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Sample records for controls b-cell fate

  1. Atypical chemokine receptor 4 shapes activated B cell fate.

    Science.gov (United States)

    Kara, Ervin E; Bastow, Cameron R; McKenzie, Duncan R; Gregor, Carly E; Fenix, Kevin A; Babb, Rachelle; Norton, Todd S; Zotos, Dimitra; Rodda, Lauren B; Hermes, Jana R; Bourne, Katherine; Gilchrist, Derek S; Nibbs, Robert J; Alsharifi, Mohammed; Vinuesa, Carola G; Tarlinton, David M; Brink, Robert; Hill, Geoffrey R; Cyster, Jason G; Comerford, Iain; McColl, Shaun R

    2018-01-31

    Activated B cells can initially differentiate into three functionally distinct fates-early plasmablasts (PBs), germinal center (GC) B cells, or early memory B cells-by mechanisms that remain poorly understood. Here, we identify atypical chemokine receptor 4 (ACKR4), a decoy receptor that binds and degrades CCR7 ligands CCL19/CCL21, as a regulator of early activated B cell differentiation. By restricting initial access to splenic interfollicular zones (IFZs), ACKR4 limits the early proliferation of activated B cells, reducing the numbers available for subsequent differentiation. Consequently, ACKR4 deficiency enhanced early PB and GC B cell responses in a CCL19/CCL21-dependent and B cell-intrinsic manner. Conversely, aberrant localization of ACKR4-deficient activated B cells to the IFZ was associated with their preferential commitment to the early PB linage. Our results reveal a regulatory mechanism of B cell trafficking via an atypical chemokine receptor that shapes activated B cell fate. © 2018 Kara et al.

  2. IgH isotype-specific B cell receptor expression influences B cell fate.

    Science.gov (United States)

    Tong, Pei; Granato, Alessandra; Zuo, Teng; Chaudhary, Neha; Zuiani, Adam; Han, Seung Seok; Donthula, Rakesh; Shrestha, Akritee; Sen, Debattama; Magee, Jennifer M; Gallagher, Michael P; van der Poel, Cees E; Carroll, Michael C; Wesemann, Duane R

    2017-10-03

    Ig heavy chain (IgH) isotypes (e.g., IgM, IgG, and IgE) are generated as secreted/soluble antibodies (sIg) or as membrane-bound (mIg) B cell receptors (BCRs) through alternative RNA splicing. IgH isotype dictates soluble antibody function, but how mIg isotype influences B cell behavior is not well defined. We examined IgH isotype-specific BCR function by analyzing naturally switched B cells from wild-type mice, as well as by engineering polyclonal Ighγ1/γ1 and Ighε/ε mice, which initially produce IgG1 or IgE from their respective native genomic configurations. We found that B cells from wild-type mice, as well as Ighγ1/γ1 and Ighε/ε mice, produce transcripts that generate IgM, IgG1, and IgE in an alternative splice form bias hierarchy, regardless of cell stage. In this regard, we found that mIgμ > mIgγ1 > mIgε, and that these BCR expression differences influence respective developmental fitness. Restrained B cell development from Ighγ1/γ1 and Ighε/ε mice was proportional to sIg/mIg ratios and was rescued by enforced expression of the respective mIgs. In addition, artificially enhancing BCR signal strength permitted IgE+ memory B cells-which essentially do not exist under normal conditions-to provide long-lived memory function, suggesting that quantitative BCR signal weakness contributes to restraint of IgE B cell responses. Our results indicate that IgH isotype-specific mIg/BCR dosage may play a larger role in B cell fate than previously anticipated.

  3. Transcription factors regulating B cell fate in the germinal centre.

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    Recaldin, T; Fear, D J

    2016-01-01

    Diversification of the antibody repertoire is essential for the normal operation of the vertebrate adaptive immune system. Following antigen encounter, B cells are activated, proliferate rapidly and undergo two diversification events; somatic hypermutation (followed by selection), which enhances the affinity of the antibody for its cognate antigen, and class-switch recombination, which alters the effector functions of the antibody to adapt the response to the challenge faced. B cells must then differentiate into antibody-secreting plasma cells or long-lived memory B cells. These activities take place in specialized immunological environments called germinal centres, usually located in the secondary lymphoid organs. To complete the germinal centre activities successfully, a B cell adopts a transcriptional programme that allows it to migrate to specific sites within the germinal centre, proliferate, modify its DNA recombination and repair pathways, alter its apoptotic potential and finally undergo terminal differentiation. To co-ordinate these processes, B cells employ a number of 'master regulator' transcription factors which mediate wholesale transcriptomic changes. These master transcription factors are mutually antagonistic and form a complex regulatory network to maintain distinct gene expression programs. Within this network, multiple points of positive and negative feedback ensure the expression of the 'master regulators', augmented by a number of 'secondary' factors that reinforce these networks and sense the progress of the immune response. In this review we will discuss the different activities B cells must undertake to mount a successful T cell-dependent immune response and describe how a regulatory network of transcription factors controls these processes. © 2015 British Society for Immunology.

  4. Human regulatory B cells control the TFH cell response.

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    Achour, Achouak; Simon, Quentin; Mohr, Audrey; Séité, Jean-François; Youinou, Pierre; Bendaoud, Boutahar; Ghedira, Ibtissem; Pers, Jacques-Olivier; Jamin, Christophe

    2017-07-01

    Follicular helper T (TFH) cells support terminal B-cell differentiation. Human regulatory B (Breg) cells modulate cellular responses, but their control of TFH cell-dependent humoral immune responses is unknown. We sought to assess the role of Breg cells on TFH cell development and function. Human T cells were polyclonally stimulated in the presence of IL-12 and IL-21 to generate TFH cells. They were cocultured with B cells to induce their terminal differentiation. Breg cells were included in these cultures, and their effects were evaluated by using flow cytometry and ELISA. B-cell lymphoma 6, IL-21, inducible costimulator, CXCR5, and programmed cell death protein 1 (PD-1) expressions increased on stimulated human T cells, characterizing TFH cell maturation. In cocultures they differentiated B cells into CD138(+) plasma and IgD(-)CD27(+) memory cells and triggered immunoglobulin secretions. Breg cells obtained by Toll-like receptor 9 and CD40 activation of B cells prevented TFH cell development. Added to TFH cell and B-cell cocultures, they inhibited B-cell differentiation, impeded immunoglobulin secretions, and expanded Foxp3(+)CXCR5(+)PD-1(+) follicular regulatory T cells. Breg cells modulated IL-21 receptor expressions on TFH cells and B cells, and their suppressive activities involved CD40, CD80, CD86, and intercellular adhesion molecule interactions and required production of IL-10 and TGF-β. Human Breg cells control TFH cell maturation, expand follicular regulatory T cells, and inhibit the TFH cell-mediated antibody secretion. These novel observations demonstrate a role for the Breg cell in germinal center reactions and suggest that deficient activities might impair the TFH cell-dependent control of humoral immunity and might lead to the development of aberrant autoimmune responses. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  5. Infiltrating regulatory B cells control neuroinflammation following viral brain infection.

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    Mutnal, Manohar B; Hu, Shuxian; Schachtele, Scott J; Lokensgard, James R

    2014-12-15

    Previous studies have demonstrated the existence of a subset of B lymphocytes, regulatory B cells (Bregs), which modulate immune function. In this study, in vivo and in vitro experiments were undertaken to elucidate the role of these Bregs in controlling neuroinflammation following viral brain infection. We used multicolor flow cytometry to phenotype lymphocyte subpopulations infiltrating the brain, along with in vitro cocultures to assess their anti-inflammatory and immunoregulatory roles. This distinctive subset of CD19(+)CD1d(hi)CD5(+) B cells was found to infiltrate the brains of chronically infected animals, reaching highest levels at the latest time point tested (30 d postinfection). B cell-deficient Jh(-/-) mice were found to develop exacerbated neuroimmune responses as measured by enhanced accumulation and/or retention of CD8(+) T cells within the brain, as well as increased levels of microglial activation (MHC class II). Conversely, levels of Foxp3(+) regulatory T cells were found to be significantly lower in Jh(-/-) mice when compared with wild-type (Wt) animals. Further experiments showed that in vitro-generated IL-10-secreting Bregs (B10) were able to inhibit cytokine responses from microglia following stimulation with viral Ags. These in vitro-generated B10 cells were also found to promote proliferation of regulatory T cells in coculture studies. Finally, gain-of-function experiments demonstrated that reconstitution of Wt B cells into Jh(-/-) mice restored neuroimmune responses to levels exhibited by infected Wt mice. Taken together, these results demonstrate that Bregs modulate T lymphocyte as well as microglial cell responses within the infected brain and promote CD4(+)Foxp3(+) T cell proliferation in vitro. Copyright © 2014 by The American Association of Immunologists, Inc.

  6. The endocytic adaptor Eps15 controls marginal zone B cell numbers.

    Directory of Open Access Journals (Sweden)

    Benedetta Pozzi

    Full Text Available Eps15 is an endocytic adaptor protein involved in clathrin and non-clathrin mediated endocytosis. In Caenorhabditis elegans and Drosophila melanogaster lack of Eps15 leads to defects in synaptic vesicle recycling and synapse formation. We generated Eps15-KO mice to investigate its function in mammals. Eps15-KO mice are born at the expected Mendelian ratio and are fertile. Using a large-scale phenotype screen covering more than 300 parameters correlated to human disease, we found that Eps15-KO mice did not show any sign of disease or neural deficits. Instead, altered blood parameters pointed to an immunological defect. By competitive bone marrow transplantation we demonstrated that Eps15-KO hematopoietic precursor cells were more efficient than the WT counterparts in repopulating B220⁺ bone marrow cells, CD19⁻ thymocytes and splenic marginal zone (MZ B cells. Eps15-KO mice showed a 2-fold increase in MZ B cell numbers when compared with controls. Using reverse bone marrow transplantation, we found that Eps15 regulates MZ B cell numbers in a cell autonomous manner. FACS analysis showed that although MZ B cells were increased in Eps15-KO mice, transitional and pre-MZ B cell numbers were unaffected. The increase in MZ B cell numbers in Eps15 KO mice was not dependent on altered BCR signaling or Notch activity. In conclusion, in mammals, the endocytic adaptor protein Eps15 is a regulator of B-cell lymphopoiesis.

  7. B cell intrinsic T-bet expression is required to control chronic viral infection

    Science.gov (United States)

    Barnett, Burton E.; Staupe, Ryan P.; Odorizzi, Pamela M.; Palko, Olesya; Tomov, Vesselin T.; Mahan, Alison E.; Gunn, Bronwyn; Chen, Diana; Paley, Michael A.; Alter, Galit; Reiner, Steven L.; Lauer, Georg M.; Teijaro, John; Wherry, E. John

    2016-01-01

    The role of antibody 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. Here we demonstrate that B cell specific loss of T-bet prevents control of persisting viral infection. T-bet in B cells not only controlled IgG2a production, but also mucosal localization, proliferation, glycosylation, and a broad transcriptional program. T-bet controlled a broad antiviral program in addition to IgG2a since T-bet in B cells was important even in the presence of virus-specific IgG2a. Our data supports a model in which T-bet is a universal controller of antiviral immunity across multiple immune lineages. PMID:27430722

  8. CD154-CD40 interactions in the control of murine B cell hematopoiesis

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    Carlring, Jennifer; Altaher, Hala M.; Clark, Susan; Chen, Xi; Latimer, Sarah L.; Jenner, Tracey; Buckle, Anne-Marie; Heath, Andrew W.

    2011-01-01

    Interactions between CD40 and CD154 play a very important role in control of immune responses, including the delivery of T cell help to B cells and other APCs. Thus far, there has been no role postulated for CD40-CD154 interactions in hematopoiesis. We show here that CD40 is expressed on murine pro-B cells and that its ligation enhances pro-B cell proliferation in vitro and in vivo. In addition, CD154 mRNA is present in the BM. Moreover, we show that a deficiency in CD154 expression has effects on B cell hematopoiesis. Aged, CD154-deficient mice have significantly lower levels of B hematopoietic subsets downstream of pro-B cells in the BM. In addition, B lineage cells reconstitute more slowly following BMT into CD154-deficient recipients. We hypothesize that CD154 is expressed by radio-resistant cells in the BM and plays a role in fine-tuning B cell hematopoiesis. PMID:21330346

  9. CXCR5(+) follicular cytotoxic T cells control viral infection in B cell follicles.

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    Leong, Yew Ann; Chen, Yaping; Ong, Hong Sheng; Wu, Di; Man, Kevin; Deleage, Claire; Minnich, Martina; Meckiff, Benjamin J; Wei, Yunbo; Hou, Zhaohua; Zotos, Dimitra; Fenix, Kevin A; Atnerkar, Anurag; Preston, Simon; Chipman, Jeffrey G; Beilman, Greg J; Allison, Cody C; Sun, Lei; Wang, Peng; Xu, Jiawei; Toe, Jesse G; Lu, Hao K; Tao, Yong; Palendira, Umaimainthan; Dent, Alexander L; Landay, Alan L; Pellegrini, Marc; Comerford, Iain; McColl, Shaun R; Schacker, Timothy W; Long, Heather M; Estes, Jacob D; Busslinger, Meinrad; Belz, Gabrielle T; Lewin, Sharon R; Kallies, Axel; Yu, Di

    2016-10-01

    During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell-derived malignancies.

  10. Control of B Cell Development by the Histone H2A Deubiquitinase MYSM1

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    Jiang, Xiao-Xia; Nguyen, Quan; Chou, YuChia; Wang, Tao; Nandakumar, Vijayalakshmi; Yates, Peter; Jones, Lindsey; Wang, Lifeng; Won, Hae-Jung; Lee, Hye-Ra; Jung, Jae U; Muschen, Markus; Huang, Xue F; Chen, Si-Yi

    2013-01-01

    Epigenetic histone modifications play critical roles in the control of gene transcription. Recently, an increasing number of histone H2A deubiquitinases have been identified and characterized. However, the physiological functions for this entire group of histone H2A deubiquitinases remain unknown. In this study, we revealed that the histone H2A deubiquitinase MYSM1 plays an essential and intrinsic role in early B-cell development. MYSM1 deficiency results in a block in early B-cell commitment and a defect of B-cell progenitors in expression of EBF1 and other B-lymphoid genes. We further demonstrated that MYSM1 de-represses EBF1 transcription in B-cell progenitors by orchestrating histone modifications and transcription factor recruitment to the EBF1 locus. Thus, this study not only uncovers the essential role for MYSM1 in gene transcription during early B cell development, but also underscores the biological significance of reversible epigenetic histone H2A ubiquitination. PMID:22169041

  11. Antibody-independent control of gamma-herpesvirus latency via B cell induction of anti-viral T cell responses.

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    Kelly B McClellan

    2006-06-01

    Full Text Available B cells can use antibody-dependent mechanisms to control latent viral infections. It is unknown whether this represents the sole function of B cells during chronic viral infection. We report here that hen egg lysozyme (HEL-specific B cells can contribute to the control of murine gamma-herpesvirus 68 (gammaHV68 latency without producing anti-viral antibody. HEL-specific B cells normalized defects in T cell numbers and proliferation observed in B cell-/- mice during the early phase of gammaHV68 latency. HEL-specific B cells also reversed defects in CD8 and CD4 T cell cytokine production observed in B cell-/- mice, generating CD8 and CD4 T cells necessary for control of latency. Furthermore, HEL-specific B cells were able to present virally encoded antigen to CD8 T cells. Therefore, B cells have antibody independent functions, including antigen presentation, that are important for control of gamma-herpesvirus latency. Exploitation of this property of B cells may allow enhanced vaccine responses to chronic virus infection.

  12. Synthetic RNA Controllers for Programming Mammalian Cell Fate and Function

    Science.gov (United States)

    2015-11-04

    Final report for “Synthetic RNA controllers for programming mammalian cell fate and function” Principal Investigator: Christina D. Smolke...SUBTITLE Synthetic RNA controllers for programming mammalian cell fate and function 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER...Form 298 (Rev. 8-98) Prescribed by ANSI Std Z39-18   2 Synthetic RNA controllers for programming mammalian cell fate and function Task 1

  13. Matrix control of stem cell fate.

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    Even-Ram, Sharona; Artym, Vira; Yamada, Kenneth M

    2006-08-25

    A key challenge in stem cell research is to learn how to direct the differentiation of stem cells toward specific fates. In this issue of Cell, Engler et al. (2006) identify a new factor regulating stem cell fate: the elasticity of the matrix microenvironment. By changing the stiffness of the substrate, human mesenchymal stem cells could be directed along neuronal, muscle, or bone lineages.

  14. Control of the B cell-intrinsic tolerance programs by ubiquitin ligases Cbl and Cbl-b.

    Science.gov (United States)

    Kitaura, Yasuyuki; Jang, Ihn Kyung; Wang, Yan; Han, Yoon-Chi; Inazu, Tetsuya; Cadera, Emily J; Schlissel, Mark; Hardy, Richard R; Gu, Hua

    2007-05-01

    B cell receptor (BCR) signaling plays a critical role in B cell tolerance and activation. Here, we show that mice with B cell-specific ablation of both Cbl and Cbl-b (Cbl-/-Cblb-/-) manifested systemic lupus erythematosus (SLE)-like autoimmune disease. The Cbl double deficiency resulted in a substantial increase in marginal zone (MZ) and B1 B cells. The mutant B cells were not hyperresponsive in terms of proliferation and antibody production upon BCR stimulation; however, B cell anergy to protein antigen appeared to be impaired. Concomitantly, BCR-proximal signaling, including tyrosine phosphorylation of Syk tyrosine kinase, Phospholipase C-gamma2 (PLC-gamma2), and Rho-family GTP-GDP exchange factor Vav, and Ca2+ mobilization were enhanced, whereas tyrosine phosphorylation of adaptor protein BLNK was substantially attenuated in the mutant B cells. These results suggested that the loss of coordination between these pathways was responsible for the impaired B cell tolerance induction. Thus, Cbl proteins control B cell-intrinsic checkpoint of immune tolerance, possibly through coordinating multiple BCR-proximal signaling pathways during anergy induction.

  15. Harnessing cell-material interaction to control cell fate: design ...

    Indian Academy of Sciences (India)

    Rajat K Das

    2017-10-26

    Oct 26, 2017 ... advancement in engineered hydrogel materials as such scaffold to control cell fate. Keywords. Extracellular matrix; hydrogel .... tandem and determine the fate of the stem cells (cytoskeletal actin re-organization, gene ..... (encapsulation and on-demand release of therapeutic cells). These examples indicate ...

  16. Control of the B Cell-Intrinsic Tolerance Program by c-Cbl and Cbl-b

    Science.gov (United States)

    Kitaura, Yasuyuki; Jang, Ihn-Kyung; Wang, Yan; Han, Yoon-Chi; Inazu, Tetsuya; Cadera, Emily J.; Schlissel, Mark; Hardy, Richard R.; Gu, Hua

    2007-01-01

    BCR signaling plays a critical role in B-cell tolerance and activation. Here, we show that mice with B cell-specific ablation of both c-Cbl and Cbl-b (Cbl-dko) manifest systemic lupus erythymatosis (SLE)-like autoimmune disease. The Cbl-dko mutation results in a significant increase in marginal zone (MZ) and B1 B cells. The mutant B cells are not hyperresponsive in terms of proliferation and antibody production upon BCR stimulation; however, B-cell anergy to protein antigen appears to be impaired. Concomitantly, BCR-proximal signaling, including tyrosine phosphorylation of Syk, PLCγ-2, and Vav and Ca2+ mobilization, are enhanced, whereas tyrosine phosphorylation of BLNK is significantly attenuated in the mutant B cells, suggesting that the loss of coordination between these pathways is responsible for the impaired B-cell tolerance induction. Thus, Cbl proteins control B cell-intrinsic checkpoint of immune tolerance, possibly through coordinating multiple BCR-proximal signaling pathways during anergy induction. PMID:17493844

  17. Cutting Edge: B Cell-Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection.

    Science.gov (United States)

    Barnett, Burton E; Staupe, Ryan P; Odorizzi, Pamela M; Palko, Olesya; Tomov, Vesselin T; Mahan, Alison E; Gunn, Bronwyn; Chen, Diana; Paley, Michael A; Alter, Galit; Reiner, Steven L; Lauer, Georg M; Teijaro, John R; Wherry, E John

    2016-08-15

    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. T-bet controlled a broad antiviral program in addition to IgG2a because T-bet in B cells was important, even in the presence of virus-specific IgG2a. Our data support a model in which T-bet is a universal controller of antiviral immunity across multiple immune lineages. Copyright © 2016 by The American Association of Immunologists, Inc.

  18. The Plasmodium falciparum translationally controlled tumor protein (TCTP is incorporated more efficiently into B cells than its human homologue.

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    Berenice Calderón-Pérez

    Full Text Available Plasmodium falciparum secretes a homologue of the translationally controlled tumor protein (TCTP into serum of infected individuals, although its role in pathogenesis or virulence is unknown. To determine the effect of P. falciparum TCTP on B cells as compared to human TCTP, fluorescently labeled proteins were incubated on primary cultures of mouse splenic B cells and analyzed by flow cytometry and confocal microscopy. Our results indicate that both recombinant proteins are incorporated into B cells, but differ significantly in their rate and percentage of incorporation, being significantly higher for P. falciparum TCTP. Furthermore, P. falciparum TCTP showed a lower B cell proliferative effect than human TCTP, suggesting a mechanism through which the former could interfere in the host's immune response.

  19. PTIP chromatin regulator controls development and activation of B cell subsets to license humoral immunity in mice

    DEFF Research Database (Denmark)

    Su, Dan; Vanhee, Stijn; Soria, Rebeca

    2017-01-01

    of follicular B cells during germinal center formation, and normal signaling through the classical NF-κB pathway. Together with the previously identified role for PTIP in promoting sterile transcription at the Igh locus, the present results establish PTIP as a licensing factor for humoral immunity that acts......B cell receptor signaling and downstream NF-κB activity are crucial for the maturation and functionality of all major B cell subsets, yet the molecular players in these signaling events are not fully understood. Here we use several genetically modified mouse models to demonstrate that expression...... of the multifunctional BRCT (BRCA1 C-terminal) domain-containing PTIP (Pax transactivation domain-interacting protein) chromatin regulator is controlled by B cell activation and potentiates steady-state and postimmune antibody production in vivo. By examining the effects of PTIP deficiency in mice at various ages during...

  20. PTEN and PI-3 kinase inhibitors control LPS signaling and the lymphoproliferative response in the CD19+ B cell compartment

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Alok R. [UCSD Department of Pediatrics, Moores UCSD Cancer Center, University of California School of Medicine, San Diego, CA 92093 (United States); Peirce, Susan K. [Department of Pediatrics, Emory University School of Medicine, Atlanta, GA (United States); Joshi, Shweta [UCSD Department of Pediatrics, Moores UCSD Cancer Center, University of California School of Medicine, San Diego, CA 92093 (United States); Durden, Donald L., E-mail: ddurden@ucsd.edu [UCSD Department of Pediatrics, Moores UCSD Cancer Center, University of California School of Medicine, San Diego, CA 92093 (United States); Division of Pediatric Hematology-Oncology, UCSD Rady Children' s Hospital, La Jolla, CA (United States)

    2014-09-10

    Pattern recognition receptors (PRRs), e.g. toll receptors (TLRs) that bind ligands within the microbiome have been implicated in the pathogenesis of cancer. LPS is a ligand for two TLR family members, TLR4 and RP105 which mediate LPS signaling in B cell proliferation and migration. Although LPS/TLR/RP105 signaling is well-studied; our understanding of the underlying molecular mechanisms controlling these PRR signaling pathways remains incomplete. Previous studies have demonstrated a role for PTEN/PI-3K signaling in B cell selection and survival, however a role for PTEN/PI-3K in TLR4/RP105/LPS signaling in the B cell compartment has not been reported. Herein, we crossed a CD19cre and PTEN{sup fl/fl} mouse to generate a conditional PTEN knockout mouse in the CD19+ B cell compartment. These mice were further crossed with an IL-14α transgenic mouse to study the combined effect of PTEN deletion, PI-3K inhibition and expression of IL-14α (a cytokine originally identified as a B cell growth factor) in CD19+ B cell lymphoproliferation and response to LPS stimulation. Targeted deletion of PTEN and directed expression of IL-14α in the CD19+ B cell compartment (IL-14+PTEN-/-) lead to marked splenomegaly and altered spleen morphology at baseline due to expansion of marginal zone B cells, a phenotype that was exaggerated by treatment with the B cell mitogen and TLR4/RP105 ligand, LPS. Moreover, LPS stimulation of CD19+ cells isolated from these mice display increased proliferation, augmented AKT and NFκB activation as well as increased expression of c-myc and cyclinD1. Interestingly, treatment of LPS treated IL-14+PTEN-/- mice with a pan PI-3K inhibitor, SF1126, reduced splenomegaly, cell proliferation, c-myc and cyclin D1 expression in the CD19+ B cell compartment and normalized the splenic histopathologic architecture. These findings provide the direct evidence that PTEN and PI-3K inhibitors control TLR4/RP105/LPS signaling in the CD19+ B cell compartment and that pan PI

  1. BTG interacts with retinoblastoma to control cell fate in Dictyostelium.

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    Daniele Conte

    Full Text Available BACKGROUND: In the genesis of many tissues, a phase of cell proliferation is followed by cell cycle exit and terminal differentiation. The latter two processes overlap: genes involved in the cessation of growth may also be important in triggering differentiation. Though conceptually distinct, they are often causally related and functional interactions between the cell cycle machinery and cell fate control networks are fundamental to coordinate growth and differentiation. A switch from proliferation to differentiation may also be important in the life cycle of single-celled organisms, and genes which arose as regulators of microbial differentiation may be conserved in higher organisms. Studies in microorganisms may thus contribute to understanding the molecular links between cell cycle machinery and the determination of cell fate choice networks. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that in the amoebozoan D. discoideum, an ortholog of the metazoan antiproliferative gene btg controls cell fate, and that this function is dependent on the presence of a second tumor suppressor ortholog, the retinoblastoma-like gene product. Specifically, we find that btg-overexpressing cells preferentially adopt a stalk cell (and, more particularly, an Anterior-Like Cell fate. No btg-dependent preference for ALC fate is observed in cells in which the retinoblastoma-like gene has been genetically inactivated. Dictyostelium btg is the only example of non-metazoan member of the BTG family characterized so far, suggesting that a genetic interaction between btg and Rb predated the divergence between dictyostelids and metazoa. CONCLUSIONS/SIGNIFICANCE: While the requirement for retinoblastoma function for BTG antiproliferative activity in metazoans is known, an interaction of these genes in the control of cell fate has not been previously documented. Involvement of a single pathway in the control of mutually exclusive processes may have relevant implication in the

  2. The B-cell receptor controls fitness of MYC-driven lymphoma cells via GSK3β inhibition.

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    Varano, Gabriele; Raffel, Simon; Sormani, Martina; Zanardi, Federica; Lonardi, Silvia; Zasada, Christin; Perucho, Laura; Petrocelli, Valentina; Haake, Andrea; Lee, Albert K; Bugatti, Mattia; Paul, Ulrike; Van Anken, Eelco; Pasqualucci, Laura; Rabadan, Raul; Siebert, Reiner; Kempa, Stefan; Ponzoni, Maurilio; Facchetti, Fabio; Rajewsky, Klaus; Casola, Stefano

    2017-06-08

    Similar to resting mature B cells, where the B-cell antigen receptor (BCR) controls cellular survival, surface BCR expression is conserved in most mature B-cell lymphomas. The identification of activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signalling is required for tumour cell survival. Consequently, the BCR signalling machinery has become an established target in the therapy of B-cell malignancies. Here we study the effects of BCR ablation on MYC-driven mouse B-cell lymphomas and compare them with observations in human Burkitt lymphoma. Whereas BCR ablation does not, per se, significantly affect lymphoma growth, BCR-negative (BCR(-)) tumour cells rapidly disappear in the presence of their BCR-expressing (BCR(+)) counterparts in vitro and in vivo. This requires neither cellular contact nor factors released by BCR(+) tumour cells. Instead, BCR loss induces the rewiring of central carbon metabolism, increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuates glycogen synthase kinase 3 beta (GSK3β) activity to support MYC-controlled gene expression. BCR(-) tumour cells exhibit increased GSK3β activity and are rescued from their competitive growth disadvantage by GSK3β inhibition. BCR(-) lymphoma variants that restore competitive fitness normalize GSK3β activity after constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate immunoglobulin-crippled tumour cells, which usually represent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR(-) tumour cells.

  3. Cis and trans regulatory mechanisms control AP2-mediated B cell receptor endocytosis via select tyrosine-based motifs.

    Directory of Open Access Journals (Sweden)

    Kathleen Busman-Sahay

    Full Text Available Following antigen recognition, B cell receptor (BCR-mediated endocytosis is the first step of antigen processing and presentation to CD4+ T cells, a crucial component of the initiation and control of the humoral immune response. Despite this, the molecular mechanism of BCR internalization is poorly understood. Recently, studies of activated B cell-like diffuse large B cell lymphoma (ABC DLBCL have shown that mutations within the BCR subunit CD79b leads to increased BCR surface expression, suggesting that CD79b may control BCR internalization. Adaptor protein 2 (AP2 is the major mediator of receptor endocytosis via clathrin-coated pits. The BCR contains five putative AP2-binding YxxØ motifs, including four that are present within two immunoreceptor tyrosine-based activation motifs (ITAMs. Using a combination of in vitro and in situ approaches, we establish that the sole mediator of AP2-dependent BCR internalization is the membrane proximal ITAM YxxØ motif in CD79b, which is a major target of mutation in ABC DLBCL. In addition, we establish that BCR internalization can be regulated at a minimum of two different levels: regulation of YxxØ AP2 binding in cis by downstream ITAM-embedded DCSM and QTAT regulatory elements and regulation in trans by the partner cytoplasmic domain of the CD79 heterodimer. Beyond establishing the basic rules governing BCR internalization, these results illustrate an underappreciated role for ITAM residues in controlling clathrin-dependent endocytosis and highlight the complex mechanisms that control the activity of AP2 binding motifs in this receptor system.

  4. Cis and trans regulatory mechanisms control AP2-mediated B cell receptor endocytosis via select tyrosine-based motifs.

    Science.gov (United States)

    Busman-Sahay, Kathleen; Drake, Lisa; Sitaram, Anand; Marks, Michael; Drake, James R

    2013-01-01

    Following antigen recognition, B cell receptor (BCR)-mediated endocytosis is the first step of antigen processing and presentation to CD4+ T cells, a crucial component of the initiation and control of the humoral immune response. Despite this, the molecular mechanism of BCR internalization is poorly understood. Recently, studies of activated B cell-like diffuse large B cell lymphoma (ABC DLBCL) have shown that mutations within the BCR subunit CD79b leads to increased BCR surface expression, suggesting that CD79b may control BCR internalization. Adaptor protein 2 (AP2) is the major mediator of receptor endocytosis via clathrin-coated pits. The BCR contains five putative AP2-binding YxxØ motifs, including four that are present within two immunoreceptor tyrosine-based activation motifs (ITAMs). Using a combination of in vitro and in situ approaches, we establish that the sole mediator of AP2-dependent BCR internalization is the membrane proximal ITAM YxxØ motif in CD79b, which is a major target of mutation in ABC DLBCL. In addition, we establish that BCR internalization can be regulated at a minimum of two different levels: regulation of YxxØ AP2 binding in cis by downstream ITAM-embedded DCSM and QTAT regulatory elements and regulation in trans by the partner cytoplasmic domain of the CD79 heterodimer. Beyond establishing the basic rules governing BCR internalization, these results illustrate an underappreciated role for ITAM residues in controlling clathrin-dependent endocytosis and highlight the complex mechanisms that control the activity of AP2 binding motifs in this receptor system.

  5. Clinical impact of metformin in diabetic diffuse large B-cell lymphoma patients: a case-control study.

    Science.gov (United States)

    Alkhatib, Yaser; Abdel Rahman, Zaid; Kuriakose, Philip

    2017-05-01

    Molecular studies have shown metformin to have a promising effect in lymphoma; however, there is lack of studies translating this effect into clinical settings. This was a case-control study to assess the clinical effect of metformin in diabetic diffuse large B-cell lymphoma (DLBCL) patients. Case subjects were diabetic on metformin with a new diagnosis of DLBCL. A total of 24 case subjects were identified, and for each case a control was matched. Outcomes of this study were to assess overall response rate, complete remission rate, progression free survival, and overall survival between the two groups. There was a significant increase in overall response rate, complete remission rate, and improved progression free survival in the metformin group compared to the control group, however, no significant overall survival difference was observed. Metformin use might be associated with an improved response rates and progression-free survival in diabetic DLBCL patients.

  6. Control of Cell Fate in the Circulatory and Ventilatory Systems

    CERN Document Server

    Thiriet, Marc

    2012-01-01

    The volumes in this authoritative series present a multidisciplinary approach to modeling and simulation of flows in the cardiovascular and ventilatory systems, especially multiscale modeling and coupled simulations. The cardiovascular and respiratory systems are tightly coupled, as their primary function is to supply oxygen to and remove carbon dioxide from the body's cells. Because physiological conduits have deformable and reactive walls, macroscopic flow behavior and prediction must be coupled to nano- and microscopic events in a corrector scheme of regulated mechanisms. Therefore, investigation of flows of blood and air in physiological conduits requires an understanding of the biology, chemistry, and physics of these systems together with the mathematical tools to describe their functioning. Volumes 1 and 2 are devoted to cell organization and fate, as well as activities that are autoregulated and/or controlled by the cell environment. Volume 1 examined cellular features that allow adaptation to env...

  7. The Unfolded Protein Response and Cell Fate Control.

    Science.gov (United States)

    Hetz, Claudio; Papa, Feroz R

    2017-10-25

    The secretory capacity of a cell is constantly challenged by physiological demands and pathological perturbations. To adjust and match the protein-folding capacity of the endoplasmic reticulum (ER) to changing secretory needs, cells employ a dynamic intracellular signaling pathway known as the unfolded protein response (UPR). Homeostatic activation of the UPR enforces adaptive programs that modulate and augment key aspects of the entire secretory pathway, whereas maladaptive UPR outputs trigger apoptosis. Here, we discuss recent advances into how the UPR integrates information about the intensity and duration of ER stress stimuli in order to control cell fate. These findings are timely and significant because they inform an evolving mechanistic understanding of a wide variety of human diseases, including diabetes mellitus, neurodegeneration, and cancer, thus opening up the potential for new therapeutic modalities to treat these diverse diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Role of MYC in B Cell Lymphomagenesis

    Directory of Open Access Journals (Sweden)

    Petra Korać

    2017-04-01

    Full Text Available B cell lymphomas mainly arise from different developmental stages of B cells in germinal centers of secondary lymphoid tissue. There are a number of signaling pathways that affect the initiation and development of B cell lymphomagenesis. The functions of several key proteins that represent branching points of signaling networks are changed because of their aberrant expression, degradation, and/or accumulation, and those events determine the fate of the affected B cells. One of the most influential transcription factors, commonly associated with unfavorable prognosis for patients with B cell lymphoma, is nuclear phosphoprotein MYC. During B cell lymphomagenesis, oncogenic MYC variant is deregulated through various mechanisms, such as gene translocation, gene amplification, and epigenetic deregulation of its expression. Owing to alterations of downstream signaling cascades, MYC-overexpressing neoplastic B cells proliferate rapidly, avoid apoptosis, and become unresponsive to most conventional treatments. This review will summarize the roles of MYC in B cell development and oncogenesis, as well as its significance for current B cell lymphoma classification. We compared communication networks within transformed B cells in different lymphomas affected by overexpressed MYC and conducted a meta-analysis concerning the association of MYC with tumor prognosis in different patient populations.

  9. Role of MYC in B Cell Lymphomagenesis.

    Science.gov (United States)

    Korać, Petra; Dotlić, Snježana; Matulić, Maja; Zajc Petranović, Matea; Dominis, Mara

    2017-04-04

    B cell lymphomas mainly arise from different developmental stages of B cells in germinal centers of secondary lymphoid tissue. There are a number of signaling pathways that affect the initiation and development of B cell lymphomagenesis. The functions of several key proteins that represent branching points of signaling networks are changed because of their aberrant expression, degradation, and/or accumulation, and those events determine the fate of the affected B cells. One of the most influential transcription factors, commonly associated with unfavorable prognosis for patients with B cell lymphoma, is nuclear phosphoprotein MYC. During B cell lymphomagenesis, oncogenic MYC variant is deregulated through various mechanisms, such as gene translocation, gene amplification, and epigenetic deregulation of its expression. Owing to alterations of downstream signaling cascades, MYC-overexpressing neoplastic B cells proliferate rapidly, avoid apoptosis, and become unresponsive to most conventional treatments. This review will summarize the roles of MYC in B cell development and oncogenesis, as well as its significance for current B cell lymphoma classification. We compared communication networks within transformed B cells in different lymphomas affected by overexpressed MYC and conducted a meta-analysis concerning the association of MYC with tumor prognosis in different patient populations.

  10. Human memory B cells.

    Science.gov (United States)

    Seifert, M; Küppers, R

    2016-12-01

    A key feature of the adaptive immune system is the generation of memory B and T cells and long-lived plasma cells, providing protective immunity against recurring infectious agents. Memory B cells are generated in germinal center (GC) reactions in the course of T cell-dependent immune responses and are distinguished from naive B cells by an increased lifespan, faster and stronger response to stimulation and expression of somatically mutated and affinity matured immunoglobulin (Ig) genes. Approximately 40% of human B cells in adults are memory B cells, and several subsets were identified. Besides IgG(+) and IgA(+) memory B cells, ∼50% of peripheral blood memory B cells express IgM with or without IgD. Further smaller subpopulations have additionally been described. These various subsets share typical memory B cell features, but likely also fulfill distinct functions. IgM memory B cells appear to have the propensity for refined adaptation upon restimulation in additional GC reactions, whereas reactivated IgG B cells rather differentiate directly into plasma cells. The human memory B-cell pool is characterized by (sometimes amazingly large) clonal expansions, often showing extensive intraclonal IgV gene diversity. Moreover, memory B-cell clones are frequently composed of members of various subsets, showing that from a single GC B-cell clone a variety of memory B cells with distinct functions is generated. Thus, the human memory B-cell compartment is highly diverse and flexible. Several B-cell malignancies display features suggesting a derivation from memory B cells. This includes a subset of chronic lymphocytic leukemia, hairy cell leukemia and marginal zone lymphomas. The exposure of memory B cells to oncogenic events during their generation in the GC, the longevity of these B cells and the ease to activate them may be key determinants for their malignant transformation.

  11. T cells specific for different latent and lytic viral proteins efficiently control Epstein-Barr virus-transformed B cells.

    Science.gov (United States)

    Nowakowska, Justyna; Stuehler, Claudia; Egli, Adrian; Battegay, Manuel; Rauser, Georg; Bantug, Glenn Robert; Brander, Christian; Hess, Christoph; Khanna, Nina

    2015-09-01

    Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorders (PTLD) belong to the most dreaded complications of immunosuppression. The efficacy of EBV-specific T-cell transfer for PTLD has been previously shown, yet the optimal choice of EBV-derived antigens inducing polyclonal CD4(+) and CD8(+) T cells that cover a wide range of human leukocyte antigen types and efficiently control PTLD remains unclear. A pool of 125 T-cell epitopes from seven latent and nine lytic EBV-derived proteins (EBVmix) and peptide pools of EBNA1, EBNA3c, LMP2a and BZLF1 were used to determine T-cell frequencies and to isolate T cells through the use of the interferon (IFN)-γ cytokine capture system. We further evaluated the phenotype and functionality of the generated T-cell lines in vitro. EBVmix induced significantly higher T-cell frequencies and allowed selecting more CD4(+)IFN-γ(+) and CD8(+)IFN-γ(+) cells than single peptide pools. T cells of all specificities expanded similarly in vitro, recognized cognate antigen, and, to a lower extent, EBV-infected cells, exerted moderate cytotoxicity and showed reduced alloreactivity. However, EBVmix-specific cells most efficiently controlled EBV-infected lymphoblastoid cell lines (LCLs). This control was mainly mediated by EBV-specific CD8(+) cells with an oligoclonal epitope signature covering both latent and lytic viral proteins. Notably, EBV-specific CD4(+) cells unable to control LCLs produced significantly less perforin and granzyme B, probably because of limited LCL epitope presentation. EBVmix induces a broader T-cell response, probably because of its coverage of latent and lytic EBV-derived proteins that may be important to control EBV-transformed B cells and might offer an improvement of T-cell therapies. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  12. Deubiquitylating enzyme UBP64 controls cell fate through stabilization of the transcriptional repressor tramtrack

    NARCIS (Netherlands)

    P.K. Bajpe (Prashanth Kumar); J.A. van der Knaap (Jan); J.A.A. Demmers (Jeroen); K. Bezstarosti (Karel); A. Bassett (Andrew); H.M.M. van Beusekom (Heleen); A.A. Travers (Andrew); C.P. Verrijzer (Peter)

    2008-01-01

    textabstractProtein ubiquitylation plays a central role in multiple signal transduction pathways. However, the substrate specificity and potential developmental roles of deubiquitylating enzymes remain poorly understood. Here, we show that the Drosophila ubiquitin protease UBP64 controls cell fate

  13. Cdc20 control of cell fate during prolonged mitotic arrest

    DEFF Research Database (Denmark)

    Nilsson, Jakob

    2011-01-01

    The fate of cells arrested in mitosis by antimitotic compounds is complex but is influenced by competition between pathways promoting cell death and pathways promoting mitotic exit. As components of both of these pathways are regulated by Cdc20-dependent degradation, I hypothesize that variations...

  14. Lung epithelial tip progenitors integrate glucocorticoid- and STAT3-mediated signals to control progeny fate

    Science.gov (United States)

    Laresgoiti, Usua; Rao, Chandrika; Brady, Jane L.; Richardson, Rachel V.; Batchen, Emma J.; Chapman, Karen E.

    2016-01-01

    Insufficient alveolar gas exchange capacity is a major contributor to lung disease. During lung development, a population of distal epithelial progenitors first produce bronchiolar-fated and subsequently alveolar-fated progeny. The mechanisms controlling this bronchiolar-to-alveolar developmental transition remain largely unknown. We developed a novel grafting assay to test if lung epithelial progenitors are intrinsically programmed or if alveolar cell identity is determined by environmental factors. These experiments revealed that embryonic lung epithelial identity is extrinsically determined. We show that both glucocorticoid and STAT3 signalling can control the timing of alveolar initiation, but that neither pathway is absolutely required for alveolar fate specification; rather, glucocorticoid receptor and STAT3 work in parallel to promote alveolar differentiation. Thus, developmental acquisition of lung alveolar fate is a robust process controlled by at least two independent extrinsic signalling inputs. Further elucidation of these pathways might provide therapeutic opportunities for restoring alveolar capacity. PMID:27578791

  15. Non-invasive bioluminescence imaging to monitor the immunological control of a plasmablastic lymphoma-like B cell neoplasia after hematopoietic cell transplantation.

    Directory of Open Access Journals (Sweden)

    Martin Chopra

    Full Text Available To promote cancer research and to develop innovative therapies, refined pre-clinical mouse tumor models that mimic the actual disease in humans are of dire need. A number of neoplasms along the B cell lineage are commonly initiated by a translocation recombining c-myc with the immunoglobulin heavy-chain gene locus. The translocation is modeled in the C.129S1-Igha(tm1(MycJanz/J mouse which has been previously engineered to express c-myc under the control of the endogenous IgH promoter. This transgenic mouse exhibits B cell hyperplasia and develops diverse B cell tumors. We have isolated tumor cells from the spleen of a C.129S1-Igha(tm1(MycJanz/J mouse that spontaneously developed a plasmablastic lymphoma-like disease. These cells were cultured, transduced to express eGFP and firefly luciferase, and gave rise to a highly aggressive, transplantable B cell lymphoma cell line, termed IM380. This model bears several advantages over other models as it is genetically induced and mimics the translocation that is detectable in a number of human B cell lymphomas. The growth of the tumor cells, their dissemination, and response to treatment within immunocompetent hosts can be imaged non-invasively in vivo due to their expression of firefly luciferase. IM380 cells are radioresistant in vivo and mice with established tumors can be allogeneically transplanted to analyze graft-versus-tumor effects of transplanted T cells. Allogeneic hematopoietic stem cell transplantation of tumor-bearing mice results in prolonged survival. These traits make the IM380 model very valuable for the study of B cell lymphoma pathophysiology and for the development of innovative cancer therapies.

  16. Avian B cell development.

    Science.gov (United States)

    Masteller, E L; Pharr, G T; Funk, P E; Thompson, C B

    1997-01-01

    Development of B cells in chickens proceeds via a series of discrete developmental stages that includes the maturation of committed B cell progenitors in the specialized microenvironment of the bursa of Fabricius. The bursa has been shown to be required for the amplification of the B cell pool and selects for cells with productive immunoglobulin rearrangement events. Other events regulating chicken B cell development such as lymphocyte trafficking and apoptosis are just beginning to be elucidated. Within the bursa, the variable regions of immunoglobulin genes of B cell progenitors are diversified by a process of intrachromosomal gene conversion, where blocks of sequence information are transferred from pseudo-V regions to the recombined variable regions of the immunoglobulin genes. Recently gene conversion has been determined to play a role in the diversification of the immune repertoire in other species. In this review we focus on the current understanding and recent advances of B cell development in the chicken.

  17. Eat, breathe, ROS: controlling stem cell fate through metabolism.

    Science.gov (United States)

    Kubli, Dieter A; Sussman, Mark A

    2017-05-01

    Research reveals cardiac regeneration exists at levels previously deemed unattainable. Clinical trials using stem cells demonstrate promising cardiomyogenic and regenerative potential but insufficient contractile recovery. Incomplete understanding of the biology of administered cells likely contributes to inconsistent patient outcomes. Metabolism is a core component of many well-characterized stem cell types, and metabolic changes fundamentally alter stem cell fate from self-renewal to lineage commitment, and vice versa. However, the metabolism of stem cells currently studied for cardiac regeneration remains incompletely understood. Areas covered: Key metabolic features of stem cells are reviewed and unique stem cell metabolic characteristics are discussed. Metabolic changes altering stem cell fate are considered from quiescence and self-renewal to lineage commitment. Key metabolic concepts are applied toward examining cardiac regeneration through stem cell-based approaches, and clinical implications of current cell therapies are evaluated to identify potential areas of improvement. Expert commentary: The metabolism and biology of stem cells used for cardiac therapy remain poorly characterized. A growing appreciation for the fundamental relationship between stem cell functionality and metabolic phenotype is developing. Future studies unraveling links between cardiac stem cell metabolism and regenerative potential may considerably improve treatment strategies and therapeutic outcomes.

  18. The pre-B-cell receptor checkpoint in acute lymphoblastic leukaemia.

    Science.gov (United States)

    Eswaran, J; Sinclair, P; Heidenreich, O; Irving, J; Russell, L J; Hall, A; Calado, D P; Harrison, C J; Vormoor, J

    2015-08-01

    The B-cell receptor (BCR) and its immature form, the precursor-BCR (pre-BCR), have a central role in the control of B-cell development, which is dependent on a sequence of cell-fate decisions at specific antigen-independent checkpoints. Pre-BCR expression provides the first checkpoint, which controls differentiation of pre-B to immature B-cells in normal haemopoiesis. Pre-BCR signalling regulates and co-ordinates diverse processes within the pre-B cell, including clonal selection, proliferation and subsequent maturation. In B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), B-cell development is arrested at this checkpoint. Moreover, malignant blasts avoid clonal extinction by hijacking pre-BCR signalling in favour of the development of BCP-ALL. Here, we discuss three mechanisms that occur in different subtypes of BCP-ALL: (i) blocking pre-BCR expression; (ii) activating pre-BCR-mediated pro-survival and pro-proliferative signalling, while inhibiting cell cycle arrest and maturation; and (iii) bypassing the pre-BCR checkpoint and activating pro-survival signalling through pre-BCR independent alternative mechanisms. A complete understanding of the BCP-ALL-specific signalling networks will highlight their application in BCP-ALL therapy.

  19. Fate and toxic effects of environmental stressors: environmental control.

    Science.gov (United States)

    Zhuang, Jie; Yu, Han-Qing; Henry, Theodore B; Sayler, Gary S

    2015-12-01

    The potential for toxicants to harm organisms in the environment is influenced by the physicochemistry of the substances and their environmental behaviors and transformation within ecosystems. This special issue is composed of 20 papers that report on studies which have investigated the fate and toxicity of various toxicants including engineered nanoparticles, pharmaceuticals and personal care products, antibiotics, pathogens, heavy metals, and agricultural nutrients. The environmental transformations of these substances and how these processes affect their toxicity are emphasized. This paper highlights the important findings and perspectives of the selected papers in this special edition, with an aim of providing insights into full-scale evaluation on the toxicity of various contaminants that exist in ecosystems. General suggestions are provided for the future directions of toxicological research.

  20. B cell phenotypes in patients with rheumatoid arthritis relapsing after rituximab: expression of B cell-activating factor-binding receptors on B cell subsets.

    Science.gov (United States)

    Becerra, E; De La Torre, I; Leandro, M J; Cambridge, G

    2017-12-01

    Serum levels of B cell-activating factor (BAFF) rise following rituximab (RTX) therapy in patients with rheumatoid arthritis (RA). Initiation of naive B cell return to the periphery and autoreactive B cell expansion leading to relapse after RTX may therefore be linked to interactions between BAFF and BAFF-binding receptors (BBR). Relationships between serum BAFF and BBR expression [(BAFFR, calcium signal modulating cyclophilic ligand interactor (TACI) and B cell maturation antigen (BCMA)] were determined on B cell subsets, defined using immunoglobulin (Ig)D/CD38. Twenty pre-RTX and 18 RA patients relapsing after B cell depletion were included. Results were analysed with respect to timing of relapse up to 7 months after peripheral B cell return (≥ 5 B cells/μl) and to serum BAFF levels. After B cell return, B cell populations from relapsing patients had significantly lower BAFFR + expression compared to HC and pre-RTX patients. The percentage of BAFFR + B cells increased with time after B cell return and was correlated inversely with serum BAFF levels. BAFFR expression remained reduced. The percentage of TACI + memory B cells were lower in RA patients after RTX compared with healthy controls (HC). BCMA expression (% and expression) did not differ between patients and HC. Relapse following B cell return appeared largely independent of the percentage of BAFFR + or percentage of BCMA + B cells or serum BAFF levels. The lower percentage of TACI + memory B cells may reduce inhibitory signalling for B cell differentiation. In patients relapsing at longer periods after B cell return, recovery of the B cell pool was more complete, suggesting that selection or expansion of autoreactive B cells may be needed to precipitate relapse. © 2017 British Society for Immunology.

  1. Social Axioms and Achievement across Cultures: The Influence of Reward for Application and Fate Control

    Science.gov (United States)

    Zhou, Fan; Leung, Kwok; Bond, Michael Harris

    2009-01-01

    The present research examined the relationships between two social axiom dimensions, reward for application and fate control, with various achievement-related indexes across a wide range of cultures. Results showed that there was no relationship between reward for application and academic achievement or economic competitiveness, but reward for…

  2. Muscle Stem Cell Fate Is Controlled by the Cell-Polarity Protein Scrib

    Directory of Open Access Journals (Sweden)

    Yusuke Ono

    2015-02-01

    Full Text Available Satellite cells are resident skeletal muscle stem cells that supply myonuclei for homeostasis, hypertrophy, and repair in adult muscle. Scrib is one of the major cell-polarity proteins, acting as a potent tumor suppressor in epithelial cells. Here, we show that Scrib also controls satellite-cell-fate decisions in adult mice. Scrib is undetectable in quiescent cells but becomes expressed during activation. Scrib is asymmetrically distributed in dividing daughter cells, with robust accumulation in cells committed to myogenic differentiation. Low Scrib expression is associated with the proliferative state and preventing self-renewal, whereas high Scrib levels reduce satellite cell proliferation. Satellite-cell-specific knockout of Scrib in mice causes a drastic and insurmountable defect in muscle regeneration. Thus, Scrib is a regulator of tissue stem cells, controlling population expansion and self-renewal with Scrib expression dynamics directing satellite cell fate.

  3. B Cell-Activating Factor Regulates Different Aspects of B Cell Functionality and Is Produced by a Subset of Splenic B Cells in Teleost Fish.

    Science.gov (United States)

    Tafalla, Carolina; González, Lucia; Castro, Rosario; Granja, Aitor G

    2017-01-01

    In mammals, B cell functionality is greatly influenced by cytokines released by innate cells, such as macrophages or dendritic cells, upon the early recognition of common pathogen patterns through invariant receptors. B cell-activating factor (BAFF) is one of these innate B cell-helper signals and plays a key role in the survival and differentiation of B cells. Although, evolutionarily, teleost fish constitute the first animal group in which adaptive immunity based on Ig receptors is present, fish still rely greatly on innate responses. In this context, we hypothesized that BAFF would play a key role in the control of B cell responses in fish. Supporting this, our results show that teleost BAFF recapitulates mammalian BAFF stimulating actions on B cells, upregulating the expression of membrane MHC II, improving the survival of fish naïve B cells and antibody-secreting cells, and increasing the secretion of IgM. Surprisingly, we also demonstrate that BAFF is not only produced in fish by myeloid cells but is also produced by a subset of splenic B cells. Thus, if this B cell-produced BAFF proves to be actively regulating this same B cell subset, our findings point to an ancient mechanism to control B cell differentiation and survival in lower vertebrates, which has been silenced in mammals in physiological conditions, but reemerges under pathological conditions, such as B cell lymphomas and autoimmune diseases.

  4. CD4(+) T cell-mediated control of a gamma-herpesvirus in B cell-deficient mice is mediated by IFN-gamma

    DEFF Research Database (Denmark)

    Christensen, Jan Pravsgaard; Cardin, R D; Branum, K C

    1999-01-01

    in the lung. However, the further neutralization of IFN-gamma diminishes the effectiveness of the CD4(+) T cell response and causes substantially increased mortality. Experiments with bone marrow radiation chimeras indicate that the immune CD4(+) effectors operate optimally when there is the potential......The lack of B cells and antibody does not prevent mice from dealing effectively with a pathogenic gamma-herpesvirus. Both CD4(+) and CD8(+) T cells contribute to the control of virus replication in the respiratory tract, with the depletion of either lymphocyte subset leading to increased titers...... for direct interaction with virus-infected targets expressing MHC class II glycoproteins, suggesting that the IFN-gamma produced by these lymphocytes is functioning at short range. The numbers of latently infected cells in the spleens of carrier mice are also significantly increased by the concurrent...

  5. Memory B cells and CD8⁺ lymphocytes do not control seasonal influenza A virus replication after homologous re-challenge of rhesus macaques.

    Directory of Open Access Journals (Sweden)

    Timothy D Carroll

    Full Text Available This study sought to define the role of memory lymphocytes in the protection from homologous influenza A virus re-challenge in rhesus macaques. Depleting monoclonal antibodies (mAb were administered to the animals prior to their second experimental inoculation with a human seasonal influenza A virus strain. Treatment with either anti-CD8α or anti-CD20 mAbs prior to re-challenge had minimal effect on influenza A virus replication. Thus, in non-human primates with pre-existing anti-influenza A antibodies, memory B cells and CD8α⁺ T cells do not contribute to the control of virus replication after re-challenge with a homologous strain of influenza A virus.

  6. Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma in the Elderly: A Matched Case-Control Analysis.

    Directory of Open Access Journals (Sweden)

    Chen-Ge Song

    Full Text Available Epstein-Barr virus (EBV-positive diffuse large B-cell lymphoma (DLBCL in the elderly has rarely been reported. This study aimed to explore the clinical characteristics and prognosis of this entity.In situ hybridization (ISH analysis of Epstein-Barr virus (EBV and immunohistochemistry was performed in 230 tumor specimens from consecutive de novo DLBCL patients over 50 years old. A matched-case control analysis (1:3 was utilized to compare EBV-positive and EBV-negative DLBCL in the elderly.A total of 16 patients (7.0% were diagnosed with EBV-positive DLBCL. Of these 16 cases, the median age was 62 years, with a male to female ratio of 11:5. Elderly EBV-positive DLBCL patients had a higher incidence of non-germinal center B-cell (non-GCB subtypes (87.5% and high Ki67 (75% and CD30 expression (93.8%. For EBV-positive patients undergoing initial chemotherapy, 7 of 16 (43.8% had complete remission, 2 (12.5% had partial remission, 2 (12.5% had stable disease, and 5 (31.3% had progressive disease. The median overall survival was 9 months for the EBV-positive patients. A matched-case control analysis suggested that EBV-positive patients had inferior survival outcomes compared with EBV-negative patients (3-year progression-free survival [PFS]: 25% vs. 76.7%, respectively; 3-year overall survival [OS]: 25% vs. 77.4%, respectively; P<0.001.EBV-positive DLBCL of the elderly is associated with an inferior clinical course and inferior survival outcomes. The role of EBV in this disease and the optimal management of this subgroup warrants further investigation.

  7. B Cell Tolerance in Health and Disease

    Directory of Open Access Journals (Sweden)

    Murali Gururajan

    2014-02-01

    Full Text Available B lymphocyte receptors are generated randomly during the bone marrow developmental phase of B cells. Hence, the B cell repertoire consists of both self and foreign antigen specificities necessitating specific tolerance mechanisms to eliminate self-reactive B cells. This review summarizes the major mechanisms of B cell tolerance, which include clonal deletion, anergy and receptor editing. In the bone marrow presentation of antigen in membrane bound form is more effective than soluble form and the role of dendritic cells in this process is discussed. Toll like receptor derived signals affect activation of B cells by certain ligands such as nucleic acids and have been shown to play crucial roles in the development of autoimmunity in several animal models. In the periphery availability of BAFF, a B cell survival factor plays a critical role in the survival of self-reactive B cells. Antibodies against BAFF have been found to be effective therapeutic agents in lupus like autoimmune diseases. Recent developments are targeting anergy to control the growth of chronic lymphocytic leukemia cells.

  8. Functionalized scaffolds to control dental pulp stem cell fate.

    Science.gov (United States)

    Piva, Evandro; Silva, Adriana F; Nör, Jacques E

    2014-04-01

    Emerging understanding about interactions between stem cells, scaffolds, and morphogenic factors has accelerated translational research in the field of dental pulp tissue engineering. Dental pulp stem cells constitute a subpopulation of cells endowed with self-renewal and multipotency. Dental pulp stem cells seeded in biodegradable scaffolds and exposed to dentin-derived morphogenic factors give rise to a pulplike tissue capable of generating new dentin. Notably, dentin-derived proteins are sufficient to induce dental pulp stem cell differentiation into odontoblasts. Ongoing work is focused on developing ways of mobilizing dentin-derived proteins and disinfecting the root canal of necrotic teeth without compromising the morphogenic potential of these signaling molecules. On the other hand, dentin by itself does not appear to be capable of inducing endothelial differentiation of dental pulp stem cells despite the well-known presence of angiogenic factors in dentin. This is particularly relevant in the context of dental pulp tissue engineering in full root canals in which access to blood supply is limited to the apical foramina. To address this challenge, scientists are looking at ways to use the scaffold as a controlled-release device for angiogenic factors. The aim of this article was to present and discuss current strategies to functionalize injectable scaffolds and customize them for dental pulp tissue engineering. The long-term goal of this work is to develop stem cell-based therapies that enable the engineering of functional dental pulps capable of generating new tubular dentin in humans. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  9. Control of epithelial cell structure and developmental fate: lessons from Helicobacter pylori.

    Science.gov (United States)

    Mimuro, Hitomi; Berg, Douglas E; Sasakawa, Chihiro

    2008-06-01

    Valuable insights into eukaryotic regulatory circuits can emerge from studying interactions of bacterial pathogens such as Helicobacter pylori with host tissues. H. pylori uses a type IV secretion system (T4SS) to deliver its CagA virulence protein to epithelial cells, where much of it becomes phosphorylated. CagA's phosphorylated and non-phosphorylated forms each interact with host regulatory proteins to alter cell structure and cell fate. Kwok and colleagues showed that CagA destined for phosphorylation is delivered using host integrin as receptor and H. pylori's CagL protein as an integrin-specific adhesin, and that CagL-integrin-binding activates the kinase cascade responsible for CagA phosphorylation. This research contributes to understanding infectious disease and the control of cell fates.

  10. Transcriptional control of stem cell fate by E2Fs and pocket proteins

    Science.gov (United States)

    Julian, Lisa M.; Blais, Alexandre

    2015-01-01

    E2F transcription factors and their regulatory partners, the pocket proteins (PPs), have emerged as essential regulators of stem cell fate control in a number of lineages. In mammals, this role extends from both pluripotent stem cells to those encompassing all embryonic germ layers, as well as extra-embryonic lineages. E2F/PP-mediated regulation of stem cell decisions is highly evolutionarily conserved, and is likely a pivotal biological mechanism underlying stem cell homeostasis. This has immense implications for organismal development, tissue maintenance, and regeneration. In this article, we discuss the roles of E2F factors and PPs in stem cell populations, focusing on mammalian systems. We discuss emerging findings that position the E2F and PP families as widespread and dynamic epigenetic regulators of cell fate decisions. Additionally, we focus on the ever expanding landscape of E2F/PP target genes, and explore the possibility that E2Fs are not simply regulators of general ‘multi-purpose’ cell fate genes but can execute tissue- and cell type-specific gene regulatory programs. PMID:25972892

  11. Transcriptional control of stem cell fate by E2Fs and Pocket Proteins

    Directory of Open Access Journals (Sweden)

    Lisa Marie Julian

    2015-04-01

    Full Text Available E2F transcription factors and their regulatory partners, the pocket proteins (PPs, have emerged as essential regulators of stem cell fate control in a number of lineages. In mammals, this role extends from both pluripotent stem cells to those encompassing all embryonic germ layers, as well as extra-embryonic lineages. E2F/PP-mediated regulation of stem cell decisions is highly evolutionarily conserved, and is likely a pivotal biological mechanism underlying stem cell homeostasis. This has immense implications for organismal development, tissue maintenance and regeneration. In this article, we discuss the roles of E2F factors and PPs in stem cell populations, focusing on mammalian systems. We discuss emerging findings that position the E2F and PP families as widespread and dynamic epigenetic regulators of cell fate decisions. Additionally, we focus on the ever expanding landscape of E2F/PP target genes, and explore the possibility that E2Fs are not simply regulators of general ‘multi-purpose’ cell fate genes but can execute tissue- and cell type-specific gene regulatory programs.

  12. Persistent Polyclonal B Cell Lymphocytosis B Cells Can Be Activated through CD40-CD154 Interaction

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    Emmanuelle Dugas-Bourdages

    2014-01-01

    Full Text Available Persistent polyclonal B cell lymphocytosis (PPBL is a rare disorder, diagnosed primarily in adult female smokers and characterized by an expansion of CD19+CD27+IgM+ memory B cells, by the presence of binucleated lymphocytes, and by a moderate elevation of serum IgM. The clinical course is usually benign, but it is not known whether or not PPBL might be part of a process leading to the emergence of a malignant proliferative disorder. In this study we sought to investigate the functional response of B cells from patients with PPBL by use of an optimal memory B cell culture model based on the CD40-CD154 interaction. We found that the proliferation of PPBL B cells was almost as important as that of B cells from normal controls, resulting in high immunoglobulin secretion with in vitro isotypic switching. We conclude that the CD40-CD154 activation pathway is functional in the memory B cell population of PPBL patients, suggesting that the disorder may be due to either a dysfunction of other cells in the microenvironment or a possible defect in another B cell activation pathway.

  13. Mitochondrial DNA copy number and future risk of B-cell lymphoma in a nested case-control study in the prospective EPIC cohort

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    Hosnijeh, Fatemeh Saberi; Lan, Qing; Rothman, Nathaniel; San Liu, Chin; Cheng, Wen-Ling; Nieters, Alexandra; Guldberg, Per; Tjønneland, Anne; Campa, Daniele; Martino, Alessandro; Boeing, Heiner; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Krogh, Vittorio; Tumino, Rosario; Panico, Salvatore; Masala, Giovanna; Weiderpass, Elisabete; Huerta Castaño, José María; Ardanaz, Eva; Sala, Núria; Dorronsoro, Miren; Quirós, J. Ramón; Sánchez, María-José; Melin, Beatrice; Johansson, Ann Sofie; Malm, Johan; Borgquist, Signe; Peeters, Petra H.; Bueno-de-Mesquita, H. Bas; Wareham, Nick; Khaw, Kay-Tee; Travis, Ruth C.; Brennan, Paul; Siddiq, Afshan; Riboli, Elio; Vineis, Paolo

    2014-01-01

    It has been suggested that mitochondrial dysfunction and DNA damage are involved in lymphomagenesis. Increased copy number of mitochondrial DNA (mtDNA) as a compensatory mechanism of mitochondrial dysfunction previously has been associated with B-cell lymphomas, in particular chronic lymphocytic leukemia (CLL). However, current evidence is limited and based on a relatively small number of cases. Using a nested case-control study, we extended these findings with a focus on subtype-specific analyses. Relative mtDNA copy number was measured in the buffy coat of prospectively collected blood of 469 lymphoma cases and 469 matched controls. The association between mtDNA copy number and the risk of developing lymphoma and histologic subtypes was examined using logistic regression models. We found no overall association between mtDNA and risk of lymphoma. Subtype analyses revealed significant increased risks of CLL (n = 102) with increasing mtDNA copy number (odds ratio = 1.34, 1.44, and 1.80 for quartiles 2-4, respectively; P trend = .001). mtDNA copy number was not associated with follow-up time, suggesting that this observation is not strongly influenced by indolent disease status. This study substantially strengthens the evidence that mtDNA copy number is related to risk of CLL and supports the importance of mitochondrial dysfunction as a possible mechanistic pathway in CLL ontogenesis. PMID:24899624

  14. CD20-negative de novo diffuse large B-cell lymphoma in HIV-negative patients: A matched case-control analysis in a single institution

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    Li Ya-Jun

    2012-05-01

    Full Text Available Abstract Background HIV-negative, CD20-negative de novo diffuse large B-cell lymphoma (DLBCL patients has rarely been reported. To elucidate the nature of this entity, we retrospectively reviewed the data of 1,456 consecutive de novo DLBCL patients who were treated at Sun Yat-Sen University Cancer Center between January 1999 and March 2011. Methods The pathologic characteristics of CD20-negative patients, clinical features, response to initial treatment, and outcomes of 28 patients with available clinical data (n = 21 were reviewed. Then, a matched case-control (1:3 analysis was performed to compare patients with CD20-negative and -positive DLBCL. Results The median age of the 28 CD20-negative DLBCL patients was 48 years, with a male-female ratio of 20:8. Seventeen of 22 (77.3% CD20-negative DLBCL cases were of the non-germinal centre B-cell (non-GCB subtype. High Ki67 expression (≥80%, an index of cell proliferation, was demonstrated in 17 of 24 (70.8% cases. Extranodal involvement (≥ 1 site was observed in 76.2% of the patients. Following initial therapy, 9 of 21 (42.9% cases achieved complete remission, 4 (19% achieved partial remission, 1 (4.8% had stable disease, and 7 (33.3% had disease progression. The median overall survival was 23 months. The 3-year progression-free survival (PFS and overall survival (OS rates were 30.5% and 35%, respectively. A matched case-control analysis showed that patients with CD20-negative and -positive DLBCL did not exhibit a statistically significant difference with respect to the main clinical characteristics (except extranodal involvement, whereas the patients with CD20-positive DLBCL had a better survival outcome with 3-year PFS (P = 0.008 and OS (P = 0.008 rates of 52% and 74.1%, respectively. Conclusions This study suggests that HIV-negative, CD20-negative de novo DLBCL patients have a higher proportion of non-GCB subtype, a higher proliferation index, more frequent extranodal involvement, a poorer

  15. CD20-negative de novo diffuse large B-cell lymphoma in HIV-negative patients: A matched case-control analysis in a single institution

    Science.gov (United States)

    2012-01-01

    Background HIV-negative, CD20-negative de novo diffuse large B-cell lymphoma (DLBCL) patients has rarely been reported. To elucidate the nature of this entity, we retrospectively reviewed the data of 1,456 consecutive de novo DLBCL patients who were treated at Sun Yat-Sen University Cancer Center between January 1999 and March 2011. Methods The pathologic characteristics of CD20-negative patients, clinical features, response to initial treatment, and outcomes of 28 patients with available clinical data (n = 21) were reviewed. Then, a matched case-control (1:3) analysis was performed to compare patients with CD20-negative and -positive DLBCL. Results The median age of the 28 CD20-negative DLBCL patients was 48 years, with a male-female ratio of 20:8. Seventeen of 22 (77.3%) CD20-negative DLBCL cases were of the non-germinal centre B-cell (non-GCB) subtype. High Ki67 expression (≥80%), an index of cell proliferation, was demonstrated in 17 of 24 (70.8%) cases. Extranodal involvement (≥ 1 site) was observed in 76.2% of the patients. Following initial therapy, 9 of 21 (42.9%) cases achieved complete remission, 4 (19%) achieved partial remission, 1 (4.8%) had stable disease, and 7 (33.3%) had disease progression. The median overall survival was 23 months. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 30.5% and 35%, respectively. A matched case-control analysis showed that patients with CD20-negative and -positive DLBCL did not exhibit a statistically significant difference with respect to the main clinical characteristics (except extranodal involvement), whereas the patients with CD20-positive DLBCL had a better survival outcome with 3-year PFS (P = 0.008) and OS (P = 0.008) rates of 52% and 74.1%, respectively. Conclusions This study suggests that HIV-negative, CD20-negative de novo DLBCL patients have a higher proportion of non-GCB subtype, a higher proliferation index, more frequent extranodal involvement, a poorer response, and

  16. miR-27b controls venous specification and tip cell fate.

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    Biyashev, Dauren; Veliceasa, Dorina; Topczewski, Jacek; Topczewska, Jolanta M; Mizgirev, Igor; Vinokour, Elena; Reddi, Alagarsamy L; Licht, Jonathan D; Revskoy, Sergei Y; Volpert, Olga V

    2012-03-15

    We discovered that miR-27b controls 2 critical vascular functions: it turns the angiogenic switch on by promoting endothelial tip cell fate and sprouting and it promotes venous differentiation. We have identified its targets, a Notch ligand Delta-like ligand 4 (Dll4) and Sprouty homologue 2 (Spry2). miR-27b knockdown in zebrafish and mouse tissues severely impaired vessel sprouting and filopodia formation. Moreover, miR-27b was necessary for the formation of the first embryonic vein in fish and controlled the expression of arterial and venous markers in human endothelium, including Ephrin B2 (EphB2), EphB4, FMS-related tyrosine kinase 1 (Flt1), and Flt4. In zebrafish, Dll4 inhibition caused increased sprouting and longer intersegmental vessels and exacerbated tip cell migration. Blocking Spry2 caused premature vessel branching. In contrast, Spry2 overexpression eliminated the tip cell branching in the intersegmental vessels. Blockade of Dll4 and Spry2 disrupted arterial specification and augmented the expression of venous markers. Blocking either Spry2 or Dll4 rescued the miR-27b knockdown phenotype in zebrafish and in mouse vascular explants, pointing to essential roles of these targets downstream of miR-27b. Our study identifies critical role of miR-27b in the control of endothelial tip cell fate, branching, and venous specification and determines Spry2 and Dll4 as its essential targets.

  17. Large B-cell lymphomas in adolescents and young adults in comparison to adult patients: a matched-control analysis in 55 patients.

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    Coso, Diane; Garciaz, Sylvain; Esterni, Benjamin; Broussais-Guillaumot, Florence; Ivanov, Vadim; Aurran-Schleinitz, Thérèse; Schiano, Jean-Marc; Stoppa, Anne-Marie; Chetaille, Bruno; Blaise, Didier; Vey, Norbert; Bouabdallah, Réda

    2014-08-01

    The aim of our study was to assess whether large B-cell lymphoma (LBCL) in adolescents and young adults (AYA) should be considered as a clinocopathological entity, and to evaluate the prognostic value of age. Fifty-five patients aged > 15-30 years were fully matched to 365 adult patients aged 31-65 years. We found a high incidence of primary mediastinal thymic LBCL subtype (33% vs. 5%), while histological transformation was rare (2% vs. 14%). LBCL in AYA presented with a bulky mediastinal mass (51% vs. 21%), and the lactate dehydrogenase (LDH) value was significantly higher (73% vs. 54%). The complete response rate to chemotherapy was similar in the two groups. Five-year overall survival (OS) and event-free survival (EFS) of AYA were 73% and 68%, respectively. The matched-control analysis showed no difference for either OS or EFS. LBCL in AYA presents with some critical features which differ from those of older adults. However, the outcome is equivalent to that observed in older patients.

  18. Prevalence of anti-citrullinated protein antibodies (ACPA) in patients with diffuse large B-cell lymphoma (DLBCL): a case-control study.

    Science.gov (United States)

    Assmann, Gunter; Shihadeh, Klara; Poeschel, Viola; Murawski, Niels; Conigliarou, Jutta; Ong, Mei Fang; Pfreundschuh, Michael

    2014-01-01

    Antibodies against citrullinated proteins (ACPA) have been recognised as the most specific serum marker for rheumatoid arthritis. However, serum autoantibodies such as anti-nuclear antibodies have also been detected in the sera of different lymphatic malignancies without accompanying rheumatologic disease. Therefore, we conducted a study to evaluate the prevalence of ACPA in diffuse large B-cell non-Hodgkin lymphoma (DLBCL). Sera of 395 DLBCL patients and 258 age-matched healthy controls were investigated to evaluate the prevalence of ACPA and RF. ACPA-positive data were stratified into subgroups of RF positivity and established prognostic parameters for DLBCL, including overall survival. In addition, the ACPA serum concentrations levels were compared to an ACPA-positive RA cohort (n = 175). The statistics were performed with χ2 test and Mann- Whitney-U test; Kaplan-Meyer curves (log rank test) were used to analyse the overall survival. P-value DLBCL patients than in healthy controls (3.5% versus 0.8%, p = 0.030). However, the ACPA serum concentration levels were significantly lower than in RA patients (median 10.4 versus 124.1 U/ml, p = 0.0001). After subgroup stratification, ACPA positivity in DLBCL was significantly associated with male gender (4.4% versus 0%, p = 0.022; odds ratio 1.046, CI 1.014-1.079) and with RF-IgM seropositivity (1.77% versus 0%, p = 0.043), but not with prognostic parameters for DLBCL. DLBCL is associated with a significantly higher prevalence of ACPA, with an increased prevalence in male patients, and simultaneous RF-IgM positivity. However, ACPA is not prognostic for DLBCL. The prevalence of RF-IgM, -IgA, or -IgG did not differ from healthy controls.

  19. Prediagnostic plasma concentrations of organochlorines and risk of B-cell non-Hodgkin lymphoma in envirogenomarkers: a nested case-control study.

    Science.gov (United States)

    Kelly, Rachel S; Kiviranta, Hannu; Bergdahl, Ingvar A; Palli, Domenico; Johansson, Ann-Sofie; Botsivali, Maria; Vineis, Paolo; Vermeulen, Roel; Kyrtopoulos, Soterios A; Chadeau-Hyam, Marc

    2017-02-16

    Evidence suggests a largely environmental component to non-Hodgkin's lymphoma (NHL). Persistent organic pollutants (POPs) including polychlorinated biphenyls (PCBs), DDE and HCB have been repeatedly implicated, but the literature is inconsistent and a causal relationship remains to be determined. The EnviroGenoMarkers study is nested within two prospective cohorts EPIC-Italy and the Northern Sweden Health and Disease Study. Six PCB congeners, DDE and HCB were measured in blood plasma samples provided at recruitment using gas-chromatography mass spectrometry. During 16 years follow-up 270 incident cases of B-cell NHL (including 76 cases of multiple myeloma) were diagnosed. Cases were matched to 270 healthy controls by centre, age, gender and date of blood collection. Cases were categorised into ordered quartiles of exposure for each POP based on the distribution of exposure in the control population. Logistic regression was applied to assess the association with risk, multivariate and stratified analyses were performed to identify confounders or effect modifiers. The exposures displayed a strong degree of correlation, particularly amongst those PCBs with similar degrees of chlorination. There was no significant difference (p cases and controls for any of the investigated exposures. However under a multivariate model PCB138, PCB153, HCB and DDE displayed significant inverse trends (Wald test p-value 90th percentile) the association was null for all POPs CONCLUSION: We report no evidence that a higher body burden of PCBs, DDE or HCB increased the risk of subsequent NHL diagnosis. Significantly inverse associations were noted for males with a number of the investigated POPs. We hypothesize these unexpected relationships may relate to the subtype composition of our population, effect modification by BMI or other unmeasured confounding. This study provides no additional support for the previously observed role of PCBs, DDE and HCB as risk factors for NHL.

  20. ¬Mesenchymal Stem Cell Fate: Applying Biomaterials for Control of Stem Cell Behaviour

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    Hilary Jane Anderson

    2016-05-01

    Full Text Available Mesenchymal Stem Cell Fate: Applying Biomaterials for Control of Stem Cell BehaviourHilary J Anderson1, Jugal Kishore Sahoo2, Rein V Ulijn2,3, Matthew J Dalby1*1 Centre for Cell Engineering, University of Glasgow, Glasgow, UK.2 Technology and Innovation centre, Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, UK. 3 Advanced Science Research Centre (ASRC and Hunter College, City University of New York, NY 10031, NY, USA. Correspondence:*Hilary Andersonh.anderson.1@research.gla.ac.ukKeywords: mesenchymal stem cells, bioengineering, materials synthesis, nanotopography, stimuli responsive material□AbstractThe materials pipeline for biomaterials and tissue engineering applications is under continuous development. Specifically, there is great interest in the use of designed materials in the stem cell arena as materials can be used to manipulate the cells providing control of behaviour. This is important as the ability to ‘engineer’ complexity and subsequent in vitro growth of tissues and organs is a key objective for tissue engineers. This review will describe the nature of the materials strategies, both static and dynamic, and their influence specifically on mesenchymal stem cell fate.

  1. Polycomb controls gliogenesis by regulating the transient expression of the Gcm/Glide fate determinant.

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    Anna Popkova

    Full Text Available The Gcm/Glide transcription factor is transiently expressed and required in the Drosophila nervous system. Threshold Gcm/Glide levels control the glial versus neuronal fate choice, and its perdurance triggers excessive gliogenesis, showing that its tight and dynamic regulation ensures the proper balance between neurons and glia. Here, we present a genetic screen for potential gcm/glide interactors and identify genes encoding chromatin factors of the Trithorax and of the Polycomb groups. These proteins maintain the heritable epigenetic state, among others, of HOX genes throughout development, but their regulatory role on transiently expressed genes remains elusive. Here we show that Polycomb negatively affects Gcm/Glide autoregulation, a positive feedback loop that allows timely accumulation of Gcm/Glide threshold levels. Such temporal fine-tuning of gene expression tightly controls gliogenesis. This work performed at the levels of individual cells reveals an undescribed mode of Polycomb action in the modulation of transiently expressed fate determinants and hence in the acquisition of specific cell identity in the nervous system.

  2. Controlling the intracellular fate of nano-bioconjugates: pathways for realizing nanoparticle-mediated theranostics

    Science.gov (United States)

    Delehanty, James B.; Blanco-Canosa, Juan B.; Bradburne, Christopher E.; Susumu, Kimihiro; Stewart, Michael H.; Prasuhn, Duane E.; Dawson, Philip E.; Medintz, Igor L.

    2014-08-01

    For nanomaterials to realize their full potential in disease diagnosis and drug delivery applications, one must be able to exert fine control over their cellular delivery, localization and long-term fate in biological systems. Our laboratory has been active in developing methodologies for the controlled and site-specific delivery of a range of nanomaterials (e.g., quantum dots, colloidal gold, nematic liquid crystals) for cellular labeling, imaging and sensing. This talk will highlight several examples from these efforts and will demonstrate the use of peptide- and protein-mediated facilitated delivery of nanomaterials to discrete cellular locations including the endocytic pathway, the plasma membrane and the cellular cytosol. The implications of the ability to exert fine control over nanomaterial constructs in biological settings will be discussed with a particular focus on their use in nanoparticle-based theranostics.

  3. B-cell receptor-associated protein 31 regulates human embryonic stem cell adhesion, stemness, and survival via control of epithelial cell adhesion molecule.

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    Kim, Won-Tae; Seo Choi, Hong; Min Lee, Hyun; Jang, Young-Joo; Ryu, Chun Jeih

    2014-10-01

    B-Cell receptor-associated protein 31 (BAP31) regulates the export of secreted membrane proteins from the endoplasmic reticulum (ER) to the downstream secretory pathway. Previously, we generated a monoclonal antibody 297-D4 against the surface molecule on undifferentiated human embryonic stem cells (hESCs). Here, we found that 297-D4 antigen was localized to pluripotent hESCs and downregulated during early differentiation of hESCs and identified that the antigen target of 297-D4 was BAP31 on the hESC-surface. To investigate the functional role of BAP31 in hESCs, BAP31 expression was knocked down by small interfering RNA. BAP31 depletion impaired hESC self-renewal and pluripotency and drove hESC differentiation into multicell lineages. BAP31 depletion hindered hESC proliferation by arresting cell cycle at G0/G1 phase and inducing caspase-independent cell death. Interestingly, BAP31 depletion reduced hESC adhesion to extracellular matrix (ECM). Analysis of cell surface molecules showed decreased expression of epithelial cell adhesion molecule (EpCAM) in BAP31-depleted hESCs, while ectopic expression of BAP31 elevated the expression of EpCAM. EpCAM depletion also reduced hESC adhesion to ECM, arrested cell cycle at G0/G1 phase and induced cell death, producing similar effects to those of BAP31 depletion. BAP31 and EpCAM were physically associated and colocalized at the ER and cell surface. Both BAP31 and EpCAM depletion decreased cyclin D1 and E expression and suppressed PI3K/Akt signaling, suggesting that BAP31 regulates hESC stemness and survival via control of EpCAM expression. These findings provide, for the first time, mechanistic insights into how BAP31 regulates hESC stemness and survival via control of EpCAM expression. © 2014 AlphaMed Press.

  4. Metabolism and the Control of Cell Fate Decisions and Stem Cell Renewal

    Science.gov (United States)

    Ito, Kyoko; Ito, Keisuke

    2016-01-01

    Although the stem cells of various tissues remain in the quiescent state to maintain their undifferentiated state, they also undergo cell divisions as required, and if necessary, even a single stem cell is able to provide for lifelong tissue homeostasis. Stem cell populations are precisely controlled by the balance between their symmetric and asymmetric divisions, with their division patterns determined by whether the daughter cells involved retain their self-renewal capacities. Recent studies have reported that metabolic pathways and the distribution of mitochondria are regulators of the division balance of stem cells and that metabolic defects can shift division balance toward symmetric commitment, which leads to stem cell exhaustion. It has also been observed that in asymmetric division, old mitochondria, which are central metabolic organelles, are segregated to the daughter cell fated to cell differentiation, whereas in symmetric division, young and old mitochondria are equally distributed between both daughter cells. Thus, metabolism and mitochondrial biology play important roles in stem cell fate decisions. As these decisions directly affect tissue homeostasis, understanding their regulatory mechanisms in the context of cellular metabolism is critical. PMID:27482603

  5. Evidence that metabolism and chromosome copy number control mutually exclusive cell fates in Bacillus subtilis

    Science.gov (United States)

    Chai, Yunrong; Norman, Thomas; Kolter, Roberto; Losick, Richard

    2011-01-01

    Bacillus subtilis chooses between matrix production and spore formation, which are both controlled by the regulator Spo0A∼P. We report that metabolism and chromosome copy number dictate which fate is adopted. Conditions that favour low Spo0A∼P levels promote matrix production, whereas conditions favouring high levels trigger sporulation. Spo0A∼P directs the synthesis of SinI, an antirepressor for the SinR repressor of matrix genes. The regulatory region of sinI contains an activator site that Spo0A∼P binds strongly and operators that bind Spo0A∼P weakly. Evidence shows that low Spo0A∼P levels turn sinI ON and high levels turn sinI OFF and instead switch sporulation ON. Cells in which sinI and sinR were transplanted from their normal position near the chromosome replication terminus to positions near the origin and cells that harboured an extra copy of the genes were blocked in matrix production. Thus, matrix gene expression is sensitive to the number of copies of sinI and sinR. Because cells at the start of sporulation have two chromosomes and matrix-producing cells one, chromosome copy number could contribute to cell-fate determination. PMID:21326214

  6. Biological pump control of the fate and distribution of hydrophobic organic pollutants in water and plankton.

    Science.gov (United States)

    Nizzetto, Luca; Gioia, Rosalinda; Li, Jun; Borgå, Katrine; Pomati, Francesco; Bettinetti, Roberta; Dachs, Jordi; Jones, Kevin C

    2012-03-20

    The goal of this study was to experimentally assess the coupling between primary producer biomass dynamics and the distribution and fate of persistent organic pollutants (POPs) in a lake pelagic ecosystem. This was done by following the short-term evolution of polychlorinated biphenyl (PCB) concentrations in water and biota (phytoplankton and zooplankton) and the variability of bioconcentration (BCF), biomagnification (BMF), and bioaccumulation (BAF) factors during the development of a typical spring ecological progression in which the phytoplankton bloom is followed by a peak in the zooplankton abundance. The bulk of compounds with log K(OW) > 6.5 in the lake epilimnion was mainly associated with primary producer biomass. The phytoplankton biological pump was a major driver of POP export from the epilimnion, causing the decline of dissolved-phase concentrations. The BCF of phytoplankton for the more hydrophobic PCBs showed minima during the period of biomass climax. The concentration in the zooplankton of all selected PCBs sharply declined from March to May, with BAFs having minima in the post algal bloom phase. Biomagnification occurred during the pre algal bloom and algal bloom phases but appeared to be absent during the post algal bloom. This study highlights the occurrence of a prompt and complex response in the fate and distribution of POPs to dynamic biogeochemical control. Within the frame of the ecological succession, phytoplankton and zooplankton biomass dynamics produced bioaccumulation metrics varying over 1-2 orders of magnitude in the time frame of a few weeks and resulted in reduced trophic web exposure.

  7. Matrix mechanics and fluid shear stress control stem cells fate in three dimensional microenvironment.

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    Chen, Guobao; Lv, Yonggang; Guo, Pan; Lin, Chongwen; Zhang, Xiaomei; Yang, Li; Xu, Zhiling

    2013-07-01

    Stem cells have the ability to self-renew and to differentiate into multiple mature cell types during early life and growth. Stem cells adhesion, proliferation, migration and differentiation are affected by biochemical, mechanical and physical surface properties of the surrounding matrix in which stem cells reside and stem cells can sensitively feel and respond to the microenvironment of this matrix. More and more researches have proven that three dimensional (3D) culture can reduce the gap between cell culture and physiological environment where cells always live in vivo. This review summarized recent findings on the studies of matrix mechanics that control stem cells (primarily mesenchymal stem cells (MSCs)) fate in 3D environment, including matrix stiffness and extracellular matrix (ECM) stiffness. Considering the exchange of oxygen and nutrients in 3D culture, the effect of fluid shear stress (FSS) on fate decision of stem cells was also discussed in detail. Further, the difference of MSCs response to matrix stiffness between two dimensional (2D) and 3D conditions was compared. Finally, the mechanism of mechanotransduction of stem cells activated by matrix mechanics and FSS in 3D culture was briefly pointed out.

  8. Hepatitis C virus and GBV-C virus prevalence among patients with B-cell lymphoma in different European regions: a case-control study of the International Extranodal Lymphoma Study Group.

    Science.gov (United States)

    Nicolosi Guidicelli, Sabrina; Lopez-Guillermo, Armando; Falcone, Umberto; Conconi, Annarita; Christinat, Alexandre; Rodriguez-Abreu, Delvys; Grisanti, Salvatore; Lobetti-Bodoni, Chiara; Piffaretti, Jean Claude; Johnson, Peter W; Mombelli, Giorgio; Cerny, Andreas; Montserrat, Emili; Cavalli, Franco; Zucca, Emanuele

    2012-09-01

    Hepatitis C virus (HCV) infection is associated with some B-cell non-Hodgkin lymphoma (B cell-NHLs). Patients with HCV infection frequently show co-infections with GB virus C (GBV-C, formerly known as hepatitis G virus), and some studies have suggested a higher incidence of GBV-C infection in patients with B cell-NHLs. The aim of this study was to prospectively evaluate the association between HCV and/or GBV-C infection and B cell-NHLs in different geographic areas. One hundred thirty-seven lymphoma cases and 125 non-lymphoma matched controls were enrolled in an international case-control study conducted in Switzerland (Bellinzona), Spain (Barcelona) and England (Southampton) on samples collected from 2001 to 2002. In Bellinzona (41 cases and 81 controls), the overall prevalence of HCV was 3.3% (4.9% in NHLs), and the overall prevalence of GBV-C was 24% (22% in NHLs). In Barcelona (46 cases and 44 controls), the prevalence of HCV was 10% (8.7% in NHLs) and the prevalence of GBV-C 20% (13% in NHLs). There was no statistically significant difference in the frequency of both infections between patients with NHL and controls. In Southampton, 50 NHL cases were analysed, none of them was found to be HCV-positive; therefore, no control group was analysed and GBV-C analysis was not performed, too. Both in Bellinzona and in Barcelona, the seropositivity rate was significantly lower for HCV than for GBV-C, suggesting that their transmission can be independent. The incidence of HCV was significantly higher in Barcelona than that in Bellinzona. This study confirmed the existence of marked geographic differences in the prevalence of HCV in NHL but cannot provide any significant evidence for an association between HCV and/or GBV-C and B-cell NHLs. Copyright © 2011 John Wiley & Sons, Ltd.

  9. Germline Stem Cell Differentiation Entails Regional Control of Cell Fate Regulator GLD-1 in Caenorhabditis elegans.

    Science.gov (United States)

    Brenner, John L; Schedl, Tim

    2016-03-01

    Germline stem cell differentiation in Caenorhabditis elegans is controlled by glp-1 Notch signaling. Cell fate regulator GLD-1 is sufficient to induce meiotic entry and expressed at a high level during meiotic prophase, inhibiting mitotic gene activity. glp-1 signaling and other regulators control GLD-1 levels post-transcriptionally (low in stem cells, high in meiotic prophase), but many aspects of GLD-1 regulation are uncharacterized, including the link between glp-1-mediated transcriptional control and post-transcriptional GLD-1 regulation. We established a sensitive assay to quantify GLD-1 levels across an ∼35-cell diameter field, where distal germline stem cells differentiate proximally into meiotic prophase cells in the adult C. elegans hermaphrodite, and applied the approach to mutants in known or proposed GLD-1 regulators. In wild-type GLD-1 levels elevated ∼20-fold in a sigmoidal pattern. We found that two direct transcriptional targets of glp-1 signaling, lst-1 and sygl-1, were individually required for repression of GLD-1. We determined that lst-1 and sygl-1 act in the same genetic pathway as known GLD-1 translational repressor fbf-1, while lst-1 also acts in parallel to fbf-1, linking glp-1-mediated transcriptional control and post-transcriptional GLD-1 repression. Additionally, we estimated the position in wild-type gonads where germ cells irreversibly commit to meiotic development based on GLD-1 levels in worms where glp-1 activity was manipulated to cause an irreversible fate switch. Analysis of known repressors and activators, as well as modeling the sigmoidal accumulation pattern, indicated that regulation of GLD-1 levels is largely regional, which we integrated with the current view of germline stem cell differentiation. Copyright © 2016 by the Genetics Society of America.

  10. Control of the T follicular helper-germinal center B-cell axis by CD8⁺ regulatory T cells limits atherosclerosis and tertiary lymphoid organ development.

    Science.gov (United States)

    Clement, Marc; Guedj, Kevin; Andreata, Francesco; Morvan, Marion; Bey, Laetitia; Khallou-Laschet, Jamila; Gaston, Anh-Thu; Delbosc, Sandrine; Alsac, Jean-Marc; Bruneval, Patrick; Deschildre, Catherine; Le Borgne, Marie; Castier, Yves; Kim, Hye-Jung; Cantor, Harvey; Michel, Jean-Baptiste; Caligiuri, Giuseppina; Nicoletti, Antonino

    2015-02-10

    The atheromodulating activity of B cells during the development of atherosclerosis is well documented, but the mechanisms by which these cells are regulated have not been investigated. Here, we analyzed the contribution of Qa-1-restricted CD8(+) regulatory T cells to the control of the T follicular helper-germinal center B-cell axis during atherogenesis. Genetic disruption of CD8(+) regulatory T cell function in atherosclerosis-prone apolipoprotein E knockout mice resulted in overactivation of this axis in secondary lymphoid organs, led to the increased development of tertiary lymphoid organs in the aorta, and enhanced disease development. In contrast, restoring control of the T follicular helper-germinal center B-cell axis by blocking the ICOS-ICOSL pathway reduced the development of atherosclerosis and the formation of tertiary lymphoid organs. Moreover, analyses of human atherosclerotic aneurysmal arteries by flow cytometry, gene expression analysis, and immunofluorescence confirmed the presence of T follicular helper cells within tertiary lymphoid organs. This study is the first to demonstrate that the T follicular helper-germinal center B-cell axis is proatherogenic and that CD8(+) regulatory T cells control the germinal center reaction in both secondary and tertiary lymphoid organs. Therefore, disrupting this axis represents an innovative therapeutic approach. © 2014 American Heart Association, Inc.

  11. Exploiting Heparan Sulfate Proteoglycans in Human Neurogenesis—Controlling Lineage Specification and Fate

    Directory of Open Access Journals (Sweden)

    Chieh Yu

    2017-10-01

    Full Text Available Unspecialized, self-renewing stem cells have extraordinary application to regenerative medicine due to their multilineage differentiation potential. Stem cell therapies through replenishing damaged or lost cells in the injured area is an attractive treatment of brain trauma and neurodegenerative neurological disorders. Several stem cell types have neurogenic potential including neural stem cells (NSCs, embryonic stem cells (ESCs, induced pluripotent stem cells (iPSCs, and mesenchymal stem cells (MSCs. Currently, effective use of these cells is limited by our lack of understanding and ability to direct lineage commitment and differentiation of neural lineages. Heparan sulfate proteoglycans (HSPGs are ubiquitous proteins within the stem cell microenvironment or niche and are found localized on the cell surface and in the extracellular matrix (ECM, where they interact with numerous signaling molecules. The glycosaminoglycan (GAG chains carried by HSPGs are heterogeneous carbohydrates comprised of repeating disaccharides with specific sulfation patterns that govern ligand interactions to numerous factors including the fibroblast growth factors (FGFs and wingless-type MMTV integration site family (Wnts. As such, HSPGs are plausible targets for guiding and controlling neural stem cell lineage fate. In this review, we provide an overview of HSPG family members syndecans and glypicans, and perlecan and their role in neurogenesis. We summarize the structural changes and subsequent functional implications of heparan sulfate as cells undergo neural lineage differentiation as well as outline the role of HSPG core protein expression throughout mammalian neural development and their function as cell receptors and co-receptors. Finally, we highlight suitable biomimetic approaches for exploiting the role of HSPGs in mammalian neurogenesis to control and tailor cell differentiation into specific lineages. An improved ability to control stem cell specific neural

  12. Systems-level quantification of division timing reveals a common genetic architecture controlling asynchrony and fate asymmetry

    Science.gov (United States)

    Ho, Vincy Wing Sze; Wong, Ming-Kin; An, Xiaomeng; Guan, Daogang; Shao, Jiaofang; Ng, Hon Chun Kaoru; Ren, Xiaoliang; He, Kan; Liao, Jinyue; Ang, Yingjin; Chen, Long; Huang, Xiaotai; Yan, Bin; Xia, Yiji; Chan, Leanne Lai Hang; Chow, King Lau; Yan, Hong; Zhao, Zhongying

    2015-01-01

    Coordination of cell division timing is crucial for proper cell fate specification and tissue growth. However, the differential regulation of cell division timing across or within cell types during metazoan development remains poorly understood. To elucidate the systems-level genetic architecture coordinating division timing, we performed a high-content screening for genes whose depletion produced a significant reduction in the asynchrony of division between sister cells (ADS) compared to that of wild-type during Caenorhabditis elegans embryogenesis. We quantified division timing using 3D time-lapse imaging followed by computer-aided lineage analysis. A total of 822 genes were selected for perturbation based on their conservation and known roles in development. Surprisingly, we find that cell fate determinants are not only essential for establishing fate asymmetry, but also are imperative for setting the ADS regardless of cellular context, indicating a common genetic architecture used by both cellular processes. The fate determinants demonstrate either coupled or separate regulation between the two processes. The temporal coordination appears to facilitate cell migration during fate specification or tissue growth. Our quantitative dataset with cellular resolution provides a resource for future analyses of the genetic control of spatial and temporal coordination during metazoan development. PMID:26063786

  13. B Cells in Autoimmune Diseases

    OpenAIRE

    Hampe, Christiane S.

    2012-01-01

    The role of B cells in autoimmune diseases involves different cellular functions, including the well-established secretion of autoantibodies, autoantigen presentation and ensuing reciprocal interactions with T cells, secretion of inflammatory cytokines, and the generation of ectopic germinal centers. Through these mechanisms B cells are involved both in autoimmune diseases that are traditionally viewed as antibody mediated and also in autoimmune diseases that are commonly classified as T cell...

  14. Evaluate and characterize mechanisms controlling transport, fate, and effects of army smokes in the aerosol wind tunnel: Transport, transformations, fate, and terrestrial ecological effects of hexachloroethane obscurant smokes

    Energy Technology Data Exchange (ETDEWEB)

    Cataldo, D.A.; Ligotke, M.W.; Bolton, H. Jr.; Fellows, R.J.; Van Voris, P.; McVeety, B.D.; Li, Shu-mei W.; McFadden, K.M.

    1989-09-01

    The terrestrial transport, chemical fate, and ecological effects of hexachloroethane (HC) smoke were evaluated under controlled wind tunnel conditions. The primary objectives of this research program are to characterize and assess the impacts of smoke and obscurants on: (1) natural vegetation characteristic of US Army training sites in the United States; (2) physical and chemical properties of soils representative of these training sites; and (3) soil microbiological and invertebrate communities. Impacts and dose/responses were evaluated based on exposure scenarios, including exposure duration, exposure rate, and sequential cumulative dosing. Key to understanding the environmental impacts of HC smoke/obscurants is establishing the importance of environmental parameters such as relative humidity and wind speed on airborne aerosol characteristics and deposition to receptor surfaces. Direct and indirect biotic effects were evaluated using five plant species and two soil types. HC aerosols were generated in a controlled atmosphere wind tunnel by combustion of hexachloroethane mixtures prepared to simulate normal pot burn rates and conditions. The aerosol was characterized and used to expose plant, soil, and other test systems. Particle sizes of airborne HC ranged from 1.3 to 2.1 {mu}m mass median aerodynamic diameter (MMAD), and particle size was affected by relative humidity over a range of 20% to 85%. Air concentrations employed ranged from 130 to 680 mg/m{sup 3}, depending on exposure scenario. Chlorocarbon concentrations within smokes, deposition rates for plant and soil surfaces, and persistence were determined. The fate of principal inorganic species (Zn, Al, and Cl) in a range of soils was assessed.

  15. Granzyme B producing B-cells in renal transplant patients.

    Science.gov (United States)

    Zhu, Jiqiao; Zeng, Ye; Dolff, Sebastian; Bienholz, Anja; Lindemann, Monika; Brinkhoff, Alexandra; Schedlowski, Manfred; Xu, Shilei; Sun, Ming; Guberina, Hana; Kirchhof, Julia; Kribben, Andreas; Witzke, Oliver; Wilde, Benjamin

    2017-11-01

    A separate subset of Granzyme B (GrB) producing B-cells regulating T-cell mediated immunity has been identified. In the present study, we investigated the role of GrB(+) B-cells in renal transplant patients (RTX). 12 healthy controls (HC) and 26 RTX patients were enrolled. In addition, 19 healthy volunteers treated with cyclosporine A (CsA) were enrolled. GrB(+) B-cells were determined via flow cytometry. RTX Patients showed a diminished fraction of GrB(+) B-cells as compared to HC. CsA treatment of healthy volunteers had no impact on the development of GrB(+) B-cells. RTX patients with a history of allograft rejection showed an increased frequency of GrB(+) B-cells. RTX patients with at least one episode of CMV viremia tended to have lower GrB(+) B-cells as compared to patients without viremic episodes. We demonstrate that treatment with CsA does not impair the development of GrB(+) B-cells. GrB(+) B-cells may have a dual role in renal transplantation as regulatory cells to maintain allospecific tolerance and as effector cells enhancing viral control. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. [Fate and balance of bulk blending controlled release fertilizer nitrogen under continuous cropping of mustard].

    Science.gov (United States)

    Zhang, Pan-Pan; Fan, Xiao-Lin

    2012-10-01

    Under the conditions of applying water soluble fertilizer and its bulk blending with controlled release fertilizer (BB-CRF), and by using micro-lysimeter, this paper quantitatively studied the nitrogen (N) uptake by mustard, the soil N losses from N2O emission, leaching and others, and the N residual in soil in three rotations of continuously cropped mustard. In the treatment of BB-CRF with 25% of controlled release nitrogen, the N uptake by mustard increased with rotations, and the yield by the end of the experiment was significantly higher than that in the treatment of water soluble fertilizer. The cumulated N2O emission loss and the N leaching loss were obviously higher in treatment water soluble fertilizer than in treatment BB-CRF. NO3(-)-N was the primary form of N in the leachate. In relative to water soluble fertilizer, BB-CRF altered the fates of fertilizer nitrogen, i.e., the N uptake by mustard and the N residual in soil increased by 75.4% and 76.0%, and the N leaching loss and other apparent N losses decreased by 27.1% and 66.3%, respectively. The application of BB-CRF could be an effective way to reduce the various losses of fertilizer N while increase the fertilizer N use efficiency, and the controlled release fertilizer is the environmentally friendly fertilizer with the property of high N use efficiency.

  17. Evaluating the fate of metals in air pollution control residues from coal-fired power plants.

    Science.gov (United States)

    Thorneloe, Susan A; Kosson, David S; Sanchez, Florence; Garrabrants, Andrew C; Helms, Gregory

    2010-10-01

    Changes in emissions control at U.S. coal-fired power plants will shift metals content from the flue gas to the air pollution control (APC) residues. To determine the potential fate of metals that are captured through use of enhanced APC practices, the leaching behavior of 73 APC residues was characterized following the approach of the Leaching Environmental Assessment Framework. Materials were tested over pH conditions and liquid-solid ratios expected during management via land disposal or beneficial use. Leachate concentrations for most metals were highly variable over a range of coal rank, facility configurations, and APC residue types. Liquid-solid partitioning (equilibrium) as a function of pH showed significantly different leaching behavior for similar residue types and facility configurations. Within a facility, the leaching behavior of blended residues was shown to follow one of four characteristic patterns. Variability in metals leaching was greater than the variability in totals concentrations by several orders of magnitude, inferring that total content is not predictive of leaching behavior. The complex leaching behavior and lack of correlation to total contents indicates that release evaluation under likely field conditions is a better descriptor of environmental performance than totals content or linear partitioning approaches.

  18. Termination factor Rho: From the control of pervasive transcription to cell fate determination in Bacillus subtilis

    Science.gov (United States)

    Nicolas, Pierre; Repoila, Francis; Bardowski, Jacek; Aymerich, Stéphane

    2017-01-01

    In eukaryotes, RNA species originating from pervasive transcription are regulators of various cellular processes, from the expression of individual genes to the control of cellular development and oncogenesis. In prokaryotes, the function of pervasive transcription and its output on cell physiology is still unknown. Most bacteria possess termination factor Rho, which represses pervasive, mostly antisense, transcription. Here, we investigate the biological significance of Rho-controlled transcription in the Gram-positive model bacterium Bacillus subtilis. Rho inactivation strongly affected gene expression in B. subtilis, as assessed by transcriptome and proteome analysis of a rho–null mutant during exponential growth in rich medium. Subsequent physiological analyses demonstrated that a considerable part of Rho-controlled transcription is connected to balanced regulation of three mutually exclusive differentiation programs: cell motility, biofilm formation, and sporulation. In the absence of Rho, several up-regulated sense and antisense transcripts affect key structural and regulatory elements of these differentiation programs, thereby suppressing motility and biofilm formation and stimulating sporulation. We dissected how Rho is involved in the activity of the cell fate decision-making network, centered on the master regulator Spo0A. We also revealed a novel regulatory mechanism of Spo0A activation through Rho-dependent intragenic transcription termination of the protein kinase kinB gene. Altogether, our findings indicate that distinct Rho-controlled transcripts are functional and constitute a previously unknown built-in module for the control of cell differentiation in B. subtilis. In a broader context, our results highlight the recruitment of the termination factor Rho, for which the conserved biological role is probably to repress pervasive transcription, in highly integrated, bacterium-specific, regulatory networks. PMID:28723971

  19. Bone structure and B-cell populations, crippled by obesity, are partially rescued by brief daily exposure to low-magnitude mechanical signals.

    Science.gov (United States)

    Chan, M Ete; Adler, Benjamin J; Green, Danielle E; Rubin, Clinton T

    2012-12-01

    Deterioration of the immune and skeletal systems, each of which parallel obesity, reflects a fragile interrelationship between adiposity and osteoimmunology. Using a murine model of diet-induced obesity, this study investigated the ability of mechanical signals to protect the skeletal-immune systems at the tissue, cellular, and molecular level. A long-term (7 mo) high-fat diet increased total adiposity (+62%), accelerated age-related loss of trabecular bone (-61%), and markedly reduced B-cell number in the marrow (-52%) and blood (-36%) compared to mice fed a regular diet. In the final 4 mo of the protocol, the application of low-magnitude mechanical signals (0.2 g at 90 Hz, 15 min/d, 5 d/wk) restored both bone structure and B cells to those levels measured in control mice fed a regular diet. These phenotypic outcomes were achieved, in part, by reductions in osteoclastic activity and a biasing of hematopoietic stem cell differentiation toward the lymphoid B-cell lineage and away from a myeloid fate. These results emphasize that obesity undermines both the skeletal and immune systems, yet brief exposure to mechanical signals, perhaps as a surrogate to the salutary influence of exercise, diminishes the consequences of diabetes and obesity, restoring bone structure and normalizing B-cell populations by biasing of the fate of stem cells through mechanosensitive pathways.

  20. FGF/MAPK signaling sets the switching threshold of a bistable circuit controlling cell fate decisions in embryonic stem cells.

    Science.gov (United States)

    Schröter, Christian; Rué, Pau; Mackenzie, Jonathan Peter; Martinez Arias, Alfonso

    2015-12-15

    Intracellular transcriptional regulators and extracellular signaling pathways together regulate the allocation of cell fates during development, but how their molecular activities are integrated to establish the correct proportions of cells with particular fates is not known. Here we study this question in the context of the decision between the epiblast (Epi) and the primitive endoderm (PrE) fate that occurs in the mammalian preimplantation embryo. Using an embryonic stem cell (ESC) model, we discover two successive functions of FGF/MAPK signaling in this decision. First, the pathway needs to be inhibited to make the PrE-like gene expression program accessible for activation by GATA transcription factors in ESCs. In a second step, MAPK signaling levels determine the threshold concentration of GATA factors required for PrE-like differentiation, and thereby control the proportion of cells differentiating along this lineage. Our findings can be explained by a simple mutual repression circuit modulated by FGF/MAPK signaling. This might be a general network architecture to integrate the activity of signal transduction pathways and transcriptional regulators, and serve to balance proportions of cell fates in several contexts. © 2015. Published by The Company of Biologists Ltd.

  1. Ligand-induced fate of embryonic species in the shape-controlled synthesis of rhodium nanoparticles.

    Science.gov (United States)

    Biacchi, Adam J; Schaak, Raymond E

    2015-02-24

    The shapes of noble metal nanoparticles directly impact their properties and applications, including in catalysis and plasmonics, and it is therefore important to understand how multiple distinct morphologies can be controllably synthesized. Solution routes offer powerful capabilities for shape-controlled nanoparticle synthesis, but the earliest stages of the reaction are difficult to interrogate experimentally and much remains unknown about how metal nanoparticle morphologies emerge and evolve. Here, we use a well-established polyol process to synthesize uniform rhodium nanoparticle cubes, icosahedra, and triangular plates using bromide, trifluoroacetate, and chloride ligands, respectively. In all of these systems, we identified rhodium clusters with diameters of 1-2 nm that form early in the reactions. The colloidally stable metal cluster intermediates served as a stock solution of embryonic species that could be transformed predictably into each type of nanoparticle morphology. The anionic ligands that were added to the embryonic species determined their eventual fate, e.g., the morphologies into which they would ultimately evolve. Extensive high-resolution transmission electron microscopy experiments revealed that the growth pathway-monomer addition, coalescence, or a combination of the two-was different for each of the morphologies, and was likely controlled by the interactions of each specific anionic adsorbate with the embryonic species. Similar phenomena were observed for related palladium and platinum nanoparticle systems. These studies provide important insights into how noble metal nanoparticles nucleate, the pathways by which they grow into several distinct morphologies, and the imperative role of the anonic ligand in controlling which route predominates in a particular system.

  2. Fate of antibiotic resistant bacteria and genes during wastewater chlorination: implication for antibiotic resistance control.

    Science.gov (United States)

    Yuan, Qing-Bin; Guo, Mei-Ting; Yang, Jian

    2015-01-01

    This study investigated fates of nine antibiotic-resistant bacteria as well as two series of antibiotic resistance genes in wastewater treated by various doses of chlorine (0, 15, 30, 60, 150 and 300 mg Cl2 min/L). The results indicated that chlorination was effective in inactivating antibiotic-resistant bacteria. Most bacteria were inactivated completely at the lowest dose (15 mg Cl2 min/L). By comparison, sulfadiazine- and erythromycin-resistant bacteria exhibited tolerance to low chlorine dose (up to 60 mg Cl2 min/L). However, quantitative real-time PCRs revealed that chlorination decreased limited erythromycin or tetracycline resistance genes, with the removal levels of overall erythromycin and tetracycline resistance genes at 0.42 ± 0.12 log and 0.10 ± 0.02 log, respectively. About 40% of erythromycin-resistance genes and 80% of tetracycline resistance genes could not be removed by chlorination. Chlorination was considered not effective in controlling antimicrobial resistance. More concern needs to be paid to the potential risk of antibiotic resistance genes in the wastewater after chlorination.

  3. Subtask 4.8 - Fate and Control of Mercury and Trace Elements

    Energy Technology Data Exchange (ETDEWEB)

    Pavlish, John; Lentz, Nicholas; Martin, Christopher; Ralston, Nicholas; Zhuang, Ye; Hamre, Lucinda

    2011-12-31

    The Center for Air Toxic Metals® (CATM®) Program at the Energy & Environmental Research Center (EERC) continues to focus on vital basic and applied research related to the fate, behavior, measurement, and control of trace metals, especially mercury, and the impact that these trace metals have on human health and the environment. For years, the CATM Program has maintained an international perspective, performing research and providing results that apply to both domestic and international audiences, with reports distributed in the United States and abroad. In addition to trace metals, CATM’s research focuses on other related emissions and issues that impact trace metal releases to the environment, such as SOx, NOx, CO2, ash, and wastewater streams. Of paramount interest and focus has been performing research that continues to enable the power and industrial sectors to operate in an environmentally responsible manner to meet regulatory standards. The research funded by the U.S. Department of Energy’s (DOE’s) National Energy Technology Laboratory (NETL) through CATM has allowed significant strides to be made to gain a better understanding of trace metals and other emissions, improve sampling and measurement techniques, fill data gaps, address emerging technical issues, and develop/test control technologies that allow industry to cost-effectively meet regulatory standards. The DOE NETL–CATM research specifically focused on the fate and control of mercury and trace elements in power systems that use CO2 control technologies, such as oxycombustion and gasification systems, which are expected to be among those technologies that will be used to address climate change issues. In addition, research addressed data gaps for systems that use conventional and multipollutant control technologies, such as electrostatic precipitators, selective catalytic reduction units, flue gas desulfurization systems, and flue gas

  4. SMAD4-mediated WNT signaling controls the fate of cranial neural crest cells during tooth morphogenesis

    Science.gov (United States)

    Li, Jingyuan; Huang, Xiaofeng; Xu, Xun; Mayo, Julie; Bringas, Pablo; Jiang, Rulang; Wang, Songling; Chai, Yang

    2011-01-01

    TGFβ/BMP signaling regulates the fate of multipotential cranial neural crest (CNC) cells during tooth and jawbone formation as these cells differentiate into odontoblasts and osteoblasts, respectively. The functional significance of SMAD4, the common mediator of TGFβ/BMP signaling, in regulating the fate of CNC cells remains unclear. In this study, we investigated the mechanism of SMAD4 in regulating the fate of CNC-derived dental mesenchymal cells through tissue-specific inactivation of Smad4. Ablation of Smad4 results in defects in odontoblast differentiation and dentin formation. Moreover, ectopic bone-like structures replaced normal dentin in the teeth of Osr2-IresCre;Smad4fl/fl mice. Despite the lack of dentin, enamel formation appeared unaffected in Osr2-IresCre;Smad4fl/fl mice, challenging the paradigm that the initiation of enamel development depends on normal dentin formation. At the molecular level, loss of Smad4 results in downregulation of the WNT pathway inhibitors Dkk1 and Sfrp1 and in the upregulation of canonical WNT signaling, including increased β-catenin activity. More importantly, inhibition of the upregulated canonical WNT pathway in Osr2-IresCre;Smad4fl/fl dental mesenchyme in vitro partially rescued the CNC cell fate change. Taken together, our study demonstrates that SMAD4 plays a crucial role in regulating the interplay between TGFβ/BMP and WNT signaling to ensure the proper CNC cell fate decision during organogenesis. PMID:21490069

  5. Anti-B cell antibody therapies for inflammatory rheumatic diseases

    DEFF Research Database (Denmark)

    Faurschou, Mikkel; Jayne, David R W

    2014-01-01

    Several monoclonal antibodies targeting B cells have been tested as therapeutics for inflammatory rheumatic diseases. We review important observations from randomized clinical trials regarding the efficacy and safety of anti-B cell antibody-based therapies for rheumatoid arthritis, systemic lupus...... erythematosus, antineutrophil cytoplasmic antibody-associated vasculitis, polymyositis/dermatomyositis, and primary Sjögren's syndrome. For some anti-B cell agents, clinical benefits have been convincingly demonstrated, while other B cell-targeted therapies failed to improve outcomes when added to standard...... and functions in rheumatic disorders. Future studies should also evaluate how to maintain disease control by means of conventional and/or biologic immunosuppressants after remission-induction with anti-B cell antibodies....

  6. Mechanistic controls on diverse fates of terrestrial organic components in the East China Sea

    Science.gov (United States)

    Zhu, Chun; Wagner, Thomas; Talbot, Helen M.; Weijers, Johan W. H.; Pan, Jian-Ming; Pancost, Richard D.

    2013-09-01

    Terrestrial carbon transferred from the land to sea is a critical component of the global carbon cycle. A range of geochemical proxies has been developed to fingerprint the fate of terrestrial organic matter (TOM) in marine sediments. However, discrepancies among different proxies limit our ability to quantify and interpret the terrestrial signals in marine sediments, with consequences for the investigation of both the modern carbon cycle and past environmental change. To mechanistically understand these discrepancies, we examined the distributions of a range of terrestrial proxies and their aquatic counterparts (i.e. marine proxies) in the Yangtze river-East China Sea (YR-ECS) shelf system, where TOM experiences extensive modification during transport and burial. TOM proxies in the YR-ECS system collectively fit a power-law model but with distinct attenuation rates (the a∗ values) for individual molecular proxy groups. Among a range of TOM proxies, the modeled a∗ values decrease in the order: soil-marker BHPs > triterpenols > lignin > HMW n-alkanols > branched GDGTs > HMW n-alkanes for biomarkers; and Rsoil > BIT > %TOMiso for proxies tracing %TOM. Rapid loss of TOM components through dissociation in the narrow estuary, followed by oxidation over the wide open shelf, are best described by power curves. Inherent chemical reactivity (i.e. the number of functional groups), responses to hydraulic sorting, and in situ production regulate the individual attenuation rates. Of them, chemical reactivity plays the most important role on proxy behavior, supported by a strong correlation between a∗ values and standard molal Gibbs energies. Both, physical protection and chemical reactivity fundamentally control the overall behavior of TOM components, with the relative importance being setting-dependant: The former is relatively important in the estuary, whereas the later is the primary control over the open shelf. Moreover, regional variation of different marine

  7. Hydrographic controls on marine organic matter fate and microbial diversity in the western Irish Sea

    Science.gov (United States)

    O'Reilly, Shane; Szpak, Michal; Monteys, Xavier; Flanagan, Paul; Allen, Christopher; Kelleher, Brian

    2014-05-01

    Cycling of organic matter (OM) is the key biological process in the marine environment1 and knowledge of the sources and the reactivity of OM, in addition to factors controlling its distribution in estuarine, coastal and shelf sediments are of key importance for understanding global biogeochemical cycles2. With recent advances in cultivation-independent molecular approaches to microbial ecology, the key role of prokaryotes in global biogeochemical cycling in marine ecosystems has been emphasised3,4. However, spatial studies combining the distribution and fate of OM with microbial community abundance and diversity remain rare. Here, a combined spatial lipid biomarker and 16S rRNA tagged pyrosequencing study was conducted in surface sediments and particulate matter across hydrographically distinct zones associated with the seasonal western Irish Sea gyre. The aim was to assess the spatial variation of, and factors controlling, marine organic cycling and sedimentary microbial communities across these distinct zones. The distribution of phospholipid fatty acids, source-specific sterols, wax esters and C25 highly branched isoprenoids indicate that diatoms, dinoflagellates and green algae were the major contributors of marine organic matter, while the distribution of cholesterol, wax esters and C20 and C22 polyunsaturated fatty acids have highlighted the importance of copepod grazing for mineralizing organic matter in the water column5. This marine OM production and mineralisation was greatest in well-mixed waters compared to offshore stratified waters. Lipid analysis and 16S rRNA PCR-DGGE profiling also suggests that sedimentary bacterial abundance increases while community diversity decreases in offshore stratified waters. The major bacterial classes are the Deltaproteobacteria, Clostridia, Flavobacteriia, Gammaproteobactera and Bacteroiidia. At the family/genus level most groups appear to be associated with organoheterotrophic processing of sedimentary OM, ranging

  8. A double blinded, placebo-controlled pilot study to examine reduction of CD34 (+)/CD117 (+)/CD133 (+) lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma.

    Science.gov (United States)

    Ito, Daisuke; Childress, Michael; Mason, Nicola; Winter, Amber; O'Brien, Timothy; Henson, Michael; Borgatti, Antonella; Lewellen, Mitzi; Krick, Erika; Stewart, Jane; Lahrman, Sarah; Rajwa, Bartek; Scott, Milcah C; Seelig, Davis; Koopmeiners, Joseph; Ruetz, Stephan; Modiano, Jaime

    2015-01-01

    We previously described a population of lymphoid progenitor cells (LPCs) in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and "slow proliferation" molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1) used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naïve large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg) or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1 (+) cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting.

  9. A double blinded, placebo-controlled pilot study to examine reduction of CD34 +/CD117 +/CD133 + lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma

    Science.gov (United States)

    Ito, Daisuke; Childress, Michael; Mason, Nicola; Winter, Amber; O’Brien, Timothy; Henson, Michael; Borgatti, Antonella; Lewellen, Mitzi; Krick, Erika; Stewart, Jane; Lahrman, Sarah; Rajwa, Bartek; Scott, Milcah C; Seelig, Davis; Koopmeiners, Joseph; Ruetz, Stephan; Modiano, Jaime

    2017-01-01

    We previously described a population of lymphoid progenitor cells (LPCs) in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and “slow proliferation” molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1) used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naïve large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg) or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1 + cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting. PMID:28357033

  10. The adaptor molecule Act1 regulates BAFF responsiveness and self-reactive B cell selection during transitional B cell maturation

    Science.gov (United States)

    Giltiay, Natalia V.; Lu, Yi; Allman, David; Jørgensen, Trine N.; Li, Xiaoxia

    2011-01-01

    The transitional stage is a key check-point for elimination of autoreactive B cells in the periphery. This selection process requires fine regulation of signals received through B-cell receptor (BCR) and B cell activating factor receptor (BAFFR). We previously identified the adaptor molecule Act1 as a negative regulator of BAFF-mediated signaling. Deficiency of Act1 in mice results in peripheral B cell hyperplasia and development of autoimmunity. In this study we demonstrate that Act1 plays a critical role in the regulation of transitional B cell survival and maturation. We found that the ratio of late-transitional (T2) to early-transitional (T1) cells was increased in spleens from Act1-deficient mice. Moreover, BAFF stimulation induced better T1 cell survival and promoted more efficient maturation of T1 cells into T2 cells ex vivo in the absence of Act1. BAFF stimulation induced higher levels of the anti-apoptotic Bcl2-member Mc1-l in Act1-deficient T1 than that in wild-type control cells, suggesting that Mcl1 might be one of the key effector molecules for BAFF-mediated survival in the Act1-deficient transitional B cells. Importantly, co-stimulation with BAFF was able to rescue Act1-deficient T1 cells from BCR-induced apoptosis more effectively than Act1-suffienct T1 B cells. Finally, by using double transgenic HEL mice, we demonstrated that Act1 deficiency can promote the maturation of HEL-specific autoreactive B cells. Taken together, our results suggest that the transitional stage is a critical point of action for Act1 in the elimination of autoreactive B cells and in the regulation of peripheral B cell homeostasis. PMID:20543113

  11. Hypovitaminosis D upscales B-cell immunoreactivity in multiple sclerosis.

    Science.gov (United States)

    Haas, Jürgen; Schwarz, Alexander; Korporal-Kuhnke, Mirjam; Faller, Simon; Jarius, Sven; Wildemann, Brigitte

    2016-05-15

    While vitamin D is increasingly recognized as a potential immune regulator of MS disease activity, its impact on B lymphocytes, however, remains ill-defined. We assessed the impact of vitamin D on B-cell proliferation and cytokine secretion ex vivo and screened for effects of hypovitaminosis D and vitamin D supplementation on the compartmentalized distribution of B-cell subtypes in peripheral blood and cerebrospinal fluid (CSF) from patients with relapsing remitting MS (n=95) and various neurologic and healthy controls (n=57). B cells from MS patients with 25(OH)D serum levels vitamin D or when retesting B cells from MS patients after prolonged supplementation with vitamin D. Hypovitaminosis D was detectable in the serum of 40/95 MS patients, correlated with decreased vitamin D concentrations in CSF and with higher disease activity, and was paralleled by intrathecal accumulation of CD27(+) B-cell subtypes and plasma cells. B-cell immunoreactivity is attenuated by vitamin D. Our finding that vitamin D deficiency affects the intrathecal compartment and coincides with increased frequencies of effector B-cell subtypes in the CSF suggests that hypovitaminosis D might contribute to augmenting disease activity in the target organ and supports a potential benefit of vitamin D supplementation in MS. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. [Targeting B cells in multiple sclerosis. Current concepts and strategies].

    Science.gov (United States)

    Menge, T; Büdingen, H-C; Dalakas, M C; Kieseier, B C; Hartung, H-P

    2009-02-01

    Multiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disease of the CNS and a leading cause of lasting neurological disability in younger adults. In the last decade our knowledge of its immunopathogenesis expanded vastly. It is now widely appreciated that B cells are key players in the autoreactive immune network. They exert far more functions than merely being the precursors of antibody-producing plasma cells. B cells act as efficient antigen-presenting cells and may stimulate an autoreactive immune response through secretion of proinflammatory cytokines. It is thus only logical to test therapeutic strategies targeting B cells in MS. Rituximab is a depleting chimeric monoclonal antibody directed against CD20 and expressed on developing, naïve, and memory B cells but not stem or plasma cells. Several smaller studies have been conducted that led to a placebo controlled, double blind phase II study on efficacy which was reported recently. The results are very promising, meeting not only the primary endpoint of reduction of the surrogate MRI marker of contrast-enhancing lesions but also showing a reduction in clinical relapse rate of patients treated with rituximab. This review discusses the role of autoreactive B cells in the context of MS, analyzes the B-cell-depleting treatment studies reported, and provides information on planned and future B-cell-directed therapeutic strategies in MS.

  13. BMP signaling orchestrates a transcriptional network to control the fate of mesenchymal stem cells in mice.

    Science.gov (United States)

    Feng, Jifan; Jing, Junjun; Li, Jingyuan; Zhao, Hu; Punj, Vasu; Zhang, Tingwei; Xu, Jian; Chai, Yang

    2017-07-15

    Signaling pathways are used reiteratively in different developmental processes yet produce distinct cell fates through specific downstream transcription factors. In this study, we used tooth root development as a model with which to investigate how the BMP signaling pathway regulates transcriptional complexes to direct the fate determination of multipotent mesenchymal stem cells (MSCs). We first identified the MSC population supporting mouse molar root growth as Gli1+ cells. Using a Gli1-driven Cre-mediated recombination system, our results provide the first in vivo evidence that BMP signaling activity is required for the odontogenic differentiation of MSCs. Specifically, we identified the transcription factors Pax9, Klf4, Satb2 and Lhx8 as being downstream of BMP signaling and expressed in a spatially restricted pattern that is potentially involved in determining distinct cellular identities within the dental mesenchyme. Finally, we found that overactivation of one key transcription factor, Klf4, which is associated with the odontogenic region, promotes odontogenic differentiation of MSCs. Collectively, our results demonstrate the functional significance of BMP signaling in regulating MSC fate during root development and shed light on how BMP signaling can achieve functional specificity in regulating diverse organ development. © 2017. Published by The Company of Biologists Ltd.

  14. B cell development in the bone marrow is regulated by homeostatic feedback exerted by mature B cells

    Directory of Open Access Journals (Sweden)

    Gitit eShahaf

    2016-03-01

    Full Text Available Cellular homeostasis in the B cell compartment is strictly imposed to balance cell production and cell loss. However, it is not clear whether B cell development in the bone marrow (BM is an autonomous process or subjected to regulation by the peripheral B cell compartment. To specifically address this question, we used mice transgenic for human CD20, where effective depletion of B lineage cells is obtained upon administration of mouse-anti-human CD20 antibodies, in the absence of any effect on other cell lineages and/or tissues. We followed the kinetics of B cell return to equilibrium by BrdU labeling and flow cytometry and analyzed the resulting data by mathematical modeling. Labeling was much faster in depleted mice. Compared to control mice, B cell-depleted mice exhibited a higher proliferation rate in the pro-/pre-B compartment, and higher cell death and lower differentiation in the immature B cell compartment. We validated the first result by analysis of the expression of Ki67, the nuclear protein expressed in proliferating cells, and the second using Annexin-V staining. Collectively, our results suggest that B lymphopoiesis is subjected to homeostatic feedback mechanisms imposed by mature B cells in the peripheral compartment.

  15. Expansion of Activated Peripheral Blood Memory B Cells in Rheumatoid Arthritis, Impact of B Cell Depletion Therapy, and Biomarkers of Response.

    Directory of Open Access Journals (Sweden)

    Diana G Adlowitz

    Full Text Available Although B cell depletion therapy (BCDT is effective in a subset of rheumatoid arthritis (RA patients, both mechanisms and biomarkers of response are poorly defined. Here we characterized abnormalities in B cell populations in RA and the impact of BCDT in order to elucidate B cell roles in the disease and response biomarkers. In active RA patients both CD27+IgD- switched memory (SM and CD27-IgD- double negative memory (DN peripheral blood B cells contained significantly higher fractions of CD95+ and CD21- activated cells compared to healthy controls. After BCD the predominant B cell populations were memory, and residual memory B cells displayed a high fraction of CD21- and CD95+ compared to pre-depletion indicating some resistance of these activated populations to anti-CD20. The residual memory populations also expressed more Ki-67 compared to pre-treatment, suggesting homeostatic proliferation in the B cell depleted state. Biomarkers of clinical response included lower CD95+ activated memory B cells at depletion time points and a higher ratio of transitional B cells to memory at reconstitution. B cell function in terms of cytokine secretion was dependent on B cell subset and changed with BCD. Thus, SM B cells produced pro-inflammatory (TNF over regulatory (IL10 cytokines as compared to naïve/transitional. Notably, B cell TNF production decreased after BCDT and reconstitution compared to untreated RA. Our results support the hypothesis that the clinical and immunological outcome of BCDT depends on the relative balance of protective and pathogenic B cell subsets established after B cell depletion and repopulation.

  16. HCV Infection and B-Cell Lymphomagenesis

    Directory of Open Access Journals (Sweden)

    Masahiko Ito

    2011-01-01

    Full Text Available Hepatitis C virus (HCV has been recognized as a major cause of chronic liver diseases worldwide. It has been suggested that HCV infects not only hepatocytes but also mononuclear lymphocytes including B cells that express the CD81 molecule, a putative HCV receptor. HCV infection of B cells is the likely cause of B-cell dysregulation disorders such as mixed cryoglobulinemia, rheumatoid factor production, and B-cell lymphoproliferative disorders that may evolve into non-Hodgkin's lymphoma (NHL. Epidemiological data indicate an association between HCV chronic infection and the occurrence of B-cell NHL, suggesting that chronic HCV infection is associated at least in part with B-cell lymphomagenesis. In this paper, we aim to provide an overview of recent literature, including our own, to elucidate a possible role of HCV chronic infection in B-cell lymphomagenesis.

  17. Critical zone properties control the fate of nitrogen during experimental rainfall in montane forests of the Colorado Front Range

    Science.gov (United States)

    Hinckley, Eve-Lyn S.; Ebel, Brian A.; Barnes, Rebecca T.; Murphy, Sheila F.; Anderson, Suzanne P.

    2017-01-01

    Several decades of research in alpine ecosystems have demonstrated links among the critical zone, hydrologic response, and the fate of elevated atmospheric nitrogen (N) deposition. Less research has occurred in mid-elevation forests, which may be important for retaining atmospheric N deposition. To explore the fate of N in the montane zone, we conducted plot-scale experimental rainfall events across a north–south transect within a catchment of the Boulder Creek Critical Zone Observatory. Rainfall events mimicked relatively common storms (20–50% annual exceedance probability) and were labeled with 15N-nitrate (NO3−">NO−3NO3−) and lithium bromide tracers. For 4 weeks, we measured soil–water and leachate concentrations of Br−, 15NO3−,">15NO−3,15NO3−, and NO3−">NO−3NO3− daily, followed by recoveries of 15N species in bulk soils and microbial biomass. Tracers moved immediately into the subsurface of north-facing slope plots, exhibiting breakthrough at 10 and 30 cm over 22 days. Conversely, little transport of Br− or 15NO3−">15NO−315NO3− occurred in south-facing slope plots; tracers remained in soil or were lost via pathways not measured. Hillslope position was a significant determinant of soil 15N-NO3−">NO−3NO3− recoveries, while soil depth and time were significant determinants of 15N recovery in microbial biomass. Overall, 15N recovery in microbial biomass and leachate was greater in upper north-facing slope plots than lower north-facing (toeslope) and both south-facing slope plots in August; by October, 15N recovery in microbial N biomass within south-facing slope plots had increased substantially. Our results point to the importance of soil properties in controlling the fate of N in mid-elevation forests during the summer season.

  18. Arabidopsis LEAFY COTYLEDON1 controls cell fate determination during post-embryonic development

    Directory of Open Access Journals (Sweden)

    Mingkun eHuang

    2015-11-01

    Full Text Available Arabidopsis LEAFY COTYLEDON1 (LEC1 transcription factor is a master regulator that shapes plant embryo development and post-embryonic seedling establishment. Loss-of-function of LEC1 alters the cotyledon identity, causing the formation of ectopic trichomes, which does not occur in wild-type seedlings, implying that LEC1 might regulate embryonic cell fate determination during post-embryonic development. To test this hypothesis, we compared the expression of trichome development-related genes between the wild-type and the lec1 mutant. We observed that transcripts of GL1, GL2 and GL3, genes encoding the positive regulators in trichome development, were significantly upregulated, while the TCL2, ETC1 and ETC2 genes, encoding the negative regulators in trichome development, were downregulated in the lec1 mutant. Furthermore, overexpression of LEC1 activated the expressions of TCL2, CPC and ETC1, resulting in production of cotyledonary leaves with no or fewer trichomes during vegetative development. In addition, we demonstrated that LEC1 interacts with TCL2 in yeast and in vitro. A genetic experiment showed that loss-of-function of GL2 rescued the ectopic trichome formation in the lec1 mutant. These findings strongly support that LEC1 regulates trichome development, providing direct evidence for the role of LEC1 in cell fate determination during post-embryonic development.

  19. TIM-1 signaling in B cells regulates antibody production.

    Science.gov (United States)

    Ma, Juan; Usui, Yoshihiko; Takeda, Kazuyoshi; Harada, Norihiro; Yagita, Hideo; Okumura, Ko; Akiba, Hisaya

    2011-03-11

    Members of the T cell Ig and mucin (TIM) family have recently been implicated in the control of T cell-mediated immune responses. In this study, we found TIM-1 expression on anti-IgM- or anti-CD40-stimulated splenic B cells, which was further up-regulated by the combination of anti-IgM and anti-CD40 Abs. On the other hand, TIM-1 ligand was constitutively expressed on B cells and inducible on anti-CD3(+) anti-CD28-stimulated CD4(+) T cells. In vitro stimulation of activated B cells by anti-TIM-1 mAb enhanced proliferation and expression of a plasma cell marker syndecan-1 (CD138). We further examined the effect of TIM-1 signaling on antibody production in vitro and in vivo. Higher levels of IgG2b and IgG3 secretion were detected in the culture supernatants of the anti-TIM-1-stimulated B cells as compared with the control IgG-stimulated B cells. When immunized with T-independent antigen TNP-Ficoll, TNP-specific IgG1, IgG2b, and IgG3 Abs were slightly increased in the anti-TIM-1-treated mice. When immunized with T-dependent antigen OVA, serum levels of OVA-specific IgG2b, IgG3, and IgE Abs were significantly increased in the anti-TIM-1-treated mice as compared with the control IgG-treated mice. These results suggest that TIM-1 signaling in B cells augments antibody production by enhancing B cell proliferation and differentiation. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Hippo pathway effectors control cardiac progenitor cell fate by acting as dynamic sensors of substrate mechanics and nanostructure

    KAUST Repository

    Mosqueira, Diogo

    2014-03-25

    Stem cell responsiveness to extracellular matrix (ECM) composition and mechanical cues has been the subject of a number of investigations so far, yet the molecular mechanisms underlying stem cell mechano-biology still need full clarification. Here we demonstrate that the paralog proteins YAP and TAZ exert a crucial role in adult cardiac progenitor cell mechano-sensing and fate decision. Cardiac progenitors respond to dynamic modifications in substrate rigidity and nanopattern by promptly changing YAP/TAZ intracellular localization. We identify a novel activity of YAP and TAZ in the regulation of tubulogenesis in 3D environments and highlight a role for YAP/TAZ in cardiac progenitor proliferation and differentiation. Furthermore, we show that YAP/TAZ expression is triggered in the heart cells located at the infarct border zone. Our results suggest a fundamental role for the YAP/TAZ axis in the response of resident progenitor cells to the modifications in microenvironment nanostructure and mechanics, thereby contributing to the maintenance of myocardial homeostasis in the adult heart. These proteins are indicated as potential targets to control cardiac progenitor cell fate by materials design. © 2014 American Chemical Society.

  1. Twist1 Controls a Cell-Specification Switch Governing Cell Fate Decisions within the Cardiac Neural Crest

    Science.gov (United States)

    Vincentz, Joshua W.; Firulli, Beth A.; Lin, Andrea; Spicer, Douglas B.; Howard, Marthe J.; Firulli, Anthony B.

    2013-01-01

    Neural crest cells are multipotent progenitor cells that can generate both ectodermal cell types, such as neurons, and mesodermal cell types, such as smooth muscle. The mechanisms controlling this cell fate choice are not known. The basic Helix-loop-Helix (bHLH) transcription factor Twist1 is expressed throughout the migratory and post-migratory cardiac neural crest. Twist1 ablation or mutation of the Twist-box causes differentiation of ectopic neuronal cells, which molecularly resemble sympathetic ganglia, in the cardiac outflow tract. Twist1 interacts with the pro-neural factor Sox10 via its Twist-box domain and binds to the Phox2b promoter to repress transcriptional activity. Mesodermal cardiac neural crest trans-differentiation into ectodermal sympathetic ganglia-like neurons is dependent upon Phox2b function. Ectopic Twist1 expression in neural crest precursors disrupts sympathetic neurogenesis. These data demonstrate that Twist1 functions in post-migratory neural crest cells to repress pro-neural factors and thereby regulate cell fate determination between ectodermal and mesodermal lineages. PMID:23555309

  2. B Cell: T Cell Interactions Occur within Hepatic Granulomas during Experimental Visceral Leishmaniasis

    Science.gov (United States)

    Moore, John W. J.; Beattie, Lynette; Dalton, Jane E.; Owens, Benjamin M. J.; Maroof, Asher; Coles, Mark C.; Kaye, Paul M.

    2012-01-01

    Hepatic resistance to Leishmania donovani infection in mice is associated with the development of granulomas, in which a variety of lymphoid and non-lymphoid populations accumulate. Although previous studies have identified B cells in hepatic granulomas and functional studies in B cell-deficient mice have suggested a role for B cells in the control of experimental visceral leishmaniasis, little is known about the behaviour of B cells in the granuloma microenvironment. Here, we first compared the hepatic B cell population in infected mice, where ≈60% of B cells are located within granulomas, with that of naïve mice. In infected mice, there was a small increase in mIgMlomIgD+ mature B2 cells, but no enrichment of B cells with regulatory phenotype or function compared to the naïve hepatic B cell population, as assessed by CD1d and CD5 expression and by IL-10 production. Using 2-photon microscopy to quantify the entire intra-granuloma B cell population, in conjunction with the adoptive transfer of polyclonal and HEL-specific BCR-transgenic B cells isolated from L. donovani-infected mice, we demonstrated that B cells accumulate in granulomas over time in an antigen-independent manner. Intra-vital dynamic imaging was used to demonstrate that within the polyclonal B cell population obtained from L. donovani-infected mice, the frequency of B cells that made multiple long contacts with endogenous T cells was greater than that observed using HEL-specific B cells obtained from the same inflammatory environment. These data indicate, therefore, that a subset of this polyclonal B cell population is capable of making cognate interactions with T cells within this unique environment, and provide the first insights into the dynamics of B cells within an inflammatory site. PMID:22479545

  3. Control of liver cell fate decision by a gradient of TGF beta signaling modulated by Onecut transcription factors.

    Science.gov (United States)

    Clotman, Frédéric; Jacquemin, Patrick; Plumb-Rudewiez, Nicolas; Pierreux, Christophe E; Van der Smissen, Patrick; Dietz, Harry C; Courtoy, Pierre J; Rousseau, Guy G; Lemaigre, Frédéric P

    2005-08-15

    During liver development, hepatocytes and biliary cells differentiate from common progenitors called hepatoblasts. The factors that control hepatoblast fate decision are unknown. Here we report that a gradient of activin/TGFbeta signaling controls hepatoblast differentiation. High activin/TGFbeta signaling is required near the portal vein for differentiation of biliary cells. The Onecut transcription factors HNF-6 and OC-2 inhibit activin/TGFbeta signaling in the parenchyma, and this allows normal hepatocyte differentiation. In the absence of Onecut factors, the shape of the activin/TGFbeta gradient is perturbed and the hepatoblasts differentiate into hybrid cells that display characteristics of both hepatocytes and biliary cells. Thus, a gradient of activin/TGFbeta signaling modulated by Onecut factors is required to segregate the hepatocytic and the biliary lineages.

  4. Control of liver cell fate decision by a gradient of TGFβ signaling modulated by Onecut transcription factors

    Science.gov (United States)

    Clotman, Frédéric; Jacquemin, Patrick; Plumb-Rudewiez, Nicolas; Pierreux, Christophe E.; Van der Smissen, Patrick; Dietz, Harry C.; Courtoy, Pierre J.; Rousseau, Guy G.; Lemaigre, Frédéric P.

    2005-01-01

    During liver development, hepatocytes and biliary cells differentiate from common progenitors called hepatoblasts. The factors that control hepatoblast fate decision are unknown. Here we report that a gradient of activin/TGFβ signaling controls hepatoblast differentiation. High activin/TGFβ signaling is required near the portal vein for differentiation of biliary cells. The Onecut transcription factors HNF-6 and OC-2 inhibit activin/TGFβ signaling in the parenchyma, and this allows normal hepatocyte differentiation. In the absence of Onecut factors, the shape of the activin/TGFβ gradient is perturbed and the hepatoblasts differentiate into hybrid cells that display characteristics of both hepatocytes and biliary cells. Thus, a gradient of activin/TGFβ signaling modulated by Onecut factors is required to segregate the hepatocytic and the biliary lineages. PMID:16103213

  5. Hairless controls hair fate decision via Wnt/β-catenin signaling.

    Science.gov (United States)

    Zhu, Kuicheng; Xu, Cunshuan; Liu, Mengduan; Zhang, Jintao

    2017-09-23

    The hairless (Hr) gene plays a central role in the hair cycle, considering that mutations in the gene result in hair loss with the exception of a few vibrissae after the first hair growth cycle in both mice and humans. This study examinedthe uncommon phenotype and using microarray analyses and functional studies, we found that β-catenin was mediated by Hr. Progenitor keratinocytes from the bulge region differentiate into both epidermis and sebaceous glands, and fail to adopt the hair keratinocytes fate in the mutant scalp, due to the decreased Wnt/β-catenin signaling in the absence of the hairless protein. This may be attributed to the dysfunction of normal epithelial-mesenchymal interactions in the hair follicle (HF). Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Sensitivity analysis of intracellular signaling pathway kinetics predicts targets for stem cell fate control.

    Directory of Open Access Journals (Sweden)

    Alborz Mahdavi

    2007-07-01

    Full Text Available Directing stem cell fate requires knowledge of how signaling networks integrate temporally and spatially segregated stimuli. We developed and validated a computational model of signal transducer and activator of transcription-3 (Stat3 pathway kinetics, a signaling network involved in embryonic stem cell (ESC self-renewal. Our analysis identified novel pathway responses; for example, overexpression of the receptor glycoprotein-130 results in reduced pathway activation and increased ESC differentiation. We used a systematic in silico screen to identify novel targets and protein interactions involved in Stat3 activation. Our analysis demonstrates that signaling activation and desensitization (the inability to respond to ligand restimulation is regulated by balancing the activation state of a distributed set of parameters including nuclear export of Stat3, nuclear phosphatase activity, inhibition by suppressor of cytokine signaling, and receptor trafficking. This knowledge was used to devise a temporally modulated ligand delivery strategy that maximizes signaling activation and leads to enhanced ESC self-renewal.

  7. Energy metabolic pathways control the fate and function of myeloid immune cells.

    Science.gov (United States)

    Al-Khami, Amir A; Rodriguez, Paulo C; Ochoa, Augusto C

    2017-08-01

    The past decade has seen a significant interest in investigating the intracellular metabolism of cells of the immune system. This has increased the realization that immune cells endure metabolic reprogramming upon responding to pathogen-derived or inflammatory signals. More importantly, not only does this metabolic switch provide for the bioenergetic and biosynthetic demands but also it, in a highly specific manner, determines the cellular fate and function. In this review, we discuss the metabolic aspects that regulate the differentiation and function of myeloid cells, pivotal for both innate and adaptive immunity. The manipulation of these pathways can alter the function of these cells and therefore, could provide novel therapeutic approaches in cancer and other chronic inflammatory conditions. © Society for Leukocyte Biology.

  8. Evaluation and characterization of mechanisms controlling fate and effects of Army smokes

    Energy Technology Data Exchange (ETDEWEB)

    Cataldo, D.A.; Ligotke, M.W.; Bolton, H. Jr.; Fellows, R.J.; Van Voris, P.; McKinley, J.P.; Mi, Shu-mei W.; McFadden, K.M.

    1990-08-01

    The primary objective of this study was to characterize the fate and response of soil and biotic components of the terrestrial environment to aerosols, deposited brass, and brass in combination with fog oil. Important physical, chemical, and biotic aspects were investigated using an environmental wind tunnel. Air/surface deposition rates were determined for foliar and soil surfaces, both in the absence and presence of fog oil. Deposition velocities for foliage ranged from 0.1 to 1.0 cm/s at wind speeds of 2 to 10 mph, respectively. Foliar contact toxicity was assessed using five different types of terrestrial vegetation representative of Army training sites and surrounding environments. No significant foliar contact toxicity was observed for brass. The weathering and chemistry of brass aerosols deposited and amended to soils was assessed, along with the impacts of acid precipitation and moisture regimes on weathering rates. Rates of brass weathering and the fate of solubilized Cu and Zn are discussed. The influence of soil weathering processes and brass solubilization on seed germination indicated no detectable effects of brass. However, moderate toxicity effects were noted after seed germination indicated no detectable effects of brass. However, moderate toxicity effects were noted after 160 days of soil incubation. The effects were proportional to soil-loading levels. Influence of soil weathering processes and contaminant solubilization on soil microbiological activities indicated that soil dehydrogenase activity was more susceptible to impacts than was phosphatase activity or microbial biomass. Nitrifying bacteria and heterotrophic bacteria were not significantly affected by brass. Invertebrates (earthworms) associated with soil contaminated with brass were only slightly impacted, and only at loading rates >445 {mu}g/cm{sup 2}.

  9. p53-regulated autophagy is controlled by glycolysis and determines cell fate.

    Science.gov (United States)

    Duan, Lei; Perez, Ricardo E; Davaadelger, Batzaya; Dedkova, Elena N; Blatter, Lothar A; Maki, Carl G

    2015-09-15

    The tumor suppressor p53 regulates downstream targets that determine cell fate. Canonical p53 functions include inducing apoptosis, growth arrest, and senescence. Non-canonical p53 functions include its ability to promote or inhibit autophagy and its ability to regulate metabolism. The extent to which autophagy and/or metabolic regulation determines cell fate by p53 is unclear. To address this, we compared cells resistant or sensitive to apoptosis by the p53 activator Nutlin-3a. In resistant cells, glycolysis was maintained upon Nutlin-3a treatment, and activated p53 promoted prosurvival autophagy. In contrast, in apoptosis sensitive cells activated p53 increased superoxide levels and inhibited glycolysis through repression of glycolytic pathway genes. Glycolysis inhibition and increased superoxide inhibited autophagy by repressing ATG genes essential for autophagic vesicle maturation. Inhibiting glycolysis increased superoxide and blocked autophagy in apoptosis-resistant cells, causing p62-dependent caspase-8 activation. Finally, treatment with 2-DG or the autophagy inhibitors chloroquine or bafilomycin A1 sensitized resistant cells to Nutlin-3a-induced apoptosis. Together, these findings reveal novel links between glycolysis and autophagy that determine apoptosis-sensitivity in response to p53. Specifically, the findings indicate 1) that glycolysis plays an essential role in autophagy by limiting superoxide levels and maintaining expression of ATG genes required for autophagic vesicle maturation, 2) that p53 can promote or inhibit autophagy depending on the status of glycolysis, and 3) that inhibiting protective autophagy can expand the breadth of cells susceptible to Nutlin-3a induced apoptosis.

  10. B-Cell Hematologic Malignancy Vaccination Registry

    Science.gov (United States)

    2016-12-28

    Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Waldenstrom Macroglobulinemia; Lymphocytosis; Lymphoma, Non-Hodgkin; B-Cell Chronic Lymphocytic Leukemia; Hematological Malignancies

  11. RITPBC: B-cell depleting therapy (rituximab) as a treatment for fatigue in primary biliary cirrhosis: study protocol for a randomised controlled trial.

    Science.gov (United States)

    Jopson, Laura; Newton, Julia L; Palmer, Jeremy; Floudas, Achilleas; Isaacs, John; Qian, Jessica; Wilkinson, Jennifer; Trenell, Mike; Blamire, Andrew; Howel, Denise; Jones, David E

    2015-08-20

    Primary biliary cirrhosis (PBC) is an autoimmune liver disease with approximately 50% of patients experiencing fatigue. This can be a particularly debilitating symptom, affecting quality of life and resulting in social isolation. Fatigue is highlighted by patients as a priority for research and patient support groups were involved in designing this trial. This is the first randomised controlled trial to investigate a treatment for fatigue in PBC. The trial protocol is innovative as it utilises novel magnetic resonance spectroscopy (MRS) techniques as an outcome measure. The protocol will be valuable to research groups planning clinical trials targeting fatigue in PBC and also transferrable to other conditions associated with fatigue. RITPBC is a Medical Research Council (MRC) and National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation Programme (EME)-funded project. It is a phase II, single-centre, randomised controlled, double-blinded trial comparing rituximab with placebo in fatigued PBC patients. 78 patients with PBC and moderate to severe fatigue will be randomised to receive two infusions of rituximab or placebo. The study aims to assess whether rituximab improves fatigue in patients with PBC, the safety, and tolerability of rituximab in PBC and the sustainability of any beneficial actions. The primary outcome will be an improvement in fatigue domain score of the PBC-40, a disease-specific quality of life measure, evaluated at 12-week assessment. Secondary outcome measures include novel MRS techniques assessing muscle bioenergetic function, physical activity, anaerobic threshold and symptom, and quality of life measures. The trial started recruiting in October 2012 and recruitment is ongoing. The trial has ethical approval from the NRES Committee North East, has Clinical Trial Authorisation from MHRA and local R&D approval. Trial results will be communicated to participants, presented at national and international meetings and published

  12. The fate of eroded soil organic carbon along a European transect – controls after deposition in terrestrial and aquatic systems

    DEFF Research Database (Denmark)

    Kirkels, Frédérique; Cammeraat, Erik; Kalbitz, Karsten

    The potential fate of eroded soil organic carbon (SOC) after deposition is key to understand carbon cycling in eroding landscapes. Globally, large quantities of sediments and SOC are redistributed by soil erosion on agricul-tural land, particularly after heavy precipitation events. Deposition...... relationships will contribute to obtain better estimates of the impact of soil erosion on carbon budgets and reduce uncertainties in the linkage between terrestrial and aquatic carbon cycling......., aggregation, C content, etc.). Turnover of SOC was determined for terrestrial and aquatic depositional conditions in a 10-week incubation study. Moreover, we studied the impact of labile carbon inputs (‘priming’) on SOC stability using 13C labelled cellulose. We evaluated potentially important controls...

  13. The identity and fate decision control of spermatogonial stem cells: where is the point of no return?

    Science.gov (United States)

    Nagano, Makoto C; Yeh, Jonathan R

    2013-01-01

    Spermatogonial stem cells (SSCs) are stem cells of the male germ line and support spermatogenesis for a lifetime after puberty by continuously self-renewing and generating committed progenitors. Accordingly, SSCs are defined functionally by their ability to regenerate and maintain spermatogenesis and are detected unequivocally based on their regenerative capacity. Here, we summarize past achievements of morphological and functional studies of SSCs and discuss issues to be addressed in future investigations. Using the mouse as a model organism, our particular foci are the heterogeneity of primitive spermatogonia and the maintenance of and exit from the stem cell state. By comparing to the biology of other stem cell types and organisms, we also propose possibilities and hypotheses for potential mechanisms of SSC fate decision control, involving stochastic entry into the commitment process and the interplay between SSCs and their descendants that coordinates SSC self-renewal and differentiation. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Notch-mediated post-translational control of Ngn3 protein stability regulates pancreatic patterning and cell fate commitment

    DEFF Research Database (Denmark)

    Qu, Xiaoling; Afelik, Solomon; Jensen, Jan Nygaard

    2013-01-01

    of ducts. On one hand, Ngn3 cell-intrinsically activates endocrine target genes; on the other, Ngn3 cell-extrinsically promotes lateral signaling via the Dll1>Notch>Hes1 pathway which substantially limits its ability to sustain endocrine formation. Prior to endocrine commitment, the Ngn3-mediated...... activation of the Notch>Hes1 pathway impacts formation of the trunk domain in the pancreas causing multipotent progenitors to lose acinar, while gaining endocrine and ductal, competence. The subsequent selection of fate from such bipotential progenitors is then governed by lateral inhibition, where Notch>Hes...... protein stabilization in the normal mouse pancreas explants. We conclude that the mutually exclusive expression pattern of Ngn3/Hes1 proteins in the mammalian pancreas is partially controlled through Notch-mediated post-translational regulation and we demonstrate that the formation of insulin...

  15. B-Cell Metabolic Remodeling and Cancer

    DEFF Research Database (Denmark)

    Franchina, Davide G.; Grusdat, Melanie; Brenner, Dirk

    2018-01-01

    of the current state of the art and describe the main metabolic features of B cells during normal development and oncogenesis, with emphasis on the major B-cell transcriptional and metabolic regulators, including myelocytomatosis virus oncogene cellular homolog (Myc) and hypoxia-inducible factor 1-α (HIF-1α)....

  16. Fez family transcription factors: control of neurogenesis and cell fate in the developing mammalian nervous system

    Science.gov (United States)

    Eckler, Matthew J.; Chen, Bin

    2017-01-01

    Fezf1 and Fezf2 are highly conserved transcription factors that were first identified by their specific expression in the anterior neuroepithelium of Xenopus and zebrafish embryos. These proteins share an N-terminal domain with homology to the canonical engrailed repressor motif and a C-terminal DNA binding domain containing six C2H2 zinc-finger repeats. Over a decade of study indicates that the Fez proteins play critical roles during nervous system development in species as diverse as fruit flies and mice. Herein we discuss recent progress in understanding the functions of Fezf1 and Fezf2 in neurogenesis and cell fate specification during mammalian nervous system development. Going forward we believe that efforts should focus on understanding how expression of these factors is precisely regulated, and on identifying target DNA sequences and interacting partners. Such knowledge may reveal the mechanisms by which Fezf1 and Fezf2 accomplish both independent and redundant functions across diverse tissue and cell types. PMID:24913420

  17. Fez family transcription factors: controlling neurogenesis and cell fate in the developing mammalian nervous system.

    Science.gov (United States)

    Eckler, Matthew J; Chen, Bin

    2014-08-01

    Fezf1 and Fezf2 are highly conserved transcription factors that were first identified by their specific expression in the anterior neuroepithelium of Xenopus and zebrafish embryos. These proteins share an N-terminal domain with homology to the canonical engrailed repressor motif and a C-terminal DNA binding domain containing six C2H2 zinc-finger repeats. Over a decade of study indicates that the Fez proteins play critical roles during nervous system development in species as diverse as fruit flies and mice. Herein we discuss recent progress in understanding the functions of Fezf1 and Fezf2 in neurogenesis and cell fate specification during mammalian nervous system development. Going forward we believe that efforts should focus on understanding how expression of these factors is precisely regulated, and on identifying target DNA sequences and interacting partners. Such knowledge may reveal the mechanisms by which Fezf1 and Fezf2 accomplish both independent and redundant functions across diverse tissue and cell types. © 2014 WILEY Periodicals, Inc.

  18. Controls on the Fate and Speciation of Np(V) During Iron (Oxyhydr)oxide Crystallization.

    Science.gov (United States)

    Bots, Pieter; Shaw, Samuel; Law, Gareth T W; Marshall, Timothy A; Mosselmans, J Frederick W; Morris, Katherine

    2016-04-05

    The speciation and fate of neptunium as Np(V)O2(+) during the crystallization of ferrihydrite to hematite and goethite was explored in a range of systems. Adsorption of NpO2(+) to iron(III) (oxyhydr)oxide phases was reversible and, for ferrihydrite, occurred through the formation of mononuclear bidentate surface complexes. By contrast, chemical extractions and X-ray absorption spectroscopy (XAS) analyses showed the incorporation of Np(V) into the structure of hematite during its crystallization from ferrihydrite (pH 10.5). This occurred through direct replacement of octahedrally coordinated Fe(III) by Np(V) in neptunate-like coordination. Subsequent analyses on mixed goethite and hematite crystallization products (pH 9.5 and 11) showed that Np(V) was incorporated during crystallization. Conversely, there was limited evidence for Np(V) incorporation during goethite crystallization at the extreme pH of 13.3. This is likely due to the formation of a Np(V) hydroxide precipitate preventing incorporation into the goethite particles. Overall these data highlight the complex behavior of Np(V) during the crystallization of iron(III) (oxyhydr)oxides, and demonstrate clear evidence for neptunium incorporation into environmentally important mineral phases. This extends our knowledge of the range of geochemical conditions under which there is potential for long-term immobilization of radiotoxic Np in natural and engineered environments.

  19. Engineering Cell Instructive Materials To Control Cell Fate and Functions through Material Cues and Surface Patterning.

    Science.gov (United States)

    Ventre, Maurizio; Netti, Paolo A

    2016-06-22

    Mastering the interaction between cells and extracellular environment is a fundamental prerequisite in order to engineer functional biomaterial interfaces able to instruct cells with specific commands. Such advanced biomaterials might find relevant application in prosthesis design, tissue engineering, diagnostics and stem cell biology. Because of the highly complex, dynamic, and multifaceted context, a thorough understanding of the cell-material crosstalk has not been achieved yet; however, a variety of material features including biological cues, topography, and mechanical properties have been proved to impact the strength and the nature of the cell-material interaction, eventually affecting cell fate and functions. Although the nature of these three signals may appear very different, they are equated by their participation in the same material-cytoskeleton crosstalk pathway as they regulate cell adhesion events. In this work we present recent and relevant findings on the material-induced cell responses, with a particular emphasis on how the presentation of biochemical/biophysical signals modulates cell behavior. Finally, we summarize and discuss the literature data to draw out unifying elements concerning cell recognition of and reaction to signals displayed by material surfaces.

  20. Cap-independent translation by DAP5 controls cell fate decisions in human embryonic stem cells

    Science.gov (United States)

    Yoffe, Yael; David, Maya; Kalaora, Rinat; Povodovski, Lital; Friedlander, Gilgi; Feldmesser, Ester; Ainbinder, Elena; Saada, Ann; Bialik, Shani; Kimchi, Adi

    2016-01-01

    Multiple transcriptional and epigenetic changes drive differentiation of embryonic stem cells (ESCs). This study unveils an additional level of gene expression regulation involving noncanonical, cap-independent translation of a select group of mRNAs. This is driven by death-associated protein 5 (DAP5/eIF4G2/NAT1), a translation initiation factor mediating IRES-dependent translation. We found that the DAP5 knockdown from human ESCs (hESCs) resulted in persistence of pluripotent gene expression, delayed induction of differentiation-associated genes in different cell lineages, and defective embryoid body formation. The latter involved improper cellular organization, lack of cavitation, and enhanced mislocalized apoptosis. RNA sequencing of polysome-associated mRNAs identified candidates with reduced translation efficiency in DAP5-depleted hESCs. These were enriched in mitochondrial proteins involved in oxidative respiration, a pathway essential for differentiation, the significance of which was confirmed by the aberrant mitochondrial morphology and decreased oxidative respiratory activity in DAP5 knockdown cells. Further analysis identified the chromatin modifier HMGN3 as a cap-independent DAP5 translation target whose knockdown resulted in defective differentiation. Thus, DAP5-mediated translation of a specific set of proteins is critical for the transition from pluripotency to differentiation, highlighting the importance of cap-independent translation in stem cell fate decisions. PMID:27664238

  1. Control of flowering and cell fate by LIF2, an RNA binding partner of the polycomb complex component LHP1.

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    David Latrasse

    Full Text Available Polycomb Repressive Complexes (PRC modulate the epigenetic status of key cell fate and developmental regulators in eukaryotes. The chromo domain protein like heterochromatin protein1 (LHP1 is a subunit of a plant PRC1-like complex in Arabidopsis thaliana and recognizes histone H3 lysine 27 trimethylation, a silencing epigenetic mark deposited by the PRC2 complex. We have identified and studied an LHP1-Interacting Factor2 (LIF2. LIF2 protein has RNA recognition motifs and belongs to the large hnRNP protein family, which is involved in RNA processing. LIF2 interacts in vivo, in the cell nucleus, with the LHP1 chromo shadow domain. Expression of LIF2 was detected predominantly in vascular and meristematic tissues. Loss-of-function of LIF2 modifies flowering time, floral developmental homeostasis and gynoecium growth determination. lif2 ovaries have indeterminate growth and produce ectopic inflorescences with severely affected flowers showing proliferation of ectopic stigmatic papillae and ovules in short-day conditions. To look at how LIF2 acts relative to LHP1, we conducted transcriptome analyses in lif2 and lhp1 and identified a common set of deregulated genes, which showed significant enrichment in stress-response genes. By comparing expression of LHP1 targets in lif2, lhp1 and lif2 lhp1 mutants we showed that LIF2 can either antagonize or act with LHP1. Interestingly, repression of the FLC floral transcriptional regulator in lif2 mutant is accompanied by an increase in H3K27 trimethylation at the locus, without any change in LHP1 binding, suggesting that LHP1 is targeted independently from LIF2 and that LHP1 binding does not strictly correlate with gene expression. LIF2, involved in cell identity and cell fate decision, may modulate the activity of LHP1 at specific loci, during specific developmental windows or in response to environmental cues that control cell fate determination. These results highlight a novel link between plant RNA

  2. Perinatal immunotoxicity of benzene toward mouse B cell development

    Energy Technology Data Exchange (ETDEWEB)

    Wierda, D.; King, A.; Luebke, R.; Reasor, M.; Smialowicz, R.J.

    1989-01-01

    Benzene is widely used by chemical industries and exposure to benzene has been shown experimentally to be immunotoxic in adult animals. The present study addressed whether exposure of fetuses in utero to benzene compromises the development of fetal B lymphopoiesis and whether B-lymphocyte development recovers postnatally. Pregnant BALB/C dams were given intraperitoneal injections of benzene (100 mg/kg, twice daily) from day 12.5 of gestation through day 19.5 of gestation. Phenotypic analysis revealed that fetal liver cell suspensions from embryos exposed in utero contained fewer pre-B cells and B cells than corresponding controls. Fetal liver cell cultures established from these embryos also produced fewer B cells. In contrast, pre-B cells were elevated in the livers of 8-day-old neonates that had been exposed to benzene in utero. Moreover, responsiveness to the B-cell mitogen, LPS, was significantly decreased in spleen cell cultures derived from these neonates. The results indicate that in utero exposure to high concentrations of benzene alters fetal B lymphopoiesis and may compromise immune responsiveness postnatally.

  3. Stochasticity of intranuclear biochemical reaction processes controls the final decision of cell fate associated with DNA damage.

    Science.gov (United States)

    Iwamoto, Kazunari; Hamada, Hiroyuki; Eguchi, Yukihiro; Okamoto, Masahiro

    2014-01-01

    A massive integrative mathematical model of DNA double-strand break (DSB) generation, DSB repair system, p53 signaling network, and apoptosis induction pathway was constructed to explore the dominant factors of unknown criteria of cell fate decision. In the proposed model, intranuclear reactions were modeled as stochastic processes and cytoplasmic reactions as deterministic processes, and both reaction sets were simulated simultaneously. The simulated results at the single-cell level showed that the model generated several sustained oscillations (pulses) of p53, Mdm2, ATM, and Wip1, and cell-to-cell variability in the number of p53 pulses depended on IR intensity. In cell populations, the model generated damped p53 oscillations, and IR intensity affected the amplitude of the first p53 oscillation. Cells were then subjected to the same IR dose exhibiting apoptosis induction variability. These simulated results are in quantitative agreement with major biological findings observed in human breast cancer epithelial MCF7, NIH3T3, and fibrosarcoma cells, demonstrating that the proposed model was concededly biologically appropriate. Statistical analysis of the simulated results shows that the generation of multiple p53 pulses is a prerequisite for apoptosis induction. Furthermore, cells exhibited considerable individual variability in p53 dynamics, which correlated with intrinsic apoptosis induction. The simulated results based on the proposed model demonstrated that the stochasticity of intranuclear biochemical reaction processes controls the final decision of cell fate associated with DNA damage. Applying stochastic simulation to an exploration of intranuclear biochemical reaction processes is indispensable in enhancing the understanding of the dynamic characteristics of biological multi-layered systems of higher organisms.

  4. B cell lymphoma and myeloma in murine Gaucher's disease.

    Science.gov (United States)

    Pavlova, E V; Wang, S Z; Archer, J; Dekker, N; Aerts, J M F G; Karlsson, S; Cox, T M

    2013-09-01

    Multiple myeloma and B cell lymphoma are leading causes of death in Gaucher's disease but the nature of the stimulus driving the often noted clonal expansion of immunoglobulin-secreting B cells and cognate lymphoid malignancy is unknown. We investigated the long-term development of B cell malignancies in an authentic model of non-neuronopathic Gaucher's disease in mice: selective deficiency of β-glucocerebrosidase in haematopoietic cells [Gba(tm1Karl/tm1Karl)Tg(Mx1-cre)1Cgn/0, with excision of exons 9-11 of the murine GBA1 gene, is induced by poly[I:C]. Mice with Gaucher's disease showed visceral storage of β-glucosylceramide and greatly elevated plasma β-glucosylsphingosine [median 57.9 (range 19.8-159) nm; n = 39] compared with control mice from the same strain [median 0.56 (range 0.04-1.38) nm; n = 29] (p < 0.0001). Sporadic fatal B cell lymphomas developed in 11 of 21 GD mice (6-24 months) but only two of eight control animals developed tumours by age 24 months. Unexpectedly, most mice with overt lymphoma had absent or few Gaucher cells but local inflammatory macrophages were present. Eleven of 39 of Gaucher mice developed monoclonal gammopathy, but in the control group only one animal of 25 had clonal immunoglobulin abnormalities. Seven of 10 of the B cell lymphomas were found to secrete a monoclonal paraprotein and the lymphomas stained intensely for pan-B cell markers; reactive T lymphocytes were also present in tumour tissue. In the Gaucher mouse strain, it was notable that, as in patients with this disease, CD138(+) plasma cells frequently surrounded splenic macrophages engorged with glycosphingolipid. Our strain of mice, with inducible deficiency of β-glucocerebrosidase in haematopoietic cells and a high frequency of sporadic lethal B cell malignancies, faithfully recapitulates human Gaucher's disease: it serves as a tractable model to investigate the putative role of bioactive sphingolipids in the control of B cell proliferation and the pathogenesis

  5. Dataset of transcriptional landscape of B cell early activation

    Directory of Open Access Journals (Sweden)

    Alexander S. Garruss

    2015-09-01

    Full Text Available Signaling via B cell receptors (BCR and Toll-like receptors (TLRs result in activation of B cells with distinct physiological outcomes, but transcriptional regulatory mechanisms that drive activation and distinguish these pathways remain unknown. At early time points after BCR and TLR ligand exposure, 0.5 and 2 h, RNA-seq was performed allowing observations on rapid transcriptional changes. At 2 h, ChIP-seq was performed to allow observations on important regulatory mechanisms potentially driving transcriptional change. The dataset includes RNA-seq, ChIP-seq of control (Input, RNA Pol II, H3K4me3, H3K27me3, and a separate RNA-seq for miRNA expression, which can be found at Gene Expression Omnibus Dataset GSE61608. Here, we provide details on the experimental and analysis methods used to obtain and analyze this dataset and to examine the transcriptional landscape of B cell early activation.

  6. B Cells and Autoantibodies in Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Anne-Katrin Pröbstel

    2015-07-01

    Full Text Available While over the past decades T cells have been considered key players in the pathogenesis of multiple sclerosis (MS, it has only recently become evident that B cells have a major contributing role. Our understanding of the role of B cells has evolved substantially following the clinical success of B cell-targeting therapies and increasing experimental evidence for significant B cell involvement. Rather than mere antibody-producing cells, it is becoming clear that they are team players with the capacity to prime and regulate T cells, and function both as pro- and anti-inflammatory mediators. However, despite tremendous efforts, the target antigen(s of B cells in MS have yet to be identified. The first part of this review summarizes the clinical evidence and results from animal studies pointing to the relevance of B cells in the pathogenesis of MS. The second part gives an overview of the currently known potential autoantigen targets. The third part recapitulates and critically appraises the currently available B cell-directed therapies.

  7. Splenectomy Associated Changes in IgM Memory B Cells in an Adult Spleen Registry Cohort

    Science.gov (United States)

    Cameron, Paul U.; Jones, Penelope; Gorniak, Malgorzata; Dunster, Kate; Paul, Eldho; Lewin, Sharon; Woolley, Ian; Spelman, Denis

    2011-01-01

    Asplenic patients have a lifelong risk of overwhelming post-splenectomy infection and have been reported to have low numbers of peripheral blood IgM memory B cells. The clinical value of quantitation of memory B cells as an indicator of splenic abnormality or risk of infection has been unclear. To assess changes in B cell sub-populations after splenectomy we studied patients recruited to a spleen registry (n = 591). A subset of 209 adult asplenic or hyposplenic subjects, and normal controls (n = 140) were tested for IgM memory B cells. We also determined a) changes in IgM memory B cells with time after splenectomy using the cross-sectional data from patients on the registry and b) the kinetics of changes in haematological markers associated with splenectomy(n = 45). Total B cells in splenectomy patients did not differ from controls, but memory B cells, IgM memory B cells and switched B cells were significantly (psplenectomy. Changes of asplenia in routine blood films including presence of Howell-Jolly bodies (HJB), occurred early (median 25 days) and splenectomy associated thrombocytosis and lymphocytosis peaked by 50 days. There was a more gradual decrease in IgM memory B cells reaching a stable level within 6 months after splenectomy. IgM memory B cells as proportion of B cells was the best discriminator between splenectomized patients and normal controls and at the optimal cut-off of 4.53, showed a true positive rate of 95% and false positive rate of 20%. In a survey of 152 registry patients stratified by IgM memory B cells around this cut-off there was no association with minor infections and no registry patients experienced OPSI during the study. Despite significant changes after splenectomy, conventional measures of IgM memory cells have limited clinical utility in this population. PMID:21829713

  8. Splenectomy associated changes in IgM memory B cells in an adult spleen registry cohort.

    Directory of Open Access Journals (Sweden)

    Paul U Cameron

    Full Text Available Asplenic patients have a lifelong risk of overwhelming post-splenectomy infection and have been reported to have low numbers of peripheral blood IgM memory B cells. The clinical value of quantitation of memory B cells as an indicator of splenic abnormality or risk of infection has been unclear. To assess changes in B cell sub-populations after splenectomy we studied patients recruited to a spleen registry (n = 591. A subset of 209 adult asplenic or hyposplenic subjects, and normal controls (n = 140 were tested for IgM memory B cells. We also determined a changes in IgM memory B cells with time after splenectomy using the cross-sectional data from patients on the registry and b the kinetics of changes in haematological markers associated with splenectomy(n = 45. Total B cells in splenectomy patients did not differ from controls, but memory B cells, IgM memory B cells and switched B cells were significantly (p<0.001 reduced. The reduction was similar for different indications for splenectomy. Changes of asplenia in routine blood films including presence of Howell-Jolly bodies (HJB, occurred early (median 25 days and splenectomy associated thrombocytosis and lymphocytosis peaked by 50 days. There was a more gradual decrease in IgM memory B cells reaching a stable level within 6 months after splenectomy. IgM memory B cells as proportion of B cells was the best discriminator between splenectomized patients and normal controls and at the optimal cut-off of 4.53, showed a true positive rate of 95% and false positive rate of 20%. In a survey of 152 registry patients stratified by IgM memory B cells around this cut-off there was no association with minor infections and no registry patients experienced OPSI during the study. Despite significant changes after splenectomy, conventional measures of IgM memory cells have limited clinical utility in this population.

  9. Cortisol is associated with low frequency of interleukin 10-producing B cells in patients with atherosclerosis.

    Science.gov (United States)

    Huo, Yizhong; Chu, Yan; Guo, Lixin; Liu, Linli; Xia, Xiaojun; Wang, Tierui

    2017-04-01

    It is accepted that inflammation plays a critical role in the development of atherosclerosis; the pathogenesis is not clear. B-cell-produced interleukin (IL) 10 is an immune regulatory cytokine that can inhibit immune inflammation. This study tests a hypothesis that a psychological stress hormone, cortisol, suppresses IL-10 expression in peripheral B cells of patients with atherosclerosis. Peripheral blood samples were collected from patients with coronary artery atherosclerosis. B cells were isolated from the blood samples to be analyzed for the expression of IL-10 and micro RNA (miR) 98 by real-time polymerase chain reaction. We observed that the frequency of IL-10 + B cell was less in patients with atherosclerosis than healthy controls. The serum cortisol levels were higher in the patients than that in healthy controls. Peripheral B-cell frequency was negatively correlated with the serum cortisol levels. Exposure of B cells to cortisol increased the expression of miR-98 in B cells. Cortisol also inhibited the expression of IL-10 in B cells, in which miR-98 played a critical role. Treating B cells from atherosclerosis patients with anti-miR-98 liposomes reversed the ability of expression of IL-10 in the cells. The expression of IL-10 is suppressed in peripheral B cells, which can be up regulated by anti-miR-98 liposomes. Copyright © 2017 John Wiley & Sons, Ltd.

  10. Engineering hyaluronic acid hydrogel degradation to control cellular interactions and adult stem cell fate in 3D

    Science.gov (United States)

    Khetan, Sudhir

    The design and implementation of extracellular matrix (ECM)-mimetic hydrogels for tissue engineering (TE) applications requires an intensive understanding of cell-material interactions, including matrix remodeling and stem cell differentiation. However, the influence of microenvironmental cues, e.g., matrix biodegradability, on cell behavior in vitro has not been well studied in the case of direct cell encapsulation within 3-dimensional (3D) hydrogels. To address these issues, a facile sequential crosslinking technique was developed that provides spatial and temporal control of 3D hydrogel degradability to investigate the importance of material design on cell behavior. Specifically, hydrogels were synthesized from hyaluronic acid (HA) macromers in a sequential process: (1) a primary Michael-type addition crosslinking using cell adhesive and matrix metalloprotease (MMP)-degradable oligopeptides to consume a portion of total reactive groups and resulting in "-UV" hydrogels permissive to cell-mediated degradation, followed by (2) a secondary, light initiated free-radical crosslinking to consume remaining reactive groups and "switch" the network to a non-degradable structure ("+UV") via the addition of non-degradable kinetic chains. Using this approach, we demonstrated control of encapsulated hMSC spreading by varying the crosslink type (i.e., the relative hydrogel biodegradability), including with spatial control. Upon incubation with bipotential soluble differentiation factors, these same degradation-mediated spreading cues resulted in an hMSC differentiation fate switch within -UV versus +UV environments. Follow-up studies demonstrated that degradation-mediated traction generation, rather than matrix mechanics or cell morphology, is the critical biophysical signal determining hMSC fate. Sequentially crosslinked HA hydrogels were also studied for the capacity to support remodeling by in vivo and ex vivo tissues, including with spatial control, toward tissue

  11. Ikaros limits follicular B cell activation by regulating B cell receptor signaling pathways

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    Heizmann, Beate [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Sellars, MacLean [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Macias-Garcia, Alejandra [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Institute for Medical Engineering and Science at MIT, Cambridge, MA 02139 (United States); Chan, Susan, E-mail: scpk@igbmc.fr [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Kastner, Philippe, E-mail: scpk@igbmc.fr [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Faculté de Médecine, Université de Strasbourg, Strasbourg (France)

    2016-02-12

    The Ikaros transcription factor is essential for early B cell development, but its effect on mature B cells is debated. We show that Ikaros is required to limit the response of naive splenic B cells to B cell receptor signals. Ikaros deficient follicular B cells grow larger and enter cell cycle faster after anti-IgM stimulation. Unstimulated mutant B cells show deregulation of positive and negative regulators of signal transduction at the mRNA level, and constitutive phosphorylation of ERK, p38, SYK, BTK, AKT and LYN. Stimulation results in enhanced and prolonged ERK and p38 phosphorylation, followed by hyper-proliferation. Pharmacological inhibition of ERK and p38 abrogates the increased proliferative response of Ikaros deficient cells. These results suggest that Ikaros functions as a negative regulator of follicular B cell activation.

  12. Signaling Proteins and Transcription Factors in Normal and Malignant Early B Cell Development

    Directory of Open Access Journals (Sweden)

    Patricia Pérez-Vera

    2011-01-01

    Full Text Available B cell development starts in bone marrow with the commitment of hematopoietic progenitors to the B cell lineage. In murine models, the IL-7 and preBCR receptors, and the signaling pathways and transcription factors that they regulate, control commitment and maintenance along the B cell pathway. E2A, EBF1, PAX5, and Ikaros are among the most important transcription factors controlling early development and thereby conditioning mice homeostatic B cell lymphopoiesis. Importantly, their gain or loss of function often results in malignant development in humans, supporting conserved roles for these transcription factors. B cell acute lymphoblastic leukemia is the most common cause of pediatric cancer, and it is characterized by unpaired early B cell development resulting from genetic lesions in these critical signaling pathways and transcription factors. Fine mapping of these genetic abnormalities is allowing more specific treatments, more accurately predicting risk profiles for this disease, and improving survival rates.

  13. Signaling Proteins and Transcription Factors in Normal and Malignant Early B Cell Development

    Science.gov (United States)

    Pérez-Vera, Patricia; Reyes-León, Adriana; Fuentes-Pananá, Ezequiel M.

    2011-01-01

    B cell development starts in bone marrow with the commitment of hematopoietic progenitors to the B cell lineage. In murine models, the IL-7 and preBCR receptors, and the signaling pathways and transcription factors that they regulate, control commitment and maintenance along the B cell pathway. E2A, EBF1, PAX5, and Ikaros are among the most important transcription factors controlling early development and thereby conditioning mice homeostatic B cell lymphopoiesis. Importantly, their gain or loss of function often results in malignant development in humans, supporting conserved roles for these transcription factors. B cell acute lymphoblastic leukemia is the most common cause of pediatric cancer, and it is characterized by unpaired early B cell development resulting from genetic lesions in these critical signaling pathways and transcription factors. Fine mapping of these genetic abnormalities is allowing more specific treatments, more accurately predicting risk profiles for this disease, and improving survival rates. PMID:22046564

  14. Phylogeny of B-cell development.

    Science.gov (United States)

    Du Pasquier, L

    1993-04-01

    All vertebrates with jaws (Gnathostomata) have B cells. With the exception of some B cells in cartilaginous fish that express germ-line joined Ig genes, all B cells, irrespective of the organization of their Ig genes (which varies among vertebrates), rearrange the Ig-gene segments somatically. Somatic diversification occurs in all species during rearrangement (junctional diversity) and later by somatic mutation of gene conversion. Somatic mutants are poorly selected in species that lack germinal centers, which may explain the differences in antibody repertoire among vertebrates. The early (larval or neonate) B-cell repertoire is restricted in all species so far studied because of a lack of N-region diversity and in some cases because of a special usage of the D segments of the heavy chain genes.

  15. CSF-1 receptor-mediated differentiation of a new type of monocytic cell with B cell-stimulating activity: its selective dependence on IL-34

    Science.gov (United States)

    Yamane, Fumihiro; Nishikawa, Yumiko; Matsui, Kazue; Asakura, Miki; Iwasaki, Eriko; Watanabe, Koji; Tanimoto, Hikaru; Sano, Hiroki; Fujiwara, Yuki; Stanley, E. Richard; Kanayama, Naoki; Mabbott, Neil A.; Magari, Masaki; Ohmori, Hitoshi

    2014-01-01

    With the use of a mouse FDC line, FL-Y, we have been analyzing roles for FDCs in controlling B cell fate in GCs. Beside these regulatory functions, we fortuitously found that FL-Y cells induced a new type of CD11b+ monocytic cells (F4/80+, Gr-1−, Ly6C−, I-A/E−/lo, CD11c−, CD115+, CXCR4+, CCR2+, CX3CR1−) when cultured with a Lin−c-kit+ population from mouse spleen cells. The developed CD11b+ cells shared a similar gene-expression profile to mononuclear phagocytes and were designated as FDMCs. Here, we describe characteristic immunological functions and the induction mechanism of FDMCs. Proliferation of anti-CD40 antibody-stimulated B cells was markedly accelerated in the presence of FDMCs. In addition, the FDMC-activated B cells efficiently acquired GC B cell-associated markers (Fas and GL-7). We observed an increase of FDMC-like cells in mice after immunization. On the other hand, FL-Y cells were found to produce CSF-1 as well as IL-34, both of which are known to induce development of macrophages and monocytes by binding to the common receptor, CSF-1R, expressed on the progenitors. However, we show that FL-Y-derived IL-34, but not CSF-1, was selectively responsible for FDMC generation using neutralizing antibodies and RNAi. We also confirmed that FDMC generation was strictly dependent on CSF-1R. To our knowledge, a CSF-1R-mediated differentiation process that is intrinsically specific for IL-34 has not been reported. Our results provide new insights into understanding the diversity of IL-34 and CSF-1 signaling pathways through CSF-1R. PMID:24052571

  16. IL-6 contributes to an immune tolerance checkpoint in post germinal center B cells.

    Science.gov (United States)

    Yan, Yi; Wang, Ying-Hua; Diamond, Betty

    2012-02-01

    The generation of a B cell repertoire involves producing and subsequently purging autoreactive B cells. Receptor editing, clonal deletion and anergy are key mechanisms of central B cell tolerance. Somatic mutation of antigen-activated B cells within the germinal center produces a second wave of autoreactivity; but the regulatory mechanisms that operate at this phase of B cell activation are poorly understood. We recently identified a post germinal center tolerance checkpoint, where receptor editing is re-induced to extinguish autoreactivity that is generated by somatic hypermutation. Re-induction of the recombinase genes RAG1 and RAG2 in antigen-activated B cells requires antigen to engage the B cell receptor and IL-7 to signal through the IL-7 receptor. We demonstrate that this process requires IL-6 to upregulate IL-7 receptor expression on post germinal center B cells. Diminishing IL-6 by blocking antibody or haplo-insufficiency leads to reduced expression of the IL-7 receptor and RAG and increased titers of anti-DNA antibodies following immunization with a peptide mimetope of DNA. The dependence on IL-6 to initiate receptor editing is B cell intrinsic. Interestingly, estradiol decreases IL-6 expression thereby increasing the anti-DNA response. Our data reveal a novel regulatory cascade to control post germinal center B cell autoreactivity. Copyright © 2011 Elsevier Ltd. All rights reserved.

  17. Lupus risk variants in the PXK locus alter B-cell receptor internalization

    Directory of Open Access Journals (Sweden)

    Samuel E. Vaughn

    2015-01-01

    Full Text Available Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus, rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls. We define a large (257kb common haplotype that confers lupus risk detected only in European ancestral populations and spans the promoter through the 3’ UTR of PXK. The strongest association was found at rs6445972 with P < 4.62 x 10-10, OR 0.81 (0.75 – 0.86. Using stepwise logistic regression analysis, we demonstrate that one signal drives the genetic association in the region. Bayesian analysis confirms our results, identifying a 95% credible set consisting of 172 variants spanning 200kb.Functionally, we found that PXK operates on the B-cell antigen receptor (BCR; we confirmed that PXK influenced the rate of BCR internalization. Furthermore, we demonstrate that individuals carrying the risk haplotype exhibited a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate. Taken together, these data define a new candidate mechanism for the genetic association of variants around PXK with lupus risk and highlight the regulation of intracellular trafficking as a genetically regulated pathway mediating human autoimmunity.

  18. B-cell activity in children with malaria

    Directory of Open Access Journals (Sweden)

    Korir Jackson C

    2012-03-01

    Full Text Available Abstract Background Recent studies implicate deficiency of red blood cell (RBC complement regulatory proteins (CR1 and CD55 in the pathogenesis of malarial anaemia. This study explored the involvement of B cell CD21, which has an analogous role to RBC CR1. Methods In a case control study conducted in Kisumu District hospital, western Kenya, children with severe malaria anaemia (SMA and those with uncomplicated malaria (UM were assessed by flow cytometry for B cells (CD20+ numbers, expression levels of CD21 and deposition of C3dg and by ELISA for soluble CD21 (sCD21. Paired t tests were used to determine statistical significance at a = 0.05. Results Children with SMA had significantly higher lymphocyte count (9,627.7 ± 8786.1 SD vs. 5,507 ± 2436 SD, P = 0.04 in the UM group and the computed geometric mean of mature B-cell numbers based on the absolute lymphocyte count was significantly higher for SMA group: 1,823 (1,126 to 2,982, 95% CI and 826.6 (564 to 1,220, 95% CI] for UM group (P = 0.003. SMA group also had a higher percentage of CD20+ B cells (26.8 ± 9.7SD vs 20.9 ± 9.01 SD in the UM (P = 0.03, indicating considerable polyclonal B-cell activation. The CD21 median flourescence intensity was lower in the SMA (246.4 ± 87.4 SD vs 369 ± 137.7 SD (P 0.0001, probably due to complement mediated shaving of CD21 by fixed tissue macrophages. The CD20+ B cells of SMAs had higher levels of the complement split product C3dg (18.35 ± 10 SD vs 11.5 ± 6.8 S.D, (P = 0.0002, confirming possible role of complement in CD21 removal. Unexpectedly, the SMAs had lower levels of sCD21 (226.5 ± 131.5 SD vs 341.4 ± 137.3 SD in the UM (P Conclusions These results implicate B-cell in pathophysiology of severe malaria that involves increased B-cell proliferation, increased complement deposition and subsequent loss of membrane-bound CD21. The loss of CD21 is not by the classical enzmatic cleavage.

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  7. EGFR signalling controls cellular fate and pancreatic organogenesis by regulating apicobasal polarity

    DEFF Research Database (Denmark)

    Nyeng, Pia

    2017-01-01

    Apicobasal polarity is known to affect epithelial morphogenesis and cell differentiation, but it remains unknown how these processes are mechanistically orchestrated. We find that ligand-specific EGFR signalling via PI(3)K and Rac1 autonomously modulates apicobasal polarity to enforce...... the sequential control of morphogenesis and cell differentiation. Initially, EGF controls pancreatic tubulogenesis by negatively regulating apical polarity induction. Subsequently, betacellulin, working via inhibition of atypical protein kinase C (aPKC), causes apical domain constriction within neurogenin3...

  8. Contrasting distributions of groundwater arsenic and uranium in the western Hetao basin, Inner Mongolia: Implication for origins and fate controls

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Huaming, E-mail: hmguo@cugb.edu.cn [State Key Laboratory of Biogeology and Environmental Geology, China University of Geosciences, Beijing 100083 (China); School of Water Resources and Environment, China University of Geosciences (Beijing), Beijing 100083 (China); Jia, Yongfeng [School of Water Resources and Environment, China University of Geosciences (Beijing), Beijing 100083 (China); Wanty, Richard B. [U.S. Geological Survey, MS 964d Denver Federal Center, Denver, CO 80225 (United States); Jiang, Yuxiao; Zhao, Weiguang [School of Water Resources and Environment, China University of Geosciences (Beijing), Beijing 100083 (China); Xiu, Wei [State Key Laboratory of Biogeology and Environmental Geology, China University of Geosciences, Beijing 100083 (China); School of Water Resources and Environment, China University of Geosciences (Beijing), Beijing 100083 (China); Shen, Jiaxing [School of Water Resources and Environment, China University of Geosciences (Beijing), Beijing 100083 (China); Li, Yuan [State Key Laboratory of Biogeology and Environmental Geology, China University of Geosciences, Beijing 100083 (China); School of Water Resources and Environment, China University of Geosciences (Beijing), Beijing 100083 (China); Cao, Yongsheng [School of Water Resources and Environment, China University of Geosciences (Beijing), Beijing 100083 (China); Wu, Yang [State Key Laboratory of Biogeology and Environmental Geology, China University of Geosciences, Beijing 100083 (China); Zhang, Di [School of Water Resources and Environment, China University of Geosciences (Beijing), Beijing 100083 (China); Wei, Chao [School of Water Resources and Environment, China University of Geosciences (Beijing), Beijing 100083 (China); The National Institute of Metrology, Beijing 100013 (China); Zhang, Yilong; Cao, Wengeng [Institute of Hydrogeology and Environmental Geology, China Academy of Geological Sciences, Shijiazhuang, Hebei, 050061 (China); and others

    2016-01-15

    Although As concentrations have been investigated in shallow groundwater from the Hetao basin, China, less is known about U and As distributions in deep groundwater, which would help to better understand their origins and fate controls. Two hundred and ninety-nine groundwater samples, 122 sediment samples, and 14 rock samples were taken from the northwest portion of the Hetao basin, and analyzed for geochemical parameters. Results showed contrasting distributions of groundwater U and As, with high U and low As concentrations in the alluvial fans along the basin margins, and low U and high As concentrations downgradient in the flat plain. The probable sources of both As and U in groundwater were ultimately traced to the bedrocks in the local mountains (the Langshan Mountains). Chemical weathering of U-bearing rocks (schist, phyllite, and carbonate veins) released and mobilized U as UO{sub 2}(CO{sub 3}){sub 2}{sup 2−} and UO{sub 2}(CO{sub 3}){sub 3}{sup 4−} species in the alluvial fans under oxic conditions and suboxic conditions where reductions of Mn and NO{sub 3}{sup −} were favorable (OSO), resulting in high groundwater U concentrations. Conversely, the recent weathering of As-bearing rocks (schist, phyllite, and sulfides) led to the formation of As-bearing Fe(III) (hydr)oxides in sediments, resulting in low groundwater As concentrations. Arsenic mobilization and U immobilization occurred in suboxic conditions where reduction of Fe(III) oxides was favorable and reducing conditions (SOR). Reduction of As-bearing Fe(III) (hydr)oxides, which were formed during palaeo-weathering and transported and deposited as Quaternary aquifer sediments, was believed to release As into groundwater. Reduction of U(VI) to U(IV) would lead to the formation of uraninite, and therefore remove U from groundwater. We conclude that the contrasting distributions of groundwater As and U present a challenge to ensuring safe drinking water in analogous areas, especially with high

  9. Immunomodulatory effect of Mesenchymal Stem Cells on B cells

    Directory of Open Access Journals (Sweden)

    Marcella eFranquesa

    2012-07-01

    Full Text Available The research on T cell immunosuppression therapies has attracted most of the attention in clinical transplantation. However, B cells and humoral immune responses are increasingly acknowledged as crucial mediators of chronic allograft rejection. Indeed, humoral immune responses can lead to renal allograft rejection even in patients whose cell-mediated immune responses are well controlled. On the other hand, newly studied B cell subsets with regulatory effects have been linked to tolerance achievement in transplantation. Better understanding of the regulatory and effector B cell responses may therefore lead to new therapeutic approaches.Mesenchymal Stem Cells (MSC are arising as a potent therapeutic tool in transplantation due to their regenerative and immunomodulatory properties. The research on MSCs has mainly focused on their effects on T cells and although data regarding the modulatory effects of MSCs on alloantigen-specific humoral response in humans is scarce, it has been demonstrated that MSCs significantly affect B cell functioning. In the present review we will analyze and discuss the results in this field.

  10. Inflammatory monocytes hinder antiviral B cell responses.

    Science.gov (United States)

    Sammicheli, Stefano; Kuka, Mirela; Di Lucia, Pietro; de Oya, Nereida Jimenez; De Giovanni, Marco; Fioravanti, Jessica; Cristofani, Claudia; Maganuco, Carmela G; Fallet, Benedict; Ganzer, Lucia; Sironi, Laura; Mainetti, Marta; Ostuni, Renato; Larimore, Kevin; Greenberg, Philip D; de la Torre, Juan Carlos; Guidotti, Luca G; Iannacone, Matteo

    2016-10-21

    Antibodies are critical for protection against viral infections. However, several viruses, such as lymphocytic choriomeningitis virus (LCMV), avoid the induction of early protective antibody responses by poorly understood mechanisms. Here we analyzed the spatiotemporal dynamics of B cell activation to show that, upon subcutaneous infection, LCMV-specific B cells readily relocate to the interfollicular and T cell areas of the draining lymph node where they extensively interact with CD11b(+)Ly6C(hi) inflammatory monocytes. These myeloid cells were recruited to lymph nodes draining LCMV infection sites in a type I interferon-, CCR2-dependent fashion and they suppressed antiviral B cell responses by virtue of their ability to produce nitric oxide. Depletion of inflammatory monocytes, inhibition of their lymph node recruitment or impairment of their nitric oxide-producing ability enhanced LCMV-specific B cell survival and led to robust neutralizing antibody production. In conclusion, our results identify inflammatory monocytes as critical gatekeepers that prevent antiviral B cell responses and suggest that certain viruses take advantage of these cells to prolong their persistence within the host.

  11. Fate of hydrocarbon pollutants in source and non-source control sustainable drainage systems.

    Science.gov (United States)

    Roinas, Georgios; Mant, Cath; Williams, John B

    2014-01-01

    Sustainable drainage (SuDs) is an established method for managing runoff from developments, and source control is part of accepted design philosophy. However, there are limited studies into the contribution source control makes to pollutant removal, especially for roads. This study examines organic pollutants, total petroleum hydrocarbons (TPH) and polycyclic aromatic hydrocarbons (PAHs), in paired source and non-source control full-scale SuDs systems. Sites were selected to cover local roads, trunk roads and housing developments, with a range of SuDs, including porous asphalt, swales, detention basins and ponds. Soil and water samples were taken bi-monthly over 12 months to assess pollutant loads. Results show first flush patterns in storm events for solids, but not for TPH. The patterns of removal for specific PAHs were also different, reflecting varying physico-chemical properties. The potential of trunk roads for pollution was illustrated by peak runoff for TPH of > 17,000 μg/l. Overall there was no significant difference between pollutant loads from source and non-source control systems, but the dynamic nature of runoff means that longer-term data are required. The outcomes of this project will increase understanding of organic pollutants behaviour in SuDs. This will provide design guidance about the most appropriate systems for treating these pollutants.

  12. Real-time imaging of bHLH transcriptional factors reveals their dynamic control in the multipotency and fate choice of neural stem cells

    Directory of Open Access Journals (Sweden)

    Itaru eImayoshi

    2015-08-01

    Full Text Available The basic-helix-loop-helix (bHLH transcription factors Ascl1/Mash1, Hes1, and Olig2 regulate the fate choice of neurons, astrocytes, and oligodendrocytes, respectively; however, these factors are coexpressed in self-renewing multipotent neural stem cells (NSCs even before cell fate determination. This fact raises the possibility these fate determination factors are differentially expressed between self-renewing and differentiating NSCs with unique expression dynamics. Real-time imaging analysis utilizing fluorescent proteins is a powerful strategy for monitoring expression dynamics. Fusion with fluorescent reporters makes it possible to analyze the dynamic behavior of specific proteins in living cells. However, it is technically challenging to conduct long-term imaging of proteins, particularly those with low expression levels, because a high-sensitivity and low-noise imaging system is required, and very often bleaching of fluorescent proteins and cell toxicity by prolonged laser exposure are problematic. Furthermore, to analyze the functional roles of the dynamic expression of cellular proteins, it is essential to image reporter fusion proteins that are expressed at comparable levels to their endogenous expression. In this review, we introduce our recent reports about the dynamic control of bHLH transcription factors in multipotency and fate choice of NSCs, focusing on real-time imaging of fluorescent reporters fused with bHLH transcription factors. Our imaging results indicate that bHLH transcription factors are expressed in an oscillatory manner by NSCs, and that one of them becomes dominant during fate choice. We propose that the multipotent state of NSCs correlates with the oscillatory expression of several bHLH transcription factors, whereas the differentiated state correlates with the sustained expression of a single bHLH transcription factor.

  13. Pre-stimulation of CD81 expression by resting B cells increases proliferation following EBV infection, but the overexpression of CD81 induces the apoptosis of EBV-transformed B cells.

    Science.gov (United States)

    Park, Ga Bin; Kim, Daejin; Park, Sung Jae; Lee, Hyun-Kyung; Kim, Ji Hyun; Kim, Yeong Seok; Park, Sae-Gwang; Choi, In-Hak; Yoon, Sung Ho; Lee, Youn Jae; Paeng, Sunghwa; Hur, Dae Young

    2015-12-01

    Hepatitis C virus (HCV) E2 protein binds to CD81, which is a component of the B cell co-stimulatory complex. The E2-CD81 interaction leads to B cell proliferation, protein tyrosine phosphorylation and to the hypermutation of immunoglobulin genes. Epidemiological studies have reported a high prevalence of B cell non-Hodgkin lymphoma (NHL) in HCV-positive patients, suggesting a potential association between HCV and Epstein-Barr virus (EBV) in the genesis of B lymphocyte proliferative disorders. In the present study, in order to investigate the association between EBV and HCV in B cells, we created an in vitro EBV-induced B cell transformation model. CD81 was gradually overexpressed during transformation by EBV. B cells isolated from HCV-positive patients grew more rapidly and clumped together earlier than B cells isolated from healthy donors following EBV infection. Pre-stimulation of CD81 expressed by resting B cells with anti-CD81 monoclonal antibody (mAb) or HCV E2 accelerated the generation of lymphoblastoid cell lines (LCLs) by EBV infection. These cells proliferated prominently through the early expression of interleukin-10 and intracellular latent membrane protein (LMP)-l. By contrast, the overexpression of CD81 on EBV-transformed B cells by anti-CD81 mAb or HCV E2 protein induced apoptosis through reactive oxygen species (ROS)-mediated mitochondrial dysfunction. These results suggest that the engagement of CD81 expressed by B cells has differential effects on B cell fate (proliferation or apoptosis) according to EBV infection and the expression level of CD81.

  14. Anti-CD20 B-cell depletion enhances monocyte reactivity in neuroimmunological disorders.

    Science.gov (United States)

    Lehmann-Horn, Klaus; Schleich, Eva; Hertzenberg, Deetje; Hapfelmeier, Alexander; Kümpfel, Tania; von Bubnoff, Nikolas; Hohlfeld, Reinhard; Berthele, Achim; Hemmer, Bernhard; Weber, Martin S

    2011-10-26

    Clinical trials evaluating anti-CD20-mediated B-cell depletion in multiple sclerosis (MS) and neuromyelitis optica (NMO) generated encouraging results. Our recent studies in the MS model experimental autoimmune encephalomyelitis (EAE) attributed clinical benefit to extinction of activated B-cells, but cautioned that depletion of naïve B-cells may be undesirable. We elucidated the regulatory role of un-activated B-cells in EAE and investigated whether anti-CD20 may collaterally diminish regulatory B-cell properties in treatment of neuroimmunological disorders. Myelin oligodendrocyte glycoprotein (MOG) peptide-immunized C57Bl/6 mice were depleted of B-cells. Functional consequences for regulatory T-cells (Treg) and cytokine production of CD11b+ antigen presenting cells (APC) were assessed. Peripheral blood mononuclear cells from 22 patients receiving anti-CD20 and 23 untreated neuroimmunological patients were evaluated for frequencies of B-cells, T-cells and monocytes; monocytic reactivity was determined by TNF-production and expression of signalling lymphocytic activation molecule (SLAM). We observed that EAE-exacerbation upon depletion of un-activated B-cells closely correlated with an enhanced production of pro-inflammatory TNF by CD11b+ APC. Paralleling this pre-clinical finding, anti-CD20 treatment of human neuroimmunological disorders increased the relative frequency of monocytes and accentuated pro-inflammatory monocyte function; when reactivated ex vivo, a higher frequency of monocytes from B-cell depleted patients produced TNF and expressed the activation marker SLAM. These data suggest that in neuroimmunological disorders, pro-inflammatory APC activity is controlled by a subset of B-cells which is eliminated concomitantly upon anti-CD20 treatment. While this observation does not conflict with the general concept of B-cell depletion in human autoimmunity, it implies that its safety and effectiveness may further advance by selectively targeting pathogenic B-cell

  15. Signaling and Dynamic Actin Responses of B Cells on Topographical Substrates

    Science.gov (United States)

    Ketchum, Christina; Sun, Xiaoyu; Fourkas, John; Song, Wenxia; Upadhyaya, Arpita

    B cells become activated upon physical contact with antigen on the surface of antigen presenting cells, such as dendritic cells. Binding of the B cell receptor with antigen initiates actin-mediated spreading of B cells, signaling cascades and eventually infection fighting antibodies. Lymphocytes, including B cells and T cells, have been shown to be responsive to the physical parameters of the contact surface, such as antigen mobility and substrate stiffness. However the roll of surface topography on lymphocyte function is unknown. Here we investigate the degree to which substrate topography controls actin-mediated spreading and B cell activation using nano-fabricated surfaces and live cell imaging. The model topographical system consists of 600 nanometer tall ridges with spacing varying between 800 nanometers and 5 micrometers. Using TIRF imaging we observe actin dynamics, B cell receptor motion and calcium signaling of B cells as they spread on the ridged substrates. We show that the spacing between ridges had a strong effect on the dynamics of actin and calcium influx on B cells. Our results indicate that B cells are highly sensitive to surface topography during cell spreading and signaling activation.

  16. Role of substrate biomechanics in controlling (stem) cell fate: Implications in regenerative medicine.

    Science.gov (United States)

    Macri-Pellizzeri, Laura; De-Juan-Pardo, Elena M; Prosper, Felipe; Pelacho, Beatriz

    2017-10-11

    Tissue-specific stem cells reside in a specialized environment known as niche. The niche plays a central role in the regulation of cell behaviour and, through the concerted action of soluble molecules, supportive somatic cells, and extracellular matrix components, directs stem cells to proliferate, differentiate, or remain quiescent. Great efforts have been done to decompose and separately analyse the contribution of these cues in the in vivo environment. Specifically, the mechanical properties of the extracellular matrix influence many aspects of cell behaviour, including self-renewal and differentiation. Deciphering the role of biomechanics could thereby provide important insights to control the stem cells responses in a more effective way with the aim to promote their therapeutic potential. In this review, we provide a wide overview of the effect that the microenvironment stiffness exerts on the control of cell behaviour with a particular focus on the induction of stem cells differentiation. We also describe the process of mechanotransduction and the molecular effectors involved. Finally, we critically discuss the potential involvement of tissue biomechanics in the design of novel tissue engineering strategies. Copyright © 2017 John Wiley & Sons, Ltd.

  17. Control of Paneth Cell Fate, Intestinal Inflammation, and Tumorigenesis by PKCλ/ι

    Directory of Open Access Journals (Sweden)

    Yuki Nakanishi

    2016-09-01

    Full Text Available Paneth cells are a highly specialized population of intestinal epithelial cells located in the crypt adjacent to Lgr5+ stem cells, from which they differentiate through a process that requires downregulation of the Notch pathway. Their ability to store and release antimicrobial peptides protects the host from intestinal pathogens and controls intestinal inflammation. Here, we show that PKCλ/ι is required for Paneth cell differentiation at the level of Atoh1 and Gfi1, through the control of EZH2 stability by direct phosphorylation. The selective inactivation of PKCλ/ι in epithelial cells results in the loss of mature Paneth cells, increased apoptosis and inflammation, and enhanced tumorigenesis. Importantly, PKCλ/ι expression in human Paneth cells decreases with progression of Crohn’s disease. Kaplan-Meier survival analysis of colorectal cancer (CRC patients revealed that low PRKCI levels correlated with significantly worse patient survival rates. Therefore, PKCλ/ι is a negative regulator of intestinal inflammation and cancer through its role in Paneth cell homeostasis.

  18. Diurnal cycles control the fate of contaminants at an Andean river confluence impacted by legacy mining

    Science.gov (United States)

    Pasten, P.; Guerra, P. A.; Simonson, K.; Bonilla, C.; Pizarro, G. E.; Escauriaza, C. R.; González, C.

    2014-12-01

    The importance of hydrologic-geochemical interactions in arid environments is a controlling factor in quality and quantity of water available for human consumption and agriculture. When acid drainage affects these watersheds, water quality is gravely degraded. Despite its effect on watersheds, the relationship between time changes in hydrological variables and water quality in arid regions has not been studied thoroughly. Temporal variations in acid drainage can control when the transport of toxic elements is increased. We performed field work at the Azufre River (pH 2, E.C~10.9 mS/cm) and Caracarani River (pH 8.7, E.C~1.2 mS/cm) confluence, located in the Northern Chilean Altiplano (at 4000 m asl). We registered stream flowrates (total flowrate~430 L/s), temperature and electric conductivity (E.C) hourly using in-stream data loggers during one year. We also measured turbidity and pH during one field survey at different distances from the junction, as a proxy of the formation of iron-aluminum particles that cycle trace elements in these environments. We found turbidity-pH diurnal cycles were caused by upstream hourly changes in upstream flowrate: when the Caracarani River flowrate reached its daily peak, particle formation occurred, while the dissolution of particles occurred when the Azufre River reached its maximum value. This last process occurred due to upstream freeze-thaw cycles. This study shows how the dynamics of natural confluences determines chemical transport. The formation of particles enriched in toxic elements can promote settling as a natural attenuation process, while their dissolution will produce their release and transport long distances downstream. It is important to consider time as an important variable in water quality monitoring and in water management infrastructure where pulses of contamination can have potentially negative effects in its use. Acknowledgements: Funding was provided by "Proyecto Fondecyt 1130936" and "CONICYT

  19. Sox17-Mediated XEN Cell Conversion Identifies Dynamic Networks Controlling Cell-Fate Decisions in Embryo-Derived Stem Cells

    Directory of Open Access Journals (Sweden)

    Angela C.H. McDonald

    2014-10-01

    Full Text Available Little is known about the gene regulatory networks (GRNs distinguishing extraembryonic endoderm (ExEn stem (XEN cells from those that maintain the extensively characterized embryonic stem cell (ESC. An intriguing network candidate is Sox17, an essential transcription factor for XEN derivation and self-renewal. Here, we show that forced Sox17 expression drives ESCs toward ExEn, generating XEN cells that contribute to ExEn when placed back into early mouse embryos. Transient Sox17 expression is sufficient to drive this fate change during which time cells transit through distinct intermediate states prior to the generation of functional XEN-like cells. To orchestrate this conversion process, Sox17 acts in autoregulatory and feedforward network motifs, regulating dynamic GRNs directing cell fate. Sox17-mediated XEN conversion helps to explain the regulation of cell-fate changes and reveals GRNs regulating lineage decisions in the mouse embryo.

  20. Effects of the allogeneic stimulation on B cell function in thalassaemic polytransfused patients.

    Science.gov (United States)

    Quintiliani, L; Iudicone, P; Sisti, P; Greca, E; Martini, F; Giuliani, E; Buzzonetti, A; Guglielmetti, M; Liotta, I

    1987-01-01

    The immunological abnormalities of polytransfused patients affected by beta-thalassaemia major have been investigated in relation to B cell function. The spontaneous in vitro production of Ig by patient peripheral mononuclear cells was not modified, while the pokeweed mitogen induced IgM synthesis was significantly reduced. However, by comparing the splenectomized and non-splenectomized patients, this alteration proved to be present only in the splenectomized group. The proliferation of patient peripheral B cells in vitro stimulated with B cell growth factor alone was not significantly enhanced in respect to the controls. These results indicate that in vivo activation state of patient B cells is not different from that of the controls. The stimulation of peripheral B cell with anti-mu or anti-alpha antibodies and anti-mu and anti-alpha antibodies plus B cells growth factor induced a significant increase in proliferative responses of B cells from the splenectomized patients. Taken together, these findings suggest that circulating B cells of thalassaemic polytransfused patients are not hyperactivated. The splenectomy can account for the immunological changes observed in our thalassaemic sample as compared to control group.

  1. Endothelial cells control pancreatic cell fate at defined stages through EGFL7 signaling.

    Science.gov (United States)

    Kao, Der-I; Lacko, Lauretta A; Ding, Bi-Sen; Huang, Chen; Phung, Kathleen; Gu, Guoqiang; Rafii, Shahin; Stuhlmann, Heidi; Chen, Shuibing

    2015-02-10

    Although endothelial cells have been shown to affect mouse pancreatic development, their precise function in human development remains unclear. Using a coculture system containing human embryonic stem cell (hESC)-derived progenitors and endothelial cells, we found that endothelial cells play a stage-dependent role in pancreatic development, in which they maintain pancreatic progenitor (PP) self-renewal and impair further differentiation into hormone-expressing cells. The mechanistic studies suggest that the endothelial cells act through the secretion of EGFL7. Consistently, endothelial overexpression of EGFL7 in vivo using a transgenic mouse model resulted in an increase of PP proliferation rate and a decrease of differentiation toward endocrine cells. These studies not only identified the role of EGFL7 as the molecular handle involved in the crosstalk between endothelium and pancreatic epithelium, but also provide a paradigm for using hESC stepwise differentiation to dissect the stage-dependent roles of signals controlling organogenesis. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  2. Endothelial Cells Control Pancreatic Cell Fate at Defined Stages through EGFL7 Signaling

    Directory of Open Access Journals (Sweden)

    Der-I Kao

    2015-02-01

    Full Text Available Although endothelial cells have been shown to affect mouse pancreatic development, their precise function in human development remains unclear. Using a coculture system containing human embryonic stem cell (hESC-derived progenitors and endothelial cells, we found that endothelial cells play a stage-dependent role in pancreatic development, in which they maintain pancreatic progenitor (PP self-renewal and impair further differentiation into hormone-expressing cells. The mechanistic studies suggest that the endothelial cells act through the secretion of EGFL7. Consistently, endothelial overexpression of EGFL7 in vivo using a transgenic mouse model resulted in an increase of PP proliferation rate and a decrease of differentiation toward endocrine cells. These studies not only identified the role of EGFL7 as the molecular handle involved in the crosstalk between endothelium and pancreatic epithelium, but also provide a paradigm for using hESC stepwise differentiation to dissect the stage-dependent roles of signals controlling organogenesis.

  3. Interaction of Staphylococci with Human B cells.

    Directory of Open Access Journals (Sweden)

    Tyler K Nygaard

    Full Text Available Staphylococcus aureus is a leading cause of human infections worldwide. The pathogen produces numerous molecules that can interfere with recognition and binding by host innate immune cells, an initial step required for the ingestion and subsequent destruction of microbes by phagocytes. To better understand the interaction of this pathogen with human immune cells, we compared the association of S. aureus and S. epidermidis with leukocytes in human blood. We found that a significantly greater proportion of B cells associated with S. epidermidis relative to S. aureus. Complement components and complement receptors were important for the binding of B cells with S. epidermidis. Experiments using staphylococci inactivated by ultraviolet radiation and S. aureus isogenic deletion mutants indicated that S. aureus secretes molecules regulated by the SaeR/S two-component system that interfere with the ability of human B cells to bind this bacterium. We hypothesize that the relative inability of B cells to bind S. aureus contributes to the microbe's success as a human pathogen.

  4. B-cell responses to HIV infection.

    Science.gov (United States)

    Moir, Susan; Fauci, Anthony S

    2017-01-01

    The induction of neutralizing antibodies directed against the human immunodeficiency virus (HIV) has received considerable attention in recent years, in part driven by renewed interest and opportunities for antibody-based strategies for prevention such as passive transfer of antibodies and the development of preventive vaccines, as well as immune-based therapeutic interventions. Advances in the ability to screen, isolate, and characterize HIV-specific antibodies have led to the identification of a new generation of potent broadly neutralizing antibodies (bNAbs). The majority of these antibodies have been isolated from B cells of chronically HIV-infected individuals with detectable viremia. In this review, we provide insight into the phenotypic and functional attributes of human B cells, with a focus on HIV-specific memory B cells and plasmablasts/cells that are responsible for sustaining humoral immune responses against HIV. We discuss the abnormalities in B cells that occur in HIV infection both in the peripheral blood and lymphoid tissues, especially in the setting of persisting viremia. Finally, we consider the opportunities and drawbacks of intensively interrogating antibodies isolated from HIV-infected individuals to guide strategies aimed at developing effective antibody-based vaccine and therapeutic interventions for HIV. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

  5. The chicken B-cell receptor complex and its role in avian B-cell development.

    Science.gov (United States)

    Sayegh, C E; Demaries, S L; Pike, K A; Friedman, J E; Ratcliffe, M J

    2000-06-01

    The bursa of Fabricius is critical to normal B-lymphocyte development in birds. During embryonic life, B-cell precursors migrate to the bursal rudiment and those which have undergone productive V(D)J recombination colonize lymphoid follicles and undergo immunoglobulin V gene diversification by gene conversion. The chicken surface IgM complex appears structurally and functionally equivalent to its mammalian counterpart, with homologs to CD79a and CD79b. Expression of a truncated Igmu chain is sufficient to drive the early stages of B-cell development in the embryo bursa. Bursal cells expressing the truncated mu receptor complex proliferate in bursal follicles, and those which contain V gene rearrangements undergo V gene diversification by gene conversion. The bursa is a gut-associated organ and antigen is focused to bursal lymphoid follicles after hatch. While expression of the truncated mu chain is sufficient to support B-cell development in the embryo, B cells expressing this receptor are rapidly eliminated after hatch. We suggest the possibility that B-cell development in the bursa after hatch is driven by encounter with antigen leading to redistribution of B cells within the lymphoid follicle, B-cell proliferation and V gene repertoire development by gene conversion.

  6. The origin of marginal zone B cells in the rat

    NARCIS (Netherlands)

    Dammers, PM; de Boer, NK; Deenen, GJ; Nieuwenhuis, P; Kroese, FGM

    The marginal zone is a unique compartment that is only found in the spleen. Rat marginal zone B cells (MZ-B) can be distinguished from other B cells, e.g. recirculating follicular B cells (RF-B), by several phenotypic characteristics. Typically MZ-B cells are surface (s)IgM(hi), sIgD(lo) and

  7. IL-15 expression on RA synovial fibroblasts promotes B cell survival.

    Directory of Open Access Journals (Sweden)

    Marta Benito-Miguel

    Full Text Available INTRODUCTION: The purpose of this study was to examine the role of RA Synovial Fibroblast (RASFib IL-15 expression on B cell survival. METHODS: Magnetically sorted peripheral blood memory B cells from 15 healthy subjects were cocultured with RASFib. RESULTS: RASFib constitutively expressed membrane IL-15. Survival of isolated B cells cultured for 6 days, below 5%, was extended in coculture with RASFib to 52+/-8% (p<0.001. IL-15 neutralizing agents but not isotype controls, reduced this rate to 31+/-6% (p<0.05. Interestingly, rhIL-15 had no effect on isolated B cells but significantly increased their survival in coculture with RASFib. In parallel, B cell IL-15R chains were upregulated in cocultures. BAFF and VCAM-1, that are expressed on RASFib, were tested as potential candidates involved in upregulating B cell IL-15R. Culture of B cells in the presence of rhBAFF or rhVCAM-1 resulted in significantly increased survival, together with upregulation of all three IL-15R chains; in parallel, rhIL-15 potentiated the anti-apoptotic effect of BAFF and VCAM-1. Both BAFF and VCAM-1 neutralizing agents downmodulated the effect of RASFib on B cell survival and IL-15R expression. In parallel, rhIL-15 had a lower effect on the survival of B cells cocultured with RASFib in the presence of BAFF or VCAM-1 neutralizing agents. Peripheral blood B cells from 15 early RA patients demonstrated an upregulated IL-15R and increased survival in cocultures. CONCLUSION: IL-15 expression on RASFib significantly contributes to the anti-apoptotic effect of RASFib on B cells. IL-15 action is facilitated by BAFF and VCAM-1 expressed on RASFib, through an upregulation of IL-15R chains.

  8. Proteasome regulation of the chromodomain protein MRG-1 controls the balance between proliferative fate and differentiation in the C. elegans germ line.

    Science.gov (United States)

    Gupta, Pratyush; Leahul, Lindsay; Wang, Xin; Wang, Chris; Bakos, Brendan; Jasper, Katie; Hansen, Dave

    2015-01-15

    The level of stem cell proliferation must be tightly controlled for proper development and tissue homeostasis. Multiple levels of gene regulation are often employed to regulate stem cell proliferation to ensure that the amount of proliferation is aligned with the needs of the tissue. Here we focus on proteasome-mediated protein degradation as a means of regulating the activities of proteins involved in controlling the stem cell proliferative fate in the C. elegans germ line. We identify five potential E3 ubiquitin ligases, including the RFP-1 RING finger protein, as being involved in regulating proliferative fate. RFP-1 binds to MRG-1, a homologue of the mammalian chromodomain-containing protein MRG15 (MORF4L1), which has been implicated in promoting the proliferation of neural precursor cells. We find that C. elegans with reduced proteasome activity, or that lack RFP-1 expression, have increased levels of MRG-1 and a shift towards increased proliferation in sensitized genetic backgrounds. Likewise, reduction of MRG-1 partially suppresses stem cell overproliferation. MRG-1 levels are controlled independently of the spatially regulated GLP-1/Notch signalling pathway, which is the primary signal controlling the extent of stem cell proliferation in the C. elegans germ line. We propose a model in which MRG-1 levels are controlled, at least in part, by the proteasome, and that the levels of MRG-1 set a threshold upon which other spatially regulated factors act in order to control the balance between the proliferative fate and differentiation in the C. elegans germ line. © 2015. Published by The Company of Biologists Ltd.

  9. Long-term fate of glyphosate associated with repeated rodeo applications to control smooth cordgrass (Spartina alterniflora) in Willapa Bay, Washington.

    Science.gov (United States)

    Kilbride, K M; Paveglio, F L

    2001-02-01

    Cordgrasses (Spartina sp.) are exotic, invasive species that threaten to degrade the intertidal zones of estuaries along the West Coast of North America. Integrated pest management (IPM) strategies primarily focus on the use of aerial and ground applications of Rodeo in conjunction with mowing, but IPM treatments over multiple years usually are necessary to control Spartina. Although information exists regarding the short-term fate and effects to marine biota of a single Rodeo application to control Spartina, little information is available regarding the fate and biotic effects associated with repeated Rodeo applications necessary for control. Consequently, we conducted a 3-year study to assess the short- and long-term fate and potential effects to marine biota associated with repeated applications of Rodeo to control smooth cordgrass in a southwestern Washington estuary. At each of three intertidal locations in Willapa Bay, we established plots on exposed mudflats and along the edge of a Spartina meadow that were hand sprayed with Rodeo (5% solution) and LI-700 (2% solution) during July 1997 and 1998. Glyphosate concentrations in sediment from mudflat plots declined 88% to 96% from 1 day posttreatment in 1997 to 1 year after the second Rodeo applications in 1999. In contrast, glyphosate concentrations in Spartina plots increased 231% to 591% from 1997 to 1999 because Spartina rhizomes likely did not readily metabolize or exude it. Comparison of concentrations from mudflat and Spartina plots with toxicity test values for marine biota indicates that under worst-case conditions short- and long-term detrimental effects to aquatic biota from repeated application of Rodeo for Spartina control would be highly unlikely.

  10. B Cell-Activating Factor Regulates Different Aspects of B Cell Functionality and Is Produced by a Subset of Splenic B Cells in Teleost Fish

    OpenAIRE

    TAFALLA, carolina; González, Lucia; Castro, Rosario; Granja, Aitor G.

    2017-01-01

    In mammals, B cell functionality is greatly influenced by cytokines released by innate cells, such as macrophages or dendritic cells, upon the early recognition of common pathogen patterns through invariant receptors. B cell-activating factor (BAFF) is one of these innate B cell-helper signals and plays a key role in the survival and differentiation of B cells. Although, evolutionarily, teleost fish constitute the first animal group in which adaptive immunity based on Ig receptors is present,...

  11. The BiP cochaperone ERdj4 is required for B cell development and function.

    Directory of Open Access Journals (Sweden)

    Jill M Fritz

    Full Text Available ERdj4 is a BiP cochaperone regulated by the unfolded protein response to facilitate degradation of unfolded and/or misfolded proteins in the endoplasmic reticulum. As the unfolded protein response plays a critical role in B cell maturation and antibody production, ERdj4 gene trap mice were generated to determine if this chaperone was required for B cell homeostasis. Homozygosity for the trapped allele resulted in hypomorphic expression of ERdj4 in bone marrow cells and abnormal development of hematopoietic lineages in the bone marrow. The number of myeloid cells was increased, while the number of erythroid and B lymphoid cells was reduced in ERdj4 gene trap mice compared to controls. An intrinsic B cell defect was identified that decreased survival of B cell precursors including large and small pre-B, and immature B cells. Consistent with impaired B lymphopoiesis, the number of mature follicular B cells was reduced in both the bone marrow and spleen of ERdj4 gene trap mice. Paradoxically, unchallenged ERdj4 gene trap mice showed non-specific hypergammaglobulinemia and gene trap B cells exhibited increased proliferation, survival and isotype switching in response to LPS stimulation. Although ERdj4 gene trap mice responded normally to T cell-independent antigen, they failed to mount a specific antibody response to T cell-dependent antigen in vivo. Collectively, these findings demonstrate that the chaperone activity of ERdj4 is required for survival of B cell progenitors and normal antibody production.

  12. Human B cells produce chemokine CXCL10 in the presence of Mycobacterium tuberculosis specific T cells.

    Science.gov (United States)

    Hoff, Soren T; Salman, Ahmed M; Ruhwald, Morten; Ravn, Pernille; Brock, Inger; Elsheikh, Nabila; Andersen, Peter; Agger, Else Marie

    2015-01-01

    The role of B cells in human host response to Mycobacterium tuberculosis (Mtb) infection is still controversial, but recent evidence suggest that B cell follicle like structures within the lung may influence host responses through regulation of the local cytokine environment. A candidate for such regulation could be the chemokine CXCL10. CXCL10 is mainly produced by human monocytes, but a few reports have also found CXCL10 production by human B cells. The objective of this study was to investigate CXCL10 production by human B cells in response to in vitro stimulation with Mtb antigens. We analyzed human blood samples from 30 volunteer donors using multiparameter flow cytometry, and identified a subgroup of B cells producing CXCL10 in response to in vitro stimulation with antigens. T cells did not produce CXCL10, but CXCL10 production by B cells appeared to be mediated via IFN-γ and dependent on contact with antigen-specific T cells recognizing the antigen. Human B cells are able to produce CXCL10 in an IFN-γ and T cell contact-dependent manner. The present findings suggest a possible mechanism through which B cells in part may influence granuloma formation in human tuberculosis (TB) and participate in infection control. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. PDK1 regulates VDJ recombination, cell-cycle exit and survival during B-cell development.

    Science.gov (United States)

    Venigalla, Ram K C; McGuire, Victoria A; Clarke, Rosemary; Patterson-Kane, Janet C; Najafov, Ayaz; Toth, Rachel; McCarthy, Pierre C; Simeons, Frederick; Stojanovski, Laste; Arthur, J Simon C

    2013-04-03

    Phosphoinositide-dependent kinase-1 (PDK1) controls the activation of a subset of AGC kinases. Using a conditional knockout of PDK1 in haematopoietic cells, we demonstrate that PDK1 is essential for B cell development. B-cell progenitors lacking PDK1 arrested at the transition of pro-B to pre-B cells, due to a cell autonomous defect. Loss of PDK1 decreased the expression of the IgH chain in pro-B cells due to impaired recombination of the IgH distal variable segments, a process coordinated by the transcription factor Pax5. The expression of Pax5 in pre-B cells was decreased in PDK1 knockouts, which correlated with reduced expression of the Pax5 target genes IRF4, IRF8 and Aiolos. As a result, Ccnd3 is upregulated in PDK1 knockout pre-B cells and they have an impaired ability to undergo cell-cycle arrest, a necessary event for Ig light chain rearrangement. Instead, these cells underwent apoptosis that correlated with diminished expression of the pro-survival gene Bcl2A1. Reintroduction of both Pax5 and Bcl2A1 together into PDK1 knockout pro-B cells restored their ability to differentiate in vitro into mature B cells.

  14. Quantitative ultrastructural changes induced by sucrose administration in the pancreatic B cells of normal hamsters.

    Science.gov (United States)

    Camihort, G; Del Zotto, H; Gómez Dumm, C L; Gagliardino, J J

    2000-04-01

    We have previously reported that young male Syrian hamsters receiving a sucrose-rich diet presented increased B-cell replication rate and size. The aim of the present study was to analyze, under the same experimental conditions, the ultrastructural changes in B cells. For this purpose, young male Syrian hamsters were fed with a commercial diet and 10% sucrose in their drinking water (S group) while the control group (C) received the same diet and tap water, for 5 weeks. Samples of the pancreas removed after that period were processed for the immunohistochemical identification of B cells as well as for measuring several ultrastructural parameters. S hamsters showed higher serum insulin levels, while similar serum glucose values were obtained in animals from both groups. The B cells from S group exhibited lesser number of dense secretory granules at expenses of an increase of the pale ones, increased number of both exocytosis profiles and fusion-granule images, as well as enlargement of the intercellular space and mitochondrial area. Marked expansions of this space, limited by junctional complexes, were observed between adjacent B cells. These results would indicate that sucrose administration to normal hamsters not only increases the pancreatic B-cell mass but also induces measurable subcellular changes in the individual B-cell characteristic of an enhanced secretory activity. The present model would represent a useful tool for testing strategies in preventing the damage or promoting the recovery of the pancreatic B cells.

  15. "I overcame fate, fate harkens to me"

    Directory of Open Access Journals (Sweden)

    Jan Bergman

    1967-02-01

    Full Text Available ”I overcome Fate (to heimarmenon; Fate harkens to me". In order to understand the tension in this proclamation of Isis, which forms the conclusion of the Isis aretalogy from Cyme, we must make a closer acquaintance with the two dramatis personae. With what right could Isis make a claim like this? How was to heimarmenon understood and experienced in the Hellenistic environment to which the Cyme hymn belongs? This paper considers the Egyptian goddess and her relation to Fate, by pointing out a few `fatalistic traits' in Isis' character. But first we have to ask another question: How did the Egyptians understand Fate in general? What concepts did they use in order to define Fate and its effects? What was the relation between the god(s and Fate?

  16. Primary Hepatosplenic Large B-Cell Lymphoma

    Directory of Open Access Journals (Sweden)

    M.R. Morales-Polanco

    2008-03-01

    Full Text Available Diffuse large B-cell lymphoma is the most common form of lymphoma. It usually begins in the lymph nodes; up to 40% may have an extranodal presentation. According to a definition of primary extranodal lymphoma with presentation only in extranodal sites, there are reports of large B-cell lymphomas limited to liver or spleen as separate entities, and to date there have been only three documented cases of primary hepatosplenic presentation. This paper reports a fourth case. Due to a review of the literature and the clinical course of the case reported, we conclude that primary hepatosplenic large B-cell lymphoma has been found predominantly in females older than 60 years. The patients reported had <2 months of evolution prior to diagnosis, prominent B symptoms, splenomegaly in three and hepatomegaly in two, none with lymph node involvement. All had thrombocytopenia and abnormal liver function tests; three had anemia and elevated serum lactic dehydrogenase levels, two with hemophagocytosis in bone marrow. Because of the previously mentioned data, it can be stated that primary hepatosplenic lymphoma is an uncommon and aggressive form of disease that requires immediate recognition and treatment.

  17. Chronic Exposure to Malaria Is Associated with Inhibitory and Activation Markers on Atypical Memory B Cells and Marginal Zone-Like B Cells

    Directory of Open Access Journals (Sweden)

    Itziar Ubillos

    2017-08-01

    Full Text Available In persistent infections that are accompanied by chronic immune activation, such as human immunodeficiency virus, hepatitis C virus, and malaria, there is an increased frequency of a phenotypically distinct subset of memory B cells lacking the classic memory marker CD27 and showing a reduced capacity to produce antibodies. However, critical knowledge gaps remain on specific B cell changes and immune adaptation in chronic infections. We hypothesized that expansion of atypical memory B cells (aMBCs and reduction of activated peripheral marginal zone (MZ-like B cells in constantly exposed individuals might be accompanied by phenotypic changes that would confer a tolerogenic profile, helping to establish tolerance to infections. To better understand malaria-associated phenotypic abnormalities on B cells, we analyzed peripheral blood mononuclear cells from 55 pregnant women living in a malaria-endemic area of Papua Nueva Guinea and 9 Spanish malaria-naïve individuals using four 11-color flow cytometry panels. We assessed the expression of markers of B cell specificity (IgG and IgM, activation (CD40, CD80, CD86, b220, TACI, and CD150, inhibition (PD1, CD95, and CD71, and migration (CCR3, CXCR3, and CD62l. We found higher frequencies of active and resting aMBC and marked reduction of MZ-like B cells, although changes in absolute cell counts could not be assessed. Highly exposed women had higher PD1+-, CD95+-, CD40+-, CD71+-, and CD80+-activated aMBC frequencies than non-exposed subjects. Malaria exposure increased frequencies of b220 and proapoptotic markers PD1 and CD95, and decreased expression of the activation marker TACI on MZ-like B cells. The increased frequencies of inhibitory and apoptotic markers on activated aMBCs and MZ-like B cells in malaria-exposed adults suggest an immune-homeostatic mechanism for maintaining B cell development and function while simultaneously downregulating hyperreactive B cells. This mechanism would keep the B cell

  18. Contrasting distributions of groundwater arsenic and uranium in the western Hetao basin, Inner Mongolia: Implication for origins and fate controls

    Science.gov (United States)

    Guo, Huaming; Jia, Yongfeng; Wanty, Richard B.; Jiang, Yuxiao; Zhao, Weiguang; Xiu, Wei; Shen, Jiaxing; Li, Yuan; Cao, Yongsheng; Wu, Yang; Zhang, Di; Wei, Chao; Zhang, Yilong; Cao, Wengeng; Foster, Andrea L.

    2016-01-01

    Although As concentrations have been investigated in shallow groundwater from the Hetao basin, China, less is known about U and As distributions in deep groundwater, which would help to better understand their origins and fate controls. Two hundred and ninety-nine groundwater samples, 122 sediment samples, and 14 rock samples were taken from the northwest portion of the Hetao basin, and analyzed for geochemical parameters. Results showed contrasting distributions of groundwater U and As, with high U and low As concentrations in the alluvial fans along the basin margins, and low U and high As concentrations downgradient in the flat plain. The probable sources of both As and U in groundwater were ultimately traced to the bedrocks in the local mountains (the Langshan Mountains). Chemical weathering of U-bearing rocks (schist, phyllite, and carbonate veins) released and mobilized U as UO2(CO3)22 − and UO2(CO3)34 − species in the alluvial fans under oxic conditions and suboxic conditions where reductions of Mn and NO3− were favorable (OSO), resulting in high groundwater U concentrations. Conversely, the recent weathering of As-bearing rocks (schist, phyllite, and sulfides) led to the formation of As-bearing Fe(III) (hydr)oxides in sediments, resulting in low groundwater As concentrations. Arsenic mobilization and U immobilization occurred in suboxic conditions where reduction of Fe(III) oxides was favorable and reducing conditions (SOR). Reduction of As-bearing Fe(III) (hydr)oxides, which were formed during palaeo-weathering and transported and deposited as Quaternary aquifer sediments, was believed to release As into groundwater. Reduction of U(VI) to U(IV) would lead to the formation of uraninite, and therefore remove U from groundwater. We conclude that the contrasting distributions of groundwater As and U present a challenge to ensuring safe drinking water in analogous areas, especially with high background values of U and As.

  19. B-cell-depleting Therapy in Systemic Lupus Erythematosus

    Science.gov (United States)

    Ramos-Casals, Manuel; Sanz, Iñaki; Bosch, Xavier; Stone, John H.; Khamashta, Munther A.

    2014-01-01

    The emergence of a new class of agents (B-cell-depleting therapies) has opened a new era in the therapeutic approach to systemic lupus erythematosus, with belimumab being the first drug licensed for use in systemic lupus erythematosus in more than 50 years. Four agents deserve specific mention: rituximab, ocrelizumab, epratuzumab, and belimumab. Controlled trials have shown negative results for rituximab, promising results for epratuzumab, and positive results for belimumab. Despite these negative results, rituximab is the most-used agent in patients who do not respond or are intolerant to standard therapy and those with life-threatening presentations. B-cell-depleting agents should not be used in patients with mild disease and should be tailored according to individual patient characteristics, including ethnicity, organ involvement, and the immunological profile. Forthcoming studies of B-cell-directed strategies, particularly data from investigations of off-label rituximab use and postmarketing studies of belimumab, will provide new insights into the utility of these treatments in the routine management of patients with systemic lupus erythematosus. PMID:22444096

  20. Technical Advance: New in vitro method for assaying the migration of primary B cells using an endothelial monolayer as substrate.

    Science.gov (United States)

    Stewart-Hutchinson, Phillip J; Szasz, Taylor P; Jaeger, Emily R; Onken, Michael D; Cooper, John A; Morley, Sharon Celeste

    2017-09-01

    Migration of B cells supports their development and recruitment into functional niches. Therefore, defining factors that control B cell migration will lead to a better understanding of adaptive immunity. In vitro cell migration assays with B cells have been limited by poor adhesion of cells to glass coated with adhesion molecules. We have developed a technique using monolayers of endothelial cells as the substrate for B cell migration and used this technique to establish a robust in vitro assay for B cell migration. We use TNF-α to up-regulate surface expression of the adhesion molecule VCAM-1 on endothelial cells. The ligand VLA-4 is expressed on B cells, allowing them to interact with the endothelial monolayer and migrate on its surface. We tested our new method by examining the role of L-plastin (LPL), an F-actin-bundling protein, in B cell migration. LPL-deficient (LPL -/- ) B cells displayed decreased speed and increased arrest coefficient compared with wild-type (WT) B cells, following chemokine stimulation. However, the confinement ratios for WT and LPL -/- B cells were similar. Thus, we demonstrate how the use of endothelial monolayers as a substrate will support future interrogation of molecular pathways essential to B cell migration. © Society for Leukocyte Biology.

  1. Differential Effects of Tacrolimus versus Sirolimus on the Proliferation, Activation and Differentiation of Human B Cells.

    Directory of Open Access Journals (Sweden)

    Opas Traitanon

    Full Text Available The direct effect of immunosuppressive drugs calcineurin inhibitor (Tacrolimus, TAC and mTOR inhibitor (Sirolimus, SRL on B cell activation, differentiation and proliferation is not well documented. Purified human B cells from healthy volunteers were stimulated through the B Cell Receptor with Anti-IgM + anti-CD40 + IL21 in the absence / presence of TAC or SRL. A variety of parameters of B cell activity including activation, differentiation, cytokine productions and proliferation were monitored by flow cytometry. SRL at clinically relevant concentrations (6 ng/ml profoundly inhibited CD19(+ B cell proliferation compared to controls whereas TAC at similar concentrations had a minimal effect. CD27(+ memory B cells were affected more by SRL than naïve CD27- B cells. SRL effectively blocked B cell differentiation into plasma cells (CD19(+CD138(+ and Blimp1(+/Pax5(low cells even at low dose (2 ng/ml, and totally eliminated them at 6 ng/ml. SRL decreased absolute B cell counts, but the residual responding cells acquired an activated phenotype (CD25(+/CD69(+ and increased the expression of HLA-DR. SRL-treated stimulated B cells on a per cell basis were able to enhance the proliferation of allogeneic CD4(+CD25(- T cells and induce a shift toward the Th1 phenotype. Thus, SRL and TAC have different effects on B lymphocytes. These data may provide insights into the clinical use of these two agents in recipients of solid organ transplants.

  2. Phenotypic and functional heterogeneity of human memory B cells.

    Science.gov (United States)

    Sanz, Iñaki; Wei, Chungwen; Lee, F Eun-Hyung; Anolik, Jennifer

    2008-02-01

    Memory B cells are more heterogeneous than previously thought. Given that B cells play powerful antibody-independent effector functions, it seems reasonable to assume division of labor between distinct memory B cells subpopulations in both protective and pathogenic immune responses. Here we review the information emerging regarding the heterogeneity of human memory B cells. A better understanding of this topic should greatly improve our ability to target specific B cell subsets either in vaccine responses or in autoimmune diseases and organ rejection among other pathological conditions where B cells play central pathogenic roles.

  3. Dynamics of B cells in germinal centres

    Science.gov (United States)

    De Silva, Nilushi S.; Klein, Ulf

    2015-01-01

    Humoral immunity depends on the germinal centre (GC) reaction during which somatically mutated high-affinity memory B cells and plasma cells are generated. Recent studies have uncovered crucial cues that are required for the formation and the maintenance of GCs and for the selection of high-affinity antibody mutants. In addition, it is now clear that these events are promoted by the dynamic movements of cells within and between GCs. These findings have resolved the complexities of the GC reaction in greater detail than ever before. This Review focuses on these recent advances and discusses their implications for the establishment of humoral immunity. PMID:25656706

  4. Chronic B-Cell Leukemias and Agent Orange

    Science.gov (United States)

    ... VA Learning University (VALU) SimLearn Libraries (VALNET) VA Software Documentation Library (VDL) About VHA Learn about VHA Forms & ... B-cell Leukemias and Agent Orange Veterans who develop chronic B-cell leukemias ...

  5. Identification of IFN-γ-producing innate B cells

    National Research Council Canada - National Science Library

    Yan Bao Xingguang Liu Chaofeng Han Sheng Xu Bin Xie Qian Zhang Yan Gu Jin Hou Li Qian Cheng Qian Huanxing Han Xuetao Cao

    2014-01-01

    Although B cells play important roles in the humoral immune response and the regulation of adaptive immunity, B cell subpopulations with unique phenotypes, particularly those with non-classical immune...

  6. Cyclin D3 is selectively required for proliferative expansion of germinal center B cells.

    Science.gov (United States)

    Cato, Matthew H; Chintalapati, Suresh K; Yau, Irene W; Omori, Sidne A; Rickert, Robert C

    2011-01-01

    The generation of robust T-cell-dependent humoral immune responses requires the formation and expansion of germinal center structures within the follicular regions of the secondary lymphoid tissues. B-cell proliferation in the germinal center drives ongoing antigen-dependent selection and the generation of high-affinity class-switched plasma and memory B cells. However, the mechanisms regulating B-cell proliferation within this microenvironment are largely unknown. Here, we report that cyclin D3 is uniquely required for germinal center progression. Ccnd3(-/-) mice exhibit a B-cell-intrinsic defect in germinal center maturation and fail to generate an affinity-matured IgG response. We determined that the defect resulted from failed proliferative expansion of GL7(+) IgD(-) PNA(+) B cells. Mechanistically, sustained expression of cyclin D3 was found to be regulated at the level of protein stability and controlled by glycogen synthase kinase 3 in a cyclic AMP-protein kinase A-dependent manner. The specific defect in proliferative expansion of GL7(+) IgD(-) PNA(+) B cells in Ccnd3(-/-) mice defines an underappreciated step in germinal center progression and solidifies a role for cyclin D3 in the immune response, and as a potential therapeutic target for germinal center-derived B-cell malignancies.

  7. Nitrogen transport within an agricultural landscape: insights on how hydrology, biogeochemistry, and the landscape intersect to control the fate and transport of nitrogen in the Mississippi Delta

    Science.gov (United States)

    Barlow, Jeannie R.; Kröger, Robert

    2014-01-01

    Nitrogen (N) is a ubiquitous contaminant throughout agricultural landscapes due to both the application of inorganic and organic fertilizers to agricultural fields and the general persistence of nitrate (NO3 ) in oxygenated aqueous environments (Denver et al. 2010; Domagalski et al. 2008; Green et al. 2008; Coupe 2001; Nolan and Stoner 2000). In order to understand why excess N occurs various hydrologic systems (environments), it is important to consider potential sources, the locations of these sources in the watershed, and the timing of the application of sources with respect to the movement of water. To learn how to manage N in a watershed, it is necessary to identify and quantify flow paths and biogeochemical conditions, which ultimately combine to determine transport and fate. If sources, transport mechanisms, and biogeochemical controls were uniformly distributed, it would be possible to manage N uniformly throughout a watershed. However, uniform conditions are rare to nonexistent in the natural world and in the landscape altered for agricultural production. In order to adjust management activities on the landscape to have the greatest effect, it is important to understand the fate and transport N within the intersection of hydrology and biogeochemistry, that is, to understand the extent and duration of the hydrologic and biogeochemical controls as N is routed through and among each hydrologic compartment.

  8. Correction of abnormal B-cell subset distribution by interleukin-6 receptor blockade in polymyalgia rheumatica.

    Science.gov (United States)

    Carvajal Alegria, Guillermo; Devauchelle-Pensec, Valérie; Renaudineau, Yves; Saraux, Alain; Pers, Jacques-Olivier; Cornec, Divi

    2017-08-01

    The aim was to study lymphocyte subsets and circulating cytokines at diagnosis of PMR and after tocilizumab monotherapy. Eighteen untreated patients with PMR were included in a prospective study and received 3-monthly tocilizumab infusions without glucocorticoids. Lymphocyte subset distribution was assessed by flow cytometry and serum cytokines were assayed by a 34-cytokine array and ELISA, at baseline and during follow-up. Baseline data were also compared with age- and sex-matched controls. At baseline, total lymphocytes, T-cell subsets and NK cell counts were similar in patients and controls, but patients had significantly lower B-cell counts attributable to lower transitional, naïve and post-switch memory B-cell subsets. Circulating B-cell counts were positively correlated with the PMR activity score (PMR-AS) in untreated active patients at baseline, but subsequently increased to normal values while disease activity was controlled after tocilizumab therapy. Among serum cytokines, IL-6 showed the largest concentration difference between patients and controls, and the serum IL-6 concentration was correlated with baseline PMR-AS. The effects of tocilizumab on serum IL-6 concentration were heterogeneous, and the patients whose serum IL-6 decreased after tocilizumab therapy exhibited a significant increase in circulating B-cell counts. In patients with PMR, B-cell lymphopenia and abnormal B-cell subset distribution are associated with disease activity and IL-6 concentration, and both are corrected by the IL-6 antagonist tocilizumab.

  9. The molecular biology of diffuse large B-cell lymphoma

    OpenAIRE

    Frick, Mareike; Dörken, Bernd; Lenz, Georg

    2011-01-01

    Diffuse large B-cell lymphoma (DLBCL) represents the most common type of malignant lymphoma. In the last few years, significant progress has been achieved in the understanding of the molecular pathogenesis of this entity. Gene expression profiling has identified three molecular DLBCL subtypes, termed germinal-center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). In this review, we summarize our current understanding of the biology o...

  10. Negative signaling in B cells: SHIP Grbs Shc.

    Science.gov (United States)

    Tridandapani, S; Kelley, T; Cooney, D; Pradhan, M; Coggeshall, K M

    1997-09-01

    Negative signaling in B cells is initiated by co-crosslinking of the antigen receptor and the Fcy receptor, resulting in cessation of B-cell signaling events and, in turn, inhibiting B-cell proliferation and antibody secretion. Here, a competitive role is proposed for SHIP in blocking the interaction of Shc with the Grb2-Sos complex of proteins that lead to Ras activation in B cells.

  11. Cell-Cycle-Dependent Reconfiguration of the DNA Methylome during Terminal Differentiation of Human B Cells into Plasma Cells

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    Gersende Caron

    2015-11-01

    Full Text Available Molecular mechanisms underlying terminal differentiation of B cells into plasma cells are major determinants of adaptive immunity but remain only partially understood. Here we present the transcriptional and epigenomic landscapes of cell subsets arising from activation of human naive B cells and differentiation into plasmablasts. Cell proliferation of activated B cells was linked to a slight decrease in DNA methylation levels, but followed by a committal step in which an S phase-synchronized differentiation switch was associated with an extensive DNA demethylation and local acquisition of 5-hydroxymethylcytosine at enhancers and genes related to plasma cell identity. Downregulation of both TGF-β1/SMAD3 signaling and p53 pathway supported this final step, allowing the emergence of a CD23-negative subpopulation in transition from B cells to plasma cells. Remarkably, hydroxymethylation of PRDM1, a gene essential for plasma cell fate, was coupled to progression in S phase, revealing an intricate connection among cell cycle, DNA (hydroxymethylation, and cell fate determination.

  12. B cell lymphoma and myeloma in murine Gaucher's disease

    NARCIS (Netherlands)

    Pavlova, E. V.; Wang, S. Z.; Archer, J.; Dekker, N. [=Nick; Aerts, J. M. F. G.; Karlsson, S.; Cox, T. M.

    2013-01-01

    Multiple myeloma and B cell lymphoma are leading causes of death in Gaucher's disease but the nature of the stimulus driving the often noted clonal expansion of immunoglobulin-secreting B cells and cognate lymphoid malignancy is unknown. We investigated the long-term development of B cell

  13. The induction of CD80 and apoptosis on B cells and CD40L in CD4+ T cells in response to seasonal influenza vaccination distinguishes responders versus non-responders in healthy controls and aviremic ART-treated HIV-infected individuals.

    Science.gov (United States)

    Powell, Anna M; Luo, Zhenwu; Martin, Lisa; Wan, Zhuang; Ma, Lei; Liao, Guoyang; Song, Yuxia; Li, Xiaochun; Michael Kilby, J; Huang, Lei; Jiang, Wei

    2017-02-01

    Studies have shown that HIV infection is associated with an impaired influenza vaccine response. We examined the role of cellular phenotypes and function in influenza vaccine responsiveness in healthy controls and aviremic HIV-infected subjects on antiretroviral treatment (ART). 16 healthy controls and 26 ART+ aviremic HIV+ subjects were enrolled in the current study. Blood was collected at pre-vaccination (D0), and on days 7-10 (D7) and 14-21 (D14) following the 2013-2014 seasonal influenza vaccine administrations. Subjects were classified as responders if neutralizing titers against H1N1 virus increased ⩾4-fold at D14 compared to D0. A serial analysis of B and CD4+ T cell frequencies and activation was performed on D0 and D7 by flow cytometry. 9 of 26 (34.6%) HIV-infected individuals and 7 of 16 (43.8%) healthy controls were classified as responders to influenza vaccines. Total B cell apoptosis (annexin V) was increased on D7 post-vaccination in non-responders but not in responders among both controls and HIV+ subjects. Surface CD80 expression on memory B cells and intracellular CD40L expression on memory CD4+ T cells were induced on D7 in responders of controls but not in non-responders. The CD80 and CD40L induction was not demonstrable in HIV-infected subjects regardless of responders and non-responders. Memory CD4+ T cell cycling tended to increase on D7 in the four study groups but did not achieve significance. All the other parameters were indistinguishable between responders and non-responders, regardless of HIV-infection status. The perturbation of activation and apoptotic induction on B cells or CD4+ T cells after seasonal influenza vaccination in non-responders and HIV-infected subjects may help understand the mechanism of impaired vaccine responsiveness. Copyright © 2016. Published by Elsevier Ltd.

  14. Germinal center B cell depletion diminishes CD4+ follicular T helper cells in autoimmune mice.

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    Isharat Yusuf

    Full Text Available BACKGROUND: Continuous support from follicular CD4(+ T helper (Tfh cells drives germinal center (GC responses, which last for several weeks to produce high affinity memory B cells and plasma cells. In autoimmune Sle1 and NZB/W F1 mice, elevated numbers of Tfh cells persist, promoting the expansion of self-reactive B cells. Expansion of circulating Tfh like cells have also been described in several autoimmune diseases. Although, the signals required for Tfh differentiation have now been well described, the mechanisms that sustain the maintenance of fully differentiated Tfh are less understood. Recent data demonstrate a role for GC B cells for Tfh maintenance after protein immunization. METHODS AND FINDING: Given the pathogenic role Tfh play in autoimmune disease, we explored whether B cells are required for maintenance of autoreactive Tfh. Our data suggest that the number of mature autoreactive Tfh cells is controlled by GC B cells. Depletion of B cells in Sle1 autoimmune mice leads to a dramatic reduction in Tfh cells. In NZB/W F1 autoimmune mice, similar to the SRBC immunization model, GC B cells support the maintenance of mature Tfh, which is dependent mainly on ICOS. The CD28-associated pathway is dispensable for Tfh maintenance in SRBC immunized mice, but is required in the spontaneous NZB/W F1 model. CONCLUSION: These data suggest that mature Tfh cells require signals from GC B cells to sustain their optimal numbers and function in both autoimmune and immunization models. Thus, immunotherapies targeting B cells in autoimmune disease may affect pathogenic Tfh cells.

  15. N-wasp is essential for the negative regulation of B cell receptor signaling.

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    Chaohong Liu

    2013-11-01

    Full Text Available Negative regulation of receptor signaling is essential for controlling cell activation and differentiation. In B-lymphocytes, the down-regulation of B-cell antigen receptor (BCR signaling is critical for suppressing the activation of self-reactive B cells; however, the mechanism underlying the negative regulation of signaling remains elusive. Using genetically manipulated mouse models and total internal reflection fluorescence microscopy, we demonstrate that neuronal Wiskott-Aldrich syndrome protein (N-WASP, which is coexpressed with WASP in all immune cells, is a critical negative regulator of B-cell signaling. B-cell-specific N-WASP gene deletion causes enhanced and prolonged BCR signaling and elevated levels of autoantibodies in the mouse serum. The increased signaling in N-WASP knockout B cells is concurrent with increased accumulation of F-actin at the B-cell surface, enhanced B-cell spreading on the antigen-presenting membrane, delayed B-cell contraction, inhibition in the merger of signaling active BCR microclusters into signaling inactive central clusters, and a blockage of BCR internalization. Upon BCR activation, WASP is activated first, followed by N-WASP in mouse and human primary B cells. The activation of N-WASP is suppressed by Bruton's tyrosine kinase-induced WASP activation, and is restored by the activation of SH2 domain-containing inositol 5-phosphatase that inhibits WASP activation. Our results reveal a new mechanism for the negative regulation of BCR signaling and broadly suggest an actin-mediated mechanism for signaling down-regulation.

  16. Intravascular Large B-Cell Lymphoma

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    Maria S. Khan MD, FACP

    2014-03-01

    Full Text Available Case Presentation. A 69-year-old Hispanic male, with a past history of diabetes and coronary disease, was admitted for fever, diarrhea, and confusion of 4 weeks duration. Physical examination showed a disoriented patient with multiple ecchymoses, possible ascites, and bilateral scrotal swelling. Hemoglobin was 6.7, prothrombin time (PT 21.4 seconds with international normalized ratio 2.1, partial thromboplastin time (PTT 55.6 seconds, fibrin split 10 µg/L, and lactate dehydrogenase (LDH 1231 IU/L. Except for a positive DNA test for Epstein–Barr virus (EBV infection, extensive diagnostic workup for infections, malignancy, or a neurological cause was negative. Mixing studies revealed a nonspecific inhibitor of PT and PTT but Factor VIII levels were normal. The patient was empirically treated with antibiotics but developed hypotension and died on day 27 of admission. At autopsy, patient was found to have intravascular diffuse large B-cell lymphoma involving skin, testes, lung, and muscles. The malignant cells were positive for CD20, CD791, Mum-1, and Pax-5 and negative for CD3, CD5, CD10, CD30, and Bcl-6. The malignant cells were 100% positive for Ki-67. Discussion. Intravascular large cell B-cell lymphoma (IVLBCL is rare form of diffuse large B-cell lymphoma and tends to proliferate within small blood vessels, particularly capillaries and postcapillary venules. The cause of its affinity for vascular bed remains unknown. In many reports, IVLBCL was associated with HIV, HHV8, and EBV infections. The fact that our case showed evidence of EBV infection lends support to the association of this diagnosis to viral illness. The available literature on this subject is scant, and in many cases, the diagnosis was made only at autopsy. The typical presentation of this disorder is with B symptoms, progressive neurologic deficits, and skin findings. Bone marrow, spleen, and liver are involved in a minority of patients. Nearly all patients have elevated LDH

  17. Altered Distribution of Peripheral Blood Maturation-Associated B-Cell Subsets in Chronic Alcoholism.

    Science.gov (United States)

    Almeida, Julia; Polvorosa, Maria Angeles; Gonzalez-Quintela, Arturo; Madruga, Ignacio; Marcos, Miguel; Pérez-Nieto, Maria Angeles; Hernandez-Cerceño, Maria Luisa; Orfao, Alberto; Laso, Francisco Javier

    2015-08-01

    Although decreased counts of peripheral blood (PB) B cells-associated with an apparently contradictory polyclonal hypergammaglobulinemia-have been reported in chronic alcoholism, no information exists about the specific subsets of circulating B cells altered and their relationship with antibody production. Here, we analyzed for the first time the distribution of multiple maturation-associated subpopulations of PB B cells in alcoholism and its potential relationship with the onset of liver disease. PB samples from 35 male patients-20 had alcoholic hepatitis (AH) and 15 chronic alcoholism without liver disease (AWLD)-were studied, in parallel to 19 male healthy donors (controls). The distribution of PB B-cell subsets (immature/regulatory, naïve, CD27(-) and CD27(+) memory B lymphocytes, and circulating plasmablasts of distinct immunoglobulin-Ig-isotypes) was analyzed by flow cytometry. Patients with AH showed significantly decreased numbers of total PB B lymphocytes (vs. controls and AWLD), at the expense of immature, memory, and, to a lesser extent, also naïve B cells. AWLD showed reduced numbers of immature and naïve B cells (vs. controls), but higher PB counts of plasmablasts (vs. the other 2 groups). Although PB memory B cells were reduced among the patients, the percentage of surface (s)IgA(+) cells (particularly CD27(-) /sIgA(+) cells) was increased in AH, whereas both sIgG(+) and sIgA(+) memory B cells were significantly overrepresented in AWLD versus healthy donors. Regarding circulating plasmablasts, patients with AH only showed significantly reduced counts of sIgG(+) cells versus controls. In contrast, the proportion of both sIgA(+) and sIgG(+) plasmablasts-from all plasmablasts-was reduced in AH and increased in AWLD (vs. the other 2 groups). AH and AWLD patients display a significantly reduced PB B-cell count, at the expense of decreased numbers of recently produced immature/regulatory B cells and naïve B cells, together with an increase in Ig

  18. Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming

    NARCIS (Netherlands)

    Kwakkenbos, Mark J.; Diehl, Sean A.; Yasuda, Etsuko; Bakker, Arjen Q.; van Geelen, Caroline M. M.; Lukens, Michaël; van Bleek, Grada M.; Widjojoatmodjo, Myra N.; Bogers, Willy M. J. M.; Mei, Henrik; Radbruch, Andreas; Scheeren, Ferenc A.; Spits, Hergen; Beaumont, Tim

    The B cell lymphoma-6 (Bcl-6) and Bcl-xL proteins are expressed in germinal center B cells and enable them to endure the proliferative and mutagenic environment of the germinal center. By introducing these genes into peripheral blood memory B cells and culturing these cells with two factors produced

  19. Regulators of B-cell activity in SLE : a better target for treatment than B-cell depletion?

    NARCIS (Netherlands)

    Dolff, S.; Abdulahad, W. H.; Bijl, M.; Kallenberg, C. G. M.

    B cells, being a source of characteristic antinuclear autoantibodies, play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). Evidences indicate that alterations in B-cell regulation are responsible for B-cell hyperactivity as seen in SLE. T cells, soluble factors, and even B

  20. Anti-CD20 B-cell depletion enhances monocyte reactivity in neuroimmunological disorders

    Directory of Open Access Journals (Sweden)

    Hohlfeld Reinhard

    2011-10-01

    Full Text Available Abstract Background Clinical trials evaluating anti-CD20-mediated B-cell depletion in multiple sclerosis (MS and neuromyelitis optica (NMO generated encouraging results. Our recent studies in the MS model experimental autoimmune encephalomyelitis (EAE attributed clinical benefit to extinction of activated B-cells, but cautioned that depletion of naïve B-cells may be undesirable. We elucidated the regulatory role of un-activated B-cells in EAE and investigated whether anti-CD20 may collaterally diminish regulatory B-cell properties in treatment of neuroimmunological disorders. Methods Myelin oligodendrocyte glycoprotein (MOG peptide-immunized C57Bl/6 mice were depleted of B-cells. Functional consequences for regulatory T-cells (Treg and cytokine production of CD11b+ antigen presenting cells (APC were assessed. Peripheral blood mononuclear cells from 22 patients receiving anti-CD20 and 23 untreated neuroimmunological patients were evaluated for frequencies of B-cells, T-cells and monocytes; monocytic reactivity was determined by TNF-production and expression of signalling lymphocytic activation molecule (SLAM. Results We observed that EAE-exacerbation upon depletion of un-activated B-cells closely correlated with an enhanced production of pro-inflammatory TNF by CD11b+ APC. Paralleling this pre-clinical finding, anti-CD20 treatment of human neuroimmunological disorders increased the relative frequency of monocytes and accentuated pro-inflammatory monocyte function; when reactivated ex vivo, a higher frequency of monocytes from B-cell depleted patients produced TNF and expressed the activation marker SLAM. Conclusions These data suggest that in neuroimmunological disorders, pro-inflammatory APC activity is controlled by a subset of B-cells which is eliminated concomitantly upon anti-CD20 treatment. While this observation does not conflict with the general concept of B-cell depletion in human autoimmunity, it implies that its safety and

  1. Dmrt5, a Novel Neurogenic Factor, Reciprocally Regulates Lhx2 to Control the Neuron-Glia Cell-Fate Switch in the Developing Hippocampus.

    Science.gov (United States)

    Muralidharan, Bhavana; Keruzore, Marc; Pradhan, Saurabh J; Roy, Basabdatta; Shetty, Ashwin S; Kinare, Veena; D'Souza, Leora; Maheshwari, Upasana; Karmodiya, Krishanpal; Suresh, Agasthya; Galande, Sanjeev; Bellefroid, Eric J; Tole, Shubha

    2017-11-15

    Regulation of the neuron-glia cell-fate switch is a critical step in the development of the CNS. Previously, we demonstrated that Lhx2 is a necessary and sufficient regulator of this process in the mouse hippocampal primordium, such that Lhx2 overexpression promotes neurogenesis and suppresses gliogenesis, whereas loss of Lhx2 has the opposite effect. We tested a series of transcription factors for their ability to mimic Lhx2 overexpression and suppress baseline gliogenesis, and also to compensate for loss of Lhx2 and suppress the resulting enhanced level of gliogenesis in the hippocampus. Here, we demonstrate a novel function of Dmrt5/Dmrta2 as a neurogenic factor in the developing hippocampus. We show that Dmrt5, as well as known neurogenic factors Neurog2 and Pax6, can each not only mimic Lhx2 overexpression, but also can compensate for loss of Lhx2 to different extents. We further uncover a reciprocal regulatory relationship between Dmrt5 and Lhx2, such that each can compensate for loss of the other. Dmrt5 and Lhx2 also have opposing regulatory control on Pax6 and Neurog2, indicating a complex bidirectionally regulated network that controls the neuron-glia cell-fate switch.SIGNIFICANCE STATEMENT We identify Dmrt5 as a novel regulator of the neuron-glia cell-fate switch in the developing hippocampus. We demonstrate Dmrt5 to be neurogenic, and reciprocally regulated by Lhx2: loss of either factor promotes gliogenesis; overexpression of either factor suppresses gliogenesis and promotes neurogenesis; each can substitute for loss of the other. Furthermore, each factor has opposing effects on established neurogenic genes Neurog2 and Pax6 Dmrt5 is known to suppress their expression, and we show that Lhx2 is required to maintain it. Our study reveals a complex regulatory network with bidirectional control of a fundamental feature of CNS development, the control of the production of neurons versus astroglia in the developing hippocampus.Finally, we confirm that Lhx2

  2. Micro RNA-17-92 cluster mediates interleukin-4-suppressed IL-10 expression in B cells.

    Science.gov (United States)

    Liu, Zhi-Qiang; Yang, Gui; Geng, Xiao-Rui; Liu, Jiang-Qi; Mo, Li-Hua; Liu, Zhi-Gang; Yang, Ping-Chang

    2016-01-01

    The pathogenesis of allergen-related inflammation in the intestine is to be further understood. Micro RNA (miR) can regulate immune responses. This study aims to investigate the role of miR-17-92 cluster in the induction of food allergen-related inflammation in the intestine. In this study, a mouse model of food allergen-related intestinal inflammation was developed. Expression of miR-17-92 cluster in B cells of the intestinal mucosa was analyzed by real time quantitative RT-PCR. The results showed that the levels of miR-19a, one of the members of the miR-17-92 cluster, were detected in the B cells of the intestine of mice sensitized to ovalbumin, which was significantly higher than that in naïve control mice. The expression of IL-10 by B cells was significantly lower in the sensitized mice as compared with naive control mice. Exposure to IL-4 in the culture increased the expression of miR-19a as well as suppression the expression of IL-10 in B cells via remolding DNA structure at the IL-10 promoter locus. We conclude that B cells from sensitized mice show higher levels of miR-19a, which plays an important role in the suppression of IL-10 in the B cells.

  3. Enforced expression of the transcriptional coactivator OBF1 impairs B cell differentiation at the earliest stage of development.

    Directory of Open Access Journals (Sweden)

    Alain Bordon

    Full Text Available OBF1, also known as Bob.1 or OCA-B, is a B lymphocyte-specific transcription factor which coactivates Oct1 and Oct2 on B cell specific promoters. So far, the function of OBF1 has been mainly identified in late stage B cell populations. The central defect of OBF1 deficient mice is a severely reduced immune response to T cell-dependent antigens and a lack of germinal center formation in the spleen. Relatively little is known about a potential function of OBF1 in developing B cells. Here we have generated transgenic mice overexpressing OBF1 in B cells under the control of the immunoglobulin heavy chain promoter and enhancer. Surprisingly, these mice have greatly reduced numbers of follicular B cells in the periphery and have a compromised immune response. Furthermore, B cell differentiation is impaired at an early stage in the bone marrow: a first block is observed during B cell commitment and a second differentiation block is seen at the large preB2 cell stage. The cells that succeed to escape the block and to differentiate into mature B cells have post-translationally downregulated the expression of transgene, indicating that expression of OBF1 beyond the normal level early in B cell development is deleterious. Transcriptome analysis identified genes deregulated in these mice and Id2 and Id3, two known negative regulators of B cell differentiation, were found to be upregulated in the EPLM and preB cells of the transgenic mice. Furthermore, the Id2 and Id3 promoters contain octamer-like sites, to which OBF1 can bind. These results provide evidence that tight regulation of OBF1 expression in early B cells is essential to allow efficient B lymphocyte differentiation.

  4. A double blinded, placebo-controlled pilot study to examine reduction of CD34+/CD117+/CD133+ lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma [version 3; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Daisuke Ito

    2017-04-01

    Full Text Available We previously described a population of lymphoid progenitor cells (LPCs in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and “slow proliferation” molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1 used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naïve large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1+ cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting.

  5. A double blinded, placebo-controlled pilot study to examine reduction of CD34+/CD117+/CD133+ lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma [version 2; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Daisuke Ito

    2017-02-01

    Full Text Available We previously described a population of lymphoid progenitor cells (LPCs in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and “slow proliferation” molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1 used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naïve large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1+ cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting.

  6. Human B cells induce dendritic cell maturation and favour Th2 polarization by inducing OX-40 ligand

    Science.gov (United States)

    Maddur, Mohan S.; Sharma, Meenu; Hegde, Pushpa; Stephen-Victor, Emmanuel; Pulendran, Bali; Kaveri, Srini V.; Bayry, Jagadeesh

    2015-01-01

    Dendritic cells (DCs) play a critical role in immune homeostasis by regulating the functions of various immune cells, including T and B cells. Notably, DCs also undergo education on reciprocal signalling by these immune cells and environmental factors. Various reports demonstrated that B cells have profound regulatory functions, although only few reports have explored the regulation of human DCs by B cells. Here we demonstrate that activated but not resting B cells induce maturation of DCs with distinct features to polarize Th2 cells that secrete interleukin (IL)-5, IL-4 and IL-13. B-cell-induced maturation of DCs is contact dependent and implicates signalling of B-cell activation molecules CD69, B-cell-activating factor receptor, and transmembrane activator and calcium-modulating cyclophilin ligand interactor. Mechanistically, differentiation of Th2 cells by B-cell-matured DCs is dependent on OX-40 ligand. Collectively, our results suggest that B cells have the ability to control their own effector functions by enhancing the ability of human DCs to mediate Th2 differentiation. PMID:24910129

  7. Monitoring, chemical fate modelling and uncertainty assessment in combination: a tool for evaluating emission control scenarios for micropollutants in stormwater systems

    DEFF Research Database (Denmark)

    Mikkelsen, Peter Steen; Vezzaro, Luca; Birch, Heidi

    2012-01-01

    management in urban areas, but it is strongly hampered by the general lack of field data on these substances. A framework for combining field monitoring campaigns with dynamic MP modelling tools and statistical methods for uncertainty analysis was hence developed to estimate MP fluxes and fate in stormwater......Stormwater discharges can represent significant sources of micropollutants (MP), including heavy metals and xenobiotic organic compounds that may pose a toxicity risk to aquatic ecosystems. Control of stormwater quality and reduction of MP loads is therefore necessary for a sustainable stormwater...... runoff and treatment systems under sparse data conditions. The framework was applied to an industrial/residential area in the outskirts of Copenhagen (Denmark), where stormwater is discharged in a separate channel system discharging to a wet detention pond. Analysis of economic activities and GIS data...

  8. Role of B cells in host defense against primary Coxiella burnetii infection.

    Science.gov (United States)

    Schoenlaub, Laura; Elliott, Alexandra; Freches, Danielle; Mitchell, William J; Zhang, Guoquan

    2015-12-01

    Despite Coxiella burnetii being an obligate intracellular bacterial pathogen, our recent study demonstrated that B cells play a critical role in vaccine-induced immunity to C. burnetii infection by producing protective antibodies. However, the role of B cells in host defense against primary C. burnetii infection remains unclear. In this study, we investigated whether B cells play an important role in host defense against primary C. burnetii infection. The results showed that peritoneal B cells were able to phagocytose virulent C. burnetii bacteria and form Coxiella-containing vacuoles (CCVs) and that C. burnetii can infect and replicate in peritoneal B1a subset B cells in vitro, demonstrating a potential role for peritoneal B cells in host defense against C. burnetii infection in vivo. In addition, the results showing that B1a cells secreted a high level of interleukin-10 (IL-10) in response to C. burnetii infection in vitro suggest that B1a cells may play an important role in inhibiting the C. burnetii infection-induced inflammatory response. The observation that adoptive transfer of peritoneal B cells did not significantly affect the severity of C. burnetii infection-induced diseases in both severe combined immunity-deficient (SCID) and μMT mice indicates that peritoneal B cells alone may not be able to control C. burnetii infection. In contrast, our finding that C. burnetii infection induced more-severe splenomegaly and a higher bacterial burden in the spleens of B1a cell-deficient Bruton's tyrosine kinase x-linked immunity-deficient (BTK(xid)) mice than in their wild-type counterparts further suggests that B1a cells play an important role in host defense against primary C. burnetii infection. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  9. Distinct cytokines balance the development of regulatory T cells and interleukin-10-producing regulatory B cells

    Science.gov (United States)

    Holan, Vladimir; Zajicova, Alena; Javorkova, Eliska; Trosan, Peter; Chudickova, Milada; Pavlikova, Michaela; Krulova, Magdalena

    2014-01-01

    Regulatory T cells have been well described and the factors regulating their development and function have been identified. Recently, a growing body of evidence has documented the existence of interleukin-10 (IL-10)-producing B cells, which are called regulatory B10 cells. These cells attenuate autoimmune, inflammatory and transplantation reactions, and the main mechanism of their inhibitory action is the production of IL-10. We show that the production of IL-10 by lipopolysaccharide-stimulated B cells is significantly enhanced by IL-12 and interferon-γ and negatively regulated by IL-21 and transforming growth factor-β. In addition, exogenous IL-10 also inhibits B-cell proliferation and the expression of the IL-10 gene in lipopolysaccharide-stimulated B cells. The negative autoregulation of IL-10 production is supported by the observation that the inclusion of anti-IL-10 receptor monoclonal antibody enhances IL-10 production and the proliferation of activated B cells. The effects of cytokines on IL-10 production by B10 cells did not correlate with their effects on B-cell proliferation or on IL-10 production by T cells or macrophages. The cytokine-induced changes in IL-10 production occurred on the level of IL-10 gene expression, as confirmed by increased or decreased IL-10 mRNA expression in the presence of a particular cytokine. The regulatory cytokines modulate the number of IL-10-producing cells rather than augmenting or decreasing the secretion of IL-10 on a single-cell level. Altogether these data show that the production of IL-10 by B cells is under the strict regulatory control of cytokines and that individual cytokines differentially regulate the development and activity of regulatory T cells and IL-10-producing regulatory B cells. PMID:24256319

  10. CRISPR/Cas9-Mediated In Vitro Mutagenesis in GC-Like B Cells.

    Science.gov (United States)

    Chu, Van Trung; Graf, Robin; Rajewsky, Klaus

    2017-01-01

    The CRISPR/Cas9 technology has developed into a powerful tool for genome editing, both in terms of gene silencing and the insertion of precise mutations. However, the application of CRISPR/Cas9-mediated mutagenesis in primary immune cells, in particular in B cells, is still in its infancy because of the difficulty to deliver the CRISPR/Cas9 system into these cells. Here, we describe a new method to use CRISPR/Cas9 for manipulating genes in germinal center (GC)-like B cells in vitro. We isolated Cas9-expressing B cells from R26-Cas9iGFP/+ mice (expressing Cas9 constitutively from the Rosa26 locus) and mixed them with control B cells. Primary B cells were cultured on CD40L- and BAFF-expressing feeder cells and transduced with retroviral particles expressing the sgRNAs of interest. Using this system, we have achieved complete gene knockouts in up to 92% of activated B cells.

  11. Obinutuzumab for B-cell malignancies.

    Science.gov (United States)

    Owen, Carolyn J; Stewart, Douglas A

    2014-08-01

    We analyse data for the use of obinutuzumab in the treatment of CD20(+) lymphoproliferative disorders with a focus on chronic lymphocytic leukaemia (CLL). Targeted therapy against CD20 with the mAb rituximab led to significant improvements in survival for patients with B-cell non-Hodgkin lymphoma (NHL) and is the current mainstay of treatment for CD20(+) malignancies. Despite this, many patients relapse or become refractory after rituximab-containing therapies, so efforts have been made to develop better anti-CD20 mAbs. Obinutuzumab recently demonstrated superiority over rituximab in the only published Phase III study comparing the two antibodies. Obinutuzumab is a humanised, anti-CD20 mAb being compared to rituximab in several Phase III studies. An overview of obinutuzumab, its mechanisms of action and results of Phase I-III studies are presented. The demonstration of superiority of obinutuzumab over rituximab in the CLL11 Phase III study is potentially practice-changing. Obinutuzumab has also proven safe and efficacious in CD20(+) NHL in Phase I/II studies and results of Phase III studies in NHL are eagerly awaited. The potential implications of improved outcomes for CLL and NHL with the introduction of this more potent anti-CD20 antibody are tremendous given the impressive results obtained after the introduction of rituximab over a decade ago.

  12. Adipose Tissue Inflammation Induces B Cell Inflammation and Decreases B Cell Function in Aging

    Directory of Open Access Journals (Sweden)

    Daniela Frasca

    2017-08-01

    Full Text Available Aging is the greatest risk factor for developing chronic diseases. Inflamm-aging, the age-related increase in low-grade chronic inflammation, may be a common link in age-related diseases. This review summarizes recent published data on potential cellular and molecular mechanisms of the age-related increase in inflammation, and how these contribute to decreased humoral immune responses in aged mice and humans. Briefly, we cover how aging and related inflammation decrease antibody responses in mice and humans, and how obesity contributes to the mechanisms for aging through increased inflammation. We also report data in the literature showing adipose tissue infiltration with immune cells and how these cells are recruited and contribute to local and systemic inflammation. We show that several types of immune cells infiltrate the adipose tissue and these include macrophages, neutrophils, NK cells, innate lymphoid cells, eosinophils, T cells, B1, and B2 cells. Our main focus is how the adipose tissue affects immune responses, in particular B cell responses and antibody production. The role of leptin in generating inflammation and decreased B cell responses is also discussed. We report data published by us and by other groups showing that the adipose tissue generates pro-inflammatory B cell subsets which induce pro-inflammatory T cells, promote insulin resistance, and secrete pathogenic autoimmune antibodies.

  13. Imaging B Cells in a Mouse Model of Multiple Sclerosis Using (64)Cu-Rituximab PET.

    Science.gov (United States)

    James, Michelle L; Hoehne, Aileen; Mayer, Aaron T; Lechtenberg, Kendra; Moreno, Monica; Gowrishankar, Gayatri; Ilovich, Ohad; Natarajan, Arutselvan; Johnson, Emily M; Nguyen, Joujou; Quach, Lisa; Han, May; Buckwalter, Marion; Chandra, Sudeep; Gambhir, Sanjiv S

    2017-11-01

    B lymphocytes are a key pathologic feature of multiple sclerosis (MS) and are becoming an important therapeutic target for this condition. Currently, there is no approved technique to noninvasively visualize B cells in the central nervous system (CNS) to monitor MS disease progression and response to therapies. Here, we evaluated (64)Cu-rituximab, a radiolabeled antibody specifically targeting the human B cell marker CD20, for its ability to image B cells in a mouse model of MS using PET. Methods: To model CNS infiltration by B cells, experimental autoimmune encephalomyelitis (EAE) was induced in transgenic mice that express human CD20 on B cells. EAE mice were given subcutaneous injections of myelin oligodendrocyte glycoprotein fragment1-125 emulsified in complete Freund adjuvant. Control mice received complete Freund adjuvant alone. PET imaging of EAE and control mice was performed 1, 4, and 19 h after (64)Cu-rituximab administration. Mice were perfused and sacrificed after the final PET scan, and radioactivity in dissected tissues was measured with a γ-counter. CNS tissues from these mice were immunostained to quantify B cells or were further analyzed via digital autoradiography. Results: Lumbar spinal cord PET signal was significantly higher in EAE mice than in controls at all evaluated time points (e.g., 1 h after injection: 5.44 ± 0.37 vs. 3.33 ± 0.20 percentage injected dose [%ID]/g, P B220 immunostaining verified that increased (64)Cu-rituximab uptake in CNS tissues corresponded with elevated B cells. Conclusion: B cells can be detected in the CNS of EAE mice using (64)Cu-rituximab PET. Results from these studies warrant further investigation of (64)Cu-rituximab in EAE models and consideration of use in MS patients to evaluate its potential for detecting and monitoring B cells in the progression and treatment of this disease. These results represent an initial step toward generating a platform to evaluate B cell-targeted therapeutics en route to the

  14. Transcription Factor Bcl11b Controls Effector and Memory CD8 T cell Fate Decision and Function During Poxvirus Infection

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    Georges Abboud

    2016-10-01

    Full Text Available CD8+ T cells play an important role in host resistance to many viral infections, but the underlying transcriptional mechanisms governing their differentiation and functionality remain poorly defined. By using a highly virulent systemic and respiratory poxvirus infection in mice, we show that the transcription factor Bcl11b provides a dual trigger that sustains the clonal expansion of virus-specific effector CD8+ T cells, while simultaneously suppressing the expression of surface markers associated with short-lived effector cell (SLEC differentiation. Additionally, we demonstrate that Bcl11b supports the acquisition of memory precursor effector cell (MPEC phenotype, and thus its absence causes near complete loss of lymphoid and lung-resident memory cells. Interestingly, despite having normal levels of T-bet and Eomesodermin, Bcl11b-deficient CD8+ T cells failed to execute effector differentiation needed for anti-viral cytokine production and degranulation, suggesting a non-redundant role of Bcl11b in regulation of this program. Thus, Bcl11b is a critical player in fate decision of SLECs and MPECs, as well as effector function and memory formation.

  15. Focal adhesion kinase protein regulates Wnt3a gene expression to control cell fate specification in the developing neural plate

    Science.gov (United States)

    Fonar, Yuri; Gutkovich, Yoni E.; Root, Heather; Malyarova, Anastasia; Aamar, Emil; Golubovskaya, Vita M.; Elias, Sarah; Elkouby, Yaniv M.; Frank, Dale

    2011-01-01

    Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase protein localized to regions called focal adhesions, which are contact points between cells and the extracellular matrix. FAK protein acts as a scaffold to transfer adhesion-dependent and growth factor signals into the cell. Increased FAK expression is linked to aggressive metastatic and invasive tumors. However, little is known about its normal embryonic function. FAK protein knockdown during early Xenopus laevis development anteriorizes the embryo. Morphant embryos express increased levels of anterior neural markers, with reciprocally reduced posterior neural marker expression. Posterior neural plate folding and convergence-extension is also inhibited. This anteriorized phenotype resembles that of embryos knocked down zygotically for canonical Wnt signaling. FAK and Wnt3a genes are both expressed in the neural plate, and Wnt3a expression is FAK dependent. Ectopic Wnt expression rescues this FAK morphant anteriorized phenotype. Wnt3a thus acts downstream of FAK to balance anterior–posterior cell fate specification in the developing neural plate. Wnt3a gene expression is also FAK dependent in human breast cancer cells, suggesting that this FAK–Wnt linkage is highly conserved. This unique observation connects the FAK- and Wnt-signaling pathways, both of which act to promote cancer when aberrantly activated in mammalian cells. PMID:21551070

  16. Identification of highly methylated genes across various types of B-cell non-hodgkin lymphoma.

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    Nicole Bethge

    Full Text Available Epigenetic alterations of gene expression are important in the development of cancer. In this study, we identified genes which are epigenetically altered in major lymphoma types. We used DNA microarray technology to assess changes in gene expression after treatment of 11 lymphoma cell lines with epigenetic drugs. We identified 233 genes with upregulated expression in treated cell lines and with downregulated expression in B-cell lymphoma patient samples (n = 480 when compared to normal B cells (n = 5. The top 30 genes were further analyzed by methylation specific PCR (MSP in 18 lymphoma cell lines. Seven of the genes were methylated in more than 70% of the cell lines and were further subjected to quantitative MSP in 37 B-cell lymphoma patient samples (diffuse large B-cell lymphoma (activated B-cell like and germinal center B-cell like subtypes, follicular lymphoma and Burkitt`s lymphoma and normal B lymphocytes from 10 healthy donors. The promoters of DSP, FZD8, KCNH2, and PPP1R14A were methylated in 28%, 67%, 22%, and 78% of the 36 tumor samples, respectively, but not in control samples. Validation using a second series of healthy donor controls (n = 42; normal B cells, peripheral blood mononuclear cells, bone marrow, tonsils and follicular hyperplasia and fresh-frozen lymphoma biopsies (n = 25, confirmed the results. The DNA methylation biomarker panel consisting of DSP, FZD8, KCNH2, and PPP1R14A was positive in 89% (54/61 of all lymphomas. Receiver operating characteristic analysis to determine the discriminative power between lymphoma and healthy control samples showed a c-statistic of 0.96, indicating a possible role for the biomarker panel in monitoring of lymphoma patients.

  17. Evaluate and Characterize Mechanisms Controlling Transport, Fate, and Effects of Army Smokes in the Aerosol Wind Tunnel

    Science.gov (United States)

    1987-10-01

    NH. - Time (hr) Control Smoke Control Smoke Control Smoke -.------..--.--.---------.------.------ ppo N03" (a) --------------------------------- 15...MICROBIOLOGICAL CONVERSION OF AMMONIUM TO NO2 " Amended sol 1 Unamended soil 50 ppm NH 500 ppm NH Time (hr) Control Smoke Control Smoke Control Smoke -(a) S

  18. Dissecting teleost B cell differentiation using transcription factors.

    Science.gov (United States)

    Zwollo, Patty

    2011-09-01

    B cell developmental pathways in teleost fishes are poorly understood. In the absence of serological reagents, an alternative approach to dissecting teleost B cell development is to use transcription factors that are differentially expressed during B cell development. This review discusses the structure and function of six transcription factors that play essential roles during teleost B cell development: Ikaros, E2A, EBF, Pax5, Blimp1, and XbpI. Research on alternative splicing of both the Ikaros and Pax5 genes in rainbow trout is presented, including their functional significance. An application is discussed that should aid in elucidating teleost B cell development and activation, by using transcription factors as developmental markers in flow cytometric analysis. Possible future studies in teleost B cell development are suggested in the context of gene regulation. Lastly, broader impacts and practical applications are discussed. Copyright © 2011 Elsevier Ltd. All rights reserved.

  19. Characterization of the B cell response to Leishmania infection after anti-CD20 B cell depletion.

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    Bockenstedt, Marie M; Boggiatto, Paola M; Jones, Douglas E

    2015-01-01

    Anti-CD20 depletion therapies targeting B cells are commonly used in malignant B cell disease and autoimmune diseases. There are concerns about the ability of B cells to respond to infectious diseases acquired either before or after B cell depletion. There is evidence that the B cell response to existing or acquired viral infections is compromised during treatment, as well as the antibody response to vaccination. Our laboratory has an experimental system using co-infection of C3H mice with both Leishmania major and Leishmania amazonensis that suggests that the B cell response is important to healing infected mice. We tested if anti-CD20 treatment would completely restrict the B cell response to these intracellular pathogens. Infected mice that received anti-CD20 B cell depletion therapy had a significant decrease in CD19(+) cells within their lymph nodes and spleens. However, splenic B cells were detected in depleted mice and an antigen-specific antibody response was produced. These results indicate that an antigen-specific B cell response towards intracellular pathogens can be generated during anti-CD20 depletion therapy.

  20. B-cell lymphopoiesis is regulated by cathepsin L.

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    Maria Noel Badano

    Full Text Available Cathepsin L (CTSL is a ubiquitously expressed lysosomal cysteine peptidase with diverse and highly specific functions. The involvement of CTSL in thymic CD4+ T-cell positive selection has been well documented. Using CTSL(nkt/nkt mice that lack CTSL activity, we have previously demonstrated that the absence of CTSL activity affects the homeostasis of the T-cell pool by decreasing CD4+ cell thymic production and increasing CD8+ thymocyte production. Herein we investigated the influence of CTSL activity on the homeostasis of peripheral B-cell populations and bone marrow (BM B-cell maturation. B-cell numbers were increased in lymph nodes (LN, spleen and blood from CTSL (nkt/nkt mice. Increases in splenic B-cell numbers were restricted to transitional T1 and T2 cells and to the marginal zone (MZ cell subpopulation. No alterations in the proliferative or apoptosis levels were detected in peripheral B-cell populations from CTSL (nkt/nkt mice. In the BM, the percentage and the absolute number of pre-pro-B, pro-B, pre-B, immature and mature B cells were not altered. However, in vitro and in vivo experiments showed that BM B-cell production was markedly increased in CTSL (nkt/nkt mice. Besides, BM B-cell emigration to the spleen was increased in CTSL (nkt/nkt mice. Colony-forming unit pre-B (CFU pre-B assays in the presence of BM stromal cells (SC and reciprocal BM chimeras revealed that both BM B-cell precursors and SC would contribute to sustain the increased B-cell hematopoiesis in CTSL (nkt/nkt mice. Overall, our data clearly demonstrate that CTSL negatively regulates BM B-cell production and output therefore influencing the homeostasis of peripheral B cells.

  1. B-cell subpopulations in children: National reference values.

    Science.gov (United States)

    Duchamp, Marie; Sterlin, Delphine; Diabate, Aminata; Uring-Lambert, Béatrice; Guérin-El Khourouj, Valérie; Le Mauff, Brigitte; Monnier, Delphine; Malcus, Christophe; Labalette, Myriam; Picard, Capucine

    2014-11-01

    Peripheral B-lymphocytes undergo a series of changes during the first few years of life. Encounters with foreign antigens lead to maturation and differentiation. Several primary antibody deficiencies (PADs) affecting B-cell development are associated with abnormalities in the composition and/or differentiation of B-cell compartments. The most recent international classifications of primary immunodeficiencies (PIDs) and common variable immunodeficiencies (CVID) have highlighted the importance of B-cell immunophenotyping and age-specific reference intervals for diagnostic purposes. We established national reference values for memory B-cell subpopulations, on the basis of CD27 and surface IgD expression in the peripheral blood of 242 healthy children. We report here the absolute counts and percentages of naive, switched and non-switched memory B-cells for seven age groups, from neonates to adults. We found that the naive B-cells percentage declined between the ages of 6 months and 8 years, after which it remained stable at about 70-80%. Memory B-cells are already present at birth and their numbers increase throughout childhood, stabilizing between the ages of 12 and 18 years. The definition of reference intervals for pediatric B-cell levels should facilitate the screening and diagnosis of various B-cell immunodeficiencies. This multicenter study, providing national reference values, should thus facilitate immunological diagnosis in children.

  2. B cells as a target of immune modulation

    Directory of Open Access Journals (Sweden)

    Hawker Kathleen

    2009-01-01

    Full Text Available B cells have recently been identified as an integral component of the immune system; they play a part in autoimmunity through antigen presentation, antibody secretion, and complement activation. Animal models of multiple sclerosis (MS suggest that myelin destruction is partly mediated through B cell activation (and plasmablasts. MS patients with evidence of B cell involvement, as compared to those without, tend to have a worse prognosis. Finally, the significant decrease in new gadolinium-enhancing lesions, new T2 lesions, and relapses in MS patients treated with rituximab (a monoclonal antibody against CD20 on B cells leads us to the conclusion that B cells play an important role in MS and that immune modulation of these cells may ameliorate the disease. This article will explore the role of B cells in MS and the rationale for the development of B cell-targeted therapeutics. MS is an immune-mediated disease that affects over 2 million people worldwide and is the number one cause of disability in young patients. Most therapeutic targets have focused on T cells; however, recently, the focus has shifted to the role of B cells in the pathogenesis of MS and the potential of B cells as a therapeutic target.

  3. B Cell Depletion: Rituximab in Glomerular Disease and Transplantation

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    S. Marinaki

    2013-12-01

    Full Text Available B cells play a central role in the pathogenesis of many autoimmune diseases. Selective targeting can be achieved with the use of the monoclonal antibody rituximab. In addition to being a drug for non-Hodgkin's lymphoma, rituximab is also an FDA-approved treatment for refractory rheumatoid arthritis and, since recently, ANCA vasculitis. It has shown efficacy in many autoimmune diseases. This review will discuss current evidence and the rationale of the use of rituximab in glomerular diseases, including randomized controlled trials. The focus will be on the use of rituximab in idiopathic membranous nephropathy, systemic lupus erythematosus and ANCA-associated vasculitis. The emerging role of rituximab in renal transplantation, where it seems to be important for the desensitization protocols for highly sensitized patients as well as for the preconditioning of ABO-incompatible recipients and the treatment of antibody-mediated rejection, will also be addressed.

  4. Quality control of Photosystem II: reversible and irreversible protein aggregation decides the fate of Photosystem II under excessive illumination

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    Yasusi eYamamoto

    2013-10-01

    Full Text Available In response to excessive light, the thylakoid membranes of higher plant chloroplasts show dynamic changes including the degradation and reassembly of proteins, a change in the distribution of proteins, and large-scale structural changes such as unstacking of the grana. Here, we examined the aggregation of light-harvesting chlorophyll-protein complexes and Photosystem II core subunits of spinach thylakoid membranes under light stress with 77K chlorophyll fluorescence; aggregation of these proteins was found to proceed with increasing light intensity. Measurement of changes in the fluidity of thylakoid membranes with fluorescence polarization of diphenylhexatriene showed that membrane fluidity increased at a light intensity of 500–1,000 µmol photons m-2 s-1, and decreased at very high light intensity (1,500 µmol photons m-2 s-1. The aggregation of light-harvesting complexes at moderately high light intensity is known to be reversible, while that of Photosystem II core subunits at extremely high light intensity is irreversible. It is likely that the reversibility of protein aggregation is closely related to membrane fluidity: increases in fluidity should stimulate reversible protein aggregation, whereas irreversible protein aggregation might decrease membrane fluidity. When spinach leaves were pre-illuminated with moderately high light intensity, the qE component of non-photochemical quenching and the optimum quantum yield of Photosystem II increased, indicating that Photosystem II/ light-harvesting complexes rearranged in the thylakoid membranes to optimize Photosystem II activity. Transmission electron microscopy revealed that the thylakoids underwent partial unstacking under these light stress conditions. Thus, protein aggregation is involved in thylakoid dynamics and regulates photochemical reactions, thereby deciding the fate of Photosystem II.

  5. Deletion of Rb1 induces both hyperproliferation and cell death in murine germinal center B cells.

    Science.gov (United States)

    He, Zhiwen; O'Neal, Julie; Wilson, William C; Mahajan, Nitin; Luo, Jun; Wang, Yinan; Su, Mack Y; Lu, Lan; Skeath, James B; Bhattacharya, Deepta; Tomasson, Michael H

    2016-03-01

    The retinoblastoma gene (RB1) has been implicated as a tumor suppressor in multiple myeloma (MM), yet its role remains unclear because in the majority of cases with 13q14 deletions, un-mutated RB1 remains expressed from the retained allele. To explore the role of Rb1 in MM, we examined the functional consequences of single- and double-copy Rb1 loss in germinal center B cells, the cells of origin of MM. We generated mice without Rb1 function in germinal center B cells by crossing Rb1(Flox/Flox) with C-γ-1-Cre (Cγ1) mice expressing the Cre recombinase in class-switched B cells in a p107(-/-) background to prevent p107 from compensating for Rb1 loss (Cγ1-Rb1(F/F)-p107(-/-)). All mice developed normally, but B cells with two copies of Rb1 deleted (Cγ1-Rb1(F/F)-p107(-/-)) exhibited increased proliferation and cell death compared with Cγ1-Rb1(+/+)-p107(-/-) controls ex vivo. In vivo, Cγ1-Rb1(F/F)-p107(-/-) mice had a lower percentage of splenic B220+ cells and reduced numbers of bone marrow antigen-specific secreting cells compared with control mice. Our data indicate that Rb1 loss induces both cell proliferation and death in germinal center B cells. Because no B-cell malignancies developed after 1 year of observation, our data also suggest that Rb1 loss is not sufficient to transform post-germinal center B cells and that additional, specific mutations are likely required to cooperate with Rb1 loss to induce malignant transformation. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  6. Dysfunction of CD24+CD38+ B cells in patients with Hashimoto's thyroiditis is associated with a lack of interleukin 10.

    Science.gov (United States)

    Yu, Shanshan; Qi, Yanhua; Wang, Hua; Jiang, Jue; Sun, Lei; Zhou, Qi

    2017-09-01

    Autoimmune thyroid disease (AITD) is characterized by immune attacks on the person's own thyroid. Hashimoto's thyroiditis (HT) is a subtype of AITD and is a common cause of hypothyroidism and related symptoms. Regulatory B (Breg) cells can express interleukin 10 (IL-10) and have recently emerged as a critical participant in suppression pathogenic inflammation and promoting peripheral tolerance. The role of Breg cells in HT is not yet clear. In this study, we first examined the IL-10 production by B cells in healthy controls and HT patients, and found that the healthy control B cells demonstrated significantly higher IL-10 expression than HT B cells after CpG stimulation. In both groups, the IL-10-producing B cells were highly enriched in the CD24 + CD38 + compartment. However, compared to healthy controls, HT patients presented higher levels of circulating CD24 + CD38 + B cells, but lower percentage of IL-10 + cells in the CD24 + CD38 + B cell compartment. In healthy controls, we performed coculture experiments of T cells with autologous total B cells, CD24 + CD38 + B cells, and non-CD24 + CD38 + B cells, and found significantly lower T cell proliferation as well as tumor necrosis factor (TNF) and interferon gamma (IFN-γ) production in cell cultures containing CD24 + CD38 + B cells. In contrast, the HT CD24 + CD38 + B cells demonstrated reduced capacity in suppressing T cell proliferation and did not suppress TNF and IFN-γ production. This lack of inhibitory activity in HT CD24 + CD38 + B cells was related to a lack of IL-10, since addition of exogenous IL-10 in CD24 + CD38 + B cell-T cell coculture significantly suppressed the proliferation of T cells and reduced proinflammatory cytokine secretion. Together, our study identified an upregulation of CD24 + CD38 + B cells but a downregulation in their regulatory activity in HT patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Pro-B cells propagated in stromal cell-free cultures reconstitute functional B-cell compartments in immunodeficient mice.

    Science.gov (United States)

    von Muenchow, Lilly; Tsapogas, Panagiotis; Albertí-Servera, Llucia; Capoferri, Giuseppina; Doelz, Marianne; Rolink, Hannie; Bosco, Nabil; Ceredig, Rhodri; Rolink, Antonius G

    2017-02-01

    Up to now long-term in vitro growth of pro-B cells was thought to require stromal cells. However, here we show that fetal liver (FL) and bone marrow (BM) derived pro-B cells can be propagated long-term in stromal cell-free cultures supplemented with IL-7, stem cell factor and FLT3 ligand. Within a week, most cells expressed surface CD19, CD79A, λ5, and VpreB antigens and had rearranged immunoglobulin D-J heavy chain genes. Both FL and BM pro-B cells reconstituted the B-cell compartments of immuno-incompetent Rag2-deficient mice, with FL pro-B cells generating follicular, marginal zone (MZB) and B1a B cells, and BM pro-B cells giving rise mainly to MZB cells. Reconstituted Rag2-deficient mice generated significant levels of IgM and IgG antibodies to a type II T-independent antigen; mice reconstituted with FL pro-B cells generated surprisingly high IgG1 titers. Finally, we show for the first time that mice reconstituted with mixtures of pro-B and pro-T cells propagated in stromal cell-free in vitro cultures mounted a T-cell-dependent antibody response. This novel stromal cell-free culture system facilitates our understanding of B-cell development and might be applied clinically. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Mediastinal B-cell lymphoma, a lymphoma type with several characteristics unique among diffuse large B-cell lymphomas.

    Science.gov (United States)

    Barth, T F; Leithäuser, F; Möller, P

    2001-01-01

    Mediastinal B-cell lymphoma is a locally highly aggressive tumor with a rather unique pattern of clinical, morphologic, imunologic, and genetic features distinct from other diffuse large B-cell lymphomas. Characterization of this disease has been hampered by the relatively low incidence of this lymphoma type. Although recent studies on larger numbers of cases have allowed new insights into biology and clinics of this lymphoma type, the histogenesis of mediastinal B-cell lymphoma is not yet fully understood. This review will list morphologic, immunlogic, and genetic properties of mediastinal B-cell lymphoma and discuss recent data regarding the biology of this lymphoma type.

  9. Tissue-specific B-cell dysfunction and generalized memory B-cell loss during acute SIV infection.

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    Sandrine Peruchon

    Full Text Available BACKGROUND: Primary HIV-infected patients display severe and irreversible damage to different blood B-cell subsets which is not restored by highly efficient anti-retroviral therapy (HAART. Because longitudinal investigations of primary HIV-infection is limited by the availability of lymphoid organs, we studied the tissue-specific B-cell dysfunctions in acutely simian immunodeficiency virus (SIV mac251-infected Cynomolgus macaques. METHODS AND FINDINGS: Experiments were performed on three groups of macaques infected for 14, 21 or 28 days and on three groups of animals treated with HAART for two-weeks either initiated at 4 h, 7 or 14 days post-infection (p.i.. We have simultaneously compared changes in B-cell phenotypes and functions and tissue organization of B-cell areas in various lymphoid organs. We showed that SIV induced a steady decline in SIgG-expressing memory (SIgD(-CD27(+ B-cells in spleen and lymph nodes during the first 4 weeks of infection, concomitant to selective homing/sequestration of B-cells to the small intestine and spleen. SIV non-specific Ig production was transiently increased before D14p.i., whereas SIV-specific Ig production was only detectable after D14p.i., coinciding with the presence of CD8(+ T-cells and IgG-expressing plasma cells within germinal centres. Transient B-cell apoptosis on D14p.i. and commitment to terminal differentiation contributed to memory B-cell loss. HAART abrogated B-cell apoptosis, homing to the small intestine and SIV-specific Ig production but had minimal effect on early Ig production, increased B-cell proportions in spleen and loss of memory B-cells. Therefore, virus-B-cell interactions and SIV-induced inflammatory cytokines may differently contribute to early B-cell dysfunction and impaired SIV/HIV-specific antibody response. CONCLUSIONS: These data establish tissue-specific impairments in B-cell trafficking and functions and a generalized and steady memory B-cell loss in secondary lymphoid

  10. Paradoxical aging in HIV: immune senescence of B Cells is most prominent in young age.

    Science.gov (United States)

    Rinaldi, Stefano; Pallikkuth, Suresh; George, Varghese K; de Armas, Lesley R; Pahwa, Rajendra; Sanchez, Celeste M; Pallin, Maria Fernanda; Pan, Li; Cotugno, Nicola; Dickinson, Gordon; Rodriguez, Allan; Fischl, Margaret; Alcaide, Maria; Gonzalez, Louis; Palma, Paolo; Pahwa, Savita

    2017-04-01

    Combination antiretroviral therapies (cART)can lead to normal life expectancy in HIV-infected persons, and people aged >50 yrs represent the fastest growing HIV group. Although HIV and aging are independently associated with impaired humoral immunity, immune status in people aging with HIV is relatively unexplored. In this study influenza vaccination was used to probe age associated perturbations in the B cell compartment of HIV-negative "healthy controls" (HC) and virologically controlled HIV-infected participants on cART (HIV) (n=124), grouped by age as young (aged (40-59yrs) or old ( > 60 yrs). H1N1 antibody response at d21 post-vaccination correlated inversely with age in both HC and HIV. Immunophenotyping of cryopreserved PBMC demonstrated increased frequencies of double negative B cells and decreased plasmablasts in old compared to young HC. Remarkably, young HIV were different from young HC but similar to old HC in B cell phenotype, influenza specific spontaneous (d7) or memory (d21) antibody secreting cells. We conclude that B cell immune senescence is a prominent phenomenon in young HIV in comparison to young HC, but distinctions between old HIV and old HC are less evident though both groups manifest age-associated B cell dysfunction.

  11. T Follicular Helper Cells and B Cell Dysfunction in Aging and HIV-1 Infection

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    Suresh Pallikkuth

    2017-10-01

    Full Text Available T follicular helper (Tfh cells are a subset of CD4 T cells that provide critical signals to antigen-primed B cells in germinal centers to undergo proliferation, isotype switching, and somatic hypermutation to generate long-lived plasma cells and memory B cells during an immune response. The quantity and quality of Tfh cells therefore must be tightly controlled to prevent immune dysfunction in the form of autoimmunity and, on the other hand, immune deficiency. Both Tfh and B cell perturbations appear during HIV infection resulting in impaired antibody responses to vaccines such as seasonal trivalent influenza vaccine, also seen in biologic aging. Although many of the HIV-associated defects improve with antiretroviral therapy (ART, excess immune activation and antigen-specific B and T cell responses including Tfh function are still impaired in virologically controlled HIV-infected persons on ART. Interestingly, HIV infected individuals experience increased risk of age-associated pathologies. This review will discuss Tfh and B cell dysfunction in HIV infection and highlight the impact of chronic HIV infection and aging on Tfh–B cell interactions.

  12. A Network Model to Describe the Terminal Differentiation of B Cells.

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    Akram Méndez

    2016-01-01

    Full Text Available Terminal differentiation of B cells is an essential process for the humoral immune response in vertebrates and is achieved by the concerted action of several transcription factors in response to antigen recognition and extracellular signals provided by T-helper cells. While there is a wealth of experimental data regarding the molecular and cellular signals involved in this process, there is no general consensus regarding the structure and dynamical properties of the underlying regulatory network controlling this process. We developed a dynamical model of the regulatory network controlling terminal differentiation of B cells. The structure of the network was inferred from experimental data available in the literature, and its dynamical behavior was analyzed by modeling the network both as a discrete and a continuous dynamical systems. The steady states of these models are consistent with the patterns of activation reported for the Naive, GC, Mem, and PC cell types. Moreover, the models are able to describe the patterns of differentiation from the precursor Naive to any of the GC, Mem, or PC cell types in response to a specific set of extracellular signals. We simulated all possible single loss- and gain-of-function mutants, corroborating the importance of Pax5, Bcl6, Bach2, Irf4, and Blimp1 as key regulators of B cell differentiation process. The model is able to represent the directional nature of terminal B cell differentiation and qualitatively describes key differentiation events from a precursor cell to terminally differentiated B cells.

  13. Bidirectional regulation between B cells and T cells

    NARCIS (Netherlands)

    Margry, B.

    2014-01-01

    B cells were often thought of as simple precursors of end-stage effector cells that are merely in charge of antibody production. Research in the last decades has shown that B cells possess important other roles as well, including their involvement in the regulation and functioning of T cell-mediated

  14. DNA breaks early in replication in B cell cancers

    Science.gov (United States)

    Research by scientists at the NCI has identified a new class of DNA sites in cells that break early in the replication process. They found that these break sites correlate with damage often seen in B cell cancers, such as diffuse large B cell lymphoma.

  15. In Silico Prediction Analysis of Idiotope-Driven T–B Cell Collaboration in Multiple Sclerosis

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    Rune A. Høglund

    2017-10-01

    Full Text Available Memory B cells acting as antigen-presenting cells are believed to be important in multiple sclerosis (MS, but the antigen they present remains unknown. We hypothesized that B cells may activate CD4+ T cells in the central nervous system of MS patients by presenting idiotopes from their own immunoglobulin variable regions on human leukocyte antigen (HLA class II molecules. Here, we use bioinformatics prediction analysis of B cell immunoglobulin variable regions from 11 MS patients and 6 controls with other inflammatory neurological disorders (OINDs, to assess whether the prerequisites for such idiotope-driven T–B cell collaboration are present. Our findings indicate that idiotopes from the complementarity determining region (CDR 3 of MS patients on average have high predicted affinities for disease associated HLA-DRB1*15:01 molecules and are predicted to be endosomally processed by cathepsin S and L in positions that allows such HLA binding to occur. Additionally, complementarity determining region 3 sequences from cerebrospinal fluid (CSF B cells from MS patients contain on average more rare T cell-exposed motifs that could potentially escape tolerance and stimulate CD4+ T cells than CSF B cells from OIND patients. Many of these features were associated with preferential use of the IGHV4 gene family by CSF B cells from MS patients. This is the first study to combine high-throughput sequencing of patient immune repertoires with large-scale prediction analysis and provides key indicators for future in vitro and in vivo analyses.

  16. A Novel VHH Antibody Targeting the B Cell-Activating Factor for B-Cell Lymphoma

    Directory of Open Access Journals (Sweden)

    Wen Wu

    2014-05-01

    Full Text Available Objective: To construct an immune alpaca phage display library, in order to obtain a single domain anti-BAFF (B cell-activating factor antibody. Methods: Using phage display technology, we constructed an immune alpaca phage display library, selected anti-BAFF single domain antibodies (sdAbs, cloned three anti-BAFF single-domain antibody genes into expression vector pSJF2, and expressed them efficiently in Escherichia coli. The affinity of different anti-BAFF sdAbs were measured by Bio layer interferometry. The in vitro biological function of three sdAbs was investigated by cell counting kit-8 (CCK-8 assay and a competitive enzyme-linked immunosorbent assay (ELISA. Results: We obtained three anti-BAFF single domain antibodies (anti-BAFF64, anti-BAFF52 and anti-BAFFG3, which were produced in high yield in Escherichia coli and inhibited tumor cell proliferation in vitro. Conclusion: The selected anti-BAFF antibodies could be candidates for B-cell lymphoma therapies.

  17. Regulatory functions of innate-like B cells

    Science.gov (United States)

    Zhang, Xiaoming

    2013-01-01

    Innate-like B cells (ILBs) are heterogeneous populations of unconventional B cells with innate sensing and responding properties. ILBs in mice are composed of B1 cells, marginal zone (MZ) B cells and other related B cells. ILBs maintain natural IgM levels at steady state, and after innate activation, they can rapidly acquire immune regulatory activities through the secretion of natural IgM and IL-10. Thus, ILBs constitute an important source of IL-10-producing regulatory B cells (Bregs), which have been shown to play critical roles in autoimmunity, inflammation and infection. The present review highlights the latest advances in the field of ILBs and focuses on their regulatory functions. Understanding the regulatory activities of ILBs and their underlying mechanisms could open new avenues in manipulating their functions in inflammatory, infectious and other relevant diseases. PMID:23396472

  18. Thymic B cells and central T cell tolerance

    Directory of Open Access Journals (Sweden)

    Ludger eKlein

    2015-07-01

    Full Text Available Central T cell tolerance is believed to be mainly induced by thymic dendritic cells and medullary thymic epithelial cells. The thymus also harbors substantial numbers of B cells. These may arise though intrathymic B lymphopoiesis or immigration from the bloodstream. Importantly, and in contrast to resting ‘mainstream’ B cells in the periphery, thymic B cells display elevated levels of MHC class II and constitutively express CD80. Arguably their most unexpected feature is the expression of Aire. These unique features of thymic B cells result from a licensing process that involves cross-talk with CD4 single-positive T cells and CD40 signaling. Together, these recent findings suggest that B cells play a more prominent role as thymic APCs than previously appreciated.

  19. The Deadly Dance of B Cells with Trypanosomatids.

    Science.gov (United States)

    Silva-Barrios, Sasha; Charpentier, Tania; Stäger, Simona

    2017-10-28

    B cells are notorious actors for the host's protection against several infectious diseases. So much so that early vaccinology seated its principles upon their long-term protective antibody secretion capabilities. Indeed, there are many examples of acute infectious diseases that are combated by functional humoral responses. However, some chronic infectious diseases actively induce immune deregulations that often lead to defective, if not deleterious, humoral immune responses. In this review we summarize how Leishmania and Trypanosoma spp. directly manipulate B cell responses to induce polyclonal B cell activation, hypergammaglobulinemia, low-specificity antibodies, limited B cell survival, and regulatory B cells, contributing therefore to immunopathology and the establishment of persistent infections. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Non-CpG Oligonucleotides Exert Adjuvant Effects by Enhancing Cognate B Cell-T Cell Interactions, Leading to B Cell Activation, Differentiation, and Isotype Switching

    Directory of Open Access Journals (Sweden)

    Melinda Herbáth

    2015-01-01

    Full Text Available Natural and synthetic nucleic acids are known to exert immunomodulatory properties. Notably, nucleic acids are known to modulate immune function via several different pathways and various cell types, necessitating a complex interpretation of their effects. In this study we set out to compare the effects of a CpG motif containing oligodeoxynucleotide (ODN with those of a control and an inhibitory non-CpG ODN during cognate B cell-T cell interactions. We employed an antigen presentation system using splenocytes from TCR transgenic DO11.10 mice and the ovalbumin peptide recognized by the TCR as model antigen. We followed early activation events by measuring CD69 expression, late activation by MHC class II expression, cell division and antibody production of switched, and nonswitched isotypes. We found that both of the tested non-CpG ODN exerted significant immunomodulatory effects on early T cell and on late B cell activation events. Importantly, a synergism between non-CpG effects and T cell help acting on B cells was observed, resulting in enhanced IgG production following cognate T cell-B cell interactions. We propose that non-CpG ODN may perform as better adjuvants when a strong antigen-independent immune activation, elicited by CpG ODNs, is undesirable.

  1. Non-CpG Oligonucleotides Exert Adjuvant Effects by Enhancing Cognate B Cell-T Cell Interactions, Leading to B Cell Activation, Differentiation, and Isotype Switching

    Science.gov (United States)

    Herbáth, Melinda; Papp, Krisztián; Erdei, Anna; Prechl, József

    2015-01-01

    Natural and synthetic nucleic acids are known to exert immunomodulatory properties. Notably, nucleic acids are known to modulate immune function via several different pathways and various cell types, necessitating a complex interpretation of their effects. In this study we set out to compare the effects of a CpG motif containing oligodeoxynucleotide (ODN) with those of a control and an inhibitory non-CpG ODN during cognate B cell-T cell interactions. We employed an antigen presentation system using splenocytes from TCR transgenic DO11.10 mice and the ovalbumin peptide recognized by the TCR as model antigen. We followed early activation events by measuring CD69 expression, late activation by MHC class II expression, cell division and antibody production of switched, and nonswitched isotypes. We found that both of the tested non-CpG ODN exerted significant immunomodulatory effects on early T cell and on late B cell activation events. Importantly, a synergism between non-CpG effects and T cell help acting on B cells was observed, resulting in enhanced IgG production following cognate T cell-B cell interactions. We propose that non-CpG ODN may perform as better adjuvants when a strong antigen-independent immune activation, elicited by CpG ODNs, is undesirable. PMID:26380319

  2. A Positive Regulatory Loop between a Wnt-Regulated Non-coding RNA and ASCL2 Controls Intestinal Stem Cell Fate

    Directory of Open Access Journals (Sweden)

    Antonis Giakountis

    2016-06-01

    Full Text Available The canonical Wnt pathway plays a central role in stem cell maintenance, differentiation, and proliferation in the intestinal epithelium. Constitutive, aberrant activity of the TCF4/β-catenin transcriptional complex is the primary transforming factor in colorectal cancer. We identify a nuclear long non-coding RNA, termed WiNTRLINC1, as a direct target of TCF4/β-catenin in colorectal cancer cells. WiNTRLINC1 positively regulates the expression of its genomic neighbor ASCL2, a transcription factor that controls intestinal stem cell fate. WiNTRLINC1 interacts with TCF4/β-catenin to mediate the juxtaposition of its promoter with the regulatory regions of ASCL2. ASCL2, in turn, regulates WiNTRLINC1 transcriptionally, closing a feedforward regulatory loop that controls stem cell-related gene expression. This regulatory circuitry is highly amplified in colorectal cancer and correlates with increased metastatic potential and decreased patient survival. Our results uncover the interplay between non-coding RNA-mediated regulation and Wnt signaling and point to the diagnostic and therapeutic potential of WiNTRLINC1.

  3. Human memory B cells isolated from blood and tonsils are functionally distinctive.

    Science.gov (United States)

    Pérez, M Eugenia; Billordo, Luis Ariel; Baz, Plácida; Fainboim, Leonardo; Arana, Eloisa

    2014-11-01

    Human B-cell studies in vitro have routinely used B lymphocytes purified from spleen, blood or tonsils irrespective of potential differences in their immunological traits. In this study, we compared the functional responses of total (CD19(+)) and memory B cells (Bmem; CD19(+)/CD27(+)) isolated from blood and tonsils to different stimuli. Peripheral B cells showed enhanced survival and proliferation compared with their tonsillar equivalents when stimulated for 10 days. Stimulated B cells from both tissues secreted significantly greater amounts of cytokines than unstimulated controls demonstrating their functional responsiveness. Analysis of CD27 expression over time indicated that the conditions that promoted survival and proliferation of peripheral Bmem, caused massive tonsillar Bmem death. Purified tonsillar Bmem failed to expand but rapidly differentiated in antibody secreting cells and subsequently underwent apoptosis. In contrast, circulating Bmem showed delayed activation and differentiation, but exhibited a longer lifespan and active proliferation. In addition, short-term stimulation of tonsillar Bmem resulted in the production of more immunoglobulin G (IgG) than their peripheral counterparts. At later time points, however, IgG production from the different B cells was reversed. Our findings imply that the tissue located and peripheral Bmem have distinct behaviors, indicating organ dependent functional responses that should not be generalizable to all Bmem. This work provides a greater understanding of how Bmem location is coupled to specialized roles of B lymphocytes.

  4. Human herpesvirus-8 infection leads to expansion of the preimmune/natural effector B cell compartment.

    Directory of Open Access Journals (Sweden)

    Silvia Della Bella

    Full Text Available BACKGROUND: Human herpesvirus-8 (HHV-8 is the etiological agent of Kaposi's sarcoma (KS and of some lymphoproliferative disorders of B cells. Most malignancies develop after long-lasting viral dormancy, and a preventing role for both humoral and cellular immune control is suggested by the high frequency of these pathologies in immunosuppressed patients. B cells, macrophages and dendritic cells of peripheral lymphoid organs and blood represent the major reservoir of HHV-8. Due to the dual role of B cells in HHV-8 infection, both as virus reservoir and as agents of humoral immune control, we analyzed the subset distribution and the functional state of peripheral blood B cells in HHV-8-infected individuals with and without cKS. METHODOLOGY/PRINCIPAL FINDINGS: Circulating B cells and their subsets were analyzed by 6-color flow cytometry in the following groups: 1- patients HHV-8 positive with classic KS (cKS (n = 47; 2- subjects HHV-8 positive and cKS negative (HSP (n = 10; 3- healthy controls, HHV-8 negative and cKS negative (HC (n = 43. The number of B cells belonging to the preimmune/natural effector compartment, including transitional, pre-naïve, naïve and MZ-like subsets, was significantly higher among HHV-8 positive subjects, with or without cKS, while was comparable to healthy controls in the antigen-experienced T-cell dependent compartment. The increased number of preimmune/natural effector B cells was associated with increased resistance to spontaneous apoptosis, while it did not correlate with HHV-8 viral load. CONCLUSIONS/SIGNIFICANCE: Our results indicate that long-lasting HHV-8 infection promotes an imbalance in peripheral B cell subsets, perturbing the equilibrium between earlier and later steps of maturation and activation processes. This observation may broaden our understanding of the complex interplay between viral and immune factors leading HHV-8-infected individuals to develop HHV-8-associated malignancies.

  5. Metabolic changes during B cell differentiation for the production of intestinal IgA antibody.

    Science.gov (United States)

    Kunisawa, Jun

    2017-04-01

    To sustain the bio-energetic demands of growth, proliferation, and effector functions, the metabolism of immune cells changes dramatically in response to immunologic stimuli. In this review, I focus on B cell metabolism, especially regarding the production of intestinal IgA antibody. Accumulating evidence has implicated not only host-derived factors (e.g., cytokines) but also gut environmental factors, including the possible involvement of commensal bacteria and diet, in the control of B cell metabolism during intestinal IgA antibody production. These findings yield new insights into the regulation of immunosurveillance and homeostasis in the gut.

  6. Cell Fate Decision Making through Oriented Cell Division

    Science.gov (United States)

    Johnston, Christopher A.

    2016-01-01

    The ability to dictate cell fate decisions is critical during animal development. Moreover, faithful execution of this process ensures proper tissue homeostasis throughout adulthood, whereas defects in the molecular machinery involved may contribute to disease. Evolutionarily conserved protein complexes control cell fate decisions across diverse tissues. Maintaining proper daughter cell inheritance patterns of these determinants during mitosis is therefore a fundamental step of the cell fate decision-making process. In this review, we will discuss two key aspects of this fate determinant segregation activity, cortical cell polarity and mitotic spindle orientation, and how they operate together to produce oriented cell divisions that ultimately influence daughter cell fate. Our focus will be directed at the principal underlying molecular mechanisms and the specific cell fate decisions they have been shown to control. PMID:26844213

  7. Comparison of EBV DNA viral load in whole blood, plasma, B-cells and B-cell culture supernatant.

    Science.gov (United States)

    Ouedraogo, David Eric; Bollore, Karine; Viljoen, Johannes; Foulongne, Vincent; Reynes, Jacques; Cartron, Guillaume; Vendrell, Jean-Pierre; Van de Perre, Philippe; Tuaillon, Edouard

    2014-05-01

    Epstein-Barr virus (EBV) genome quantitation in whole blood is used widely for therapeutic monitoring of EBV-associated disorders in immunosuppressed individuals and in patients with EBV-associated lymphoma. However, the most appropriate biological material to be used for EBV DNA quantitation remains a subject of debate. This study compare the detection rate and levels of EBV DNA from whole blood, plasma, enriched B-cells, and B-cell short-term culture supernatant using quantitative real-time PCR. Samples were collected from 33 subjects with either HIV infection or B-cell lymphoma. Overall, EBV DNA was detected in 100% of enriched B-cell samples, in 82% of B-cell culture supernatants, in 57% of plasma, and 42% of whole blood samples. A significant correlation for EBV viral load was found between enriched B-cell and B-cell culture supernatant material (ρ = 0.92; P cells (ρ = -0.02; P = 0.89), whole blood and plasma (ρ = 0.24; P = 0.24), or enriched B-cells and plasma (ρ = 0.08; P = 0.77). Testing of enriched B-cells appeared to be the most sensitive method for detection of EBV DNA as well as for exploration of the cellular reservoir. Quantitation of EBV DNA in plasma and B-cell culture supernatant may be of interest to assess EBV reactivation dynamics and response to treatment as well as to decipher EBV host-pathogen interactions in various clinical scenarios. © 2013 Wiley Periodicals, Inc.

  8. Exploiting human memory B cell heterogeneity for improved vaccine efficacy.

    Science.gov (United States)

    Pauli, Noel T; Henry Dunand, Carole J; Wilson, Patrick C

    2011-01-01

    The major goal in vaccination is establishment of long-term, prophylactic humoral memory to a pathogen. Two major components to long-lived humoral memory are plasma cells for the production of specific immunoglobulin and memory B cells that survey for their specific antigen in the periphery for later affinity maturation, proliferation, and differentiation. The study of human B cell memory has been aided by the discovery of a general marker for B cell memory, expression of CD27; however, new data suggests the existence of CD27⁻ memory B cells as well. These recently described non-canonical memory populations have increasingly pointed to the heterogeneity of the memory compartment. The novel B memory subsets in humans appear to have unique origins, localization, and functions compared to what was considered to be a "classical" memory B cell. In this article, we review the known B cell memory subsets, the establishment of B cell memory in vaccination and infection, and how understanding these newly described subsets can inform vaccine design and disease treatment.

  9. Exploiting human memory B cell heterogeneity for improved vaccine efficacy

    Directory of Open Access Journals (Sweden)

    Noel Thomas Pauli

    2011-12-01

    Full Text Available The major goal in vaccination is establishment of long-term, prophylactic humoral memory to a pathogen. Two major components to long-lived humoral memory are plasma cells for the production of specific immunoglobulin and memory B cells that survey for their specific antigen in the periphery for later affinity maturation, proliferation, and differentiation. The study of human B cell memory has been aided by the discovery of a general marker for B cell memory, expression of CD27; however, new data suggests the existence of CD27- memory B cells as well. These recently described non-canonical memory populations have increasingly pointed to the heterogeneity of the memory compartment. The novel B memory subsets in humans appear to have unique origins, localization, and functions compared to what was considered to be a classical memory B cell. In this article, we review the known B cell memory subsets, the establishment of B cell memory in vaccination and infection, and how understanding these newly described subsets can inform vaccine design and disease treatment.

  10. YY1 Is Required for Germinal Center B Cell Development.

    Science.gov (United States)

    Banerjee, Anupam; Sindhava, Vishal; Vuyyuru, Raja; Jha, Vibha; Hodewadekar, Suchita; Manser, Tim; Atchison, Michael L

    2016-01-01

    YY1 has been implicated as a master regulator of germinal center B cell development as YY1 binding sites are frequently present in promoters of germinal center-expressed genes. YY1 is known to be important for other stages of B cell development including the pro-B and pre-B cells stages. To determine if YY1 plays a critical role in germinal center development, we evaluated YY1 expression during B cell development, and used a YY1 conditional knock-out approach for deletion of YY1 in germinal center B cells (CRE driven by the immunoglobulin heavy chain γ1 switch region promoter; γ1-CRE). We found that YY1 is most highly expressed in germinal center B cells and is increased 3 fold in splenic B cells activated by treatment with anti-IgM and anti-CD40. In addition, deletion of the yy1 gene by action of γ1-CRE recombinase resulted in significant loss of GC cells in both un-immunized and immunized contexts with corresponding loss of serum IgG1. Our results show a crucial role for YY1 in the germinal center reaction.

  11. The Relationship Between B-Cell Epitope and Mimotope Sequences

    Science.gov (United States)

    Zhang, Chunhua; Li, Yunyun; Tang, Weina; Zhou, Zhiguo; Sun, Pingping; Ma, Zhiqiang

    2016-01-01

    B-cell epitope is a group of residues which is on the surface of an antigen. It invokes humoral responses. Locating B-cell epitope is important for effective vaccine design, and the development of diagnostic reagents. Mimotope-based B-cell epitope prediction method is a kind of conformational B-cell epitope prediction, and the core idea of the method is mapping the mimotope sequences which are obtained from a random phage display library. However, current mimotope-based B-cell epitope prediction methods cannot maintain a high degree of satisfaction in the circumstances of employing only mimotope sequences. In this study, we did a multi-perspective analysis on parameters for conformational B-cell epitopes and characteristics between epitope and mimotope on a benchmark datasets which contains 67 mimotope sets, corresponding to 40 unique complex structures. In these 67 cases, there are 25 antigen-antibody complexes and 42 protein-protein interactions. We analyzed the two parts separately. The results showed the mimotope sequences do have some epitope features, but there are also some epitope properties that mimotope sequences do not contain. In addition, the numbers of epitope segments with different lengths were obviously different between the antigen-antibody complexes and the protein-protein interactions. This study reflects how similar do mimotope sequence and genuine epitopes have; and evaluates existing mimotope-based B-cell epitope prediction methods from a novel viewpoint. PMID:26715528

  12. Regulatory B cells in autoimmune diseases and mucosal immune homeostasis

    Science.gov (United States)

    LI, XIAOXIAO; BRAUN, JONATHAN; WEI, BO

    2013-01-01

    B lymphocytes contribute to physiological immunity through organogenesis of secondary lymphoid organs, presentation of antigen to T cells, production of antibodies, and secretion of cytokines. Their role in several autoimmune diseases, mainly as producers of pathogenic antibodies, is also well known. However, certain subsets of B cells are emerging as the important regulatory cell populations in both mouse and human. The regulatory functions of B cells have been demonstrated in a variety of mouse models of autoimmune diseases including collagen-induced arthritis (CIA), experiment autoimmune encephalomyelitis (EAE), anterior chamber-associated immune deviation (ACAID), diabetes, contact hypersensitivity (CHS), and intestinal mucosal inflammation. Accumulating evidence from both mouse and human studies confirms the existence of regulatory B cells, and is beginning to define their mechanisms of action. In this article, we first review the history of B cells with regulatory function in autoimmune diseases, and summarize the current understanding about the characterizations of such B-cell subsets. We then discuss the possible regulatory mechanisms of B cells, and specifically define the role of regulatory B cells in immune homeostasis in the intestine. PMID:20701454

  13. Identifying activated T cells in reconstituted RAG deficient mice using retrovirally transduced Pax5 deficient pro-B cells.

    Directory of Open Access Journals (Sweden)

    Nadesan Gajendran

    Full Text Available Various methods have been used to identify activated T cells such as binding of MHC tetramers and expression of cell surface markers in addition to cytokine-based assays. In contrast to these published methods, we here describe a strategy to identify T cells that respond to any antigen and track the fate of these activated T cells. We constructed a retroviral double-reporter construct with enhanced green fluorescence protein (EGFP and a far-red fluorescent protein from Heteractis crispa (HcRed. LTR-driven EGFP expression was used to enrich and identify transduced cells, while HcRed expression is driven by the CD40Ligand (CD40L promoter, which is inducible and enables the identification and cell fate tracing of T cells that have responded to infection/inflammation. Pax5 deficient pro-B cells that can give rise to different hematopoietic cells like T cells, were retrovirally transduced with this double-reporter cassette and were used to reconstitute the T cell pool in RAG1 deficient mice that lack T and B cells. By using flow cytometry and histology, we identified activated T cells that had developed from Pax5 deficient pro-B cells and responded to infection with the bacterial pathogen Listeria monocytogenes. Microscopic examination of organ sections allowed visual identification of HcRed-expressing cells. To further characterize the immune response to a given stimuli, this strategy can be easily adapted to identify other cells of the hematopoietic system that respond to infection/inflammation. This can be achieved by using an inducible reporter, choosing the appropriate promoter, and reconstituting mice lacking cells of interest by injecting gene-modified Pax5 deficient pro-B cells.

  14. Human Memory B Cells in Healthy Gingiva, Gingivitis, and Periodontitis.

    Science.gov (United States)

    Mahanonda, Rangsini; Champaiboon, Chantrakorn; Subbalekha, Keskanya; Sa-Ard-Iam, Noppadol; Rattanathammatada, Warattaya; Thawanaphong, Saranya; Rerkyen, Pimprapa; Yoshimura, Fuminobu; Nagano, Keiji; Lang, Niklaus P; Pichyangkul, Sathit

    2016-08-01

    The presence of inflammatory infiltrates with B cells, specifically plasma cells, is the hallmark of periodontitis lesions. The composition of these infiltrates in various stages of homeostasis and disease development is not well documented. Human tissue biopsies from sites with gingival health (n = 29), gingivitis (n = 8), and periodontitis (n = 21) as well as gingival tissue after treated periodontitis (n = 6) were obtained and analyzed for their composition of B cell subsets. Ag specificity, Ig secretion, and expression of receptor activator of NF-κB ligand and granzyme B were performed. Although most of the B cell subsets in healthy gingiva and gingivitis tissues were CD19(+)CD27(+)CD38(-) memory B cells, the major B cell component in periodontitis was CD19(+)CD27(+)CD38(+)CD138(+)HLA-DR(low) plasma cells, not plasmablasts. Plasma cell aggregates were observed at the base of the periodontal pocket and scattered throughout the gingiva, especially apically toward the advancing front of the lesion. High expression of CXCL12, a proliferation-inducing ligand, B cell-activating factor, IL-10, IL-6, and IL-21 molecules involved in local B cell responses was detected in both gingivitis and periodontitis tissues. Periodontitis tissue plasma cells mainly secreted IgG specific to periodontal pathogens and also expressed receptor activator of NF-κB ligand, a bone resorption cytokine. Memory B cells resided in the connective tissue subjacent to the junctional epithelium in healthy gingiva. This suggested a role of memory B cells in maintaining periodontal homeostasis. Copyright © 2016 by The American Association of Immunologists, Inc.

  15. Adult survivors of invasive pneumococcal disease exhibit defective B cell function.

    Science.gov (United States)

    Darton, Tom C; Wing, James B; Lees, Andrew; Heath, Andrew W; Read, Robert C

    2011-05-01

    Adults who have recovered from an episode of invasive pneumococcal disease demonstrate defective B cell activation in response to αδ-dex, a polyclonal polysaccharide mimic, compared with matched control subjects. The defect is not overcome by CD4(+) T cell assistance and may explain the relatively poor response to pneumococcal vaccination in survivors of invasive pneumococcal disease.

  16. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma

    NARCIS (Netherlands)

    Cerhan, James R.; Berndt, Sonja I.; Vijai, Joseph; Ghesquières, Hervé; McKay, James; Wang, Sophia S.; Wang, Zhaoming; Yeager, Meredith; Conde, Lucia; De Bakker, Paul I W; Nieters, Alexandra; Cox, David; Burdett, Laurie; Monnereau, Alain; Flowers, Christopher R.; De Roos, Anneclaire J.; Brooks-Wilson, Angela R.; Lan, Qing; Severi, Gianluca; Melbye, Mads; Gu, Jian; Jackson, Rebecca D.; Kane, Eleanor; Teras, Lauren R.; Purdue, Mark P.; Vajdic, Claire M.; Spinelli, John J.; Giles, Graham G.; Albanes, Demetrius; Kelly, Rachel S.; Zucca, Mariagrazia; Bertrand, Kimberly A.; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Hutchinson, Amy; Zhi, Degui; Habermann, Thomas M.; Link, Brian K.; Novak, Anne J.; Dogan, Ahmet; Asmann, Yan W.; Liebow, Mark; Thompson, Carrie A.; Ansell, Stephen M.; Witzig, Thomas E.; Weiner, George J.; Veron, Amelie S.; Zelenika, Diana; Tilly, Hervé; Haioun, Corinne; Molina, Thierry Jo; Hjalgrim, Henrik; Glimelius, Bengt; Adami, Hans Olov; Bracci, Paige M.; Riby, Jacques; Smith, Martyn T.; Holly, Elizabeth A.; Cozen, Wendy; Hartge, Patricia; Morton, Lindsay M.; Severson, Richard K.; Tinker, Lesley F.; North, Kari E.; Becker, Nikolaus; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; Staines, Anthony; Lightfoot, Tracy; Crouch, Simon; Smith, Alex; Roman, Eve; Diver, W. Ryan; Offit, Kenneth; Zelenetz, Andrew; Klein, Robert J.; Villano, Danylo J.; Zheng, Tongzhang; Zhang, Yawei; Holford, Theodore R.; Kricker, Anne; Turner, Jenny; Southey, Melissa C.; Clavel, Jacqueline; Virtamo, Jarmo; Weinstein, Stephanie; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Trichopoulos, Dimitrios; Vermeulen, Roel C H; Boeing, Heiner; Tjonneland, Anne; Angelucci, Emanuele; Di Lollo, Simonetta; Rais, Marco; Birmann, Brenda M.; Laden, Francine; Giovannucci, Edward; Kraft, Peter; Huang, Jinyan; Ma, Baoshan; Ye, Yuanqing; Chiu, Brian C H; Sampson, Joshua; Liang, Liming; Park, Ju Hyun; Chung, Charles C.; Weisenburger, Dennis D.; Chatterjee, Nilanjan; Fraumeni, Joseph F.; Slager, Susan L.; Wu, Xifeng; De Sanjose, Silvia; Smedby, Karin E.; Salles, Gilles; Skibola, Christine F.; Rothman, Nathaniel; Chanock, Stephen J.

    2014-01-01

    Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of

  17. Chemokine receptor expression on B cells and effect of interferon-beta in multiple sclerosis

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke; Roed, Hanne; Sellebjerg, Finn

    2002-01-01

    We investigated the B-cell expression of chemokine receptors CXCR3, CXCR5 and CCR5 in the blood and cerebrospinal fluid (CSF) from patients in relapse of multiple sclerosis (MS) and in neurological controls. Chemokine receptor expression was also studied in interferon-beta-treated patients with r...

  18. The acquisition of cytokine responsiveness by murine B cells

    DEFF Research Database (Denmark)

    Poudrier, J; Owens, T

    1994-01-01

    The mechanism whereby small resting (high buoyant density) murine B cells are induced to express interleukin-2 receptors (IL-2R) and to respond to IL-2 was addressed by staining with anti-IL-2R alpha and -IL-2R beta monoclonal antibodies (mAb), and using receptor-specific cDNA probes. Resting B c......-5 and LPS for B-cell responses shows a requirement for complementary stimuli such as would be provided by cytokines, and either cellular interaction or antigen recognition in regulation of B-cell responsiveness to IL-2....

  19. Lineage, Fate, and Fate Potential of NG2-glia

    Science.gov (United States)

    Nishiyama, Akiko; Boshans, Linda; Goncalves, Christopher M.; Wegrzyn, Jill; Patel, Kiran D.

    2015-01-01

    NG2 cells represent a fourth major glial cell population in the mammalian central nervous system (CNS). They arise from discrete germinal zones in mid-gestation embryos and expand to occupy the entire CNS parenchyma. Genetic fate mapping studies have shown that oligodendrocytes and a subpopulation of ventral protoplasmic astrocytes arise from NG2 cells. This review describes recent findings on the fate and fate potential of NG2 cells under physiological and pathological conditions. We discuss age-dependent changes in the fate and fate potential of NG2 cells and possible mechanisms that could be involved in restricting their oligodendrocyte differentiation or fate plasticity. PMID:26301825

  20. Extended B cell phenotype in patients with myalgic encephalomyelitis/chronic fatigue syndrome: a cross‐sectional study

    Science.gov (United States)

    Mensah, F.; Bansal, A.; Berkovitz, S.; Sharma, A.; Reddy, V.; Leandro, M. J.

    2016-01-01

    Summary Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous condition of unknown aetiology characterized by multiple symptoms including fatigue, post‐exertional malaise and cognitive impairment, lasting for at least 6 months. Recently, two clinical trials of B cell depletion therapy with rituximab (anti‐CD20) reported convincing improvement in symptoms. A possible but undefined role for B cells has therefore been proposed. Studies of the relative percentages of B cell subsets in patients with ME/CFS have not revealed any reproducible differences from healthy controls (HC). In order to explore whether more subtle alterations in B cell subsets related to B cell differentiation exist in ME/CFS patients we used flow cytometry to immunophenotype CD19+ B cells. The panel utilized immunoglobulin (Ig)D, CD27 and CD38 (classical B cell subsets) together with additional markers. A total of 38 patients fulfilling Canadian, Centre for Disease Control and Fukuda ME/CFS criteria and 32 age‐ and sex‐matched HC were included. We found no difference in percentages of classical subsets between ME/CFS patients and HC. However, we observed an increase in frequency (P 20%) was associated with the presence of ME/CFS [odds ratio: 3·47 (1·15–10·46); P = 0·03] compared with HC, and there was a negative correlation with disease duration. In conclusion, we identified possible changes in B cell phenotype in patients with ME/CFS. These may reflect altered B cell function and, if confirmed in other patient cohorts, could provide a platform for studies based on clinical course or responsiveness to rituximab therapy. PMID:26646713

  1. Extended B cell phenotype in patients with myalgic encephalomyelitis/chronic fatigue syndrome: a cross-sectional study.

    Science.gov (United States)

    Mensah, F; Bansal, A; Berkovitz, S; Sharma, A; Reddy, V; Leandro, M J; Cambridge, G

    2016-05-01

    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous condition of unknown aetiology characterized by multiple symptoms including fatigue, post-exertional malaise and cognitive impairment, lasting for at least 6 months. Recently, two clinical trials of B cell depletion therapy with rituximab (anti-CD20) reported convincing improvement in symptoms. A possible but undefined role for B cells has therefore been proposed. Studies of the relative percentages of B cell subsets in patients with ME/CFS have not revealed any reproducible differences from healthy controls (HC). In order to explore whether more subtle alterations in B cell subsets related to B cell differentiation exist in ME/CFS patients we used flow cytometry to immunophenotype CD19⁺ B cells. The panel utilized immunoglobulin (Ig)D, CD27 and CD38 (classical B cell subsets) together with additional markers. A total of 38 patients fulfilling Canadian, Centre for Disease Control and Fukuda ME/CFS criteria and 32 age- and sex-matched HC were included. We found no difference in percentages of classical subsets between ME/CFS patients and HC. However, we observed an increase in frequency (P 20%) was associated with the presence of ME/CFS [odds ratio: 3·47 (1·15-10·46); P = 0·03] compared with HC, and there was a negative correlation with disease duration. In conclusion, we identified possible changes in B cell phenotype in patients with ME/CFS. These may reflect altered B cell function and, if confirmed in other patient cohorts, could provide a platform for studies based on clinical course or responsiveness to rituximab therapy. © 2016 British Society for Immunology.

  2. Overexpression of Fc receptor-like 1 associated with B-cell activation during hepatitis B virus infection

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    Ke Wang

    2012-12-01

    Full Text Available The role of B cells in the pathogenesis of hepatitis B virus (HBV infection has not been explored in depth. In the present study, the activation status of B cells from peripheral blood of healthy controls (N = 20 and patients with acute hepatitis B (AHB, N = 15 or chronic hepatitis B (CHB, N = 30 was evaluated by measuring the expression levels of B-cell activation markers CD69 and CD86, using quantitative real-time PCR and flow cytometry. Moreover, the potential mechanism underlying B-cell activation during HBV infection was further investigated by analyzing the expression profile of FCRL1, an intrinsic activation molecule of B cells. An elevation in the levels of B-cell activation markers including CD69 and CD86 was observed in the AHB patients (44.31 ± 9.27, 27.64 ± 9.26% compared to CHB patients (30.35 ± 11.27, 18.41 ± 6.56%, P < 0.05, which was still higher than healthy controls (12.23 ± 7.84, 8.22 ± 3.43%, P < 0.05. Furthermore, the expression of FCRL1 was found to be similar to B-cell activation markers, which was highest in AHB patients (70.15 ± 17.11%, lowest in healthy donors (36.32 ± 9.98%, P < 0.05 and half-way between these levels in patients with CHB (55.17 ± 12.03%, P < 0.05. The results were positively associated with aberrant B-cell activation. These data suggest that B cells can play a role in HBV infection, and therefore more effort should be devoted to exploring their functions.

  3. Overexpression of Fc receptor-like 1 associated with B-cell activation during hepatitis B virus infection

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    Wang, Ke [Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu Province (China); Pei, Hao [Wuxi Hospital of Infectious Disease, Wuxi, Jiangsu Province (China); Huang, Biao; Yang, Run-Lin [Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu Province (China); Wu, Hang-Yuan [Wuxi Hospital of Infectious Disease, Wuxi, Jiangsu Province (China); Zhu, Xue; Zhu, Lan [Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu Province (China)

    2012-08-17

    The role of B cells in the pathogenesis of hepatitis B virus (HBV) infection has not been explored in depth. In the present study, the activation status of B cells from peripheral blood of healthy controls (N = 20) and patients with acute hepatitis B (AHB, N = 15) or chronic hepatitis B (CHB, N = 30) was evaluated by measuring the expression levels of B-cell activation markers CD69 and CD86, using quantitative real-time PCR and flow cytometry. Moreover, the potential mechanism underlying B-cell activation during HBV infection was further investigated by analyzing the expression profile of FCRL1, an intrinsic activation molecule of B cells. An elevation in the levels of B-cell activation markers including CD69 and CD86 was observed in the AHB patients (44.31 ± 9.27, 27.64 ± 9.26%) compared to CHB patients (30.35 ± 11.27, 18.41 ± 6.56%, P < 0.05), which was still higher than healthy controls (12.23 ± 7.84, 8.22 ± 3.43%, P < 0.05). Furthermore, the expression of FCRL1 was found to be similar to B-cell activation markers, which was highest in AHB patients (70.15 ± 17.11%), lowest in healthy donors (36.32 ± 9.98%, P < 0.05) and half-way between these levels in patients with CHB (55.17 ± 12.03%, P < 0.05). The results were positively associated with aberrant B-cell activation. These data suggest that B cells can play a role in HBV infection, and therefore more effort should be devoted to exploring their functions.

  4. COMPUTATION MODELING OF TCDD DISRUPTION OF B CELL TERMINAL DIFFERENTIATION

    Science.gov (United States)

    In this study, we established a computational model describing the molecular circuit underlying B cell terminal differentiation and how TCDD may affect this process by impinging upon various molecular targets.

  5. Tertiary lymphoid structure-associated B cells are key players in anti-tumor immunity

    Directory of Open Access Journals (Sweden)

    Claire eGermain

    2015-02-01

    Full Text Available It is now admitted that the immune system plays a major role in tumor control. Besides the existence of tumor-specific T cells and B cells, many studies have demonstrated that high numbers of tumor-infiltrating lymphocytes are associated with good clinical outcome. In addition, not only the density but also the organization of tumor-infiltrating immune cells has been shown to determine patient survival. Indeed, more and more studies describe the development within the tumor microenvironment of tertiary lymphoid structures (TLS, whose presence has a positive impact on tumor prognosis. TLS are transient ectopic lymphoid aggregates displaying the same organization and functionality as canonical secondary lymphoid organs, with T cell-rich and B cell-rich areas that are sites for the differentiation of effector and memory T cells and B cells. However, factors favoring the emergence of such structures within tumors still need to be fully characterized. In this review, we survey the state of the art of what is known about the general organization, induction and functionality of TLS during chronic inflammation, and more especially in cancer, with a particular focus on the B cell compartment. We detail the role played by TLS B cells in anti-tumor immunity, both as antigen-presenting cells and tumor antigen-specific antibody-secreting cells, and raise the question of the capacity of chemotherapeutic and immunotherapeutic agents to induce the development of TLS within tumors. Finally, we explore how to take advantage of our knowledge on TLS B cells to develop new therapeutic tools.

  6. Tertiary Lymphoid Structure-Associated B Cells are Key Players in Anti-Tumor Immunity.

    Science.gov (United States)

    Germain, Claire; Gnjatic, Sacha; Dieu-Nosjean, Marie-Caroline

    2015-01-01

    It is now admitted that the immune system plays a major role in tumor control. Besides the existence of tumor-specific T cells and B cells, many studies have demonstrated that high numbers of tumor-infiltrating lymphocytes are associated with good clinical outcome. In addition, not only the density but also the organization of tumor-infiltrating immune cells has been shown to determine patient survival. Indeed, more and more studies describe the development within the tumor microenvironment of tertiary lymphoid structures (TLS), whose presence has a positive impact on tumor prognosis. TLS are transient ectopic lymphoid aggregates displaying the same organization and functionality as canonical secondary lymphoid organs, with T-cell-rich and B-cell-rich areas that are sites for the differentiation of effector and memory T cells and B cells. However, factors favoring the emergence of such structures within tumors still need to be fully characterized. In this review, we survey the state of the art of what is known about the general organization, induction, and functionality of TLS during chronic inflammation, and more especially in cancer, with a particular focus on the B-cell compartment. We detail the role played by TLS B cells in anti-tumor immunity, both as antigen-presenting cells and tumor antigen-specific antibody-secreting cells, and raise the question of the capacity of chemotherapeutic and immunotherapeutic agents to induce the development of TLS within tumors. Finally, we explore how to take advantage of our knowledge on TLS B cells to develop new therapeutic tools.

  7. B-cell Lymphoma in retrieved femoral heads: a long term follow up

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    van Kemenade Folkert J

    2009-05-01

    Full Text Available Abstract Background A relatively high incidence of pathological conditions in retrieved femoral heads, including a group of patients having low grade B-cell lymphoma, has been described before. At short term follow up none of these patients with low-grade B-cell lymphoma showed evidence of systemic disease. However, the long term follow up of these patients is not known. Methods From November 1994 up to and including December 2005 we screened all femoral heads removed at the time of primary total hip replacement histopathologically and included them in the bone banking protocol according to the guidelines of the American Associations of Tissue Banks (AATB and the European Association of Musculo-Skeletal Transplantation (EAMST. We determined the percentage of B-cell lymphoma in all femoral heads and in the group that fulfilled all criteria of the bone banking protocol and report on the long-term follow-up. Results Of 852 femoral heads fourteen (1.6% were highly suspicious for low-grade B-cell lymphoma. Of these 852 femoral heads, 504 were eligible for bone transplantation according to the guidelines of the AATB and the EAMST. Six femoral heads of this group of 504 were highly suspicious for low-grade B-cell lymphoma (1.2%. At long term follow up two (0.2% of all patients developed systemic malignant disease and one of them needed medical treatment for her condition. Conclusion In routine histopathological screening we found variable numbers of low-grade B-cell lymphoma throughout the years, even in a group of femoral heads that were eligible for bone transplantation. Allogenic transmission of malignancy has not yet been reported on, but surviving viruses are proven to be transmissible. Therefore, we recommend the routine histopathological evaluation of all femoral heads removed at primary total hip arthroplasty as a tool for quality control, whether the femoral head is used for bone banking or not.

  8. The role of regulatory B cells in digestive system diseases.

    Science.gov (United States)

    Zhou, Zhenyu; Gong, Lei; Wang, Xiaoyun; Hu, Zhen; Wu, Gaojue; Tang, Xuejun; Peng, Xiaobin; Tang, Shuan; Meng, Miao; Feng, Hui

    2017-04-01

    The past decade has provided striking insights into a newly identified subset of B cells known as regulatory B cells (Bregs). In addition to producing antibody, Bregs also regulate diseases via cytokine production and antigen presentation. This subset of B cells has protective and potentially therapeutic effects. However, the particularity of Bregs has caused some difficulties in conducting research on their roles. Notably, human B10 cells, which are Bregs that produce interleukin 10, share phenotypic characteristics with other previously defined B cell subsets, and currently, there is no known surface phenotype that is unique to B10 cells. An online search was performed in the PubMed and Web of Science databases for articles published providing evidences on the role of regulatory B cells in digestive system diseases. Abundant evidence has demonstrated that Bregs play a regulatory role in inflammatory, autoimmune, and tumor diseases, and regulatory B cells play different roles in different diseases, but future work needs to determine the mechanisms by which Bregs are activated and how these cells affect their target cells.

  9. Transient reduction in IgA+ and IgG+ memory B cell numbers in young EBV-seropositive children: the Generation R Study.

    Science.gov (United States)

    van den Heuvel, Diana; Jansen, Michelle A E; Bell, Andrew I; Rickinson, Alan B; Jaddoe, Vincent W V; van Dongen, Jacques J M; Moll, Henriette A; van Zelm, Menno C

    2017-04-01

    The EBV is known to persist in memory B cells, but it remains unclear how this affects cell numbers and humoral immunity. We here studied EBV persistence in memory B cell subsets and consequences on B cell memory in young children. EBV genome loads were quantified in 6 memory B cell subsets in EBV+ adults. The effects of EBV infection on memory B cell numbers and vaccination responses were studied longitudinally in children within the Generation R population cohort between 14 mo and 6 yr of age. EBV genomes were more numerous in CD27+IgG+, CD27+IgA+, and CD27-IgA+ memory B cells than in IgM-only, natural effector, and CD27-IgG+ B cells. The blood counts of IgM-only, CD27+IgA+, CD27-IgG+, and CD27+IgG+ memory B cells were significantly lower in EBV+ children than in uninfected controls at 14 mo of age-the age when these cells peak in numbers. At 6 yr, all of these memory B cell counts had normalized, as had plasma IgG levels to previous primary measles and booster tetanus vaccinations. In conclusion, EBV persists predominantly in Ig class-switched memory B cells, even when derived from T cell-independent responses (CD27-IgA+), and EBV infection results in a transient depletion of these cells in young children. © Society for Leukocyte Biology.

  10. Combinatorial Control of mRNA Fates by RNA-Binding Proteins and Non-Coding RNAs

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    Valentina Iadevaia

    2015-09-01

    Full Text Available Post-transcriptional control of gene expression is mediated by RNA-binding proteins (RBPs and small non-coding RNAs (e.g., microRNAs that bind to distinct elements in their mRNA targets. Here, we review recent examples describing the synergistic and/or antagonistic effects mediated by RBPs and miRNAs to determine the localisation, stability and translation of mRNAs in mammalian cells. From these studies, it is becoming increasingly apparent that dynamic rearrangements of RNA-protein complexes could have profound implications in human cancer, in synaptic plasticity, and in cellular differentiation.

  11. Malaria-associated atypical memory B cells exhibit markedly reduced B cell receptor signaling and effector function.

    Science.gov (United States)

    Portugal, Silvia; Tipton, Christopher M; Sohn, Haewon; Kone, Younoussou; Wang, Jing; Li, Shanping; Skinner, Jeff; Virtaneva, Kimmo; Sturdevant, Daniel E; Porcella, Stephen F; Doumbo, Ogobara K; Doumbo, Safiatou; Kayentao, Kassoum; Ongoiba, Aissata; Traore, Boubacar; Sanz, Inaki; Pierce, Susan K; Crompton, Peter D

    2015-05-08

    Protective antibodies in Plasmodium falciparum malaria are only acquired after years of repeated infections. Chronic malaria exposure is associated with a large increase in atypical memory B cells (MBCs) that resemble B cells expanded in a variety of persistent viral infections. Understanding the function of atypical MBCs and their relationship to classical MBCs will be critical to developing effective vaccines for malaria and other chronic infections. We show that VH gene repertoires and somatic hypermutation rates of atypical and classical MBCs are indistinguishable indicating a common developmental history. Atypical MBCs express an array of inhibitory receptors and B cell receptor (BCR) signaling is stunted in atypical MBCs resulting in impaired B cell responses including proliferation, cytokine production and antibody secretion. Thus, in response to chronic malaria exposure, atypical MBCs appear to differentiate from classical MBCs becoming refractory to BCR-mediated activation and potentially interfering with the acquisition of malaria immunity.

  12. Genetic variation in B-cell-activating factor is associated with an increased risk of developing B-cell non-Hodgkin lymphoma.

    Science.gov (United States)

    Novak, Anne J; Slager, Susan L; Fredericksen, Zachary S; Wang, Alice H; Manske, Michelle M; Ziesmer, Steven; Liebow, Mark; Macon, William R; Dillon, Stacey R; Witzig, Thomas E; Cerhan, James R; Ansell, Stephen M

    2009-05-15

    Elevated B-cell-activating factor (BAFF; TNFSF13B) levels have been found in patients with B-cell malignancies and autoimmune diseases, suggesting that it may play a pathogenic role. We previously found that a single nucleotide polymorphism (SNP) in the TNFSF13B promoter resulted in increased transcription, suggesting that genetic variation in TNFSF13B may influence its expression. We therefore wanted to determine if genetic variation in TNFSF13B is associated with high BAFF levels and non-Hogkin lymphoma (NHL) risk. We genotyped 9 tagSNPs within TNFSF13B in a clinic-based study of 441 NHL cases and 475 matched controls and evaluated the association of individual SNPs with risk of NHL; 3 tagSNPs were significant (P TNFSF13B gene is significantly associated with NHL risk and elevated serum BAFF levels.

  13. B Cell Intrinsic Mechanisms Constraining IgE Memory

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    Brice Laffleur

    2017-11-01

    Full Text Available Memory B cells and long-lived plasma cells are key elements of adaptive humoral immunity. Regardless of the immunoglobulin class produced, these cells can ensure long-lasting protection but also long-lasting immunopathology, thus requiring tight regulation of their generation and survival. Among all antibody classes, this is especially true for IgE, which stands as the most potent, and can trigger dramatic inflammatory reactions even when present in minute amounts. IgE responses and memory crucially protect against parasites and toxic components of venoms, conferring selective advantages and explaining their conservation in all mammalian species despite a parallel broad spectrum of IgE-mediated immunopathology. Long-term memory of sensitization and anaphylactic responses to allergens constitute the dark side of IgE responses, which can trigger multiple acute or chronic pathologic manifestations, some punctuated with life-threatening events. This Janus face of the IgE response and memory, both necessary and potentially dangerous, thus obviously deserves the most elaborated self-control schemes.

  14. B cells and their role in the teleost gut.

    Science.gov (United States)

    Parra, David; Korytář, Tomáš; Takizawa, Fumio; Sunyer, J Oriol

    2016-11-01

    Mucosal surfaces are the main route of entry for pathogens in all living organisms. In the case of teleost fish, mucosal surfaces cover the vast majority of the animal. As these surfaces are in constant contact with the environment, fish are perpetually exposed to a vast number of pathogens. Despite the potential prevalence and variety of pathogens, mucosal surfaces are primarily populated by commensal non-pathogenic bacteria. Indeed, a fine balance between these two populations of microorganisms is crucial for animal survival. This equilibrium, controlled by the mucosal immune system, maintains homeostasis at mucosal tissues. Teleost fish possess a diffuse mucosa-associated immune system in the intestine, with B cells being one of the main responders. Immunoglobulins produced by these lymphocytes are a critical line of defense against pathogens and also prevent the entrance of commensal bacteria into the epithelium. In this review we will summarize recent literature regarding the role of B-lymphocytes and immunoglobulins in gut immunity in teleost fish, with specific focus on immunoglobulin isotypes and the microorganisms, pathogenic and non-pathogenic that interact with the immune system. Copyright © 2016. Published by Elsevier Ltd.

  15. Hepatocyte growth factor regulated tyrosine kinase substrate in the peripheral development and function of B-cells

    Energy Technology Data Exchange (ETDEWEB)

    Nagata, Takayuki [Department of Pharmacy, Iwaki Meisei University, 5-5-1 Chuodai Iino, Iwaki, Fukushima 970-8551 (Japan); Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575 (Japan); Murata, Kazuko, E-mail: murata-k@iwakimu.ac.jp [Department of Pharmacy, Iwaki Meisei University, 5-5-1 Chuodai Iino, Iwaki, Fukushima 970-8551 (Japan); Murata, Ryo [Department of Pharmacy, Iwaki Meisei University, 5-5-1 Chuodai Iino, Iwaki, Fukushima 970-8551 (Japan); Sun, Shu-lan [Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575 (Japan); Saito, Yutaro; Yamaga, Shuhei [Department of Pharmacy, Iwaki Meisei University, 5-5-1 Chuodai Iino, Iwaki, Fukushima 970-8551 (Japan); Tanaka, Nobuyuki; Tamai, Keiichi [Division of Immunology, Miyagi Cancer Research Institute, 47-1 Nodayama, Medeshima-Shiode, Natori 981-1293 (Japan); Moriya, Kunihiko [Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575 (Japan); Kasai, Noriyuki [Institute for Animal Experimentation, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575 (Japan); Sugamura, Kazuo [Division of Immunology, Miyagi Cancer Research Institute, 47-1 Nodayama, Medeshima-Shiode, Natori 981-1293 (Japan); Ishii, Naoto [Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575 (Japan)

    2014-01-10

    Highlights: •ESCRT-0 protein regulates the development of peripheral B-cells. •BCR expression on cell surface should be controlled by the endosomal-sorting system. •Hrs plays important roles in responsiveness to Ag stimulation in B lymphocytes. -- Abstract: Hepatocyte growth factor (HGF)-regulated tyrosine kinase substrate (Hrs) is a vesicular sorting protein that functions as one of the endosomal-sorting proteins required for transport (ESCRT). Hrs, which binds to ubiquitinated proteins through its ubiquitin-interacting motif (UIM), contributes to the lysosomal transport and degradation of ubiquitinated membrane proteins. However, little is known about the relationship between B-cell functions and ESCRT proteins in vivo. Here we examined the immunological roles of Hrs in B-cell development and functions using B-cell-specific Hrs-deficient (Hrs{sup flox/flox};mb1{sup cre/+}:Hrs-cKO) mice, which were generated using a cre-LoxP recombination system. Hrs deficiency in B-cells significantly reduced T-cell-dependent antibody production in vivo and impaired the proliferation of B-cells treated in vitro with an anti-IgM monoclonal antibody but not with LPS. Although early development of B-cells in the bone marrow was normal in Hrs-cKO mice, there was a significant decrease in the number of the peripheral transitional B-cells and marginal zone B-cells in the spleen of Hrs-cKO mice. These results indicate that Hrs plays important roles during peripheral development and physiological functions of B lymphocytes.

  16. Dynamic Epstein-Barr Virus Gene Expression on the Path to B-Cell Transformation

    Science.gov (United States)

    Price, Alexander M.; Luftig, Micah A.

    2016-01-01

    Epstein-Barr Virus is an oncogenic human herpesvirus in the γ-herpesvirinae sub-family that contains a 170–180 kb double stranded DNA genome. In vivo, EBV commonly infects B and epithelial cells and persists for the life of the host in a latent state in the memory B cell compartment of the peripheral blood. EBV can be reactivated from its latent state leading to increased expression of lytic genes that primarily encode for enzymes necessary to replicate the viral genome as well as structural components of the virion. Lytic cycle proteins also aid in immune evasion, inhibition of apoptosis, and the modulation of other host responses to infection. In vitro, EBV has the potential to infect primary human B cells and induce cellular proliferation to yield effectively immortalized lymphoblastoid cell lines, or LCLs. EBV immortalization of B cells in vitro serves as a model system for studying EBV-mediated lymphomagenesis. While much is known about the steady state viral gene expression within EBV immortalized LCLs and other EBV-positive cell lines, relatively little is known about the early events after primary B-cell infection. It was previously thought that upon latent infection EBV only expressed the well-characterized latency associated transcripts found in LCLs. However, recent work has characterized the early, but transient, expression of lytic genes necessary for efficient transformation as well as delayed responses in the known latency genes. This review summarizes these recent findings that show how dynamic and controlled expression of multiple EBV genes can control the activation of B cells, entry into the cell cycle, inhibition of apoptosis, and control of innate and adaptive immune responses. PMID:24373315

  17. Activation and proliferation signals in mouse B cells. VII. Calcium ionophores are non-mitogenic polyclonal B-cell activators.

    Science.gov (United States)

    Klaus, G G; Bijsterbosch, M K; Holman, M

    1985-01-01

    Calcium ionophores cause polyclonal proliferation of lymphocytes from man, rabbit and pig, but are not mitogenic for mouse T or B lymphocytes. We show here that two Ca2+ ionophores (A23187 and ionomycin) nonetheless activate a substantial proportion of mouse B lymphocytes at concentrations which effectively inhibit DNA synthesis induced by conventional mitogens, such as anti-immunoglobulin antibodies. Activation of B cells was detected by (i) increased expression of Ia antigen after 24 hr culture with ionophores, and (ii) the accelerated onset of DNA synthesis in B cells primed with ionophores for 24 hr, washed and then rechallenged with anti-Ig. Unlike anti-Ig, the ionophores did not induce either the breakdown of inositol phospholipids, or RNA synthesis in B cells. Finally, activation of B cells by ionophores is highly susceptible to inhibition by cyclosporine. These results therefore suggest that elevation of intracellular Ca2+ induced by these ionophores is sufficient to cause B cells to leave Go, but not to enter the G1 phase of the cell cycle. Clearly, additional signals are required for B cells to progress further into cycle and eventually become committed to DNA synthesis. PMID:2414214

  18. Utility of quantitative flow cytometry immunophenotypic analysis of CD5 expression in small B-cell neoplasms.

    Science.gov (United States)

    Challagundla, Pramoda; Jorgensen, Jeffrey L; Kanagal-Shamanna, Rashmi; Gurevich, Inga; Pierson, Diane M; Ferrajoli, Alessandra; Reyes, Steven R; Medeiros, L Jeffrey; Miranda, Roberto N

    2014-07-01

    The value of assessing CD5 expression in the differential diagnosis of small B-cell neoplasms is well established. Assessment is usually done qualitatively. To assess CD5 expression levels by quantitative flow cytometry immunophenotyping and to determine possible differences among various small B-cell neoplasms. We performed 4-color flow cytometry analysis on specimens of peripheral blood and bone marrow aspirate and quantified CD5 expression in various small B-cell lymphomas and leukemias. We also assessed CD5 levels in peripheral blood samples of healthy blood donors. Cases of chronic lymphocytic leukemia and mantle cell lymphoma had higher levels of CD5 compared with control B cells (P < .001). Cases of marginal zone lymphoma and hairy cell leukemia had CD5 levels similar to control B cells (P = .35 and P = .14, respectively), whereas cases of follicular lymphoma and lymphoplasmacytic lymphoma had significantly lower CD5 levels than control B cells (P < .001 and P = .04, respectively). In B-cell neoplasms, a high level of CD5 expression was correlated with a homogeneous pattern of positive events, whereas lower CD5 levels were correlated with heterogeneous patterns of positive events. Using flow cytometric immunophenotypic analysis to quantify CD5 levels can aid in diagnosis. CD5 expression levels are higher in patients with chronic lymphocytic leukemia and mantle cell lymphoma, and expression is observed in a homogeneous pattern, as compared with other B-cell neoplasms that are either negative for CD5 or express CD5 at lower levels with a heterogeneous pattern. However, there is some overlap in CD5 expression levels between a subset of atypical chronic lymphocytic leukemia and marginal zone lymphoma cases.

  19. Cell fate determination in the Caenorhabditis elegans epidermal lineages

    NARCIS (Netherlands)

    Soete, G.A.J.

    2007-01-01

    The starting point for this work was to use the hypodermal seam of C. elegans as a model system to study cell fate determination. Even though the seam is a relatively simple developmental system, the mechanisms that control cell fate determination in the seam lineages are connected in a highly

  20. Interleukin 21 - its potential role in the therapy of B-cell lymphomas.

    Science.gov (United States)

    Bhatt, Shruti; Sarosiek, Kristopher A; Lossos, Izidore S

    2017-01-01

    Interleukin-21 (IL-21), a member of IL-2 cytokine family, has pleotropic biological effects on lymphoid and myeloid cells. During the past 15 years, since the discovery of IL-21, great advances have been made regarding its biological activity and the mechanisms controlling IL-21-mediated cellular responses, especially in hematological malignancies. Preclinical studies have shown that IL-21R is expressed on healthy and neoplastic B-cells and exogenous IL-21 can induce direct apoptosis of IL-21R expressing B-cell non-Hodgkin lymphomas (NHL), making it a potentially attractive anti-lymphoma therapy. However, in some hematological malignancies such as multiple myeloma, Hodgkin lymphoma and Burkitt lymphoma, IL-21 can induce proliferation of neoplastic B-cells. In NHL, the underlying mechanism of cell death was found to be different between the various subtypes, including activation of different JAK/STAT signal transduction pathways or other factors. Immunomodulatory effects of IL-21 have also been reported to contribute to its anti-tumor effects as described by earlier studies in solid tumors and B-cell associated malignancies. These effects are predominantly mediated by IL-21's ability to activate cytolytic activities by NK-cells and CD4 + /CD8 + T-cells. In this review, we provide an overview of IL-21's effects in NHL, results from clinical trials utilizing IL-21, and propose how IL-21 can be therapeutically exploited for treating these lymphomas.

  1. Dual Mechanism of Rag Gene Repression by c-Myb during Pre-B Cell Proliferation.

    Science.gov (United States)

    Timblin, Greg A; Xie, Liangqi; Tjian, Robert; Schlissel, Mark S

    2017-06-15

    Developing B lymphocytes undergo clonal expansion following successful immunoglobulin heavy chain gene rearrangement. During this proliferative burst, expression of the Rag genes is transiently repressed to prevent the generation of double-stranded DNA (dsDNA) breaks in cycling large pre-B cells. The Rag genes are then reexpressed in small, resting pre-B cells for immunoglobulin light chain gene rearrangement. We previously identified c-Myb as a repressor of Rag transcription during clonal expansion using Abelson murine leukemia virus-transformed B cells. Nevertheless, the molecular mechanisms by which c-Myb achieved precise spatiotemporal repression of Rag expression remained obscure. Here, we identify two mechanisms by which c-Myb represses Rag transcription. First, c-Myb negatively regulates the expression of the Rag activator Foxo1, an activity dependent on M303 in c-Myb's transactivation domain, and likely the recruitment of corepressors to the Foxo1 locus by c-Myb. Second, c-Myb represses Rag transcription directly by occupying the Erag enhancer and antagonizing Foxo1 binding to a consensus forkhead site in this cis-regulatory element that we show is crucial for Rag expression in Abelson pre-B cell lines. This work provides important mechanistic insight into how spatiotemporal expression of the Rag genes is tightly controlled during B lymphocyte development to prevent mistimed dsDNA breaks and their deleterious consequences. Copyright © 2017 American Society for Microbiology.

  2. Organizational structure and the periphery of the gene regulatory network in B-cell lymphoma.

    Science.gov (United States)

    de Matos Simoes, Ricardo; Tripathi, Shailesh; Emmert-Streib, Frank

    2012-05-14

    The physical periphery of a biological cell is mainly described by signaling pathways which are triggered by transmembrane proteins and receptors that are sentinels to control the whole gene regulatory network of a cell. However, our current knowledge about the gene regulatory mechanisms that are governed by extracellular signals is severely limited. The purpose of this paper is three fold. First, we infer a gene regulatory network from a large-scale B-cell lymphoma expression data set using the C3NET algorithm. Second, we provide a functional and structural analysis of the largest connected component of this network, revealing that this network component corresponds to the peripheral region of a cell. Third, we analyze the hierarchical organization of network components of the whole inferred B-cell gene regulatory network by introducing a new approach which exploits the variability within the data as well as the inferential characteristics of C3NET. As a result, we find a functional bisection of the network corresponding to different cellular components. Overall, our study allows to highlight the peripheral gene regulatory network of B-cells and shows that it is centered around hub transmembrane proteins located at the physical periphery of the cell. In addition, we identify a variety of novel pathological transmembrane proteins such as ion channel complexes and signaling receptors in B-cell lymphoma.

  3. Regulation of germinal center B-cell differentiation.

    Science.gov (United States)

    Zhang, Yang; Garcia-Ibanez, Laura; Toellner, Kai-Michael

    2016-03-01

    Germinal centers (GC) are the main sites where antigen-activated B-cell clones expand and undergo immunoglobulin gene hypermutation and selection. Iterations of this process will lead to affinity maturation, replicating Darwinian evolution on the cellular level. GC B-cell selection can lead to four different outcomes: further expansion and evolution, apoptosis (non-selection), or output from the GC with differentiation into memory B cells or plasma cells. T-helper cells in GC have been shown to have a central role in regulating B-cell selection by sensing the density of major histocompatibility complex (MHC):peptide antigen complexes. Antigen is provided on follicular dendritic cells in the form of immune complex. Antibody on these immune complexes regulates antigen accessibility by shielding antigen from B-cell receptor access. Replacement of antibody on immune complexes by antibody generated from GC-derived plasma cell output will gradually reduce the availability of antigen. This antibody feedback can lead to a situation where a slow rise in selection stringency caused by a changing environment leads to directional evolution toward higher affinity antibody. © 2016 The Authors. Immunological Reviews Published by John Wiley & Sons Ltd.

  4. B cells: from early development to regulating allergic diseases.

    Science.gov (United States)

    Samitas, Konstantinos; Lötvall, Jan; Bossios, Apostolos

    2010-06-01

    B lymphocytes are characterized by a unique and highly specialized developmental pathway that is responsible for their vast phenotypic and function diversity. B cell development is strictly regulated to ensure sufficient specific humoral immunity while at the same time avoiding any errors that would compromise B cell functionality. The generation and maintenance of mature B cells from the constant flux of bone marrow progenitors is a complex process that is generally poorly understood, although great progress has been made in recent years. B cells have for long been considered mainly as antibody-producing cells and therefore believed to play an important role in the pathophysiology of allergic diseases, primarily through their ability to produce IgE antibodies. However, recent findings have revealed new aspects of their role in immune responses that place them again under the spotlight as important immune regulators, independent of antibody production. This review focuses on the developmental processes responsible for the numerous phenotypes and functions of the B-lymphocyte pool and the different aspects of effector B cell functionality in the context of allergy.

  5. Th1 and Th2 help for B cells

    DEFF Research Database (Denmark)

    Poudrier, J; Owens, T

    1995-01-01

    Sustained interaction with Th1 cells has been shown to induce IL-2 responsiveness by murine B cells. This is equivalently dependent on CD40, CD54/ICAM-1 and MHC II ligation, and co-cross-linking of CD54 and MHC II in the presence of IL-5 up-regulates a functional IL-2R on B cells. We now show...... that IL-5 (125 U/ml) synergizes with Th1 cells to induce B cell responses to IL-2, that are maintained following T-cell removal, e.g. autonomous. Th1 help in the absence of IL-5 resulted in weak or undetectable responses following T cell removal. The mechanism of IL-5 synergy involved persistence of IL-2R...... beta expression following T cell removal, as opposed to enhancement of IL-2R induction or function. The level of contact-induced IL-2R expression on B cells was not itself modified by IL-5. The effects of IL-5 did not overcome the requirement for T contact signals and treatment of B cells with soluble...

  6. A gene panel, including LRP12, is frequently hypermethylated in major types of B-cell lymphoma.

    Directory of Open Access Journals (Sweden)

    Nicole Bethge

    Full Text Available Epigenetic modifications and DNA methylation in particular, have been recognized as important mechanisms to alter gene expression in malignant cells. Here, we identified candidate genes which were upregulated after an epigenetic treatment of B-cell lymphoma cell lines (Burkitt's lymphoma, BL; Follicular lymphoma, FL; Diffuse large B-cell lymphoma, DLBCL activated B-cell like, ABC; and germinal center like, GCB and simultaneously expressed at low levels in samples from lymphoma patients. Qualitative methylation analysis of 24 candidate genes in cell lines revealed five methylated genes (BMP7, BMPER, CDH1, DUSP4 and LRP12, which were further subjected to quantitative methylation analysis in clinical samples from 59 lymphoma patients (BL, FL, DLBCL ABC and GCB; and primary mediastinal B-cell lymphoma, PMBL. The genes LRP12 and CDH1 showed the highest methylation frequencies (94% and 92%, respectively. BMPER (58%, DUSP4 (32% and BMP7 (22%, were also frequently methylated in patient samples. Importantly, all gene promoters were unmethylated in various control samples (CD19+ peripheral blood B cells, peripheral blood mononuclear cells and tonsils as well as in follicular hyperplasia samples, underscoring a high specificity. The combination of LRP12 and CDH1 methylation could successfully discriminate between the vast majority of the lymphoma and control samples, emphasized by receiver operating characteristic analysis with a c-statistic of 0.999. These two genes represent promising epigenetic markers which may be suitable for monitoring of B-cell lymphoma.

  7. Impaired maintenance of naturally acquired T-cell memory to the meningococcus in patients with B-cell immunodeficiency.

    Science.gov (United States)

    Morales-Aza, Begonia; Glennie, Sarah J; Garcez, Tomaz Pereira; Davenport, Victoria; Johnston, Sarah L; Williams, Neil A; Heyderman, Robert S

    2009-04-30

    The importance of T cells in the generation of antigen-specific B-cell immunity has been extensively described, but the role B cells play in shaping T-cell memory is uncertain. In healthy controls, exposure to Neisseria meningitidis in the upper respiratory tract is associated with the generation of memory T cells in the mucosal and systemic compartments. However, we demonstrate that in B cell-deficient subjects with X-linked agammaglobulinemia (XLA), naturally acquired T-cell memory responses to meningococcal antigens are reduced compared with healthy control patients. This difference is not found in T-cell memory to an obligate respiratory pathogen, influenza virus. Accordingly, we show that meningococcal antigens up-regulate major histocompatibility complex (MHC) class II, CD40, CD86/80 expression on mucosal and systemic associated B cells and that antigen presentation stimulates T-cell proliferation. A similar reduction in N meningitidis but not influenza antigen-specific T-cell memory was observed in subjects with X-linked hyper IgM syndrome (X-HIM), implicating the interaction of CD40-CD40L in this process. Together, these data implicate B cells in the induction and maintenance of T-cell memory to mucosal colonizing bacteria such as N meningitidis and highlight the importance of B cells beyond antibody production but as a target for immune reconstitution.

  8. Self-Antigen-Driven Thymic B Cell Class Switching Promotes T Cell Central Tolerance

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    Jason Perera

    2016-10-01

    Full Text Available B cells are unique antigen-presenting cells because their antigen presentation machinery is closely tied to the B cell receptor. Autoreactive thymic B cells can efficiently present cognate self-antigens to mediate CD4+ T cell-negative selection. However, the nature of thymocyte-thymic B cell interaction and how this interaction affects the selection of thymic B cell repertoire and, in turn, the T cell repertoire are not well understood. Here we demonstrate that a large percentage of thymic B cells have undergone class switching intrathymically. Thymic B cell class switching requires cognate interaction with specific T cells. Class-switched thymic B cells have a distinct repertoire compared with unswitched thymic B cells or splenic B cells. Particularly, autoreactive B cell specificities preferentially expand in the thymus by undergoing class switching, and these enriched, class-switched autoreactive thymic B cells play an important role in CD4 T cell tolerance.

  9. Microenvironment-Centred Dynamics in Aggressive B-Cell Lymphomas

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    Matilde Cacciatore

    2012-01-01

    Full Text Available Aggressive B-cell lymphomas share high proliferative and invasive attitudes and dismal prognosis despite heterogeneous biological features. In the interchained sequence of events leading to cancer progression, neoplastic clone-intrinsic molecular events play a major role. Nevertheless, microenvironment-related cues have progressively come into focus as true determinants for this process. The cancer-associated microenvironment is a complex network of nonneoplastic immune and stromal cells embedded in extracellular components, giving rise to a multifarious crosstalk with neoplastic cells towards the induction of a supportive milieu. The immunological and stromal microenvironments have been classically regarded as essential partners of indolent lymphomas, while considered mainly negligible in the setting of aggressive B-cell lymphomas that, by their nature, are less reliant on external stimuli. By this paper we try to delineate the cardinal microenvironment-centred dynamics exerting an influence over lymphoid clone progression in aggressive B-cell lymphomas.

  10. Biomaterial stiffness determines stem cell fate.

    Science.gov (United States)

    Lv, Hongwei; Wang, Heping; Zhang, Zhijun; Yang, Wang; Liu, Wenbin; Li, Yulin; Li, Lisha

    2017-06-01

    Stem cells have potential to develop into numerous cell types, thus they are good cell source for tissue engineering. As an external physical signal, material stiffness is capable of regulating stem cell fate. Biomaterial stiffness is an important parameter in tissue engineering. We summarize main measurements of material stiffness under different condition, then list and compare three main methods of controlling stiffness (material amount, crosslinking density and photopolymeriztion time) which interplay with one another and correlate with stiffness positively, and current advances in effects of biomaterial stiffness on stem cell fate. We discuss the unsolved problems and future directions of biomaterial stiffness in tissue engineering. Copyright © 2017. Published by Elsevier Inc.

  11. The interplay between chromatin and transcription factor networks during B cell development: who pulls the trigger first?

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    Mohamed-Amin eChoukrallah

    2014-04-01

    Full Text Available All mature blood cells derive from hematopoietic stem cells (HSCs through gradual restriction of their cell fate potential and acquisition of specialized functions. Lineage specification and cell commitment require the establishment of specific transcriptional programs involving the activation of lineage-specific genes and the repression of lineage-inappropriate genes. This process requires the concerted action of transcription factors (TFs and epigenetic modifying enzymes. Within the hematopoietic system, B lymphopoiesis is one of the most-studied differentiation programs. Loss of function studies allowed the identification of many TFs and epigenetic modifiers required for B cell development. The usage of systematic analytical techniques such as transcriptome determination, genome-wide mapping of TF binding and epigenetic modifications and mass spectrometry analyses, allowed to gain a systemic description of the intricate networks that guide B cell development. However, the precise mechanisms governing the interaction between TFs and chromatin are still unclear. Generally, chromatin structure can be remodeled by some TFs but in turn can also regulate (i.e. prevent or promote the binding of other TFs. This conundrum leads to the crucial questions of who is on first, when and how. We review here the current knowledge about TF networks and epigenetic regulation during hematopoiesis, with an emphasis on B cell development, and discuss in particular the current models about the interplay between chromatin and transcription factors.

  12. MicroRNAs as B-cell lymphoma biomarkers

    Directory of Open Access Journals (Sweden)

    Manterola L

    2015-02-01

    Full Text Available Lorea Manterola,1 Marta Fernandez-Mercado,1 Erika Larrea,1 Ibai Goicoechea,1 María Arestin,1 María Armesto,1 Luiza Hernandez,1 Charles H Lawrie1,2,3 1Oncology Area, Biodonostia Research Institute, San Sebastián, Spain; 2Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, UK; 3Ikerbasque, Basque Foundation for Science, Bilbao, Spain Abstract: B-cell lymphomas represent a group of more than 35 recognized mature B-cell neoplasms differentiated largely on the basis of immunohistochemical staining patterns that are often challenging to accurately diagnose. Despite having been only formally recognized just over 10 years ago, microRNAs (miRNAs have become one of the trendiest topics in biology. Dysregulation of miRNAs is a ubiquitous feature of cancer in general, including B-cell lymphomas. Many of the miRNAs aberrantly expressed in B-cell lymphomas also play a crucial regulatory role in normal hematopoietic function. MiRNAs show great potential as novel biomarkers of cancer, as they can differentiate cancers according to diagnosis and developmental stage, even discriminating between cancers that are poorly separated histologically. Furthermore, they can be robustly measured from routinely prepared formalin-fixed paraffin-embedded biopsy material and biological fluids such as blood. Here, we consider the identity, function, and biomarker potential of miRNAs in B-cell lymphomas and, most importantly, the hurdles that remain to be overcome if they are really to become part of future clinical practice. Keywords: microRNA, lymphoma, biomarker, B-cell 

  13. A case with pachyonychia congenita and B-cell lymphoma.

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    Vitorino Modesto dos Santos

    2014-07-01

    Full Text Available Pachyonychia congenital (PC is a rare autosomal dominant genodermatosis characterized hyperkeratosis affecting the nails and palmoplantar areas, oral leukokeratosis, and cystic lesions. A 39-year-old woman with PC type 1 (Jadassohn-Lewandowsky syndrome and B-cell lymphoma is described. No similar disorders or parental consanguinity were found in her family. Typical features of PC developed since her early childhood and the diagnosis of B-cell lymphoma was established seven years ago, without a clear causal relation between these entities. Despite inherent limitations of a single case, this report may contribute to PC understanding.

  14. Intravascular large B cell lymphoma masquerading as acute disseminated encephalomyelitis

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    James Lee

    2016-04-01

    Full Text Available Intravascular large B cell lymphoma (IVLBCL is a rare condition with a predilection for central nervous system involvement and is often misdiagnosed. This case report describes a 58-year-old gentleman who presented with paraparesis and subsequent dramatic neurological deterioration initially attributed to acute disseminated encephalomyelitis. Upon post-mortem examination, the correct diagnosis of intravascular large B cell lymphoma was reached. This condition has a poor prognosis but can be chemotherapy responsive. It is hoped that this case report will raise awareness of a rare and diagnostically challenging illness.

  15. Cerebrospinal fluid B cells and disease progression in multiple sclerosis - A longitudinal prospective study.

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    Sebastian Wurth

    Full Text Available There is evidence that B cells play an important role in disease pathology of multiple sclerosis (MS. The aim of this prospective observational study was to determine the predictive value of cerebrospinal fluid (CSF B cell subtypes in disease evolution of patients with MS.128 patients were included between 2004 and 2012. Median follow up time was 7.9 years (range 3.3-10.8 years. 10 patients were lost to follow-up. 32 clinically isolated syndrome- (CIS, 25 relapsing remitting MS- (RRMS, 2 secondary progressive MS- (SPMS and 9 primary progressive MS- (PPMS patients were included. The control group consisted of 40 patients with other neurological diseases (OND. CSF samples were analyzed for routine diagnostic parameters. B cell phenotypes were characterized by flow cytometry using CD19 and CD138 specific antibodies. Standardized baseline brain MRI was conducted at the time of diagnostic lumbar puncture. Main outcome variables were likelihood of progressive disease course, EDSS progression, conversion to clinical definite MS (CDMS and relapse rate.CSF mature B cells (CD19+CD138- were increased in bout-onset MS compared to PPMS (p<0.05 and OND (p<0.001, whereas plasma blasts (CD19+CD138+ were increased in bout-onset MS (p<0.001 and PPMS (p<0.05 compared to OND. CSF B cells did not predict a progressive disease course, EDSS progression, an increased relapse rate or the conversion to CDMS. Likelihood of progressive disease course (p<0.05 and EDSS (p<0.01 was predicted by higher age at baseline, whereas conversion to CDMS was predicted by a lower age at onset (p<0.01 and the presence of ≥9 MRI T2 lesions (p<0.05.We detected significant differences in the CSF B cell subsets between different clinical MS subtypes and OND patients. CSF B cells were neither predictive for disease and EDSS progression nor conversion to CDMS after a CIS.

  16. Interleukin 35 Rescues Regulatory B Cell Function, but the Effect Is Dysregulated in Ulcerative Colitis.

    Science.gov (United States)

    Wang, Shaoxuan; Qin, Chengyong

    2017-05-01

    Ulcerative colitis (UC) is a long-time inflammatory condition arising from aberrant immune activation in the colon and the rectum. Interleukin (IL)-35 plays critical roles in autoimmune disorders. In this study, we explored the pathways of IL-35 in affecting UC. First, peripheral blood mononuclear cells (PBMCs) from UC patients were obtained. Pretreating PBMCs with IL-35 resulted in significantly elevated IL-10 production from whole PBMCs as well as B cells, whereas pretreating PBMCs with IL-12 or IL-27 did not demonstrate a similar effect. IL-35 suppressed the proliferation of CD4 + CD25 - conventional T cells, CD4 + CD25 + regulatory T (Treg) cells, and CD8 + T cells, but did not inhibit the proliferation of B cells. IL-35-mediated IL-10 secretion in B cells did not require the presence of Treg cells. After treatment with IL-35, B cells from UC patients presented significantly enhanced regulatory function, characterized by inhibiting cell proliferation and interferon (IFN)-γ, IL-17, and tumor necrosis factor (TNF)-α secretion from autologous CD4 + CD25 - T cells and CD8 + T cells, which was dependent on IL-10 signaling. However, IL-35-treatment did not demonstrate an effect on regulating IL-5 and IL-13 responses. These discoveries identified a Th1, Th17, and CD8 + T cell-targeting role of IL-35 in UC patients. Next, we examined the IL-35 expression in the intestinal mucosal in UC patients. Data showed that both noninflamed and inflamed tissues from UC patients presented significantly lower IL-35 secretion compared to healthy control tissues, which was associated with suppressed p35 transcription. UC patients with higher IL-35 also presented higher IL-10 secretion in gut mucosa. Together, our study identified that IL-35 could mediate anti-inflammatory function through promoting regulatory B cell functions, but this effect was suppressed in UC patients.

  17. Differential and site specific impact of B cells in the protective immune response to Mycobacterium tuberculosis in the mouse.

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    Egídio Torrado

    Full Text Available Cell-mediated immune responses are known to be critical for control of mycobacterial infections whereas the role of B cells and humoral immunity is unclear. B cells can modulate immune responses by secretion of immunoglobulin, production of cytokines and antigen-presentation. To define the impact of B cells in the absence of secreted immunoglobulin, we analyzed the progression of Mycobacterium tuberculosis (Mtb infection in mice that have B cells but which lack secretory immunoglobulin (AID(-/-µS(-/-mice. AID(-/-µS(-/- mice accumulated a population of activated B cells in the lungs when infected and were more susceptible to aerosol Mtb when compared to wild type (C57BL/6 mice or indeed mice that totally lack B cells. The enhanced susceptibility of AID(-/-µS(-/- mice was not associated with defective T cell activation or expression of a type 1 immune response. While delivery of normal serum to AID(-/-µS(-/- mice did not reverse susceptibility, susceptibility in the spleen was dependent upon the presence of B cells and susceptibility in the lungs of AID(-/-µS(-/-mice was associated with elevated expression of the cytokines IL-6, GM-CSF, IL-10 and molecules made by alternatively activated macrophages. Blocking of IL-10 signaling resulted in reversal of susceptibility in the spleens and lungs of AID(-/-µS(-/- mice. These data support the hypothesis that B cells can modulate immunity to Mtb in an organ specific manner via the modulation of cytokine production and macrophage activation.

  18. Human CD40 ligand-expressing type 3 innate lymphoid cells induce IL-10-producing immature transitional regulatory B cells.

    Science.gov (United States)

    Komlósi, Zsolt I; Kovács, Nóra; van de Veen, Willem; Kirsch, Anna Isabella; Fahrner, Heinz Benedikt; Wawrzyniak, Marcin; Rebane, Ana; Stanic, Barbara; Palomares, Oscar; Rückert, Beate; Menz, Günter; Akdis, Mübeccel; Losonczy, György; Akdis, Cezmi A

    2017-09-20

    Type 3 innate lymphoid cells (ILC3s) are involved in maintenance of mucosal homeostasis; however, their role in immunoregulation has been unknown. Immature transitional regulatory B (itBreg) cells are innate-like B cells with immunosuppressive properties, and the in vivo mechanisms by which they are induced have not been fully clarified. We aimed to investigate the ILC3-B-cell interaction that probably takes place in human tonsils. ILC3s were isolated from peripheral blood and palatine tonsils, expanded, and cocultured with naive B cells. Tonsillar ILC3s and regulatory B cells were visualized with immunofluorescence histology. ILC3 frequencies were measured in tonsil tissue of allergic and nonallergic patients and in peripheral blood of allergic asthmatic patients and healthy control subjects. A mutually beneficial relationship was revealed between ILC3s and B cells: ILC3s induced IL-15 production in B cells through B cell-activating factor receptor, whereas IL-15, a potent growth factor for ILC3s, induced CD40 ligand (CD40L) expression on circulating and tonsillar ILC3s. IL-15-activated CD40L + ILC3s helped B-cell survival, proliferation, and differentiation of IL-10-secreting, PD-L1-expressing functional itBreg cells in a CD40L- and B cell-activating factor receptor-dependent manner. ILC3s and regulatory B cells were in close connection with each other in palatine tonsils. ILC3 frequency was reduced in tonsil tissue of allergic patients and in peripheral blood of allergic asthmatic patients. Human CD40L + ILC3s provide innate B-cell help and are involved in an innate immunoregulatory mechanism through induction of itBreg cell differentiation, which takes place in palatine tonsils in vivo. This mechanism, which can contribute to maintenance of immune tolerance, becomes insufficient in allergic diseases. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  19. B-cell targeted therapies in systemic lupus erythematosus: successes and challenges.

    Science.gov (United States)

    Harvey, Philip R; Gordon, Caroline

    2013-04-01

    Systemic lupus erythematosus is a multisystem autoimmune disease characterized by the formation of autoantibodies that target a variety of self antigens. B cells are fundamental to the development of these antibodies and are a target for intervention in the disease. This review discusses four therapies that target B cells by inducing B-cell depletion, reduction in B-cell proliferation and differentiation, or modulation of B-cell function. Rituximab is an anti-CD20 chimeric monoclonal antibody that depletes B cells but not plasma cells. Systematic reviews of open label studies, particularly in lupus patients refractory to conventional therapy, have suggested that rituximab can be an effective treatment for non-renal lupus and lupus nephritis. However, randomized, double-blind, controlled trials comparing rituximab with placebo in addition to standard of care therapy for non-renal lupus and lupus nephritis over 12 months failed to demonstrate efficacy using the planned primary endpoints, although there were some post-hoc analyses suggesting that rituximab may have beneficial effects that would be worthy of further study as no significant toxicity has been demonstrated. Treatment with belimumab, a humanized monoclonal antibody targeted against B lymphocyte stimulator (BLys), was more efficacious than placebo and had no significant increase in adverse events in two non-renal, phase III lupus trials when given in addition to standard of care therapy for 52 weeks. Belimumab is licensed for the management of lupus in the US and in Europe. Atacicept is a humanized fusion protein that binds BLys and APRIL (a proliferation-inducing ligand) that might be more effective than belimumab in the management of lupus. Unfortunately a phase II/III trial of atacicept in lupus nephritis had to be stopped due to the development of low immunoglobulin levels and pneumonias in some patients. However, in retrospect these complications may have been due to concomitant treatment with

  20. B-cell Function Gene Mutations in Diffuse Large B-cell Lymphoma: A Retrospective Cohort Study.

    Science.gov (United States)

    Xu, Peng-Peng; Zhong, Hui-Juan; Huang, Yao-Hui; Gao, Xiao-Dong; Zhao, Xia; Shen, Yang; Cheng, Shu; Huang, Jin-Yan; Chen, Sai-Juan; Wang, Li; Zhao, Wei-Li

    2017-02-01

    Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous subtype of non-Hodgkin lymphoma. In addition to clinical and immunophenotypic characteristics, recurrent gene mutations have recently been identified in patients with DLBCL using next-generation sequencing technologies. The aim of this study is to investigate the clinical relevance of B-cell function gene mutations in DLBCL. Clinical analysis was performed on 680 Chinese DLBCL patients (146 non-CR and 534 CR cases) treated with six cycles of 21-day R-CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), alone or followed by two additional doses of rituximab consolidation on patients' own intention. Somatic mutations of B-cell function genes were further screened on 275 (71 non-CR and 204 CR) cases with available tumor samples by targeted sequencing, including genes involved in B-cell receptors (BCRs) pathway (CARD11, LYN, CD79A, and CD79B), Toll-like receptors (TLRs) pathway (MYD88), and tumor necrotic factor receptor (TNFR) pathway (TRAF2 and TNFAIP3). B-cell function gene mutations occurred in 44.0% (121/275) of DLBCL patients. The TLRs and TNFR related gene mutations were more frequently observed in non-CR patients (p=0.019 and p=0.032, respectively). BCRs related gene mutations, as well as revised IPI (R-IPI) and double BCL-2/MYC expression, were independently related to short progression-free survival in DLBCL after CR. The adverse prognostic effect of BCRs related gene mutations could be overcome by two additional doses of rituximab consolidation. These results highlight the molecular heterogeneity of DLBCL and identify a significant role of B-cell function gene mutations on lymphoma progression and response to rituximab in DLBCL. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  1. Toll-like receptor agonists synergize with CD40L to induce either proliferation or plasma cell differentiation of mouse B cells.

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    Emmanuelle Boeglin

    Full Text Available In a classical dogma, pathogens are sensed (via recognition of Pathogen Associated Molecular Patterns (PAMPs by innate immune cells that in turn activate adaptive immune cells. However, recent data showed that TLRs (Toll Like Receptors, the most characterized class of Pattern Recognition Receptors, are also expressed by adaptive immune B cells. B cells play an important role in protective immunity essentially by differentiating into antibody-secreting cells (ASC. This differentiation requires at least two signals: the recognition of an antigen by the B cell specific receptor (BCR and a T cell co-stimulatory signal provided mainly by CD154/CD40L acting on CD40. In order to better understand interactions of innate and adaptive B cell stimulatory signals, we evaluated the outcome of combinations of TLRs, BCR and/or CD40 stimulation. For this purpose, mouse spleen B cells were activated with synthetic TLR agonists, recombinant mouse CD40L and agonist anti-BCR antibodies. As expected, TLR agonists induced mouse B cell proliferation and activation or differentiation into ASC. Interestingly, addition of CD40 signal to TLR agonists stimulated either B cell proliferation and activation (TLR3, TLR4, and TLR9 or differentiation into ASC (TLR1/2, TLR2/6, TLR4 and TLR7. Addition of a BCR signal to CD40L and either TLR3 or TLR9 agonists did not induce differentiation into ASC, which could be interpreted as an entrance into the memory pathway. In conclusion, our results suggest that PAMPs synergize with signals from adaptive immunity to regulate B lymphocyte fate during humoral immune response.

  2. Cytotoxic lymphocytes in B-cell chronic lymphocytic leukemia

    NARCIS (Netherlands)

    Terstappen, Leonardus Wendelinus Mathias Marie; de Grooth, B.G.; Segers-Nolten, Gezina M.J.; Greve, Jan

    1990-01-01

    The occurrence of cytotoxic lymphocyte subpopulations (i.e., CD 16+, CD57+ and cytotoxic CD 8+) was studied in the peripheral blood of 18 B-cell chronic lymphocytic leukemia (B-CLL) patients. The absolute numbers of CD 57+, CD 16+ and cytotoxic CD 8+ lymphocytes were increased in the peripheral

  3. Prognostic significance of metallothionein in B-cell lymphomas

    DEFF Research Database (Denmark)

    Poulsen, Christian Bjørn; Borup, Rehannah; Borregaard, Niels

    2006-01-01

    We have investigated metallothionein (MT) I and II mRNA and protein in B-cell lymphomas with particular reference to diffuse large B-cell lymphoma (DLBCL). The mRNA profiling was performed on Affymetrix arrays and showed up-regulated MT mRNA in 15 of 48 DLBCLs, including 12 of 23 activated B......-cell (ABC) and 3 of 9 type-3 lesions. In contrast, MT mRNA was low to undetectable in 16 germinal center B-cell (GCB)-type DLBCLs. Only 1 of 15 patients with up-regulated MT mRNA achieved a sustained remission, suggesting that up-regulated MT mRNA constitutes a significant risk factor for treatment failure....... This was confirmed in 2 independent series, which showed significantly shorter 5-year survival in DLBCL with high versus low MT-IIa levels. By immunohistology, MT was shown to be present in both macrophages and lymphoma cells. The proportion of MT-positive macrophages did not correlate with the survival. In contrast...

  4. The Histological Classification of Diffuse Large B-cell Lymphomas

    Science.gov (United States)

    Xie, Yi; Pittaluga, Stefania; Jaffe, Elaine S.

    2015-01-01

    Diffuse large B cell lymphomas (DLBCLs) are aggressive B-cell neoplasms with considerable clinical, biologic and pathologic diversity, in part reflecting the functional diversity of the B-cell system and multiple pathways of transformation. In recent years, the advent of new high-throughput genomic technologies has provided new insights into the biology of DLBCL, leading to the identification of distinct molecular identities and novel pathogenetic pathways. This increasing complexity had led to an expanding number of entities in the WHO classification. Using a multi-modality approach, the updated 2008 classification delineated some new subgroups, including DLBCLs associated with particular age groups or specific anatomic sites, as well as two borderline categories: tumors at the interface between classical Hodgkin lymphoma (cHL) and DLBCL as well as between Burkitt Lymphoma (BL) and DLBCL. This article reviews the histopathologic features of the various aggressive B-cell lymphoma subtypes included in the 2008 classification, with emphasis on some of the new entities as well as areas of diagnostic challenge. PMID:25805585

  5. Teriflunomide treatment reduces B cells in patients with MS.

    Science.gov (United States)

    Gandoglia, Ilaria; Ivaldi, Federico; Laroni, Alice; Benvenuto, Federica; Solaro, Claudio; Mancardi, Gianluigi; Kerlero de Rosbo, Nicole; Uccelli, Antonio

    2017-11-01

    To study the immunomodulatory effect of teriflunomide on innate and adaptive immune cell populations through a pilot, open-label, observational study in a cohort of patients with relapsing-remitting MS. Blood lymphocytes were isolated from 10 patients with MS before and after 3 or 12 months of treatment. Adaptive and innate immune cell subsets were analyzed by flow cytometry as follows: B cells (memory, regulatory, and mature subsets), T cells (effector and regulatory subsets), and natural killer (NK) cells (CD56dim and CD56bright subsets). Our results show that teriflunomide significantly reduces absolute counts of total CD19+ B cells and mature and regulatory B-cell subsets. T cells were affected to a lesser extent, with a trend in reduction of absolute counts for both T effector CD4+ cells (Th1, Th17 and Th1/17) and T regulatory CD8+ and CD4+ cells. Teriflunomide had no detectable effect on NK-cell numbers. In our small cohort, teriflunomide treatment affects mainly and significantly on B-cell numbers, while having a milder effect on T-cell numbers. Larger cohorts are necessary to confirm these findings and understand the effect of teriflunomide on the functionality of these cells.

  6. New Insights into Monoclonal B-Cell Lymphocytosis

    Directory of Open Access Journals (Sweden)

    Christina Kalpadakis

    2014-01-01

    Full Text Available Monoclonal B-cell lymphocytosis (MBL is a premalignant condition characterized by the presence of less than 5000/μL circulating clonal B cells in otherwise healthy individuals. Three subcategories have been identified according to the immunophenotypic features: CLL-like, CD5(+ atypical, and CD5(− MBL. CLL-like MBL is by far the most frequent and best studied category and further divided in low-count [LC] and high-count [HC] MBL, based on a cutoff value of 500/μL clonal B cells. LC-MBL typically remains stable and probably does not represent a truly premalignant condition, but rather an age-related immune senescence. On the other hand, HC-MBL is closely related to CLL-Rai0, bearing similar immunogenetic profile, and is associated with an annual risk of progression to CLL requiring therapy at a rate of 1.1%. Currently there are no reproducible factors for evaluating the risk of progression to CLL. CD5(− MBL is characterized by an immunophenotype consistent with marginal zone origin and displays many similarities with marginal zone lymphomas (MZL, mainly the splenic MZL. The cutoff value of 5000/μL clonal B cells cannot probably be applied in CD5(− MBL, requiring a new definition to describe those cases.

  7. An analysis of B-cell epitope discontinuity.

    Science.gov (United States)

    Sivalingam, Ganesh N; Shepherd, Adrian J

    2012-07-01

    Although it is widely acknowledged that most B-cell epitopes are discontinuous, the degree of discontinuity is poorly understood. For example, given that an antigen having a single epitope that has been chopped into peptides of a specific length, what is the likelihood that one of the peptides will span all the residues belonging to that epitope? Or, alternatively, what is the largest proportion of the epitope's residues that any peptide is likely to contain? These and similar questions are of direct relevance both to computational methods that aim to predict the location of epitopes from sequence (linear B-cell epitope prediction methods) and window-based experimental methods that aim to locate epitopes by assessing the strength of antibody binding to synthetic peptides on a chip. In this paper we present an analysis of the degree of B-cell epitope discontinuity, both in terms of the structural epitopes defined by a set of antigen-antibody complexes in the Protein Data Bank, and with respect to the distribution of key residues that form functional epitopes. We show that, taking a strict definition of discontinuity, all the epitopes in our data set are discontinuous. More significantly, we provide explicit guidance about the choice of peptide length when using window-based B-cell epitope prediction and mapping techniques based on a detailed analysis of the likely effectiveness of different lengths. Copyright © 2012 Elsevier Ltd. All rights reserved.

  8. B-cell Development and Primary Antibody Deficiencies

    NARCIS (Netherlands)

    M.C. van Zelm (Menno)

    2007-01-01

    textabstractB lymphocytes are generated throughout life from hematopoietic stem cells in bone marrow, and contribute to the immune system by the production of antigen-specific antibodies (immunoglobulins; Ig). Two distinct phase of B-cell development can be distinguished: 1) antigen-independent

  9. Comparison of murine B-cell proliferative response to bacterial ...

    Indian Academy of Sciences (India)

    tribpo

    Comparison of murine B-cell proliferative response to bacterial lipopolysaccharide and DNP derivative of. Mycobacterium tuberculosis antigens. ANILA PRABHU and R Κ SAXENA. School of Life Sciences, Jawaharlal Nehru University, New Delhi 110 067, India. MS received 21 July 1993; revised 29 October 1993. Abstract.

  10. Lymphoma classification update: B-cell non-Hodgkin lymphomas.

    Science.gov (United States)

    Jiang, Manli; Bennani, N Nora; Feldman, Andrew L

    2017-05-01

    Lymphomas are classified based on the normal counterpart, or cell of origin, from which they arise. Because lymphocytes have physiologic immune functions that vary both by lineage and by stage of differentiation, the classification of lymphomas arising from these normal lymphoid populations is complex. Recent genomic data have contributed additional complexity. Areas covered: Lymphoma classification follows the World Health Organization (WHO) system, which reflects international consensus and is based on pathological, genetic, and clinical factors. A 2016 revision to the WHO classification of lymphoid neoplasms recently was reported. The present review focuses on B-cell non-Hodgkin lymphomas, the most common group of lymphomas, and summarizes recent changes most relevant to hematologists and other clinicians who care for lymphoma patients. Expert commentary: Lymphoma classification is a continually evolving field that needs to be responsive to new clinical, pathological, and molecular understanding of lymphoid neoplasia. Among the entities covered in this review, the 2016 revision of the WHO classification particularly impact the subclassification and genetic stratification of diffuse large B-cell lymphoma and high-grade B-cell lymphomas, and reflect evolving criteria and nomenclature for indolent B-cell lymphomas and lymphoproliferative disorders.

  11. CD20(+) B Cell Depletion Alters T Cell Homing

    NARCIS (Netherlands)

    Kap, Yolanda S.; van Driel, Nikki; Laman, Jon D.; Tak, Paul P.; 't Hart, Bert A.

    2014-01-01

    Depleting mAbs against the pan B cell marker CD20 are remarkably effective in the treatment of autoimmune-mediated inflammatory disorders, but the underlying mechanisms are poorly defined. The primary objective of this study was to find a mechanistic explanation for the remarkable clinical effect of

  12. Profiling of diffuse large B-cell lymphoma by immunohistochemistry

    DEFF Research Database (Denmark)

    Sjö, Lene Dissing; Poulsen, Christian Bjørn; Hansen, Mads

    2007-01-01

    Diffuse large B-cell lymphoma (DLBCL) is a frequent lymphoma subtype with a heterogeneous behavior and a variable response to conventional chemotherapy. This clinical diversity is believed to reflect differences in the molecular pathways leading to lymphomagenesis. In this study, we have analyzed...

  13. Antigen receptor function in chronic lymphocytic leukemia B cells

    NARCIS (Netherlands)

    Lankester, A. C.; Schijndel, G. M.; Pakker, N. G.; van Oers, R. H.; van Lier, R. A.

    1996-01-01

    Functional studies revealed that two groups of B chronic lymphocytic leukemia (B-CLL) can be distinguished based on their capacity to mount a proliferative response following B-cell antigen receptor (BCR) cross-linking. The molecular basis for the functional distinction between these B-CLL groups

  14. Autoantibodies in autoimmune thyroid disease promote immune complex formation with self antigens and increase B cell and CD4+ T cell proliferation in response to self antigens

    DEFF Research Database (Denmark)

    Nielsen, Claus Henrik; Hegedüs, Laszlo; Leslie, Robert Graham Quinton

    2004-01-01

    B cells are centrally involved as antigen-presenting cells in certain autoimmune diseases. To establish whether autoantibodies form immune complexes (IC) with self-antigens in autoimmune thyroid disease (AITD) and promote B cell uptake of self-antigen, sera from patients with Hashimoto......'s thyroiditis (HT), Graves' disease (GD) and healthy controls were incubated with human thyroglobulin (Tg) before adding normal peripheral blood mononuclear cells. The deposition of immunoglobulins and C3 fragments on B cells was then assessed. Inclusion of Tg in serum from HT patients promoted B cell capture...... of IgG and C3 fragments. Furthermore, the binding of Tg to B cells in preparations of normal blood cells was higher in HT serum than in serum from controls and correlated positively with the serum anti-Tg activity, as did the B and CD4+ T cell proliferation. Disruption of the three-dimensional structure...

  15. Modeling Engineered Nanomaterials (ENMs) Fate and Transport in Aquatic Ecosystems

    Science.gov (United States)

    Under the Toxic Substances Control Act (TSCA), the Environmental Protection Agency (EPA) is required to perform new chemical reviews of engineered nanomaterials (ENMs) identified in pre-manufacture notices. However, environmental fate models developed for traditional contaminants...

  16. Notch signaling in the pancreas: patterning and cell fate specification.

    Science.gov (United States)

    Afelik, Solomon; Jensen, Jan

    2013-07-01

    Notch signaling is an evolutionarily conserved mechanism adapted to control binary fate decisions. The first evidence of Notch in pancreatic development focused on its critical role in controlling endocrine fate decisions. Since then, we have come to understand that this signaling system operates iteratively in the pancreas, and is not limited to the control of endocrine fate decision. Notch appears to play a role in early organ development, then during organ domain patterning, and only during a final refinement process, in the control of terminal cell fates. In so doing, Notch receptors and their ligands are under the influence of a wealth of genetic components that together help orchestrate the building of a complex, glandular organ. Copyright © 2012 Wiley Periodicals, Inc.

  17. PAX8 Distinguishes Diffuse Large B-Cell Lymphoma Mimicking Sarcoma

    Directory of Open Access Journals (Sweden)

    Michelle S. Hirsch

    2017-01-01

    Full Text Available PAX8 is important for embryogenesis of the thyroid, Müllerian system, and upper urinary/renal tract, and expression of PAX8 has been described in carcinomas from each of these sites. The sensitivity and specificity of the polyclonal PAX8 antibody in a large cohort of epithelial tumors as well as lymphomas have been previously determined, the latter because polyclonal PAX8 is known to be immunoreactive in nonneoplastic B-cell lymphocytes which are often used as the positive internal control for immunohistochemistry. In this case report, PAX8 was a diagnostic clue for revising a previous diagnosis of unclassified high grade sarcoma to diffuse large B-cell lymphoma. This case report demonstrates a pitfall for PAX8 immunoreactivity and acts as a reminder that lymphoma should be included in the differential diagnosis of a PAX8 positive, epithelial cell marker negative tumor of unknown primary origin.

  18. Characterization of Regulatory B Cells in Graves' Disease and Hashimoto's Thyroiditis

    DEFF Research Database (Denmark)

    Kristensen, Birte; Hegedüs, Laszlo; Lundy, Steven K

    2015-01-01

    A hallmark of regulatory B cells is IL-10 production, hence their designation as IL-10+ B cells. Little is known about the ability of self-antigens to induce IL-10+ B cells in Graves' disease (GD), Hashimoto's thyroiditis (HT), or other autoimmune disease. Here we pulsed purified B cells from 12 HT...

  19. ZBTB32 restricts the duration of memory B cell recall responses1

    Science.gov (United States)

    Jash, Arijita; Wang, Yinan; Weisel, Florian J.; Scharer, Christopher D.; Boss, Jeremy M.; Shlomchik, Mark J.; Bhattacharya, Deepta

    2016-01-01

    Memory B cell responses are more rapid and of greater magnitude than are primary antibody responses. The mechanisms by which these secondary responses are eventually attenuated remain unknown. We demonstrate that the transcription factor ZBTB32 limits the rapidity and duration of antibody recall responses. ZBTB32 is highly expressed by mouse and human memory B cells, but not by their naïve counterparts. Zbtb32−/− mice mount normal primary antibody responses to T-dependent antigens. However, Zbtb32−/− memory B cell-mediated recall responses occur more rapidly and persist longer than do control responses. Microarray analyses demonstrate that Zbtb32−/− secondary bone marrow plasma cells display elevated expression of genes that promote cell cycle progression and mitochondrial function relative to wild-type controls. BrdU labeling and adoptive transfer experiments confirm more rapid production and a cell-intrinsic survival advantage of Zbtb32−/− secondary plasma cells relative to wild-type counterparts. ZBTB32 is therefore a novel negative regulator of antibody recall responses. PMID:27357154

  20. The B cell antigen receptor and overexpression of MYC can cooperate in the genesis of B cell lymphomas.

    Directory of Open Access Journals (Sweden)

    Yosef Refaeli

    2008-06-01

    Full Text Available A variety of circumstantial evidence from humans has implicated the B cell antigen receptor (BCR in the genesis of B cell lymphomas. We generated mouse models designed to test this possibility directly, and we found that both the constitutive and antigen-stimulated state of a clonal BCR affected the rate and outcome of lymphomagenesis initiated by the proto-oncogene MYC. The tumors that arose in the presence of constitutive BCR differed from those initiated by MYC alone and resembled chronic B cell lymphocytic leukemia/lymphoma (B-CLL, whereas those that arose in response to antigen stimulation resembled large B-cell lymphomas, particularly Burkitt lymphoma (BL. We linked the genesis of the BL-like tumors to antigen stimulus in three ways. First, in reconstruction experiments, stimulation of B cells by an autoantigen in the presence of overexpressed MYC gave rise to BL-like tumors that were, in turn, dependent on both MYC and the antigen for survival and proliferation. Second, genetic disruption of the pathway that mediates signaling from the BCR promptly killed cells of the BL-like tumors as well as the tumors resembling B-CLL. And third, growth of the murine BL could be inhibited by any of three distinctive immunosuppressants, in accord with the dependence of the tumors on antigen-induced signaling. Together, our results provide direct evidence that antigenic stimulation can participate in lymphomagenesis, point to a potential role for the constitutive BCR as well, and sustain the view that the constitutive BCR gives rise to signals different from those elicited by antigen. The mouse models described here should be useful in exploring further the pathogenesis of lymphomas, and in preclinical testing of new therapeutics.

  1. Assessment of CD37 B-cell antigen and cell-of-origin significantly improves risk prediction in diffuse large B-cell lymphoma

    DEFF Research Database (Denmark)

    Xu-Monette, Zijun Y; Li, Ling; Byrd, John C

    2016-01-01

    CD37 (tetraspanin TSPAN26) is a B-cell surface antigen widely expressed on mature B cells. CD37 is involved in immune regulation and tumor suppression but its function has not been fully elucidated. We assessed CD37 expression in de novo diffuse large B-cell lymphoma (DLBCL), and investigated its...

  2. Trafficking of B cell antigen in lymph nodes

    DEFF Research Database (Denmark)

    Gonzalez, Santiago F.; Degn, Søren Egedal; Pitcher, Lisa A.

    2011-01-01

    ). The experimental demonstration by Nossal & Lederberg ( 3 ) that B lymphocytes bear receptors for a single antigen raised the central question of where B lymphocytes encounter antigen. This question has remained mostly unanswered until recently. Advances in techniques such as multiphoton intravital microscopy ( 4......The clonal selection theory first proposed by Macfarlane Burnet is a cornerstone of immunology ( 1 ). At the time, it revolutionized the thinking of immunologists because it provided a simple explanation for lymphocyte specificity, immunological memory, and elimination of self-reactive clones ( 2......, 5 ) have provided new insights into the trafficking of B cells and their antigen. In this review, we summarize these advances in the context of our current view of B cell circulation and activation....

  3. Epigenetic Impact on EBV Associated B-Cell Lymphomagenesis

    Directory of Open Access Journals (Sweden)

    Shatadru Ghosh Roy

    2016-11-01

    Full Text Available Epigenetic modifications leading to either transcriptional repression or activation, play an indispensable role in the development of human cancers. Epidemiological study revealed that approximately 20% of all human cancers are associated with tumor viruses. Epstein-Barr virus (EBV, the first human tumor virus, demonstrates frequent epigenetic alterations on both viral and host genomes in associated cancers—both of epithelial and lymphoid origin. The cell type-dependent different EBV latent gene expression patterns appear to be determined by the cellular epigenetic machinery and similarly viral oncoproteins recruit epigenetic regulators in order to deregulate the cellular gene expression profile resulting in several human cancers. This review elucidates the epigenetic consequences of EBV–host interactions during development of multiple EBV-induced B-cell lymphomas, which may lead to the discovery of novel therapeutic interventions against EBV-associated B-cell lymphomas by alteration of reversible patho-epigenetic markings.

  4. Cutaneous B cell lymphomas: Report of two interesting cases

    Directory of Open Access Journals (Sweden)

    Ravichandran Gurumurthy

    2015-01-01

    Full Text Available Cutaneous B cell lymphomas can arise primarily from the skin or may occur due to secondary spread from nodal lymphomas. Primary lymphomas are confined to the skin without systemic spread and they differ from secondary lymphomas in their clinical behavior, treatment and prognosis. Cutaneous lymphomas being relatively rare, lack of precise definition and understanding of their clinical behavior diseases leads to pitfalls in the diagnosis. We report two cases of cutaneous B cell lymphomas who presented with fever of unknown origin initially and later found to have skin lesions. Hence, skin can be a potential diagnostic clue in the evaluation of patients with fever of unknown origin. The distinctions between the primary and the secondary lymphomas become important in choosing the treatment and assessing the prognosis.

  5. Micro RNA-19a suppresses thrombospondin-1 in CD35(+) B cells in the intestine of mice with food allergy.

    Science.gov (United States)

    Yang, Li-Tao; Li, Xiao-Xi; Qiu, Shu-Qi; Zeng, Lu; Li, Lin-Jing; Feng, Bai-Sui; Zheng, Peng-Yuan; Liu, Zhi-Gang; Yang, Ping-Chang

    2016-01-01

    Disruption of immune tolerance is associated in the pathogenesis of allergy. Thrombospondin-1 (TSP1) plays a role in the maintenance of immune tolerance, which is compromised in allergic disorders. Micro RNA (miR) is involved in the regulation of immune responses. This study tests a hypothesis that miR-17-92 cluster is involved in the regulation of TSP1 in the intestinal CD35(+) B cells. In this study, a food allergy mouse model was developed. The intestinal B cells were isolated to be analyzed for the expression of a miR-17-92 cluster and TSP1. The role of miR-19a in the suppression of TSP1 in B cells was tested in a cell culture model. We observed that the levels of TSP1 were significantly decreased; the levels of miR-19a were significantly increased in intestinal CD35(+) B cells of mice sensitized to ovalbumin (OVA) as compared with naïve controls. Exposure to interleukin (IL)-4 suppressed the expression of TSP1 in B cells, which was abolished by inhibition of miR-19a. miR-19a mediated the effects of IL-4 on repressing TSP1 expression in B cells. We conclude that IL-4 suppresses the expression of TSP1 in the intestinal CD35(+) B cells via up regulating miR-19a. The miR-19a may be a target to regulate the immune tolerant status in the body.

  6. Complement-dependent transport of antigen into B cell follicles

    DEFF Research Database (Denmark)

    Gonzalez, Santiago F.; Lukacs-Kornek, Veronika; Kuligowski, Michael P.

    2010-01-01

    an additional novel pathway in which complement C3 and its receptors enhance humoral immunity through delivery of Ag to the B cell compartment. In this review, we discuss this pathway and highlight several novel exceptions recently found with a model influenza vaccine, such as mannose-binding lectin...... opsonization of influenza and uptake by macrophages, and the capture of virus by dendritic cells residing in the medullary compartment of peripheral lymph nodes....

  7. Bilateral proliferative retinopathy in B-cell acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Devesh Kumawat

    2018-01-01

    Full Text Available A 4-year-old child with B-cell acute lymphoblastic leukemia presented with vitreous hemorrhage due to proliferative retinopathy in both eyes. Pars plana vitrectomy was performed in both eyes to clear nonresolving vitreous hemorrhage after systemic stabilization. Visual recovery was limited by the disc drag in the right eye and subfoveal exudation in the left eye. Etiopathogenesis and management of proliferative retinopathy in acute leukemias are discussed.

  8. Fate in intermittent claudication

    DEFF Research Database (Denmark)

    Jelnes, Rolf; Gaardsting, O; Hougaard Jensen, K

    1986-01-01

    The fate of 257 consecutive patients (100 women) aged 36-85 years (mean 65) first seen with intermittent claudication in 1977 was analysed after a mean of 6.5 (SD 0.5) years. When first seen none of the patients complained of rest pain or had ulcers or gangrenous lesions on the feet. At follow up......, or an ankle/arm pressure index below 50% were individually significantly associated with progression of the arteriosclerotic disease. These findings show the importance of peripheral blood pressure measurements in the management of patients with intermittent claudication due to arteriosclerotic disease....

  9. Lenalidomide in Diffuse Large B-Cell Lymphomas

    Directory of Open Access Journals (Sweden)

    Annalisa Chiappella

    2012-01-01

    Full Text Available Diffuse Large B-cell Lymphomas (DLBCL are the most frequent Non-Hodgkin Lymphomas (NHL. The addition of Rituximab to the standard chemotherapy CHOP improved the outcome in this patients, but so far 40% of patients experienced relapse or progressive disease. Lenalidomide, an immunomodulatory agent, had direct tumoricidal and antiangiogenetic actions on tumor cells and was able to modulate tumor-cell microenvironment, with the restoration of impaired T-cell activity and the formation of immuno-synapsis. Based on these actions, lenalidomide represented an active drug on aggressive relapsed NHL. In this review, the most relevant clinical trials for the use of lenalidomide in DLBCL were reported. Monotherapy with lenalidomide showed an activity in term of overall response rate, with acceptable hematological and extrahematological toxicities in relapsed/refractory aggressive NHL. The role of lenalidomide as salvage therapy in both cell of origin patterns in DLBCL (germinal center B-cell/activated B-cell was reported in preliminary data. Preliminary data regarding the role of lenalidomide in addition to chemoimmunotherapy (R-CHOP in first line clinical trials were discussed; data of safety, feasibility and efficacy were promising.

  10. Management of diffuse large B-cell lymphoma (DLBCL).

    Science.gov (United States)

    Kubuschok, Boris; Held, Gerhard; Pfreundschuh, Michael

    2015-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. While CHOP was the standard combination chemotherapy for 25 years, the incorporation of the CD20 antibody rituximab at the beginning of this century has considerably improved the outcome of all patients with DLBCL: Depending on the prognostic subgroup, only half to one-third of the patients die of their DLBCL compared to pre-rituximab era. Treatment is usually tailored according to the individual risk profile of a DLBCL patient according to the International Prognostic Index (IPI). Assignment of DLBCL according to the gene expression profile into DLBLC originating from a germinal center B cell (GC type) or from an activated B cell (ABC type) has provided novel insights into the pathogenesis of the respective DLBCL, identified molecules which are indispensable for the survival of the lymphoma cells and provided targets for novel "targeted therapies" drugs. Incorporating these new drugs into combination immunochemotherapy or substituting single drugs in the R-CHOP combination will result in even higher cure rates of and/or less toxicity for patients with DLBCL in the decade to come.

  11. Large anaplastic spinal B-cell lymphoma in a cat.

    Science.gov (United States)

    Flatland, Bente; Fry, Michael M; Newman, Shelley J; Moore, Peter F; Smith, Joanne R; Thomas, William B; Casimir, Roslyn H

    2008-12-01

    A 5-year-old female spayed domestic shorthair cat was presented for evaluation of tetraparesis. The neurologic lesion was localized to the cervical spinal segment (C1-C6). A left axillary mass was identified, and the results of fine needle aspiration cytology indicated malignant round cell neoplasia of possible histiocytic origin. The cells were large, had marked anisocytosis and anisokaryosis, occasional bi- and multinucleation, and cytoplasmic vacuolation. Euthanasia was performed due to the poor prognosis associated with severe, progressive neurologic signs and a malignant neoplasm. Postmortem examination revealed spinal cord compression and an extradural mass at the C1-C2 spinal segment, with neoplastic cells in the adjacent vertebral bodies, surrounding skeletal muscle, left axillary lymph node, and bone marrow from the right femur. The initial histologic diagnosis was anaplastic sarcoma, but immunohistochemical results indicated the cells were CD20+ and CD45R+ and CD3-, compatible with a diagnosis of B-cell lymphoma. CD79a staining was nonspecific and uninterpretable. Weak to moderate CD18 positivity and E-cadherin positivity were also observed. Clonality of the B-cell population could not be demonstrated using PCR testing for antigen receptor gene rearrangement. To the authors' knowledge, this is the first reported case of a feline spinal anaplastic B-cell lymphoma exhibiting bi- and multinucleated cells. The prognostic significance of this cell morphology and immunophenotype is unknown.

  12. Effects of IRF5 Lupus Risk Haplotype on Pathways Predicted to Influence B Cell Functions

    Science.gov (United States)

    Guthridge, Joel M.; Clark, Daniel N.; Templeton, Amanda; Dominguez, Nicolas; Lu, Rufei; Vidal, Gabriel S.; Kelly, Jennifer A.; Kauffman, Kenneth M.; Harley, John B.; Gaffney, Patrick M.; James, Judith A.; Poole, Brian D.

    2012-01-01

    Both genetic and environmental interactions affect systemic lupus erythematosus (SLE) development and pathogenesis. One known genetic factor associated with lupus is a haplotype of the interferon regulatory factor 5 (IRF5) gene. Analysis of global gene expression microarray data using gene set enrichment analysis identified multiple interferon- and inflammation-related gene sets significantly overrepresented in cells with the risk haplotype. Pathway analysis using expressed genes from the significant gene sets impacted by the IRF5 risk haplotype confirmed significant correlation with the interferon pathway, Toll-like receptor pathway, and the B-cell receptor pathway. SLE patients with the IRF5 risk haplotype have a heightened interferon signature, even in an unstimulated state (P = 0.011), while patients with the IRF5 protective haplotype have a B cell interferon signature similar to that of controls. These results identify multiple genes in functionally significant pathways which are affected by IRF5 genotype. They also establish the IRF5 risk haplotype as a key determinant of not only the interferon response, but also other B-cell pathways involved in SLE. PMID:22500098

  13. Protection against Pertussis in Humans Correlates to Elevated Serum Antibodies and Memory B Cells

    Directory of Open Access Journals (Sweden)

    Valentina Marcellini

    2017-09-01

    Full Text Available Pertussis is a respiratory infection caused by Bordetella pertussis that may be particularly severe and even lethal in the first months of life when infants are still too young to be vaccinated. Adults and adolescents experience mild symptoms and are the source of infection for neonates. Adoptive maternal immunity does not prevent pertussis in the neonate. We compared the specific immune response of mothers of neonates diagnosed with pertussis and mothers of control children. We show that women have pre-existing pertussis-specific antibodies and memory B cells and react against the infection with a recall response increasing the levels specific serum IgG, milk IgA, and the frequency of memory B cells of all isotypes. Thus, the maternal immune system is activated in response to pertussis and effectively prevents the disease indicating that the low levels of pre-formed serum antibodies are insufficient for protection. For this reason, memory B cells play a major role in the adult defense. The results of this study suggest that new strategies for vaccine design should aim at increasing long-lived plasma cells and their antibodies.

  14. Effects of IRF5 Lupus Risk Haplotype on Pathways Predicted to Influence B Cell Functions

    Directory of Open Access Journals (Sweden)

    Joel M. Guthridge

    2012-01-01

    Full Text Available Both genetic and environmental interactions affect systemic lupus erythematosus (SLE development and pathogenesis. One known genetic factor associated with lupus is a haplotype of the interferon regulatory factor 5 (IRF5 gene. Analysis of global gene expression microarray data using gene set enrichment analysis identified multiple interferon- and inflammation-related gene sets significantly overrepresented in cells with the risk haplotype. Pathway analysis using expressed genes from the significant gene sets impacted by the IRF5 risk haplotype confirmed significant correlation with the interferon pathway, Toll-like receptor pathway, and the B-cell receptor pathway. SLE patients with the IRF5 risk haplotype have a heightened interferon signature, even in an unstimulated state (P=0.011, while patients with the IRF5 protective haplotype have a B cell interferon signature similar to that of controls. These results identify multiple genes in functionally significant pathways which are affected by IRF5 genotype. They also establish the IRF5 risk haplotype as a key determinant of not only the interferon response, but also other B-cell pathways involved in SLE.

  15. γδ T cells affect IL-4 production and B-cell tolerance.

    Science.gov (United States)

    Huang, Yafei; Heiser, Ryan A; Detanico, Thiago O; Getahun, Andrew; Kirchenbaum, Greg A; Casper, Tamara L; Aydintug, M Kemal; Carding, Simon R; Ikuta, Koichi; Huang, Hua; Cambier, John C; Wysocki, Lawrence J; O'Brien, Rebecca L; Born, Willi K

    2015-01-06

    γδ T cells can influence specific antibody responses. Here, we report that mice deficient in individual γδ T-cell subsets have altered levels of serum antibodies, including all major subclasses, sometimes regardless of the presence of αβ T cells. One strain with a partial γδ deficiency that increases IgE antibodies also displayed increases in IL-4-producing T cells (both residual γδ T cells and αβ T cells) and in systemic IL-4 levels. Its B cells expressed IL-4-regulated inhibitory receptors (CD5, CD22, and CD32) at diminished levels, whereas IL-4-inducible IL-4 receptor α and MHCII were increased. They also showed signs of activation and spontaneously formed germinal centers. These mice displayed IgE-dependent features found in hyper-IgE syndrome and developed antichromatin, antinuclear, and anticytoplasmic autoantibodies. In contrast, mice deficient in all γδ T cells had nearly unchanged Ig levels and did not develop autoantibodies. Removing IL-4 abrogated the increases in IgE, antichromatin antibodies, and autoantibodies in the partially γδ-deficient mice. Our data suggest that γδ T cells, controlled by their own cross-talk, affect IL-4 production, B-cell activation, and B-cell tolerance.

  16. Altered Distribution of Peripheral Blood Memory B Cells in Humans Chronically Infected with Trypanosoma cruzi

    Science.gov (United States)

    Fernández, Esteban R.; Olivera, Gabriela C.; Quebrada Palacio, Luz P.; González, Mariela N.; Hernandez-Vasquez, Yolanda; Sirena, Natalia María; Morán, María L.; Ledesma Patiño, Oscar S.; Postan, Miriam

    2014-01-01

    Numerous abnormalities of the peripheral blood T cell compartment have been reported in human chronic Trypanosoma cruzi infection and related to prolonged antigenic stimulation by persisting parasites. Herein, we measured circulating lymphocytes of various phenotypes based on the differential expression of CD19, CD4, CD27, CD10, IgD, IgM, IgG and CD138 in a total of 48 T. cruzi-infected individuals and 24 healthy controls. Infected individuals had decreased frequencies of CD19+CD27+ cells, which positively correlated with the frequencies of CD4+CD27+ cells. The contraction of CD19+CD27+ cells was comprised of IgG+IgD-, IgM+IgD- and isotype switched IgM-IgD- memory B cells, CD19+CD10+CD27+ B cell precursors and terminally differentiated CD19+CD27+CD138+ plasma cells. Conversely, infected individuals had increased proportions of CD19+IgG+CD27-IgD- memory and CD19+IgM+CD27-IgD+ transitional/naïve B cells. These observations prompted us to assess soluble CD27, a molecule generated by the cleavage of membrane-bound CD27 and used to monitor systemic immune activation. Elevated levels of serum soluble CD27 were observed in infected individuals with Chagas cardiomyopathy, indicating its potentiality as an immunological marker for disease progression in endemic areas. In conclusion, our results demonstrate that chronic T. cruzi infection alters the distribution of various peripheral blood B cell subsets, probably related to the CD4+ T cell deregulation process provoked by the parasite in humans. PMID:25111833

  17. A Brake for B Cell Proliferation: Appropriate responses to metabolic stress are crucial to maintain B cell viability and prevent malignant outgrowth.

    Science.gov (United States)

    Jellusova, Julia; Rickert, Robert C

    2017-11-01

    B cell activation is accompanied by metabolic adaptations to meet the increased energetic demands of proliferation. The metabolic composition of the microenvironment is known to change during a germinal center response, in inflamed tissue and to vary significantly between different organs. To sustain cellular homeostasis B cells need to be able to dynamically adapt to changes in their environment. An inability to take up and process available nutrients can result in impaired B cell growth and a diminished humoral immune response. Furthermore, the metabolic microenvironment can affect B cell signaling and provide a means to avoid aberrant proliferation or modulate B cell function. Thus, a better understanding of the intricate interplay between cell signaling and metabolism could provide novel insight into how B cell function is regulated and have implications for the development of vaccines or treatment of autoimmune disorders and B cell derived malignancies. © 2017 WILEY Periodicals, Inc.

  18. Racial differences in B cell receptor signaling pathway activation

    Directory of Open Access Journals (Sweden)

    Longo Diane M

    2012-06-01

    Full Text Available Abstract Background Single-cell network profiling (SCNP is a multi-parametric flow cytometry-based approach that simultaneously measures basal and modulated intracellular signaling activity in multiple cell subpopulations. Previously, SCNP analysis of a broad panel of immune signaling pathways in cell subsets within PBMCs from 60 healthy donors identified a race-associated difference in B cell anti-IgD-induced PI3K pathway activity. Methods The present study extended this analysis to a broader range of signaling pathway components downstream of the B cell receptor (BCR in European Americans and African Americans using a subset of donors from the previously analyzed cohort of 60 healthy donors. Seven BCR signaling nodes (a node is defined as a paired modulator and intracellular readout were measured at multiple time points by SCNP in PBMCs from 10 healthy donors [5 African Americans (36-51 yrs, 5 European Americans (36-56 yrs, all males]. Results Analysis of BCR signaling activity in European American and African American PBMC samples revealed that, compared to the European American donors, B cells from African Americans had lower anti-IgD induced phosphorylation of multiple BCR pathway components, including the membrane proximal proteins Syk and SFK as well as proteins in the PI3K pathway (S6 and Akt, the MAPK pathways (Erk and p38, and the NF-κB pathway (NF-κB. In addition to differences in the magnitude of anti-IgD-induced pathway activation, racial differences in BCR signaling kinetic profiles were observed. Further, the frequency of IgD+ B cells differed by race and strongly correlated with BCR pathway activation. Thus, the race-related difference in BCR pathway activation appears to be attributable at least in part to a race-associated difference in IgD+ B cell frequencies. Conclusions SCNP analysis enabled the identification of statistically significant race-associated differences in BCR pathway activation within PBMC samples from

  19. Racial differences in B cell receptor signaling pathway activation.

    Science.gov (United States)

    Longo, Diane M; Louie, Brent; Mathi, Kavita; Pos, Zoltan; Wang, Ena; Hawtin, Rachael E; Marincola, Francesco M; Cesano, Alessandra

    2012-06-06

    Single-cell network profiling (SCNP) is a multi-parametric flow cytometry-based approach that simultaneously measures basal and modulated intracellular signaling activity in multiple cell subpopulations. Previously, SCNP analysis of a broad panel of immune signaling pathways in cell subsets within PBMCs from 60 healthy donors identified a race-associated difference in B cell anti-IgD-induced PI3K pathway activity. The present study extended this analysis to a broader range of signaling pathway components downstream of the B cell receptor (BCR) in European Americans and African Americans using a subset of donors from the previously analyzed cohort of 60 healthy donors. Seven BCR signaling nodes (a node is defined as a paired modulator and intracellular readout) were measured at multiple time points by SCNP in PBMCs from 10 healthy donors [5 African Americans (36-51 yrs), 5 European Americans (36-56 yrs), all males]. Analysis of BCR signaling activity in European American and African American PBMC samples revealed that, compared to the European American donors, B cells from African Americans had lower anti-IgD induced phosphorylation of multiple BCR pathway components, including the membrane proximal proteins Syk and SFK as well as proteins in the PI3K pathway (S6 and Akt), the MAPK pathways (Erk and p38), and the NF-κB pathway (NF-κB). In addition to differences in the magnitude of anti-IgD-induced pathway activation, racial differences in BCR signaling kinetic profiles were observed. Further, the frequency of IgD+ B cells differed by race and strongly correlated with BCR pathway activation. Thus, the race-related difference in BCR pathway activation appears to be attributable at least in part to a race-associated difference in IgD+ B cell frequencies. SCNP analysis enabled the identification of statistically significant race-associated differences in BCR pathway activation within PBMC samples from healthy donors. Understanding race-associated contrasts in immune

  20. Simultaneous Assessment of Rotavirus-Specific Memory B Cells and Serological Memory after B Cell Depletion Therapy with Rituximab

    Science.gov (United States)

    Herrera, Daniel; Rojas, Olga L.; Duarte-Rey, Carolina; Mantilla, Rubén D.; Ángel, Juana; Franco, Manuel A.

    2014-01-01

    The mechanisms that contribute to the maintenance of serological memory are still unclear. Rotavirus (RV) memory B cells (mBc) are enriched in IgM+ and CD27- subpopulations, which are associated with autoimmune diseases pathogenesis. In patients with autoimmune diseases treated with Rituximab (RTX), some autoantibodies (auto-Abs) decrease after treatment, but other auto-Abs and pathogen-specific IgG Abs remain unchanged. Thus, maintenance of autoimmune and pathogen-specific serological memory may depend on the type of antigen and/or Ab isotype evaluated. Antigen-specific mBc and antigen-specific Abs of different isotypes have not been simultaneously assessed in patients after RTX treatment. To study the relationship between mBc subpopulations and serological memory we characterized total, RV- and tetanus toxoid (TT)-specific mBc by flow cytometry in patients with autoimmune diseases before and after treatment with RTX. We also measured total, RV- and TT-Abs, and some auto-Abs by kinetic nephelometry, ELISA, and EliA tests, respectively. Minor differences were observed between the relative frequencies of RV-mBc in healthy controls and patients with autoimmune disease. After RTX treatment, naïve Bc and total, RV- and TT-specific mBc [IgM+, switched (IgA+/IgG+), IgM+ only, IgD+ only, and CD27- (IgA+/IgG+/IgM+)] were significantly diminished. An important decrease in total plasma IgM and minor decreases in total IgG and IgA levels were also observed. IgM rheumatoid factor, IgG anti-CCP, and IgG anti-dsDNA were significantly diminished. In contrast, RV-IgA, RV-IgG and RV-IgG1, and TT-IgG titers remained stable. In conclusion, in patients with autoimmunity, serological memory against RV and TT seem to be maintained by long-lived plasma cells, unaffected by RTX, and an important proportion of total IgM and serological memory against some auto-antigens seem to be maintained by short-lived plasma cells, dependent on mBc precursors depleted by RTX. PMID:24819618

  1. In kidney transplant patients, alemtuzumab but not basiliximab/low-dose rabbit anti-thymocyte globulin induces B cell depletion and regeneration, which associates with a high incidence of de novo donor-specific anti-HLA antibody development.

    Science.gov (United States)

    Todeschini, Marta; Cortinovis, Monica; Perico, Norberto; Poli, Francesca; Innocente, Annalisa; Cavinato, Regiane Aparecida; Gotti, Eliana; Ruggenenti, Piero; Gaspari, Flavio; Noris, Marina; Remuzzi, Giuseppe; Casiraghi, Federica

    2013-09-01

    In this single-center matched-cohort study, we evaluated the phenotype of repopulating B cells and its correlation with donor-specific anti-HLA Ab development and long-term graft function in 16 renal transplant recipients and 32 age- and gender-matched controls induced with alemtuzumab or basiliximab (Bas)/low-dose rabbit anti-thymocyte globulin (rATG), respectively. Alemtuzumab, but not Bas/rATG, profoundly depleted peripheral B cells in the first 2 mo posttransplantation. Early posttransplant, naive B cells were significantly depleted, whereas Ag-experienced and memory B cells were partially spared. Transitional B cells transiently increased 2 mo posttransplant. At month 6 posttransplant, pregerminal center B cells emerged, a process promoted by increased BAFF serum levels. Thereafter, B cell counts increased progressively, mainly due to expansion of naive B cells. Conversely, Bas/rATG did not modify the B cell phenotype throughout the follow-up period. Alemtuzumab was associated with a higher incidence of de novo DSA compared with Bas/rATG. DSA development was predicted by changes in the B cell compartment and correlated with worse long-term graft function. Thus, alemtuzumab-induced B cell depletion/reconstitution may promote chronic humoral responses against the graft.

  2. Reduced CD5(+) CD24(hi) CD38(hi) and interleukin-10(+) regulatory B cells in active anti-neutrophil cytoplasmic autoantibody-associated vasculitis permit increased circulating autoantibodies.

    Science.gov (United States)

    Aybar, L T; McGregor, J G; Hogan, S L; Hu, Y; Mendoza, C E; Brant, E J; Poulton, C J; Henderson, C D; Falk, R J; Bunch, D O

    2015-05-01

    Pathogenesis of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is B cell-dependent, although how particular B cell subsets modulate immunopathogenesis remains unknown. Although their phenotype remains controversial, regulatory B cells (Bregs ), play a role in immunological tolerance via interleukin (IL)-10. Putative CD19(+) CD24(hi) CD38(hi) and CD19(+) CD24(hi) CD27(+) Bregs were evaluated in addition to their CD5(+) subsets in 69 patients with ANCA-associated vasculitis (AAV). B cell IL-10 was verified by flow cytometry following culture with CD40 ligand and cytosine-phosphate-guanosine (CpG) DNA. Patients with active disease had decreased levels of CD5(+) CD24(hi) CD38(hi) B cells and IL-10(+) B cells compared to patients in remission and healthy controls (HCs). As IL-10(+) and CD5(+) CD24(hi) CD38(hi) B cells normalized in remission within an individual, ANCA titres decreased. The CD5(+) subset of CD24(hi) CD38(hi) B cells decreases in active disease and rebounds during remission similarly to IL-10-producing B cells. Moreover, CD5(+) B cells are enriched in the ability to produce IL-10 compared to CD5(neg) B cells. Together these results suggest that CD5 may identify functional IL-10-producing Bregs . The malfunction of Bregs during active disease due to reduced IL-10 expression may thus permit ANCA production. © 2014 British Society for Immunology.

  3. TRPM4 expression is associated with activated B cell subtype and poor survival in diffuse large B cell lymphoma

    DEFF Research Database (Denmark)

    Loo, Suet K.; Ch'ng, Ewe S.; Md Salleh, Md Salzihan

    2017-01-01

    Aims: Transient receptor potential channel melastatin 4 (TRPM4) is an ion channel that regulates influx of calcium cations (Ca2+). Recent studies suggest that TRPM4 is an oncoprotein, and its up-regulated transcript level has been reported in diffuse large B cell lymphoma (DLBCL). We aimed...... to normal germinal centre B (GCB) cells, were expressed more highly in the activated B cell-like DLBCL (ABC-DLBCL) subtype and higher TRPM4 transcripts conferred worse overall survival (OS) in R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-treated DLBCL cases (P ... with more aggressive clinical parameters, including higher lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group (ECOG) scores or stage (P

  4. Stream dynamics and chemical transformations control the environmental fate of silver and zinc oxide nanoparticles in a watershed-scale model.

    Science.gov (United States)

    Dale, Amy L; Lowry, Gregory V; Casman, Elizabeth A

    2015-06-16

    Mathematical models are needed to estimate environmental concentrations of engineered nanoparticles (NPs), which enter the environment upon the use and disposal of consumer goods and other products. We present a spatially resolved environmental fate model for the James River Basin, Virginia, that explores the influence of daily variation in streamflow, sediment transport, and stream loads from point and nonpoint sources on water column and sediment concentrations of zinc oxide (ZnO) and silver (Ag) NPs and their reaction byproducts over 20 simulation years. Spatial and temporal variability in sediment transport rates led to high NP transport such that less than 6% of NP-derived metals were retained in the river and sediments. Chemical transformations entirely eliminated ZnO NPs and doubled Zn mobility in the stream relative to Ag. Agricultural runoff accounted for 23% of total metal stream loads from NPs. Average NP-derived metal concentrations in the sediment varied spatially up to 9 orders of magnitude, highlighting the need for high-resolution models. Overall, our results suggest that "first generation" NP risk models have probably misrepresented NP fate in freshwater rivers due to low model resolutions and the simplification of NP chemistry and sediment transport.

  5. Access to follicular dendritic cells is a pivotal step in murine chronic lymphocytic leukemia B-cell activation and proliferation.

    Science.gov (United States)

    Heinig, Kristina; Gätjen, Marcel; Grau, Michael; Stache, Vanessa; Anagnostopoulos, Ioannis; Gerlach, Kerstin; Niesner, Raluca A; Cseresnyes, Zoltan; Hauser, Anja E; Lenz, Peter; Hehlgans, Thomas; Brink, Robert; Westermann, Jörg; Dörken, Bernd; Lipp, Martin; Lenz, Georg; Rehm, Armin; Höpken, Uta E

    2014-12-01

    In human chronic lymphocytic leukemia (CLL) pathogenesis, B-cell antigen receptor signaling seems important for leukemia B-cell ontogeny, whereas the microenvironment influences B-cell activation, tumor cell lodging, and provision of antigenic stimuli. Using the murine Eμ-Tcl1 CLL model, we demonstrate that CXCR5-controlled access to follicular dendritic cells confers proliferative stimuli to leukemia B cells. Intravital imaging revealed a marginal zone B cell-like leukemia cell trafficking route. Murine and human CLL cells reciprocally stimulated resident mesenchymal stromal cells through lymphotoxin-β-receptor activation, resulting in CXCL13 secretion and stromal compartment remodeling. Inhibition of lymphotoxin/lymphotoxin-β-receptor signaling or of CXCR5 signaling retards leukemia progression. Thus, CXCR5 activity links tumor cell homing, shaping a survival niche, and access to localized proliferation stimuli. CLL and other indolent lymphoma are not curable and usually relapse after treatment, a process in which the tumor microenvironment plays a pivotal role. We dissect the consecutive steps of CXCR5-dependent tumor cell lodging and LTβR-dependent stroma-leukemia cell interaction; moreover, we provide therapeutic solutions to interfere with this reciprocal tumor-stroma cross-talk. ©2014 American Association for Cancer Research.

  6. MYC Protein-positive Diffuse Large B-Cell Lymphoma Features an Activated B-Cell Receptor Signal Pathway.

    Science.gov (United States)

    Wang, Wei-Ge; Jiang, Xiang-Nan; Liu, Ze-Bing; Zhou, Xiao-Yan; Li, Xiao-Qiu

    2017-04-01

    Components of the B-cell receptor (BCR) signaling pathway represent promising therapeutic targets in diffuse large B-cell lymphoma (DLBCL) and other B-cell malignancies. MYC, a transcriptional factor and oncoprotein, is overexpressed in a fraction of DLBCL and indicates poor prognosis and aggressive clinical course when treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, BCR signaling status in MYC-positive DLBCL cases and the potential efficacy of BCR signal inhibitors in treating this aggressive disease are unknown. To further elucidate the BCR signaling pathway in MYC-positive DLBCL, we analyzed the levels of BCR-associated genes according to MYC gene status, detected phosphorylated protein with primary DLBCL samples, and estimated the patient survival with MYC expression. In addition, we manipulated MYC gene expression and tested its effects on BCR signaling in vitro. We found that CD19, SYK, and BLK were highly expressed in DLBCL with MYC gene overexpression. MYC-positive DLBCL had higher levels of pSYK and pBLK, but only pSYK level correlated with patient survival. The in vitro studies demonstrated that overexpression of the MYC gene augmented BCR signaling, whereas MYC gene knockdown attenuated BCR signaling. Thus, MYC protein-positive DLBCL features highly activated BCR signaling and may represent a potential candidate for BCR inhibitor therapy.

  7. Type i CD20 antibodies recruit the B cell receptor for complement-dependent lysis of malignant B cells

    DEFF Research Database (Denmark)

    Engelberts, P. J.; Voorhorst, M.; Schuurman, J.

    2016-01-01

    Human IgG1 type I CD20 Abs, such as rituximab and ofatumumab (OFA), efficiently induce complement-dependent cytotoxicity (CDC) of CD20+ B cells by binding of C1 to hexamerized Fc domains. Unexpectedly, we found that type I CD20 Ab F(ab')2 fragments, as well as C1q-binding-deficient IgG mutants......, retained an ability to induce CDC, albeit with lower efficiency than for whole or unmodified IgG. Experiments using human serum depleted of specific complement components demonstrated that the observed lytic activity, which we termed "accessory CDC," remained to be dependent on C1 and the classical pathway....... We hypothesized that CD20 Ab-induced clustering of the IgM or IgG BCR was involved in accessory CDC. Indeed, accessory CDC was consistently observed in B cell lines expressing an IgM BCR and in some cell lines expressing an IgG BCR, but it was absent in BCR- B cell lines. A direct relationship...

  8. Reprint of: B cell elimination in systemic lupus erythematosus. Clin. Immunol. 146(2) 90-103.

    Science.gov (United States)

    Furtado, João; Isenberg, David A

    2013-09-01

    Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution, potentially life-threatening with considerable morbidity. The elimination of pathogenic B cells has emerged as a rational therapeutic option. Many open label studies have reported encouraging results in which clinical and serological remission have invariably been described, often enabling the reduction of steroid and immunosuppressive treatment. However, the results from randomized controlled studies have been disappointing and several questions remain to be answered. In this review we will focus on results of B cell direct depletion in the treatment of patients with systemic lupus erythematosus. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

  9. Pleural innate response activator B cells protect against pneumonia via a GM-CSF-IgM axis.

    Science.gov (United States)

    Weber, Georg F; Chousterman, Benjamin G; Hilgendorf, Ingo; Robbins, Clinton S; Theurl, Igor; Gerhardt, Louisa M S; Iwamoto, Yoshiko; Quach, Tam D; Ali, Muhammad; Chen, John W; Rothstein, Thomas L; Nahrendorf, Matthias; Weissleder, Ralph; Swirski, Filip K

    2014-06-02

    Pneumonia is a major cause of mortality worldwide and a serious problem in critical care medicine, but the immunophysiological processes that confer either protection or morbidity are not completely understood. We show that in response to lung infection, B1a B cells migrate from the pleural space to the lung parenchyma to secrete polyreactive emergency immunoglobulin M (IgM). The process requires innate response activator (IRA) B cells, a transitional B1a-derived inflammatory subset which controls IgM production via autocrine granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling. The strategic location of these cells, coupled with the capacity to produce GM-CSF-dependent IgM, ensures effective early frontline defense against bacteria invading the lungs. The study describes a previously unrecognized GM-CSF-IgM axis and positions IRA B cells as orchestrators of protective IgM immunity. © 2014 Weber et al.

  10. Constitutive CD40L Expression on B Cells Prematurely Terminates Germinal Center Response and Leads to Augmented Plasma Cell Production in T Cell Areas

    Science.gov (United States)

    Bolduc, Anna; Long, Eugene; Stapler, Dale; Cascalho, Marilia; Tsubata, Takeshi; Koni, Pandelakis A.; Shimoda, Michiko

    2013-01-01

    CD40/CD40L engagement is essential to T cell-dependent B cell proliferation and differentiation. However, the precise role of CD40 signaling through cognate T–B interaction in the generation of germinal center and memory B cells is still incompletely understood. To address this issue, a B cell-specific CD40L transgene (CD40LBTg) was introduced into mice with B cell-restricted MHC class II deficiency. Using this mouse model, we show that constitutive CD40L expression on B cells alone could not induce germinal center differentiation of MHC class II-deficient B cells after immunization with T cell-dependent Ag. Thus, some other MHC class II-dependent T cell-derived signals are essential for the generation of germinal center B cells in response to T cell-dependent Ag. In fact, CD40LBTg mice generated a complex Ag-specific IgG1 response, which was greatly enhanced in early, but reduced in late, primary response compared with control mice. We also found that the frequency of Ag-specific germinal center B cells in CD40LBTg mice was abruptly reduced 1 wk after immunization. As a result, the numbers of Ag-specific IgG1 long-lived plasma cells and memory B cells were reduced. By histology, large numbers of Ag-specific plasma cells were found in T cell areas adjacent to Ag-specific germinal centers of CD40LBTg mice, temporarily during the second week of primary response. These results indicate that CD40L expression on B cells prematurely terminated their ongoing germinal center response and produced plasma cells. Our results support the notion that CD40 signaling is an active termination signal for germinal center reaction. PMID:20505142

  11. B Cell Activity Is Impaired in Human and Mouse Obesity and Is Responsive to an Essential Fatty Acid upon Murine Influenza Infection.

    Science.gov (United States)

    Kosaraju, Rasagna; Guesdon, William; Crouch, Miranda J; Teague, Heather L; Sullivan, E Madison; Karlsson, Erik A; Schultz-Cherry, Stacey; Gowdy, Kymberly; Bridges, Lance C; Reese, Lauren R; Neufer, P Darrell; Armstrong, Michael; Reisdorph, Nichole; Milner, J Justin; Beck, Melinda; Shaikh, Saame Raza

    2017-06-15

    Obesity is associated with increased risk for infections and poor responses to vaccinations, which may be due to compromised B cell function. However, there is limited information about the influence of obesity on B cell function and underlying factors that modulate B cell responses. Therefore, we studied B cell cytokine secretion and/or Ab production across obesity models. In obese humans, B cell IL-6 secretion was lowered and IgM levels were elevated upon ex vivo anti-BCR/TLR9 stimulation. In murine obesity induced by a high fat diet, ex vivo IgM and IgG were elevated with unstimulated B cells. Furthermore, the high fat diet lowered bone marrow B cell frequency accompanied by diminished transcripts of early lymphoid commitment markers. Murine B cell responses were subsequently investigated upon influenza A/Puerto Rico/8/34 infection using a Western diet model in the absence or presence of docosahexaenoic acid (DHA). DHA, an essential fatty acid with immunomodulatory properties, was tested because its plasma levels are lowered in obesity. Relative to controls, mice consuming the Western diet had diminished Ab titers whereas the Western diet plus DHA improved titers. Mechanistically, DHA did not directly target B cells to elevate Ab levels. Instead, DHA increased the concentration of the downstream specialized proresolving lipid mediators (SPMs) 14-hydroxydocosahexaenoic acid, 17-hydroxydocosahexaenoic acid, and protectin DX. All three SPMs were found to be effective in elevating murine Ab levels upon influenza infection. Collectively, the results demonstrate that B cell responses are impaired across human and mouse obesity models and show that essential fatty acid status is a factor influencing humoral immunity, potentially through an SPM-mediated mechanism. Copyright © 2017 by The American Association of Immunologists, Inc.

  12. Photoreceptor cell fate specification in vertebrates

    Science.gov (United States)

    Brzezinski, Joseph A.; Reh, Thomas A.

    2015-01-01

    Photoreceptors – the light-sensitive cells in the vertebrate retina – have been extremely well-characterized with regards to their biochemistry, cell biology and physiology. They therefore provide an excellent model for exploring the factors and mechanisms that drive neural progenitors into a differentiated cell fate in the nervous system. As a result, great progress in understanding the transcriptional network that controls photoreceptor specification and differentiation has been made over the last 20 years. This progress has also enabled the production of photoreceptors from pluripotent stem cells, thereby aiding the development of regenerative medical approaches to eye disease. In this Review, we outline the signaling and transcription factors that drive vertebrate photoreceptor development and discuss how these function together in gene regulatory networks to control photoreceptor cell fate specification. PMID:26443631

  13. B cells require Type 1 interferon to produce alloantibodies to transfused KEL-expressing red blood cells in mice.

    Science.gov (United States)

    Gibb, David R; Liu, Jingchun; Santhanakrishnan, Manjula; Natarajan, Prabitha; Madrid, David J; Patel, Seema; Eisenbarth, Stephanie C; Tormey, Christopher A; Stowell, Sean R; Iwasaki, Akiko; Hendrickson, Jeanne E

    2017-11-01

    Alloantibodies to red blood cell (RBC) antigens can cause significant hemolytic events. Prior studies have demonstrated that inflammatory stimuli in animal models and inflammatory states in humans, including autoimmunity and viremia, promote alloimmunization. However, molecular mechanisms underlying these findings are poorly understood. Given that Type 1 interferons (IFN-α/β) regulate antiviral immunity and autoimmune pathology, the hypothesis that IFN-α/β regulates RBC alloimmunization was tested in a murine model. Leukoreduced murine RBCs expressing the human KEL glycoprotein were transfused into control mice (WT), mice lacking the unique IFN-α/β receptor (IFNAR1-/- ), or bone marrow chimeric mice lacking IFNAR1 on specific cell populations. Anti-KEL IgG production, expressed as mean fluorescence intensity (MFI), and B-cell differentiation were examined. Transfused WT mice produced anti-KEL IgG alloantibodies (peak response MFI, 50.4). However, the alloimmune response of IFNAR1-/- mice was almost completely abrogated (MFI, 4.2; p IFNAR1 expression in all hematopoietic cells or specifically in B cells was also diminished (MFI, 3.8 and 5.4, respectively, compared to control chimeras, MFI, 65.6; p IFNAR1-/- B cells into germinal center B cells and plasma cells was significantly reduced, compared to WT B cells. This study demonstrates that B cells require signaling from IFN-α/β to produce alloantibodies to the human KEL glycoprotein in mice. These findings provide a potential mechanistic basis for inflammation-induced alloimmunization. If these findings extend to human studies, patients with IFN-α/β-associated conditions may have an elevated risk of alloimmunization and benefit from personalized transfusion protocols. © 2017 AABB.

  14. B-cell activation with CD40L or CpG measures the function of B-cell subsets and identifies specific defects in immunodeficient patients.

    Science.gov (United States)

    Marasco, Emiliano; Farroni, Chiara; Cascioli, Simona; Marcellini, Valentina; Scarsella, Marco; Giorda, Ezio; Piano Mortari, Eva; Leonardi, Lucia; Scarselli, Alessia; Valentini, Diletta; Cancrini, Caterina; Duse, Marzia; Grimsholm, Ola; Carsetti, Rita

    2017-01-01

    Around 65% of primary immunodeficiencies are antibody deficiencies. Functional tests are useful tools to study B-cell functions in vitro. However, no accepted guidelines for performing and evaluating functional tests have been issued yet. Here, we report our experience on the study of B-cell functions in infancy and throughout childhood. We show that T-independent stimulation with CpG measures proliferation and differentiation potential of memory B cells. Switched memory B cells respond better than IgM memory B cells. On the other hand, CD40L, a T-dependent stimulus, does not induce plasma cell differentiation, but causes proliferation of naïve and memory B cells. During childhood, the production of plasmablasts in response to CpG increases with age mirroring the development of memory B cells. The response to CD40L does not change with age. In patients with selective IgA deficiency (SIgAD), we observed that switched memory B cells are reduced due to the absence of IgA memory B cells. In agreement, IgA plasma cells are not generated in response to CpG. Unexpectedly, B cells from SIgAD patients show a reduced proliferative response to CD40L. Our results demonstrate that functional tests are an important tool to assess the functions of the humoral immune system. © 2016 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Intrinsic Plasma Cell Differentiation Defects in B Cell Expansion with NF-κB and T Cell Anergy Patient B Cells

    Directory of Open Access Journals (Sweden)

    Swadhinya Arjunaraja

    2017-08-01

    Full Text Available B cell Expansion with NF-κB and T cell Anergy (BENTA disease is a novel B cell lymphoproliferative disorder caused by germline, gain-of-function mutations in the lymphocyte scaffolding protein CARD11, which drives constitutive NF-κB signaling. Despite dramatic polyclonal expansion of naive and immature B cells, BENTA patients also present with signs of primary immunodeficiency, including markedly reduced percentages of class-switched/memory B cells and poor humoral responses to certain vaccines. Using purified naive B cells from our BENTA patient cohort, here we show that BENTA B cells exhibit intrinsic defects in B cell differentiation. Despite a profound in vitro survival advantage relative to normal donor B cells, BENTA patient B cells were severely impaired in their ability to differentiate into short-lived IgDloCD38hi plasmablasts or CD138+ long-lived plasma cells in response to various stimuli. These defects corresponded with diminished IgG antibody production and correlated with poor induction of specific genes required for plasma cell commitment. These findings provide important mechanistic clues that help explain both B cell lymphocytosis and humoral immunodeficiency in BENTA disease.

  16. Dimethyl fumarate alters B-cell memory and cytokine production in MS patients.

    Science.gov (United States)

    Smith, Matthew D; Martin, Kyle A; Calabresi, Peter A; Bhargava, Pavan

    2017-05-01

    We evaluated the effect of dimethyl fumarate (DMF) treatment on B-cell memory and cytokine production in 18 patients with relapsing remitting multiple sclerosis (RRMS) using peripheral blood mononuclear cells obtained prior to and at 6 months post-DMF initiation. We noted a decline in the absolute B-cell number with DMF treatment, with a preferential depletion of memory B cells and a concurrent increase in naïve B cells. We noted significant reductions in GM-CSF, TNF- α , and IL-6 producing B cells with DMF treatment. These effects on the B-cell compartment may underlie the beneficial effects of DMF in RRMS.

  17. Mucosal immunoglobulins and B cells of Teleost fish

    Science.gov (United States)

    Salinas, Irene; Zhang, Yong-An; Sunyer, J. Oriol

    2012-01-01

    As physical barriers that separate teleost fish from the external environment, mucosae are also active immunological sites that protect them against exposure to microbes and stressors. In mammals, the sites where antigens are sampled from mucosal surfaces and where stimulation of naive T and B lymphocytes occurs are known as inductive sites and are constituted by mucosa-associated lymphoid tissue (MALT). According to anatomical location, the MALT in teleost fish is subdivided into gut-associated lymphoid tissue (GALT), skin-associated lymphoid tissue (SALT), and gill-associated lymphoid tissue (GIALT). All MALT contain a variety of leukocytes, including, but not limited to, T cells, B cells, plasma cells, macrophages and granulocytes. Secretory immunoglobulins are produced mainly by plasmablasts and plasma cells, and play key roles in the maintenance of mucosal homeostasis. Until recently, teleost fish B cells were thought to express only two classes of immunoglobulins, IgM and IgD, in which IgM was thought to be the only one responding to pathogens both in systemic and mucosal compartments. However, a third teleost immunoglobulin class, IgT/IgZ, was discovered in 2005, and it has recently been shown to behave as the prevalent immunoglobulin in gut mucosal immune responses. The purpose of this review is to summarise the current knowledge of mucosal immunoglobulins and B cells of fish MALT. Moreover, we attempt to integrate the existing knowledge on both basic and applied research findings on fish mucosal immune responses, with the goal to provide new directions that may facilitate the development of novel vaccination strategies that stimulate not only systemic, but also mucosal immunity. PMID:22133710

  18. Abortive lytic reactivation of KSHV in CBF1/CSL deficient human B cell lines.

    Directory of Open Access Journals (Sweden)

    Barbara A Scholz

    Full Text Available Since Kaposi's sarcoma associated herpesvirus (KSHV establishes a persistent infection in human B cells, B cells are a critical compartment for viral pathogenesis. RTA, the replication and transcription activator of KSHV, can either directly bind to DNA or use cellular DNA binding factors including CBF1/CSL as DNA adaptors. In addition, the viral factors LANA1 and vIRF4 are known to bind to CBF1/CSL and modulate RTA activity. To analyze the contribution of CBF1/CSL to reactivation in human B cells, we have successfully infected DG75 and DG75 CBF1/CSL knock-out cell lines with recombinant KSHV.219 and selected for viral maintenance by selective medium. Both lines maintained the virus irrespective of their CBF1/CSL status. Viral reactivation could be initiated in both B cell lines but viral genome replication was attenuated in CBF1/CSL deficient lines, which also failed to produce detectable levels of infectious virus. Induction of immediate early, early and late viral genes was impaired in CBF1/CSL deficient cells at multiple stages of the reactivation process but could be restored to wild-type levels by reintroduction of CBF1/CSL. To identify additional viral RTA target genes, which are directly controlled by CBF1/CSL, we analyzed promoters of a selected subset of viral genes. We show that the induction of the late viral genes ORF29a and ORF65 by RTA is strongly enhanced by CBF1/CSL. Orthologs of ORF29a in other herpesviruses are part of the terminase complex required for viral packaging. ORF65 encodes the small capsid protein essential for capsid shell assembly. Our study demonstrates for the first time that in human B cells viral replication can be initiated in the absence of CBF1/CSL but the reactivation process is severely attenuated at all stages and does not lead to virion production. Thus, CBF1/CSL acts as a global hub which is used by the virus to coordinate the lytic cascade.

  19. Genetic lesions in diffuse large B-cell lymphomas

    Science.gov (United States)

    Testoni, M.; Zucca, E.; Young, K. H.; Bertoni, F.

    2015-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults, accounting for 35%–40% of all cases. The combination of the anti-CD20 monoclonal antibody rituximab with anthracycline-based combination chemotherapy (R-CHOP, rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone) lead to complete remission in most and can cure more than half of patients with DLBCL. The diversity in clinical presentation, as well as the pathologic and biologic heterogeneity, suggests that DLBCL comprises several disease entities that might ultimately benefit from different therapeutic approaches. In this review, we summarize the current literature focusing on the genetic lesions identified in DLBCL. PMID:25605746

  20. B-cell lymphoma, thiamine deficiency, and lactic acidosis.

    Science.gov (United States)

    Masood, Umair; Sharma, Anuj; Nijjar, Sonny; Sitaraman, Karthikeyan

    2017-01-01

    Type B lactic acidosis is found in the absence of tissue hypoperfusion, can be associated with malignancies, and can be caused by thiamine deficiency. We present a patient who presented with an abdominal mass that biopsy disclosed to be a diffuse large B-cell lymphoma. Because thiamine deficiency is a rare cause of lactic acidosis in cancer, the patient was treated with intravenous thiamine with rapid normalization of the lactic acid level. The level prior to treatment was low. The case emphasizes a rare cause of lactic acidosis.

  1. Tumor-infiltrating B cells come into vogue.

    Science.gov (United States)

    Linnebacher, Michael

    2013-01-07

    Lymphocyte infiltration into solid tumors has been recognized as a main determinator of positive prognosis. For the most part this is attributed to cytotoxic T cells capable of directly destroying malignant cells. However, when considering the complex composition of the human immune system, recent findings of Nielsen et al on a potentially central role of tumor-infiltrating B cells is not really surprising. In this commentary article, I want to highlight the enormous potential impact of this observation for basic and translational research, prognostic procedures and ultimately for the development of future therapeutic concepts.

  2. Diffuse Large B-Cell Lymphoma with Calf Muscle Localization

    Directory of Open Access Journals (Sweden)

    Laura Bourdeanu

    2011-01-01

    Full Text Available Although diffuse large B-cell lymphoma (DLBCL usually occurs in the lymph nodes, approximately 30–40% of the time it can have an extranodal site of involvement and it can arise in nearly every body site such as intestine, bone, breast, liver, skin, lung, and central nervous system. Muscle involvement of DLBCL is especially uncommon, comprising 0.5% of extranodal NHL. We report a case of a 72-year-old man with extranodal DLBCL of a unique manifestation in the calf muscle, involving predominantly the gastrocnemius muscle. The patient achieved complete response and remained free of local recurrence or metastasis following diagnosis.

  3. Primary Malignant B-cell Lymphoma of the Epididymis

    Directory of Open Access Journals (Sweden)

    Jungyo Suh

    2016-01-01

    Full Text Available Primary epididymal lymphomas are very rare condition, only 6 case report was published. In 4 of them, initial presentation was non-tender, continuous growth of testis. It can be misdiagnosed with epididymitis, 5 of them was treated by antibiotics before surgery. One patients treated by surgery another 5 makes neoadjuvant therapy, 2 of radiotherapy 3 of chemotherapy. Only one man died after treatment. This case is about 54-year male patients, diagnosed by diffuse large B-cell lymphoma, who treated by surgery and neoadjuvant chemotherapy combined with radiotherapy.

  4. CD47 limits antibody dependent phagocytosis against non-malignant B cells.

    Science.gov (United States)

    Gallagher, Sandra; Turman, Sean; Lekstrom, Kristen; Wilson, Susan; Herbst, Ronald; Wang, Yue

    2017-05-01

    Recent studies have demonstrated the importance of CD47 in protecting malignant B cells from antibody dependent cellular phagocytosis (ADCP). Combined treatment of anti-CD47 and -CD20 antibodies synergistically augment elimination of tumor B cells in xenograft mouse models. This has led to the development of novel reagents that can potentially enhance killing of malignant B cells in patients. B cell depleting therapy is also a promising treatment for autoimmune patients. In the current study, we aimed to investigate whether or not CD47 protects non-malignant B cells from ADCP. We show that CD47 is expressed on all B cells in mice, with the highest level on plasma cells in bone marrow and spleen. Although its expression is dispensable for B cell development in mice, CD47 on B cells limits antibody mediated phagocytosis. B cell depletion following in vivo anti-CD19 treatment is more efficient in CD47-/- mice than in wild type mice. In vitro, both naïve and activated B cells from CD47-/- mice are more sensitive to ADCP than wild type B cells. Lastly, we show in an ADCP assay that blocking CD47 can enhance anti-CD19 antibody mediated phagocytosis of wild type B cells. These results suggest that in addition to its already demonstrated benefit in cancer, targeting CD47 may be used as an adjunct in combination with B cell depletion antibodies for treatment of autoimmune diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Maternal Serum B-Cell Activating Factor Levels: Candidate Early Biomarker for Hypertensive Disorders of Pregnancy.

    Science.gov (United States)

    Stohl, Hindi E; Lee, Richard H; Manetta, Joseph; Kikly, Kristine; Korst, Lisa M; Stohl, William

    2017-11-01

    Hypertensive disorders of pregnancy are a leading cause of maternal and perinatal morbidity and mortality. Early suppression of B-cell lymphopoiesis is necessary for a normal pregnancy. Dysregulation of factors critical to B-cell survival may result in pregnancy complications, including hypertension. In this prospective observational study at a single medical center, serum levels of BAFF (B-cell activating factor) were measured in pregnant participants at each trimester, at delivery, and postpartum and in nonpregnant controls at a single time point. Comparisons were made between nonpregnant and pregnant subjects and between time periods of pregnancy. First-trimester serum BAFF levels were further tested for association with hypertensive disorders of pregnancy. The study included 149 healthy pregnant women, 25 pregnant women with chronic hypertension, and 48 nonpregnant controls. Median first-trimester serum BAFF level (ng/mL) for healthy women (0.90) was lower than median serum BAFF levels for women with chronic hypertension (0.96; P=0.013) and controls (1.00; P=0.002). Serum BAFF levels steadily declined throughout pregnancy, with the median second-trimester level lower than the corresponding first-trimester level (0.77; P=0.003) and the median third-trimester level lower than the corresponding second-trimester level (0.72; P=0.025). The median first-trimester serum BAFF level was elevated in women who subsequently developed hypertension compared with women who remained normotensive (1.02 versus 0.85; P=0.012), with the area under the receiver operating characteristic curve being 0.709. First-trimester serum BAFF level may be an early and clinically useful predictor of hypertensive disorders of pregnancy. © 2017 American Heart Association, Inc.

  6. B cells as a critical node in the microbiota-host immune system network.

    Science.gov (United States)

    Slack, Emma; Balmer, Maria L; Macpherson, Andrew J

    2014-07-01

    Mutualism with our intestinal microbiota is a prerequisite for healthy existence. This requires physical separation of the majority of the microbiota from the host (by secreted antimicrobials, mucus, and the intestinal epithelium) and active immune control of the low numbers of microbes that overcome these physical and chemical barriers, even in healthy individuals. In this review, we address how B-cell responses to members of the intestinal microbiota form a robust network with mucus, epithelial integrity, follicular helper T cells, innate immunity, and gut-associated lymphoid tissues to maintain host-microbiota mutualism. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Successful treatment of recurrent pancreatitis secondary to systemic lupus erythematosus with B-cell depletion therapy.

    Science.gov (United States)

    Al-Musawi, Zakiya S; Nabar, Umesh J

    2011-01-01

    Recurrent pancreatitis secondary to systemic lupus erythematosus is a rare entity of unknown etiology. We report an adolescent with systemic lupus erythematosus and recurrent attacks of acute pancreatitis, which were poorly controlled with conventional therapy for approximately four years. Rituximab, a chimeric anti-CD20 monoclonal antibody therapy resulted in remission of symptoms for more than two years without major toxicity of treatment. Based on tolerability and high efficiency of rituximab therapy, we would suggest using B-cell depletion therapy as an alternative therapy for refractory pancreatitis secondary to systemic lupus erythematosus.

  8. Interleukin-35 induces regulatory B cells that suppress autoimmune disease.

    Science.gov (United States)

    Wang, Ren-Xi; Yu, Cheng-Rong; Dambuza, Ivy M; Mahdi, Rashid M; Dolinska, Monika B; Sergeev, Yuri V; Wingfield, Paul T; Kim, Sung-Hye; Egwuagu, Charles E

    2014-06-01

    Interleukin-10 (IL-10)-producing regulatory B (Breg) cells suppress autoimmune disease, and increased numbers of Breg cells prevent host defense to infection and promote tumor growth and metastasis by converting resting CD4(+) T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of Breg cells remain unclear. Here we show that IL-35 induces Breg cells and promotes their conversion to a Breg subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12Rβ2 KO mice) produced less Breg cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of Breg cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 (TH17) and TH1 cells while promoting Treg cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12Rβ2 and IL-27Rα subunits. As IL-35 also induced the conversion of human B cells into Breg cells, these findings suggest that IL-35 may be used to induce autologous Breg and IL-35(+) Breg cells and treat autoimmune and inflammatory disease.

  9. Engaging the lysosomal compartment to combat B cell malignancies

    DEFF Research Database (Denmark)

    Gronbaek, K.; Jaattela, M.

    2009-01-01

    The combination of rituximab, a type I anti-CD20 mAb, with conventional chemotherapy has significantly improved the outcome of patients with B cell malignancies. Regardless of this success, many patients still relapse with therapy-resistant disease, highlighting the need for the development of m......Abs with higher capacity to induce programmed cell death. The so-called type II anti-CD20 mAbs (e.g., tositumomab) that trigger caspase-independent B cell lymphoma cell death in vitro and show superior efficacy as compared with rituximab in eradicating target cells in mouse models are emerging as the next...... generation of therapeutic anti-CD20 mAbs. In this issue of the JCI, Ivanov and colleagues identify the lysosomal compartment as a target for type II mAbs (see the related article beginning on page 2143). These data encourage the further clinical development of type II mAbs as well as other lysosome...

  10. Unusual cutaneous manifestations of B-cell chronic lymphocytic leukemia.

    Science.gov (United States)

    Plaza, Jose Antonio; Comfere, Nneka I; Gibson, Lawrence E; Colgan, Michael; Davis, Dawn Marie R; Pittelkow, Mark R; Colgan, Joseph P

    2009-05-01

    B-cell chronic lymphocytic leukemia (B-CLL) is a low-grade lymphoproliferative disorder with characteristic histomorphologic features and an identifiable immunophenotype. The skin can be involved in the context of known disease, but cutaneous signs are rarely the presenting findings. Evaluation of unusual clinical cutaneous presentations of B-CLL. We conducted a retrospective case series analysis of 3 patients with unusual cutaneous clinicopathologic presentations of B-cell chronic lymphocytic leukemia, including erythematous plaques, angiomatosis/telangiectasia, and erosive skin changes, respectively, without a previous clinical history of chronic lymphocytic lymphoma. Main outcome measures were clinical cutaneous presentations and histopathologic results in the diagnosis of underlying disease. In the 3 cases, lesion locations were the lower cheek, lower extremity, and penis (groin region). Histomorphologic testing showed mild to dense perivascular and periadnexal lymphoid aggregates throughout the dermis and extending into the panniculus, consistent with B-CLL. The diagnosis was confirmed with immunohistochemical studies that showed coexpression of CD5 and CD20 in the neoplastic lymphocytic infiltrate. None. Cutaneous manifestations are an uncommon presentation of subclinical B-CLL. Cutaneous changes were the presenting features of underlying lymphoma in all 3 cases, highlighting the importance of maintaining a high index of suspicion for a lymphoproliferative process in cases with unusual or atypical clinicopathologic features. Additional investigations into the behavior of B-CLL in the skin may elucidate further the evolution of cutaneous lesions in this disease.

  11. Bcl-2 antisense therapy in B-cell malignancies.

    Science.gov (United States)

    Chanan-Khan, Asher

    2005-07-01

    Bcl-2 is an apoptosis regulating protein, overexpression of which is associated with chemotherapy resistant disease, aggressive clinical course, and poor survival in patients with B-cell lymphoproliferative disorders. Overexpression of Bcl-2 protein results in an aberrant intrinsic apoptotic pathway that confers a protective effect on malignant cells against a death signal (e.g., chemotherapy or radiotherapy). Downregulation of this oncoprotein, thus, represents a possible new way to target clinically aggressive disease. Preclinical studies have shown that this oncoprotein can be effectively decreased by Bcl-2 antisense in malignant lymphoid cells and can reverse chemotherapy resistance, as well as enhance the anti-apoptotic potential of both chemotherapeutic and biologic agents. Ongoing clinical trials are exploring the role of Bcl-2 downregulation with oblimersen (Bcl-2 antisense) in patients with non-Hodgkin's lymphoma, chronic lymphocytic leukemia and multiple myeloma. Early results from these studies are promising and support the proof of the principle. As these studies are completed and mature data emerges, the role of Bcl-2 antisense therapy in the treatment of B-cell malignancies will become clearer.

  12. B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma: Report of a case in the oral cavity

    Directory of Open Access Journals (Sweden)

    Jumana M Jaradat

    2013-01-01

    Full Text Available B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (DLBCL/BL is a new category of B-cell lymphoma according to the 4 th edition of the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (2008. The following report presents a case of this rare, newly described entity on the palate of a 59 year-old male.

  13. Primary testicular diffuse large B-cell lymphoma belongs to the nongerminal center B-cell-like subgroup: A study of 18 cases.

    Science.gov (United States)

    Al-Abbadi, Mousa A; Hattab, Eyas M; Tarawneh, Musleh S; Amr, Samir S; Orazi, Attilio; Ulbright, Thomas M

    2006-12-01

    The most common type of primary testicular lymphoma is diffuse large B-cell type, which has the potential for aggressive clinical behavior. Diffuse large B-cell lymphoma can be further subclassified into two major prognostic categories: germinal center B-cell-like and nongerminal center B-cell-like. Such distinction is made possible using the immunohistochemical expression of CD10, Bcl-6 and MUM1. The aim of this study was to stratify primary testicular lymphoma of the diffuse large B-cell type according to this scheme. Immunohistochemical stains for CD10, Bcl-6 and MUM1 were performed on 18 cases of primary testicular lymphoma of diffuse large B-cell type. Subclassification was carried out as previously described where CD10 and/or Bcl-6 positivity and negativity for MUM1 were considered indicative of germinal center B-cell-like type and the opposite expression as nongerminal center B-cell-like type. The proliferative activity was determined using immunostaining with the Ki-67 antibody. Of 18 cases, 16 (89%) were found to belong to the nongerminal center B-cell-like type. Two cases (11%) were classified as germinal center B-cell-like type; one had a CD10-positive, Bcl-6-positive and MUM1-negative profile, and the other was CD10 negative, Bcl-6 positive and MUM1 negative. The former occurred in a 38-year-old patient who was human immunodeficiency virus positive. All the cases expressed high proliferative activity (> or =50% Ki-67 labeling). We conclude that most (89%) primary testicular lymphomas of the diffuse large B-cell type belong to the nongerminal center B-cell-like subgroup and have high proliferative activity.

  14. Modelling the fate of organic micropollutants in stormwater ponds

    DEFF Research Database (Denmark)

    Vezzaro, Luca; Eriksson, Eva; Ledin, Anna

    2011-01-01

    Urban water managers need to estimate the potential removal of organic micropollutants (MP) in stormwater treatment systems to support MP pollution control strategies. This study documents how the potential removal of organic MP in stormwater treatment systems can be quantified by using multimedia......). The four simulated organic stormwater MP (iodopropynyl butylcarbamate — IPBC, benzene, glyphosate and pyrene) were selected according to their different urban sources and environmental fate. This ensures that the results can be extended to other relevant stormwater pollutants. All three models use...... models. The fate of four different MP in a stormwater retention pond was simulated by applying two steady-state multimedia fate models (EPI Suite and SimpleBox) commonly applied in chemical risk assessment and a dynamic multimedia fate model (Stormwater Treatment Unit Model for Micro Pollutants — STUMP...

  15. Modulation of Igβ is essential for the B cell selection in germinal center

    National Research Council Canada - National Science Library

    Todo, Kagefumi; Koga, Orie; Nishikawa, Miwako; Hikida, Masaki

    2015-01-01

    .... We found that expression levels of Igα and Igβ, which are the essential components of B cell antigen-receptor complex, were differentially regulated in GC B cells and that the expression of Igβ...

  16. Unaltered levels of transplant arteriosclerosis in the absence of the B cell homing chemokine receptor CXCR5.

    Science.gov (United States)

    Ensminger, Stephan M; Abele-Ohl, Silke; Ohl, Lars; Spriewald, Bernd M; Ramsperger-Gleixner, Martina; Weyand, Michael; Förster, Reinhold

    2009-03-01

    Chemokine receptors and their ligands are crucial for lymphocyte trafficking under both homeostatic and inflammatory conditions. The chemokine receptor CXCR5 controls B cell migration and the organization of B cell follicles. The aim of this study was to investigate the impact of CXCR5 on the development of transplant arteriosclerosis. Fully MHC mismatched BALB/c (H2(d)) donor aortas were transplanted into C57BL/6-CXCR5(-/-) (H2(b)), C57BL/6-CXCR5(+/-) (H2(b)) or C57BL/6-CXCR5(+/+) (H2(b)) recipients. Grafts were analysed by morphometry and immunofluorescence and intra-graft cytokine mRNA production was analysed by RT-PCR. Transplant arteriosclerosis was evident in CXCR5+/+ and CXCR5+/- mice and only mildly reduced in CXCR5-/- recipients indicating that absence of CXCR5 had no substantial effect on the development of transplant arteriosclerosis. Analysis of the cellular infiltrate of aortic grafts implanted in CXCR5-/- recipients revealed no differences in the number of T-cells, macrophages and B cells as compared to controls. Intra-graft cytokine production showed no significant changes in Th1 (IL-12) and Th2 (IL-4) cytokines as well as in TGF-beta and iNOS production. These data suggest that lack of CXCR5 expression by recipient T- and B-cells has little effect on the development of transplant arteriosclerosis.

  17. Germinal center B cells regulate their capability to present antigen by modulation of HLA-DO.

    Science.gov (United States)

    Glazier, Kim S; Hake, Sandra B; Tobin, Helen M; Chadburn, Amy; Schattner, Elaine J; Denzin, Lisa K

    2002-04-15

    Peptide acquisition by MHC class II molecules is catalyzed by HLA-DM (DM). In B cells, HLA-DO (DO) inhibits or modifies the peptide exchange activity of DM. We show here that DO protein levels are modulated during B cell differentiation. Remarkably, germinal center (GC) B cells, which have low levels of DO relative to naive and memory B cells, are shown to have enhanced antigen presentation capabilities. DM protein levels also were somewhat reduced in GC B cells; however, the ratio of DM to DO in GC B cells was substantially increased, resulting in more free DM in GC B cells. We conclude that modulation of DM and DO in distinct stages of B cell differentiation represents a mechanism by which B cells regulate their capacity to function as antigen-presenting cells. Efficient antigen presentation in GC B cells would promote GC B cell-T cell interactions that are essential for B cells to survive positive selection in the GC.

  18. File list: ALL.Bld.20.AllAg.Pro-B_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  19. File list: Oth.Bld.50.AllAg.Lymphoma,_B-Cell [Chip-atlas[Archive

    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  5. File list: Oth.Bld.10.AllAg.Lymphoma,_B-Cell [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  6. File list: Oth.Bld.20.AllAg.Lymphoma,_B-Cell [Chip-atlas[Archive

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  7. File list: His.Bld.20.AllAg.Lymphoma,_B-Cell [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  8. File list: Oth.Bld.05.AllAg.Lymphoma,_B-Cell [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  9. File list: ALL.Bld.10.AllAg.Lymphoma,_B-Cell [Chip-atlas[Archive

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  10. File list: ALL.Bld.50.AllAg.Lymphoma,_B-Cell [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  11. Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients

    Science.gov (United States)

    Pala, Francesca; Morbach, Henner; Castiello, Maria Carmina; Schickel, Jean-Nicolas; Scaramuzza, Samantha; Chamberlain, Nicolas; Cassani, Barbara; Glauzy, Salome; Romberg, Neil; Candotti, Fabio; Aiuti, Alessandro; Bosticardo, Marita; Villa, Anna; Meffre, Eric

    2015-01-01

    Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by microthrombocytopenia, eczema, and high susceptibility to developing tumors and autoimmunity. Recent evidence suggests that B cells may be key players in the pathogenesis of autoimmunity in WAS. Here, we assessed whether WAS protein deficiency (WASp deficiency) affects the establishment of B cell tolerance by testing the reactivity of recombinant antibodies isolated from single B cells from 4 WAS patients before and after gene therapy (GT). We found that pre-GT WASp-deficient B cells were hyperreactive to B cell receptor stimulation (BCR stimulation). This hyperreactivity correlated with decreased frequency of autoreactive new emigrant/transitional B cells exiting the BM, indicating that the BCR signaling threshold plays a major role in the regulation of central B cell tolerance. In contrast, mature naive B cells from WAS patients were enriched in self-reactive clones, revealing that peripheral B cell tolerance checkpoint dysfunction is associated with impaired suppressive function of WAS regulatory T cells. The introduction of functional WASp by GT corrected the alterations of both central and peripheral B cell tolerance checkpoints. We conclude that WASp plays an important role in the establishment and maintenance of B cell tolerance in humans and that restoration of WASp by GT is able to restore B cell tolerance in WAS patients. PMID:26368308

  12. Monocytes mediate shaving of B-cell-bound anti-CD20 antibodies

    DEFF Research Database (Denmark)

    Pedersen, Anders Elm; Jungersen, Mette B; Pedersen, Charlotte D

    2011-01-01

    complex from the B-cell surface. Here, we confirm, that in vitro co-culture of human monocytes and RTX-labelled syngeneic B cells results in reduced expression of CD20/RTX complex on the B cell surface. This shaving mechanism was the result of active protease activity because EDTA and PMSF were able...

  13. File list: His.Bld.20.AllAg.Pro-B_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  14. File list: His.Bld.50.AllAg.Pro-B_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  15. Enhanced selection of high affinity DNA-reactive B cells following cyclophosphamide treatment in mice.

    Directory of Open Access Journals (Sweden)

    Daisuke Kawabata

    Full Text Available A major goal for the treatment of patients with systemic lupus erythematosus with cytotoxic therapies is the induction of long-term remission. There is, however, a paucity of information concerning the effects of these therapies on the reconstituting B cell repertoire. Since there is recent evidence suggesting that B cell lymphopenia might attenuate negative selection of autoreactive B cells, we elected to investigate the effects of cyclophosphamide on the selection of the re-emerging B cell repertoire in wild type mice and transgenic mice that express the H chain of an anti-DNA antibody. The reconstituting B cell repertoire in wild type mice contained an increased frequency of DNA-reactive B cells; in heavy chain transgenic mice, the reconstituting repertoire was characterized by an increased frequency of mature, high affinity DNA-reactive B cells and the mice expressed increased levels of serum anti-DNA antibodies. This coincided with a significant increase in serum levels of BAFF. Treatment of transgene-expressing mice with a BAFF blocking agent or with DNase to reduce exposure to autoantigen limited the expansion of high affinity DNA-reactive B cells during B cell reconstitution. These studies suggest that during B cell reconstitution, not only is negative selection of high affinity DNA-reactive B cells impaired by increased BAFF, but also that B cells escaping negative selection are positively selected by autoantigen. There are significant implications for therapy.

  16. Nivolumab With or Without Varlilumab in Treating Patients With Relapsed or Refractory Aggressive B-cell Lymphomas

    Science.gov (United States)

    2017-10-16

    ALK-Positive Large B-Cell Lymphoma; Atypical Burkitt/Burkitt-Like Lymphoma; Burkitt-Like Lymphoma With 11q Aberration; Diffuse Large B-Cell Lymphoma Activated B-Cell Type; Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation; Diffuse Large B-Cell Lymphoma Germinal Center B-Cell Type; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; EBV-Positive Mucocutaneous Ulcer; High-Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements; Human Herpesvirus-8-Positive Neoplastic Cells Present; Intravascular Large B-Cell Lymphoma; Large B-Cell Lymphoma With IRF4 Rearrangement; Plasmablastic Lymphoma; Primary Cutaneous Diffuse Large B-Cell Lymphoma; Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type; Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System; Primary Effusion Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Lymphomatoid Granulomatosis; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Burkitt Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Skin Ulcer; Small Intestinal High Grade B-Cell Lymphoma, Not Otherwise Specified; T-Cell/Histiocyte-Rich Large B-Cell Lymphoma

  17. Hydrogeologic controls on the transport and fate of nitrate in ground water beneath riparian buffer zones: results from thirteen studies across the United States.

    Science.gov (United States)

    Puckett, L J

    2004-01-01

    During the last two decades there has been growing interest in the capacity of riparian buffer zones to remove nitrate from ground waters moving through them. Riparian zone sediments often contain organic carbon, which favors formation of reducing conditions that can lead to removal of nitrate through denitrification. Over the past decade the National Water Quality Assessment (NAWQA) Program has investigated the transport and fate of nitrate in ground and surface waters in study areas across the United States. In these studies riparian zone efficiency in removing nitrate varied widely as a result of variations in hydrogeologic factors. These factors include (1) denitrification in the up-gradient aquifer due to the presence of organic carbon or other electron donors, (2) long residence times (>50 years) along ground-water flow paths allowing even slow reactions to completely remove nitrate, (3) dilution of nitrate enriched waters with older water having little nitrate, (4) bypassing of riparian zones due to extensive use of drains and ditches, and (5) movement of ground water along deep flow paths below reducing zones. By developing a better understanding of the hydrogeologic settings in which riparian buffer zones are likely to be inefficient we can develop improved nutrient management plans.

  18. Anthropometrics and Prognosis in Diffuse Large B-Cell Lymphoma

    DEFF Research Database (Denmark)

    Bendtsen, Mette Dahl; Munksgaard, Peter Svenssen; Severinsen, Marianne Tang

    2017-01-01

    OBJECTIVE: The impact of body mass index (BMI) and body surface area (BSA) on survival in diffuse large B-cell lymphoma (DLBCL) is controversial. Recent studies show superior outcomes for overweight and obese patients. PATIENTS AND METHODS: A total of 653 R-CHOP(-like)-treated DLBCL patients were...... included in this retrospective cohort study. Patients, baseline clinicopathologic characteristics and treatment information were retrieved from the Danish Lymphoma Registry. Anthropometric measures were obtained from chemotherapy prescription charts. RESULTS: Underweight (BMI ... = 0.037, for women). In multivariate analyses, however, these associations diminished. CONCLUSIONS: Our study demonstrates that underweight DLBCL patients have worse outcomes following R-CHOP as compared to normal as well as overweight patients....

  19. [Primary cutaneous B-cell lymphomas: study of 22 cases].

    Science.gov (United States)

    Martín Carrasco, Pablo; Morillo Andújar, Mercedes; Pérez Ruiz, Carmen; de Zulueta Dorado, Teresa; Cabrera Pérez, Rocío; Conejo-Mir, Julián

    2016-09-02

    Primary cutaneous B-cell lymphoma (CBCL) is a very low prevalence neoplasm and constitutes 25% of all primary cutaneous lymphomas. Our objective was to discover the epidemiological, clinic and histologic characteristics of CBCL in our area. Retrospective descriptive study with patients with histologic diagnosis of CBCL followed up in our department between 2004 and 2015. Twenty-two patients with CBCL were included; 65% were men and 35% were women. Follicle centre lymphoma was the most common subtype (41%). Only 3 cases presented with node involvement and one with bone marrow invasion. Five recurrences were detected and one patient died because of the CBCL. This is one of the first CBCL series in theSpanish population. The incidence, sex, age, subtype distribution, clinical features and immunohistochemical patterns are very similar to those of the other series. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  20. Follicular lymphoma, a B cell malignancy addicted to epigenetic mutations.

    Science.gov (United States)

    Korfi, Koorosh; Ali, Sara; Heward, James A; Fitzgibbon, Jude

    2017-05-04

    While follicular lymphoma (FL) is exquisitely responsive to immuno-chemotherapy, many patients follow a relapsing remitting clinical course driven in part by a common precursor cell (CPC) population. Advances in next generation sequencing have provided valuable insights into the genetic landscape of FL and its clonal evolution in response to therapy, implicating perturbations of epigenetic regulators as a hallmark of the disease. Recurrent mutations of histone modifiers KMT2D, CREBBP, EP300, EZH2, ARIDIA, and linker histones are likely early events arising in the CPC pool, rendering epigenetic based therapies conceptually attractive for treatment of indolent and transformed FL. This review provides a synopsis of the main epigenetic aberrations and the current efforts in development and testing of epigenetic therapies in this B cell malignancy.

  1. Monoclonal B-cell lymphocytosis in blood donors in Turkey.

    Science.gov (United States)

    Yağcı, Münci; Yegin, Zeynep Arzu; Yenicesu, İdil; Suyanı, Elif; Ulu, Bahar Uncu; İnci, Kamil; Çetin, Zeynep; Yılmaz, Zeynep; Kurşunoğlu, Nevruz; Özkurt, Zübeyde Nur

    2017-06-05

    Monoclonal B-cell lymphocytosis (MBL) is a precursor state of chronic lymphocytic leukemia (CLL) with peripheral lymphocytosis below 5 × 10(9)/l. The diagnostic criteria exclude the presence of lymphadenopathy, organomegaly, infections, autoimmune diseases or any sign of a lymphoproliferative disorder. This prospective study was designed in order to evaluate the frequency of MBL in blood donors in Turkey. The diagnosis of MBL was identified by flow cytometry method based on the International Familial CLL Consortium Report. A total of 999 volunteers [median age 34 (18-78) years; male/female: 705/294] were included in the study. Monoclonal B-cell lymphocytosis was demonstrated in 18 cases (1.8%). A total of 16 cases (1.6%) was evaluated as CLL-like MBL, while 2 (0.2%) had a non-CLL-like phenotype. The subjects were divided into three groups according to age, as 60 years. The prevalence of MBL was 1.1% below 40 years, 0.6% between 40 and 60 years and 0.1% in cases over 60 years, without statistical significance (p > 0.05). The sensitivity of the flow cytometry method is essential and may be responsible for the variations in the prevalence of MBL in different populations which can also be attributed to study design, higher detection rates in the elderly and families with genetic predisposition to CLL. Large population-based studies and standardized laboratory methods are needed to determine the potential risk factors of progression to CLL, including molecular markers and genetic profile.

  2. Biological fate of low-calorie sweeteners.

    Science.gov (United States)

    Magnuson, Bernadene A; Carakostas, Michael C; Moore, Nadia H; Poulos, Sylvia P; Renwick, Andrew G

    2016-11-01

    With continued efforts to find solutions to rising rates of obesity and diabetes, there is increased interest in the potential health benefits of the use of low- and no-calorie sweeteners (LNCSs). Concerns about safety often deter the use of LNCSs as a tool in helping control caloric intake, even though the safety of LNCS use has been affirmed by regulatory agencies worldwide. In many cases, an understanding of the biological fate of the different LNSCs can help health professionals to address safety concerns. The objectives of this review are to compare the similarities and differences in the chemistry, regulatory status, and biological fate (including absorption, distribution, metabolism, and excretion) of the commonly used LNCSs: acesulfame potassium, aspartame, saccharin, stevia leaf extract (steviol glycoside), and sucralose. Understanding the biological fate of the different LNCSs is helpful in evaluating whether reports of biological effects in animal studies or in humans are indicative of possible safety concerns. Illustrations of the usefulness of this information to address questions about LNCSs include discussion of systemic exposure to LNCSs, the use of sweetener combinations, and the potential for effects of LNCSs on the gut microflora. © The Author(s) 2016. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  3. Specific regulation of c-myc oncogene expression in a murine B-cell lymphoma.

    Science.gov (United States)

    McCormack, J E; Pepe, V H; Kent, R B; Dean, M; Marshak-Rothstein, A; Sonenshein, G E

    1984-01-01

    The c-myc oncogene has been implicated in a wide spectrum of B-cell neoplasias. In normal cells, the level of expression of the c-myc gene correlates with growth status. In the present study, we examined the effect of receptor-mediated inhibition of growth on c-myc expression in a B-cell lymphoma. The murine lymphoma line WEHI 231 has been characterized as an early B cell; it bears surface-bound IgM and has unrearranged c-myc genes. Following treatment of a WEHI 231 culture with anti-mouse Ig antiserum, the cells undergo one round of division and further proliferation is inhibited. We observed that this treatment specifically affected cytoplasmic levels of c-myc mRNA. An initial early increase is followed by a precipitous drop such that by 4 hr (after exposure) the amount of c-myc mRNA is below control values by a factor of approximately equal to 10. The drop in c-myc precedes cessation of DNA synthesis. During the 2- to 4-hr period, c-myc mRNA had a maximal half-life of between 20 and 30 min. In contrast, even 24 hr after anti-Ig exposure, the amounts of most major mRNAs, including mu heavy chain and actin, were not significantly altered. These results indicate that expression of an unrearranged c-myc gene can be selectively responsive to receptor-mediated regulatory events. Images PMID:6206500

  4. B-cells and their targeting in rheumatoid arthritis--current concepts and future perspectives.

    Science.gov (United States)

    Nakken, Britt; Munthe, Ludvig A; Konttinen, Yrjö T; Sandberg, Anna Klokk; Szekanecz, Zoltan; Alex, Philip; Szodoray, Peter

    2011-11-01

    Rheumatoid arthritis (RA) is a chronic, autoimmune disease that affects primarily the joints and without proper treatment results in their progressive destruction. In addition to T-cells, B-cells play a central role in the pathogenesis of this disease. The synovial tissue is an active site of B-cell accumulation, plasma cell differentiation and in situ antibody-production in RA. As part of the complex role of B-cells in the joints and synovial membrane of RA patients, B cells secrete chemokines and cytokines and may function as antigen presenting cells. The multifaceted pathogenic function of B-cells identifies them as excellent targets for immunosuppressive therapy. B-cell targeting involves a wide spectrum of molecules, for example the B-cell antigen CD20 that allows specific and effective B-cell depletion. Another target, CD79, expressed by B-cell and plasma cell precursors is an obvious candidate that induces apoptosis as well as inhibition of B-cell receptor (BCR) activation and possibly depletion of ectopic germinal centers (GC). Inhibition of B-cell co-stimulatory molecules such as CD40, CD80/86 and ICOS, can lead to diminished B-cell activation. Moreover, anti-chemokine and anti-cytokine therapies can be efficacious in RA by the disruption of B-cell activation and autoantibody production, B-cell synovial migration and ectopic GC formation. Finally, targeting the signal transduction pathways required for proximal BCR signaling has also been found efficacious in early clinical trials in RA. Even so, some B cells inhibit immune responses, these regulatory B cells may play a part in immune regulation in patients and it is unclear what effects B cell depletion strategies have in terms of such B cell subsets. This review discusses current strategies of targeting B-cells as therapeutic candidates in the management of RA. Better insights into the pathogenic role of B-cells provide efficacious opportunities to improve both therapy and prognosis of patients with RA

  5. B-cell exposure to self-antigen induces IL-10 producing B cells as well as IL-6- and TNF-α-producing B-cell subsets in healthy humans

    DEFF Research Database (Denmark)

    Langkjær, Anina; Kristensen, Birte; Hansen, Bjarke E

    2012-01-01

    Human B cells are able to secrete IL-10 after stimulation with mitogens, but their ability to produce IL-10 and regulate T-cell responses after stimulation with self-antigens is unclear. We co-cultured thyroglobulin-pulsed B cells from healthy donors with autologous T cells and observed production...... of IL-10 and TGF-β, in addition to TNF-α and IL-6. Pulsing with foreign antigen, tetanus toxoid (TT), induced a Th1-response with minimal IL-10 production. After thyroglobulin-pulsing, 1.10±0.50% of B cells and 1.00±0.20% of CD4(+) T cells produced IL-10, compared to 0.29±0.19% of B cells (P=0.01) and 0.......13±0.15% of CD4(+) T cells (P=0.006) following TT-pulsing. Thyroglobulin-stimulated, IL-10-secreting B cells were enriched within CD5(+) and CD24(high) cells. While thyroglobulin-pulsed B cells induced only modest proliferation of CD4(+) T cells, B cells pulsed with TT induced vigorous proliferation. Thus, B...

  6. Dysregulated CXCR4 expression promotes lymphoma cell survival and independently predicts disease progression in germinal center B-cell-like diffuse large B-cell lymphoma

    NARCIS (Netherlands)

    Chen, J.; Xu-Monette, Z.Y.; Deng, L.; Shen, Q.; Manyam, G.C.; Martinez-Lopez, A.; Zhang, L.; Montes-Moreno, S.; Visco, C.; Tzankov, A.; Yin, L.; Dybkaer, K.; Chiu, A.; Orazi, A.; Zu, Y.; Bhagat, G.; Richards, K.L.; Hsi, E.D.; Choi, W.W.; Krieken, J.H.J.M. van; Huh, J.; Ponzoni, M.; Ferreri, A.J.; Zhao, X.; Moller, M.B.; Farnen, J.P.; Winter, J.N.; Piris, M.A.; Pham, L.; Young, K.H.

    2015-01-01

    Abnormal expression of the chemokine receptor CXCR4 plays an essential role in tumor cell dissemination and disease progression. However, the significance of CXCR4 overexpression in de novo diffuse large B cell lymphoma (DLBCL) is unknown. In 743 patients with de novo diffuse large B cell lymphoma

  7. Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma

    NARCIS (Netherlands)

    Xia, Y.; Xu-Monette, Z.Y.; Tzankov, A.; Li, X.; Manyam, G.C.; Murty, V.; Bhagat, G.; Zhang, S.; Pasqualucci, L.; Visco, C.; Dybkaer, K.; Chiu, A.; Orazi, A.; Zu, Y.; Richards, K.L.; Hsi, E.D.; Choi, W.W.; Krieken, J.H.J.M. van; Huh, J.; Ponzoni, M.; Ferreri, A.J.; Moller, M.B.; Parsons, B.M.; Winter, J.N.; Piris, M.A.; Westin, J.; Fowler, N.; Miranda, R.N.; Ok, C.Y.; Li, Y.; Li, J.; Medeiros, L.J.; Young, K.H.

    2017-01-01

    PRDM1/BLIMP-1, a master regulator of plasma-cell differentiation, is frequently inactivated in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) patients. Little is known about its genetic aberrations and relevant clinical implications. A large series of patients with de novo DLBCL

  8. Loss of Xist RNA from the inactive X during B cell development is restored in a dynamic YY1-dependent two-step process in activated B cells.

    Science.gov (United States)

    Syrett, Camille M; Sindhava, Vishal; Hodawadekar, Suchita; Myles, Arpita; Liang, Guanxiang; Zhang, Yue; Nandi, Satabdi; Cancro, Michael; Atchison, Michael; Anguera, Montserrat C

    2017-10-01

    X-chromosome inactivation (XCI) in female lymphocytes is uniquely regulated, as the inactive X (Xi) chromosome lacks localized Xist RNA and heterochromatin modifications. Epigenetic profiling reveals that Xist RNA is lost from the Xi at the pro-B cell stage and that additional heterochromatic modifications are gradually lost during B cell development. Activation of mature B cells restores Xist RNA and heterochromatin to the Xi in a dynamic two-step process that differs in timing and pattern, depending on the method of B cell stimulation. Finally, we find that DNA binding domain of YY1 is necessary for XCI in activated B cells, as ex-vivo YY1 deletion results in loss of Xi heterochromatin marks and up-regulation of X-linked genes. Ectopic expression of the YY1 zinc finger domain is sufficient to restore Xist RNA localization during B cell activation. Together, our results indicate that Xist RNA localization is critical for maintaining XCI in female lymphocytes, and that chromatin changes on the Xi during B cell development and the dynamic nature of YY1-dependent XCI maintenance in mature B cells predisposes X-linked immunity genes to reactivation.

  9. Maintaining faith in agency under immutable constraints: cognitive consequences of believing in negotiable fate.

    Science.gov (United States)

    Au, Evelyn W M; Chiu, Chi-yue; Chaturvedi, Avinish; Mallorie, LeeAnn; Viswanathan, Madhu; Zhang, Zhi-Xue; Savani, Krishna

    2011-12-01

    Negotiable fate refers to the idea that one can negotiate with fate for control, and that people can exercise personal agency within the limits that fate has determined. Research on negotiable fate has found greater prevalence of related beliefs in Southeast Asia, East Asia, and Eastern Europe than in Western Europe and English-speaking countries. The present research extends previous findings by exploring the cognitive consequences of the belief in negotiable fate. It was hypothesized that this belief enables individuals to maintain faith in the potency of their personal actions and to remain optimistic in their goal pursuits despite the immutable constraints. The belief in negotiable fate was predicted to (a) facilitate sense-making of surprising outcomes; (b) increase persistence in goal pursuits despite early unfavorable outcomes; and (c) increase risky choices when individuals have confidence in their luck. Using multiple methods (e.g., crosscultural comparisons, culture priming, experimental induction of fate beliefs), we found supporting evidence for our hypotheses in three studies. Furthermore, as expected, the cognitive effects of negotiable fate are observed only in cultural contexts where the fate belief is relatively prevalent. Implications of these findings are discussed in relation to the intersubjective approach to understanding the influence of culture on cognitive processes (e.g., Chiu, Gelfand, Yamagishi, Shteynberg, & Wan, 2010), the sociocultural foundations that foster the development of a belief in negotiable fate, and an alternative perspective for understanding the nature of agency in contexts where constraints are severe. Future research avenues are also discussed.

  10. CD4+ T cell-mediated cytotoxicity is associated with MHC class II expression on malignant CD19+ B cells in diffuse large B cell lymphoma.

    Science.gov (United States)

    Zhou, Yong; Zha, Jie; Lin, Zhijuan; Fang, Zhihong; Zeng, Hanyan; Zhao, Jintao; Luo, Yiming; Li, Zhifeng; Xu, Bing

    2018-01-15

    Diffuse large B cell lymphoma (DLBCL) is a common B cell malignancy with approximately 30% of patients present relapsed or refractory disease after first-line therapy. Research of further treatment options is needed. Cytotoxic CD4+ T cells express cytolytic molecules and have potential antitumor function. Here, we showed that the CD19+ cells from DLBCL patients presented significantly reduced expression of MHC II molecules than those from healthy controls. Three years after the first-line treatment, patients that presented relapsed disease had significantly lower MHC II expression on their CD19+ cells than patients who did not show recurrence. Examining cytotoxic CD4+ T cells show that DLBCL patients presented significantly elevated frequencies of granzyme A-, granzyme B-, and/or perforin-expressing cytotoxic CD4+ T cells. Also, frequency of cytotoxic CD4+ T cells in DLBCL patients was positively correlated with the MHC II expression level. Subsequently, the cytotoxic potential of CD4+ T cells against autologous CD19+ cells was investigated. We found that the cytotoxic potential of CD4+ T cells was highest in MHC II-high, intermediate in MHC II-mid, and lowest in MHC II-low patients. The percentage of MHC II-expressing viable CD19+ cells presented a significant reduction after longer incubation with cytotoxic CD4+ T cells, suggesting that cytotoxic CD4+ T cells preferentially eliminated MHC II-expressing CD19+ cells. Blocking MHC II on CD19+ cells significantly reduced the cytolytic capacity of CD4+ T cells. Despite these discoveries, the frequency of cytotoxic CD4+ T cells did not predict the clinical outcome of DLBCL patients. Together, these results demonstrated that cytotoxic CD4+ T cells presented an MHC II-dependent cytotoxic potential against autologous CD19+ cells and could potentially represent a future treatment option for DLBCL. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Enhanced and sustained activation of human B cells by anti-immunoglobulin conjugated to the EBV glycoprotein gp350.

    Science.gov (United States)

    Goeckeritz, B E; Lees, A; Vos, Q; Tsokos, G C; Kuhlbusch, K; Mond, J J

    2000-03-01

    We coupled a monoclonal anti-human IgD to the gp350 gylcoprotein of Epstein-Barr virus, which has been shown to bind to the complement receptor 2 (CR2), and compared its B cell stimulatory ability to that of anti-Ig and to a multivalent anti-Ig-dextran conjugate. The anti-Ig-gp350 conjugate stimulated higher levels of human B cell proliferation in vitro than did anti-Ig or anti-Ig conjugated to control viral protein, comparable to the proliferation stimulated by the multivalent anti-Ig-dextran. This enhanced proliferation was dependent on binding of the conjugate to CR2, inasmuch as an anti-CD2 antibody blocked the enhanced proliferative response. This enhanced proliferative response was associated with prolonged elevations of intracellular ionized calcium, which was comparable to the response stimulated by anti-Ig-dextran. These findings suggest the use of gp350 as a carrier molecule for weakly immunogenic peptides or antigens which, when bound to gp350, would enhance B cell clonal expansion and activation of antigen-specific B cells.

  12. Importance of B cell co-stimulation in CD4(+) T cell differentiation: X-linked agammaglobulinaemia, a human model.

    Science.gov (United States)

    Martini, H; Enright, V; Perro, M; Workman, S; Birmelin, J; Giorda, E; Quinti, I; Lougaris, V; Baronio, M; Warnatz, K; Grimbacher, B

    2011-06-01

    We were interested in the question of whether the congenital lack of B cells actually had any influence on the development of the T cell compartment in patients with agammaglobulinaemia. Sixteen patients with X-linked agammaglobulinaemia (XLA) due to mutations in Btk, nine patients affected by common variable immune deficiency (CVID) with <2% of peripheral B cells and 20 healthy volunteers were enrolled. The T cell phenotype was determined with FACSCalibur and CellQuest Pro software. Mann-Whitney two-tailed analysis was used for statistical analysis. The CD4 T cell memory compartment was reduced in patients with XLA of all ages. This T cell subset encompasses both CD4(+)CD45RO(+) and CD4(+)CD45RO(+)CXCR5(+) cells and both subsets were decreased significantly when compared to healthy controls: P = 0·001 and P < 0·0001, respectively. This observation was confirmed in patients with CVID who had <2% B cells, suggesting that not the lack of Bruton's tyrosine kinase but the lack of B cells is most probably the cause of the impaired CD4 T cell maturation. We postulate that this defect is a correlate of the observed paucity of germinal centres in XLA. Our results support the importance of the interplay between B and T cells in the germinal centre for the activation of CD4 T cells in humans. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.

  13. B cells exposed to enterobacterial components suppress development of experimental colitis

    DEFF Research Database (Denmark)

    Schmidt, Esben Gjerløff Wedebye; Larsen, Hjalte List; Kristensen, Nanna Ny

    2012-01-01

    ). RESULTS: We demonstrate that splenic B cells exposed to ebx produce large amounts of IL-10 in vitro and express CD1d and CD5 previously known to be associated with regulatory B cells. In SCID mice transplanted with colitogenic CD4(+) CD25(-) T cells, co-transfer of ebx-B cells significantly suppressed...... development of colitis. Suppression was dependent on B cell-derived IL-10, as co-transfer of IL-10 knockout ebx-B cells failed to suppress colitis. Ebx-B cell-mediated suppression of colitis was associated with a decrease in interferon gamma (IFN-¿)-producing T(H) 1 cells and increased frequencies of Foxp3......-expressing T cells. CONCLUSIONS: These data demonstrate that splenic B cells exposed to enterobacterial components acquire immunosuppressive functions by which they can suppress development of experimental T cell-mediated colitis in an IL-10-dependent way. (Inflamm Bowel Dis 2011;)....

  14. Signals from activation of B-cell receptor with anti-IgD can override the stimulatory effects of excess BAFF on mature B cells in vivo.

    Science.gov (United States)

    Nguyen, Tue G; Morris, Jonathan M

    2014-09-01

    The selection and maturation of B-cell clones are critically determined by tonic signals from activated B cell receptors (BCR) and survival signals from BAFF cytokine. These finely tuned and coordinated signals provide a net positive signal that can promote the selection, maturation, proliferation and differentiation of a developing B cell. Stimulation with an anti-IgD antibody can also activate BCR but can lead to depletion and an arrest of mature B-cell development in vivo. It is not known whether survival signals from excess BAFF can override the suppressive effects of treatment with anti-IgD on mature B cells in vivo. Herein, we examined the effects of co-treatment of BAFF and anti-IgD on the mature B-cell compartment and antibody production in vivo by treating mice with either 1mg/kg BAFF or anti-IgD alone or in combination for 3 consecutive days. We found that co-treatment with anti-IgD significantly abrogated these stimulatory effects of BAFF treatment on splenic CD19+ B cells as well as mature CD19+IgD(hi)IgM+ B cells in vivo. Anti-IgD down-regulated the expression of the BCR complex (mIgM, mIgD and CD19) and the BAFF receptor TACI without regard to the presence of BAFF. Anti-IgD treatment also significantly negated BAFF-induced IgM production in vivo. Both BAFF and anti-IgD could individually stimulate IL-10 synthesis in B cells but did not affect one another. Taken together, our data suggest that activation of BCR with an anti-IgD antibody can override the stimulatory effects from excess BAFF on B cell proliferation and antibody production by down-regulating the expression of BCR complex and BAFF receptors. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. B cell follicle-like structures in multiple sclerosis-with focus on the role of B cell activating factor

    DEFF Research Database (Denmark)

    Morten, Haugen; Frederiksen, Jette L; Vinter, Matilda Degn

    2014-01-01

    B lymphocytes play an important role in the pathogenesis of multiple sclerosis (MS). Follicle-like structures (FLS) have recently been found in the subarachnoid space in the leptomeninges in some patients with secondary progressive MS (SPMS). They contain proliferating B lymphocytes, plasma cells......, helper T lymphocytes and a network of follicular dendritic cells. FLS have been shown to correlate with increased cortical demyelination, neuronal loss, meningeal infiltration and central nervous system inflammation, as well as lower age at disease onset and progression to severe disability and death....... In this review, we will discuss the role of FLS in MS pathogenesis and disease course and the possible influence by B cell activating factor (BAFF) and C-X-C motif chemokine 13 (CXCL13)....

  16. Engineered T Cells for the Adoptive Therapy of B-Cell Chronic Lymphocytic Leukaemia

    Directory of Open Access Journals (Sweden)

    Philipp Koehler

    2012-01-01

    Full Text Available B-cell chronic lymphocytic leukaemia (B-CLL remains an incurable disease due to the high risk of relapse, even after complete remission, raising the need to control and eliminate residual tumor cells in long term. Adoptive T cell therapy with genetically engineered specificity is thought to fulfil expectations, and clinical trials for the treatment of CLL are initiated. Cytolytic T cells from patients are redirected towards CLL cells by ex vivo engineering with a chimeric antigen receptor (CAR which binds to CD19 on CLL cells through an antibody-derived domain and triggers T cell activation through CD3ζ upon tumor cell engagement. Redirected T cells thereby target CLL cells in an MHC-unrestricted fashion, secret proinflammatory cytokines, and eliminate CD19+ leukaemia cells with high efficiency. Cytolysis of autologous CLL cells by patient's engineered T cells is effective, however, accompanied by lasting elimination of healthy CD19+ B-cells. In this paper we discuss the potential of the strategy in the treatment of CLL, the currently ongoing trials, and the future challenges in the adoptive therapy with CAR-engineered T cells.

  17. A human B cell methylome at 100−base pair resolution

    Science.gov (United States)

    Rauch, Tibor A.; Wu, Xiwei; Zhong, Xueyan; Riggs, Arthur D.; Pfeifer, Gerd P.

    2009-01-01

    Using a methylated-DNA enrichment technique (methylated CpG island recovery assay, MIRA) in combination with whole-genome tiling arrays, we have characterized by MIRA-chip the entire B cell “methylome” of an individual human at 100-bp resolution. We find that at the chromosome level high CpG methylation density is correlated with subtelomeric regions and Giemsa-light bands (R bands). The majority of the most highly methylated regions that could be identified on the tiling arrays were associated with genes. Approximately 10% of all promoters in B cells were found to be methylated, and this methylation correlates with low gene expression. Notably, apparent exceptions to this correlation were the result of transcription from previously unidentified, unmethylated transcription start sites, suggesting that methylation may control alternate promoter usage. Methylation of intragenic (gene body) sequences was found to correlate with increased, not decreased, transcription, and a methylated region near the 3′ end was found in approximately 12% of all genes. The majority of broad regions (10–44 kb) of high methylation were at segmental duplications. Our data provide a valuable resource for the analysis of CpG methylation patterns in a differentiated human cell type and provide new clues regarding the function of mammalian DNA methylation. PMID:19139413

  18. Telomere length analysis in monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia Binet A

    Directory of Open Access Journals (Sweden)

    F.M. Furtado

    Full Text Available Monoclonal B-cell lymphocytosis (MBL is an asymptomatic clinical entity characterized by the proliferation of monoclonal B cells not meeting the diagnosis criteria for chronic lymphocytic leukemia (CLL. MBL may precede the development of CLL, but the molecular mechanisms responsible for disease progression and evolution are not completely known. Telomeres are usually short in CLL and their attrition may contribute to disease evolution. Here, we determined the telomere lengths of CD5+CD19+ cells in MBL, CLL, and healthy volunteers. Twenty-one CLL patients, 11 subjects with high-count MBL, and 6 with low-count MBL were enrolled. Two hundred and sixty-one healthy volunteers aged 0 to 88 years were studied as controls. After diagnosis confirmation, a flow cytometry CD19+CD5+-based cell sorting was performed for the study groups. Telomere length was determined by qPCR. Telomere length was similar in the 3 study groups but shorter in these groups compared to normal age-matched subjects that had been enrolled in a previous study from our group. These findings suggest that telomere shortening is an early event in CLL leukemogenesis.

  19. Asymmetric PI3K Signaling Driving Developmental and Regenerative Cell Fate Bifurcation

    Directory of Open Access Journals (Sweden)

    Wen-Hsuan W. Lin

    2015-12-01

    Full Text Available Metazoan sibling cells often diverge in activity and identity, suggesting links between growth signals and cell fate. We show that unequal transduction of nutrient-sensitive PI3K/AKT/mTOR signaling during cell division bifurcates transcriptional networks and fates of kindred cells. A sibling B lymphocyte with stronger signaling, indexed by FoxO1 inactivation and IRF4 induction, undergoes PI3K-driven Pax5 repression and plasma cell determination, while its sibling with weaker PI3K activity renews a memory or germinal center B cell fate. PI3K-driven effector T cell determination silences TCF1 in one sibling cell, while its PI3K-attenuated sibling self-renews in tandem. Prior to bifurcations achieving irreversible plasma or effector cell fate determination, asymmetric signaling during initial divisions specifies a more proliferative, differentiation-prone lymphocyte in tandem with a more quiescent memory cell sibling. By triggering cell division but transmitting unequal intensity between sibling cells, nutrient-sensitive signaling may be a frequent arbiter of cell fate bifurcations during development and repair.

  20. Applying near-infrared photoimmunotherapy to B-cell lymphoma: comparative evaluation with radioimmunotherapy in tumor xenografts.

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    Heryanto, Yusri-Dwi; Hanaoka, Hirofumi; Nakajima, Takahito; Yamaguchi, Aiko; Tsushima, Yoshito

    2017-11-01

    Radioimmunotherapy (RIT) has proven effective for patients with relapsed and refractory lymphoma. However, new types of therapy are strongly desired as B-cell lymphoma remains incurable for many patients. Photoimmunotherapy (PIT) is an emerging targeted cancer therapy that uses photosensitizer (IR700)-conjugated monoclonal antibodies (mAbs) to specifically kill cancer cells. To evaluate the usefulness and potential role of PIT for treating B-cell lymphoma in a comparison with RIT, we performed in vivo PIT and RIT studies with an IR700 or (90)Y-conjugated anti-CD20 mAb, NuB2. IR700 or (90)Y were conjugated to NuB2. Since cell aggressiveness greatly affects the therapeutic effect, we selected both an indolent (RPMI 1788) and an aggressive (Ramos) type of B-cell lymphoma cell line. The in vitro therapeutic effect of PIT and the biodistribution profiles of IR700-NuB2 were evaluated. In vivo PIT and RIT studies were performed with 100 or 500 μg of IR700-NuB2 and 150 μCi/20 μg of (90)Y-NuB2, respectively, in two types of B-cell lymphoma-bearing mice. The in vitro studies revealed that Ramos was more sensitive than RPMI 1788 to PIT. The therapeutic effect of PIT with 500 µg IR700-NuB2 was superior to any other therapies against aggressive Ramos tumors, whereas RIT showed the highest therapeutic effect in indolent RPMI 1788 tumors. Since the uptake levels and intratumoral distribution of IR700-NuB2 were comparable in both tumors, a possible cause of this difference is the tumor growth rate. The PIT with 500 µg (IR700-NuB2) group showed a significantly greater therapeutic effect than the PIT with 100 µg group due to the higher and more homogeneous tumor distribution of IR700-NuB2. PIT was effective for both indolent and aggressive B-cell lymphoma, and the higher dose provided a better therapeutic effect. In aggressive tumors, PIT was more effective than RIT. Thus, PIT would be a promising strategy for the locoregional treatment or control of B-cell lymphoma

  1. Pathway-selective suppression of chemokine receptor signaling in B cells by LPS through downregulation of PLC-β2

    Science.gov (United States)

    Shirakawa, Aiko-Konno; Liao, Fang; Zhang, Hongwei H; Hedrick, Michael N; Singh, Satya P; Wu, Dianqing; Farber, Joshua M

    2010-01-01

    Lymphocyte activation leads to changes in chemokine receptor expression. There are limited data, however, on how lymphocyte activators can alter chemokine signaling by affecting downstream pathways. We hypothesized that B cell-activating agents might alter chemokine responses by affecting downstream signal transducers, and that such effects might differ depending on the activator. We found that activating mouse B cells using either anti-IgM or lipopolysaccharide (LPS) increased the surface expression of CCR6 and CCR7 with large increases in chemotaxis to their cognate ligands. By contrast, while anti-IgM also led to enhanced calcium responses, LPS-treated cells showed only small changes in calcium signaling as compared with cells that were freshly isolated. Of particular interest, we found that LPS caused a reduction in the level of B-cell phospholipase C (PLC)-β2 mRNA and protein. Data obtained using PLC-β2−/− mice showed that the β2 isoform mediates close to one-half the chemokine-induced calcium signal in resting and anti-IgM-activated B cells, and we found that calcium signals in the LPS-treated cells were boosted by increasing the level of PLC-β2 using transfection, consistent with a functional effect of downregulating PLC-β2. Together, our results show activator-specific effects on responses through B-cell chemokine receptors that are mediated by quantitative changes in a downstream signal-transducing protein, revealing an activity for LPS as a downregulator of PLC-β2, and a novel mechanism for controlling chemokine-induced signals in lymphocytes. PMID:20871625

  2. B cells in chronic obstructive pulmonary disease: moving to center stage

    Science.gov (United States)

    Polverino, Francesca; Seys, Leen J. M.; Bracke, Ken R.

    2016-01-01

    Chronic inflammatory responses in the lungs contribute to the development and progression of chronic obstructive pulmonary disease (COPD). Although research studies focused initially on the contributions of the innate immune system to the pathogenesis of COPD, more recent studies have implicated adaptive immune responses in COPD. In particular, studies have demonstrated increases in B cell counts and increases in the number and size of B cell-rich lymphoid follicles in COPD lungs that correlate directly with COPD severity. There are also increases in lung levels of mediators that promote B cell maturation, activation, and survival in COPD patients. B cell products such as autoantibodies directed against lung cells, components of cells, and extracellular matrix proteins are also present in COPD lungs. These autoantibodies may contribute to lung inflammation and injury in COPD patients, in part, by forming immune complexes that activate complement components. Studies of B cell-deficient mice and human COPD patients have linked B cells most strongly to the emphysema phenotype. However, B cells have protective activities during acute exacerbations of COPD by promoting adaptive immune responses that contribute to host defense against pathogens. This review outlines the evidence that links B cells and B cell-rich lymphoid follicles to the pathogenesis of COPD and the mechanisms involved. It also reviews the potential and limitations of B cells as therapeutic targets to slow the progression of human COPD. PMID:27542809

  3. B cells in chronic obstructive pulmonary disease: moving to center stage.

    Science.gov (United States)

    Polverino, Francesca; Seys, Leen J M; Bracke, Ken R; Owen, Caroline A

    2016-10-01

    Chronic inflammatory responses in the lungs contribute to the development and progression of chronic obstructive pulmonary disease (COPD). Although research studies focused initially on the contributions of the innate immune system to the pathogenesis of COPD, more recent studies have implicated adaptive immune responses in COPD. In particular, studies have demonstrated increases in B cell counts and increases in the number and size of B cell-rich lymphoid follicles in COPD lungs that correlate directly with COPD severity. There are also increases in lung levels of mediators that promote B cell maturation, activation, and survival in COPD patients. B cell products such as autoantibodies directed against lung cells, components of cells, and extracellular matrix proteins are also present in COPD lungs. These autoantibodies may contribute to lung inflammation and injury in COPD patients, in part, by forming immune complexes that activate complement components. Studies of B cell-deficient mice and human COPD patients have linked B cells most strongly to the emphysema phenotype. However, B cells have protective activities during acute exacerbations of COPD by promoting adaptive immune responses that contribute to host defense against pathogens. This review outlines the evidence that links B cells and B cell-rich lymphoid follicles to the pathogenesis of COPD and the mechanisms involved. It also reviews the potential and limitations of B cells as therapeutic targets to slow the progression of human COPD. Copyright © 2016 the American Physiological Society.

  4. A two-scale model for correlation between B cell VDJ usage in zebrafish

    Science.gov (United States)

    Pan, Keyao; Deem, Michael

    2011-03-01

    The zebrafish (Danio rerio) is one of the model animals for study of immunology. The dynamics of the adaptive immune system in zebrafish is similar to that in higher animals. In this work, we built a two-scale model to simulate the dynamics of B cells in primary and secondary immune reactions in zebrafish and to explain the reported correlation between VDJ usage of B cell repertoires in distinct zebrafish. The first scale of the model consists of a generalized NK model to simulate the B cell maturation process in the 10-day primary immune response. The second scale uses a delay ordinary differential equation system to model the immune responses in the 6-month lifespan of zebrafish. The generalized NK model shows that mature B cells specific to one antigen mostly possess a single VDJ recombination. The probability that mature B cells in two zebrafish have the same VDJ recombination increases with the B cell population size or the B cell selection intensity and decreases with the B cell hypermutation rate. The ODE model shows a distribution of correlation in the VDJ usage of the B cell repertoires in two six-month-old zebrafish that is highly similar to that from experiment. This work presents a simple theory to explain the experimentally observed correlation in VDJ usage of distinct zebrafish B cell repertoires after an immune response.

  5. SAP modulates B cell functions in a genetic background-dependent manner.

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    Detre, Cynthia; Yigit, Burcu; Keszei, Marton; Castro, Wilson; Magelky, Erica M; Terhorst, Cox

    2013-06-01

    Mutations affecting the SLAM-associated protein (SAP) are responsible for the X-linked lympho-proliferative syndrome (XLP), a severe primary immunodeficiency syndrome with disease manifestations that include fatal mononucleosis, B cell lymphoma and dysgammaglobulinemia. It is well accepted that insufficient help by SAP-/- CD4+ T cells, in particular during the germinal center reaction, is a component of dysgammaglobulinemia in XLP patients and SAP-/- animals. It is however not well understood whether in XLP patients and SAP-/- mice B cell functions are affected, even though B cells themselves do not express SAP. Here we report that B cell intrinsic responses to haptenated protein antigens are impaired in SAP-/- mice and in Rag-/- mice into which B cells derived from SAP-/- mice together with wt CD4+ T cells had been transferred. This impaired B cells functions are in part depending on the genetic background of the SAP-/- mouse, which affects B cell homeostasis. Surprisingly, stimulation with an agonistic anti-CD40 causes strong in vivo and in vitro B cell responses in SAP-/- mice. Taken together, the data demonstrate that genetic factors play an important role in the SAP-related B cell functions. The finding that anti-CD40 can in part restore impaired B cell responses in SAP-/- mice, suggests potentially novel therapeutic interventions in subsets of XLP patients. Copyright © 2013 Elsevier B.V. All rights reserved.

  6. Toll-like receptors regulate B cell cytokine production in patients with diabetes

    Science.gov (United States)

    Jagannathan, M.; McDonnell, M.; Liang, Y.; Hasturk, H.; Hetzel, J.; Rubin, D.; Kantarci, A.; Van Dyke, T. E.; Ganley-Leal, L. M.

    2010-01-01

    Aims/hypothesis Understanding cellular and molecular events in diabetes mellitus will identify new approaches for therapy. Immune system cells are important modulators of chronic inflammation in diabetes mellitus, but the role of B cells is not adequately studied. The aim of this work was to define the function of B cells in diabetes mellitus patients through focus on B cell responses to pattern recognition receptors. Methods We measured expression and function of Toll-like receptors (TLRs) on peripheral blood B cells from diabetes mellitus patients by flow cytometry and multiplexed cytokine analysis. We similarly analysed B cells from non-diabetic donors and periodontal disease patients as comparative cohorts. Results B cells from diabetes mellitus patients secrete multiple pro-inflammatory cytokines, and IL-8 production is significantly elevated in B cells from diabetic patients compared with those from non-diabetic individuals. These data, plus modest elevation of TLR surface expression, suggest B cell IL-8 hyperproduction is a cytokine-specific outcome of altered TLR function in B cells from diabetes mellitus patients. Altered TLR function is further evidenced by demonstration of an unexpected, albeit modest ‘anti-inflammatory’ function for TLR4. Importantly, B cells from diabetes mellitus patients fail to secrete IL-10, an anti-inflammatory cytokine implicated in inflammatory disease resolution, under a variety of TLR-stimulating conditions. Comparative analyses of B cells from patients with a second chronic inflammatory disease, periodontal disease, indicated that some alterations in B cell TLR function associate specifically with diabetes mellitus. Conclusions/interpretation Altered TLR function in B cells from diabetes mellitus patients increases inflammation by two mechanisms: elevation of pro-inflammatory IL-8 and lack of anti-inflammatory/protective IL-10 production. PMID:20383694

  7. Inflammation Causes Resistance to Anti-CD20-Mediated B Cell Depletion.

    Science.gov (United States)

    Laws, L H; Parker, C E; Cherala, G; Koguchi, Y; Waisman, A; Slifka, M K; Oberbarnscheidt, M H; Obhrai, J S; Yeung, M Y; Riella, L V

    2016-11-01

    B cells play a central role in antibody-mediated rejection and certain autoimmune diseases. However, B cell-targeted therapy such as anti-CD20 B cell-depleting antibody (aCD20) has yielded mixed results in improving outcomes. In this study, we investigated whether an accelerated B cell reconstitution leading to aCD20 depletion resistance could account for these discrepancies. Using a transplantation model, we found that antigen-independent inflammation, likely through toll-like receptor (TLR) signaling, was sufficient to mitigate B cell depletion. Secondary lymphoid organs had a quicker recovery of B cells when compared to peripheral blood. Inflammation altered the pharmacokinetics (PK) and pharmacodynamics (PD) of aCD20 therapy by shortening drug half-life and accelerating the reconstitution of the peripheral B cell pool by bone marrow-derived B cell precursors. IVIG (intravenous immunoglobulin) coadministration also shortened aCD20 drug half-life and led to accelerated B cell recovery. Repeated aCD20 dosing restored B cell depletion and delayed allograft rejection, especially B cell-dependent, antibody-independent allograft rejection. These data demonstrate the importance of further clinical studies of the PK/PD of monoclonal antibody treatment in inflammatory conditions. The data also highlight the disconnect between B cell depletion on peripheral blood compared to secondary lymphoid organs, the deleterious effect of IVIG when given with aCD20 and the relevance of redosing of aCD20 for effective B cell depletion in alloimmunity. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

  8. CD16+ monocyte subset was enriched and functionally exacerbated in driving T-cell activation and B-cell response in systemic lupus erythematosus

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    Huaqun Zhu

    2016-11-01

    Full Text Available Background: The roles that CD16+ monocyte subset plays in T-cell activation and B-cell response have not been well studied in systemic lupus erythematosus (SLE. Objective: The present study aimed to investigate the distribution of CD16+ monocyte subsets in SLE and explore their possible roles in T-cell activation and B-cell differentiation. Methods: The frequencies of monocyte subsets in the peripheral blood of healthy controls (HCs and patients with SLE were determined by flow cytometry. Monocyte subsets were sorted and co-cultured with CD4+ T cells and CD19+ B cells. Then, T and B cells were collected for different subset detection, while the supernatants were collected for immunoglobulin G (IgG, IgA, and IgM or interferon (IFN-γ and interleukin (IL-17A detection by enzyme-linked immunosorbent assay. Results: Our results showed that CD16+ monocytes exhibited a pro-inflammatory phenotype with elevated CD80, CD86, HLA-DR, and CX3CR1 expression on the cell surface. It’s further demonstrated that CD16+ monocytes from patients and HCs shared different cell-surface marker profiles. The CD16+ subset was enriched in SLE and had an exacerbated capacity to promote CD4+ T cell polarization into a Th17 phenotype. Also, CD16+ monocytes had enhanced impacts on CD19+ B cells to differentiate into plasma B cells and regulatory B cells with more Ig production. Conclusions: This study demonstrated that CD16+ monocytes, characterized by different cell-surface marker profiles, were enriched and played a critical role in driving the pathogenic T- and B-cell responses in patients with SLE.

  9. TGFβ activated kinase 1 (TAK1 at the crossroad of B cell receptor and Toll-like receptor 9 signaling pathways in human B cells.

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    Dániel Szili

    Full Text Available B cell development and activation are regulated by combined signals mediated by the B cell receptor (BCR, receptors for the B-cell activating factor of the tumor necrosis factor family (BAFF-R and the innate receptor, Toll-like receptor 9 (TLR9. However, the underlying mechanisms by which these signals cooperate in human B cells remain unclear. Our aim was to elucidate the key signaling molecules at the crossroads of BCR, BAFF-R and TLR9 mediated pathways and to follow the functional consequences of costimulation.Therefore we stimulated purified human B cells by combinations of anti-Ig, B-cell activating factor of the tumor necrosis factor family (BAFF and the TLR9 agonist, CpG oligodeoxynucleotide. Phosphorylation status of various signaling molecules, B cell proliferation, cytokine secretion, plasma blast generation and the frequency of IgG producing cells were investigated. We have found that BCR induced signals cooperate with BAFF-R- and TLR9-mediated signals at different levels of cell activation. BCR and BAFF- as well as TLR9 and BAFF-mediated signals cooperate at NFκB activation, while BCR and TLR9 synergistically costimulate mitogen activated protein kinases (MAPKs, ERK, JNK and p38. We show here for the first time that the MAP3K7 (TGF beta activated kinase, TAK1 is responsible for the synergistic costimulation of B cells by BCR and TLR9, resulting in an enhanced cell proliferation, plasma blast generation, cytokine and antibody production. Specific inhibitor of TAK1 as well as knocking down TAK1 by siRNA abrogates the synergistic signals. We conclude that TAK1 is a key regulator of receptor crosstalk between BCR and TLR9, thus plays a critical role in B cell development and activation.

  10. Percentage of Peripheral CD19+CD24hiCD38hi Regulatory B Cells in Neonatal Sepsis Patients and Its Functional Implication.

    Science.gov (United States)

    Pan, Xiao; Ji, Zuoquan; Xue, Jiang

    2016-07-07

    BACKGROUND As a major cause of mortality in neonates, neonatal sepsis is often accompanied by immune dysfunctions, which are frequently caused by dysregulated T cell sub-populations. The role of regulatory B cells in neonatal sepsis, however, remains unknown. Therefore, this study investigated the percentage and functional variation of CD19+CD24hiCD38hi regulatory B cells in peripheral blood of neonatal sepsis patients in an attempt to elucidate the role of these regulatory B cells in pathogenesis of sepsis. MATERIAL AND METHODS Flow cytometry was used to quantify the percentage of CD19+CD24hiCD38hi regulatory B cells from peripheral blood samples. The correlation between B cell percentage and C reactive protein (CRP) level was analyzed. Secretion level of interleukin-10 (IL-10) and effects on the proliferation of naïve CD4+ T cells were further analyzed. RESULTS The percentage of CD19+CD24hiCD38hi regulatory B cells in neonatal sepsis patients was significantly higher compared to healthy controls (psepsis patients, and also had more potent inhibition on naïve CD4+ T cells (pneonatal sepsis can inhibit body immune function and thus may participate in the pathogenesis of sepsis.

  11. EVALUATION OF CYTOKINE GENE POLYMORPHISM IN B CELL LYMPHOID MALIGNANCIES

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    E. L. Nazarova

    2014-01-01

    Full Text Available Previous studies with some solid tumors has shown that polymorphisms of certain cytokine genes may be used as predictors of clinical outcome in the patients. It seemed important to evaluate potential correlations between production of certain pro- and anti-inflammatory cytokines and co-receptor molecules, and promoter polymorphism of the cytokine genes involved into regulation of cell proliferation, differentiation, apoptosis, lipid metabolism and blood clotting in the patients with hematological malignancies. The article contains our results concerning associations between of IL-1β, -2, -4, -10, -17, TNFα, and allelic polymorphisms of their genes in 62 patients with B cell lymphoid malignancies in an ethnically homogenous group (self-identified as Russians. We have shown that the GА and AA genotypes of the G-308A polymorphism in TNFα gene are significantly associated with increased production of this cytokine, being more common in aggressive non-Hodgkin lymphomas, more rare in multiple myeloma and in indolent non-Hodgkin lymphomas.

  12. Multifocal Extranodal Involvement of Diffuse Large B-Cell Lymphoma

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    Devrim Cabuk

    2013-01-01

    Full Text Available Endobronchial involvement of extrapulmonary malignant tumors is uncommon and mostly associated with breast, kidney, colon, and rectum carcinomas. A 68-year-old male with a prior diagnosis of colon non-Hodgkin lymphoma (NHL was admitted to the hospital with a complaint of cough, sputum, and dyspnea. The chest radiograph showed right hilar enlargement and opacity at the right middle zone suggestive of a mass lesion. Computed tomography of thorax revealed a right-sided mass lesion extending to thoracic wall with the destruction of the third and the fourth ribs and a right hilar mass lesion. Fiberoptic bronchoscopy was performed in order to evaluate endobronchial involvement and showed stenosis with mucosal tumor infiltration in right upper lobe bronchus. The pathological examination of bronchoscopic biopsy specimen reported diffuse large B-cell lymphoma and the patient was accepted as the endobronchial recurrence of sigmoid colon NHL. The patient is still under treatment of R-ICE (rituximab-ifosfamide-carboplatin-etoposide chemotherapy and partial regression of pulmonary lesions was noted after 3 courses of treatment.

  13. Antibody and B cell responses to Plasmodium sporozoites

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    Johanna N Dups

    2014-11-01

    Full Text Available Antibodies are capable of blocking infection of the liver by Plasmodium sporozoites. Accordingly the induction of anti-sporozoite antibodies is a major aim of various vaccine approaches to malaria. In recent years our knowledge of the specificity and quantities of antibodies required for protection has been greatly expanded by clinical trials of various whole sporozoite and subunit vaccines. Moreover, the development of humanized mouse models and transgenic parasites have also aided our ability to assess the specificity of antibodies and their ability to block infection. Nonetheless, considerable gaps remain in our knowledge - in particular in understanding what antigens are recognized by infection blocking antibodies and in knowing how we can induce robust, long-lived antibody responses. Maintaining high levels of circulating antibodies is likely to be of primary importance, as antibodies must block infection in the short time it takes for sporozoites to reach the liver from the skin. It is clear that a better understanding of the development of protective B cell-mediated immunity will aid the development and refinement of malaria vaccines.

  14. Primary Mediastinal Large B-Cell Lymphoma during Pregnancy

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    Cesar A. Perez

    2012-01-01

    Full Text Available Non-Hodgkin’s Lymphoma (NHL rarely presents during pregnancy and primary mediastinal large B-cell lymphoma (PMLBCL accounts for approximately 2.5% of patients with NHL. The case of a 22-year-old woman who was diagnosed with Stage IIA PMLBCL during week 13 of her intrauterine pregnancy is described. The staging consisted in computed tomography (CT of the chest and magnetic resonance imaging (MRI of the abdomen and pelvis. She was managed with R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for a total of six cycles and, because of the early presentation during the second trimester, she received the entire chemotherapy course during the pregnancy. She delivered a healthy baby at 34 weeks of pregnancy and a 18FDG-PET/CT scan demonstrated complete remission after delivery. After 20 months of follow up she remains with no evidence of disease and her 1-year-old son has shown no developmental delays or physical abnormalities. PMLBCL, although an uncommon subgroup of DLBCL, may present during pregnancy and R-CHOP should be considered as one suitable option in this complex scenario.

  15. Ocrelizumab: a B-cell depleting therapy for multiple sclerosis.

    Science.gov (United States)

    Jakimovski, Dejan; Weinstock-Guttman, Bianca; Ramanathan, Murali; Kolb, Channa; Hojnacki, David; Minagar, Alireza; Zivadinov, Robert

    2017-09-01

    Multiple sclerosis (MS) is the most common neurological disease responsible for early disability in the young working population. In the last two decades, based on retrospective/prospective data, the use of disease-modifying therapies has been shown to slow the rate of disability progression and prolonged the time to conversion into secondary-progressive MS (SPMS). However, despite the availability of several approved therapies, disability progression cannot be halted significantly in all MS patients. Areas covered: This article reviews the immunopathology of the B-cells, and their role in pathogenesis of MS and their attractiveness as a potential therapeutic target in MS. The review focuses on the recently published ocrelizumab phase III trials in terms of its efficacy, safety, and tolerability as well as its future considerations. Expert opinion: B lymphocyte cell depletion therapy offers a compelling and promising new option for MS patients. Nonetheless, there is a need for heightened vigilance and awareness in detecting potential long-term consequences that currently remain unknown.

  16. A Positive Correlation between Atypical Memory B Cells and Plasmodium falciparum Transmission Intensity in Cross-Sectional Studies in Peru and Mali

    Science.gov (United States)

    Weiss, Greta E.; Clark, Eva H.; Li, Shanping; Traore, Boubacar; Kayentao, Kassoum; Ongoiba, Aissata; Hernandez, Jean N.; Doumbo, Ogobara K.; Pierce, Susan K.; Branch, OraLee H.; Crompton, Peter D.

    2011-01-01

    Background Antibodies that protect against Plasmodium falciparum (Pf) malaria are only acquired after years of repeated infections. The B cell biology that underlies this observation is poorly understood. We previously reported that “atypical” memory B cells are increased in children and adults exposed to intense Pf transmission in Mali, similar to what has been observed in individuals infected with HIV. In this study we examined B cell subsets of Pf -infected adults in Peru and Mali to determine if Pf transmission intensity correlates with atypical memory B cell expansion. Methodology/Principal Findings In this cross-sectional study venous blood was collected from adults in areas of zero (U.S., n = 10), low (Peru, n = 18) and high (Mali, n = 12) Pf transmission. Adults in Peru and Mali were infected with Pf at the time of blood collection. Thawed lymphocytes were analyzed by flow cytometry to quantify B cell subsets, including atypical memory B cells, defined by the cell surface markers CD19+ CD20+ CD21− CD27− CD10−. In Peru, the mean level of atypical memory B cells, as a percent of total B cells, was higher than U.S. adults (Peru mean: 5.4% [95% CI: 3.61–7.28]; U.S. mean: 1.4% [95% CI: 0.92–1.81]; p<0.0001) but lower than Malian adults (Mali mean 13.1% [95% CI: 10.68–15.57]; p = 0.0001). In Peru, individuals self-reporting ≥1 prior malaria episodes had a higher percentage of atypical memory B cells compared to those reporting no prior episodes (≥1 prior episodes mean: 6.6% [95% CI: 4.09–9.11]; no prior episodes mean: 3.1% [95% CI: 1.52–4.73]; p = 0.028). Conclusions/Significance Compared to Pf-naive controls, atypical memory B cells were increased in Peruvian adults exposed to low Pf transmission, and further increased in Malian adults exposed to intense Pf transmission. Understanding the origin, function and antigen specificity of atypical memory B cells in the context of Pf infection could contribute to our

  17. Accumulation of self-reactive naive and memory B cell reveals sequential defects in B cell tolerance checkpoints in Sjogren's syndrome.

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    Elisa Corsiero

    Full Text Available Sjögren's syndrome (SS is an autoimmune disease characterised by breach of self-tolerance towards nuclear antigens resulting in high affinity circulating autoantibodies. Although peripheral B cell disturbances have been described in SS, with predominance of naïve and reduction of memory B cells, the stage at which errors in B cell tolerance checkpoints accumulate in SS is unknown. Here we determined the frequency of self- and poly-reactive B cells in the circulating naïve and memory compartment of SS patients. Single CD27-IgD+ naïve, CD27+IgD+ memory unswitched and CD27+IgD- memory switched B cells were sorted by FACS from the peripheral blood of 7 SS patients. To detect the frequency of polyreactive and autoreactive clones, paired Ig VH and VL genes were amplified, cloned and expressed as recombinant monoclonal antibodies (rmAbs displaying identical specificity of the original B cells. IgVH and VL gene usage and immunoreactivity of SS rmAbs were compared with those obtained from healthy donors (HD. From a total of 353 VH and 293 VL individual sequences, we obtained 114 rmAbs from circulating naïve (n = 66 and memory (n = 48 B cells of SS patients. Analysis of the Ig V gene repertoire did not show significant differences in SS vs. HD B cells. In SS patients, circulating naïve B cells (with germline VH and VL genes displayed a significant accumulation of clones autoreactive against Hep-2 cells compared to HD (43.1% vs. 25%. Moreover, we demonstrated a progressive increase in the frequency of circulating anti-nuclear naïve (9.3%, memory unswitched (22.2% and memory switched (27.3% B cells in SS patients. Overall, these data provide novel evidence supporting the existence of both early and late defects in B cell tolerance checkpoints in patients with SS resulting in the accumulation of autoreactive naïve and memory B cells.

  18. EBI2 overexpression in mice leads to B1 B cell expansion and chronic lymphocytic leukemia-(CLL)-like B cell malignancies

    DEFF Research Database (Denmark)

    Niss Arfelt, Kristine; Barington, Line; Benned-Jensen, Tau

    2017-01-01

    Human and mouse chronic lymphocytic leukemia (CLL) develop from CD5+ B cells that in mice and macaques are known to define the distinct B1a B cell lineage. B1a cells are characterized by lack of germinal center development and the B1a cell population is increased in mice with reduced germinal...... days after birth, late-onset lymphoid cancer development and premature death. These findings are highly similar to those observed in CLL patients and identify EBI2 as a promoter of B cell malignancies....

  19. Unambiguous observation of shape effects on cellular fate of nanoparticles

    Science.gov (United States)

    Chu, Zhiqin; Zhang, Silu; Zhang, Bokai; Zhang, Chunyuan; Fang, Chia-Yi; Rehor, Ivan; Cigler, Petr; Chang, Huan-Cheng; Lin, Ge; Liu, Renbao; Li, Quan

    2014-03-01

    Cellular fate of nanoparticles is vital to application of nanoparticles to cell imaging, bio-sensing, drug delivery, suppression of drug resistance, gene delivery, and cytotoxicity analysis. However, the current studies on cellular fate of nanoparticles have been controversial due to complications of interplay between many possible factors. By well-controlled experiments, we demonstrated unambiguously that the morphology of nanoparticles independently determined their cellular fate. We found that nanoparticles with sharp shapes, regardless of their surface chemistry, size, or composition, could pierce the membranes of endosomes that carried them into the cells and escape to the cytoplasm, which in turn significantly reduced the cellular excretion rate of the nanoparticles. Such features of sharp-shaped nanoparticles are essential for drug delivery, gene delivery, subcellular targeting, and long-term tracking. This work opens up a controllable, purely geometrical and hence safe, degree of freedom for manipulating nanoparticle-cell interaction, with numerous applications in medicine, bio-imaging, and bio-sensing.

  20. Exhaustion of CTL memory and recrudescence of viremia in lymphocytic choriomeningitis virus-infected MHC class II-deficient mice and B cell-deficient mice

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    Thomsen, Allan Randrup; Johansen, J; Marker, O

    1996-01-01

    To study the contribution of CD4+ T cells and B cells to antiviral immunity and long term virus control, MHC class II-deficient and B cell-deficient mice were infected with lymphocytic choriomeningitis virus. In class II-deficient mice, which lack CD4+ T cells, the primary CTL response is virtual...... and that in their absence, the virus-specific CTL potential becomes exhausted. Together our results indicate that while CD8+ cells play a dominant role in acute virus control, all three major components of the immune system are required for long term virus control....

  1. Impaired removal of H3K4 methylation affects cell fate determination and gene transcription

    DEFF Research Database (Denmark)

    Lussi, Yvonne C; Mariani, Luca; Rundsten, Carsten Friis

    2016-01-01

    genetic locus, a direct RBR-2 target gene required for vulva precursor cell fate acquisition, shows that RBR-2 controls the epigenetic signature of the lin-11 vulva-specific enhancer and lin-11 expression, providing in vivo evidences that RBR-2 can positively regulate transcription and cell fate...

  2. Aggressive B-cell lymphomas: how many categories do we need?

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    Said, Jonathan W

    2015-01-01

    Aggressive B-cell lymphomas are diverse group of neoplasms that arise at different stages of B-cell development and by various mechanisms of neoplastic transformation. The aggressive B-cell lymphomas include many types, subtypes and variants of diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), mantle cell lymphoma and its blastoid variant, and B lymphoblastic lymphoma. Differences in histology, cytogenetic and molecular abnormalities, as well as the relationship with the tumor microenvironment, help define characteristic signatures for these neoplasms, and in turn dictate potential therapeutic targets. Rather than survey the entire spectrum of aggressive B-cell lymphomas, this report aims to identify and characterize important clinically aggressive subtypes of DLBCL, and explore the relationship of DLBCL to BL and the gray zone between them (B-cell lymphoma unclassifiable with features intermediate between DLBCL and BL). PMID:23154748

  3. Regulation of B cell functions by Toll-like receptors and complement.

    Science.gov (United States)

    Kremlitzka, Mariann; Mácsik-Valent, Bernadett; Erdei, Anna

    2016-10-01

    B cell functions triggered by the clonally-rearranged antigen-specific B cell receptor (BCR) are regulated by several germ-line encoded receptors - including Toll-like receptors (TLRs) and complement receptors (CRs). Simultaneous or sequential engagement of these structures expressed either on the cell membrane or intracellularly, may fundamentally alter and fine tune activation, antibody and cytokine production of B cells. Here we review the expression and function of TLRs and various C3 fragment binding CRs on B cells, emphasizing their role in different human B cell subsets under physiological and pathological conditions. Studies underlining the importance of the crosstalk between TLRs and CRs in regulating B cell functions are also highlighted. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  4. DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation

    DEFF Research Database (Denmark)

    Shaknovich, Rita; Cerchietti, Leandro; Tsikitas, Lucas

    2011-01-01

    The phenotype of germinal center (GC) B cells includes the unique ability to tolerate rapid proliferation and the mutagenic actions of activation induced cytosine deaminase (AICDA). Given the importance of epigenetic patterning in determining cellular phenotypes, we examined DNA methylation...... and the role of DNA methyltransferases in the formation of GCs. DNA methylation profiling revealed a marked shift in DNA methylation patterning in GC B cells versus resting/naive B cells. This shift included significant differential methylation of 235 genes, with concordant inverse changes in gene expression...... affecting most notably genes of the NFkB and MAP kinase signaling pathways. GC B cells were predominantly hypomethylated compared with naive B cells and AICDA binding sites were highly overrepresented among hypomethylated loci. GC B cells also exhibited greater DNA methylation heterogeneity than naive B...

  5. Uptake and presentation of myelin basic protein by normal human b cells

    DEFF Research Database (Denmark)

    Brimnes, Marie Klinge; Hansen, Bjarke Endel; Nielsen, Leif Kofoed

    2014-01-01

    B cells may play both pathogenic and protective roles in T-cell mediated autoimmune diseases such as multiple sclerosis (MS). These functions relate to the ability of B cells to bind and present antigens. Under serum-free conditions we observed that 3-4% of circulating B cells from healthy donors...... were capable of binding the MS-associated self-antigen myelin basic protein (MBP) and of presenting the immunodominant peptide MBP85-99, as determined by staining with the mAb MK16 recognising the peptide presented by HLA-DR15-positive cells. In the presence of serum, however, the majority of B cells....... The mechanisms described here refute the general assumption that B-cell presentation of self-antigens requires uptake via specific B-cell receptors, and may be important for maintenance of tolerance as well as for driving T-cell responses in autoimmune diseases....

  6. Human B cells produce chemokine CXCL10 in the presence of Mycobacterium tuberculosis specific T cells

    DEFF Research Database (Denmark)

    Hoff, Soren T; Salman, Ahmed M; Ruhwald, Morten

    2015-01-01

    BACKGROUND: The role of B cells in human host response to Mycobacterium tuberculosis (Mtb) infection is still controversial, but recent evidence suggest that B cell follicle like structures within the lung may influence host responses through regulation of the local cytokine environment. A candid......BACKGROUND: The role of B cells in human host response to Mycobacterium tuberculosis (Mtb) infection is still controversial, but recent evidence suggest that B cell follicle like structures within the lung may influence host responses through regulation of the local cytokine environment....... A candidate for such regulation could be the chemokine CXCL10. CXCL10 is mainly produced by human monocytes, but a few reports have also found CXCL10 production by human B cells. The objective of this study was to investigate CXCL10 production by human B cells in response to in vitro stimulation with Mtb...

  7. Primary human cytomegalovirus infection induces the expansion of virus-specific activated and atypical memory B cells.

    Science.gov (United States)

    Dauby, Nicolas; Kummert, Caroline; Lecomte, Sandra; Liesnard, Corinne; Delforge, Marie-Luce; Donner, Catherine; Marchant, Arnaud

    2014-10-15

    Although neutralizing antibodies play a central role in the control of cytomegalovirus (CMV) dissemination, little is known about the response of B lymphocytes to primary human CMV infection. The proportion, phenotype, specificity, and functionality of B-cell subsets were studied in a cohort of pregnant women with primary CMV infection. CMV-seronegative pregnant women, as well as CMV-seronegative and CMV-seropositive healthy adults, were included as controls. Primary CMV infection was associated with a sustained expansion of activated (CD27(+)CD20(+)CD21(low)) and atypical (CD27(-)CD20(+)CD21(low)) memory B cells (MBCs). Both subsets expressed an effector phenotype, and their proportions were correlated with viremia. Activated MBCs expressed high levels of activation markers and included high frequencies of tumor necrosis α (TNF-α)-producing cells, whereas atypical MBCs expressed high levels of inhibitory receptors and had low TNF-α responses. Fluorescent-labeled antigen experiments indicated that activated and atypical MBCs were enriched in CMV-specific cells. Primary CMV infection mobilizes a large pool of memory B cells that includes activated and atypical MBCs. The functional regulation of CMV-specific MBCs may limit the production of antibodies and the control of viral dissemination. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  8. Comprehensive microRNA profiling in B-cells of human centenarians by massively parallel sequencing

    Directory of Open Access Journals (Sweden)

    Gombar Saurabh

    2012-07-01

    Full Text Available Abstract Background MicroRNAs (miRNAs are small, non-coding RNAs that regulate gene expression and play a critical role in development, homeostasis, and disease. Despite their demonstrated roles in age-associated pathologies, little is known about the role of miRNAs in human aging and longevity. Results We employed massively parallel sequencing technology to identify miRNAs expressed in B-cells from Ashkenazi Jewish centenarians, i.e., those living to a hundred and a human model of exceptional longevity, and younger controls without a family history of longevity. With data from 26.7 million reads comprising 9.4 × 108 bp from 3 centenarian and 3 control individuals, we discovered a total of 276 known miRNAs and 8 unknown miRNAs ranging several orders of magnitude in expression levels, a typical characteristics of saturated miRNA-sequencing. A total of 22 miRNAs were found to be significantly upregulated, with only 2 miRNAs downregulated, in centenarians as compared to controls. Gene Ontology analysis of the predicted and validated targets of the 24 differentially expressed miRNAs indicated enrichment of functional pathways involved in cell metabolism, cell cycle, cell signaling, and cell differentiation. A cross sectional expression analysis of the differentially expressed miRNAs in B-cells from Ashkenazi Jewish individuals between the 50th and 100th years of age indicated that expression levels of miR-363* declined significantly with age. Centenarians, however, maintained the youthful expression level. This result suggests that miR-363* may be a candidate longevity-associated miRNA. Conclusion Our comprehensive miRNA data provide a resource for further studies to identify genetic pathways associated with aging and longevity in humans.

  9. Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies

    Science.gov (United States)

    Rodgers, David T.; Mazagova, Magdalena; Hampton, Eric N.; Cao, Yu; Ramadoss, Nitya S.; Hardy, Ian R.; Schulman, Andrew; Du, Juanjuan; Wang, Feng; Singer, Oded; Ma, Jennifer; Nunez, Vanessa; Shen, Jiayin; Woods, Ashley K.; Wright, Timothy M.; Schultz, Peter G.; Kim, Chan Hyuk; Young, Travis S.

    2016-01-01

    Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive results in clinical trials for B-cell malignancies. However, safety concerns related to the inability to control CAR-T cells once infused into the patient remain a significant challenge. Here we report the engineering of recombinant antibody-based bifunctional switches that consist of a tumor antigen-specific Fab molecule engrafted with a peptide neo-epitope, which is bound exclusively by a peptide-specific switchable CAR-T cell (sCAR-T). The switch redirects the activity of the bio-orthogonal sCAR-T cells through the selective formation of immunological synapses, in which the sCAR-T cell, switch, and target cell interact in a structurally defined and temporally controlled manner. Optimized switches specific for CD19 controlled the activity, tissue-homing, cytokine release, and phenotype of sCAR-T cells in a dose-titratable manner in a Nalm-6 xenograft rodent model of B-cell leukemia. The sCAR–T-cell dosing regimen could be tuned to provide efficacy comparable to the corresponding conventional CART-19, but with lower cytokine levels, thereby offering a method of mitigating cytokine release syndrome in clinical translation. Furthermore, we demonstrate that this methodology is readily adaptable to targeting CD20 on cancer cells using the same sCAR-T cell, suggesting that this approach may be broadly applicable to heterogeneous and resistant tumor populations, as well as other liquid and solid tumor antigens. PMID:26759369

  10. Inflammatory Conditions Dictate the Effect of Mesenchymal Stem or Stromal Cells on B Cell Function

    Science.gov (United States)

    Luk, Franka; Carreras-Planella, Laura; Korevaar, Sander S.; de Witte, Samantha F. H.; Borràs, Francesc E.; Betjes, Michiel G. H.; Baan, Carla C.; Hoogduijn, Martin J.; Franquesa, Marcella

    2017-01-01

    The immunomodulatory capacity of mesenchymal stem or stromal cells (MSC) makes them a promising tool for treatment of immune disease and organ transplantation. The effects of MSC on B cells are characterized by an abrogation of plasmablast formation and induction of regulatory B cells (Bregs). It is, however, unknown how MSC interact with B cells under inflammatory conditions. In this study, adipose tissue-derived MSC were pretreated with 50 ng/ml IFN-γ for 96 h (MSC–IFN-γ) to simulate inflammatory conditions. Mature B cells were obtained from spleens by CD43− selection. B cells were co-cultured with MSC and stimulated with anti-IgM, anti-CD40, and IL-2; and after 7 days, B cell proliferation, phenotype, Immunoglobulin-G (IgG), and IL-10 production were analyzed. MSC did not inhibit B cell proliferation but increased the percentage of CD38high CD24high B cells (Bregs) and IL-10 production, while MSC–IFN-γ significantly reduced B cell proliferation and inhibited IgG production by B cells in a more potent fashion but did not induce Bregs or IL-10 production. Both MSC and MSC–IFN-γ required proximity to target cells and being metabolically active to exert their effects. Indoleamine 2,3 dioxygenase expression was highly induced in MSC–IFN-γ and was responsible of the anti-proliferative and Breg reduction since addition of tryptophan (TRP) restored MSC properties. Immunological conditions dictate the effect of MSC on B cell function. Under immunological quiescent conditions, MSC stimulate Breg induction; whereas, under inflammatory conditions, MSC inhibit B cell proliferation and maturation through depletion of TRP. This knowledge is useful for customizing MSC therapy for specific purposes by appropriate pretreatment of MSC. PMID:28894451

  11. Activation of B Cells by a Dendritic Cell-Targeted Oral Vaccine

    OpenAIRE

    Sahay, Bikash; Owen, Jennifer L.; Yang, Tao; Zadeh, Mojgan; Lightfoot, Yaíma L.; Ge, Jun-wei; Mohamadzadeh, Mansour

    2013-01-01

    Production of long-lived, high affinity humoral immunity is an essential characteristic of successful vaccination and requires cognate interactions between T and B cells in germinal centers. Within germinal centers, specialized T follicular helper cells assist B cells and regulate the antibody response by mediating the differentiation of B cells into memory or plasma cells after exposure to T cell-dependent antigens. It is now appreciated that local immune responses are also essential for pro...

  12. B Cells Producing Type I Interferon Modulate Macrophage Polarization in Tuberculosis.

    Science.gov (United States)

    Bénard, Alan; Sakwa, Imme; Schierloh, Pablo; Colom, André; Mercier, Ingrid; Tailleux, Ludovic; Jouneau, Luc; Boudinot, Pierre; Al-Saati, Talal; Lang, Roland; Rehwinkel, Jan; Loxton, Andre G; Kaufmann, Stefan He; Anton-Leberre, Véronique; O'Garra, Anne; Del Carmen Sasiain, Maria; Gicquel, Brigitte; Fillatreau, Simon; Neyrolles, Olivier; Hudrisier, Denis

    2017-11-21

    In addition to their well-known function as antibody-producing cells, B lymphocytes can markedly influence the course of infectious or non-infectious diseases via antibody-independent mechanisms. In tuberculosis, B cells accumulate in lungs, yet their functional contribution to the host response remains poorly understood. To document the role of B cells in tuberculosis in an unbiased manner. We generated the transcriptome of B cells isolated from Mycobacterium tuberculosis (Mtb)-infected mice, and validated the identified key pathways using in vitro and in vivo assays. The obtained data were substantiated using B cells from pleural effusion of tuberculosis patients. B cells isolated from Mtb-infected mice displayed a STAT1-centered signature, suggesting a role for interferons in B cell response to infection. B cells stimulated in vitro with Mtb produced type I interferon, via a mechanism involving the innate sensor STING, and antagonized by MyD88 signaling. In vivo, B cells expressed type I interferon in the lungs of Mtb-infected mice and, of clinical relevance, in pleural fluid from patients with tuberculosis. Type I interferon expression by B cells induced an altered polarization of macrophages towards a regulatory/anti-inflammatory profile in vitro. In vivo, increased provision of type I interferon by B cells in a murine model of B cell-restricted Myd88-deficiency correlated with an enhanced accumulation of regulatory/anti-inflammatory macrophages in Mtb infected lungs. Type I interferon produced by Mtb-stimulated B cells favors macrophage polarization towards a regulatory/anti-inflammatory phenotype during Mtb infection.

  13. Changes in tonsil B cell phenotypes and EBV receptor expression in children under 5 years old.

    Science.gov (United States)

    Wohlford, Eric M; Baresel, Paul C; Wilmore, Joel R; Mortelliti, Anthony J; Coleman, Carrie B; Rochford, Rosemary

    2017-09-08

    Palatine tonsils are principally B cell organs that are the initial line of defense against many oral pathogens, as well as the site of infection for others. While the size of palatine tonsils changes greatly in the first five years of life, the cellular changes during this period are not well studied. Epstein Barr virus (EBV) is a common orally transmitted virus that infects tonsillar B cells. Naïve B cells are thought to be the target of primary infection with EBV in vivo, suggesting that they are targeted by the virus. EBV enters B cells through CD21, but studies of older children and adults have not shown differences in surface CD21 between naïve B cells and other tonsil B cell populations. In this study we used an 11-color flow cytometry panel to detail the changes in B cell subpopulations in human tonsils over the first five years of life from 33 healthy US children. We provide reference ranges for tonsil B cell subpopulations over this age range. We show that the frequency of naïve tonsil B cells decreases over the early years of life, and that naïve B cells expressed higher surface levels of CD21 relative to other tonsil B cell populations. We show that young children have a higher frequency of naïve tonsil B cells, and importantly that these cells express increased surface EBV receptor, suggesting that young children have a larger pool of cells that can be infected by the virus. This article is protected by copyright. All rights reserved. © 2017 International Clinical Cytometry Society.

  14. Effect of cytokine inhibition on peripheral memory B cells in patients with Rheumatoid arthtritis

    OpenAIRE

    Mahmood, Zafar

    2015-01-01

    Objective: Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease. Enhanced B cell activity has been proposed in the pathogenesis of RA along with different pro-inflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), critically involved in chronic inflammation. Biological agents targeting these cytokines IL-6 and TNF-α have considerably advanced treatment of autoimmunity. Enhanced B cell activity, particularly memory B cells gain...

  15. Uptake and presentation of myelin basic protein by normal human B cells.

    Directory of Open Access Journals (Sweden)

    Marie Klinge Brimnes

    Full Text Available B cells may play both pathogenic and protective roles in T-cell mediated autoimmune diseases such as multiple sclerosis (MS. These functions relate to the ability of B cells to bind and present antigens. Under serum-free conditions we observed that 3-4% of circulating B cells from healthy donors were capable of binding the MS-associated self-antigen myelin basic protein (MBP and of presenting the immunodominant peptide MBP85-99, as determined by staining with the mAb MK16 recognising the peptide presented by HLA-DR15-positive cells. In the presence of serum, however, the majority of B cells bound MBP in a complement-dependent manner, and almost half of the B cells became engaged in presentation of MBP85-99. Even though complement receptor 1 (CR1, CD35 and CR2 (CD21 both contributed to binding of MBP to B cells, only CR2 was important for the subsequent presentation of MBP85-99. A high proportion of MBP85-99 presenting B cells expressed CD27, and showed increased expression of CD86 compared to non-presenting B cells. MBP-pulsed B cells induced a low frequency of IL-10-producing CD4+ T cells in 3 out of 6 donors, indicating an immunoregulatory role of B cells presenting MBP-derived peptides. The mechanisms described here refute the general assumption that B-cell presentation of self-antigens requires uptake via specific B-cell receptors, and may be important for maintenance of tolerance as well as for driving T-cell responses in autoimmune diseases.

  16. Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma

    DEFF Research Database (Denmark)

    Hertel, Christina B; Zhou, Xiao-ge; Hamilton-Dutoit, Stephen J

    2002-01-01

    In classical Hodgkin lymphoma the malignant Hodgkin/Reed-Sternberg (HRS) cells characteristically constitute only a small minority of the tumour load. Their origin has been debated for decades, but on the basis of rearrangement and somatic hypermutations of their immunoglubulin (Ig) genes, HRS...... cells are now ascribed to the B-cell lineage. Nevertheless, phenotypically HRS cells have lost their B cell identity: they usually lack common B cell-specific surface markers such as CD19 and CD79a as well as Ig gene transcripts. Here we demonstrate that Ig promoters as well as both intronic and 3......' enhancer sequences are transcriptionally inactive in HRS cell lines. This inactivity correlates with either reduced levels or even a complete lack of several B cell-specific transcription factors required for their expression: Oct-2, OBF-1, PU.1, E47/E12, PAX-5 and EBF. Moreover, we demonstrate that PU.1...

  17. The Fas/CD95 receptor regulates the death of autoreactive B cells and the selection of antigen-specific B cells

    Directory of Open Access Journals (Sweden)

    Anne-Odile eHUEBER

    2012-07-01

    Full Text Available Cell death receptors have crucial roles in the regulation of immune responses. Here we review recent in vivo data confirming that the Fas death receptor (TNFSR6 on B cells is important for the regulation of autoimmunity since the impairment of only Fas function on B cells results in uncontrolled autoantibody production and autoimmunity. Fas plays a role in the elimination of the non-specific and auto-reactive B cells in germinal center, while during the selection of antigen specific B cells different escape signals ensure the resistance to Fas-mediated apoptosis. Antigen specific survival such as BCR or MHCII signal or coreceptors (CD19 cooperating with BCR inhibits the formation of death inducing signaling complex. Antigen-specific survival can be reinforced by antigen-independent signals of IL4 or CD40 overproducing the anti-apoptotic members of the Bcl-2 family proteins.

  18. Hepatic B cells are readily activated by Toll‐like receptor‐4 ligation and secrete less interleukin‐10 than lymphoid tissue B cells

    National Research Council Canada - National Science Library

    Zhang, H; Stolz, D. B; Chalasani, G; Thomson, A. W

    2013-01-01

    ... their secretion of interleukin ( IL )‐10. While the liver is regarded both as an important immune organ and a tolerogenic environment, little is known about the functional biology of hepatic B cells...

  19. Adhesion of Human B Cells to Germinal Centers in Vitro Involves VLA-4 and INCAM-110

    Science.gov (United States)

    Freedman, Arnold S.; Munro, J. Michael; Rice, G. Edgar; Bevilacqua, Michael P.; Morimoto, Chikao; McIntyre, Bradley W.; Rhynhart, Kurt; Pober, Jordan S.; Nadler, Lee M.

    1990-08-01

    Human B lymphocytes localize and differentiate within the microenvironment of lymphoid germinal centers. A frozen section binding assay was developed for the identification of those molecules involved in the adhesive interactions between B cells and lymphoid follicles. Activated human B cells and B cell lines were found to selectively adhere to germinal centers. The VLA-4 molecule on the lymphocyte and the adhesion molecule INCAM-110, expressed on follicular dendritic cells, supported this interaction. This cellular interaction model can be used for the study of how B cells differentiate.

  20. Lis1 Regulates Germinal Center B Cell Antigen Acquisition and Affinity Maturation.

    Science.gov (United States)

    Chen, Jingjing; Cai, Zhenming; Zhang, Le; Yin, Yuye; Chen, Xufeng; Chen, Chao; Zhang, Yang; Zhai, Sulan; Long, Xuehui; Liu, Xiaolong; Wang, Xiaoming

    2017-06-01

    The germinal center (GC) is the site where activated B cells undergo rapid expansions, somatic hypermutation, and affinity maturation. Affinity maturation is a process of Ag-driven selection. The amount of Ag acquired and displayed by GC B cells determines whether it can be positively selected, and therefore Ag acquisition has to be tightly regulated to ensure the efficient affinity maturation. Cell expansion provides sufficient quantity of GC B cells and Abs, whereas affinity maturation improves the quality of Abs. In this study, we found that Lis1 is a cell-intrinsic regulator of Ag acquisition capability of GC B cells. Lack of Lis1 resulted in redistribution of polymerized actin and accumulation of F-actin at uropod; larger amounts of Ags were acquired and displayed by GC B cells, which presumably reduced the selection stringency. Affinity maturation was thus compromised in Lis1-deficient mice. Consistently, overexpression of Lis1 in GC B cells led to less Ag acquisition and display. Additionally, Lis1 is required for GC B cell expansion, and Lis1 deficiency blocked the cell cycle at the mitotic phase and GC B cells were prone to apoptosis. Overall, we suggest that Lis1 is required for GC B cell expansion, affinity maturation, and maintaining functional intact GC response, thus ensuring both the quantity and quality of Ab response. Copyright © 2017 by The American Association of Immunologists, Inc.

  1. Micro RNA-19a suppresses IL-10 in peripheral B cells from patients with atherosclerosis.

    Science.gov (United States)

    Ren, Zhong-Qiao; Liu, Ning; Zhao, Kan

    2016-10-01

    The interleukin (IL)-10-production B cells play an important role in the pathogenesis of atherosclerosis (Asro) with unknown mechanism. Micro RNA (miR)-17-92 cluster has strong immune regulatory activities. This study tests a hypothesis that miR-17-92 cluster suppresses IL-10 expression in B cells of Asro patients. Patients with Asro were recruited into this study. Peripheral blood samples were collected from the patients. B cells were isolated from the blood samples and analyzed to elucidate the role of miR-17-92 in the regulation of IL-10 expression. Peripheral B cells from patients with Asro show lower levels of IL-10 than that from healthy subjects. The IL-10 expression in the B cells is negatively correlated with the expression of miR-19a in the B cells. The serum levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-4 in Asro patients were higher than healthy subjects. Exposure to TNF-α or IFN-γ or IL-4 suppressed IL-10 expression in B cells via increasing the expression of miR-19a in B cells, which could be abolished by Inhibition of miR-19a. TNF-α or IFN-γ or IL-4 suppresses IL-10 in B cells via up regulating miR-19a expression. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Rituximab efficiently depletes B cells in lung tumors and normal lung tissue.

    Science.gov (United States)

    Joly-Battaglini, Albane; Hammarström, Clara; Stankovic, Branislava; Aamodt, Henrik; Stjärne, Johan; Brustugun, Odd Terje; Helland, Åslaug; Øynebråten, Inger; Corthay, Alexandre

    2016-01-01

    Rituximab is a monoclonal antibody that targets the CD20 B-cell-specific antigen and is widely used as therapy for B-cell lymphoma. Since rituximab depletes both malignant and normal B cells, it is increasingly being used to treat various conditions in which normal B cells have a pathogenic role, such as rheumatoid arthritis and multiple sclerosis. It is well-established that rituximab efficiently eliminates B cells in blood, lymph nodes, and spleen. In contrast, the effect of rituximab in non-lymphoid tissues remains poorly documented and is debated. Here, we report a rheumatoid arthritis patient who was treated with rituximab before receiving thoracic surgery for non-small cell lung cancer. Using flow cytometry and immunohistochemistry, we show that rituximab efficiently depleted CD20-positive B cells in a primary lung tumor, in lung-associated lymph nodes, and in normal lung tissue. We conclude that rituximab may be very efficient at depleting normal B cells in the lungs. This property of rituximab may potentially be exploited for the treatment of conditions in which pathogenic B cells reside in the lungs. On the other hand, the clearance of lung B cells may provide an explanation for the rare cases of severe non-infectious pulmonary toxicity of rituximab.

  3. B-cell exhaustion in HIV infection: the role of immune activation.

    Science.gov (United States)

    Moir, Susan; Fauci, Anthony S

    2014-09-01

    To discuss a component of the pathogenic mechanisms of HIV infection in the context of phenotypic and functional alterations in B cells that are due to persistent viral replication leading to aberrant immune activation and cellular exhaustion. We explore how B-cell exhaustion arises during persistent viremia and how it compares with T-cell exhaustion and similar B-cell alterations in other diseases. HIV-associated B-cell exhaustion was first described in 2008, soon after the demonstration of persistent virus-induced T-cell exhaustion, as well as the identification of a subset B cells in tonsil tissues with immunoregulatory features similar to those observed in T-cell exhaustion. Our understanding of B-cell exhaustion has since expanded in two important areas: the role of inhibitory receptors in the unresponsiveness of exhausted B cells and the increasing evidence that similar B cells are found in other diseases that are associated with aberrant immune activation and inflammation. The phenomenon of B-cell exhaustion is now well established in HIV infection and other diseases characterized by immune activation. Over the coming years, it will be important to understand how cellular exhaustion affects the capacity of the immune system to respond to persisting primary pathogens, as well as to other microbial antigens, whether encountered as secondary infections or following immunization.

  4. B cells promote tumor progression via STAT3 regulated-angiogenesis.

    Directory of Open Access Journals (Sweden)

    Chunmei Yang

    Full Text Available The role of B cells in cancer and the underlying mechanisms remain to be further explored. Here, we show that tumor-associated B cells with activated STAT3 contribute to tumor development by promoting tumor angiogenesis. B cells with or without Stat3 have opposite effects on tumor growth and tumor angiogenesis in both B16 melanoma and Lewis Lung Cancer mouse models. Ex vivo angiogenesis assays show that B cell-mediated tumor angiogenesis is mainly dependent on the induction of pro-angiogenic gene expression, which requires Stat3 signaling in B cells. Furthermore, B cells with activated STAT3 are mainly found in or near tumor vasculature and correlate significantly with overall STAT3 activity in human tumors. Moreover, the density of B cells in human tumor tissues correlates significantly with expression levels of several STAT3-downstream pro-angiogenic genes, as well as the degree of tumor angiogenesis. Together, these findings define a novel role of B cells in promoting tumor progression through angiogenesis and identify STAT3 in B cells as potential therapeutic target for anti-angiogenesis therapy.