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Class switch recombination

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https://www.readbyqxmd.com/read/28610800/human-igg-repertoire-of-malaria-antigen-immunized-human-immune-system-his-mice
#1
Raquel Tayar Nogueira, Vincent Sahi, Jing Huang, Moriya Tsuji
Humanized mouse models present an important tool for preclinical evaluation of new vaccines and therapeutics. Here we show the human variable repertoire of antibody sequences cloned from a previously described human immune system (HIS) mouse model that possesses functional human CD4+ T cells and B cells, namely HIS-CD4/B mice. We sequenced variable IgG genes from single memory B-cell and plasma-cell sorted from splenocytes or whole blood lymphocytes of HIS-CD4/B mice that were vaccinated with a human plasmodial antigen, a recombinant Plasmodium falciparum circumsporozoite protein (rPfCSP)...
June 10, 2017: Immunology Letters
https://www.readbyqxmd.com/read/28607112/cutting-edge-active-tgf-%C3%AE-1-released-from-garp-tgf-%C3%AE-1-complexes-on-the-surface-of-stimulated-human-b-lymphocytes-increases-class-switch-recombination-and-production-of-iga
#2
Olivier Dedobbeleer, Julie Stockis, Bas van der Woning, Pierre G Coulie, Sophie Lucas
Production of active TGF-β is regulated at a posttranslational level and implies release of the mature cytokine dimer from the inactive, latent TGF-β precursor. There are several cell-type specific mechanisms of TGF-β activation. We identified a new mechanism operating on the surface of human regulatory T cells and involving membrane protein GARP, which binds latent TGF-β1. The paracrine activity of regulatory T cell-derived TGF-β1 contributes to immunosuppression and can be inhibited with anti-GARP Abs...
June 12, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28574479/r-loops-in-the-regulation-of-antibody-gene-diversification
#3
REVIEW
Rushad Pavri
For nearly three decades, R loops have been closely linked with class switch recombination (CSR), the process that generates antibody isotypes and that occurs via a complex cascade initiated by transcription-coupled mutagenesis in switch recombination sequences. R loops form during transcription of switch recombination sequences in vitro and in vivo, and there is solid evidence that R loops are required for efficient class switching. The classical model of R loops posits that they boost mutation rates by generating stable and long tracts of single-stranded DNA that serve as the substrate for activation induced deaminase (AID), the enzyme that initiates the CSR reaction cascade by co-transcriptionally mutating ssDNA in switch recombination sequences...
June 2, 2017: Genes
https://www.readbyqxmd.com/read/28570559/analysis-of-dna-polymerase-%C3%AE-function-in-meiotic-recombination-immunoglobulin-class-switching-and-dna-damage-tolerance
#4
Kei-Ichi Takata, Shelley Reh, Matthew J Yousefzadeh, Maciej J Zelazowski, Sarita Bhetawal, David Trono, Megan G Lowery, Maria Sandoval, Yoko Takata, Yue Lu, Kevin Lin, Jianjun Shen, Donna F Kusewitt, Kevin M McBride, Francesca Cole, Richard D Wood
DNA polymerase ν (pol ν), encoded by the POLN gene, is an A-family DNA polymerase in vertebrates and some other animal lineages. Here we report an in-depth analysis of pol ν-defective mice and human cells. POLN is very weakly expressed in most tissues, with the highest relative expression in testis. We constructed multiple mouse models for Poln disruption and detected no anatomic abnormalities, alterations in lifespan, or changed causes of mortality. Mice with inactive Poln are fertile and have normal testis morphology...
June 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28550350/recent-advances-in-the-study-of-immunodeficiency-and-dna-damage-response
#5
REVIEW
Tomohiro Morio
DNA breaks can be induced by exogenous stimuli or by endogenous stress, but are also generated during recombination of V, D, and J genes (V(D)J recombination), immunoglobulin class switch recombination (CSR). Among various DNA breaks generated, DNA double strand break (DSB) is the most deleterious one. DNA damage response (DDR) is initiated when DSBs are detected, leading to DNA break repair by non-homologous end joining (NHEJ). The process is critically important for the generation of diversity for foreign antigens; and failure to exert DNA repair leads to immunodeficiency such as severe combined immunodeficiency and hyper-IgM syndrome...
May 26, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28544931/role-for-rif1-interacting-partner-ddx1-in-blm-recruitment-to-dna-double-strand-breaks
#6
Lei Li, Ho-Yin Poon, Matthew R Hildebrandt, Elizabeth A Monckton, Devon R Germain, Richard P Fahlman, Roseline Godbout
Human Rap1-interacting factor 1 (RIF1) is an important player in the repair of DNA double strand breaks (DSBs). RIF1 acts downstream of 53BP1, with well-documented roles in class switch recombination in B-cells and inhibition of end resection initiation in BRCA1-defective cells. Here, we report that DEAD Box 1 (DDX1), a RNA helicase also implicated in DSB repair, interacts with RIF1, with co-localization of DDX1 and RIF1 observed throughout interphase. Recruitment of DDX1 to DSBs is dependent on RIF1, with RIF1 depletion abolishing DDX1-mediated facilitation of homologous recombination at DSBs...
May 13, 2017: DNA Repair
https://www.readbyqxmd.com/read/28535205/a-transcriptional-serenaid-the-role-of-noncoding-rnas-in-class-switch-recombination
#7
William T Yewdell, Jayanta Chaudhuri
During an immune response, activated B cells may undergo class switch recombination (CSR), a molecular rearrangement that allows B cells to switch from expressing IgM and IgD to a secondary antibody heavy chain isotype such as IgG, IgA, or IgE. Secondary antibody isotypes provide the adaptive immune system with distinct effector functions to optimally combat various pathogens. CSR occurs between repetitive DNA elements within the immunoglobulin heavy chain (Igh) locus, termed switch (S) regions, and requires the DNA modifying enzyme activation-induced cytidine deaminase (AID)...
May 23, 2017: International Immunology
https://www.readbyqxmd.com/read/28533409/inducible-ctcf-insulator-delays-the-igh-3-regulatory-region-mediated-activation-of-germline-promoters-and-alters-class-switching
#8
Fatima-Zohra Braikia, Chloé Oudinet, Dania Haddad, Zeliha Oruc, Domenico Orlando, Audrey Dauba, Marc Le Bert, Ahmed Amine Khamlichi
Class switch recombination (CSR) plays an important role in adaptive immune response by enabling mature B cells to switch from IgM expression to the expression of downstream isotypes. CSR is preceded by inducible germline (GL) transcription of the constant genes and is controlled by the 3' regulatory region (3'RR) in a stimulus-dependent manner. Why the 3'RR-mediated up-regulation of GL transcription is delayed to the mature B-cell stage is presently unknown. Here we show that mice devoid of an inducible CTCF binding element, located in the α constant gene, display a marked isotype-specific increase of GL transcription in developing and resting splenic B cells and altered CSR in activated B cells...
June 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28515723/different-somatic-hypermutation-levels-among-antibody-subclasses-disclosed-by-a-new-next-generation-sequencing-based-antibody-repertoire-analysis
#9
Kazutaka Kitaura, Hiroshi Yamashita, Hitomi Ayabe, Tadasu Shini, Takaji Matsutani, Ryuji Suzuki
A diverse antibody repertoire is primarily generated by the rearrangement of V, D, and J genes and subsequent somatic hypermutation (SHM). Class-switch recombination (CSR) produces various isotypes and subclasses with different functional properties. Although antibody isotypes and subclasses are considered to be produced by both direct and sequential CSR, it is still not fully understood how SHMs accumulate during the process in which antibody subclasses are generated. Here, we developed a new next-generation sequencing (NGS)-based antibody repertoire analysis capable of identifying all antibody isotype and subclass genes and used it to examine the peripheral blood mononuclear cells of 12 healthy individuals...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28499720/t-follicular-helper-and-th2-cells-in-allergic-responses
#10
REVIEW
Masato Kubo
IL-4 is a cytokine commonly secreted by TH2 and follicular helper T (TFH) cells after antigenic sensitization. TH2 cells have been thought to be the major contributor of B cell help as a source of IL-4 responsible for class switch recombination to Immunoglobulin G1 (IgG1) and Immunoglobulin E (IgE). Importantly, there are some differences in transcriptional regulation between these two T cell subsets. The IL-4 production by TH2 and TFH cells is distinctively regulated by two pathways, GATA-3-mediated Il4-HS2 enhancer and Notch mediated Il4-CNS-2 enhancer...
May 9, 2017: Allergology International: Official Journal of the Japanese Society of Allergology
https://www.readbyqxmd.com/read/28466095/survival-of-the-fetus-fetal-b-and-t-cell-receptor-repertoire-development
#11
REVIEW
Erez Rechavi, Raz Somech
A mature and diverse T and B cell receptor repertoire is a prerequisite for immunocompetence. In light of its increased susceptibility to infection, the human fetus has long been considered deficient in this regard. However, data accumulated since the 1990s and in earnest in the past couple of years paints a more complicated picture. As we describe in this review, mechanisms responsible for generating a diverse receptor repertoire, such as somatic recombination, class switch recombination, and somatic hypermutation, are all operational to surprising extents in the growing fetus...
May 2, 2017: Seminars in Immunopathology
https://www.readbyqxmd.com/read/28461573/genetic-and-small-molecule-disruption-of-the-aid-rad51-axis-similarly-protects-nonobese-diabetic-mice-from-type-1-diabetes-through-expansion-of-regulatory-b-lymphocytes
#12
Jeremy J Ratiu, Jeremy J Racine, Muneer G Hasham, Qiming Wang, Jane A Branca, Harold D Chapman, Jing Zhu, Nina Donghia, Vivek Philip, William H Schott, Clive Wasserfall, Mark A Atkinson, Kevin D Mills, Caroline M Leeth, David V Serreze
B lymphocytes play a key role in type 1 diabetes (T1D) development by serving as a subset of APCs preferentially supporting the expansion of autoreactive pathogenic T cells. As a result of their pathogenic importance, B lymphocyte-targeted therapies have received considerable interest as potential T1D interventions. Unfortunately, the B lymphocyte-directed T1D interventions tested to date failed to halt β cell demise. IgG autoantibodies marking humans at future risk for T1D indicate that B lymphocytes producing them have undergone the affinity-maturation processes of class switch recombination and, possibly, somatic hypermutation...
June 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28445143/the-igh-locus-relocalizes-to-a-recombination-compartment-in-the-perinucleolar-region-of-differentiating-b-lymphocytes
#13
Andrey Pichugin, Olga V Iarovaia, Alexey Gavrilov, Ilya Sklyar, Natalja Barinova, Aleksandr Barinov, Evgeny Ivashkin, Gersende Caron, Said Aoufouchi, Sergey V Razin, Thierry Fest, Marc Lipinski, Yegor S Vassetzky
The immunoglobulin heavy chain (IGH) gene loci are subject to specific recombination events during B-cell differentiation including somatic hypermutation and class switch recombination which mark the end of immunoglobulin gene maturation in germinal centers of secondary lymph nodes. These two events rely on the activity of activation-induced cytidine deaminase (AID) which requires DNA double strand breaks be created, a potential danger to the cell. Applying 3D-fluorescence in situ hybridization coupled with immunofluorescence staining to a previously described experimental system recapitulating normal B-cell differentiation ex vivo, we have kinetically analyzed the radial positioning of the two IGH gene loci as well as their proximity with the nucleolus, heterochromatin and γH2AX foci...
June 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28442572/the-phospholipase-ipla2%C3%AE-is-a-major-mediator-releasing-oxidized-aliphatic-chains-from-cardiolipin-integrating-mitochondrial-bioenergetics-and-signaling
#14
Gao-Yuan Liu, Sung Ho Moon, Christopher M Jenkins, Maoyin Li, Harold F Sims, Shaoping Guan, Richard W Gross
Cardiolipin (CL) is a dimeric phospholipid with critical roles in mitochondrial bioenergetics and signaling. Recently, inhibition of the release of oxidized fatty acyl chains from CL by the calcium independent phospholipase A2γ (iPLA2γ) selective inhibitor (R)-BEL suggested that iPLA2γ is responsible for the hydrolysis of oxidized CL and subsequent signaling mediated by the released oxidized fatty acids. However, chemical inhibition by BEL is subject to off-target pharmacologic effects. Accordingly, to unambiguously determine the role of iPLA2γ in the hydrolysis of oxidized CL, we compared alterations in oxidized CLs and the release of oxidized aliphatic chains from CL in experiments with purified recombinant iPLA2γ, germline iPLA2γ(-/-) mice, cardiac myocyte-specific iPLA2γ transgenic mice, and wild-type mice...
April 25, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28416602/antigen-receptor-galaxy-a-user-friendly-web-based-tool-for-analysis-and-visualization-of-t-and-b-cell-receptor-repertoire-data
#15
Hanna IJspeert, Pauline A van Schouwenburg, David van Zessen, Ingrid Pico-Knijnenburg, Andrew P Stubbs, Mirjam van der Burg
Antigen Receptor Galaxy (ARGalaxy) is a Web-based tool for analyses and visualization of TCR and BCR sequencing data of 13 species. ARGalaxy consists of four parts: the demultiplex tool, the international ImMunoGeneTics information system (IMGT) concatenate tool, the immune repertoire pipeline, and the somatic hypermutation (SHM) and class switch recombination (CSR) pipeline. Together they allow the analysis of all different aspects of the immune repertoire. All pipelines can be run independently or combined, depending on the available data and the question of interest...
May 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28416601/csreport-a-new-computational-tool-designed-for-automatic-analysis-of-class-switch-recombination-junctions-sequenced-by-high-throughput-sequencing
#16
François Boyer, Hend Boutouil, Iman Dalloul, Zeinab Dalloul, Jeanne Cook-Moreau, Jean-Claude Aldigier, Claire Carrion, Bastien Herve, Erwan Scaon, Michel Cogné, Sophie Péron
B cells ensure humoral immune responses due to the production of Ag-specific memory B cells and Ab-secreting plasma cells. In secondary lymphoid organs, Ag-driven B cell activation induces terminal maturation and Ig isotype class switch (class switch recombination [CSR]). CSR creates a virtually unique IgH locus in every B cell clone by intrachromosomal recombination between two switch (S) regions upstream of each C region gene. Amount and structural features of CSR junctions reveal valuable information about the CSR mechanism, and analysis of CSR junctions is useful in basic and clinical research studies of B cell functions...
May 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28407558/cd11b-regulates-antibody-class-switching-via-induction-of-aid
#17
Seohyun Park, Hyunsub Sim, Hye-In Kim, Daecheol Jeong, Guang Wu, Soo Young Cho, Young Seek Lee, Hyung-Joo Kwon, Keunwook Lee
The integrin CD11b, which is encoded by the integrin subunit alpha M (ITGAM), is primarily expressed on the surface of innate immune cells. Genetic variations in ITGAM are among the strongest risk factors for systemic lupus erythematosus, an autoimmune disease characterized by the presence of autoantibodies. However, the regulatory function of CD11b in the antibody responses remains unclear. Here, we report the induction of CD11b in activated B2 B cells and define its unexpected role in immunoglobulin heavy chain class switch recombination (CSR)...
April 10, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28404847/characterization-of-pre-f-gcn4t-a-modified-human-respiratory-syncytial-virus-fusion-protein-stabilized-in-a-non-cleaved-pre-fusion-conformation
#18
Normand Blais, Martin Gagné, Yoshitomo Hamuro, Patrick Rheault, Martine Boyer, Ann-Muriel Steff, Guy Baudoux, Vincent Dewar, Josée Demers, Jean-Louis Ruelle, Denis Martin
Human respiratory syncytial virus (hRSV) fusion protein (F) is considered a major target of the neutralizing antibody response to hRSV. This glycoprotein undergoes a major structural shift from pre- (pre-F) to post-fusion (post-F) state at the time of virus-host cell membrane fusion. Recent evidences suggest that the pre-F state may be a superior target for neutralizing antibodies than post-F. Therefore, for vaccine purposes, we have designed and characterized a recombinant hRSV F protein, called Pre-F-GCN4t, stabilized in a pre-F conformation...
April 12, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28388279/investigation-of-aid-dicer-and-drosha-expressions-in-patients-with-chronic-lymphocytic-leukemia
#19
Metin Yusuf Gelmez, Ender Coskunpinar, Basak Saracoglu, Gunnur Deniz, Melih Aktan
Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries. Cytogenetic lesions such as del13q14, del11q22.3, and del17p13 are identified in 50-60% of patients. Activation-induced cytidine deaminase (AID) plays a central role in somatic hyper mutation (SHM) and class switch recombination (CSR) and functions on Ig genes, but also target non-Ig genes, and over-expression of AID can lead to point mutations or translocations in non-Ig genes such as IgH/Myc translocation. Dicer and Drosha, which have a role in activation process of miRNA, also act in a double-strand DNA break (DSB) repair mechanism...
July 2017: Immunological Investigations
https://www.readbyqxmd.com/read/28373876/il-21-receptor-antagonist-inhibits-differentiation-of-b-cells-toward-plasmablasts-upon-alloantigen-stimulation
#20
Kitty de Leur, Frank J M F Dor, Marjolein Dieterich, Luc J W van der Laan, Rudi W Hendriks, Carla C Baan
Interaction between T follicular helper (Tfh) cells and B cells is complex and involves various pathways, including the production of IL-21 by the Tfh cells. Secretion of IL-21 results in B cell differentiation toward immunoglobulin-producing plasmablasts. In patients after kidney transplantation, the formation of alloantibodies produced by donor antigen-activated B cells are a major cause of organ failure. In this allogeneic response, the role of IL-21-producing Tfh cells that regulate B cell differentiation is unknown...
2017: Frontiers in Immunology
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