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Isotype class switching

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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
#1
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
#2
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/28535205/a-transcriptional-serenaid-the-role-of-noncoding-rnas-in-class-switch-recombination
#3
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
#4
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
#5
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/28455167/protective-and-pathogenic-memory-plasma-cells
#6
REVIEW
Bimba F Hoyer, Andreas Radbruch
The immune system can be divided into two major parts: innate and adaptive immunity. Adaptive immunity is characterized by its major cellular players: the B and T cells. B cells will, in the context of an immune reaction, differentiate into plasma cells. These plasma cells produce antibodies, which are secreted. Antibodies are characterized by their specificity against a selected antigen and by their isotype. The isotype changes with the duration or phase of the immune reaction. Early immune reactions are usually characterized by the predominant production of IgM antibodies...
April 25, 2017: Immunology Letters
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
#7
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/28333576/epstein-barr-virus-lytic-reactivation-activates-b-cells-polyclonally-and-induces-activation-induced-cytidine-deaminase-expression-a-mechanism-underlying-autoimmunity-and-its-contribution-to-graves-disease
#8
Keiko Nagata, Keisuke Kumata, Yuji Nakayama, Yukio Satoh, Hirotsugu Sugihara, Sayuri Hara, Michiko Matsushita, Satoshi Kuwamoto, Masako Kato, Ichiro Murakami, Kazuhiko Hayashi
Graves' disease is an autoimmune disease that results in and is the most common cause of hyperthyroidism, and the reactivation of persisting Epstein-Barr virus (EBV) in B lymphocytes induces the differentiation of host B cells into plasma cells. We previously reported that some EBV-infected B cells had thyrotropin receptor antibodies (TRAbs) as surface immunoglobulins (Igs), and EBV reactivation induced these TRAb+EBV+ cells to produce TRAbs. EBV reactivation induces Ig production from host B cells. The purpose of the present study was to examine total Ig productions from B cell culture fluids and to detect activation-induced cytidine deaminase (AID), nuclear factor kappa B (NF-κB), and EBV latent membrane protein (LMP) 1 in culture B cells during EBV reactivation induction and then we discussed the mechanisms of EBV reactivation-induced Ig production in relation to autoimmunity...
April 2017: Viral Immunology
https://www.readbyqxmd.com/read/28137874/igd-class-switching-is-initiated-by-microbiota-and-limited-to-mucosa-associated-lymphoid-tissue-in-mice
#9
Jin Huk Choi, Kuan-Wen Wang, Duanwu Zhang, Xiaowei Zhan, Tao Wang, Chun-Hui Bu, Cassie L Behrendt, Ming Zeng, Ying Wang, Takuma Misawa, Xiaohong Li, Miao Tang, Xiaoming Zhan, Lindsay Scott, Sara Hildebrand, Anne R Murray, Eva Marie Y Moresco, Lora V Hooper, Bruce Beutler
Class-switch recombination (CSR) alters the Ig isotype to diversify antibody effector functions. IgD CSR is a rare event, and its regulation is poorly understood. We report that deficiency of 53BP1, a DNA damage-response protein, caused age-dependent overproduction of secreted IgD resulting from increased IgD CSR exclusively within B cells of mucosa-associated lymphoid tissues. IgD overproduction was dependent on activation-induced cytidine deaminase, hematopoietic MyD88 expression, and an intact microbiome, against which circulating IgD, but not IgM, was reactive...
February 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28125732/dysregulation-of-systemic-and-mucosal-humoral-responses-to-microbial-and-food-antigens-as-a-factor-contributing-to-microbial-translocation-and-chronic-inflammation-in-hiv-1-infection
#10
Zdenek Hel, Jun Xu, Warren L Denning, E Scott Helton, Richard P H Huijbregts, Sonya L Heath, E Turner Overton, Benjamin S Christmann, Charles O Elson, Paul A Goepfert, Jiri Mestecky
HIV-1 infection is associated with an early and profound depletion of mucosal memory CD4+ T cells, a population that plays an indispensable role in the regulation of isotype switching and transepithelial transport of antibodies. In this study, we addressed whether the depletion of CD4+ T cell in HIV-1-infected individuals results in altered humoral responses specific to antigens encountered at mucosal surfaces. Comprehensive protein microarray of systemic humoral responses to intestinal microbiota demonstrated reduced IgG responses to antigens derived from Proteobacteria and Firmicutes but not Bacteroidetes...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28107431/characterization-of-a-broadly-reactive-anti-cd40-agonistic-monoclonal-antibody-for-potential-use-as-an-adjuvant
#11
Cameron Martin, Suryakant D Waghela, Shehnaz Lokhandwala, Andy Ambrus, Jocelyn Bray, Christina Vuong, Vanitha Vinodkumar, Paul J Dominowski, Sharath Rai, Duncan Mwangi, Dennis L Foss, Waithaka Mwangi
Lack of safe and effective adjuvants is a major hindrance to the development of efficacious vaccines. Signaling via CD40 pathway leads to enhanced antigen processing and presentation, nitric oxide expression, pro-inflammatory cytokine expression by antigen presenting cells, and stimulation of B-cells to undergo somatic hypermutation, immunoglobulin class switching, and proliferation. Agonistic anti-CD40 antibodies have shown promising adjuvant qualities in human and mouse vaccine studies. An anti-CD40 monoclonal antibody (mAb), designated 2E4E4, was identified and shown to have strong agonistic effects on primary cells from multiple livestock species...
2017: PloS One
https://www.readbyqxmd.com/read/28086979/b-cell-repertoires-in-hla-sensitized-kidney-transplant-candidates-undergoing-desensitization-therapy
#12
John F Beausang, H Christina Fan, Rene Sit, Maria U Hutchins, Kshama Jirage, Rachael Curtis, Edward Hutchins, Stephen R Quake, Julie M Yabu
BACKGROUND: Kidney transplantation is the most effective treatment for end-stage renal disease. Sensitization refers to pre-existing antibodies against human leukocyte antigen (HLA) protein and remains a major barrier to successful transplantation. Despite implementation of desensitization strategies, many candidates fail to respond. Our objective was to determine whether measuring B cell repertoires could differentiate candidates that respond to desensitization therapy. METHODS: We developed an assay based on high-throughput DNA sequencing of the variable domain of the heavy chain of immunoglobulin genes to measure changes in B cell repertoires in 19 highly HLA-sensitized kidney transplant candidates undergoing desensitization and 7 controls with low to moderate HLA sensitization levels...
January 13, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28065739/r-loop-depletion-by-over-expressed-rnase-h1-in-mouse-b-cells-increases-activation-induced-deaminase-access-to-the-transcribed-strand-without-altering-frequency-of-isotype-switching
#13
Robert W Maul, Hyongi Chon, Kiran Sakhuja, Susana M Cerritelli, Lina A Gugliotti, Patricia J Gearhart, Robert J Crouch
R-loops, three-strand structures consisting of mRNA hybridized to the complementary DNA and a single-stranded DNA loop, are formed in switch regions on the heavy-chain immunoglobulin locus. To determine if R-loops have a direct effect on any of the steps involved in isotype switching, we generated a transgenic mouse that over-expressed RNase H1, an enzyme that cleaves the RNA of RNA/DNA hybrids in B cells. R-loops in the switch μ region were depleted by 70% in ex vivo activated splenic B cells. Frequencies of isotype switching to IgG1, IgG2b, IgG2c, and IgG3 were the same as C57BL/6 control cells...
January 6, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28053999/b-cell-populations-discriminate-between-pediatric-and-adult-onset-multiple-sclerosis
#14
Alexander Schwarz, Bettina Balint, Mirjam Korporal-Kuhnke, Sven Jarius, Kathrin von Engelhardt, Alexandra Fürwentsches, Cornelia Bussmann, Friedrich Ebinger, Brigitte Wildemann, Jürgen Haas
OBJECTIVE: To comparatively assess the B-cell composition in blood and CSF of patients with pediatric-onset multiple sclerosis (pedMS) and adult-onset multiple sclerosis (adMS). METHODS: In this cross-sectional study, we obtained blood and CSF samples from 25 patients with pedMS (8-18 years) and 40 patients with adMS (23-65 years) and blood specimens from 66 controls (1-55 years). By using multicolor flow cytometry, we identified naive, transitional, isotype class-switched memory, nonswitched memory, and double-negative memory B-cell subsets as well as plasmablasts (PB) and terminally differentiated plasma cells (PC)...
January 2017: Neurology® Neuroimmunology & Neuroinflammation
https://www.readbyqxmd.com/read/28011866/the-aryl-hydrocarbon-receptor-controls-cell-fate-decisions-in-b-cells
#15
Bharat Vaidyanathan, Ashutosh Chaudhry, William T Yewdell, Davide Angeletti, Wei-Feng Yen, Adam K Wheatley, Christopher A Bradfield, Adrian B McDermott, Jonathan W Yewdell, Alexander Y Rudensky, Jayanta Chaudhuri
Generation of cellular heterogeneity is an essential feature of the adaptive immune system. This is best exemplified during humoral immune response when an expanding B cell clone assumes multiple cell fates, including class-switched B cells, antibody-secreting plasma cells, and memory B cells. Although each cell type is essential for immunity, their generation must be exquisitely controlled because a class-switched B cell cannot revert back to the parent isotype, and a terminally differentiated plasma cell cannot contribute to the memory pool...
January 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27974207/dna-replication-origins-in-immunoglobulin-switch-regions-regulate-class-switch-recombination-in-an-r-loop-dependent-manner
#16
Eva-Maria Wiedemann, Mihaela Peycheva, Rushad Pavri
Class switch recombination (CSR) at the immunoglobulin heavy chain (IgH) locus generates antibody isotypes. CSR depends on double-strand breaks (DSBs) induced by activation-induced cytidine deaminase (AID). Although DSB formation and repair machineries are active in G1 phase, efficient CSR is dependent on cell proliferation and S phase entry; however, the underlying mechanisms are obscure. Here, we show that efficient CSR requires the replicative helicase, the Mcm complex. Mcm proteins are enriched at IgH switch regions during CSR, leading to assembly of facultative replication origins that require Mcm helicase function for productive CSR...
December 13, 2016: Cell Reports
https://www.readbyqxmd.com/read/27897229/global-gene-regulation-during-activation-of-immunoglobulin-class-switching-in-human-b-cells
#17
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/27881702/roles-of-aluminum-hydroxide-and-monophosphoryl-lipid-a-adjuvants-in-overcoming-cd4-t-cell-deficiency-to-induce-isotype-switched-igg-antibody-responses-and-protection-by-t-dependent-influenza-vaccine
#18
Eun-Ju Ko, Young-Tae Lee, Ki-Hye Kim, Youri Lee, Yu-Jin Jung, Min-Chul Kim, Yu-Na Lee, Taeuk Kang, Sang-Moo Kang
Vaccine adjuvant effects in the CD4-deficient condition largely remain unknown. We investigated the roles of combined monophosphoryl lipid A (MPL) and aluminum hydroxide (Alum) adjuvant (MPL+Alum) in inducing immunity after immunization of CD4 knockout (CD4KO) and wild-type (WT) mice with T-dependent influenza vaccine. MPL+Alum adjuvant mediated IgG isotype-switched Abs, IgG-secreting cell responses, and protection in CD4KO mice, which were comparable to those in WT mice. In contrast, Alum adjuvant effects were dependent on CD4(+) T cells...
January 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27833954/the-role-of-autoantibodies-in-health-and-disease
#19
REVIEW
Isabela Siloşi, Cristian Adrian Siloşi, Mihail Virgil Boldeanu, Manole Cojocaru, Viorel Biciuşcă, Carmen Silvia Avrămescu, Inimioara Mihaela Cojocaru, Maria Bogdan, Roxana Mihaela FolcuŢi
Serum of healthy individuals contains antibodies that react with self and non-self antigens, generated in absence of external antigen stimulation. These antibodies, called natural antibodies, are particularly IgM isotype, are considered natural autoantibodies (NAA), displaying a moderate affinity for self-antigens. Although incidence of NAA in healthy individuals is not reported, it is established that autoreactive antibodies and B-cells, as well as autoreactive T-cells, are present in healthy persons. The functional abilities of NAA are not clear but is well accepted that they may participate in a variety of activities, such as maintenance of immune homeostasis, regulation of the immune response, resistance to infections, transport and functional modulation of biologically active molecules...
2016: Romanian Journal of Morphology and Embryology, Revue Roumaine de Morphologie et Embryologie
https://www.readbyqxmd.com/read/27815447/efficient-culture-of-human-naive-and-memory-b-cells-for-use-as-apcs
#20
Kuei-Ying Su, Akiko Watanabe, Chen-Hao Yeh, Garnett Kelsoe, Masayuki Kuraoka
The ability to culture and expand B cells in vitro has become a useful tool for studying human immunity. A limitation of current methods for human B cell culture is the capacity to support mature B cell proliferation. We developed a culture method to support the efficient activation and proliferation of naive and memory human B cells. This culture supports extensive B cell proliferation, with ∼10(3)-fold increases following 8 d in culture and 10(6)-fold increases when cultures are split and cultured for 8 more days...
November 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
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