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Class switch recombination

René Winkler, Christian Kosan
Histone deacetylase inhibitors (HDACi) are used as therapeutics for several B cell-derived malignancies. Furthermore, they have been shown to modulate the response of the immune system, like the B cell function. HDACi treatment affects differentiation, proliferation, and survival of B cells. Here we describe how to investigate the effects of HDACi treatment on naïve B cells regarding class-switch recombination (CSR) in vitro using flow cytometry.
2017: Methods in Molecular Biology
Ravendra Garg, Michael Theaker, Elisa C Martinez, Sylvia van Drunen Littel-van den Hurk
Respiratory syncytial virus (RSV) causes serious respiratory illness in infants and elderly. RSV infection induces short-lived immunity, which leaves people prone to re-infection. In contrast, the RSV fusion (F) protein formulated with a novel adjuvant (∆F/TriAdj) elicits long term protective immunity. A comparison of RSV-immunized mice to mice vaccinated with a single dose of ∆F/TriAdj showed no difference in IgG1 and IgG2a production; however, local IgA secreting memory B cell development and B cell IgA production were significantly lower in RSV vaccinated mice than in ∆F/TriAdj-immunized mice...
October 6, 2016: Virology
Lei Wang
The genetic code can be expanded to include unnatural amino acids (Uaas) by engineering orthogonal components involved in protein translation. To be compatible with live cells, side chains of Uaas have been limited to either chemically inert or bio-orthogonal (i.e., nonreactive toward biomolecules) functionalities. To introduce bioreactivity into live systems, the genetic code has recently been engineered to encode a new class of Uaas, the bioreactive Uaas. These Uaas, after being incorporated into proteins, specifically react with target natural amino acid residues via proximity-enabled bioreactivity, enabling the selective formation of new covalent linkages within and between proteins both in vitro and in live systems...
October 6, 2016: New Biotechnology
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...
October 4, 2016: Molecular Immunology
María Belén Almejún, Bárbara Carolina Campos, Virginia Patiño, Miguel Galicchio, Marta Zelazko, Matías Oleastro, Pablo Oppezzo, Silvia Danielian
BACKGROUND: Common variable immunodeficiency is a heterogeneous syndrome characterized by impaired immunoglobulin production and usually presents with a normal quantity of peripheral B cells. Most attempts aiming to classify these patients have mainly been focused on T cell phenotypes or B cell phenotypes and their ability to produce protective antibodies, but it is still a major challenge to find a suitable classification that includes the clinical and immunological heterogeneity of these patients...
October 3, 2016: Journal of Allergy and Clinical Immunology
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...
October 4, 2016: Journal of Clinical Investigation
Giulia Bastianello, Hiroshi Arakawa
All three B cell-specific activities of the immunoglobulin (Ig) gene re-modeling system-gene conversion, somatic hypermutation and class switch recombination-require activation-induced deaminase (AID). AID-induced DNA lesions must be further processed and dissected into different DNA recombination pathways. In order to characterize potential intermediates for Ig gene conversion, we inserted an I-SceI recognition site into the complementarity determining region 1 (CDR1) of the Ig light chain locus of the AID knockout DT40 cell line, and conditionally expressed I-SceI endonuclease...
October 3, 2016: Nucleic Acids Research
R Cianci, S Lolli, D Pagliari, G Gambassi, S Frosali, R Marmo, G Melioli, A Orlando, E E Newton, E Serone, R Landolfi, F Pandolfi, D Frezza
OBJECTIVE: To study the 3' immunoglobulin heavy-chain regulatory region (3'RR) enhancer complex, active in class switching recombination and in B-cells, in Crohn's disease. PATIENTS AND METHODS: A total of 167 patients [79 females (47.3%) and 88 males (52.7%)] affected by Crohn's disease were enrolled in the study. As a control, we included 64 healthy subjects, age and sex matched, from the same geographical area. Blood tests were performed on all subjects to determine their antibody levels and to detect the presence of any possible infections...
September 2016: European Review for Medical and Pharmacological Sciences
Vipul Kumar, Frederick W Alt, Richard L Frock
Classical nonhomologous end joining (C-NHEJ) is a major mammalian DNA double-strand break (DSB) repair pathway. Core C-NHEJ factors, such as XRCC4, are required for joining DSB intermediates of the G1 phase-specific V(D)J recombination reaction in progenitor lymphocytes. Core factors also contribute to joining DSBs in cycling mature B-lineage cells, including DSBs generated during antibody class switch recombination (CSR) and DSBs generated by ionizing radiation. The XRCC4-like-factor (XLF) C-NHEJ protein is dispensable for V(D)J recombination in normal cells, but because of functional redundancy, it is absolutely required for this process in cells deficient for the ataxia telangiectasia-mutated (ATM) DSB response factor...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
Sachini U Siriwardena, Kang Chen, Ashok S Bhagwat
The AID/APOBEC family enzymes convert cytosines in single-stranded DNA to uracils, causing base substitutions and strand breaks. They are induced by cytokines produced during the body's inflammatory response to infections, and they help combat infections through diverse mechanisms. AID is essential for the maturation of antibodies and causes mutations and deletions in antibody genes through somatic hypermutation (SHM) and class-switch recombination (CSR) processes. One member of the APOBEC family, APOBEC1, edits mRNA for a protein involved in lipid transport...
September 1, 2016: Chemical Reviews
Elisa Ferretti, Maurilio Ponzoni, Claudio Doglioni, Vito Pistoia
The germinal center (GC) is a dynamic structure formed by proliferating B cells in the follicles of secondary lymphoid organs during T cell-dependent antibody responses to exogenous antigens. GC is composed by a dark zone, enriched in proliferating centroblasts (CBs), and a light zone where CBs migrate and transform into centrocytes (CCs), a minority of which is selected to survive, undergoes Ig class-switch recombination, and differentiates into memory B cells or long-lived plasma cells. CBs express CXCR4 and are attracted to the dark zone by stromal cell-derived CXCL12, whereas CCs express CXCR5 and are recruited to the light zone along a gradient of CXCL13 produced by follicular dendritic cells (FDCs)...
August 26, 2016: Journal of Leukocyte Biology
Ahrom Kim, Li Han, Gabriel E Santiago, Ramiro E Verdun, Kefei Yu
The ∼28-kb 3' regulatory region (3'RR), which is located at the most distal 3' region of the Ig H chain locus, has multiple regulatory functions that control IgH expression, class-switch recombination (CSR), and somatic hypermutation. In this article, we report that deletion of the entire 3'RR in a mouse B cell line that is capable of robust cytokine-dependent CSR to IgA results in reduced, but not abolished, CSR. These data suggest that 3'RR is not absolutely required for CSR and, thus, is not essential for targeting activation-induced cytidine deaminase to S regions, as was suggested...
October 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Jakob Kreye, Nina K Wenke, Mariya Chayka, Jonas Leubner, Rajagopal Murugan, Nikolaus Maier, Betty Jurek, Lam-Thanh Ly, Doreen Brandl, Benjamin R Rost, Alexander Stumpf, Paulina Schulz, Helena Radbruch, Anja E Hauser, Florence Pache, Andreas Meisel, Lutz Harms, Friedemann Paul, Ulrich Dirnagl, Craig Garner, Dietmar Schmitz, Hedda Wardemann, Harald Prüss
SEE ZEKERIDOU AND LENNON DOI101093/AWW213 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesias, and seizures. Little is known about the cerebrospinal fluid autoantibody repertoire. Antibodies against the NR1 subunit of the NMDAR are thought to be pathogenic; however, direct proof is lacking as previous experiments could not distinguish the contribution of further anti-neuronal antibodies...
October 2016: Brain: a Journal of Neurology
Joseph W Brewer, Viktoriya Solodushko, Ileana Aragon, Robert A Barrington
In activated B cells, increased production of phosphatidylcholine (PtdCho), the most abundant cellular phospholipid, is handled primarily by the CDP-choline pathway. B cell-specific deletion of CTP:phosphocholine cytidylyltransferase α (CCTα), the rate-limiting enzyme in the CDP-choline pathway, led to augmented IgM secretion and reduced IgG production, suggesting that PtdCho synthesis is required for germinal center reactions. To specifically assess whether PtdCho influences B cell fate during germinal center responses, we examined immune responses in mice whereby PtdCho synthesis is disrupted in B cells that have undergone class switch recombination to IgG1 (referred to as either Cγ1(wt/wt), Cγ1(Cre/wt) or Cγ1(Cre/Cre) based on Cre copy number)...
August 3, 2016: Cellular Immunology
Bart G Jones, Rhiannon R Penkert, Beisi Xu, Yiping Fan, Geoff Neale, Patricia J Gearhart, Julia L Hurwitz
Females and males differ in antibody isotype expression patterns and in immune responses to foreign- and self-antigens. For example, systemic lupus erythematosus is a condition that associates with the production of isotype-skewed anti-self antibodies, and exhibits a 9:1 female:male disease ratio. To explain differences between B cell responses in males and females, we sought to identify direct interactions of the estrogen receptor (ER) with the immunoglobulin heavy chain locus. This effort was encouraged by our previous identification of estrogen response elements (ERE) in heavy chain switch (S) regions...
September 2016: Molecular Immunology
Daan J Aan de Kerk, Machiel H Jansen, Stephen Jolles, Klaus Warnatz, Suranjith L Seneviratne, Ineke J M Ten Berge, Ester M M van Leeuwen, Taco W Kuijpers
Primary antibody deficiencies (PADs) are the most common immunodeficiency in humans, characterized by low levels of immunoglobulins and inadequate antibody responses upon immunization. These PADs may result from an early block in B cell development with a complete absence of peripheral B cells and lack of immunoglobulins. In the presence of circulating B cells, some PADs are genetically caused by a class switch recombination (CSR) defect, but in the most common PAD, common variable immunodeficiency (CVID), very few gene defects have as yet been characterized despite various phenotypic classifications...
October 2016: Journal of Clinical Immunology
Andres Canela, Sriram Sridharan, Nicholas Sciascia, Anthony Tubbs, Paul Meltzer, Barry P Sleckman, André Nussenzweig
DNA double-strand breaks (DSBs) arise during physiological transcription, DNA replication, and antigen receptor diversification. Mistargeting or misprocessing of DSBs can result in pathological structural variation and mutation. Here we describe a sensitive method (END-seq) to monitor DNA end resection and DSBs genome-wide at base-pair resolution in vivo. We utilized END-seq to determine the frequency and spectrum of restriction-enzyme-, zinc-finger-nuclease-, and RAG-induced DSBs. Beyond sequence preference, chromatin features dictate the repertoire of these genome-modifying enzymes...
September 1, 2016: Molecular Cell
Pei-cheng Shen, Li-qun He
OBJECTIVE: To explore the underlying mechanism of "Gubentongluo Formula" in treatment of IgA nephropathy (IgAN). METHODS: After the IgAN model was successfully induced at week 12, the Kunming mice were randomly divided into three groups: normal control group (n = 15), IgAN group (n = 15) and Traditional Chinese Medicine (TCM) group. The mice in normal control and IgAN group were intragastriclly administrated with normal saline for 8 weeks; meanwhile, the mice in TCM group were intragastriclly administrated with "Gubentongluo Formula" 1...
May 2016: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
Shuwen Chen, Masaki Miyazaki, Vivek Chandra, Kathleen M Fisch, Aaron N Chang, Cornelis Murre
Previous studies have demonstrated that E proteins induce activation-induced deaminase (AID) expression in activated B cells. Here, we examined the role of Id3 in germinal center (GC) cells. We found that Id3 expression is high in follicular B lineage cells but declines in GC cells. Immunized mice with Id3 expression depleted displayed a block in germinal center B cell maturation, showed reduced numbers of marginal zone B cells and class-switched cells, and were associated with decreased antibody titers and lower numbers of plasma cells...
October 15, 2016: Molecular and Cellular Biology
Kari Hemminki, Xiangdong Liu, Jianguang Ji, Asta Försti
Autoimmune diseases (ADs) are associated with a number of B-cell neoplasms but the associations are selective in regard to the type of neoplasm and the conferred risks are variable. So far no mechanistic bases for these differential associations have been demonstrated. We speculate that developmental origin of B-cells might propose a mechanistic rationale for their carcinogenic response to autoimmune stimuli and tested the hypothesis on our previous studies on the risks of B-cell neoplasms after any of 33 ADs...
2016: PloS One
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