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Isotype switching

Tatiana Pochechueva, Alexander Chinarev, Andreas Schoetzau, André Fedier, Nicolai V Bovin, Neville F Hacker, Francis Jacob, Viola Heinzelmann-Schwarz
Altered levels of naturally occurring anti-glycan antibodies (AGA) circulating in human blood plasma are found in different pathologies including cancer. Here the levels of AGA directed against 22 negatively charged (sialylated and sulfated) glycans were assessed in high-grade serous ovarian cancer (HGSOC, n = 22) patients and benign controls (n = 31) using our previously developed suspension glycan array (SGA). Specifically, the ability of AGA to differentiate between controls and HGSOC, the most common and aggressive type of ovarian cancer with a poor outcome was determined...
2016: PloS One
Rui Yang, April R Masters, Karen A Fortner, Devin P Champagne, Natalia Yanguas-Casás, Daniel J Silberger, Casey T Weaver, Laura Haynes, Mercedes Rincon
IL-6 is known to contribute to the differentiation of CD4(+) T cells into different subsets of effector T helper cells. Less is known about the potential of IL-6 in regulating CD8(+) T cell effector function. Here, we identify IL-6 as a master regulator of IL-21 in effector CD8(+) T cells. IL-6 promotes the differentiation of a subset of naive CD8(+) T cells that express IL-6R into a unique population of effector CD8(+) T cells characterized by the production of high levels of IL-21 and low levels of IFN-γ...
September 26, 2016: Journal of Experimental Medicine
Prabhu S Arunachalam, Ria Mishra, Krithika Badarinath, Deepak Selvam, Sravan K Payeli, Richard R Stout, Udaykumar Ranga
The delivery of plasmid DNA to the skin can target distinct subsets of dermal dendritic cells to confer a superior immune response. The needle-free immunization technology offers a reliable, safe and efficient means to administer intradermal (ID) injections. We report here that the ID injection of DNA vectors using an NF device (NF-ID) elicits a superior cell-mediated immune response, at much lesser DNA dosage, comparable in magnitude to the traditional intramuscular immunization. However, the humoral response is significantly impaired, possibly at the stage of B cell isotype switching...
2016: Scientific Reports
Krista D DiSano, Stephen A Stohlman, Cornelia C Bergmann
Central nervous system (CNS) inflammation associated with viral infection and autoimmune disease results in the accumulation of B cells in various differentiation stages. However, the contribution between peripheral and CNS activation remains unclear. During gliatropic coronavirus induced encephalomyelitis, accumulation of protective antibody secreting cells is preceded by infiltration of B cells with a naïve and early differentiation phenotype (Phares et al., 2014). Investigation of the temporal dynamics of B cell activation in draining cervical lymph nodes (CLN) and the CNS revealed that peak CNS infiltration of early activated, unswitched IgD(+) and IgM(+) B cells coincided with polyclonal activation in CLN...
September 19, 2016: Brain, Behavior, and Immunity
Shehnaz Lokhandwala, Suryakant D Waghela, Jocelyn Bray, Cameron L Martin, Neha Sangewar, Chloe Charendoff, Rashmi Shetti, Clay Ashley, Chang-Hsin Chen, Luc R Berghman, Duncan Mwangi, Paul J Dominowski, Dennis L Foss, Sharath Rai, Shaunak Vora, Lindsay Gabbert, Thomas G Burrage, David Brake, John Neilan, Waithaka Mwangi
The African Swine Fever Virus (ASFV) causes a fatal hemorrhagic disease in domestic swine and, at present, no treatment or vaccine is available. Natural and gene-deleted, live attenuated strains protect against closely related virulent strains, however, they are yet to be deployed and evaluated in the field to rule out chronic persistence and potential for reversion to virulence. Previous studies suggest that antibodies play a role in protection, but induction of cytotoxic T-lymphocytes (CTLs) could be the key to complete protection...
September 14, 2016: Clinical and Vaccine Immunology: CVI
Isabella Pali-Schöll, Erika Jensen-Jarolim
For proteins to become allergenic, they need to acquire features enabling them to induce B cell activation and isotype switch to IgE production. Crosslinking of the B-cell receptor (BCR) is the most efficient way to productively activate B-cells. The IgE-crosslinking capability of allergens is equally crucial in the effector phase of immediate type allergy. Antigens, which acquire enhanced crosslinking capacity by oligomerization, aggregation, or the expression of repetitive epitopes may therefore gain allergenic potency...
September 9, 2016: Current Opinion in Immunology
Haifa H Jabara, John J Lee, Erin Janssen, Sumana Ullas, Kyriaki Liadaki, Lilit Garibyan, Halli Benson, Tatyana Sannikova, Richard Bram, Lennart Hammarstrom, Anthony C Cruz, Richard Siegel, John Manis, Richard Malley, Raif S Geha
BACKGROUND: The B-cell receptor transmembrane activator and calcium modulator ligand interactor (TACI) is important for T-independent antibody responses. One in 200 blood donors are heterozygous for the TACI A181E mutation. OBJECTIVE: We sought to investigate the effect on B-cell function of TACI A181E heterozygosity in reportedly healthy subjects and of the corresponding TACI A144E mutation in mice. METHODS: Nuclear factor κB (NF-κB) activation was measured by using the luciferase assay in 293T cells cotransfected with wild-type and mutant TACI...
September 5, 2016: Journal of Allergy and Clinical Immunology
Ana E Suárez, M J Artiga, Carlos Santonja, Santiago Montes-Moreno, P De Pablo, Luis Requena, Miguel A Piris, Socorro M Rodríguez-Pinilla
Plasma cell proliferations in specific cutaneous lesions of angioimmunoblastic T-cell lymphoma(AITL) are very uncommon. Here, we report a case of clonal plasma cell proliferation in skin with heavy-chain-immunoglobulin-isotype-switch after cutaneous disease progression. Histopathologically, initial plaque lesions were suggestive of marginal-zone B-cell-lymphoma. Nevertheless, this 77-year-old lady was diagnosed with AITL after the progression of skin lesions from plaques to nodular tumors. A lymph node biopsy confirmed the diagnosis...
September 6, 2016: Journal of Cutaneous Pathology
Anthony B Eason, Sang-Hoon Sin, Carolina Lin, Blossom Damania, Steven Park, Yuri Fedoriw, Carlos E Bacchi, Dirk P Dittmer
Endemic Burkitt lymphoma (eBL) is primarily a childhood cancer in parts of Africa and Brazil. Classic studies describe eBL as a homogeneous entity based on t(8;14) IgH-Myc translocation and clinical response to cytotoxic therapy. By contrast, sporadic BL (sBL) in Western countries is considered more heterogeneous, and affects both children and adults. It is overrepresented in AIDS patients. Unlike diffuse large B cell lymphoma (DLBCL), molecular subtypes within BL have not been well defined. We find that differential IgM positivity can be used to describe two subtypes of pediatric Burkitt lymphoma both in a high incidence region (Brazil), as well as in a sporadic region (US), suggesting the phenotype is not necessarily geographically isolated...
August 23, 2016: Oncotarget
Shuang Wu, Sophia R Majeed, Timothy M Evans, Marine D Camus, Nicole M L Wong, Yvette Schollmeier, Minjong Park, Jagan R Muppidi, Andrea Reboldi, Peter Parham, Jason G Cyster, Frances M Brodsky
Clathrin, a cytosolic protein composed of heavy and light chain subunits, assembles into a vesicle coat, controlling receptor-mediated endocytosis. To establish clathrin light chain (CLC) function in vivo, we engineered mice lacking CLCa, the major CLC isoform in B lymphocytes, generating animals with CLC-deficient B cells. In CLCa-null mice, the germinal centers have fewer B cells, and they are enriched for IgA-producing cells. This enhanced switch to IgA production in the absence of CLCa was attributable to increased transforming growth factor β receptor 2 (TGFβR2) signaling resulting from defective endocytosis...
August 30, 2016: Proceedings of the National Academy of Sciences of the United States of America
Sung Hoon Cho, Ariel L Raybuck, Kristy Stengel, Mei Wei, Thomas C Beck, Emmanuel Volanakis, James W Thomas, Scott Hiebert, Volker H Haase, Mark R Boothby
Germinal centers (GCs) promote humoral immunity and vaccine efficacy. In GCs, antigen (Ag)-activated B lymphocytes proliferate, are selected for high affinity antibody (Ab), promote Ab class switching, and yield B cell memory1,2. Whereas the cytokine milieu has long been known to regulate effector functions that include the choice of immunoglobulin class 3,4, both cell-autonomous5 and extrinsic6,7 metabolic programming have emerged as modulators of T cell-mediated immunity8. We now show that GC light zones are hypoxic and low oxygen (pO2) alters B cell physiology and function...
August 8, 2016: Nature
John E Butler, Kristina Santiago-Mateo, Nancy Wertz, Xiuzhu Sun, Marek Sinkora, David L Francis
The ileal Peyers patches (IPP) of newborn germfree (GF) piglets were isolated into blind loops and the piglets colonized with a defined probiotic microflora. After 5 weeks, IgA levels in the intestinal lavage (IL) of loop piglets remained at GF levels and IgM comprised ∼70% while in controls, IgA levels were elevated 5-fold and comprised ∼70% of total Igs. Loop piglets also had reduced serum IgA levels suggesting the source of serum IgA had been interrupted. The isotype profile for loop contents was intermediate between that in the IL of GF and probiotic controls...
December 2016: Developmental and Comparative Immunology
Nathan L Sanders, Anil Mishra
Interleukin (IL)-18 is an IL-1 family cytokine expressed by macrophages, dendritic cells, epithelial cells, and keratinocytes and is implicated in various aspects of both the innate and adaptive immune systems. IL-18 signals similar to IL-1β intracellularly to activate gene transcription. Since its discovery, IL-18 has been demonstrated to play a key role in pathogen defense from helminths and some bacteria. Recently however, evidence has accumulated that IL-18 expression is increased in many presentations of allergic disease...
July 15, 2016: Cytokine & Growth Factor Reviews
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
E Svirshchevskaya, G Fattakhova, S Khlgatian, D Chudakov, E Kashirina, D Ryazantsev, O Kotsareva, S Zavriev
Allergy is characterized by IgE production to innocuous antigens. The question whether the switch to IgE synthesis occurs via direct or sequential pathways is still unresolved. The aim of this work was to analyze the distribution of immunoglobulins (Ig) to house dust mite D. farinae and A. alternata fungus in allergic children with primarily established diagnosis and compare it to Epstein-Barr antiviral (EBV) response in the same patients. In allergy patients the only significant difference was found in allergen specific IgE, likely mediated by a direct isotype switch, while antiviral response was dominated by EBV specific IgG and low level of concordant IgA and IgG4 production consistent with a minor sequential Ig switches...
September 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Sanjay Khandelwal, Gowthami M Arepally
The immune response to heparin is one of the most common drug-induced allergies, and yet, atypical for a drug hypersensitivity reaction. Whereas most drug-induced allergies are rare, idiosyncratic and life-long, the allergic response to heparin is common, predictable in certain clinical settings and transient. Advances in the last decade with regards to structural characterisation of the PF4/heparin antigenic complex, contributions of innate immunity and development of animal models have provided insights into the distinctive features of the HIT immune response...
July 28, 2016: Thrombosis and Haemostasis
Viqar S Banday, Radha Thyagarajan, Mia Sundström, Kristina Lejon
B cells have an important pathogenic role in the development of type 1 diabetes in the non-obese diabetic (NOD) mouse. We have previously reported that NOD mice display an increased percentage of TACI(high) -expressing B cells compared with C57BL/6 mice and this trait is linked to chromosomes 1 and 8. In this paper the genetic association of the transmembrane activator, calcium modulator and cyclophilin ligand interactor (TACI) trait was confirmed using double congenic NOD.B6C1/Idd22 mice. TACI ligation by a proliferation-inducing ligand (APRIL) has been shown to influence plasma cell differentiation, immunoglobulin production and isotype switch...
November 2016: Immunology
Burton E Barnett, Ryan P Staupe, Pamela M Odorizzi, Olesya Palko, Vesselin T Tomov, Alison E Mahan, Bronwyn Gunn, Diana Chen, Michael A Paley, Galit Alter, Steven L Reiner, Georg M Lauer, John R Teijaro, E John Wherry
The role of Ab and B cells in preventing infection is established. In contrast, the role of B cell responses in containing chronic infections remains poorly understood. IgG2a (IgG1 in humans) can prevent acute infections, and T-bet promotes IgG2a isotype switching. However, whether IgG2a and B cell-expressed T-bet influence the host-pathogen balance during persisting infections is unclear. We demonstrate that B cell-specific loss of T-bet prevents control of persisting viral infection. T-bet in B cells controlled IgG2a production, as well as mucosal localization, proliferation, glycosylation, and a broad transcriptional program...
August 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Martin S Naradikian, Arpita Myles, Daniel P Beiting, Kenneth J Roberts, Lucas Dawson, Ramin Sedaghat Herati, Bertram Bengsch, Susanne L Linderman, Erietta Stelekati, Rosanne Spolski, E John Wherry, Christopher Hunter, Scott E Hensley, Warren J Leonard, Michael P Cancro
T-bet and CD11c expression in B cells is linked with IgG2c isotype switching, virus-specific immune responses, and humoral autoimmunity. However, the activation requisites and regulatory cues governing T-bet and CD11c expression in B cells remain poorly defined. In this article, we reveal a relationship among TLR engagement, IL-4, IL-21, and IFN-γ that regulates T-bet expression in B cells. We find that IL-21 or IFN-γ directly promote T-bet expression in the context of TLR engagement. Further, IL-4 antagonizes T-bet induction...
August 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Lin-Jing Li, Na Ma, Lu Zeng, Li-Hua Mo, Xiao-Xi Li, Ling-Zhi Xu, Bo Yang, Zhi-Gang Liu, Bai-Sui Feng, Peng-Yuan Zheng, Huan-Ping Zhang, Ping-Chang Yang
The initiation mechanism of IgE expression has not been fully understood. Flagellin (FGN) is an important microbial factor in the regulation of immune responses in the intestine. This study tests a hypothesis that FGN plays a crucial role in the isotype switching of IgE in B cells and the initiation of food allergy. In this study, the expression of IgE in B cells was analyzed by real time RT-PCR, Western blotting and chromatin immunoprecipitation. A mouse model was developed to assess the role of Toll like receptor-5 in the development of IgE-mediated allergic reaction in the intestinal mucosa...
2016: American Journal of Translational Research
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