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Isotype switching

Emily C Sheppard, Rikke Brandstrup Morrish, Michael J Dillon, Rebecca Leyland, Richard Chahwan
Epigenetic modifications, such as histone modifications, DNA methylation status, and non-coding RNAs (ncRNA), all contribute to antibody maturation during somatic hypermutation (SHM) and class-switch recombination (CSR). Histone modifications alter the chromatin landscape and, together with DNA primary and tertiary structures, they help recruit Activation-Induced Cytidine Deaminase (AID) to the immunoglobulin (Ig) locus. AID is a potent DNA mutator, which catalyzes cytosine-to-uracil deamination on single-stranded DNA to create U:G mismatches...
2018: Frontiers in Immunology
Yue Yang, Long Chen, Yuan Jia, Yang Liu, Lei Wen, Yaoxian Liang, Yuan An, Shi Chen, Yin Su, Zhanguo Li
To analyze the clinical spectrum, laboratory characteristics, and outcomes of monoclonal gammopathy (MG) in patients with rheumatic diseases. Screening for the presence of MG was performed in 872 inpatients with rheumatic diseases from January 2010 to July 2017. A total of 41 patients were enrolled. Their clinical and biological features in addition to outcomes were described. For each patient with primary Sjögren syndrome (pSS), 2 age- and sex-matched pSS patients without MG were selected as controls. Risk factors for the presence of MG and malignant hematological neoplasias were assessed...
March 13, 2018: Clinical Rheumatology
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
Anna E Schager, C Coral Dominguez-Medina, Francesca Necchi, Francesca Micoli, Yun Shan Goh, Margaret Goodall, Adriana Flores-Langarica, Saeeda Bobat, Charlotte N L Cook, Melissa Arcuri, Arianna Marini, Lloyd D W King, Faye C Morris, Graham Anderson, Kai-Michael Toellner, Ian R Henderson, Constantino López-Macías, Calman A MacLennan, Adam F Cunningham
Antibodies acquired after vaccination or natural infection with Gram-negative bacteria, such as invasive Salmonella enterica serovar Typhimurium, can protect against disease. Immunization with naturally shed outer membrane vesicles from Gram-negative bacteria is being studied for its potential to protect against many infections, since antigens within vesicles maintain their natural conformation and orientation. Shedding can be enhanced through genetic modification, and the resulting particles, generalized modules for membrane antigens (GMMA), not only offer potential as vaccines but also can facilitate the study of B-cell responses to bacterial antigens...
March 6, 2018: MBio
Elena Blanco, Martín Pérez-Andrés, Sonia Arriba-Méndez, Teresa Contreras-Sanfeliciano, Ignacio Criado, Ondrej Pelak, Ana Serra-Caetano, Alfonso Romero, Noemí Puig, Ana Remesal, Juan Torres Canizales, Eduardo López-Granados, Tomas Kalina, Ana E Sousa, Menno Van Zelm, Mirjam Van der Burg, Jacques J M van Dongen, Alberto Orfao
BACKGROUND: Humoral immunocompetence develops stepwise throughout life and contributes to individual susceptibility to infection, immunodeficiency, autoimmunity and neoplasia. Immunoglobulin heavy chain (IgH)-isotype serum levels can partly explain such age-related differences, but their relationship with the IgH-isotype distribution within memory B-cell (MBCs) and plasma cell (PCs) compartments remains to be investigated. OBJECTIVE: We studied the age-related distribution of MBCs and PCs expressing different IgH-isotypes, in addition to the immature/transitional and naive B-cell compartments...
March 2, 2018: Journal of Allergy and Clinical Immunology
Sang-Hoon Lee, Seok-Rae Park
Interaction between pathogen-associated molecular patterns and pattern recognition receptors triggers innate and adaptive immune responses. Several studies have reported that toll-like receptors (TLRs) are involved in B cell proliferation, differentiation, and Ig class switch recombination (CSR). However, roles of TLRs in B cell activation and differentiation are not completely understood. In this study, we investigated the direct effect of stimulation of TLR1/2 agonist Pam3CSK4 on mouse B cell viability, proliferation, activation, Ig production, and Ig CSR in vitro ...
February 2018: Immune Network
Emma C de Moel, Veerle F A M Derksen, Gerrie Stoeken, Leendert A Trouw, Holger Bang, Robbert J Goekoop, Irene Speyer, Tom W J Huizinga, Cornelia F Allaart, René E M Toes, Diane van der Woude
BACKGROUND: The autoantibody profile of seropositive rheumatoid arthritis (RA) is very diverse and consists of various isotypes and antibodies to multiple post-translational modifications. It is yet unknown whether this varying breadth of the autoantibody profile is associated with treatment outcomes. Therefore, we investigated whether the composition of the autoantibody profile in RA, as a marker of the underlying immunopathology, influences initial and long-term treatment outcomes. METHODS: In serum from 399 seropositive patients with RA in the IMPROVED study, drawn at baseline and at the moment of drug tapering, we measured IgG, IgM, and IgA isotypes for anti-cyclic citrullinated peptide-2 and anti-carbamylated protein antibodies, IgM and IgA rheumatoid factor, and reactivity against four citrullinated and two acetylated peptides (anti-modified protein antibodies (AMPAs))...
February 26, 2018: Arthritis Research & Therapy
Florencia Barrionuevo, Sebastián Di Giacomo, Danilo Bucafusco, Andrea Ayude, Juan Schammas, M Cruz Miraglia, Alejandra Capozzo, Manuel V Borca, Mariano Perez-Filgueira
The role of passively transferred sera in the protection against aerogenous foot-and-mouth disease (FMD) virus infection in cattle was evaluated using vaccine-induced immune serum preparations obtained at 7 and 26 days post-vaccination (dpv). We showed that circulating antibodies were sufficient to prevent disease generalization after oronasal infection in animals passively transferred with 26-dpv serum but not with the 7-dpv serum. Conversely, conventional FMD vaccination provided clinical protection at 7 dpv, promoting fast and robust antibody responses upon challenge and even though antibody titers were similar to those found in animals passively immunized with 7-dpv serum...
February 23, 2018: Virology
Tom T P Seijkens, Claudia M van Tiel, Pascal J H Kusters, Dorothee Atzler, Oliver Soehnlein, Barbara Zarzycka, Suzanne A B M Aarts, Marnix Lameijer, Marion J Gijbels, Linda Beckers, Myrthe den Toom, Bram Slütter, Johan Kuiper, Johan Duchene, Maria Aslani, Remco T A Megens, Cornelis van 't Veer, Gijs Kooij, Roy Schrijver, Marten A Hoeksema, Louis Boon, Francois Fay, Jun Tang, Samantha Baxter, Aldo Jongejan, Perry D Moerland, Gert Vriend, Boris Bleijlevens, Edward A Fisher, Raphael Duivenvoorden, Norbert Gerdes, Menno P J de Winther, Gerry A Nicolaes, Willem J M Mulder, Christian Weber, Esther Lutgens
BACKGROUND: Disrupting the costimulatory CD40-CD40L dyad reduces atherosclerosis, but can result in immune suppression. The authors recently identified small molecule inhibitors that block the interaction between CD40 and tumor necrosis factor receptor-associated factor (TRAF) 6 (TRAF-STOPs), while leaving CD40-TRAF2/3/5 interactions intact, thereby preserving CD40-mediated immunity. OBJECTIVES: This study evaluates the potential of TRAF-STOP treatment in atherosclerosis...
February 6, 2018: Journal of the American College of Cardiology
Girja S Shukla, Stephanie C Pero, Yu-Jing Sun, Chelsea L Carman, Seth Harlow, David N Krag
Autoantibodies to breast and other cancers are commonly present in cancer patients. A method to rapidly produce these anti-cancer autoantibodies in the lab would be valuable for understanding immune events and to generate candidate reagents for therapy and diagnostics. The purpose of this report is to evaluate sentinel nodes (SNs) of breast cancer patients as a source of anti-cancer antibodies. Radiotracer lymphatic mapping in 29 patients with breast cancer confirmed the identity of the SNs which provided source cells for this study...
January 27, 2018: Journal of Immunological Methods
David Allard, Roxanne Charlebois, Loise Gilbert, John Stagg, Pavel Chrobak
Many individuals at risk of streptococcal infection respond poorly to the pneumococcal polysaccharide vaccine Pneumovax 23. Identification of actionable pathways able to enhance Pneumovax responsiveness is highly relevant. We investigated the contribution of the extracellular adenosine pathway regulated by the ecto-nucleotidase CD73 in Pneumovax-induced antibody responses. Using gene-targeted mice, we demonstrated that CD73-or A2a adenosine receptor deficiency significantly delayed isotype switching. Nevertheless, CD73- or A2aR- deficient adult mice ultimately produced antigen-specific IgG3 and controlled Streptococcus pneumoniae infection as efficiently as wild type (WT) mice...
2018: PloS One
Rupinder Kaur, Sukhbir Kaur
Background: Medicinal plants with immunomodulatory properties can provide good alternative therapeutics for curing visceral leishmaniasis. Bergenia ligulata (Wall.) Engl. is an interesting plant with strong antioxidant, antimicrobial, immunomodulatory and hepatoprotective properties. Aim: The present study was planned to determine the antileishmanial activity of plant extract by modulating the immune responses of inbred BALB/c mice. Methodology: Bergenin, the principle active component of B...
January 2018: Journal of Traditional and Complementary Medicine
Meijie Tian, Zhaolin Hua, Sheng Hong, Zhimin Zhang, Can Liu, Lin Lin, Jiaorong Chen, Wei Zhang, Xuyu Zhou, Fuping Zhang, Anthony L DeFranco, Baidong Hou
Although TLR signaling in B cells has been implicated in the germinal center (GC) responses during viral infections and autoimmune diseases, the underlying mechanism is unclear. Bacterial phage Qβ-derived virus-like particle (Qβ-VLP) contains TLR ligands, which can enhance Qβ-VLP-induced Ab response, including GC response, through TLR/MyD88 signaling in B cells. In this study, by examining Ag-specific B cell response to Qβ-VLP, we found that lack of B cell MyD88 from the beginning of the immune response led to a more severe defect in the GC scale than abolishing MyD88 at later time points of the immune response...
December 27, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Willem J J Falkenburg, Dirkjan van Schaardenburg
Autoantibodies such as rheumatoid factors (RFs), anti-citrullinated protein antibodies (ACPAs), and other anti-modified protein antibodies are important risk factors for the development of rheumatoid arthritis (RA) and probably play an important role in its pathogenesis. In the phase before clinical arthritis becomes apparent, different autoantibody responses can evolve because of increases in their level, isotype switching, affinity maturation, epitope spreading, and a changing glycosylation profile. This evolution may be crucial for the pathogenic properties of the autoantibody responses, and interfering with this process in individuals at risk may become a route to prevent RA...
February 2017: Best Practice & Research. Clinical Rheumatology
Jason S Weinstein, Brian J Laidlaw, Yisi Lu, Jessica K Wang, Vincent P Schulz, Ningcheng Li, Edward I Herman, Susan M Kaech, Patrick G Gallagher, Joe Craft
Follicular helper T (Tfh) cells promote germinal center (GC) B cell survival and proliferation and guide their differentiation and immunoglobulin isotype switching by delivering contact-dependent and soluble factors, including IL-21, IL-4, IL-9, and IFN-γ. IL-21 and IFN-γ are coexpressed by Tfh cells during viral infections, but transcriptional regulation of these cytokines is not completely understood. In this study, we show that the T helper type 1 cell (Th1 cell) transcriptional regulators T-bet and STAT4 are coexpressed with Bcl6 in Tfh cells after acute viral infection, with a temporal decline in T-bet in the waning response...
January 2, 2018: Journal of Experimental Medicine
Ufuk Kirik, Helena Persson, Fredrik Levander, Lennart Greiff, Mats Ohlin
B cells produce antibodies, key effector molecules in health and disease. They mature their properties, including their affinity for antigen, through hypermutation events; processes that involve, e.g., base substitution, codon insertion and deletion, often in association with an isotype switch. Investigations of antibody evolution define modes whereby particular antibody responses are able to form, and such studies provide insight important for instance for development of efficient vaccines. Antibody evolution is also used in vitro for the design of antibodies with improved properties...
2017: Frontiers in Immunology
Maria Zurek Munk-Madsen, Lars Toft, Tina Kube, Rolf Richter, Lars Ostergaard, Ole S Søgaard, Martin Tolstrup, Andreas M Kaufmann
Human papillomavirus (HPV) infection is a frequent cause of malignant and non-malignant disease, in particular among persons with HIV. HPV serotype-specific anti L1 antibodies protect against HPV infection but little is known about prophylactic HPV vaccine-induced cell-mediated immunity against HPV in high-risk individuals. We recently showed that both HPV vaccines (Gardasil® and Cervarix®) induce solid, serological immune responses in HIV-infected persons. This study aimed to characterize HPV-specific CD4 T cells in HIV-infected HPV-vaccine recipients, T cell responses being critical for B cell activation and antibody-isotype switching...
November 27, 2017: Human Vaccines & Immunotherapeutics
Xiangxue Meng, Bin Yang, Wen-Chen Suen
The critical role of the CD40/CD40L pathway in B-cell proliferation, immunoglobulin (Ig) isotype switching and germinal center formation has been studied and described extensively in previous literature. Interruption of the CD40/CD40L signal causes hyper-IgM (HIGM) syndrome, which has been classified and recognized as a group of rare inherited immune deficiency disorders. Defects in CD40 and CD40L interactions or in downstream signaling molecules, including activation-induced cytidine deaminase, uracyl-DNA-glycosylase, NF-κB and DNA repair enzymes, result in an increased level of serum IgM and a significantly decreased or absent level of IgA, IgG and IgE that is accompanied by severe recurrent infections and autoimmune diseases...
January 1, 2017: Innate Immunity
Rohan Ameratunga, Wikke Koopmans, See-Tarn Woon, Euphemia Leung, Klaus Lehnert, Charlotte A Slade, Jessica C Tempany, Anselm Enders, Richard Steele, Peter Browett, Philip D Hodgkin, Vanessa L Bryant
Common variable immunodeficiency disorders (CVID) are a group of primary immunodeficiencies where monogenetic causes account for only a fraction of cases. On this evidence, CVID is potentially polygenic and epistatic although there are, as yet, no examples to support this hypothesis. We have identified a non-consanguineous family, who carry the C104R (c.310T>C) mutation of the Transmembrane Activator Calcium-modulator and cyclophilin ligand Interactor (TACI, TNFRSF13B) gene. Variants in TNFRSF13B/TACI are identified in up to 10% of CVID patients, and are associated with, but not solely causative of CVID...
October 2017: Clinical & Translational Immunology
Eun Seon Lee, Chang Ho Kang, Joung Hun Park, Sang Yeol Lee
<b><i>Significance:</i></b> Sessile plants respond to oxidative stress caused by internal and external stimuli by producing diverse forms of enzymatic and non-enzymatic antioxidant molecules. Peroxiredoxins (Prxs) in plants, including the Prx1, Prx5, Prx6, and PrxQ isoforms, constitute a family of antioxidant enzymes and play important functions in cells. Each Prx localizes to a specific subcellular compartment and has a distinct function in the control of plant growth, development, cellular metabolism, and various aspects of defense signaling...
November 7, 2017: Antioxidants & Redox Signaling
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