2.75 Å resolution. Both protein and DNA exhibit structural plasticity and undergo dramatic conformational changes. Coding-flank DNAs extensively rotate, shift, and deform for nicking and hairpin formation...
March 29, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29601977/surf1-knockout-cloned-pigs-early-onset-of-a-severe-lethal-phenotype
#6
C Quadalti, D Brunetti, I Lagutina, R Duchi, A Perota, G Lazzari, R Cerutti, I Di Meo, M Johnson, E Bottani, P Crociara, C Corona, S Grifoni, V Tiranti, E Fernandez-Vizarra, A J Robinson, C Viscomi, C Casalone, M Zeviani, C Galli
Leigh syndrome (LS) associated with cytochrome c oxidase (COX) deficiency is an early onset, fatal mitochondrial encephalopathy, leading to multiple neurological failure and eventually death, usually in the first decade of life. Mutations in SURF1, a nuclear gene encoding a mitochondrial protein involved in COX assembly, are among the most common causes of LS. LSSURF1 patients display severe, isolated COX deficiency in all tissues, including cultured fibroblasts and skeletal muscle. Recombinant, constitutive SURF1-/- mice show diffuse COX deficiency, but fail to recapitulate the severity of the human clinical phenotype...
March 27, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29582559/preclinical-pharmacokinetics-and-biodistribution-of-subcutaneously-administered-glycopegylated-recombinant-factor-viii-n8-gp-and-development-of-a-human-pharmacokinetic-prediction-model
#7
F Rode, K Almholt, M Petersen, M Kreilgaard, M Kjalke, D M Karpf, A V Groth, P B Johansen, L F Larsen, M Loftager, J Haaning
BACKGROUND: N8-GP is an extended half-life recombinant factor VIII (FVIII) for hemophilia A. Subcutaneous (SC) administration of FVIII may reduce treatment burden of prophylaxis; however, standard FVIII products have low bioavailability after SC dosing in animals. OBJECTIVE: Evaluate the pharmacokinetics (PK), effectiveness and local distribution of SC-administered N8-GP (SC N8-GP) in preclinical models and predict the human PK profile. METHODS: PK of SC N8-GP were evaluated in FVIII knockout (F8-KO) mice and cynomolgus monkeys; a human PK prediction model in hemophilia A patients was developed...
March 26, 2018: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29574022/analysis-of-tcr%C3%AE-and-tcr%C3%AE-genes-in-chinese-alligator-provides-insights-into-the-evolution-of-tcr-genes-in-jawed-vertebrates
#8
Xifeng Wang, Peng Wang, Renping Wang, Chaolin Wang, Jianhui Bai, Cuncun Ke, Di Yu, Kongpan Li, Yonghe Ma, Haitang Han, Yaofeng Zhao, Xin Zhou, Liming Ren
All jawed vertebrates have four T cell receptor (TCR) chains that are expressed by thymus-derived lymphocytes and play a major role in animal immune defence. However, few studies have investigated the TCR chains of crocodilians compared with those of birds and mammals, despite their key evolutionary position linking amphibians, reptiles, birds and mammals. Here, employing an Alligator sinensis genomic bacterial artificial chromosome (BAC) library and available genome data, we characterized the genomic organization, evolution and expression of TRB and TRG loci in Alligator sinensis...
March 21, 2018: Developmental and Comparative Immunology
https://www.readbyqxmd.com/read/29559980/next-generation-sequencing-analysis-of-the-human-tcr%C3%AE-%C3%AE-t-cell-repertoire-reveals-shifts-in-v%C3%AE-and-v%C3%AE-usage-in-memory-populations-upon-aging
#9
Martine J Kallemeijn, François G Kavelaars, Michèle Y van der Klift, Ingrid L M Wolvers-Tettero, Peter J M Valk, Jacques J M van Dongen, Anton W Langerak
Immunological aging remodels the immune system at several levels. This has been documented in particular for the T-cell receptor (TCR)αβ+ T-cell compartment, showing reduced naive T-cell outputs and an accumulation of terminally differentiated clonally expanding effector T-cells, leading to increased proneness to autoimmunity and cancer development at older age. Even though TCRαβ+ and TCRγδ+ T-cells follow similar paths of development involving V(D)J-recombination of TCR genes in the thymus, TCRγδ+ T-cells tend to be more subjected to peripheral rather than central selection...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29559655/industrial-brewing-yeast-engineered-for-the-production-of-primary-flavor-determinants-in-hopped-beer
#10
Charles M Denby, Rachel A Li, Van T Vu, Zak Costello, Weiyin Lin, Leanne Jade G Chan, Joseph Williams, Bryan Donaldson, Charles W Bamforth, Christopher J Petzold, Henrik V Scheller, Hector Garcia Martin, Jay D Keasling
Flowers of the hop plant provide both bitterness and "hoppy" flavor to beer. Hops are, however, both a water and energy intensive crop and vary considerably in essential oil content, making it challenging to achieve a consistent hoppy taste in beer. Here, we report that brewer's yeast can be engineered to biosynthesize aromatic monoterpene molecules that impart hoppy flavor to beer by incorporating recombinant DNA derived from yeast, mint, and basil. Whereas metabolic engineering of biosynthetic pathways is commonly enlisted to maximize product titers, tuning expression of pathway enzymes to affect target production levels of multiple commercially important metabolites without major collateral metabolic changes represents a unique challenge...
March 20, 2018: Nature Communications
https://www.readbyqxmd.com/read/29556105/discovery-of-enzymes-for-toluene-synthesis-from-anoxic-microbial-communities
#11
Harry R Beller, Andria V Rodrigues, Kamrun Zargar, Yu-Wei Wu, Avneesh K Saini, Renee M Saville, Jose H Pereira, Paul D Adams, Susannah G Tringe, Christopher J Petzold, Jay D Keasling
Microbial toluene biosynthesis was reported in anoxic lake sediments more than three decades ago, but the enzyme catalyzing this biochemically challenging reaction has never been identified. Here we report the toluene-producing enzyme PhdB, a glycyl radical enzyme of bacterial origin that catalyzes phenylacetate decarboxylation, and its cognate activating enzyme PhdA, a radical S-adenosylmethionine enzyme, discovered in two distinct anoxic microbial communities that produce toluene. The unconventional process of enzyme discovery from a complex microbial community (>300,000 genes), rather than from a microbial isolate, involved metagenomics- and metaproteomics-enabled biochemistry, as well as in vitro confirmation of activity with recombinant enzymes...
March 19, 2018: Nature Chemical Biology
https://www.readbyqxmd.com/read/29520062/the-h2b-deubiquitinase-usp22-promotes-antibody-class-switch-recombination-by-facilitating-non-homologous-end-joining
#12
Conglei Li, Thergiory Irrazabal, Clare C So, Maribel Berru, Likun Du, Evelyn Lam, Alexanda K Ling, Jennifer L Gommerman, Qiang Pan-Hammarström, Alberto Martin
Class switch recombination (CSR) has a fundamental function during humoral immune response and involves the induction and subsequent repair of DNA breaks in the immunoglobulin (Ig) switch regions. Here we show the role of Usp22, the SAGA complex deubiquitinase that removes ubiquitin from H2B-K120, in the repair of programmed DNA breaks in vivo. Ablation of Usp22 in primary B cells results in defects in γH2AX and impairs the classical non-homologous end joining (c-NHEJ), affecting both V(D)J recombination and CSR...
March 8, 2018: Nature Communications
https://www.readbyqxmd.com/read/29515575/high-throughput-sequencing-of-the-expressed-torafugu-takifugu-rubripes-antibody-sequences-distinguishes-igm-and-igt-repertoires-and-reveals-evidence-of-convergent-evolution
#13
Xi Fu, Jianqiang Sun, Engkong Tan, Kentaro Shimizu, Md Shaheed Reza, Shugo Watabe, Shuichi Asakawa
B-cell antigen receptor (BCR) or antibody diversity arises from somatic recombination of immunoglobulin (Ig) gene segments and is concentrated within the Ig heavy (H) chain complementarity-determining region 3 (CDR-H3). We performed high-throughput sequencing of the expressed antibody heavy-chain repertoire from adult torafugu. We found that torafugu use between 70 and 82% of all possible V (variable), D (diversity), and J (joining) gene segment combinations and that they share a similar frequency distribution of these VDJ combinations...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29512722/expression-of-immunoglobulin-g-in-human-podocytes-and-its-role-in-cell-viability-and-adhesion
#14
Ziyang Jing, Hui Deng, Junfan Ma, Yanhong Guo, Yaoxian Liang, Rui Wu, Lata A, Zihan Geng, Xiaoyan Qiu, Yue Wang
Podocyte injury occurs during the initiation and development of numerous forms of glomerular disease, and antibodies targeting podocytes have become a biomarker for diagnosis and monitoring treatment response. Accumulating evidence has suggested that immunoglobulin (Ig) is expressed in non‑B lineage cells, including epithelial cancer cells, myeloid cells and several types of normal cells. The main aim of the present study was to ascertain the expression of IgG in human podocytes and to determine its potential role in cellular bioactivity...
March 1, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29511621/robust-dna-repair-in-paxx-deficient-mammalian-cells
#15
Alisa Dewan, Mengtan Xing, Marie Benner Lundbæk, Raquel Gago-Fuentes, Carole Beck, Per Arne Aas, Nina-Beate Liabakk, Siri Sæterstad, Khac Thanh Phong Chau, Bodil Merete Kavli, Valentyn Oksenych
To ensure genome stability, mammalian cells employ several DNA repair pathways. Nonhomologous DNA end joining (NHEJ) is the DNA repair process that fixes double-strand breaks throughout the cell cycle. NHEJ is involved in the development of B and T lymphocytes through its function in V(D)J recombination and class switch recombination (CSR). NHEJ consists of several core and accessory factors, including Ku70, Ku80, XRCC4, DNA ligase 4, DNA-PKcs, Artemis, and XLF. Paralog of XRCC4 and XLF (PAXX) is the recently described accessory NHEJ factor that structurally resembles XRCC4 and XLF and interacts with Ku70/Ku80...
March 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29511619/normal-development-of-mice-lacking-paxx-the-paralogue-of-xrcc4-and-xlf
#16
Raquel Gago-Fuentes, Mengtan Xing, Siri Sæterstad, Antonio Sarno, Alisa Dewan, Carole Beck, Stefano Bradamante, Magnar Bjørås, Valentyn Oksenych
DNA repair consists of several cellular pathways which recognize and repair damaged DNA. The classical nonhomologous DNA end-joining (NHEJ) pathway repairs double-strand breaks in DNA. It is required for maturation of both B and T lymphocytes by supporting V(D)J recombination as well as B-cell differentiation during class switch recombination (CSR). Inactivation of NHEJ factors Ku70, Ku80, XRCC4, DNA ligase 4, DNA-PKcs, and Artemis impairs V(D)J recombination and blocks lymphocyte development. Paralogue of XRCC4 and XLF (PAXX) is an accessory NHEJ factor that has a significant impact on the repair of DNA lesions induced by ionizing radiation in human, murine, and chicken cells...
March 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29508024/t-cell-receptor-%C3%AE-v-and-j-usage-in-combination-with-particular-hla-class-i-and-class-ii-alleles-correlates-with-cancer-survival-patterns
#17
Blake M Callahan, John M Yavorski, Yaping N Tu, Wei Lue Tong, Jacob C Kinskey, Kendall R Clark, Timothy J Fawcett, George Blanck
Class I and class II HLA proteins, respectively, have been associated with subsets of V(D)J usage resulting from recombination of the T-cell receptor (TCR) genes. Additionally, particular HLA alleles, in combination with dominant TCR V(D)J recombinations, have been associated with several autoimmune diseases. The recovery of TCR recombination reads from tumor specimen exome files has allowed rapid and extensive assessments of V(D)J usage, likely for cancer resident T-cells, across relatively large cancer datasets...
March 5, 2018: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29459861/in-depth-analysis-of-human-neonatal-and-adult-igm-antibody-repertoires
#18
Binbin Hong, Yanling Wu, Wei Li, Xun Wang, Yumei Wen, Shibo Jiang, Dimiter S Dimitrov, Tianlei Ying
Although high-throughput sequencing and associated bioinformatics technologies have enabled the in-depth, sequence-based characterization of human immune repertoires, only a few studies on a relatively small number of sequences explored the characteristics of antibody repertoires in neonates, with contradictory conclusions. To gain a more comprehensive understanding of the human IgM antibody repertoire, we performed Illumina sequencing and IMGT/HighV-QUEST analysis of IgM heavy chain repertoire of the B lymphocytes from the cord blood (CB) of neonates, as well as the repertoire from peripheral blood of healthy human adults (HH)...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29459202/inhibition-of-non-homologous-end-joining-in-fanconi-anemia-cells-results-in-rescue-of-survival-after-interstrand-crosslinks-but-sensitization-to-replication-associated-double-strand-breaks
#19
Laura J Eccles, Andrew C Bell, Simon N Powell
When Fanconi Anemia (FA) proteins were depleted in human U2OS cells with integrated DNA repair reporters, we observed decreases in homologous recombination (HR), decreases in mutagenic non-homologous end joining (m-NHEJ) and increases in canonical NHEJ, which was independently confirmed by measuring V(D)J recombination. Furthermore, depletion of FA proteins resulted in reduced HR protein foci and increased NHEJ protein recruitment to replication-associated DSBs, consistent with our observation that the use of canonical NHEJ increases after depletion of FA proteins in cycling cells...
February 10, 2018: DNA Repair
https://www.readbyqxmd.com/read/29457375/evidence-for-alternate-modes-of-b-cell-activation-involving-fab-acquired-n-glycosylations-in-antibody-secreting-cells-infiltrating-the-labial-salivary-glands-of-sj%C3%A3-gren-s-syndrome-patients
#20
Kristi A Koelsch, Joshua Cavett, Kenneth Smith, Jacen S Moore, Sylvain D Lehoux, Nan Jia, Tim Mather, Syed M S Quadri, Astrid Rasmussen, C Erick Kaufman, David M Lewis, Lida Radfar, Teresa A Scordino, Christopher J Lessard, Biji T Kurien, Richard D Cummings, Judith A James, Kathy L Sivils, A Darise Farris, R Hal Scofield
OBJECTIVE: To better understand the role of B cells, potential mechanisms for their aberrant activation, and the production of autoantibodies in the pathogenesis of Sjögren's Syndrome (SS), we explored selection pressures and N-glycosylation acquired by somatic mutation (acN-glyc) in the immunoglobulin (Ig) variable regions (V-regions) of antibody secreting cells (ASCs) isolated from the minor salivary glands of SS patients and non-SS controls with sicca symptoms. METHODS: We report a novel method to produce and characterize recombinant monoclonal antibodies (mAbs) from SS patient and control labial salivary gland single-cell sorted ASC infiltrates that can be utilized to concurrently probe any other expressed genes...
February 18, 2018: Arthritis & Rheumatology
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