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Sample records for cell immunological synapse

  1. The immunological synapse

    DEFF Research Database (Denmark)

    Klemmensen, Thomas; Pedersen, Lars Ostergaard; Geisler, Carsten

    2003-01-01

    . A distinct 3-dimensional supramolecular structure at the T cell/APC interface has been suggested to be involved in the information transfer. Due to its functional analogy to the neuronal synapse, the structure has been termed the "immunological synapse" (IS). Here, we review molecular aspects concerning...

  2. Navigating barriers: the challenge of directed secretion at the natural killer cell lytic immunological synapse.

    Science.gov (United States)

    Sanborn, Keri B; Orange, Jordan S

    2010-05-01

    Natural killer (NK) cells have an inherent ability to recognize and destroy a wide array of cells rendered abnormal by stress or disease. NK cells can kill a targeted cell by forming a tight interface-the lytic immunological synapse. This represents a dynamic molecular arrangement that over time progresses through a series of steps to ultimately deliver the contents of specialized organelles known as lytic granules. In order to mediate cytotoxicity, the NK cell faces the challenge of mobilizing the lytic granules, polarizing them to the targeted cell, facilitating their approximation to the NK cell membrane, and releasing their contents. This review is focused upon the final steps in accessing function through the lytic immunological synapse.

  3. Centriole polarisation to the immunological synapse directs secretion from cytolytic cells of both the innate and adaptive immune systems

    Directory of Open Access Journals (Sweden)

    Arico Maurizo

    2011-06-01

    Full Text Available Abstract Background Cytolytic cells of the immune system destroy pathogen-infected cells by polarised exocytosis of secretory lysosomes containing the pore-forming protein perforin. Precise delivery of this lethal hit is essential to ensuring that only the target cell is destroyed. In cytotoxic T lymphocytes (CTLs, this is accomplished by an unusual movement of the centrosome to contact the plasma membrane at the centre of the immunological synapse formed between killer and target cells. Secretory lysosomes are directed towards the centrosome along microtubules and delivered precisely to the point of target cell recognition within the immunological synapse, identified by the centrosome. We asked whether this mechanism of directing secretory lysosome release is unique to CTL or whether natural killer (NK and invariant NKT (iNKT cytolytic cells of the innate immune system use a similar mechanism to focus perforin-bearing lysosome release. Results NK cells were conjugated with B-cell targets lacking major histocompatibility complex class I 721.221 cells, and iNKT cells were conjugated with glycolipid-pulsed CD1-bearing targets, then prepared for thin-section electron microscopy. High-resolution electron micrographs of the immunological synapse formed between NK and iNKT cytolytic cells with their targets revealed that in both NK and iNKT cells, the centrioles could be found associated (or 'docked' with the plasma membrane within the immunological synapse. Secretory clefts were visible within the synapses formed by both NK and iNKT cells, and secretory lysosomes were polarised along microtubules leading towards the docked centrosome. The Golgi apparatus and recycling endosomes were also polarised towards the centrosome at the plasma membrane within the synapse. Conclusions These results reveal that, like CTLs of the adaptive immune system, the centrosomes of NK and iNKT cells (cytolytic cells of the innate immune system direct secretory lysosomes to

  4. Comparative anatomy of phagocytic and immunological synapses

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    Florence eNiedergang

    2016-01-01

    Full Text Available The generation of phagocytic cups and immunological synapses are crucial events of the innate and adaptive immune responses, respectively. They are triggered by distinct immune receptors and performed by different cell types. However, growing experimental evidence shows that a very close series of molecular and cellular events control these two processes. Thus, the tight and dynamic interplay between receptor signaling, actin and microtubule cytoskeleton, and targeted vesicle traffic are all critical features to build functional phagosomes and immunological synapses. Interestingly, both phagocytic cups and immunological synapses display particular spatial and temporal patterns of receptors and signaling molecules, leading to the notion of phagocytic synapse. Here we discuss both types of structures, their organization and the mechanisms by which they are generated and regulated.

  5. Resolving dynamics of cell signaling via real-time imaging of the immunological synapse.

    Energy Technology Data Exchange (ETDEWEB)

    Stevens, Mark A.; Pfeiffer, Janet R. (University of New Mexico, Albuquerque, NM); Wilson, Bridget S. (University of New Mexico, Albuquerque, NM); Timlin, Jerilyn Ann; Thomas, James L. (University of New Mexico, Albuquerque, NM); Lidke, Keith A. (University of New Mexico, Albuquerque, NM); Spendier, Kathrin (University of New Mexico, Albuquerque, NM); Oliver, Janet M. (University of New Mexico, Albuquerque, NM); Carroll-Portillo, Amanda (University of New Mexico, Albuquerque, NM); Aaron, Jesse S.; Mirijanian, Dina T.; Carson, Bryan D.; Burns, Alan Richard; Rebeil, Roberto

    2009-10-01

    This highly interdisciplinary team has developed dual-color, total internal reflection microscopy (TIRF-M) methods that enable us to optically detect and track in real time protein migration and clustering at membrane interfaces. By coupling TIRF-M with advanced analysis techniques (image correlation spectroscopy, single particle tracking) we have captured subtle changes in membrane organization that characterize immune responses. We have used this approach to elucidate the initial stages of cell activation in the IgE signaling network of mast cells and the Toll-like receptor (TLR-4) response in macrophages stimulated by bacteria. To help interpret these measurements, we have undertaken a computational modeling effort to connect the protein motion and lipid interactions. This work provides a deeper understanding of the initial stages of cellular response to external agents, including dynamics of interaction of key components in the signaling network at the 'immunological synapse,' the contact region of the cell and its adversary.

  6. The immunological synapse

    DEFF Research Database (Denmark)

    Klemmensen, Thomas; Pedersen, Lars Ostergaard; Geisler, Carsten

    2003-01-01

    The induction of a proper adaptive immune response is dependent on the correct transfer of information between antigen-presenting cells (APCs) and antigen-specific T cells. Defects in information transfer may result in the development of diseases, e.g. immunodeficiencies and autoimmunity. A disti...

  7. Quantal concept of T-cell activation: adhesion domains as immunological synapses

    International Nuclear Information System (INIS)

    Sackmann, Erich

    2011-01-01

    Adhesion micro-domains (ADs) formed during encounters of lymphocytes with antigen-presenting cells (APC) mediate the genetic expression of quanta of cytokines interleukin-2 (IL-2). The IL-2-induced activation of IL-2 receptors promotes the stepwise progression of the T-cells through the cell cycle, hence their name, immunological synapses. The ADs form short-lived reaction centres controlling the recruitment of activators of the biochemical pathway (the kinases Lck and ZAP) while preventing the access of inhibitors (phosphatase CD45) through steric repulsion forces. CD45 acts as the generator of adhesion domains and, through its role as a spacer protein, also as the promoter of the reaction. In a second phase of T-cell-APC encounters, long-lived global reaction spaces (called supramolecular activation complexes (SMAC)) form by talin-mediated binding of the T-cell integrin (LFA-1) to the counter-receptor ICAM-1, resulting in the formation of ring-like tight adhesion zones (peripheral SMAC). The ADs move to the centre of the intercellular adhesion zone forming the central SMAC, which serve in the recycling of the AD. We propose that cell stimulation is triggered by integrating the effect evoked by the short-lived adhesion domains. Similar global reaction platforms are formed by killer cells to destruct APC. We present a testable mechanical model showing that global reaction spaces (SMAC or dome-like contacts between cytotoxic cells and APC) form by self-organization through delayed activation of the integrin-binding affinity and stabilization of the adhesion zones by F-actin recruitment. The mechanical stability and the polarization of the adhering T-cells are mediated by microtubule-actin cross-talk.

  8. Quantal concept of T-cell activation: adhesion domains as immunological synapses

    Energy Technology Data Exchange (ETDEWEB)

    Sackmann, Erich, E-mail: sackmann@ph.tum.de [Physics Department E22, Technical University Munich, D-85748 Garching (Germany)

    2011-06-15

    Adhesion micro-domains (ADs) formed during encounters of lymphocytes with antigen-presenting cells (APC) mediate the genetic expression of quanta of cytokines interleukin-2 (IL-2). The IL-2-induced activation of IL-2 receptors promotes the stepwise progression of the T-cells through the cell cycle, hence their name, immunological synapses. The ADs form short-lived reaction centres controlling the recruitment of activators of the biochemical pathway (the kinases Lck and ZAP) while preventing the access of inhibitors (phosphatase CD45) through steric repulsion forces. CD45 acts as the generator of adhesion domains and, through its role as a spacer protein, also as the promoter of the reaction. In a second phase of T-cell-APC encounters, long-lived global reaction spaces (called supramolecular activation complexes (SMAC)) form by talin-mediated binding of the T-cell integrin (LFA-1) to the counter-receptor ICAM-1, resulting in the formation of ring-like tight adhesion zones (peripheral SMAC). The ADs move to the centre of the intercellular adhesion zone forming the central SMAC, which serve in the recycling of the AD. We propose that cell stimulation is triggered by integrating the effect evoked by the short-lived adhesion domains. Similar global reaction platforms are formed by killer cells to destruct APC. We present a testable mechanical model showing that global reaction spaces (SMAC or dome-like contacts between cytotoxic cells and APC) form by self-organization through delayed activation of the integrin-binding affinity and stabilization of the adhesion zones by F-actin recruitment. The mechanical stability and the polarization of the adhering T-cells are mediated by microtubule-actin cross-talk.

  9. Quantal concept of T-cell activation: adhesion domains as immunological synapses

    Science.gov (United States)

    Sackmann, Erich

    2011-06-01

    Adhesion micro-domains (ADs) formed during encounters of lymphocytes with antigen-presenting cells (APC) mediate the genetic expression of quanta of cytokines interleukin-2 (IL-2). The IL-2-induced activation of IL-2 receptors promotes the stepwise progression of the T-cells through the cell cycle, hence their name, immunological synapses. The ADs form short-lived reaction centres controlling the recruitment of activators of the biochemical pathway (the kinases Lck and ZAP) while preventing the access of inhibitors (phosphatase CD45) through steric repulsion forces. CD45 acts as the generator of adhesion domains and, through its role as a spacer protein, also as the promoter of the reaction. In a second phase of T-cell-APC encounters, long-lived global reaction spaces (called supramolecular activation complexes (SMAC)) form by talin-mediated binding of the T-cell integrin (LFA-1) to the counter-receptor ICAM-1, resulting in the formation of ring-like tight adhesion zones (peripheral SMAC). The ADs move to the centre of the intercellular adhesion zone forming the central SMAC, which serve in the recycling of the AD. We propose that cell stimulation is triggered by integrating the effect evoked by the short-lived adhesion domains. Similar global reaction platforms are formed by killer cells to destruct APC. We present a testable mechanical model showing that global reaction spaces (SMAC or dome-like contacts between cytotoxic cells and APC) form by self-organization through delayed activation of the integrin-binding affinity and stabilization of the adhesion zones by F-actin recruitment. The mechanical stability and the polarization of the adhering T-cells are mediated by microtubule-actin cross-talk.

  10. T cells' immunological synapses induce polarization of brain astrocytes in vivo and in vitro: a novel astrocyte response mechanism to cellular injury.

    Science.gov (United States)

    Barcia, Carlos; Sanderson, Nicholas S R; Barrett, Robert J; Wawrowsky, Kolja; Kroeger, Kurt M; Puntel, Mariana; Liu, Chunyan; Castro, Maria G; Lowenstein, Pedro R

    2008-08-20

    Astrocytes usually respond to trauma, stroke, or neurodegeneration by undergoing cellular hypertrophy, yet, their response to a specific immune attack by T cells is poorly understood. Effector T cells establish specific contacts with target cells, known as immunological synapses, during clearance of virally infected cells from the brain. Immunological synapses mediate intercellular communication between T cells and target cells, both in vitro and in vivo. How target virally infected astrocytes respond to the formation of immunological synapses established by effector T cells is unknown. Herein we demonstrate that, as a consequence of T cell attack, infected astrocytes undergo dramatic morphological changes. From normally multipolar cells, they become unipolar, extending a major protrusion towards the immunological synapse formed by the effector T cells, and withdrawing most of their finer processes. Thus, target astrocytes become polarized towards the contacting T cells. The MTOC, the organizer of cell polarity, is localized to the base of the protrusion, and Golgi stacks are distributed throughout the protrusion, reaching distally towards the immunological synapse. Thus, rather than causing astrocyte hypertrophy, antiviral T cells cause a major structural reorganization of target virally infected astrocytes. Astrocyte polarization, as opposed to hypertrophy, in response to T cell attack may be due to T cells providing a very focused attack, and thus, astrocytes responding in a polarized manner. A similar polarization of Golgi stacks towards contacting T cells was also detected using an in vitro allogeneic model. Thus, different T cells are able to induce polarization of target astrocytes. Polarization of target astrocytes in response to immunological synapses may play an important role in regulating the outcome of the response of astrocytes to attacking effector T cells, whether during antiviral (e.g. infected during HIV, HTLV-1, HSV-1 or LCMV infection), anti

  11. T cells' immunological synapses induce polarization of brain astrocytes in vivo and in vitro: a novel astrocyte response mechanism to cellular injury.

    Directory of Open Access Journals (Sweden)

    Carlos Barcia

    2008-08-01

    Full Text Available Astrocytes usually respond to trauma, stroke, or neurodegeneration by undergoing cellular hypertrophy, yet, their response to a specific immune attack by T cells is poorly understood. Effector T cells establish specific contacts with target cells, known as immunological synapses, during clearance of virally infected cells from the brain. Immunological synapses mediate intercellular communication between T cells and target cells, both in vitro and in vivo. How target virally infected astrocytes respond to the formation of immunological synapses established by effector T cells is unknown.Herein we demonstrate that, as a consequence of T cell attack, infected astrocytes undergo dramatic morphological changes. From normally multipolar cells, they become unipolar, extending a major protrusion towards the immunological synapse formed by the effector T cells, and withdrawing most of their finer processes. Thus, target astrocytes become polarized towards the contacting T cells. The MTOC, the organizer of cell polarity, is localized to the base of the protrusion, and Golgi stacks are distributed throughout the protrusion, reaching distally towards the immunological synapse. Thus, rather than causing astrocyte hypertrophy, antiviral T cells cause a major structural reorganization of target virally infected astrocytes.Astrocyte polarization, as opposed to hypertrophy, in response to T cell attack may be due to T cells providing a very focused attack, and thus, astrocytes responding in a polarized manner. A similar polarization of Golgi stacks towards contacting T cells was also detected using an in vitro allogeneic model. Thus, different T cells are able to induce polarization of target astrocytes. Polarization of target astrocytes in response to immunological synapses may play an important role in regulating the outcome of the response of astrocytes to attacking effector T cells, whether during antiviral (e.g. infected during HIV, HTLV-1, HSV-1 or LCMV

  12. Recruitment of dynein to the Jurkat immunological synapse

    Science.gov (United States)

    Combs, Jeffrey; Kim, Soo Jin; Tan, Sarah; Ligon, Lee A.; Holzbaur, Erika L. F.; Kuhn, Jeffrey; Poenie, Martin

    2006-10-01

    Binding of T cells to antigen-presenting cells leads to the formation of the immunological synapse, translocation of the microtubule-organizing center (MTOC) to the synapse, and focused secretion of effector molecules. Here, we show that upon activation of Jurkat cells microtubules project from the MTOC to a ring of the scaffolding protein ADAP, localized at the synapse. Loss of ADAP, but not lymphocyte function-associated antigen 1, leads to a severe defect in MTOC polarization at the immunological synapse. The microtubule motor protein cytoplasmic dynein clusters into a ring at the synapse, colocalizing with the ADAP ring. ADAP coprecipitates with dynein from activated Jurkat cells, and loss of ADAP prevents MTOC translocation and the specific recruitment of dynein to the synapse. These results suggest a mechanism that links signaling through the T cell receptor to translocation of the MTOC, in which the minus end-directed motor cytoplasmic dynein, localized at the synapse through an interaction with ADAP, reels in the MTOC, allowing for directed secretion along the polarized microtubule cytoskeleton. microtubules | T cell polarization | -catenin | PLAC-24

  13. αII-spectrin in T cells is involved in the regulation of cell-cell contact leading to immunological synapse formation?

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    Justyna M Meissner

    Full Text Available T-lymphocyte activation after antigen presentation to the T-Cell Receptor (TCR is a critical step in the development of proper immune responses to infection and inflammation. This dynamic process involves reorganization of the actin cytoskeleton and signaling molecules at the cell membrane, leading to the formation of the Immunological Synapse (IS. The mechanisms regulating the formation of the IS are not completely understood. Nonerythroid spectrin is a membrane skeletal protein involved in the regulation of many cellular processes, including cell adhesion, signaling and actin cytoskeleton remodeling. However, the role of spectrin in IS formation has not been explored. We used molecular, imaging and cellular approaches to show that nonerythroid αII-spectrin redistributes to the IS during T-cell activation. The redistribution of spectrin coincides with the relocation of CD45 and LFA-1, two components essential for IS formation and stability. We assessed the role of spectrin by shRNA-mediated depletion from Jurkat T cells and show that spectrin-depleted cells exhibit decreased adhesion and are defective in forming lamellipodia and filopodia. Importantly, IS formation is impaired in spectrin-depleted cells. Thus, spectrin may be engaged in regulation of distinct events necessary for the establishment and maturity of the IS: besides the involvement of spectrin in the control of CD45 and LFA-1 surface display, spectrin acts in the establishment of cell-cell contact and adhesion processes during the formation of the IS.

  14. New views of the human NK cell immunological synapse: recent advances enabled by super- and high- resolution imaging techniques

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    Emily M. Mace

    2013-01-01

    Full Text Available Imaging technology has undergone rapid growth with the development of super resolution microscopy, which enables resolution below the diffraction barrier of light (~200 nm. In addition, new techniques for single molecule imaging are being added to the cell biologist’s arsenal. Immunologists have exploited these techniques to advance understanding of NK biology, particularly that of the immune synapse. The immune synapse’s relatively small size and complex architecture combined with its exquisitely controlled signaling milieu have made it a challenge to visualize. In this review we highlight and discuss new insights into NK cell immune synapse formation and regulation revealed by cutting edge imaging techniques, including super resolution microscopy and high resolution total internal reflection microscopy and Förster resonance energy transfer.

  15. Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses

    Science.gov (United States)

    Orange, Jordan S.; Ramesh, Narayanaswamy; Remold-O'Donnell, Eileen; Sasahara, Yoji; Koopman, Louise; Byrne, Michael; Bonilla, Francisco A.; Rosen, Fred S.; Geha, Raif S.; Strominger, Jack L.

    2002-08-01

    The Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disorder caused by a mutation in WAS protein (WASp) that results in defective actin polymerization. Although the function of many hematopoietic cells requires WASp, the specific expression and function of this molecule in natural killer (NK) cells is unknown. Here, we report that WAS patients have increased percentages of peripheral blood NK cells and that fresh enriched NK cells from two patients with a WASp mutation have defective cytolytic function. In normal NK cells, WASp was expressed and localized to the activating immunologic synapse (IS) with filamentous actin (F-actin). Perforin also localized to the NK cell-activating IS but at a lesser frequency than F-actin and WASp. The accumulation of F-actin and WASp at the activating IS was decreased significantly in NK cells that had been treated with the inhibitor of actin polymerization, cytochalasin D. NK cells from WAS patients lacked expression of WASp and accumulated F-actin at the activating IS infrequently. Thus, WASp has an important function in NK cells. In patients with WASp mutations, the resulting NK cell defects are likely to contribute to their disease.

  16. Cytoskeletal actin dynamics shape a ramifying actin network underpinning immunological synapse formation

    DEFF Research Database (Denmark)

    Fritzsche, Marco; Fernandes, Ricardo A.; Chang, Veronica T.

    2017-01-01

    optical microscopes to analyze resting and activated T cells, we show that, following contact formation with activating surfaces, these cells sequentially rearrange their cortical actin across the entire cell, creating a previously unreported ramifying actin network above the immunological synapse....... This network shows all the characteristics of an inward-growing transportation network and its dynamics correlating with T cell receptor rearrangements. This actin reorganization is accompanied by an increase in the nanoscale actin meshwork size and the dynamic adjustment of the turnover times and filament...... as well as a central ramified transportation network apparently directed at the consolidation of the contact and the delivery of effector functions....

  17. Despite disorganized synapse structure, Th2 cells maintain directional delivery of CD40L to antigen-presenting B cells.

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    Jennifer L Gardell

    Full Text Available Upon recognition of peptide displayed on MHC molecules, Th1 and Th2 cells form distinct immunological synapse structures. Th1 cells have a bull's eye synapse structure with TCR/ MHC-peptide interactions occurring central to a ring of adhesion molecules, while Th2 cells have a multifocal synapse with small clusters of TCR/MHC interactions throughout the area of T cell/antigen-presenting cell interaction. In this study, we investigated whether this structural difference in the immunological synapse affects delivery of T cell help. The immunological synapse is thought to ensure antigen-specific delivery of cytolytic granules and killing of target cells by NK cells and cytolytic T cells. In helper T cells, it has been proposed that the immunological synapse may direct delivery of other effector molecules including cytokines. CD40 ligand (CD40L is a membrane-bound cytokine essential for antigen-specific T cell help for B cells in the antibody response. We incubated Th1 and Th2 cells overnight with a mixture of antigen-presenting and bystander B cells, and the delivery of CD40L to B cells and subsequent B cell responses were compared. Despite distinct immunological synapse structures, Th1 and Th2 cell do not differ in their ability to deliver CD40L and T cell help in an antigen-specific fashion, or in their susceptibility to inhibition of help by a blocking anti-CD40L antibody.

  18. Despite disorganized synapse structure, Th2 cells maintain directional delivery of CD40L to antigen-presenting B cells.

    Science.gov (United States)

    Gardell, Jennifer L; Parker, David C

    2017-01-01

    Upon recognition of peptide displayed on MHC molecules, Th1 and Th2 cells form distinct immunological synapse structures. Th1 cells have a bull's eye synapse structure with TCR/ MHC-peptide interactions occurring central to a ring of adhesion molecules, while Th2 cells have a multifocal synapse with small clusters of TCR/MHC interactions throughout the area of T cell/antigen-presenting cell interaction. In this study, we investigated whether this structural difference in the immunological synapse affects delivery of T cell help. The immunological synapse is thought to ensure antigen-specific delivery of cytolytic granules and killing of target cells by NK cells and cytolytic T cells. In helper T cells, it has been proposed that the immunological synapse may direct delivery of other effector molecules including cytokines. CD40 ligand (CD40L) is a membrane-bound cytokine essential for antigen-specific T cell help for B cells in the antibody response. We incubated Th1 and Th2 cells overnight with a mixture of antigen-presenting and bystander B cells, and the delivery of CD40L to B cells and subsequent B cell responses were compared. Despite distinct immunological synapse structures, Th1 and Th2 cell do not differ in their ability to deliver CD40L and T cell help in an antigen-specific fashion, or in their susceptibility to inhibition of help by a blocking anti-CD40L antibody.

  19. Microtubule-organizing center polarity and the immunological synapse: protein kinase C and beyond.

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    Huse, Morgan

    2012-01-01

    Cytoskeletal polarization is crucial for many aspects of immune function, ranging from neutrophil migration to the sampling of gut flora by intestinal dendritic cells. It also plays a key role during lymphocyte cell-cell interactions, the most conspicuous of which is perhaps the immunological synapse (IS) formed between a T cell and an antigen-presenting cell (APC). IS formation is associated with the reorientation of the T cell's microtubule-organizing center (MTOC) to a position just beneath the cell-cell interface. This cytoskeletal remodeling event aligns secretory organelles inside the T cell with the IS, enabling the directional release of cytokines and cytolytic factors toward the APC. MTOC polarization is therefore crucial for maintaining the specificity of a T cell's secretory and cytotoxic responses. It has been known for some time that T cell receptor (TCR) stimulation activates the MTOC polarization response. It has been difficult, however, to identify the machinery that couples early TCR signaling to cytoskeletal remodeling. Over the past few years, considerable progress has been made in this area. This review will present an overview of recent advances, touching on both the mechanisms that drive MTOC polarization and the effector responses that require it. Particular attention will be paid to both novel and atypical members of the protein kinase C family, which are now known to play important roles in both the establishment and the maintenance of the polarized state.

  20. Microtubule-organizing center polarity and the immunological synapse: protein kinase C and beyond

    Directory of Open Access Journals (Sweden)

    Morgan eHuse

    2012-07-01

    Full Text Available Cytoskeletal polarization is crucial for many aspects of immune function, ranging from neutrophil migration to the sampling of gut flora by intestinal dendritic cells. It also plays a key role during lymphocyte cell-cell interactions, the most conspicuous of which is perhaps the immunological synapse (IS formed between a T cell and an antigen-presenting cell (APC. IS formation is associated with the reorientation of the T cell’s microtubule-organizing center (MTOC to a position just beneath the cell-cell interface. This cytoskeletal remodeling event aligns secretory organelles inside the T cell with the IS, enabling the directional release of cytokines and cytolytic factors toward the APC. MTOC polarization is therefore crucial for maintaining the specificity of a T cell’s secretory and cytotoxic responses. It has been known for some time that T cell receptor (TCR stimulation activates the MTOC polarization response. It has been difficult, however, to identify the machinery that couples early TCR signaling to cytoskeletal remodeling. Over the past few years, considerable progress has been made in this area. This review will present an overview of recent advances, touching on both the mechanisms that drive MTOC polarization and the effector responses that require it. Particular attention will be paid to both novel and atypical members of the protein kinase C family, which are now known to play important roles in both the establishment and the maintenance of the polarized state.

  1. Autophagy Attenuates the Adaptive Immune Response by Destabilizing the Immunologic Synapse

    NARCIS (Netherlands)

    Wildenberg, Manon E.; Vos, Anne Christine W.; Wolfkamp, Simone C. S.; Duijvestein, Marjolijn; Verhaar, Auke P.; te Velde, Anje A.; van den Brink, Gijs R.; Hommes, Daniel W.

    2012-01-01

    BACKGROUND & AIMS: Variants in the genes ATG16L1 and IRGM affect autophagy and are associated with the development of Crohn's disease. It is not clear how autophagy is linked to loss of immune tolerance in the intestine. We investigated the involvement of the immunologic synapse-the site of contact

  2. NKp46 clusters at the immune synapse and regulates NK cell polarization

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    Uzi eHadad

    2015-09-01

    Full Text Available Natural killer cells play an important role in first-line defense against tumor and virus-infected cells. The activity of NK cells is tightly regulated by a repertoire of cell-surface expressed inhibitory and activating receptors. NKp46 is a major NK cell activating receptor that is involved in the elimination of target cells. NK cells form different types of synapses that result in distinct functional outcomes: cytotoxic, inhibitory, and regulatory. Recent studies revealed that complex integration of NK receptor signaling controls cytoskeletal rearrangement and other immune synapse-related events. However the distinct nature by which NKp46 participates in NK immunological synapse formation and function remains unknown. In this study we determined that NKp46 forms microclusters structures at the immune synapse between NK cells and target cells. Over-expression of human NKp46 is correlated with increased accumulation of F-actin mesh at the immune synapse. Concordantly, knock-down of NKp46 in primary human NK cells decreased recruitment of F-actin to the synapse. Live cell imaging experiments showed a linear correlation between NKp46 expression and lytic granules polarization to the immune synapse. Taken together, our data suggest that NKp46 signaling directly regulates the NK lytic immune synapse from early formation to late function.

  3. The Dendritic Cell Synapse: A Life Dedicated to T Cell Activation.

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    Benvenuti, Federica

    2016-01-01

    T-cell activation within immunological synapses is a complex process whereby different types of signals are transmitted from antigen-presenting cells to T cells. The molecular strategies developed by T cells to interpret and integrate these signals have been systematically dissected in recent years and are now in large part understood. On the other side of the immune synapse, dendritic cells (DCs) participate actively in synapse formation and maintenance by remodeling of membrane receptors and intracellular content. However, the details of such changes have been only partially characterized. The DCs actin cytoskeleton has been one of the first systems to be identified as playing an important role in T-cell priming and some of the underlying mechanisms have been elucidated. Similarly, the DCs microtubule cytoskeleton undergoes major spatial changes during synapse formation that favor polarization of the DCs subcellular space toward the interacting T cell. Recently, we have begun to investigate the trafficking machinery that controls polarized delivery of endosomal vesicles at the DC-T immune synapse with the aim of understanding the functional relevance of polarized secretion of soluble factors during T-cell priming. Here, we will review the current knowledge of events occurring in DCs during synapse formation and discuss the open questions that still remain unanswered.

  4. Cell Biology of Astrocyte-Synapse Interactions.

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    Allen, Nicola J; Eroglu, Cagla

    2017-11-01

    Astrocytes, the most abundant glial cells in the mammalian brain, are critical regulators of brain development and physiology through dynamic and often bidirectional interactions with neuronal synapses. Despite the clear importance of astrocytes for the establishment and maintenance of proper synaptic connectivity, our understanding of their role in brain function is still in its infancy. We propose that this is at least in part due to large gaps in our knowledge of the cell biology of astrocytes and the mechanisms they use to interact with synapses. In this review, we summarize some of the seminal findings that yield important insight into the cellular and molecular basis of astrocyte-neuron communication, focusing on the role of astrocytes in the development and remodeling of synapses. Furthermore, we pose some pressing questions that need to be addressed to advance our mechanistic understanding of the role of astrocytes in regulating synaptic development. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Function and Dynamics of Tetraspanins during Antigen Recognition and Immunological Synapse Formation

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    Vera eRocha-Perugini

    2016-01-01

    Full Text Available Tetraspanin-enriched microdomains (TEMs are specialized membrane platforms driven by protein-protein interactions that integrate membrane receptors and adhesion molecules. Tetraspanins participate in antigen recognition and presentation by antigen presenting cells (APCs through the organization of pattern recognition receptors (PRRs and their downstream induced-signaling, as well as the regulation of MHC-II-peptide trafficking. T lymphocyte activation is triggered upon specific recognition of antigens present on the APC surface during immunological synapse (IS formation. This dynamic process is characterized by a defined spatial organization involving the compartmentalization of receptors and adhesion molecules in specialized membrane domains that are connected to the underlying cytoskeleton and signaling molecules. Tetraspanins contribute to the spatial organization and maturation of the IS by controlling receptor clustering and local accumulation of adhesion receptors and integrins, their downstream signaling and linkage to the actin cytoskeleton. This review offers a perspective on the important role of TEMs in the regulation of antigen recognition and presentation, and in the dynamics of IS architectural organization.

  6. Transcellular communication at the immunological synapse: a vesicular traffic-mediated mutual exchange [version 1; referees: 3 approved

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    Francesca Finetti

    2017-10-01

    Full Text Available The cell’s ability to communicate with the extracellular environment, with other cells, and with itself is a crucial feature of eukaryotic organisms. In the immune system, T lymphocytes assemble a specialized structure upon contact with antigen-presenting cells bearing a peptide-major histocompatibility complex ligand, known as the immunological synapse (IS. The IS has been extensively characterized as a signaling platform essential for T-cell activation. Moreover, emerging evidence identifies the IS as a device for vesicular traffic-mediated cell-to-cell communication as well as an active release site of soluble molecules. Here, we will review recent advances in the role of vesicular trafficking in IS assembly and focused secretion of microvesicles at the synaptic area in naïve T cells and discuss the role of the IS in transcellular communication.

  7. Interplay between membrane elasticity and active cytoskeleton forces regulates the aggregation dynamics of the immunological synapse

    Science.gov (United States)

    Dharan, Nadiv; Farago, Oded

    Adhesion between a T cell and an antigen presenting cell is achieved by TCR-pMHC and LFA1-ICAM1 protein complexes. These segregate to form a special pattern, known as the immunological synapse (IS), consisting of a central quasi-circular domain of TCR-pMHC bonds surrounded by a peripheral domain of LFA1-ICAM1 complexes. Insights gained from imaging studies had led to the conclusion that the formation of the central adhesion domain in the IS is driven by active (ATP-driven) mechanisms. Recent studies, however, suggested that passive (thermodynamic) mechanisms may also play an important role in this process. Here, we present a simple physical model, taking into account the membrane-mediated thermodynamic attraction between the TCR-pMHC bonds and the effective forces that they experience due to ATP-driven actin retrograde flow and transport by dynein motor proteins. Monte Carlo simulations of the model exhibit a good spatio-temporal agreement with the experimentally observed pattern evolution of the TCR-pMHC microclusters. The agreement is lost when one of the aggregation mechanisms is "muted", which helps to identify the respective roles in the process. We conclude that actin retrograde flow drives the centripetal motion of TCR-pMHC bonds, while the membrane-mediated interactions facilitate microcluster formation and growth. In the absence of dynein motors, the system evolves into a ring-shaped pattern, which highlights the role of dynein motors in the formation of the final concentric pattern. The interplay between the passive and active mechanisms regulates the rate of the accumulation process, which in the absence of one them proceeds either too quickly or slowly.

  8. Mast cells and dendritic cells form synapses that facilitate antigen transfer for T cell activation.

    Science.gov (United States)

    Carroll-Portillo, Amanda; Cannon, Judy L; te Riet, Joost; Holmes, Anna; Kawakami, Yuko; Kawakami, Toshiaki; Cambi, Alessandra; Lidke, Diane S

    2015-08-31

    Mast cells (MCs) produce soluble mediators such as histamine and prostaglandins that are known to influence dendritic cell (DC) function by stimulating maturation and antigen processing. Whether direct cell-cell interactions are important in modulating MC/DC function is unclear. In this paper, we show that direct contact between MCs and DCs occurs and plays an important role in modulating the immune response. Activation of MCs through FcεRI cross-linking triggers the formation of stable cell-cell interactions with immature DCs that are reminiscent of the immunological synapse. Direct cellular contact differentially regulates the secreted cytokine profile, indicating that MC modulation of DC populations is influenced by the nature of their interaction. Synapse formation requires integrin engagement and facilitates the transfer of internalized MC-specific antigen from MCs to DCs. The transferred material is ultimately processed and presented by DCs and can activate T cells. The physiological outcomes of the MC-DC synapse suggest a new role for intercellular crosstalk in defining the immune response. © 2015 Carroll-Portillo et al.

  9. Recruitment of activation receptors at inhibitory NK cell immune synapses.

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    Nicolas Schleinitz

    2008-09-01

    Full Text Available Natural killer (NK cell activation receptors accumulate by an actin-dependent process at cytotoxic immune synapses where they provide synergistic signals that trigger NK cell effector functions. In contrast, NK cell inhibitory receptors, including members of the MHC class I-specific killer cell Ig-like receptor (KIR family, accumulate at inhibitory immune synapses, block actin dynamics, and prevent actin-dependent phosphorylation of activation receptors. Therefore, one would predict inhibition of actin-dependent accumulation of activation receptors when inhibitory receptors are engaged. By confocal imaging of primary human NK cells in contact with target cells expressing physiological ligands of NK cell receptors, we show here that this prediction is incorrect. Target cells included a human cell line and transfected Drosophila insect cells that expressed ligands of NK cell activation receptors in combination with an MHC class I ligand of inhibitory KIR. The two NK cell activation receptors CD2 and 2B4 accumulated and co-localized with KIR at inhibitory immune synapses. In fact, KIR promoted CD2 and 2B4 clustering, as CD2 and 2B4 accumulated more efficiently at inhibitory synapses. In contrast, accumulation of KIR and of activation receptors at inhibitory synapses correlated with reduced density of the integrin LFA-1. These results imply that inhibitory KIR does not prevent CD2 and 2B4 signaling by blocking their accumulation at NK cell immune synapses, but by blocking their ability to signal within inhibitory synapses.

  10. Murine Tim-1 is excluded from the immunological synapse [v2; ref status: indexed, http://f1000r.es/QSgUx0

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    Jean Lin

    2012-10-01

    Full Text Available The interaction between T cells and APCs bearing cognate antigen results in the formation of an immunological synapse (IS. During this process, many receptors and signaling proteins segregate to regions proximal to the synapse. This protein movement is thought to influence T cell function. However, some proteins are transported away from the IS, which is controlled in part by ERM family proteins. Tim-1 is a transmembrane protein with co-stimulatory functions that is found on many immune cells, including T cells. However, the expression pattern of Tim-1 on T cells upon activation by APCs has not been explored. Interestingly, in this study we demonstrate that the majority of Tim-1 on activated T cells is excluded from the IS. Tim-1 predominantly resides outside of the IS, and structure/function studies indicate that the cytoplasmic tail influences Tim-1 polarization. Specifically, a putative ERM binding motif (KRK 244-246 in the Tim-1 cytoplasmic tail appears necessary for proper Tim-1 localization. Furthermore, mutation of the KRK motif results in enhanced early tyrosine phosphorylation downstream of TCR/CD28 stimulation upon ectopic expression of Tim-1. Paradoxically however, the KRK motif is necessary for Tim-1 co-stimulation of NFAT/AP-1 activation and co-stimulation of cytokine production. This work reveals unexpected complexity underlying Tim-1 localization and suggests potentially novel mechanisms by which Tim-1 modulates T cell activity.

  11. Immunologic Targeting Of Cancer Cells

    Science.gov (United States)

    T.; Chen, M. R.; Linden, R.

    1989-06-01

    A number of laboratories have demonstrated that immunoconjugates may have potential in phototherapy of cancer. The phototoxic effectiveness of these conjugates may be increased by manipulation of irradiation parameters and by biochemical and immunologic modulation. Results from experiments aimed at potentiation of immunoconjugate photosensitization are presented.

  12. Mammalian Cochlear Hair Cell Regeneration and Ribbon Synapse Reformation

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    Xiaoling Lu

    2016-01-01

    Full Text Available Hair cells (HCs are the sensory preceptor cells in the inner ear, which play an important role in hearing and balance. The HCs of organ of Corti are susceptible to noise, ototoxic drugs, and infections, thus resulting in permanent hearing loss. Recent approaches of HCs regeneration provide new directions for finding the treatment of sensor neural deafness. To have normal hearing function, the regenerated HCs must be reinnervated by nerve fibers and reform ribbon synapse with the dendrite of spiral ganglion neuron through nerve regeneration. In this review, we discuss the research progress in HC regeneration, the synaptic plasticity, and the reinnervation of new regenerated HCs in mammalian inner ear.

  13. The adaptor molecule SAP plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation.

    Science.gov (United States)

    Das, Rupali; Bassiri, Hamid; Guan, Peng; Wiener, Susan; Banerjee, Pinaki P; Zhong, Ming-Chao; Veillette, André; Orange, Jordan S; Nichols, Kim E

    2013-04-25

    The adaptor molecule signaling lymphocytic activation molecule-associated protein (SAP) plays critical roles during invariant natural killer T (iNKT) cell ontogeny. As a result, SAP-deficient humans and mice lack iNKT cells. The strict developmental requirement for SAP has made it difficult to discern its possible involvement in mature iNKT cell functions. By using temporal Cre recombinase-mediated gene deletion to ablate SAP expression after completion of iNKT cell development, we demonstrate that SAP is essential for T-cell receptor (TCR)-induced iNKT cell cytotoxicity against T-cell and B-cell leukemia targets in vitro and iNKT-cell-mediated control of T-cell leukemia growth in vivo. These findings are not restricted to the murine system: silencing RNA-mediated suppression of SAP expression in human iNKT cells also significantly impairs TCR-induced cytolysis. Mechanistic studies reveal that iNKT cell killing requires the tyrosine kinase Fyn, a known SAP-binding protein. Furthermore, SAP expression is required within iNKT cells to facilitate their interaction with T-cell targets and induce reorientation of the microtubule-organizing center to the immunologic synapse (IS). Collectively, these studies highlight a novel and essential role for SAP during iNKT cell cytotoxicity and formation of a functional IS.

  14. Immunology: Is Actin at the Lytic Synapse a Friend or a Foe?

    Science.gov (United States)

    Hammer, John A

    2018-02-19

    Cytotoxic T cells and natural killer cells defend us against disease by secreting lytic granules. Whether actin facilitates or thwarts lytic granule secretion has been an open question. Recent results now indicate that the answer depends on the maturation stage of the immune cell-target cell contact. Published by Elsevier Ltd.

  15. Immunology of Langerhans Cells

    OpenAIRE

    TAMAKI,Kunihiko

    1990-01-01

    Langerhans cells (LC) are antigen-presenting cells residing in the epidermis of the skin. These cells show characteristic dendritic features and are continually repopulated by precursor cells originating in bone marrow. In this review, we will discuss about the characteristics of these cells.

  16. Neuron-NG2 Cell Synapses: Novel Functions for Regulating NG2 Cell Proliferation and Differentiation

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    Qian-Kun Yang

    2013-01-01

    Full Text Available NG2 cells are a population of CNS cells that are distinct from neurons, mature oligodendrocytes, astrocytes, and microglia. These cells can be identified by their NG2 proteoglycan expression. NG2 cells have a highly branched morphology, with abundant processes radiating from the cell body, and express a complex set of voltage-gated channels, AMPA/kainate, and GABA receptors. Neurons notably form classical and nonclassical synapses with NG2 cells, which have varied characteristics and functions. Neuron-NG2 cell synapses could fine-tune NG2 cell activities, including the NG2 cell cycle, differentiation, migration, and myelination, and may be a novel potential therapeutic target for NG2 cell-related diseases, such as hypoxia-ischemia injury and periventricular leukomalacia. Furthermore, neuron-NG2 cell synapses may be correlated with the plasticity of CNS in adulthood with the synaptic contacts passing onto their progenies during proliferation, and synaptic contacts decrease rapidly upon NG2 cell differentiation. In this review, we highlight the characteristics of classical and nonclassical neuron-NG2 cell synapses, the potential functions, and the fate of synaptic contacts during proliferation and differentiation, with the emphasis on the regulation of the NG2 cell cycle by neuron-NG2 cell synapses and their potential underlying mechanisms.

  17. The Regulated Secretory Pathway in CD4+ T cells Contributes to Human Immunodeficiency Virus Type-1 Cell-to-Cell Spread at the Virological Synapse

    Science.gov (United States)

    Jolly, Clare; Welsch, Sonja; Michor, Stefanie; Sattentau, Quentin J.

    2011-01-01

    Direct cell-cell spread of Human Immunodeficiency Virus type-1 (HIV-1) at the virological synapse (VS) is an efficient mode of dissemination between CD4+ T cells but the mechanisms by which HIV-1 proteins are directed towards intercellular contacts is unclear. We have used confocal microscopy and electron tomography coupled with functional virology and cell biology of primary CD4+ T cells from normal individuals and patients with Chediak-Higashi Syndrome and report that the HIV-1 VS displays a regulated secretion phenotype that shares features with polarized secretion at the T cell immunological synapse (IS). Cell-cell contact at the VS re-orientates the microtubule organizing center (MTOC) and organelles within the HIV-1-infected T cell towards the engaged target T cell, concomitant with polarization of viral proteins. Directed secretion of proteins at the T cell IS requires specialized organelles termed secretory lysosomes (SL) and we show that the HIV-1 envelope glycoprotein (Env) localizes with CTLA-4 and FasL in SL-related compartments and at the VS. Finally, CD4+ T cells that are disabled for regulated secretion are less able to support productive cell-to-cell HIV-1 spread. We propose that HIV-1 hijacks the regulated secretory pathway of CD4+ T cells to enhance its dissemination. PMID:21909273

  18. The regulated secretory pathway in CD4(+ T cells contributes to human immunodeficiency virus type-1 cell-to-cell spread at the virological synapse.

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    Clare Jolly

    2011-09-01

    Full Text Available Direct cell-cell spread of Human Immunodeficiency Virus type-1 (HIV-1 at the virological synapse (VS is an efficient mode of dissemination between CD4(+ T cells but the mechanisms by which HIV-1 proteins are directed towards intercellular contacts is unclear. We have used confocal microscopy and electron tomography coupled with functional virology and cell biology of primary CD4(+ T cells from normal individuals and patients with Chediak-Higashi Syndrome and report that the HIV-1 VS displays a regulated secretion phenotype that shares features with polarized secretion at the T cell immunological synapse (IS. Cell-cell contact at the VS re-orientates the microtubule organizing center (MTOC and organelles within the HIV-1-infected T cell towards the engaged target T cell, concomitant with polarization of viral proteins. Directed secretion of proteins at the T cell IS requires specialized organelles termed secretory lysosomes (SL and we show that the HIV-1 envelope glycoprotein (Env localizes with CTLA-4 and FasL in SL-related compartments and at the VS. Finally, CD4(+ T cells that are disabled for regulated secretion are less able to support productive cell-to-cell HIV-1 spread. We propose that HIV-1 hijacks the regulated secretory pathway of CD4(+ T cells to enhance its dissemination.

  19. Quantitative 3D video microscopy of HIV transfer across T cell virological synapses.

    Science.gov (United States)

    Hübner, Wolfgang; McNerney, Gregory P; Chen, Ping; Dale, Benjamin M; Gordon, Ronald E; Chuang, Frank Y S; Li, Xiao-Dong; Asmuth, David M; Huser, Thomas; Chen, Benjamin K

    2009-03-27

    The spread of HIV between immune cells is greatly enhanced by cell-cell adhesions called virological synapses, although the underlying mechanisms have been unclear. With use of an infectious, fluorescent clone of HIV, we tracked the movement of Gag in live CD4 T cells and captured the direct translocation of HIV across the virological synapse. Quantitative, high-speed three-dimensional (3D) video microscopy revealed the rapid formation of micrometer-sized "buttons" containing oligomerized viral Gag protein. Electron microscopy showed that these buttons were packed with budding viral crescents. Viral transfer events were observed to form virus-laden internal compartments within target cells. Continuous time-lapse monitoring showed preferential infection through synapses. Thus, HIV dissemination may be enhanced by virological synapse-mediated cell adhesion coupled to viral endocytosis.

  20. Spatial distribution of synapses on tyrosine hydroxylase-expressing juxtaglomerular cells in the mouse olfactory glomerulus.

    Science.gov (United States)

    Kiyokage, Emi; Kobayashi, Kazuto; Toida, Kazunori

    2017-04-01

    Olfactory sensory axons converge in specific glomeruli where they form excitatory synapses onto dendrites of mitral/tufted (M/T) and juxtaglomerular (JG) cells, including periglomerular (PG), external tufted (ET), and superficial-short axon cells. JG cells consist of heterogeneous subpopulations with different neurochemical, physiological, and morphological properties. Among JG cells, previous electron microscopic (EM) studies have shown that the majority of synaptic inputs to tyrosine hydroxylase (TH)-immunoreactive neurons were asymmetrical synapses from olfactory nerve (ON) terminals. However, recent physiological results revealed that 70% of dopaminergic/γ-aminobutyric acid (GABA)ergic neurons received polysynaptic inputs via ET cells, whereas the remaining 30% received monosynaptic ON inputs. To understand the discrepancies between EM and physiological data, we used serial EM analysis combined with confocal laser scanning microscope images to examine the spatial distribution of synapses on dendrites using mice expressing enhanced green fluorescent protein under the control of the TH promoter. The majority of synaptic inputs to TH-expressing JG cells were from ON terminals, and they preferentially targeted distal dendrites from the soma. On the other hand, the numbers of non-ON inputs were fewer and targeted proximal dendrites. Furthermore, individual TH-expressing JG cells formed serial synapses, such as M/T→TH→another presumed M/T or ON→TH→presumed M/T, but not reciprocal synapses. Serotonergic fibers also associated with somatic regions of TH neurons, displaying non-ON profiles. Thus, fewer proximal non-ON synapses provide more effective inputs than large numbers of distal ON synapses and may occur on the physiologically characterized population of dopaminergic-GABAergic neurons (70%) that receive their most effective inputs indirectly via an ON→ET→TH circuit. J. Comp. Neurol. 525:1059-1074, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley

  1. Spatial distribution of excitatory synapses on the dendrites of ganglion cells in the mouse retina.

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    Yin-Peng Chen

    Full Text Available Excitatory glutamatergic inputs from bipolar cells affect the physiological properties of ganglion cells in the mammalian retina. The spatial distribution of these excitatory synapses on the dendrites of retinal ganglion cells thus may shape their distinct functions. To visualize the spatial pattern of excitatory glutamatergic input into the ganglion cells in the mouse retina, particle-mediated gene transfer of plasmids expressing postsynaptic density 95-green fluorescent fusion protein (PSD95-GFP was used to label the excitatory synapses. Despite wide variation in the size and morphology of the retinal ganglion cells, the expression of PSD95 puncta was found to follow two general rules. Firstly, the PSD95 puncta are regularly spaced, at 1-2 µm intervals, along the dendrites, whereby the presence of an excitatory synapse creates an exclusion zone that rules out the presence of other glutamatergic synaptic inputs. Secondly, the spatial distribution of PSD95 puncta on the dendrites of diverse retinal ganglion cells are similar in that the number of excitatory synapses appears to be less on primary dendrites and to increase to a plateau on higher branch order dendrites. These observations suggest that synaptogenesis is spatially regulated along the dendritic segments and that the number of synaptic contacts is relatively constant beyond the primary dendrites. Interestingly, we also found that the linear puncta density is slightly higher in large cells than in small cells. This may suggest that retinal ganglion cells with a large dendritic field tend to show an increased connectivity of excitatory synapses that makes up for their reduced dendrite density. Mapping the spatial distribution pattern of the excitatory synapses on retinal ganglion cells thus provides explicit structural information that is essential for our understanding of how excitatory glutamatergic inputs shape neuronal responses.

  2. The need to connect: on the cell biology of synapses, behaviors, and networks in science.

    Science.gov (United States)

    Colón-Ramos, Daniel A

    2016-11-01

    My laboratory is interested in the cell biology of the synapse. Synapses, which are points of cellular communication between neurons, were first described by Santiago Ramón y Cajal as "protoplasmic kisses that appear to constitute the final ecstasy of an epic love story." Who would not want to work on that?! My lab examines the biological mechanisms neurons use to find and connect to each other. How are synapses formed during development, maintained during growth, and modified during learning? In this essay, I reflect about my scientific journey to the synapse, the cell biological one, but also a metaphorical synapse-my role as a point of contact between the production of knowledge and its dissemination. In particular, I discuss how the architecture of scientific networks propels knowledge production but can also exclude certain groups in science. © 2016 Colón-Ramos This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  3. Modulation, plasticity and pathophysiology of the parallel fiber-Purkinje cell synapse

    Directory of Open Access Journals (Sweden)

    Eriola Hoxha

    2016-11-01

    Full Text Available The parallel fiber-Purkinje cell synapse represents the point of maximal signal divergence in the cerebellar cortex with an estimated number of about 60 billion synaptic contacts in the rat and 100,000 billions in humans. At the same time, the Purkinje cell dendritic tree is a site of remarkable convergence of more than 100,000 parallel fiber synapses. Parallel fibers activity generates fast postsynaptic currents via AMPA receptors, and slower signals, mediated by mGlu1 receptors, resulting in Purkinje cell depolarization accompanied by sharp calcium elevation within dendritic regions. Long-term depression and long-term potentiation have been widely described for the parallel fiber-Purkinje cell synapse and have been proposed as mechanisms for motor learning. The mechanisms of induction for LTP and LTD involve different signaling mechanisms within the presynaptic terminal and/or at the postsynaptic site, promoting enduring modification in the neurotransmitter release and change in responsiveness to the neurotransmitter. The parallel fiber-Purkinje cell synapse is finely modulated by several neurotransmitters, including serotonin, noradrenaline, and acetylcholine. The ability of these neuromodulators to gate LTP and LTD at the parallel fiber-Purkinje cell synapse could, at least in part, explain their effect on cerebellar-dependent learning and memory paradigms. Overall, these findings have important implications for understanding the cerebellar involvement in a series of pathological conditions, ranging from ataxia to autism. For example, parallel fiber-Purkinje cell synapse dysfunctions have been identified in several murine models of spinocerebellar ataxia (SCA types 1, 3, 5 and 27. In some cases, the defect is specific for the AMPA receptor signaling (SCA27, while in others the mGlu1 pathway is affected (SCA1, 3, 5. Interestingly, the parallel fiber-Purkinje cell synapse has been shown to be hyper-functional in a mutant mouse model of autism

  4. Layer Specific Development of Neocortical Pyramidal to Fast Spiking Cells Synapses.

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    Olga eVoinova

    2016-01-01

    Full Text Available All cortical neurons are engaged in inhibitory feedback loops which ensure excitation-inhibition balance and are key elements for the development of coherent network activity. The resulting network patterns are strongly dependent on the strength and dynamic properties of these excitatory-inhibitory loops which show pronounced regional and developmental diversity. We therefore compared the properties and postnatal maturation of two different synapses between rat neocortical pyramidal cells (layer 2/3 and layer 5, respectively and fast spiking (FS interneurons in the corresponding layer. At P14, both synapses showed synaptic depression upon repetitive activation. Synaptic release properties between layer 2/3 pyramidal cells and FS cells were stable from P14 to P28. In contrast, layer 5 pyramidal to FS cell connections showed a significant increase in paired pulse ratio by P28. Presynaptic calcium dynamics did also change at these synapses, including the sensitivity to exogenously loaded calcium buffers and expression of presynaptic calcium channels subtypes. These results underline the large variety of properties at different, yet similar, synapses in the neocortex. They also suggest that postnatal maturation of the brain goes along with increasing differences between synaptically driven network activity in layer 5 and layer 2/3.

  5. A cortical attractor network with Martinotti cells driven by facilitating synapses.

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    Pradeep Krishnamurthy

    Full Text Available The population of pyramidal cells significantly outnumbers the inhibitory interneurons in the neocortex, while at the same time the diversity of interneuron types is much more pronounced. One acknowledged key role of inhibition is to control the rate and patterning of pyramidal cell firing via negative feedback, but most likely the diversity of inhibitory pathways is matched by a corresponding diversity of functional roles. An important distinguishing feature of cortical interneurons is the variability of the short-term plasticity properties of synapses received from pyramidal cells. The Martinotti cell type has recently come under scrutiny due to the distinctly facilitating nature of the synapses they receive from pyramidal cells. This distinguishes these neurons from basket cells and other inhibitory interneurons typically targeted by depressing synapses. A key aspect of the work reported here has been to pinpoint the role of this variability. We first set out to reproduce quantitatively based on in vitro data the di-synaptic inhibitory microcircuit connecting two pyramidal cells via one or a few Martinotti cells. In a second step, we embedded this microcircuit in a previously developed attractor memory network model of neocortical layers 2/3. This model network demonstrated that basket cells with their characteristic depressing synapses are the first to discharge when the network enters an attractor state and that Martinotti cells respond with a delay, thereby shifting the excitation-inhibition balance and acting to terminate the attractor state. A parameter sensitivity analysis suggested that Martinotti cells might, in fact, play a dominant role in setting the attractor dwell time and thus cortical speed of processing, with cellular adaptation and synaptic depression having a less prominent role than previously thought.

  6. ON Cone Bipolar Cell Axonal Synapses in the OFF Inner Plexiform Layer of the Rabbit Retina

    Science.gov (United States)

    Lauritzen, J. Scott; Anderson, James R.; Jones, Bryan W.; Watt, Carl B.; Mohammed, Shoeb; Hoang, John V.; Marc, Robert E.

    2012-01-01

    Analysis of the rabbit retinal connectome RC1 reveals that the division between the ON and OFF inner plexiform layer (IPL) is not structurally absolute. ON cone bipolar cells make non-canonical axonal synapses onto specific targets and receive amacrine cell synapses in the nominal OFF layer, creating novel motifs, including inhibitory crossover networks. Automated transmission electron microscope (ATEM) imaging, molecular tagging, tracing, and rendering of ≈ 400 bipolar cells reveals axonal ribbons in 36% of ON cone bipolar cells, throughout the OFF IPL. The targets include GABA-positive amacrine cells (γACs), glycine-positive amacrine cells (GACs) and ganglion cells. Most ON cone bipolar cell axonal contacts target GACs driven by OFF cone bipolar cells, forming new architectures for generating ON-OFF amacrine cells. Many of these ON-OFF GACs target ON cone bipolar cell axons, ON γACs and/or ON-OFF ganglion cells, representing widespread mechanisms for OFF to ON crossover inhibition. Other targets include OFF γACs presynaptic to OFF bipolar cells, forming γAC-mediated crossover motifs. ON cone bipolar cell axonal ribbons drive bistratified ON-OFF ganglion cells in the OFF layer and provide ON drive to polarity-appropriate targets such as bistratified diving ganglion cells (bsdGCs). The targeting precision of ON cone bipolar cell axonal synapses shows that this drive incidence is necessarily a joint distribution of cone bipolar cell axonal frequency and target cell trajectories through a given volume of the OFF layer. Such joint distribution sampling is likely common when targets are sparser than sources and when sources are coupled, as are ON cone bipolar cells. PMID:23042441

  7. Cell adhesion and matricellular support by astrocytes of the tripartite synapse

    NARCIS (Netherlands)

    Hillen, Anne E J; Burbach, J Peter H; Hol, Elly M

    2018-01-01

    Astrocytes contribute to the formation, function, and plasticity of synapses. Their processes enwrap the neuronal components of the tripartite synapse, and due to this close interaction they are perfectly positioned to modulate neuronal communication. The interaction between astrocytes and synapses

  8. Lenalidomide enhances the function of chimeric antigen receptor T cells against the epidermal growth factor receptor variant III by enhancing immune synapses.

    Science.gov (United States)

    Kuramitsu, S; Ohno, M; Ohka, F; Shiina, S; Yamamichi, A; Kato, A; Tanahashi, K; Motomura, K; Kondo, G; Kurimoto, M; Senga, T; Wakabayashi, T; Natsume, A

    2015-10-01

    The epidermal growth factor receptor variant III (EGFRvIII) is exclusively expressed on the cell surface in ~50% of glioblastoma multiforme (GBM). This variant strongly and persistently activates the phosphatidylinositol 3-kinase-Akt signaling pathway in a ligand-independent manner resulting in enhanced tumorigenicity, cellular motility and resistance to chemoradiotherapy. Our group generated a recombinant single-chain variable fragment (scFv) antibody specific to the EGFRvIII, referred to as 3C10-scFv. In the current study, we constructed a lentiviral vector transducing the chimeric antigen receptor (CAR) that consisted of 3C10-scFv, CD3ζ, CD28 and 4-1BB (3C10-CAR). The 3C10-CAR-transduced peripheral blood mononuclear cells (PBMCs) and CD3(+) T cells specifically lysed the glioma cells that express EGFRvIII. Moreover, we demonstrated that CAR CD3(+) T cells migrated to the intracranial xenograft of GBM in the mice treated with 3C10-CAR PBMCs. An important and novel finding of our study was that a thalidomide derivative lenalidomide induced 3C10-CAR PBMC proliferation and enhanced the persistent antitumor effect of the cells in vivo. Lenalidomide also exhibited enhanced immunological synapses between the effector cells and the target cells as determined by CD11a and F-actin polymerization. Collectively, lentiviral-mediated transduction of CAR effectors targeting the EGFRvIII showed specific efficacy, and lenalidomide even intensified CAR cell therapy by enhanced formation of immunological synapses.

  9. Transglial transmission at the dorsal root ganglion sandwich synapse: glial cell to postsynaptic neuron communication.

    Science.gov (United States)

    Rozanski, Gabriela M; Li, Qi; Stanley, Elise F

    2013-04-01

    The dorsal root ganglion (DRG) contains a subset of closely-apposed neuronal somata (NS) separated solely by a thin satellite glial cell (SGC) membrane septum to form an NS-glial cell-NS trimer. We recently reported that stimulation of one NS with an impulse train triggers a delayed, noisy and long-lasting response in its NS pair via a transglial signaling pathway that we term a 'sandwich synapse' (SS). Transmission could be unidirectional or bidirectional and facilitated in response to a second stimulus train. We have shown that in chick or rat SS the NS-to-SGC leg of the two-synapse pathway is purinergic via P2Y2 receptors but the second SGC-to-NS synapse mechanism remained unknown. A noisy evoked current in the target neuron, a reversal potential close to 0 mV, and insensitivity to calcium scavengers or G protein block favored an ionotropic postsynaptic receptor. Selective block by D-2-amino-5-phosphonopentanoate (AP5) implicated glutamatergic transmission via N-methyl-d-aspartate receptors. This agent also blocked NS responses evoked by puff of UTP, a P2Y2 agonist, directly onto the SGC cell, confirming its action at the second synapse of the SS transmission pathway. The N-methyl-d-aspartate receptor NR2B subunit was implicated by block of transmission with ifenprodil and by its immunocytochemical localization to the NS membrane, abutting the glial septum P2Y2 receptor. Isolated DRG cell clusters exhibited daisy-chain and branching NS-glial cell-NS contacts, suggestive of a network organization within the ganglion. The identification of the glial-to-neuron transmitter and receptor combination provides further support for transglial transmission and completes the DRG SS molecular transmission pathway. © 2013 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  10. MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells

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    Migneault Martine

    2010-01-01

    Full Text Available Abstract Background Cancer cells utilize a variety of mechanisms to evade immune detection and attack. Effective immune detection largely relies on the formation of an immune synapse which requires close contact between immune cells and their targets. Here, we show that MUC16, a heavily glycosylated 3-5 million Da mucin expressed on the surface of ovarian tumor cells, inhibits the formation of immune synapses between NK cells and ovarian tumor targets. Our results indicate that MUC16-mediated inhibition of immune synapse formation is an effective mechanism employed by ovarian tumors to evade immune recognition. Results Expression of low levels of MUC16 strongly correlated with an increased number of conjugates and activating immune synapses between ovarian tumor cells and primary naïve NK cells. MUC16-knockdown ovarian tumor cells were more susceptible to lysis by primary NK cells than MUC16 expressing controls. This increased lysis was not due to differences in the expression levels of the ligands for the activating receptors DNAM-1 and NKG2D. The NK cell leukemia cell line (NKL, which does not express KIRs but are positive for DNAM-1 and NKG2D, also conjugated and lysed MUC16-knockdown cells more efficiently than MUC16 expressing controls. Tumor cells that survived the NKL challenge expressed higher levels of MUC16 indicating selective lysis of MUC16low targets. The higher csMUC16 levels on the NKL resistant tumor cells correlated with more protection from lysis as compared to target cells that were never exposed to the effectors. Conclusion MUC16, a carrier of the tumor marker CA125, has previously been shown to facilitate ovarian tumor metastasis and inhibits NK cell mediated lysis of tumor targets. Our data now demonstrates that MUC16 expressing ovarian cancer cells are protected from recognition by NK cells. The immune protection provided by MUC16 may lead to selective survival of ovarian cancer cells that are more efficient in

  11. Immunology: Exhausted T cells perk up

    Science.gov (United States)

    Williams, Matthew A.; Bevan, Michael J.

    2006-02-01

    During persistent infections, the immune cells responsible for killing infected cells and maintaining inflammation gradually stop functioning, allowing the pathogen to thrive. But can this process be reversed?

  12. Peptide modification in T cell immunology - from molecule to animal

    NARCIS (Netherlands)

    Haan, Ellen Christine de

    2003-01-01

    Chemical knowledge can be applied in the field of immunology. It provides a better understanding of how a peptide interacts with proteins and cells of the immune system. However, it is not possible to predict the outcome of peptide administration in an animal. Peptides are used in experimental

  13. In Vivo Ribbon Mobility and Turnover of Ribeye at Zebrafish Hair Cell Synapses.

    Science.gov (United States)

    Graydon, Cole W; Manor, Uri; Kindt, Katie S

    2017-08-07

    Ribbons are presynaptic structures that mediate synaptic vesicle release in some sensory cells of the auditory and visual systems. Although composed predominately of the protein Ribeye, very little is known about the structural dynamics of ribbons. Here we describe the in vivo mobility and turnover of Ribeye at hair cell ribbon synapses by monitoring fluorescence recovery after photobleaching (FRAP) in transgenic zebrafish with GFP-tagged Ribeye. We show that Ribeye can exchange between halves of a ribbon within ~1 minute in a manner that is consistent with a simple diffusion mechanism. In contrast, exchange of Ribeye between other ribbons via the cell's cytoplasm takes several hours.

  14. A directionally-selective neuromorphic circuit based on reciprocal synapses in Starburst Amacrine Cells.

    Science.gov (United States)

    Tseng, Ko-Chung; Parker, Alice C; Joshi, Jonathan

    2011-01-01

    Starburst Amacrine Cells (SACs) play a major role in the detection of directional motion in the biological retina. The starburst amacrine cell has intrinsic electrical mechanisms for producing directional selectivity (DS). GABA transmitter-receptor interactions between two overlapping SACs make DS more robust. We present a compartmentalized CMOS neuromorphic circuit that models a portion of two biological starburst amacrine cells in the retina and includes a simplified model of reciprocal interaction between the dendritic branches of SACs. We demonstrate that a neuromorphic circuit incorporating the reciprocal synapses enhances the responses in the neuromorphic dendritic tip and generates robust directional selectivity.

  15. Immunological Considerations in In Utero Hematopoetic Stem Cell Transplantation (IUHCT

    Directory of Open Access Journals (Sweden)

    Andrea Ivonne Loewendorf

    2015-01-01

    Full Text Available In utero hematopoetic Stem cell transplantation (IUHCT is an attractive approach and a potentially curative surgery for several congenical hematopoetic diseases. In practice, this application has succeeded only in the context of Severe Combined Immunodeficiency Disorders. Here, we review potential immunological hurdles for the long-term establishment of chimerism and discuss relevant models and findings from both postnatal hematopoetic stem cell transplantation and IUHCT.

  16. Alcohol Impairs Long-Term Depression at the Cerebellar Parallel Fiber–Purkinje Cell Synapse

    Science.gov (United States)

    Belmeguenai, Amor; Botta, Paolo; Weber, John T.; Carta, Mario; De Ruiter, Martijn; De Zeeuw, Chris I.; Valenzuela, C. Fernando; Hansel, Christian

    2008-01-01

    Acute alcohol consumption causes deficits in motor coordination and gait, suggesting an involvement of cerebellar circuits, which play a role in the fine adjustment of movements and in motor learning. It has previously been shown that ethanol modulates inhibitory transmission in the cerebellum and affects synaptic transmission and plasticity at excitatory climbing fiber (CF) to Purkinje cell synapses. However, it has not been examined thus far how acute ethanol application affects long-term depression (LTD) and long-term potentiation (LTP) at excitatory parallel fiber (PF) to Purkinje cell synapses, which are assumed to mediate forms of cerebellar motor learning. To examine ethanol effects on PF synaptic transmission and plasticity, we performed whole cell patch-clamp recordings from Purkinje cells in rat cerebellar slices. We found that ethanol (50 mM) selectively blocked PF–LTD induction, whereas it did not change the amplitude of excitatory postsynaptic currents at PF synapses. In contrast, ethanol application reduced voltage-gated calcium currents and type 1 metabotropic glutamate receptor (mGluR1)–dependent responses in Purkinje cells, both of which are involved in PF–LTD induction. The selectivity of these effects is emphasized by the observation that ethanol did not impair PF–LTP and that PF–LTP could readily be induced in the presence of the group I mGluR antagonist AIDA or the mGluR1a antagonist LY367385. Taken together, these findings identify calcium currents and mGluR1-dependent signaling pathways as potential ethanol targets and suggest that an ethanol-induced blockade of PF–LTD could contribute to the motor coordination deficits resulting from alcohol consumption. PMID:18922952

  17. Live cell linear dichroism imaging reveals extensive membrane ruffling within the docking structure of natural killer cell immune synapses

    DEFF Research Database (Denmark)

    Benninger, Richard K P; Vanherberghen, Bruno; Young, Stephen

    2009-01-01

    We have applied fluorescence imaging of two-photon linear dichroism to measure the subresolution organization of the cell membrane during formation of the activating (cytolytic) natural killer (NK) cell immune synapse (IS). This approach revealed that the NK cell plasma membrane is convoluted...... into ruffles at the periphery, but not in the center of a mature cytolytic NK cell IS. Time-lapse imaging showed that the membrane ruffles formed at the initial point of contact between NK cells and target cells and then spread radialy across the intercellular contact as the size of the IS increased, becoming...

  18. Aging-related impairments of hippocampal mossy fibers synapses on CA3 pyramidal cells.

    Science.gov (United States)

    Villanueva-Castillo, Cindy; Tecuatl, Carolina; Herrera-López, Gabriel; Galván, Emilio J

    2017-01-01

    The network interaction between the dentate gyrus and area CA3 of the hippocampus is responsible for pattern separation, a process that underlies the formation of new memories, and which is naturally diminished in the aged brain. At the cellular level, aging is accompanied by a progression of biochemical modifications that ultimately affects its ability to generate and consolidate long-term potentiation. Although the synapse between dentate gyrus via the mossy fibers (MFs) onto CA3 neurons has been subject of extensive studies, the question of how aging affects the MF-CA3 synapse is still unsolved. Extracellular and whole-cell recordings from acute hippocampal slices of aged Wistar rats (34 ± 2 months old) show that aging is accompanied by a reduction in the interneuron-mediated inhibitory mechanisms of area CA3. Several MF-mediated forms of short-term plasticity, MF long-term potentiation and at least one of the critical signaling cascades necessary for potentiation are also compromised in the aged brain. An analysis of the spontaneous glutamatergic and gamma-aminobutyric acid-mediated currents on CA3 cells reveal a dramatic alteration in amplitude and frequency of the nonevoked events. CA3 cells also exhibited increased intrinsic excitability. Together, these results demonstrate that aging is accompanied by a decrease in the GABAergic inhibition, reduced expression of short- and long-term forms of synaptic plasticity, and increased intrinsic excitability. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Cell Adhesion, the Backbone of the Synapse: “Vertebrate” and “Invertebrate” Perspectives

    OpenAIRE

    Giagtzoglou, Nikolaos; Ly, Cindy V.; Bellen, Hugo J.

    2009-01-01

    Synapses are asymmetric intercellular junctions that mediate neuronal communication. The number, type, and connectivity patterns of synapses determine the formation, maintenance, and function of neural circuitries. The complexity and specificity of synaptogenesis relies upon modulation of adhesive properties, which regulate contact initiation, synapse formation, maturation, and functional plasticity. Disruption of adhesion may result in structural and functional imbalance that may lead to neu...

  20. Normal function of immunologic stem cells from aged mice

    International Nuclear Information System (INIS)

    Harrison, D.E.; Doubleday, J.W.

    1975-01-01

    Marrow or spleen grafts from aged donor mice produced antibody-forming cells as effectively as did grafts from younger controls in recipients tested 3 to 10 months after the transplantation. All recipients were lethally irradiated, and the T6 chromosome marker was used to demonstrate that they were populated by donor cell lines. Recipients of aged or younger control grafts gave similar responses when stimulated with varying doses of antigen and when tested at different times after the transplantation except in two cases. Recipients of aged spleen grafts gave significantly lower responses than younger controls for the first few weeks after the transplantation. If recipients had been thymectomized before lethal irradiation, aged cell lines (pooled marrow and spleen cells) gave only 37 percent of the responses of younger controls. Given sufficient time and intact young recipients, immunologic stem cell lines from old donors populated recipients with cells having normal immune responses. These results suggest that age-related immunologic defects are not intrinsically timed in the precursor cell lines that populate the immune system. (U.S.)

  1. Synapses between parallel fibres and stellate cells express long-term changes in synaptic efficacy in rat cerebellum.

    Science.gov (United States)

    Rancillac, Armelle; Crépel, Francis

    2004-02-01

    Various forms of synaptic plasticity underlying motor learning have already been well characterized at cerebellar parallel fibre (PF)-Purkinje cell (PC) synapses. Inhibitory interneurones play an important role in controlling the excitability and synchronization of PCs. We have therefore tested the possibility that excitatory synapses between PFs and stellate cells (SCs) are also able to exhibit long-term changes in synaptic efficacy. In the present study, we show that long-term potentiation (LTP) and long-term depression (LTD) were induced at these synapses by a low frequency stimulation protocol (2 Hz for 60 s) and that pairing this low frequency stimulation protocol with postsynaptic depolarization induced a marked shift of synaptic plasticity in favour of LTP. This LTP was cAMP independent, but required nitric oxide (NO) production from pre- and/or postsynaptic elements, depending on the stimulation or pairing protocol used, respectively. In contrast, LTD was not dependent on NO production but it required activation of postsynaptic group II and possibly of group I metabotropic glutamate receptors. Finally, stimulation of PFs at 8 Hz for 15 s also induced LTP at PF-SC synapses. But in this case, LTP was cAMP dependent, as was also observed at PF-PC synapses for presynaptic LTP induced in the same conditions. Thus, long-term changes in synaptic efficacy can be accomplished by PF-SCs synapses as well as by PF-PC synapses, suggesting that both types of plasticity might co-operate during cerebellar motor learning.

  2. The influence of Listeria monocytogenes cells on the primary immunologic response in irradiated mice

    International Nuclear Information System (INIS)

    Borowski, J.; Jokoniuk, P.

    1977-01-01

    The influence of killed Listeria monocytogenes cells on the primary immunologic response in mice irradiated with 300 or 500 R was studied. The immunologic response of the mice to sheep red blood cells used as antigen was assessed at the cellular level (by counting PFC) and humoral level. Injection of killed Listeria monocytogenes cells before irradiation of the mice diminished the immunosuppressive effect of roentgen radiation. Injection of the cells after irradiation accelerated regeneration of immunologic reactivity in the irradiated mice. (author)

  3. Systems immunology allows a new view on human dendritic cells.

    Science.gov (United States)

    Schultze, Joachim L; Aschenbrenner, Anna C

    2018-02-24

    As the most important antigen-presenting cells, dendritic cells connect the innate and adaptive part of our immune system and play a pivotal role in our course of action against invading pathogens as well as during successful vaccination. Immunologists have therefore studied these cells in great detail using flow cytometry-based analyses, in vitro assays and in vivo models, both in murine models and in humans. Albeit, sophisticated, classical immunological, and molecular approaches were often unable to unequivocally determine the subpopulation structure of the dendritic cell lineage and not surprisingly, conflicting results about dendritic cell subsets co-existed throughout the last decades. With the advent of systems approaches and the most recent introduction of -omics approaches on the single cell level combined with multi-colour flow cytometry or mass cytometry, we now enter an era allowing us to define cell population structures with an unprecedented precision. We will report here on the most recent studies applying these technologies to human dendritic cells. Proper delineation of and definition of molecular signatures for the different human dendritic cell subsets will greatly facilitate studying these cells in the future: understanding their function under physiological as well as pathological conditions. Copyright © 2018 Elsevier Ltd. All rights reserved.

  4. Microfluidic single-cell technology in immunology and antibody screening.

    Science.gov (United States)

    Seah, Yu Fen Samantha; Hu, Hongxing; Merten, Christoph A

    2018-02-01

    Single-cell technology has a major impact on the field of immunology. It enables the kinetics and logic of immune signaling and immune cell migration to be elucidated, facilitates antibody screening and allows massively parallelized analysis of B- and T-cell repertoires. Impressive progress has been made over the last decade, strongly boosted by microfluidic approaches. In this review, we summarize the most powerful microfluidic systems based on continuous flow, nanowells, valves and droplets and we analyze their benefits for phenotypic characterization, drug discovery and next generation sequencing experiments. We describe current limitations and provide an outlook on important future applications. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  5. Neural Cell Adhesion Molecules of the Immunoglobulin Superfamily Regulate Synapse Formation, Maintenance, and Function.

    Science.gov (United States)

    Sytnyk, Vladimir; Leshchyns'ka, Iryna; Schachner, Melitta

    2017-05-01

    Immunoglobulin superfamily adhesion molecules are among the most abundant proteins in vertebrate and invertebrate nervous systems. Prominent family members are the neural cell adhesion molecules NCAM and L1, which were the first to be shown to be essential not only in development but also in synaptic function and as key regulators of synapse formation, synaptic activity, plasticity, and synaptic vesicle recycling at distinct developmental and activity stages. In addition to interacting with each other, adhesion molecules interact with ion channels and cytokine and neurotransmitter receptors. Mutations in their genes are linked to neurological disorders associated with abnormal development and synaptic functioning. This review presents an overview of recent studies on these molecules and their crucial impact on neurological disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Cell source determines the immunological impact of biomimetic nanoparticles.

    Science.gov (United States)

    Evangelopoulos, Michael; Parodi, Alessandro; Martinez, Jonathan O; Yazdi, Iman K; Cevenini, Armando; van de Ven, Anne L; Quattrocchi, Nicoletta; Boada, Christian; Taghipour, Nima; Corbo, Claudia; Brown, Brandon S; Scaria, Shilpa; Liu, Xuewu; Ferrari, Mauro; Tasciotti, Ennio

    2016-03-01

    Recently, engineering the surface of nanotherapeutics with biologics to provide them with superior biocompatibility and targeting towards pathological tissues has gained significant popularity. Although the functionalization of drug delivery vectors with cellular materials has been shown to provide synthetic particles with unique biological properties, these approaches may have undesirable immunological repercussions upon systemic administration. Herein, we comparatively analyzed unmodified multistage nanovectors and particles functionalized with murine and human leukocyte cellular membrane, dubbed Leukolike Vectors (LLV), and the immunological effects that may arise in vitro and in vivo. Previously, LLV demonstrated an avoidance of opsonization and phagocytosis, in addition to superior targeting of inflammation and prolonged circulation. In this work, we performed a comprehensive evaluation of the importance of the source of cellular membrane in increasing their systemic tolerance and minimizing an inflammatory response. Time-lapse microscopy revealed LLV developed using a cellular coating derived from a murine (i.e., syngeneic) source resulted in an active avoidance of uptake by macrophage cells. Additionally, LLV composed of a murine membrane were found to have decreased uptake in the liver with no significant effect on hepatic function. As biomimicry continues to develop, this work demonstrates the necessity to consider the source of biological material in the development of future drug delivery carriers. Copyright © 2015. Published by Elsevier Ltd.

  7. Taurine Induces Proliferation of Neural Stem Cells and Synapse Development in the Developing Mouse Brain

    Science.gov (United States)

    Shivaraj, Mattu Chetana; Marcy, Guillaume; Low, Guoliang; Ryu, Jae Ryun; Zhao, Xianfeng; Rosales, Francisco J.; Goh, Eyleen L. K.

    2012-01-01

    Taurine is a sulfur-containing amino acid present in high concentrations in mammalian tissues. It has been implicated in several processes involving brain development and neurotransmission. However, the role of taurine in hippocampal neurogenesis during brain development is still unknown. Here we show that taurine regulates neural progenitor cell (NPC) proliferation in the dentate gyrus of the developing brain as well as in cultured early postnatal (P5) hippocampal progenitor cells and hippocampal slices derived from P5 mice brains. Taurine increased cell proliferation without having a significant effect on neural differentiation both in cultured P5 NPCs as well as cultured hippocampal slices and in vivo. Expression level analysis of synaptic proteins revealed that taurine increases the expression of Synapsin 1 and PSD 95. We also found that taurine stimulates the phosphorylation of ERK1/2 indicating a possible role of the ERK pathway in mediating the changes that we observed, especially in proliferation. Taken together, our results demonstrate a role for taurine in neural stem/progenitor cell proliferation in developing brain and suggest the involvement of the ERK1/2 pathways in mediating these actions. Our study also shows that taurine influences the levels of proteins associated with synapse development. This is the first evidence showing the effect of taurine on early postnatal neuronal development using a combination of in vitro, ex-vivo and in vivo systems. PMID:22916184

  8. Taurine induces proliferation of neural stem cells and synapse development in the developing mouse brain.

    Directory of Open Access Journals (Sweden)

    Mattu Chetana Shivaraj

    Full Text Available Taurine is a sulfur-containing amino acid present in high concentrations in mammalian tissues. It has been implicated in several processes involving brain development and neurotransmission. However, the role of taurine in hippocampal neurogenesis during brain development is still unknown. Here we show that taurine regulates neural progenitor cell (NPC proliferation in the dentate gyrus of the developing brain as well as in cultured early postnatal (P5 hippocampal progenitor cells and hippocampal slices derived from P5 mice brains. Taurine increased cell proliferation without having a significant effect on neural differentiation both in cultured P5 NPCs as well as cultured hippocampal slices and in vivo. Expression level analysis of synaptic proteins revealed that taurine increases the expression of Synapsin 1 and PSD 95. We also found that taurine stimulates the phosphorylation of ERK1/2 indicating a possible role of the ERK pathway in mediating the changes that we observed, especially in proliferation. Taken together, our results demonstrate a role for taurine in neural stem/progenitor cell proliferation in developing brain and suggest the involvement of the ERK1/2 pathways in mediating these actions. Our study also shows that taurine influences the levels of proteins associated with synapse development. This is the first evidence showing the effect of taurine on early postnatal neuronal development using a combination of in vitro, ex-vivo and in vivo systems.

  9. Critical immunological pathways are downregulated in APECED patient dendritic cells.

    Science.gov (United States)

    Pöntynen, Nora; Strengell, Mari; Sillanpää, Niko; Saharinen, Juha; Ulmanen, Ismo; Julkunen, Ilkka; Peltonen, Leena

    2008-10-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. AIRE functions as a transcriptional regulator, and it has a central role in the development of immunological tolerance. AIRE regulates the expression of ectopic antigens in epithelial cells of the thymic medulla and has been shown to participate in the development of peripheral tolerance. However, the mechanism of action of AIRE has remained elusive. To further investigate the role of AIRE in host immune functions, we studied the properties and transcript profiles in in vitro monocyte-differentiated dendritic cells (moDCs) obtained from APECED patients and healthy controls. AIRE-deficient monocytes showed typical DC morphology and expressed DC marker proteins cluster of differentiation 86 and human leukocyte antigen class II. APECED patient-derived moDCs were functionally impaired: the transcriptional response of cytokine genes to pathogens was drastically reduced. Interestingly, some changes were observable already at the immature DC stage. Pathway analyses of transcript profiles revealed that the expression of the components of the host cell signaling pathways involved in cell-cell signalling, innate immune responses, and cytokine activity were reduced in APECED moDCs. Our observations support a role for AIRE in peripheral tolerance and are the first ones to show that AIRE has a critical role in DC responses to microbial stimuli in humans.

  10. Accelerated intoxication of GABAergic synapses by botulinum neurotoxin A disinhibits stem cell-derived neuron networks prior to network silencing

    Directory of Open Access Journals (Sweden)

    Phillip H Beske

    2015-04-01

    Full Text Available Botulinum neurotoxins (BoNTs are extremely potent toxins that specifically cleave SNARE proteins in peripheral synapses, preventing neurotransmitter release. Neuronal responses to BoNT intoxication are traditionally studied by quantifying SNARE protein cleavage in vitro or monitoring physiological paralysis in vivo. Consequently, the dynamic effects of intoxication on synaptic behaviors are not well understood. We have reported that mouse embryonic stem cell-derived neurons (ESNs are highly sensitive to BoNT based on molecular readouts of intoxication. Here we study the time-dependent changes in synapse- and network-level behaviors following addition of BoNT/A to spontaneously active networks of glutamatergic and GABAergic ESNs. Whole-cell patch-clamp recordings indicated that BoNT/A rapidly blocked synaptic neurotransmission, confirming that ESNs replicate the functional pathophysiology responsible for clinical botulism. Quantitation of spontaneous neurotransmission in pharmacologically isolated synapses revealed accelerated silencing of GABAergic synapses compared to glutamatergic synapses, which was consistent with the selective accumulation of cleaved SNAP-25 at GAD1+ presynaptic terminals at early timepoints. Different latencies of intoxication resulted in complex network responses to BoNT/A addition, involving rapid disinhibition of stochastic firing followed by network silencing. Synaptic activity was found to be highly sensitive to SNAP-25 cleavage, reflecting the functional consequences of the localized cleavage of the small subpopulation of SNAP-25 that is engaged in neurotransmitter release in the nerve terminal. Collectively these findings illustrate that use of synaptic function assays in networked neurons cultures offers a novel and highly sensitive approach for mechanistic studies of toxin:neuron interactions and synaptic responses to BoNT.

  11. Thyroid hormone is required for pruning, functioning and long-term maintenance of afferent inner hair cell synapses.

    Science.gov (United States)

    Sundaresan, Srividya; Kong, Jee-Hyun; Fang, Qing; Salles, Felipe T; Wangsawihardja, Felix; Ricci, Anthony J; Mustapha, Mirna

    2016-01-01

    Functional maturation of afferent synaptic connections to inner hair cells (IHCs) involves pruning of excess synapses formed during development, as well as the strengthening and survival of the retained synapses. These events take place during the thyroid hormone (TH)-critical period of cochlear development, which is in the perinatal period for mice and in the third trimester for humans. Here, we used the hypothyroid Snell dwarf mouse (Pit1(dw)) as a model to study the role of TH in afferent type I synaptic refinement and functional maturation. We observed defects in afferent synaptic pruning and delays in calcium channel clustering in the IHCs of Pit1(dw) mice. Nevertheless, calcium currents and capacitance reached near normal levels in Pit1(dw) IHCs by the age of onset of hearing, despite the excess number of retained synapses. We restored normal synaptic pruning in Pit1(dw) IHCs by supplementing with TH from postnatal day (P)3 to P8, establishing this window as being critical for TH action on this process. Afferent terminals of older Pit1(dw) IHCs showed evidence of excitotoxic damage accompanied by a concomitant reduction in the levels of the glial glutamate transporter, GLAST. Our results indicate that a lack of TH during a critical period of inner ear development causes defects in pruning and long-term homeostatic maintenance of afferent synapses. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  12. Diversity of Spine Synapses in Animals

    Science.gov (United States)

    Wang, Ya-Xian; Mattson, Mark P.; Yao, Pamela J.

    2016-01-01

    Here we examine the structure of the various types of spine synapses throughout the animal kingdom. Based on available evidence, we suggest that there are two major categories of spine synapses: invaginating and non-invaginating, with distributions that vary among different groups of animals. In the simplest living animals with definitive nerve cells and synapses, the cnidarians and ctenophores, most chemical synapses do not form spine synapses. But some cnidarians have invaginating spine synapses, especially in photoreceptor terminals of motile cnidarians with highly complex visual organs, and also in some mainly sessile cnidarians with rapid prey capture reflexes. This association of invaginating spine synapses with complex sensory inputs is retained in the evolution of higher animals in photoreceptor terminals and some mechanoreceptor synapses. In contrast to invaginating spine synapse, non-invaginating spine synapses have been described only in animals with bilateral symmetry, heads and brains, associated with greater complexity in neural connections. This is apparent already in the simplest bilaterians, the flatworms, which can have well-developed non-invaginating spine synapses in some cases. Non-invaginating spine synapses diversify in higher animal groups. We also discuss the functional advantages of having synapses on spines and more specifically, on invaginating spines. And finally we discuss pathologies associated with spine synapses, concentrating on those systems and diseases where invaginating spine synapses are involved. PMID:27230661

  13. Chronic Fluoxetine Induces the Enlargement of Perforant Path-Granule Cell Synapses in the Mouse Dentate Gyrus.

    Science.gov (United States)

    Kitahara, Yosuke; Ohta, Keisuke; Hasuo, Hiroshi; Shuto, Takahide; Kuroiwa, Mahomi; Sotogaku, Naoki; Togo, Akinobu; Nakamura, Kei-ichiro; Nishi, Akinori

    2016-01-01

    A selective serotonin reuptake inhibitor is the most commonly prescribed antidepressant for the treatment of major depression. However, the mechanisms underlying the actions of selective serotonin reuptake inhibitors are not fully understood. In the dentate gyrus, chronic fluoxetine treatment induces increased excitability of mature granule cells (GCs) as well as neurogenesis. The major input to the dentate gyrus is the perforant path axons (boutons) from the entorhinal cortex (layer II). Through voltage-sensitive dye imaging, we found that the excitatory neurotransmission of the perforant path synapse onto the GCs in the middle molecular layer of the mouse dentate gyrus (perforant path-GC synapse) is enhanced after chronic fluoxetine treatment (15 mg/kg/day, 14 days). Therefore, we further examined whether chronic fluoxetine treatment affects the morphology of the perforant path-GC synapse, using FIB/SEM (focused ion beam/scanning electron microscopy). A three-dimensional reconstruction of dendritic spines revealed the appearance of extremely large-sized spines after chronic fluoxetine treatment. The large-sized spines had a postsynaptic density with a large volume. However, chronic fluoxetine treatment did not affect spine density. The presynaptic boutons that were in contact with the large-sized spines were large in volume, and the volumes of the mitochondria and synaptic vesicles inside the boutons were correlated with the size of the boutons. Thus, the large-sized perforant path-GC synapse induced by chronic fluoxetine treatment contains synaptic components that correlate with the synapse size and that may be involved in enhanced glutamatergic neurotransmission.

  14. Immunologic effects of hydroxyurea in sickle cell anemia.

    Science.gov (United States)

    Lederman, Howard M; Connolly, Margaret A; Kalpatthi, Ram; Ware, Russell E; Wang, Winfred C; Luchtman-Jones, Lori; Waclawiw, Myron; Goldsmith, Jonathan C; Swift, Andrea; Casella, James F

    2014-10-01

    Susceptibility to encapsulated bacteria is well known in sickle cell disease (SCD). Hydroxyurea use is common in adults and children with SCD, but little is known about hydroxyurea's effects on immune function in SCD. Because hydroxyurea inhibits ribonucleotide reductase, causing cell cycle arrest at the G1-S interface, we postulated that hydroxyurea might delay transition from naive to memory T cells, with inhibition of immunologic maturation and vaccine responses. T-cell subsets, naive and memory T cells, and antibody responses to pneumococcal and measles, mumps, and rubella vaccines were measured among participants in a multicenter, randomized, double-blind, placebo-controlled trial of hydroxyurea in infants and young children with SCD (BABY HUG). Compared with placebo, hydroxyurea treatment resulted in significantly lower total lymphocyte, CD4, and memory T-cell counts; however, these numbers were still within the range of historical healthy controls. Antibody responses to pneumococcal vaccination were not affected, but a delay in achieving protective measles antibody levels occurred in the hydroxyurea group. Antibody levels to measles, mumps, and rubella showed no differences between groups at exit, indicating that effective immunization can be achieved despite hydroxyurea use. Hydroxyurea does not appear to have significant deleterious effects on the immune function of infants and children with SCD. Additional assessments of lymphocyte parameters of hydroxyurea-treated children may be warranted. No changes in current immunization schedules are recommended; however, for endemic disease or epidemics, adherence to accelerated immunization schedules for the measles, mumps, and rubella vaccine should be reinforced. Copyright © 2014 by the American Academy of Pediatrics.

  15. Cell Biological Mechanisms of Activity-Dependent Synapse to Nucleus Translocation of CRTC1 in Neurons

    Directory of Open Access Journals (Sweden)

    Toh Hean eCh'ng

    2015-09-01

    Full Text Available Previous studies have revealed a critical role for CREB-regulated transcriptional coactivator (CRTC1 in regulating neuronal gene expression during learning and memory. CRTC1 localizes to synapses but undergoes activity-dependent nuclear translocation to regulate the transcription of CREB target genes. Here we investigate the long-distance retrograde transport of CRTC1 in hippocampal neurons. We show that local elevations in calcium, triggered by activation of synaptic glutamate receptors and L-type voltage-gated calcium channels, initiate active, dynein-mediated retrograde transport of CRTC1 along microtubules. We identify a nuclear localization signal within CRTC1, and characterize three conserved serine residues whose dephosphorylation is required for nuclear import. Domain analysis reveals that the amino-terminal third of CRTC1 contains all of the signals required for regulated nucleocytoplasmic trafficking. We fuse this region to Dendra2 to generate a reporter construct and perform live-cell imaging coupled with local uncaging of glutamate and photoconversion to characterize the dynamics of stimulus-induced retrograde transport and nuclear accumulation.

  16. The urodelean Mauthner cell. Morphology of the afferent synapses to the M-cell of larval Salamandra salamandra

    Energy Technology Data Exchange (ETDEWEB)

    Cioni, C.; De Palma, F.; De Vito, L.; Stefanelli, A. [Rome, Univ. (Italy). Dipt. di Biologia Animale e dell`Uomo

    1997-12-31

    In the present work the fine morphology and the distribution of the afferent synapses to the Mauthner cell of larval Salamandra salamandra are described. The aim of the study is to characterize the synaptic bed in the larvae of this terrestrial salamander in order to compare it with that of larval axolotl and larval anurans. Four main types of afferent endings have been identified: myelinated club endings, round-vesicle end bulbs, flattened-vesicle end bulbs and spiral fibers endings. The M-cell afferent synaptology of larval stages of terrestrial amphibians is quite similar to that previously observed in larval stages of aquatic species. This fact can be related to the fundamental similarities between the larval lifestyles.

  17. Facial stimulation induces long-term depression at cerebellar molecular layer interneuron–Purkinje cell synapses in vivo in mice

    Directory of Open Access Journals (Sweden)

    De-Lai eQiu

    2015-06-01

    Full Text Available Cerebellar long-term synaptic plasticity has been proposed to provide a cellular mechanism for motor learning. Numerous studies have demonstrated the induction and mechanisms of synaptic plasticity at parallel fiber–Purkinje cell (PF–PC, parallel fiber–molecular layer interneurons (PF–MLI and mossy fiber–granule cell (MF–GC synapses, but no study has investigated sensory stimulation-evoked synaptic plasticity at MLI–PC synapses in the cerebellar cortex of living animals. We studied the expression and mechanism of MLI–PC GABAergic synaptic plasticity induced by a train of facial stimulation in urethane-anesthetized mice by cell-attached recordings and pharmacological methods. We found that 1 Hz, but not a 2 Hz or 4 Hz, facial stimulation induced a long-term depression (LTD of GABAergic transmission at MLI–PC synapses, which was accompanied with a decrease in the stimulation-evoked pause of spike firing in PCs, but did not induce a significant change in the properties of the sensory-evoked spike events of MLIs. The MLI–PC GABAergic LTD could be prevented by blocking cannabinoid type 1 (CB1 receptors, and could be pharmacologically induced by a CB1 receptor agonist. Additionally, 1 Hz facial stimulation delivered in the presence of a metabotropic glutamate receptor 1 (mGluR1 antagonist, JNJ16259685, still induced the MLI–PC GABAergic LTD, whereas blocking N-methyl-D-aspartate (NMDA receptors during 1 Hz facial stimulation abolished the expression of MLI–PC GABAergic LTD. These results indicate that sensory stimulation can induce an endocannabinoid (eCB-dependent LTD of GABAergic transmission at MLI–PC synapses via activation of NMDA receptors in cerebellar cortical Crus II in vivo in mice. Our results suggest that the sensory stimulation-evoked MLI–PC GABAergic synaptic plasticity may play a critical role in motor learning in animals.

  18. Developmental changes in NMDA receptor subunit composition at ON and OFF bipolar cell synapses onto direction-selective retinal ganglion cells.

    Science.gov (United States)

    Stafford, Benjamin K; Park, Silvia J H; Wong, Kwoon Y; Demb, Jonathan B

    2014-01-29

    In the developing mouse retina, spontaneous and light-driven activity shapes bipolar→ganglion cell glutamatergic synapse formation, beginning around the time of eye-opening (P12-P14) and extending through the first postnatal month. During this time, glutamate release can spill outside the synaptic cleft and possibly stimulate extrasynaptic NMDA-type glutamate receptors (NMDARs) on ganglion cells. Furthermore, the role of NMDARs during development may differ between ON and OFF bipolar synapses as in mature retina, where ON synapses reportedly include extrasynaptic NMDARs with GluN2B subunits. To better understand the function of glutamatergic synapses during development, we made whole-cell recordings of NMDAR-mediated responses, in vitro, from two types of genetically identified direction-selective ganglion cells (dsGCs): TRHR (thyrotropin-releasing hormone receptor) and Drd4 (dopamine receptor 4). Both dsGC types responded to puffed NMDA between P7 and P28; and both types exhibited robust light-evoked NMDAR-mediated responses at P14 and P28 that were quantified by conductance analysis during nicotinic and GABA(A) receptor blockade. For a given cell type and at a given age, ON and OFF bipolar cell inputs evoked similar NMDAR-mediated responses, suggesting that ON-versus-OFF differences in mature retina do not apply to the cell types or ages studied here. At P14, puff- and light-evoked NMDAR-mediated responses in both dsGCs were partially blocked by the GluN2B antagonist ifenprodil, whereas at P28 only TRHR cells remained ifenprodil-sensitive. NMDARs contribute at both ON and OFF bipolar cell synapses during a period of robust activity-dependent synaptic development, with declining GluN2B involvement over time in specific ganglion cell types.

  19. Endocannabinoid release modulates electrical coupling between CCK cells connected via chemical and electrical synapses in CA1

    Directory of Open Access Journals (Sweden)

    Jonathan eIball

    2011-11-01

    Full Text Available Electrical coupling between some subclasses of interneurons is thought to promote coordinated firing that generates rhythmic synchronous activity in cortical regions. Synaptic activity of cholesystokinin (CCK interneurons which co-express cannbinoid type-1 (CB1 receptors are powerful modulators of network activity via the actions of endocannabinoids. We investigated the modulatory actions of endocannabinoids between chemically and electrically connected synapses of CCK cells using paired whole-cell recordings combined with biocytin and double immunofluorescence labelling in acute slices of rat hippocampus at P18-20 days. CA1 stratum radiatum CCK Schaffer collateral associated (SCA cells were coupled electrically with each other as well as CCK basket cells and CCK cells with axonal projections expanding to dentate gyrus. Approximately 50% of electrically coupled cells received facilitating, asynchronously released IPSPs that curtailed the steady-state coupling coefficient by 57%. Tonic CB1 receptor activity which reduces inhibition enhanced electrical coupling between cells that were connected via chemical and electrical synapses. Blocking CB1 receptors with antagonist, AM-251 (5M resulted in the synchronized release of larger IPSPs and this enhanced inhibition further reduced the steady-state coupling coefficient by 85%. Depolarization induced suppression of inhibition (DSI, maintained the asynchronicity of IPSP latency, but reduced IPSP amplitudes by 95% and enhanced the steady-state coupling coefficient by 104% and IPSP duration by 200%. However, DSI did not did not enhance electrical coupling at purely electrical synapses. These data suggest that different morphological subclasses of CCK interneurons are interconnected via gap junctions. The synergy between the chemical and electrical coupling between CCK cells probably plays a role in activity-dependent endocannabinoid modulation of rhythmic synchronization.

  20. Reduced sensory stimulation alters the molecular make-up of glutamatergic hair cell synapses in the developing cochlea.

    Science.gov (United States)

    Barclay, M; Constable, R; James, N R; Thorne, P R; Montgomery, J M

    2016-06-14

    Neural activity during early development is known to alter innervation pathways in the central and peripheral nervous systems. We sought to examine how reduced sound-induced sensory activity in the cochlea affected the consolidation of glutamatergic synapses between inner hair cells (IHC) and the primary auditory neurons as these synapses play a primary role in transmitting sound information to the brain. A unilateral conductive hearing loss was induced prior to the onset of sound-mediated stimulation of the sensory hair cells, by rupturing the tympanic membrane and dislocating the auditory ossicles in the left ear of P11 mice. Auditory brainstem responses at P15 and P21 showed a 40-50-dB increase in thresholds for frequencies 8-32kHz in the dislocated ear relative to the control ear. Immunohistochemistry and confocal microscopy were subsequently used to examine the effect of this attenuation of sound stimulation on the expression of RIBEYE, which comprises the presynaptic ribbons, Shank-1, a postsynaptic scaffolding protein, and the GluA2/3 and 4 subunits of postsynaptic AMPA receptors. Our results show that dislocation did not alter the number of pre- or postsynaptic protein puncta. However, dislocation did increase the size of RIBEYE, GluA4, GluA2/3 and Shank-1 puncta, with postsynaptic changes preceding presynaptic changes. Our data suggest that a reduction in sound stimulation during auditory development induces plasticity in the molecular make-up of IHC glutamatergic synapses, but does not affect the number of these synapses. Up-regulation of synaptic proteins with sound attenuation may facilitate a compensatory increase in synaptic transmission due to the reduced sensory stimulation of the IHC. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  1. Immunological Demyelination Triggers Macrophage/Microglial Cells Activation without Inducing Astrogliosis

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    Frank Cloutier

    2013-01-01

    Full Text Available The glial scar formed by reactive astrocytes and axon growth inhibitors associated with myelin play important roles in the failure of axonal regeneration following central nervous system (CNS injury. Our laboratory has previously demonstrated that immunological demyelination of the CNS facilitates regeneration of severed axons following spinal cord injury. In the present study, we evaluate whether immunological demyelination is accompanied with astrogliosis. We compared the astrogliosis and macrophage/microglial cell responses 7 days after either immunological demyelination or a stab injury to the dorsal funiculus. Both lesions induced a strong activated macrophage/microglial cells response which was significantly higher within regions of immunological demyelination. However, immunological demyelination regions were not accompanied by astrogliosis compared to stab injury that induced astrogliosis which extended several millimeters above and below the lesions, evidenced by astroglial hypertrophy, formation of a glial scar, and upregulation of intermediate filaments glial fibrillary acidic protein (GFAP. Moreover, a stab or a hemisection lesion directly within immunological demyelination regions did not induced astrogliosis within the immunological demyelination region. These results suggest that immunological demyelination creates a unique environment in which astrocytes do not form a glial scar and provides a unique model to understand the putative interaction between astrocytes and activated macrophage/microglial cells.

  2. The Multiscale Systems Immunology project: software for cell-based immunological simulation

    Directory of Open Access Journals (Sweden)

    Kepler Thomas B

    2008-04-01

    Full Text Available Abstract Background Computer simulations are of increasing importance in modeling biological phenomena. Their purpose is to predict behavior and guide future experiments. The aim of this project is to model the early immune response to vaccination by an agent based immune response simulation that incorporates realistic biophysics and intracellular dynamics, and which is sufficiently flexible to accurately model the multi-scale nature and complexity of the immune system, while maintaining the high performance critical to scientific computing. Results The Multiscale Systems Immunology (MSI simulation framework is an object-oriented, modular simulation framework written in C++ and Python. The software implements a modular design that allows for flexible configuration of components and initialization of parameters, thus allowing simulations to be run that model processes occurring over different temporal and spatial scales. Conclusion MSI addresses the need for a flexible and high-performing agent based model of the immune system.

  3. Human Cytotoxic T Lymphocytes Form Dysfunctional Immune Synapses with B Cells Characterized by Non-Polarized Lytic Granule Release

    Directory of Open Access Journals (Sweden)

    Anna Kabanova

    2016-04-01

    Full Text Available Suppression of the cytotoxic T cell (CTL immune response has been proposed as one mechanism for immune evasion in cancer. In this study, we have explored the underlying basis for CTL suppression in the context of B cell malignancies. We document that human B cells have an intrinsic ability to resist killing by freshly isolated cytotoxic T cells (CTLs, but are susceptible to lysis by IL-2 activated CTL blasts and CTLs isolated from immunotherapy-treated patients with chronic lymphocytic leukemia (CLL. Impaired killing was associated with the formation of dysfunctional non-lytic immune synapses characterized by the presence of defective linker for activation of T cells (LAT signaling and non-polarized release of the lytic granules transported by ADP-ribosylation factor-like protein 8 (Arl8. We propose that non-lytic degranulation of CTLs are a key regulatory mechanism of evasion through which B cells may interfere with the formation of functional immune synapses by CTLs.

  4. The Scaffolding Protein Synapse-Associated Protein 97 is Required for Enhanced Signaling Through Isotype-Switched IgG Memory B Cell Receptors

    Science.gov (United States)

    Liu, Wanli; Chen, Elizabeth; Zhao, Xing Wang; Wan, Zheng Peng; Gao, Yi Ren; Davey, Angel; Huang, Eric; Zhang, Lijia; Crocetti, Jillian; Sandoval, Gabriel; Joyce, M. Gordon; Miceli, Carrie; Lukszo, Jan; Aravind, L.; Swat, Wojciech; Brzostowski, Joseph; Pierce, Susan K.

    2012-01-01

    Memory B cells are generated during an individual's first encounter with a foreign antigen and respond to re-encounter with the same antigen through cell surface immunoglobulin G (IgG) B cell receptors (BCRs) resulting in rapid, high-titered IgG antibody responses. Despite a central role for IgG BCRs in B cell memory, our understanding of the molecular mechanism by which IgG BCRs enhance antibody responses is incomplete. Here, we showed that the conserved cytoplasmic tail of the IgG BCR, which contains a putative PDZ-binding motif, associated with synapse-associated protein 97 (SAP97), a member of the PDZ domain–containing, membrane-associated guanylate-kinase family of scaffolding molecules that play key roles in controlling receptor density and signal strength at neuronal synapses. We showed that SAP97 accumulated and bound to IgG BCRs in the immune synapses that formed in response to engagement of the B cell with antigen. Knocking down SAP97 in IgG-expressing B cells or mutating the putative PDZ-binding motif in the tail impaired immune synapse formation, the initiation of IgG BCR signaling, and downstream activation of p38 mitogen-activated protein kinase. Thus, heightened B cell memory responses are encoded, in part, by a mechanism that involves SAP97 serving as a scaffolding protein in the IgG BCR immune synapse. PMID:22855505

  5. Regulatory T Cells in HIV-Infected Immunological Nonresponders Are Increased in Blood but Depleted in Lymphoid Tissue and Predict Immunological Reconstitution

    DEFF Research Database (Denmark)

    Gaardbo, Julie C; Hartling, Hans J; Ronit, Andreas

    2014-01-01

    . In contrast, responders resembled healthy controls. Finally, in INR, high level of Tregs in blood and Foxp3 cells in lymphoid tissue were associated with higher level of immunological reconstitution after 1 year of follow-up. CONCLUSIONS: In conclusion, altered distribution of Tregs was found in INR......BACKGROUND: HIV-infected immunological nonresponders fail to immune reconstitute despite optimal treatment. We hypothesized that regulatory T cells (Tregs) are involved in immunological reconstitution. Tregs and Treg subpopulations were measured in blood and Foxp3 cells in lymphoid tissue...... (CD4 T-cell count 200-500 cells/μL), 30 responders (CD4 T-cell count >500 cells/μL), and 34 healthy controls. Tregs, Treg subpopulations, and intracellular staining for interleukin 10 in peripheral blood were measured using flow cytometry. Foxp3 cells in lymphoid tissue were evaluated using...

  6. IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs.

    Science.gov (United States)

    Chen, Chien-Chang; Kobayashi, Takao; Iijima, Koji; Hsu, Fan-Chi; Kita, Hirohito

    2017-11-01

    Airway exposure to environmental antigens generally leads to immunologic tolerance. A fundamental question remains: Why is airway tolerance compromised in patients with allergic airway diseases? IL-33 promotes innate and adaptive type 2 immunity and might provide the answer to this question. The goal of this study was to investigate the roles played by IL-33 in altering regulatory T (Treg) cells in the lungs and in affecting previously established airway immunologic tolerance. We analyzed CD4 + forkhead box P3 (Foxp3) + Treg cells that were isolated from the lungs of naive BALB/c mice and those treated with IL-33. Airway tolerance and allergen-induced airway inflammation models in mice were used to investigate how IL-33 affects established immunologic tolerance in vivo. CD4 + Foxp3 + Treg cells in the lungs expressed the IL-33 receptor ST2. When exposed to IL-33, Treg cells upregulated their expression of the canonical T H 2 transcription factor GATA3, as well as ST2, and produced type 2 cytokines. Treg cells lost their ability to suppress effector T cells in the presence of IL-33. Airway administration of IL-33 with an antigen impaired immunologic tolerance in the lungs that had been established by prior exposure to the antigen. Dysregulated Foxp3 + Treg cells with distinct characteristics of T H 2 cells increased in the lungs of mice undergoing IL-33-dependent allergen-driven airway inflammation. IL-33 dysregulated lung Treg cells and impaired immunologic tolerance to inhaled antigens. Established airway tolerance might not be sustained in the presence of an innate immunologic stimulus, such as IL-33. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  7. [The time course of changes in cell immunological parameters during administration of live dry plague vaccine].

    Science.gov (United States)

    Bogacheva, N V; Darmov, I V; Borisevich, I V; Kriuchkov, A V; Pechenkin, D V

    2009-08-01

    The study of the time course of changes in cell immunological parameters by a magnetic separation technique in human beings during the administration of plague vaccine in relation to the immunological load revealed the higher blood levels of all T lymphocyte subpopulations on day 14 after vaccination. These changes are most typical of a primary vaccinated cohort. The increased frequency of plague vaccine administration and multiple immunizations with live plague, anthrax, and tularemia vaccines produce the time-course of changes in T lymphocyte populations (subpopulations) in response to the regular administration of plague vaccine. A high immunological load in man also promotes a significant reduction in the level of B lymphocytes.

  8. Functional properties of a metabotropic glutamate receptor at dendritic synapses of ON bipolar cells in the amphibian retina.

    Science.gov (United States)

    Tian, N; Slaughter, M M

    1995-01-01

    Perforated patch-voltage and current-clamp recordings were obtained from ON bipolar cells in the amphibian retinal slice preparation. The currents produced by the photoreceptor transmitter were compared to the currents produced by selective metabotropic glutamate agonists: L-2-amino-4-phosphonobutyrate (L-AP4, APB) and IS,3R 1-amino-1,3 cyclopentanedicarboxylic acid (1S, 3R ACPD). Both agonists produced currents that were very similar to that produced by the photoreceptor transmitter in terms of conductance and reversal potential. The similarities suggest that the metabotropic glutamate receptors are functionally localized to the synaptic region of ON bipolar dendrites. The synaptic conductance rarely exceeded the non-synaptic conductance. The mean input resistance of ON bipolar neurons was 770 M omega in the light and 1.2 G omega in the dark. The average light-regulated synaptic conductance was 57% of the non-synaptic conductance. The L-AP4 regulated conductance averaged 77% of the non-synaptic conductance, while the 1S, 3R ACPD regulated conductance averaged 95% of the non-synaptic conductance. This balance between synaptic and non-synaptic conductance indicates that the synapse will not shunt the cell and the conductance ratio serves to maximize incremental gain at the photoreceptor to ON bipolar synapse. This conductance mechanism makes the ON bipolar cell well equipped to relay rod signals.

  9. Associations of unilateral whisker and olfactory signals induce synapse formation and memory cell recruitment in bilateral barrel cortices: cellular mechanism for unilateral training toward bilateral memory

    Directory of Open Access Journals (Sweden)

    Zilong Gao

    2016-12-01

    Full Text Available Somatosensory signals and operative skills learned by unilateral limbs can be retrieved bilaterally. In terms of cellular mechanism underlying this unilateral learning toward bilateral memory, we hypothesized that associative memory cells in bilateral cortices and synapse innervations between them were produced. In the examination of this hypothesis, we have observed that paired unilateral whisker and odor stimulations led to odorant-induced whisker motions in bilateral sides, which were attenuated by inhibiting the activity of barrel cortices. In the mice that showed bilateral cross-modal responses, the neurons in both sides of barrel cortices became to encode this new odor signal alongside the innate whisker signal. Axon projections and synapse formations from the barrel cortex, which was co-activated with the piriform cortex, toward its contralateral barrel cortex were upregulated. Glutamatergic synaptic transmission in bilateral barrel cortices was upregulated and GABAergic synaptic transmission was downregulated. The associative activations of the sensory cortices facilitate new axon projection, glutamatergic synapse formation and GABAergic synapse downregulation, which drive the neurons to be recruited as associative memory cells in the bilateral cortices. Our data reveals the productions of associative memory cells and synapse innervations in bilateral sensory cortices for unilateral training toward bilateral memory.

  10. Visualization of HIV T Cell Virological Synapses and Virus-Containing Compartments by Three-Dimensional Correlative Light and Electron Microscopy

    Science.gov (United States)

    Wang, Lili; Eng, Edward T.; Law, Kenneth; Gordon, Ronald E.; Rice, William J.

    2016-01-01

    ABSTRACT Virological synapses (VS) are adhesive structures that form between infected and uninfected cells to enhance the spread of HIV-1. During T cell VS formation, viral proteins are actively recruited to the site of cell-cell contact where the viral material is efficiently translocated to target cells into heterogeneous, protease-resistant, antibody-inaccessible compartments. Using correlative light and electron microscopy (CLEM), we define the membrane topography of the virus-containing compartments (VCC) where HIV is found following VS-mediated transfer. Focused ion beam scanning electron microscopy (FIB-SEM) and serial sectioning transmission electron microscopy (SS-TEM) were used to better resolve the fluorescent Gag-containing structures within the VCC. We found that small punctate fluorescent signals correlated with single viral particles in enclosed vesicular compartments or surface-localized virus particles and that large fluorescent signals correlated with membranous Gag-containing structures with unknown pathological function. CLEM imaging revealed distinct pools of newly deposited viral proteins within endocytic and nonendocytic compartments in VS target T cells. IMPORTANCE This study directly correlates individual virus-associated objects observed in light microscopy with ultrastructural features seen by electron microscopy in the HIV-1 virological synapse. This approach elucidates which infection-associated ultrastructural features represent bona fide HIV protein complexes. We define the morphology of some HIV cell-to-cell transfer intermediates as true endocytic compartments and resolve unique synapse-associated viral structures created by transfer across virological synapses. PMID:27847357

  11. Cells containing aragonite crystals mediate responses to gravity in Trichoplax adhaerens (Placozoa), an animal lacking neurons and synapses.

    Science.gov (United States)

    Mayorova, Tatiana D; Smith, Carolyn L; Hammar, Katherine; Winters, Christine A; Pivovarova, Natalia B; Aronova, Maria A; Leapman, Richard D; Reese, Thomas S

    2018-01-01

    Trichoplax adhaerens has only six cell types. The function as well as the structure of crystal cells, the least numerous cell type, presented an enigma. Crystal cells are arrayed around the perimeter of the animal and each contains a birefringent crystal. Crystal cells resemble lithocytes in other animals so we looked for evidence they are gravity sensors. Confocal microscopy showed that their cup-shaped nuclei are oriented toward the edge of the animal, and that the crystal shifts downward under the influence of gravity. Some animals spontaneously lack crystal cells and these animals behaved differently upon being tilted vertically than animals with a typical number of crystal cells. EM revealed crystal cell contacts with fiber cells and epithelial cells but these contacts lacked features of synapses. EM spectroscopic analyses showed that crystals consist of the aragonite form of calcium carbonate. We thus provide behavioral evidence that Trichoplax are able to sense gravity, and that crystal cells are likely to be their gravity receptors. Moreover, because placozoans are thought to have evolved during Ediacaran or Cryogenian eras associated with aragonite seas, and their crystals are made of aragonite, they may have acquired gravity sensors during this early era.

  12. Sharp Ca²⁺ nanodomains beneath the ribbon promote highly synchronous multivesicular release at hair cell synapses.

    Science.gov (United States)

    Graydon, Cole W; Cho, Soyoun; Li, Geng-Lin; Kachar, Bechara; von Gersdorff, Henrique

    2011-11-16

    Hair cell ribbon synapses exhibit several distinguishing features. Structurally, a dense body, or ribbon, is anchored to the presynaptic membrane and tethers synaptic vesicles; functionally, neurotransmitter release is dominated by large EPSC events produced by seemingly synchronous multivesicular release. However, the specific role of the synaptic ribbon in promoting this form of release remains elusive. Using complete ultrastructural reconstructions and capacitance measurements of bullfrog amphibian papilla hair cells dialyzed with high concentrations of a slow Ca²⁺ buffer (10 mM EGTA), we found that the number of synaptic vesicles at the base of the ribbon correlated closely to those vesicles that released most rapidly and efficiently, while the rest of the ribbon-tethered vesicles correlated to a second, slower pool of vesicles. Combined with the persistence of multivesicular release in extreme Ca²⁺ buffering conditions (10 mM BAPTA), our data argue against the Ca²⁺-dependent compound fusion of ribbon-tethered vesicles at hair cell synapses. Moreover, during hair cell depolarization, our results suggest that elevated Ca²⁺ levels enhance vesicle pool replenishment rates. Finally, using Ca²⁺ diffusion simulations, we propose that the ribbon and its vesicles define a small cytoplasmic volume where Ca²⁺ buffer is saturated, despite 10 mM BAPTA conditions. This local buffer saturation permits fast and large Ca²⁺ rises near release sites beneath the synaptic ribbon that can trigger multiquantal EPSCs. We conclude that, by restricting the available presynaptic volume, the ribbon may be creating conditions for the synchronous release of a small cohort of docked vesicles.

  13. Regulatory T Cells in HIV-Infected Immunological Nonresponders Are Increased in Blood but Depleted in Lymphoid Tissue and Predict Immunological Reconstitution

    DEFF Research Database (Denmark)

    Gaardbo, Julie C; Hartling, Hans J; Ronit, Andreas

    2014-01-01

    BACKGROUND: HIV-infected immunological nonresponders fail to immune reconstitute despite optimal treatment. We hypothesized that regulatory T cells (Tregs) are involved in immunological reconstitution. Tregs and Treg subpopulations were measured in blood and Foxp3 cells in lymphoid tissue...... (CD4 T-cell count 200-500 cells/μL), 30 responders (CD4 T-cell count >500 cells/μL), and 34 healthy controls. Tregs, Treg subpopulations, and intracellular staining for interleukin 10 in peripheral blood were measured using flow cytometry. Foxp3 cells in lymphoid tissue were evaluated using...... immunolabeling. The CD4 T-cell count was determined at inclusion and after 1 year of follow-up. RESULTS: INR displayed high percentage of Tregs and activated Tregs in peripheral blood accompanied by a high percentage of Tregs expressing interleukin 10, whereas numbers of Foxp3 cells in lymphoid tissue were low...

  14. Immunologic analyses of mouse cystathionase in normal and leukemic cells

    International Nuclear Information System (INIS)

    Bikel, I.; Faibes, D.; Uren, J.R.; Livingston, D.M.

    1978-01-01

    Rabbit antisera have been raised against mouse liver cystathionase and shown to possess enzyme neutralizing activity. Agar gel double immunodiffusion analyses demonstrated that both mouse liver cystathionase and rat liver cystathionase react with the antisera, the latter enzyme being completely cross-reactive with the former. Following radioiodination of the purified rat liver enzyme, a double antibody radioimmunoassay was developed in which greater than 90% of the labeled protein could be specifically precipitated with the anti-mouse cystathionase antibodies. In this test the purified rat liver and mouse liver enzymes were virtually indistinguishable, generating superimposable competition displacement curves on a protein mass basis. These results indicate that both enzymes are immunologically identical, thus validating the use of the rat in lieu of the murine liver enzyme as radiolabeled tracer in an assay for mouse cystathionase. In addition, competition radioimmunoassays demonstrated that the immunological reactivities of both the purified rat liver and mouse liver enzymes were equally heat sensitive. The sensitivity of the assay was determined to be 1 ng of enzyme protein/0.22 mL of assay mixture, and the assay could be used to detect the presence of enzyme protein in tissue homogenates of single mouse organs. Mouse or rat cross-reactivity with human liver cystathionase was incomplete; but, with the exception of heart and spleen, parallel radioimmunoassay competition displacement curves were obtained for cystathionase from different mouse organs including thymus. Extracts of 7-, 9-, and 10-month-old spontaneous AKR mouse thymomas were tested in the radioimmunoassay along with extracts of age-matched thymuses which were grossly tumor free. A reaction of nonidentity was observed for all of the tumor extracts while a reaction identical with that of the pure liver enzyme was found with all of the normal thymus extracts

  15. Sniff-Like Patterned Input Results in Long-Term Plasticity at the Rat Olfactory Bulb Mitral and Tufted Cell to Granule Cell Synapse

    Directory of Open Access Journals (Sweden)

    Mahua Chatterjee

    2016-01-01

    Full Text Available During odor sensing the activity of principal neurons of the mammalian olfactory bulb, the mitral and tufted cells (MTCs, occurs in repetitive bursts that are synchronized to respiration, reminiscent of hippocampal theta-gamma coupling. Axonless granule cells (GCs mediate self- and lateral inhibitory interactions between the excitatory MTCs via reciprocal dendrodendritic synapses. We have explored long-term plasticity at this synapse by using a theta burst stimulation (TBS protocol and variations thereof. GCs were excited via glomerular stimulation in acute brain slices. We find that TBS induces exclusively long-term depression in the majority of experiments, whereas single bursts (“single-sniff paradigm” can elicit both long-term potentiation and depression. Statistical analysis predicts that the mechanism underlying this bidirectional plasticity involves the proportional addition or removal of presynaptic release sites. Gamma stimulation with the same number of APs as in TBS was less efficient in inducing plasticity. Both TBS- and “single-sniff paradigm”-induced plasticity depend on NMDA receptor activation. Since the onset of plasticity is very rapid and requires little extra activity, we propose that these forms of plasticity might play a role already during an ongoing search for odor sources. Our results imply that components of both short-term and long-term olfactory memory may be encoded at this synapse.

  16. The number and distribution of AMPA receptor channels containing fast kinetic GluA3 and GluA4 subunits at auditory nerve synapses depend on the target cells.

    Science.gov (United States)

    Rubio, María E; Matsui, Ko; Fukazawa, Yugo; Kamasawa, Naomi; Harada, Harumi; Itakura, Makoto; Molnár, Elek; Abe, Manabu; Sakimura, Kenji; Shigemoto, Ryuichi

    2017-11-01

    The neurotransmitter receptor subtype, number, density, and distribution relative to the location of transmitter release sites are key determinants of signal transmission. AMPA-type ionotropic glutamate receptors (AMPARs) containing GluA3 and GluA4 subunits are prominently expressed in subsets of neurons capable of firing action potentials at high frequencies, such as auditory relay neurons. The auditory nerve (AN) forms glutamatergic synapses on two types of relay neurons, bushy cells (BCs) and fusiform cells (FCs) of the cochlear nucleus. AN-BC and AN-FC synapses have distinct kinetics; thus, we investigated whether the number, density, and localization of GluA3 and GluA4 subunits in these synapses are differentially organized using quantitative freeze-fracture replica immunogold labeling. We identify a positive correlation between the number of AMPARs and the size of AN-BC and AN-FC synapses. Both types of AN synapses have similar numbers of AMPARs; however, the AN-BC have a higher density of AMPARs than AN-FC synapses, because the AN-BC synapses are smaller. A higher number and density of GluA3 subunits are observed at AN-BC synapses, whereas a higher number and density of GluA4 subunits are observed at AN-FC synapses. The intrasynaptic distribution of immunogold labeling revealed that AMPAR subunits, particularly GluA3, are concentrated at the center of the AN-BC synapses. The central distribution of AMPARs is absent in GluA3-knockout mice, and gold particles are evenly distributed along the postsynaptic density. GluA4 gold labeling was homogenously distributed along both synapse types. Thus, GluA3 and GluA4 subunits are distributed at AN synapses in a target-cell-dependent manner.

  17. Tumor Immunology meets…Immunology: Modified cancer cells as professional APC for priming naïve tumor-specific CD4+ T cells.

    Science.gov (United States)

    Bou Nasser Eddine, Farah; Ramia, Elise; Tosi, Giovanna; Forlani, Greta; Accolla, Roberto S

    2017-01-01

    Although recent therapeutic approaches have revitalized the enthusiasm of the immunological way to combat cancer, still the comprehension of immunity against tumors is largely incomplete. Due to their specific function, CD8+ T cells with cytolytic activity (CTL) have attracted the attention of most investigators because CTL are considered the main effectors against tumor cells. Nevertheless, CTL activity and persistence is largely dependent on the action of CD4+ T helper cells (TH). Thus establishment of tumor-specific TH cell response is key to the optimal response against cancer. Here we describe emerging new strategies to increase the TH cell recognition of tumor antigens. In particular, we review recent data indicating that tumor cells themselves can act as surrogate antigen presenting cells for triggering TH response and how these findings can help in constructing immunotherapeutic protocols for anti-cancer vaccine development.

  18. T cell uptake for the use of boron neutron capture as an immunologic research tool

    Energy Technology Data Exchange (ETDEWEB)

    Binello, E. E-mail: ebinello@mit.edu; Mitchell, R.N.; Harling, O.K

    2004-11-01

    An immunologic tool based on manipulation of the boron neutron capture reaction was previously proposed in the context of heart transplantation research to examine the temporal relationship between parenchymal rejection (representing immune cell infiltration) and transplantation-associated arteriosclerosis (characterized by progressive vascular occlusion). Critical to the development of this method is the uptake of boron by specific cells of the immune system, namely T cells, without adverse effects on cell function, which may be assessed by the ability of boron-loaded cells to produce IFN{gamma}, a protein with substantial impact on rejection. This work presents the evaluation of two carboranyl thymidine analogs. Advantages of this type of boron compound are reduced risk of leakage and effective dose delivery based on their incorporation into cellular nuclear material. Results indicate that uptake of these boronated nucleosides is high with no adverse effects on cell function, thereby warranting the continued development of this technique that has potentially wide applicability in immunological models.

  19. Innate immunological function of TH2 cells in vivo

    Science.gov (United States)

    Th2 cells produce IL-13 when stimulated by papain or house dust mites (HDM) and induce eosinophilic inflammation. This innate response of cells of the adaptive immune system is dependent on IL-33-, not T cell receptor-, based stimulation. While type 2 innate lymphoid cells (ILC2s) are the dominant ...

  20. Tumor Immunology and Immunotherapy for Head and Neck Squamous Cell Carcinoma.

    Science.gov (United States)

    Moskovitz, J M; Ferris, R L

    2018-02-01

    The immune system plays an important role in the evolution of malignancy and has become an important target for novel antineoplastic agents. This review article focuses on key features of tumor immunology, including the role of immunotherapy in general and as it pertains to head and neck squamous cell carcinoma. Side effects, resistance mechanisms, and therapeutic monitoring strategies pertaining to immunotherapy are discussed.

  1. Immunologic targeting of FOXP3 in inflammatory breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Smita Nair

    Full Text Available The forkhead transcription factor FOXP3 is necessary for induction of regulatory T lymphocytes (Tregs and their immunosuppressive function. We have previously demonstrated that targeting Tregs by vaccination of mice with murine FOXP3 mRNA-transfected dendritic cells (DCs elicits FOXP3-specific T cell responses and enhances tumor immunity. It is clear that FOXP3 expression is not restricted to T-cell lineage and herein, using RT-PCR, flow cytometry, and western immunoblot we demonstrate for the first time that FOXP3 is expressed in inflammatory breast cancer (IBC cells, SUM149 (triple negative, ErbB1-activated and SUM190 (ErbB2-overexpressing. Importantly, FOXP3-specific T cells generated in vitro using human FOXP3 RNA-transfected DCs as stimulators efficiently lyse SUM149 cells. Interestingly, an isogenic model (rSUM149 derived from SUM149 with an enhanced anti-apoptotic phenotype was resistant to FOXP3-specific T cell mediated lysis. The MHC class I cellular processing mechanism was intact in both cell lines at the protein and transcription levels suggesting that the resistance to cytolysis by rSUM149 cells was not related to MHC class I expression or to the MHC class I antigen processing machinery in these cells. Our data suggest that FOXP3 may be an effective tumor target in IBC cells however increased anti-apoptotic signaling can lead to immune evasion.

  2. Immunologic glycosphingolipidomics and NKT cell development in mouse thymus

    DEFF Research Database (Denmark)

    Li, Yunsen; Thapa, Prakash; Hawke, David

    2009-01-01

    Invariant NKT cells are a hybrid cell type of Natural Killer cells and T cells, whose development is dependent on thymic positive selection mediated by double positive thymocytes through their recognition of natural ligands presented by CD1d, a nonpolymorphic, non-MHC, MHC-like antigen presenting...... molecule. Genetic evidence suggested that beta-glucosylceramide derived glycosphingolipids (GSLs) are natural ligands for NKT cells. N-butyldeoxygalactonojirimycin (NB-DGJ), a drug that specifically inhibits the glucosylceramide synthase, inhibits the endogenous ligands for NKT cells. Furthermore, we...... in mouse thymus, which are specifically regulated by rate-limiting glycosidases. Among the identified thymic glycosphingolipids, only iGb3 is a stimulatory ligand for NKT cells, suggesting that large-scale fractionation, enrichment and characterization of minor species of glycosphingolipids are necessary...

  3. Retinal afferents synapse with relay cells targeting the middle temporal area in the pulvinar and lateral geniculate nuclei

    Directory of Open Access Journals (Sweden)

    Claire E Warner

    2010-02-01

    Full Text Available Considerable debate continues regarding thalamic inputs to the middle temporal area (MT of the visual cortex that bypass the primary visual cortex (V1 and the role they might have in the residual visual capability following a lesion of V1. Two specific retinothalamic projections to area MT have been speculated to relay through the medial portion of the inferior pulvinar nucleus (PIm and the koniocellular layers of the dorsal lateral geniculate nucleus (LGN. Although a number of studies have demonstrated retinal inputs to regions of the thalamus where relays to area MT have been observed, the relationship between the retinal terminals and area MT relay cells has not been established. Here we examined direct retino-recipient regions of the marmoset monkey (Callithrix jacchus pulvinar nucleus and the LGN following binocular injections of anterograde tracer, as well as area MT relay cells in these nuclei by injection of retrograde tracer into area MT. Retinal afferents were shown to synapse with area MT relay cells as demonstrated by colocalization with the presynaptic vesicle membrane protein synaptophysin. We also established the presence of direct synapes of retinal afferents on area MT relay cells within the PIm, as well as the koniocellular K1 and K3 layers of the LGN, thereby corroborating the existence of two disynaptic pathways from the retina to area MT that bypass V1.

  4. Single-Cell Genomics: A Stepping Stone for Future Immunology Discoveries.

    Science.gov (United States)

    Giladi, Amir; Amit, Ido

    2018-01-11

    The immunology field has invested great efforts and ingenuity to characterize the various immune cell types and elucidate their functions. However, accumulating evidence indicates that current technologies and classification schemes are limited in their ability to account for the functional heterogeneity of immune processes. Single-cell genomics hold the potential to revolutionize the way we characterize complex immune cell assemblies and study their spatial organization, dynamics, clonal distribution, pathways, function, and crosstalks. In this Perspective, we consider recent and forthcoming technological and analytical advances in single-cell genomics and the potential impact of those advances on the future of immunology research and immunotherapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Targeting CD28, CTLA-4 and PD-L1 costimulation differentially controls immune synapses and function of human regulatory and conventional T-cells.

    Directory of Open Access Journals (Sweden)

    Nahzli Dilek

    Full Text Available CD28, CTLA-4 and PD-L1, the three identified ligands for CD80/86, are pivotal positive and negative costimulatory molecules that, among other functions, control T cell motility and formation of immune synapse between T cells and antigen-presenting cells (APCs. What remains incompletely understood is how CD28 leads to the activation of effector T cells (Teff but inhibition of suppression by regulatory T cells (Tregs, while CTLA-4 and PD-L1 inhibit Teff function but are crucial for the suppressive function of Tregs. Using alloreactive human T cells and blocking antibodies, we show here by live cell dynamic microscopy that CD28, CTLA-4, and PD-L1 differentially control velocity, motility and immune synapse formation in activated Teff versus Tregs. Selectively antagonizing CD28 costimulation increased Treg dwell time with APCs and induced calcium mobilization which translated in increased Treg suppressive activity, in contrast with the dampening effect on Teff responses. The increase in Treg suppressive activity after CD28 blockade was also confirmed with polyclonal Tregs. Whereas CTLA-4 played a critical role in Teff by reversing TCR-induced STOP signals, it failed to affect motility in Tregs but was essential for formation of the Treg immune synapse. Furthermore, we identified a novel role for PD-L1-CD80 interactions in suppressing motility specifically in Tregs. Thus, our findings reveal that the three identified ligands of CD80/86, CD28, CTLA-4 and PD-L1, differentially control immune synapse formation and function of the human Teff and Treg cells analyzed here. Individually targeting CD28, CTLA-4 and PD-L1 might therefore represent a valuable therapeutic strategy to treat immune disorders where effector and regulatory T cell functions need to be differentially targeted.

  6. Synthetic Immunology: Hacking Immune Cells to Expand Their Therapeutic Capabilities.

    Science.gov (United States)

    Roybal, Kole T; Lim, Wendell A

    2017-04-26

    The ability of immune cells to survey tissues and sense pathologic insults and deviations makes them a unique platform for interfacing with the body and disease. With the rapid advancement of synthetic biology, we can now engineer and equip immune cells with new sensors and controllable therapeutic response programs to sense and treat diseases that our natural immune system cannot normally handle. Here we review the current state of engineered immune cell therapeutics and their unique capabilities compared to small molecules and biologics. We then discuss how engineered immune cells are being designed to combat cancer, focusing on how new synthetic biology tools are providing potential ways to overcome the major roadblocks for treatment. Finally, we give a long-term vision for the use of synthetic biology to engineer immune cells as a general sensor-response platform to precisely detect disease, to remodel disease microenvironments, and to treat a potentially wide range of challenging diseases.

  7. Tumor immunology

    International Nuclear Information System (INIS)

    Otter, W. den

    1987-01-01

    Tumor immunology, the use of immunological techniques for tumor diagnosis and approaches to immunotherapy of cancer are topics covered in this multi-author volume. Part A, 'Tumor Immunology', deals with present views on tumor-associated antigens, the initiation of immune reactions of tumor cells, effector cell killing, tumor cells and suppression of antitumor immunity, and one chapter dealing with the application of mathematical models in tumor immunology. Part B, 'Tumor Diagnosis and Imaging', concerns the use of markers to locate the tumor in vivo, for the histological diagnosis, and for the monitoring of tumor growth. In Part C, 'Immunotherapy', various experimental approaches to immunotherapy are described, such as the use of monoclonal antibodies to target drugs, the use of interleukin-2 and the use of drugs inhibiting suppression. In the final section, the evaluation, a pathologist and a clinician evaluate the possibilities and limitations of tumor immunology and the extent to which it is useful for diagnosis and therapy. refs.; figs.; tabs

  8. The sticky synapse

    DEFF Research Database (Denmark)

    Owczarek, Sylwia Elzbieta; Kristiansen, Lars Villiam; Hortsch, Michael

    NCAM-type proteins modulate multiple neuronal functions, including the outgrowth and guidance of neurites, the formation, maturation, and plasticity of synapses, and the induction of both long-term potentiation and long-term depression. The ectodomains of NCAM proteins have a basic structure...... signal transduction. A central feature of the synaptic function of NCAM proteins is the regulation of their extracellular interactions by adhesion-modulating glycoepitopes, their removal from the cell surface by endocytosis, and the elimination of their adhesion-mediating interactions by the proteolytic...

  9. Characterization of lymphoid cells in the blood of healthy adults: sequential immunological, cytochemical and cytokinetic studies

    International Nuclear Information System (INIS)

    Hirt, A.; Wagner, H.P.

    1980-01-01

    With a new method, sequential immunological, cytochemical and cytokinetic studies were done on lymphoid cells in the peripheral blood of 12 healthy adults. Every single lymphoid cell could therefore be characterized by the following markers: surface immunoglobulins (sIg); rosetting with sheep red blood cells (E); unspecific acid alpha-naphthyl acetate esterase (ANAE); and 3HdT incorporation. Significantly more E+sIg-ANAE-cells (51% and 22% of all lymphoid cells, respectively). Of all ANAE+ cells 90% were E+, but 64% of all ANAE- cells were also E+. In all individuals a subpopulation of E+sIg+ cells was found. The esterase pattern of these cells was similar to that of E-sIg+ cells. The overall labeling index of the lymphoid cells examined was less than or equal to 0.2%

  10. Biology and immunology of cancer stem(-like) cells in head and neck cancer.

    Science.gov (United States)

    Qian, Xu; Ma, Chenming; Nie, Xiaobo; Lu, Jianxin; Lenarz, Minoo; Kaufmann, Andreas M; Albers, Andreas E

    2015-09-01

    Immunological approaches against tumors including head and neck squamous cell carcinoma (HNSCC) have been investigated for about 50 years. Such immunotherapeutic treatments are still not sufficiently effective for therapy of HNSCC. Despite the existence of immunosurveillance tumor cells may escape from the host immune system by a variety of mechanisms. Recent findings have indicated that cancer stem(-like) cells (CSCs) in HNSCC have the ability to reconstitute the heterogeneity of the bulk tumor and contribute to immunosuppression and resistance to current therapies. With regard to the CSC model, future immunotherapy possibly in combination with other modes of treatment should target this subpopulation specifically to reduce local recurrence and metastasis. In this review, we will summarize recent research findings on immunological features of CSCs and the potential of immune targeting of CSCs. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  11. From cell biology to immunology: Controlling metastatic progression of cancer via microRNA regulatory networks.

    Science.gov (United States)

    Park, Jae Hyon; Theodoratou, Evropi; Calin, George A; Shin, Jae Il

    2016-01-01

    Recently, the study of microRNAs has expanded our knowledge of the fundamental processes of cancer biology and the underlying mechanisms behind tumor metastasis. Extensive research in the fields of microRNA and its novel mechanisms of actions against various cancers has more recently led to the trial of a first cancer-targeted microRNA drug, MRX34. Yet, these microRNAs are mostly being studied and clinically trialed solely based on the understanding of their cell biologic effects, thus, neglecting the important immunologic effects that are sometimes opposite of the cell biologic effects. Here, we summarize both the cell biologic and immunologic effects of various microRNAs and discuss the importance of considering both effects before using them in clinical settings. We stress the importance of understanding the miRNA's effect on cancer metastasis from a "systems" perspective before developing a miRNA-targeted therapeutic in treating cancer metastasis.

  12. Developmental Hypothyroxinemia and Hypothyroidism Reduce Parallel Fiber-Purkinje Cell Synapses in Rat Offspring by Downregulation of Neurexin1/Cbln1/GluD2 Tripartite Complex.

    Science.gov (United States)

    Wang, Yuan; Dong, Jing; Wang, Yi; Wei, Wei; Song, Binbin; Shan, Zhongyan; Teng, Weiping; Chen, Jie

    2016-10-01

    Iodine is a significant micronutrient. Iodine deficiency (ID)-induced hypothyroxinemia and hypothyroidism during developmental period can cause cerebellar dysfunction. However, mechanisms are still unclear. Therefore, the present research aims to study effects of developmental hypothyroxinemia caused by mild ID and hypothyroidism caused by severe ID or methimazole (MMZ) on parallel fiber-Purkinje cell (PF-PC) synapses in filial cerebellum. Maternal hypothyroxinemia and hypothyroidism models were established in Wistar rats using ID diet and deionized water supplemented with different concentrations of potassium iodide or MMZ water. Birth weight and cerebellum weight were measured. We also examined PF-PC synapses using immunofluorescence, and western blot analysis was conducted to investigate the activity of Neurexin1/cerebellin1 (Cbln1)/glutamate receptor d2 (GluD2) tripartite complex. Our results showed that hypothyroxinemia and hypothyroidism decreased birth weight and cerebellum weight and reduced the PF-PC synapses on postnatal day (PN) 14 and PN21. Accordingly, the mean intensity of vesicular glutamate transporter (VGluT1) and Calbindin immunofluorescence was reduced in mild ID, severe ID, and MMZ groups. Moreover, maternal hypothyroxinemia and hypothyroidism reduced expression of Neurexin1/Cbln1/GluD2 tripartite complex. Our study supports the hypothesis that developmental hypothyroxinemia and hypothyroidism reduce PF-PC synapses, which may be attributed to the downregulation of Neurexin1/Cbln1/GluD2 tripartite complex.

  13. Allergy-immunology glossary

    African Journals Online (AJOL)

    ahmed

    Allergy-immunology glossary. Zeinab A. El-Sayed, Nesrine Radwan. Pediatric Allergy and Immunology Unit, Children's Hospital, Ain-Shams University. Towards a clear designation of some of the terms used in allergology and immunology. Natural killer (NK) cells. NK cells account for up to 15% of peripheral blood.

  14. Designing bovine T-cell vaccines via reverse immunology

    Science.gov (United States)

    T-cell responses contribute to immunity against many intra-cellular infections. There is, for example, strong evidence that major histocompatibility complex (MHC) class I restricted cytotoxic T lymphocytes (CTLs) play an essential role in mediating immunity to East Coast fever (ECF), a fatal lymphop...

  15. Designing bovine T cell vaccines via reverse immunology

    DEFF Research Database (Denmark)

    Nene, Vishvanath; Svitek, Nicholas; Toye, Philip

    2012-01-01

    by experimental verification of T cell specificity to candidate epitopes using peptide–MHC (pMHC) tetramers. This system, adapted from human and rodent studies, is in the process of being developed for cattle. Briefly, we have used an artificial neural network called NetMHCpan, which has been trained mainly...

  16. Glycan Markers as Potential Immunological Targets in Circulating Tumor Cells.

    Science.gov (United States)

    Wang, Denong; Wu, Lisa; Liu, Xiaohe

    2017-01-01

    We present here an experimental approach for exploring a new class of tumor biomarkers that are overexpressed by circulating tumor cells (CTCs) and are likely targetable in immunotherapy against tumor metastasis. Using carbohydrate microarrays, anti-tumor monoclonal antibodies (mAbs) were scanned against a large panel of carbohydrate antigens to identify potential tumor glycan markers. Subsequently, flow cytometry and fiber-optic array scanning technology (FAST) were applied to determine whether the identified targets are tumor-specific cell-surface markers and are, therefore, likely suitable for targeted immunotherapy. Finally, the tumor glycan-specific antibodies identified were validated using cancer patients' blood samples for their performance in CTC-detection and immunotyping analysis. In this article, identifying breast CTC-specific glycan markers and targeting mAbs serve as examples to illustrate this tumor biomarker discovery strategy.

  17. Immunology of oligodendrocyte precursor cells in vivo and in vitro.

    Science.gov (United States)

    Antel, Jack P; Lin, Yun Hsuan; Cui, Qiao-Ling; Pernin, Florian; Kennedy, Timothy E; Ludwin, Samuel K; Healy, Luke M

    2018-03-13

    Remyelination following myelin/oligodendrocyte injury in the central nervous system (CNS) is dependent on oligodendrocyte progenitor cells (OPCs) migrating into lesion sites, differentiating into myelinating oligodendrocytes (OLs), and ensheathing axons. Experimental models indicate that robust OPC-dependent remyelination can occur in the CNS; in contrast, histologic and imaging studies of lesions in the human disease multiple sclerosis (MS) indicate the variable extent of this response, which is particularly limited in more chronic MS lesions. Immune-mediated mechanisms can contribute either positively or negatively to the presence and functional responses of OPCs. This review addresses i) the molecular signature and functional properties of OPCs in the adult human brain; ii) the status (presence and function) of OPCs in MS lesions; iii) experimental models and in vitro data highlighting the contribution of adaptive and innate immune constituents to OPC injury and remyelination; and iv) effects of MS-directed immunotherapies on OPCs, either directly or indirectly via effects on specific immune constituents. Copyright © 2018. Published by Elsevier B.V.

  18. Effect of UV-irradiation on immunological and histochemical markers of Langerhans cells in normal appearing skin of psoriatic patients

    International Nuclear Information System (INIS)

    Tjernlund, U.; Juhlin, L.

    1982-01-01

    A total of 12 patients with moderately severe psoriasis was treated with psoralen baths and/or ultraviolet radiation. Punch biopsies were taken for mimunological markers and shave biopsies for ATPase detection. As immunological marker immunosorbent purified antibodies against Ia antigens and monoclonal antigens against thymocyte antigens were used. The study showed that in the clinical relevant situation PUVA treatment had a more profound effect on the immunological markers of epidermal Langerhans cells than had light treatment without psoralens. With UV treatment without psoralens the ATPase activity of the Langerhans cells seemed to be more influenced than the immunological markers. (orig.)

  19. Invaginating Structures in Mammalian Synapses

    Science.gov (United States)

    Petralia, Ronald S.; Wang, Ya-Xian; Mattson, Mark P.; Yao, Pamela J.

    2018-01-01

    Invaginating structures at chemical synapses in the mammalian nervous system exist in presynaptic axon terminals, postsynaptic spines or dendrites, and glial processes. These invaginating structures can be divided into three categories. The first category includes slender protrusions invaginating into axonal terminals, postsynaptic spines, or glial processes. Best known examples of this category are spinules extending from postsynaptic spines into presynaptic terminals in forebrain synapses. Another example of this category are protrusions from inhibitory presynaptic terminals invaginating into postsynaptic neuronal somas. Regardless of the direction and location, the invaginating structures of the first category do not have synaptic active zones within the invagination. The second category includes postsynaptic spines invaginating into presynaptic terminals, whereas the third category includes presynaptic terminals invaginating into postsynaptic spines or dendrites. Unlike the first category, the second and third categories have active zones within the invagination. An example of the second category are mossy terminal synapses of the hippocampal CA3 region, in which enlarged spine-like structures invaginate partly or entirely into mossy terminals. An example of the third category is the neuromuscular junction (NMJ) where substantial invaginations of the presynaptic terminals invaginate into the muscle fibers. In the retina, rod and cone synapses have invaginating processes from horizontal and bipolar cells. Because horizontal cells act both as post and presynaptic structures, their invaginating processes represent both the second and third category. These invaginating structures likely play broad yet specialized roles in modulating neuronal cell signaling.

  20. Harnessing the properties of dendritic cells in the pursuit of immunological tolerance

    Directory of Open Access Journals (Sweden)

    Christopher Horton

    2017-04-01

    Full Text Available The acquisition of self-perpetuating, immunological tolerance specific for graft alloantigens has long been described as the “holy grail” of clinical transplantation. By removing the need for life-long immunosuppression following engraftment, the adverse consequences of immunosuppressive regimens, including chronic infections and malignancy, may be avoided. Furthermore, autoimmune diseases and allergy are, by definition, driven by aberrant immunological responses to ordinarily innocuous antigens. The re-establishment of permanent tolerance towards instigating antigens may, therefore, provide a cure to these common diseases. Whilst various cell types exhibiting a tolerogenic phenotype have been proposed for such a task, tolerogenic dendritic cells (tol-DCs are exquisitely adapted for antigen presentation and interact with many facets of the immune system: as such, they are attractive candidates for use in strategies for immune intervention. We review here our current understanding of tol-DC mediated induction and maintenance of immunological tolerance. Additionally, we discuss recent in vitro findings from animal models and clinical trials of tol-DC immunotherapy in the setting of transplantation, autoimmunity and allergy which highlight their promising therapeutic potential, and speculate how tol-DC therapy may be developed in the future.

  1. Organization of central synapses by adhesion molecules.

    Science.gov (United States)

    Tallafuss, Alexandra; Constable, John R L; Washbourne, Philip

    2010-07-01

    Synapses are the primary means for transmitting information from one neuron to the next. They are formed during the development of the nervous system, and the formation of appropriate synapses is crucial for the establishment of neuronal circuits that underlie behavior and cognition. Understanding how synapses form and are maintained will allow us to address developmental disorders such as autism, mental retardation and possibly also psychological disorders. A number of biochemical and proteomic studies have revealed a diverse and vast assortment of molecules that are present at the synapse. It is now important to untangle this large array of proteins and determine how it assembles into a functioning unit. Here we focus on recent reports describing how synaptic cell adhesion molecules interact with and organize the presynaptic and postsynaptic specializations of both excitatory and inhibitory central synapses. © The Authors (2010). Journal Compilation © Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  2. Effect of conductance linearity and multi-level cell characteristics of TaOx-based synapse device on pattern recognition accuracy of neuromorphic system

    Science.gov (United States)

    Sung, Changhyuck; Lim, Seokjae; Kim, Hyungjun; Kim, Taesu; Moon, Kibong; Song, Jeonghwan; Kim, Jae-Joon; Hwang, Hyunsang

    2018-03-01

    To improve the classification accuracy of an image data set (CIFAR-10) by using analog input voltage, synapse devices with excellent conductance linearity (CL) and multi-level cell (MLC) characteristics are required. We analyze the CL and MLC characteristics of TaOx-based filamentary resistive random access memory (RRAM) to implement the synapse device in neural network hardware. Our findings show that the number of oxygen vacancies in the filament constriction region of the RRAM directly controls the CL and MLC characteristics. By adopting a Ta electrode (instead of Ti) and the hot-forming step, we could form a dense conductive filament. As a result, a wide range of conductance levels with CL is achieved and significantly improved image classification accuracy is confirmed.

  3. Loss of GPRC5B impairs synapse formation of Purkinje cells with cerebellar nuclear neurons and disrupts cerebellar synaptic plasticity and motor learning.

    Science.gov (United States)

    Sano, Takamitsu; Kohyama-Koganeya, Ayako; Kinoshita, Masami O; Tatsukawa, Tetsuya; Shimizu, Chika; Oshima, Eriko; Yamada, Kazuyuki; Le, Tung Dinh; Akagi, Takumi; Tohyama, Koujiro; Nagao, Soichi; Hirabayashi, Yoshio

    2018-02-23

    GPRC5B is a membrane glycoprotein robustly expressed in mouse cerebellar Purkinje cells (PCs). Its function is unknown. In Gprc5b -/- mice that lack GPRC5B, PCs develop distal axonal swellings in deep cerebellar nuclei (DCN). Numerous misshapen mitochondria, which generated excessive amounts of reactive oxygen species (ROS), accumulated in these distal axonal swellings. In primary cell cultures of Gprc5b -/- PCs, pharmacological reduction of ROS prevented the appearance of such swellings. To examine the physiological role of GPRC5B in PCs, we analyzed cerebellar synaptic transmission and cerebellum-dependent motor learning in Gprc5b -/- mice. Patch-clamp recordings in cerebellum slices in vitro revealed that the induction of long-term depression (LTD) at parallel fiber-PC synapses was normal in adult Gprc5b -/- mice, whereas the induction of long-term potentiation (LTP) at mossy fiber-DCN neuron synapses was attenuated in juvenile Gprc5b -/- mice. In Gprc5b -/- mice, long-term motor learning was impaired in both the rotarod test and the horizontal optokinetic response eye movement (HOKR) test. These observations suggest that GPRC5B plays not only an important role in the development of distal axons of PCs and formation of synapses with DCN neurons, but also in the synaptic plasticity that underlies long-term motor learning. Copyright © 2018 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.

  4. A Combined Nutritional and Immunological Intervention to Activate Natural Cytotoxicity Against Breast Cancer Cells In Vitro and In Vivo

    Science.gov (United States)

    2008-07-01

    intervention to activate natural cytotoxicity against breast cancer cells in vitro and in vivo PRINCIPAL...NUMBER activate natural cytotoxicity against breast cancer cells in vitro and in vivo 5b. GRANT NUMBER W81XWH-07-1-0478 5c. PROGRAM ELEMENT...TERMS Breast cancer cells ; immunological activation; retinoic acid; natural killer T cells; 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF

  5. Immunological approaches to plant cell wall and biomass characterization: Glycome Profiling.

    Science.gov (United States)

    Pattathil, Sivakumar; Avci, Utku; Miller, Jeffrey S; Hahn, Michael G

    2012-01-01

    The native complexity of plant cell walls makes research on them challenging. Hence, it is advantageous to have a diversity of tools that can be used to analyze and characterize plant cell walls. In this chapter, we describe one of two immunological approaches that can be employed for screening of plant cell wall/biomass materials from diverse plants and tissues. This approach, Glycome Profiling, lends itself well to moderate to high-throughput screening of plant cell wall/biomass samples. Glycome Profiling is being further optimized to reduce the amount of sample required for the analysis, and to improve the sensitivity and throughput of the assay. We are optimistic that Glycome Profiling will prove to be a broadly applicable experimental approach that will find increasing application to a wide variety of studies on plant cell wall/biomass samples.

  6. Fine processes of Nestin-GFP-positive radial glia-like stem cells in the adult dentate gyrus ensheathe local synapses and vasculature.

    Science.gov (United States)

    Moss, Jonathan; Gebara, Elias; Bushong, Eric A; Sánchez-Pascual, Irene; O'Laoi, Ruadhan; El M'Ghari, Imane; Kocher-Braissant, Jacqueline; Ellisman, Mark H; Toni, Nicolas

    2016-05-03

    Adult hippocampal neurogenesis relies on the activation of neural stem cells in the dentate gyrus, their division, and differentiation of their progeny into mature granule neurons. The complex morphology of radial glia-like (RGL) stem cells suggests that these cells establish numerous contacts with the cellular components of the neurogenic niche that may play a crucial role in the regulation of RGL stem cell activity. However, the morphology of RGL stem cells remains poorly described. Here, we used light microscopy and electron microscopy to examine Nestin-GFP transgenic mice and provide a detailed ultrastructural reconstruction analysis of Nestin-GFP-positive RGL cells of the dentate gyrus. We show that their primary processes follow a tortuous path from the subgranular zone through the granule cell layer and ensheathe local synapses and vasculature in the inner molecular layer. They share the ensheathing of synapses and vasculature with astrocytic processes and adhere to the adjacent processes of astrocytes. This extensive interaction of processes with their local environment could allow them to be uniquely receptive to signals from local neurons, glia, and vasculature, which may regulate their fate.

  7. Fine processes of Nestin-GFP–positive radial glia-like stem cells in the adult dentate gyrus ensheathe local synapses and vasculature

    Science.gov (United States)

    Moss, Jonathan; Gebara, Elias; Sánchez-Pascual, Irene; O’Laoi, Ruadhan; El M’Ghari, Imane; Kocher-Braissant, Jacqueline; Ellisman, Mark H.; Toni, Nicolas

    2016-01-01

    Adult hippocampal neurogenesis relies on the activation of neural stem cells in the dentate gyrus, their division, and differentiation of their progeny into mature granule neurons. The complex morphology of radial glia-like (RGL) stem cells suggests that these cells establish numerous contacts with the cellular components of the neurogenic niche that may play a crucial role in the regulation of RGL stem cell activity. However, the morphology of RGL stem cells remains poorly described. Here, we used light microscopy and electron microscopy to examine Nestin-GFP transgenic mice and provide a detailed ultrastructural reconstruction analysis of Nestin-GFP–positive RGL cells of the dentate gyrus. We show that their primary processes follow a tortuous path from the subgranular zone through the granule cell layer and ensheathe local synapses and vasculature in the inner molecular layer. They share the ensheathing of synapses and vasculature with astrocytic processes and adhere to the adjacent processes of astrocytes. This extensive interaction of processes with their local environment could allow them to be uniquely receptive to signals from local neurons, glia, and vasculature, which may regulate their fate. PMID:27091993

  8. Muscarinic acetylcholine receptor activation blocks long-term potentiation at cerebellar parallel fiber–Purkinje cell synapses via cannabinoid signaling

    Science.gov (United States)

    Rinaldo, Lorenzo; Hansel, Christian

    2013-01-01

    Muscarinic acetylcholine receptors (mAChRs) are known to modulate synaptic plasticity in various brain areas. A signaling pathway triggered by mAChR activation is the production and release of endocannabinoids that bind to type 1 cannabinoid receptors (CB1R) located on synaptic terminals. Using whole-cell patch-clamp recordings from rat cerebellar slices, we have demonstrated that the muscarinic agonist oxotremorine-m (oxo-m) blocks the induction of presynaptic long-term potentiation (LTP) at parallel fiber (PF)–Purkinje cell synapses in a CB1R-dependent manner. Under control conditions, LTP was induced by delivering 120 PF stimuli at 8 Hz. In contrast, no LTP was observed when oxo-m was present during tetanization. PF-LTP was restored when the CB1R antagonist N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251) was coapplied with oxo-m. Furthermore, the suppressive effect of oxo-m on PF-LTP was abrogated by the GDP analog GDP-β-S (applied intracellularly), the phospholipase C inhibitor U-73122, and the diacylglycerol lipase inhibitor tetrahydrolipstatin (THL), suggesting that cannabinoid synthesis results from the activation of Gq-coupled mAChRs present on Purkinje cells. The oxo-m–mediated suppression of LTP was also prevented in the presence of the M3 receptor antagonist DAU 5884, and was absent in M1/M3 receptor double-KO mice, identifying M3 receptors as primary oxo-m targets. Our findings allow for the possibility that cholinergic signaling in the cerebellum—which may result from long-term depression (LTD)-related disinhibition of cholinergic neurons in the vestibular nuclei—suppresses presynaptic LTP to prevent an up-regulation of transmitter release that opposes the reduction of postsynaptic responsiveness. This modulatory capacity of mAChR signaling could promote the functional penetrance of LTD. PMID:23776234

  9. Chromosomal in situ suppression hybridization of immunologically classified mitotic cells in hematologic malignancies

    OpenAIRE

    Tiainen, Marianne; Knuutila, Sakari; Popp, Susanne; Emmerich, Patricia; Cremer, Thomas; Parlier, Valerie; Jotterand Bellomo, Martine; Ruutu, Tapani

    1992-01-01

    Chromosomal in situ suppression (CISS) hybridization was performed with library DNA from sorted human chromosomes 8, 9, 15, 17, 21, and 22 on immunologically stained bone marrow cells of four patients with a hematologic neoplasm, including two patients with myelodysplastic syndrome and trisomy 8, one patient with promyelocytic leukemia bearing the translocation t(15;17)(q22;q11-12), and one patient with chronic myeloid leukemia and the translocation t(9;22)(q34;q11). In all patients, the resu...

  10. The Diversity of Cortical Inhibitory Synapses

    Directory of Open Access Journals (Sweden)

    Yoshiyuki eKubota

    2016-04-01

    Full Text Available The most typical and well known inhibitory action in the cortical microcircuit is a strong inhibition on the target neuron by axo-somatic synapses. However, it has become clear that synaptic inhibition in the cortex is much more diverse and complicated. Firstly, at least ten or more inhibitory non-pyramidal cell subtypes engage in diverse inhibitory functions to produce the elaborate activity characteristic of the different cortical states. Each distinct non-pyramidal cell subtype has its own independent inhibitory function. Secondly, the inhibitory synapses innervate different neuronal domains, such as axons, spines, dendrites and soma, and their IPSP size is not uniform. Thus cortical inhibition is highly complex, with a wide variety of anatomical and physiological modes. Moreover, the functional significance of the various inhibitory synapse innervation styles and their unique structural dynamic behaviors differ from those of excitatory synapses. In this review, we summarize our current understanding of the inhibitory mechanisms of the cortical microcircuit.

  11. Chromosomal in situ suppression hybridization of immunologically classified mitotic cells in hematologic malignancies.

    Science.gov (United States)

    Tiainen, M; Popp, S; Parlier, V; Emmerich, P; Bellomo, M J; Ruutu, T; Cremer, T; Knuutila, S

    1992-03-01

    Chromosomal in situ suppression (CISS) hybridization was performed with library DNA from sorted human chromosomes 8, 9, 15, 17, 21, and 22 on immunologically stained bone marrow cells of four patients with a hematologic neoplasm, including two patients with myelodysplastic syndrome and trisomy 8, one patient with promyelocytic leukemia bearing the translocation t(15;17)(q22;q11-12), and one patient with chronic myeloid leukemia and the translocation t(9;22)(q34;q11). In all patients, the results of conventional karyotype analysis could be confirmed by one- or two-color CISS hybridization using the appropriate chromosome-specific libraries. Our results show that CISS hybridization can detect both numerical and structural chromosome changes in immunologically classified cells with high specificity and reliability. The fact that chromosome spreads of very poor quality can now be included in such analyses is a decisive advantage of this approach. In addition, the suitability of this approach for interphase cytogenetics is discussed.

  12. Grafted c-kit+/SSEA1- eye-wall progenitor cells delay retinal degeneration in mice by regulating neural plasticity and forming new graft-to-host synapses.

    Science.gov (United States)

    Chen, Xi; Chen, Zehua; Li, Zhengya; Zhao, Chen; Zeng, Yuxiao; Zou, Ting; Fu, Caiyun; Liu, Xiaoli; Xu, Haiwei; Yin, Zheng Qin

    2016-12-30

    Despite diverse pathogenesis, the common pathological change observed in age-related macular degeneration and in most hereditary retinal degeneration (RD) diseases is photoreceptor loss. Photoreceptor replacement by cell transplantation may be a feasible treatment for RD. The major obstacles to clinical translation of stem cell-based cell therapy in RD remain the difficulty of obtaining sufficient quantities of appropriate and safe donor cells and the poor integration of grafted stem cell-derived photoreceptors into the remaining retinal circuitry. Eye-wall c-kit + /stage-specific embryonic antigen 1 (SSEA1) - cells were isolated via fluorescence-activated cell sorting, and their self-renewal and differentiation potential were detected by immunochemistry and flow cytometry in vitro. After labeling with quantum nanocrystal dots and transplantation into the subretinal space of rd1 RD mice, differentiation and synapse formation by daughter cells of the eye-wall c-kit + /SSEA1 - cells were evaluated by immunochemistry and western blotting. Morphological changes of the inner retina of rd1 mice after cell transplantation were demonstrated by immunochemistry. Retinal function of rd1 mice that received cell grafts was tested via flash electroretinograms and the light/dark transition test. Eye-wall c-kit + /SSEA1 - cells were self-renewing and clonogenic, and they retained their proliferative potential through more than 20 passages. Additionally, eye-wall c-kit + /SSEA1 - cells were capable of differentiating into multiple retinal cell types including photoreceptors, bipolar cells, horizontal cells, amacrine cells, Müller cells, and retinal pigment epithelium cells and of transdifferentiating into smooth muscle cells and endothelial cells in vitro. The levels of synaptophysin and postsynaptic density-95 in the retinas of eye-wall c-kit + /SSEA1 - cell-transplanted rd1 mice were significantly increased at 4 weeks post transplantation. The c-kit + /SSEA1 - cells were

  13. Evaluation of immunological interaction between spermatozoa and fallopian tube epithelial cells.

    Science.gov (United States)

    Zandieh, Z; Ashrafi, M; Jameie, B; Amanpour, S; Mosaffa, N; Salman Yazdi, R; Pacey, A; Aflatoonian, R

    2015-12-01

    Toll-like receptors (TLR) are one of the major compartments of innate immune system. It was revealed that the TLR have relevance in ovulation, sperm capacitation and fertilisation. So, in this study, the expression of TLR, their adaptor molecules and cytokines in human fallopian tube cell line under the effect of human normal spermatozoa was evaluated. TLR mRNA and protein were evaluated in OE-E6/E7 cell line. Semen samples from 10 donors were collected and co-incubated with OE-E6/E7 cell line and used as sperm group, and cell line without spermatozoa was used as control group. Afterwards, the level of TLR, their adaptor molecule and cytokine mRNA expression was compared using qPCR in sperm and control groups, and supernatant was used for ELISA. To determine whether elevated cytokine reaction to spermatozoa in OE-E6/E7 cell line is mediated via TLR, TLR3 function-blocking antibody was used. OE-E6/E7 cell line expressed TLR1-6 genes and proteins. TLR expressions, especially TLR3 and TLR5, in OE-E6/E7 cell line under the effect of spermatozoa were significantly higher. Also, levels of adaptor molecules and cytokine production were increased in sperm group than in control group (P spermatozoa and fallopian tube immunological interaction and for preparing safe environment for important events in fallopian tube. © 2015 Blackwell Verlag GmbH.

  14. Elementary properties of Ca(2+) channels and their influence on multivesicular release and phase-locking at auditory hair cell ribbon synapses.

    Science.gov (United States)

    Magistretti, Jacopo; Spaiardi, Paolo; Johnson, Stuart L; Masetto, Sergio

    2015-01-01

    Voltage-gated calcium (Cav1.3) channels in mammalian inner hair cells (IHCs) open in response to sound and the resulting Ca(2+) entry triggers the release of the neurotransmitter glutamate onto afferent terminals. At low to mid sound frequencies cell depolarization follows the sound sinusoid and pulses of transmitter release from the hair cell generate excitatory postsynaptic currents (EPSCs) in the afferent fiber that translate into a phase-locked pattern of action potential activity. The present article summarizes our current understanding on the elementary properties of single IHC Ca(2+) channels, and how these could have functional implications for certain, poorly understood, features of synaptic transmission at auditory hair cell ribbon synapses.

  15. Elementary properties of Ca2+ channels and their influence on multivesicular release and phase-locking at auditory hair cell ribbon synapses

    Science.gov (United States)

    Magistretti, Jacopo; Spaiardi, Paolo; Johnson, Stuart L.; Masetto, Sergio

    2015-01-01

    Voltage-gated calcium (Cav1.3) channels in mammalian inner hair cells (IHCs) open in response to sound and the resulting Ca2+ entry triggers the release of the neurotransmitter glutamate onto afferent terminals. At low to mid sound frequencies cell depolarization follows the sound sinusoid and pulses of transmitter release from the hair cell generate excitatory postsynaptic currents (EPSCs) in the afferent fiber that translate into a phase-locked pattern of action potential activity. The present article summarizes our current understanding on the elementary properties of single IHC Ca2+ channels, and how these could have functional implications for certain, poorly understood, features of synaptic transmission at auditory hair cell ribbon synapses. PMID:25904847

  16. Immunological Effects of Oenothein B, an Ellagitannin Dimer, on Dendritic Cells

    Directory of Open Access Journals (Sweden)

    Reiko Teshima

    2012-12-01

    Full Text Available Oenothein B is a unique macrocyclic ellagitannin dimer that has been found in various medicinal plants belonging to Onagraceae, Lythraceae, and Myrtaceae, with diverse biological activities. The immunological effects of tannins in terms of cytokine-release from macrophages and monocytes have been discussed, while the effects on other immunocompetent cells have been the subject of minimal investigation. We evaluated the immunomodulatory effects induced by tannin treatment in human dendritic cells (DCs, which play a critical role in the initial immune response, by measuring the changes in cytokine production, cell differentiation, and cell viability. Oenothein B showed significant down-regulation of the expression of cell surface molecules, CD1a and CD83, suggesting the inhibition of DC differentiation and/or maturation. The suppressive effect on DCs was associated with the induction of apoptosis without the activation of caspase-3/7, 8, and 9, and this was supported by the morphological features indicating significant nuclear condensation. Oenothein B also markedly suppressed the production of inflammatory cytokines, such as IL-1β and IL-6, in a dose-dependent manner. These data may, in part, be able to explain the traditional use of tannin-containing medicinal plants for the treatment of a variety of inflammatory diseases, including inflammatory bowel disease, celiac disease, and rheumatoid arthritis.

  17. Improvement of Impaired Immunological Status of Patients with Various Types of Advanced Cancers by Autologous Immune Cell Therapy.

    Science.gov (United States)

    Kamigaki, Takashi; Ibe, Hiroshi; Okada, Sachiko; Matsuda, Eriko; Tanaka, Masanori; Oguma, Eri; Kinoshita, Yoshihiro; Ogasawara, Shun; Ono, Atsuko; Makita, Kaori; Naitoh, Keiko; Goto, Shigenori

    2015-08-01

    We evaluated the immunological status of patients with various solid tumors by flow cytometry of immune cell populations and their frequencies in peripheral blood samples. The change in immunological status was also analyzed in patients given autologous immune cell therapy, such as αβT cell, γδT cell, NK cell or DC vaccine therapy. The frequency of regulatory T-cells (Tregs) was shown to be high in patients with cancers of the lung (squamous carcinoma cells), head and neck, esophagus and uterus, although there were no significant differences in effector cell population or Th1/2 ratio between various types of cancers except for a few. The cellular immunological status was impaired in most patients with advanced solid tumors before immune cell therapy and the impaired T-cell immune status was restored by infusion of effector cells, such as αβT cells or γδT cells, although the number of NK cells in the peripheral blood did not always increase after autologous NK cell therapy. The concurrent αβT cell therapy and DC vaccine therapy could successfully increase the number of CD8(+) T-cells in the peripheral blood of patients with various types of cancers. Two or three injections of αβT cells could potentially reduce Tregs frequency prior to DC vaccine, as well as the concurrent αβT cell and DC vaccine therapy. However, an increase in the Tregs frequency was observed in some patients who received NK cell therapy. These findings suggest that it is necessary to include or combine certain types of immune cell therapy when the Tregs frequency of cancer patients is high before or after autologous immune cell therapy. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  18. Regulatory T Cells: Serious Contenders in the Promise for Immunological Tolerance in Transplantation.

    Science.gov (United States)

    Safinia, Niloufar; Scotta, Cristiano; Vaikunthanathan, Trishan; Lechler, Robert I; Lombardi, Giovanna

    2015-01-01

    Regulatory T cells (Tregs) play an important role in immunoregulation and have been shown in animal models to promote transplantation tolerance and curb autoimmunity following their adoptive transfer. The safety and potential therapeutic efficacy of these cells has already been reported in Phase I trials of bone-marrow transplantation and type I diabetes, the success of which has motivated the broadened application of these cells in solid-organ transplantation. Despite major advances in the clinical translation of these cells, there are still key questions to be addressed to ensure that Tregs attest their reputation as ideal candidates for tolerance induction. In this review, we will discuss the unique traits of Tregs that have attracted such fame in the arena of tolerance induction. We will outline the protocols used for their ex vivo expansion and discuss the future directions of Treg cell therapy. In this regard, we will review the concept of Treg heterogeneity, the desire to isolate and expand a functionally superior Treg population and report on the effect of differing culture conditions. The relevance of Treg migratory capacity will also be discussed together with methods of in vivo visualization of the infused cells. Moreover, we will highlight key advances in the identification and expansion of antigen-specific Tregs and discuss their significance for cell therapy application. We will also summarize the clinical parameters that are of importance, alongside cell manufacture, from the choice of immunosuppression regimens to the number of injections in order to direct the success of future efficacy trials of Treg cell therapy. Years of research in the field of tolerance have seen an accumulation of knowledge and expertise in the field of Treg biology. This perpetual progression has been the driving force behind the many successes to date and has put us now within touching distance of our ultimate success, immunological tolerance.

  19. Regulatory T cells: serious contenders in the promise for immunological tolerance in transplantation

    Directory of Open Access Journals (Sweden)

    Niloufar eSafinia

    2015-08-01

    Full Text Available Regulatory T cells (Tregs play an important role in immunoregulation and have been shown in animal models to promote transplantation tolerance and curb autoimmunity following their adoptive transfer. The safety and potential therapeutic efficacy of these cells has already been reported in Phase I trials of bone marrow transplantation and type I diabetes, the success of which has motivated the broadened application of these cells in solid organ transplantation. Despite major advances in the clinical translation of these cells, there are still key questions to be addressed to ensure that Tregs attest their reputation as ideal candidates for tolerance induction. In this review, we will discuss the unique traits of Tregs that have attracted such fame in the arena of tolerance induction. We will outline the protocols used for their ex vivo expansion and discuss the future directions of Treg cell therapy. In this regard, we will review the concept of Treg heterogeneity, the desire to isolate and expand a functionally superior Treg population and report on the effect of differing culture conditions. The relevance of Treg migratory capacity will also be discussed together with methods of in vivo visualization of the infused cells. Moreover, we will highlight key advances in the identification and expansion of antigen specific Tregs and discuss their significance for cell therapy application. We will also summarize the clinical parameters that are of importance, alongside cell manufacture, from the choice of immunosuppression regimens to the number of injections in order to direct the success of future efficacy trials of Treg cell therapy.Years of research in the field of tolerance have seen an accumulation of knowledge and expertise in the field of Treg biology. This perpetual progression has been the driving force behind the many successes to date and has put us now within touching distance of our ultimate success, immunological tolerance.

  20. A systems immunology approach to plasmacytoid dendritic cell function in cytopathic virus infections.

    Directory of Open Access Journals (Sweden)

    Gennady Bocharov

    Full Text Available Plasmacytoid dendritic cell (pDC-mediated protection against cytopathic virus infection involves various molecular, cellular, tissue-scale, and organism-scale events. In order to better understand such multiscale interactions, we have implemented a systems immunology approach focusing on the analysis of the structure, dynamics and operating principles of virus-host interactions which constrain the initial spread of the pathogen. Using high-resolution experimental data sets coming from the well-described mouse hepatitis virus (MHV model, we first calibrated basic modules including MHV infection of its primary target cells, i.e. pDCs and macrophages (Mphis. These basic building blocks were used to generate and validate an integrative mathematical model for in vivo infection dynamics. Parameter estimation for the system indicated that on a per capita basis, one infected pDC secretes sufficient type I IFN to protect 10(3 to 10(4 Mphis from cytopathic viral infection. This extremely high protective capacity of pDCs secures the spleen's capability to function as a 'sink' for the virus produced in peripheral organs such as the liver. Furthermore, our results suggest that the pDC population in spleen ensures a robust protection against virus variants which substantially down-modulate IFN secretion. However, the ability of pDCs to protect against severe disease caused by virus variants exhibiting an enhanced liver tropism and higher replication rates appears to be rather limited. Taken together, this systems immunology analysis suggests that antiviral therapy against cytopathic viruses should primarily limit viral replication within peripheral target organs.

  1. Differential presynaptic and postsynaptic expression of m1-m4 muscarinic acetylcholine receptors at the perforant pathway/granule cell synapse.

    Science.gov (United States)

    Rouse, S T; Gilmor, M L; Levey, A I

    1998-09-01

    A family of muscarinic acetylcholine receptor proteins mediates diverse pre- and postsynaptic functions in the hippocampus. However the roles of individual receptors are not understood. The present study identified the pre- and postsynaptic muscarinic acetylcholine receptors at the perforant pathway synapses in rat brain using a combination of lesioning, immunocytochemistry and electron microscopic techniques. Entorhinal cortex lesions resulted in lamina-specific reductions of m2, m3, and m4 immunoreactivity in parallel with the degeneration of the medial and lateral perforant pathway terminals in the middle and outer thirds of the molecular layer, respectively. In contrast, granule cell lesions selectively reduced m1 and m3 receptors consistent with degeneration of postsynaptic dendrites. Direct visualization of m1-m4 by electron microscopic immunocytochemistry confirmed their differential pre- and postsynaptic localizations. Together, these findings provide strong evidence for both redundancy and spatial selectivity of presynaptic (m2, m3 and m4) and postsynaptic (m1 and m3) muscarinic acetylcholine receptors at the perforant pathway synapse.

  2. Distinct target cell-dependent forms of short-term plasticity of the central visceral afferent synapses of the rat

    Directory of Open Access Journals (Sweden)

    Watabe Ayako M

    2010-10-01

    Full Text Available Abstract Background The visceral afferents from various cervico-abdominal sensory receptors project to the dorsal vagal complex (DVC, which is composed of the nucleus of the solitary tract (NTS, the area postrema and the dorsal motor nucleus of the vagus nerve (DMX, via the vagus and glossopharyngeal nerves and then the solitary tract (TS in the brainstem. While the excitatory transmission at the TS-NTS synapses shows strong frequency-dependent suppression in response to repeated stimulation of the afferents, the frequency dependence and short-term plasticity at the TS-DMX synapses, which also transmit monosynaptic information from the visceral afferents to the DVC neurons, remain largely unknown. Results Recording of the EPSCs activated by paired or repeated TS stimulation in the brainstem slices of rats revealed that, unlike NTS neurons whose paired-pulse ratio (PPR is consistently below 0.6, the distribution of the PPR of DMX neurons shows bimodal peaks that are composed of type I (PPR, 0.6-1.5; 53% of 120 neurons recorded and type II (PPR, Conclusions These two general types of short-term plasticity might contribute to the differential activation of distinct vago-vagal reflex circuits, depending on the firing frequency and type of visceral afferents.

  3. In situ single molecule imaging of cell membranes: linking basic nanotechniques to cell biology, immunology and medicine

    Science.gov (United States)

    Pi, Jiang; Jin, Hua; Yang, Fen; Chen, Zheng W.; Cai, Jiye

    2014-10-01

    The cell membrane, which consists of a viscous phospholipid bilayer, different kinds of proteins and various nano/micrometer-sized domains, plays a very important role in ensuring the stability of the intracellular environment and the order of cellular signal transductions. Exploring the precise cell membrane structure and detailed functions of the biomolecules in a cell membrane would be helpful to understand the underlying mechanisms involved in cell membrane signal transductions, which could further benefit research into cell biology, immunology and medicine. The detection of membrane biomolecules at the single molecule level can provide some subtle information about the molecular structure and the functions of the cell membrane. In particular, information obtained about the molecular mechanisms and other information at the single molecule level are significantly different from that detected from a large amount of biomolecules at the large-scale through traditional techniques, and can thus provide a novel perspective for the study of cell membrane structures and functions. However, the precise investigations of membrane biomolecules prompts researchers to explore cell membranes at the single molecule level by the use of in situ imaging methods, as the exact conformation and functions of biomolecules are highly controlled by the native cellular environment. Recently, the in situ single molecule imaging of cell membranes has attracted increasing attention from cell biologists and immunologists. The size of biomolecules and their clusters on the cell surface are set at the nanoscale, which makes it mandatory to use high- and super-resolution imaging techniques to realize the in situ single molecule imaging of cell membranes. In the past few decades, some amazing imaging techniques and instruments with super resolution have been widely developed for molecule imaging, which can also be further employed for the in situ single molecule imaging of cell membranes. In

  4. A Novel Growth-Promoting Pathway Formed by GDNF-Overexpressing Schwann Cells Promotes Propriospinal Axonal Regeneration, Synapse formation, and Partial Recovery of Function after Spinal Cord Injury

    Science.gov (United States)

    Deng, Lingxiao; Deng, Ping; Ruan, Yiwen; Xu, Zao Cheng; Liu, Naikui; Wen, Xuejun; Smith, George M.; Xu, Xiao-Ming

    2013-01-01

    Descending propriospinal neurons (DPSN) are known to establish functional relays for supraspinal signals, and they display a greater growth response after injury than do the long projecting axons. However, their regenerative response is still deficient due to their failure to depart from growth supportive cellular transplants back into the host spinal cord, which contains numerous impediments to axon growth. Here we report the construction of a continuous growth-promoting pathway in adult rats, formed by grafted Schwann cells (SCs) overexpressing glial cell line-derived neurotrophic factor (GDNF). We demonstrate that such a growth-promoting pathway, extending from the axonal cut ends to the site of innervation in the distal spinal cord, promoted regeneration of DPSN axons through and beyond the lesion gap of a spinal cord hemisection. Within the distal host spinal cord, regenerated DPSN axons formed synapses with host neurons leading to the restoration of action potentials and partial recovery of function. PMID:23536080

  5. DC-SIGN-mediated infectious synapse formation enhances X4 HIV-1 transmission from dendritic cells to T cells

    NARCIS (Netherlands)

    Arrighi, Jean-François; Pion, Marjorie; Garcia, Eduardo; Escola, Jean-Michel; van Kooyk, Yvette; Geijtenbeek, Teunis B.; Piguet, Vincent

    2004-01-01

    Dendritic cells (DCs) are essential for the early events of human immunodeficiency virus (HIV) infection. Model systems of HIV sexual transmission have shown that DCs expressing the DC-specific C-type lectin DC-SIGN capture and internalize HIV at mucosal surfaces and efficiently transfer HIV to CD4+

  6. Clinical and Immunological Effects in Patients with Advanced Non-Small Cell Lung-Cancer after Vaccination with Dendritic Cells Exposed to an Allogeneic Tumor Cell Lysate*

    DEFF Research Database (Denmark)

    Engell-Noerregaard, Lotte; Kvistborg, Pia; Zocca, Mai-Britt

    2013-01-01

    Background: We evaluated the clinical and immunological effects of dendritic cell (DC) vaccination of patients with NSCLC. Autologous DCs were pulsed with a MAGE containing allogeneic melanoma cell lysate (MelCancerVac®, Dandrit Biotech, Copenhagen, Denmark). Imiquimod cream, proleukin and celeco......Background: We evaluated the clinical and immunological effects of dendritic cell (DC) vaccination of patients with NSCLC. Autologous DCs were pulsed with a MAGE containing allogeneic melanoma cell lysate (MelCancerVac®, Dandrit Biotech, Copenhagen, Denmark). Imiquimod cream, proleukin...... one patient with progressive disease (PD) showed vaccine-specific re- sponses. Conclusion: This DC-based vaccine trial has indicated a correlation between vaccine-specific immunity and sustained SD. Furthermore, we observed an unexpectedly prolonged survival in some patients, which may indicate de...

  7. Immunological reactivity

    International Nuclear Information System (INIS)

    Shubik, V.M.

    1984-01-01

    Materials on comparative characteristics of state of some immunological parameters under the effect of toxic radioactive and non-radioactive chemical substances on organism of experimental animas as well as data on possible role of disclosed immunological changes are presented. Data on the possible role of immunological mechanisms in shortening life span and distortions of reproduction function are given

  8. A bionics chemical synapse.

    Science.gov (United States)

    Thanapitak, Surachoke; Toumazou, Christofer

    2013-06-01

    Implementation of the current mode CMOS circuit for chemical synapses (AMPA and NMDA receptors) with dynamic change of glutamate as the neurotransmitter input is presented in this paper. Additionally, circuit realisation for receptor GABA(A) and GABA(B) with an electrical signal which symbolises γ-Aminobutyric Acid (GABA) perturbation is introduced. The chemical sensor for glutamate sensing is the modified ISFET with enzyme (glutamate oxidase) immobilisation. The measured results from these biomimetics chemical synapse circuits closely match with the simulation result from the mathematical model. The total power consumption of the whole chip (four chemical synapse circuits and all auxiliary circuits) is 168.3 μW. The total chip area is 3 mm(2) in 0.35-μm AMS CMOS technology.

  9. Protection of lethally irradiated mice with allogeneic fetal liver cells: influence of irradiation dose on immunologic reconstitution

    International Nuclear Information System (INIS)

    Tulunay, O.; Good, R.A.; Yunis, E.J.

    1975-01-01

    After lethal irradiation long-lived, immunologically vigorous C3Hf mice were produced by treatment with syngeneic fetal liver cells or syngeneic newborn or adult spleen cells. Treatment of lethally irradiated mice with syngeneic or allogeneic newborn thymus cells or allogeneic newborn or adult spleen cells regularly led to fatal secondary disease or graft-versus-host reactions. Treatment of the lethally irradiated mice with fetal liver cells regularly yielded long-lived, immunologically vigorous chimeras. The introduction of the fetal liver cells into the irradiated mice appeared to be followed by development of immunological tolerance of the donor cells. The findings suggest that T-cells at an early stage of differentiation are more susceptible to tolerance induction than are T-lymphocytes at later stages of differentiation. These investigations turned up a perplexing paradox which suggests that high doses of irradiation may injure the thymic stroma, rendering it less capable of supporting certain T-cell populations in the peripheral lymphoid tissue. Alternatively, the higher and not the lower dose of irradiation may have eliminated a host cell not readily derived from fetal liver precursors which represents an important helper cell in certain cell-mediated immune functions, e.g., graft-versus-host reactions, but which is not important in others, e.g., allograft rejections. The higher dose of lethal irradiation did not permit development or maintenance of a population of spleen cells that could initiate graft-versus-host reactions but did permit the development of a population of donor cells capable of achieving vigorous allograft rejection

  10. A cell adhesion molecule mimetic, FGL peptide, induces alterations in synapse and dendritic spine structure in the dentate gyrus of aged rats: a three-dimensional ultrastructural study

    DEFF Research Database (Denmark)

    Popov, Victor I; Medvedev, Nikolay I; Kraev, Igor V

    2008-01-01

    The FGL peptide is a neural cell adhesion molecule (NCAM) mimetic comprising a 15-amino-acid-long sequence of the FG loop region of the second fibronectin type III module of NCAM. It corresponds to the binding site of NCAM for the fibroblast growth factor receptor 1. FGL improves cognitive function...... through enhancement of synaptic function. We examined the effect of FGL on synaptic and dendritic structure in the brains of aged (22-month-old) rats that were injected subcutaneously (8 mg/kg) at 2-day intervals until 19 days after the start of the experiment. Animals were perfused with fixative, brains...... structure of synapses and dendritic spines in hippocampus of aged rats, complementing data showing its effect on cognitive processes....

  11. Clinical and immunological significance of HLA-E in stem cell transplantation and cancer.

    Science.gov (United States)

    Wieten, L; Mahaweni, N M; Voorter, C E M; Bos, G M J; Tilanus, M G J

    2014-12-01

    Human leukocyte antigen-E (HLA-E) is a nonclassical HLA class I molecule that canonically binds peptides derived from the leader sequence of classical HLA class I. HLA-E can also bind peptides from stress protein [e.g. heat shock protein 60 (Hsp60)] and pathogens, illustrating the importance of HLA-E for anti-viral and anti-tumor immunity. Like classical HLA class I molecules, HLA-E is ubiquitously expressed, however, it is characterized by only a very limited sequence variability and two dominant protein forms have been described (HLA-E*01:01 and HLA-E*01:03). HLA-E influences both the innate and the adaptive arms of the immune system by the engagement of inhibitory (e.g. NKG2A) and activating receptors [e.g. αβ T cell receptor (αβTCR) or NKG2C] on NK cells and CD8 T cells. The effects of HLA-E on the cellular immune response are therefore complex and not completely understood yet. Here, we aim to provide an overview of the immunological and clinical relevance of HLA-E and HLA-E polymorphism in stem cell transplantation and in cancer. We review novel insights in the mechanism via which HLA-E expression levels are controlled and how the cellular immune response in transplantation and cancer is influenced by HLA-E. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Improving immunological tumor microenvironment using electro-hyperthermia followed by dendritic cell immunotherapy

    International Nuclear Information System (INIS)

    Tsang, Yuk-Wah; Huang, Cheng-Chung; Yang, Kai-Lin; Chi, Mau-Shin; Chiang, Hsin-Chien; Wang, Yu-Shan; Andocs, Gabor; Szasz, Andras; Li, Wen-Tyng; Chi, Kwan-Hwa

    2015-01-01

    The treatment of intratumoral dentritic cells (DCs) commonly fails because it cannot evoke immunity in a poor tumor microenvironment (TME). Modulated electro-hyperthermia (mEHT, trade-name: oncothermia) represents a significant technological advancement in the hyperthermia field, allowing the autofocusing of electromagnetic power on a cell membrane to generate massive apoptosis. This approach turns local immunogenic cancer cell death (apoptosis) into a systemic anti-tumor immune response and may be implemented by treatment with intratumoral DCs. The CT26 murine colorectal cancer model was used in this investigation. The inhibition of growth of the tumor and the systemic anti-tumor immune response were measured. The tumor was heated to a core temperature of 42 °C for 30 min. The matured synergetic DCs were intratumorally injected 24 h following mEHT was applied. mEHT induced significant apoptosis and enhanced the release of heat shock protein70 (Hsp70) in CT26 tumors. Treatment with mEHT-DCs significantly inhibited CT26 tumor growth, relative to DCs alone or mEHT alone. The secondary tumor protection effect upon rechallenging was observed in mice that were treated with mEHT-DCs. Immunohistochemical staining of CD45 and F4/80 revealed that mEHT-DC treatment increased the number of leukocytes and macrophages. Most interestingly, mEHT also induced infiltrations of eosinophil, which has recently been reported to be an orchestrator of a specific T cell response. Cytotoxic T cell assay and ELISpot assay revealed a tumor-specific T cell activity. This study demonstrated that mEHT induces tumor cell apoptosis and enhances the release of Hsp70 from heated tumor cells, unlike conventional hyperthermia. mEHT can create a favorable tumor microenvironment for an immunological chain reaction that improves the success rate of intratumoral DC immunotherapy. The online version of this article (doi:10.1186/s12885-015-1690-2) contains supplementary material, which is available to

  13. Some notes on radiation immunology

    International Nuclear Information System (INIS)

    Sado, Toshihiko

    1977-01-01

    Immunological movement related to radiation immunology were reviewed. Basic items about cell mechanism of immunological reaction were explained, and then, relationship between immunity and radiation was given an outline. As to radiation effects on immunological lymphatic system, radiosensitivity of lymphocytes and immunological reaction, radiation effects on T and B cells, and radiosensitivity of lymphatic system, especially thymus were mentioned, and furthermore, delayed effects of radiation on immunological system were described. Radiation effects on relationship between bone marrow transplantation and genesis of reticulum cell tumor and delayed effects of radiation on them were mentioned, and genetic resistance against hematopoietic cell transplantation and its radiosensitivity were also described. Relationship between carcinogenesis due to radiation and immunity, and a state of specific immunological in an individual non-responsiveness having cancer, were also referred to. (Kanao, N.)

  14. Tumor Immunology and Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Jung, Chi Young; Antonia, Scott J

    2018-01-01

    Lung cancer is one of the most commonly diagnosed cancers and the leading cause of cancer-related deaths worldwide. Although progress in the treatment of advanced non-small cell lung cancer (NSCLC) has been made over the past decade, the 5-year survival rate in patients with lung cancer remains only 10%-20%. Obviously, new therapeutic options are required for patients with advanced NSCLC and unmet medical needs. Cancer immunotherapy is an evolving treatment modality that uses a patient's own immune systems to fight cancer. Theoretically, cancer immunotherapy can result in long-term cancer remission and may not cause the same side effects as chemotherapy and radiation. Immuno-oncology has become an important focus of basic research as well as clinical trials for the treatment of NSCLC. Immune checkpoint inhibitors are the most promising approach for cancer immunotherapy and they have become the standard of care for patients with advanced NSCLC. This review summarizes basic tumor immunology and the relevant clinical data on immunotherapeutic approaches, especially immune checkpoint inhibitors in NSCLC. Copyright©2018. The Korean Academy of Tuberculosis and Respiratory Diseases.

  15. Immunological profiling of haemodialysis patients and young healthy individuals with implications for clinical regulatory T cell sorting.

    Science.gov (United States)

    Bergström, M; Joly, A-L; Seiron, P; Isringhausen, S; Modig, E; Fellström, B; Andersson, J; Berglund, D

    2015-05-01

    With the increasing interest in clinical trials with regulatory T cells (Tregs), immunological profiling of prospective target groups and standardized procedures for Treg isolation are needed. In this study, flow cytometry was used to assess peripheral blood lymphocyte profiles of young healthy individuals and patients undergoing haemodialysis treatment. Tregs obtained from the former may be used in haematopoietic stem cell transplantation and Tregs from the latter in the prevention of kidney transplant rejection. FOXP3 mRNA expression with accompanying isoform distribution was also assessed by the quantitative reverse transcriptase polymerase chain reaction. Flow-cytometric gating strategies were systematically analysed to optimize the isolation of Tregs. Our findings showed an overall similar immunological profile of both cohorts in spite of great differences in both age and health. Analysis of flow-cytometric gating techniques highlighted the importance of gating for both CD25high and CD127low expression in the isolation of FOXP3-positive cells. This study provides additional insight into the immunological profile of young healthy individuals and uraemic patients as well as in-depth analysis of flow-cytometric gating strategies for Treg isolation, supporting the development of Treg therapy using cells from healthy donors and uraemic patients. © 2015 John Wiley & Sons Ltd.

  16. Murine Splenic Natural Killer Cells Do Not Develop Immunological Memory after Re-Encounter with Mycobacterium bovis BCG

    Science.gov (United States)

    Kawahara, Mamoru; Hasegawa, Nozomi; Takaku, Hiroshi

    2016-01-01

    Several lines of evidence have recently suggested that natural killer (NK) cells develop immunological memory against viral infections. However, there is no apparent evidence that NK cells acquire specific memory against Mycobacterium bovis bacillus Calmette—Guérin (BCG), the only currently licensed vaccine for preventing tuberculosis. In the present study, we investigated whether murine splenic NK cells can be activated by BCG in a dendritic cell (DC)-independent or -dependent manner, and furthermore examined whether these NK cells acquire specific memory following BCG vaccination. NK cells isolated from spleens of BCG-immunized mice produced interferon (IFN)γ through direct BCG stimulation in the absence of antigen-presenting cells; however, NK cells from control animals similarly directly responded to BCG, and the response level was not statistically significant between the immunized and the naïve NK cells. When purified NK cells that had been exposed to BCG were cocultured with RAW murine macrophages infected with BCG, the antibacterial activity of the macrophages was strongly enhanced; however, its level was similar to that by naïve NK cells, which had not been exposed to BCG. When splenocytes harvested from BCG-immunized mice were stimulated with purified protein derivative (PPD) derived from Mycobacterium tuberculosis, a specific IFNγ response was clearly observed, mainly attributed to NK cells and memory CD4+ T cells. To investigate whether these NK cells as well as the T cells are activated by cell−cell interaction with DCs presenting mycobacterial antigens, NK cells isolated from BCG-immunized mice were cocultured with splenocytes harvested from naïve mice in the presence of PPD stimulation. However, no IFNγ response was found in the NK cells. These results suggest that murine splenic NK cells do not develop BCG-specific immunological memory in either a DC-independent or -dependent manner. PMID:26999357

  17. Elucidating the immunological effects of 5-azacytidine treatment in patients with myelodysplastic syndrome and identifying new conditional ligands and T-cell epitopes of relevance in melanoma

    DEFF Research Database (Denmark)

    Frøsig, Thomas Mørch

    2015-01-01

    This review is focused on research within three different areas of tumor immunology: discovery of new T-cell epitopes and a new immunological antigen (reported in Paper I and II), elucidation of the immunological effects of treatment with a hypomethylating drug (reported in Paper III) and discovery...... of new conditional ligands (reported in Paper IV). Many melanoma-associated T-cell epitopes have been described, but 45% of these are restricted to human leukocyte antigen (HLA)-A2, leaving the remaining 36 different HLA molecules with only a few described T-cell epitopes each. Therefore we wanted...... frequently recognized by T cells from HLA-A2 patients. On contrary, in Paper II we wanted to investigate the protein Nodal as a novel immunological target. We took advantage of a T-cell epitope mapping platform in which HLA ligands are predicted by computer-based algorithms, further tested in the laboratory...

  18. Comparison of immunological properties of bone marrow stromal cells and adipose tissue-derived stem cells before and after osteogenic differentiation in vitro

    DEFF Research Database (Denmark)

    Niemeyer, Philipp; Kornacker, Martin; Mehlhorn, Alexander

    2007-01-01

    T cells in vitro. Therefore, BMSCs are said to be available for allogenic cell therapy. Although the immunological characteristics of BMSCs have been the subject of various investigations, those of stem cells isolated from adipose tissue (ASCs) have not been adequately described. In addition......Mesenchymal stem cells (MSCs) can be isolated from various tissues and represent an attractive cell population for tissue-engineering purposes. MSCs from bone marrow (bone marrow stromal cells [BMSCs]) are negative for immunologically relevant surface markers and inhibit proliferation of allogenic...... were sought. The pattern of surface antigen expression of BMSCs is the same as that of ASCs. Analogous to BMSCs, undifferentiated cells isolated from adipose tissue lack expression of MHC-II; this is not lost in the course of the osteogenic differentiation process. In co-culture with allogenic PBMCs...

  19. Face classification using electronic synapses

    Science.gov (United States)

    Yao, Peng; Wu, Huaqiang; Gao, Bin; Eryilmaz, Sukru Burc; Huang, Xueyao; Zhang, Wenqiang; Zhang, Qingtian; Deng, Ning; Shi, Luping; Wong, H.-S. Philip; Qian, He

    2017-05-01

    Conventional hardware platforms consume huge amount of energy for cognitive learning due to the data movement between the processor and the off-chip memory. Brain-inspired device technologies using analogue weight storage allow to complete cognitive tasks more efficiently. Here we present an analogue non-volatile resistive memory (an electronic synapse) with foundry friendly materials. The device shows bidirectional continuous weight modulation behaviour. Grey-scale face classification is experimentally demonstrated using an integrated 1024-cell array with parallel online training. The energy consumption within the analogue synapses for each iteration is 1,000 × (20 ×) lower compared to an implementation using Intel Xeon Phi processor with off-chip memory (with hypothetical on-chip digital resistive random access memory). The accuracy on test sets is close to the result using a central processing unit. These experimental results consolidate the feasibility of analogue synaptic array and pave the way toward building an energy efficient and large-scale neuromorphic system.

  20. Synaptotagmin 7 confers frequency invariance onto specialized depressing synapses

    Science.gov (United States)

    Turecek, Josef; Jackman, Skyler L.; Regehr, Wade G.

    2017-11-01

    At most synapses in the brain, short-term plasticity dynamically modulates synaptic strength. Rapid frequency-dependent changes in synaptic strength have key roles in sensory adaptation, gain control and many other neural computations. However, some auditory, vestibular and cerebellar synapses maintain constant strength over a wide range of firing frequencies, and as a result efficiently encode firing rates. Despite its apparent simplicity, frequency-invariant transmission is difficult to achieve because of inherent synaptic nonlinearities. Here we study frequency-invariant transmission at synapses from Purkinje cells to deep cerebellar nuclei and at vestibular synapses in mice. Prolonged activation of these synapses leads to initial depression, which is followed by steady-state responses that are frequency invariant for their physiological activity range. We find that synaptotagmin 7 (Syt7), a calcium sensor for short-term facilitation, is present at both synapses. It was unclear why a sensor for facilitation would be present at these and other depressing synapses. We find that at Purkinje cell and vestibular synapses, Syt7 supports facilitation that is normally masked by depression, which can be revealed in wild-type mice but is absent in Syt7 knockout mice. In wild-type mice, facilitation increases with firing frequency and counteracts depression to produce frequency-invariant transmission. In Syt7-knockout mice, Purkinje cell and vestibular synapses exhibit conventional use-dependent depression, weakening to a greater extent as the firing frequency is increased. Presynaptic rescue of Syt7 expression restores both facilitation and frequency-invariant transmission. Our results identify a function for Syt7 at synapses that exhibit overall depression, and demonstrate that facilitation has an unexpected and important function in producing frequency-invariant transmission.

  1. Activity-dependent long-term plasticity of afferent synapses on grafted stem/progenitor cell-derived neurons

    DEFF Research Database (Denmark)

    Sørensen, Andreas Toft; Rogelius, Nina; Lundberg, Cecilia

    2011-01-01

    Stem cell-based cell replacement therapies aiming at restoring injured or diseased brain function ultimately rely on the capability of transplanted cells to promote functional recovery. The mechanisms by which stem cell-based therapies for neurological conditions can lead to functional recovery...

  2. Liver Immunology

    Science.gov (United States)

    Bogdanos, Dimitrios P.; Gao, Bin; Gershwin, M. Eric

    2014-01-01

    The liver is the largest organ in the body and is generally regarded by non-immunologists as not having lymphoid function. However, such is far from accurate. This review highlights the importance of the liver as a lymphoid organ. Firstly, we discuss experimental data surrounding the role of liver as a lymphoid organ. The liver facilitates a tolerance rather than immunoreactivity, which protects the host from antigenic overload of dietary components and drugs derived from the gut and is also instrumental to fetal immune tolerance. Loss of liver tolerance leads to autoaggressive phenomena which if are not controlled by regulatory lymphoid populations may lead to the induction of autoimmune liver diseases. Liver-related lymphoid subpopulations also act as critical antigen-presenting cells. The study of the immunological properties of liver and delineation of the microenvironment of the intrahepatic milieu in normal and diseased livers provides a platform to understand the hierarchy of a series of detrimental events which lead to immune-mediated destruction of the liver and the rejection of liver allografts. The majority of emphasis within this review will be on the normal mononuclear cell composition of the liver. However, within this context, we will discus select, but not all, immune mediated liver disease and attempt to place these data in the context of human autoimmunity. PMID:23720323

  3. Intercellular protein-protein interactions at synapses.

    Science.gov (United States)

    Yang, Xiaofei; Hou, Dongmei; Jiang, Wei; Zhang, Chen

    2014-06-01

    Chemical synapses are asymmetric intercellular junctions through which neurons send nerve impulses to communicate with other neurons or excitable cells. The appropriate formation of synapses, both spatially and temporally, is essential for brain function and depends on the intercellular protein-protein interactions of cell adhesion molecules (CAMs) at synaptic clefts. The CAM proteins link pre- and post-synaptic sites, and play essential roles in promoting synapse formation and maturation, maintaining synapse number and type, accumulating neurotransmitter receptors and ion channels, controlling neuronal differentiation, and even regulating synaptic plasticity directly. Alteration of the interactions of CAMs leads to structural and functional impairments, which results in many neurological disorders, such as autism, Alzheimer's disease and schizophrenia. Therefore, it is crucial to understand the functions of CAMs during development and in the mature neural system, as well as in the pathogenesis of some neurological disorders. Here, we review the function of the major classes of CAMs, and how dysfunction of CAMs relates to several neurological disorders.

  4. CA1 Pyramidal Cell Theta-Burst Firing Triggers Endocannabinoid-Mediated Long-Term Depression at Both Somatic and Dendritic Inhibitory Synapses

    Science.gov (United States)

    Younts, Thomas J.; Chevaleyre, Vivien

    2013-01-01

    Endocannabinoids (eCBs) are retrograde lipid messengers that, by targeting presynaptic type 1 cannabinoid receptors (CB1Rs), mediate short- and long-term synaptic depression of neurotransmitter release throughout the brain. Short-term depression is typically triggered by postsynaptic, depolarization-induced calcium rises, whereas long-term depression is induced by synaptic activation of Gq/11 protein-coupled receptors. Here we report that a physiologically relevant pattern of postsynaptic activity, in the form of theta-burst firing (TBF) of hippocampal CA1 pyramidal neurons, can trigger long-term depression of inhibitory transmission (iLTD) in rat hippocampal slices. Paired recordings between CA1 interneurons and pyramidal cells, followed by post hoc morphological reconstructions of the interneurons' axon, revealed that somatic and dendritic inhibitory synaptic inputs equally expressed TBF-induced iLTD. Simultaneous recordings from neighboring pyramidal cells demonstrated that eCB signaling triggered by TBF was highly restricted to only a single, active cell. Furthermore, pairing submaximal endogenous activation of metabotropic glutamate or muscarinic acetylcholine receptors with submaximal TBF unmasked associative iLTD. Although CB1Rs are also expressed at Schaffer-collateral excitatory terminals, long-term plasticity under various recording conditions was spared at these synapses. Consistent with this observation, TBF also shifted the balance of excitation and inhibition in favor of excitatory throughput, thereby altering information flow through the CA1 circuit. Given the near ubiquity of burst-firing activity patterns and CB1R expression in the brain, the properties described here may be a general means by which neurons fine tune the strength of their inputs in a cell-wide and cell-specific manner. PMID:23966696

  5. B-cell activating factor BAFF reflects patients' immunological risk profile after kidney transplantation.

    Science.gov (United States)

    Schuster, A; Jung, B; Hofbauer, J; Kühne, L; Zecher, D; Banas, B; Bergler, T

    2017-12-01

    The B-cell activating factor BAFF plays an important role in the development and maturation of B-lymphocytes, which can contribute to the generation of donor-specific antibodies and thus may influence graft function and graft survival. Inconsistent data on the role of BAFF levels after renal transplantation for the formation of donor-specific antibodies and the contribution for allograft rejection exist. The aim of the current study was to determine to what extent the degree of pre-immunization is reflected by each patient's BAFF levels before transplantation and in the follow-up. Furthermore, the impact of BAFF on allograft rejection frequency as well as severity and resulting allograft function over time was analyzed. Additionally, the impact of viral infections on BAFF levels after transplantation - as a potential confounder - was examined. For this purpose, a group of pre-sensitized patients (PRA>0%, (52±24% on average), n=40) was compared with non-sensitized patients (PRA=0%, n=62) and in a subsequent analysis stratification in accordance to the detected BAFF level was performed. Pre-sensitized patients had significantly higher BAFF levels before transplantation and suffered significantly more often from early steroid-resistant, mainly antibody-mediated rejections. A result which was confirmed also in highly sensitized patients with PRA levels >50%. Additionally, in the follow-up patients with either rising BAFF levels over time or BAFF levels above the median also had significantly more often antibody mediated rejections. Additionally, patients with BAFF levels above detected median even displayed impaired creatinine values as well as an induced eGFR slope up to month 48 after transplantation. The occurrence of viral infections (CMV, BKV) was only an additional influencing factor in the absence of concomitant allograft rejections. Therefore, the B-cell proliferation factor BAFF appears not only to reflect the immunological risk profile of patients in the

  6. Effects of Salmeterol Xinafoate and Fluticasone Propionate on Immunological Activation of Human Cultured Mast Cells

    Directory of Open Access Journals (Sweden)

    Hirotomo Akabane

    2006-01-01

    Conclusions: The immunological release of chemical mediators (histamine, LT, PGD2 from HCMC was inhibited by SX but not by FP. SX and FP inhibited the production of GM-CSF by HCMC and both drug showed synergistic inhibition in the production of GM-CSF.

  7. Tumor-necrosis factor impairs CD4(+) T cell-mediated immunological control in chronic viral infection.

    Science.gov (United States)

    Beyer, Marc; Abdullah, Zeinab; Chemnitz, Jens M; Maisel, Daniela; Sander, Jil; Lehmann, Clara; Thabet, Yasser; Shinde, Prashant V; Schmidleithner, Lisa; Köhne, Maren; Trebicka, Jonel; Schierwagen, Robert; Hofmann, Andrea; Popov, Alexey; Lang, Karl S; Oxenius, Annette; Buch, Thorsten; Kurts, Christian; Heikenwalder, Mathias; Fätkenheuer, Gerd; Lang, Philipp A; Hartmann, Pia; Knolle, Percy A; Schultze, Joachim L

    2016-05-01

    Persistent viral infections are characterized by the simultaneous presence of chronic inflammation and T cell dysfunction. In prototypic models of chronicity--infection with human immunodeficiency virus (HIV) or lymphocytic choriomeningitis virus (LCMV)--we used transcriptome-based modeling to reveal that CD4(+) T cells were co-exposed not only to multiple inhibitory signals but also to tumor-necrosis factor (TNF). Blockade of TNF during chronic infection with LCMV abrogated the inhibitory gene-expression signature in CD4(+) T cells, including reduced expression of the inhibitory receptor PD-1, and reconstituted virus-specific immunity, which led to control of infection. Preventing signaling via the TNF receptor selectively in T cells sufficed to induce these effects. Targeted immunological interventions to disrupt the TNF-mediated link between chronic inflammation and T cell dysfunction might therefore lead to therapies to overcome persistent viral infection.

  8. Unscheduled brain DNA synthesis, long-term potentiation, and depression at the perforant path-granule cell synapse in the rat.

    Science.gov (United States)

    Sadile, A G; Neugebauer, A; Giuditta, A

    1995-01-01

    We investigated the effect of long-term potentiation (LTP) of the perforant path-granule cell synapse, on the synthesis of DNA in the target area and in polysynaptically stimulated hippocampal (CA3/CA1) and cortical areas (entorhinal, temporal, and occipital cortices) in the rat. The contralateral nonstimulated side was used as a control. The degree of LTP was indexed by the field EPSP and population spike amplitude recorded in the dentate area of the stimulated side before and after high frequency stimulation (250 Hz, 250 ms) every 30 min. DNA synthesis was evaluated in tissue homogenates after a 3-h period of incorporation of 3H-thymidine. DNA synthesis was significantly lower in the stimulated side in the hippocampal cortex CA3/CA1 (-25%), and in the entorhinal cortex (-50%), but not in the dentate area. In addition, the occurrence of preparations without expression of LTP allowed the analysis of unscheduled brain DNA synthesis (UBDS) in a supposedly long-term depression (LTD) subgroup. UBDS was higher in the group without LTP (no-LTP group) than in that with a significant LTP expression (LTP-group) on both sides of the brain. Furthermore, correlative analyses revealed that UBDS covaried with LTP of the EPSP (but not of population spike) in the dentate area and in extratarget hippocampal subregions on both sides and in dorsal cortex on the stimulated side. Further, regional crosscorrelation analyses revealed a high degree of coupling among brain sites following LTP.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. A Review of the Physiological and Immunological Functions of Biliary Epithelial Cells: Targets for Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis and Drug-induced Ductopenias

    Directory of Open Access Journals (Sweden)

    Chih-Te Wu

    2004-01-01

    Full Text Available Our understanding of biliary epithelial cells (BEC in physiobiology and immunology has steadily expanded. BEC transports IgA as well as IgM into bile, synthesizes and secretes various chemokines, cytokines, and expresses adhesion molecules involved in cell interaction and signal transduction. These then suggest a myriad of potential roles for BEC in defense from invading microorganisms as well as the pathogenesis of diverse immunologically driven diseases such as primary biliary cirrhosis (PBC, graft-versus-host disease, and primary sclerosing cholangitis (PSC. Despite the progress, there still remain many areas of BEC biology that require further investigation. Most importantly, it remains to be clarified that the extent to which the immunologic activities observed in BEC represent a BEC response to tissue injury or whether BEC themselves are the active participants in the pathogenesis of various cholestatic immunological diseases, including PBC and PSC.

  10. Human neural progenitor cells decrease photoreceptor degeneration, normalize opsin distribution and support synapse structure in cultured porcine retina.

    Science.gov (United States)

    Mollick, Tanzina; Mohlin, Camilla; Johansson, Kjell

    2016-09-01

    Retinal neurodegenerative disorders like retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy and retinal detachment decrease retinal functionality leading to visual impairment. The pathological events are characterized by photoreceptor degeneration, synaptic disassembly, remodeling of postsynaptic neurons and activation of glial cells. Despite intense research, no effective treatment has been found for these disorders. The current study explores the potential of human neural progenitor cell (hNPC) derived factors to slow the degenerative processes in adult porcine retinal explants. Retinas were cultured for 3 days with or without hNPCs as a feeder layer and investigated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), immunohistochemical, western blot and quantitative real time-polymerase chain reaction (qRT-PCR) techniques. TUNEL showed that hNPCs had the capacity to limit photoreceptor cell death. Among cone photoreceptors, hNPC coculture resulted in better maintenance of cone outer segments and reduced opsin mislocalization. Additionally, maintained synaptic structural integrity and preservation of second order calbindin positive horizontal cells was also observed. However, Müller cell gliosis only seemed to be alleviated in terms of reduced Müller cell density. Our observations indicate that at 3 days of coculture, hNPC derived factors had the capacity to protect photoreceptors, maintain synaptic integrity and support horizontal cell survival. Human neural progenitor cell applied treatment modalities may be an effective strategy to help maintain retinal functionality in neurodegenerative pathologies. Whether hNPCs can independently hinder Müller cell gliosis by utilizing higher concentrations or by combination with other pharmacological agents still needs to be determined. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Different Immunological Phenotypes Associated with Preserved CD4+ T Cell Counts in HIV-Infected Controllers and Viremic Long Term Non-Progressors

    DEFF Research Database (Denmark)

    Gaardbo, Julie Christine; Hartling, Hans J; Ronit, Andreas

    2013-01-01

    HIV-infected controllers control viral replication and maintain normal CD4+ T cell counts. Long Term Non-Progressors (LTNP) also maintain normal CD4+ T cell counts, but have on-going viral replication. We hypothesized that different immunological mechanisms are responsible for preserved CD4+ T cell...

  12. Evaluation of engraftment and immunological tolerance after reduced intensity conditioning in a rhesus hematopoietic stem cell gene therapy model.

    Science.gov (United States)

    Uchida, N; Weitzel, R P; Evans, M E; Green, R; Bonifacino, A C; Krouse, A E; Metzger, M E; Hsieh, M M; Donahue, R E; Tisdale, J F

    2014-02-01

    Reduced intensity conditioning (RIC) is desirable for hematopoietic stem cell (HSC) targeted gene therapy; however, RIC may be insufficient for efficient engraftment and inducing immunological tolerance to transgenes. We previously established long-term gene marking in our rhesus macaque autologous HSC transplantation model following 10 Gy total body irradiation (TBI). In this study, we evaluated RIC transplantation with 4 Gy TBI in two rhesus macaques that received equal parts of CD34(+) cells transduced with green fluorescent protein (GFP)-expressing lentiviral vector and empty vector not expressing transgenes. In both animals, equivalently low gene marking between GFP and empty vectors was observed 6 months post-transplantation, even with efficient transduction of CD34(+) cells in vitro. Autologous lymphocyte infusion with GFP marking resulted in an increase of gene marking in lymphocytes in a control animal with GFP tolerance, but not in the two RIC-transplanted animals. In vitro assays revealed strong cellular and humoral immune responses to GFP protein in the two RIC-transplanted animals, but this was not observed in controls. In summary, 4 Gy TBI is insufficient to permit engraftment of genetically modified HSCs and induce immunological tolerance to transgenes. Our findings should help in the design of conditioning regimens in gene therapy trials.

  13. Intraoral administration of a T-cell epitope peptide induces immunological tolerance in Cry j 2-sensitized mice.

    Science.gov (United States)

    Yoshitomi, Tomomi; Nakagami, Yasuhiro; Hirahara, Kazuki; Taniguchi, Yoshifumi; Sakaguchi, Masahiro; Yamashita, Makoto

    2007-08-01

    Sublingual immunotherapy using allergen-derived peptides is feasible as a novel specific immunotherapy, but its efficacy has not yet been demonstrated in either humans or animals. In addition, it remains obscure whether the oral immune system is involved in the mechanism of sublingual immunotherapy. Here, we show that the intraoral administration of the T-cell epitope peptide P2-246-259 derived from Cry j 2, a major Japanese cedar (Cryptomeria japonica) pollen allergen, to Cry j 2-sensitized mice induces immunological tolerance, and that ex vivo lymph node cell proliferation to P2-246-259 and Cry j 2 was inhibited. In addition, intraoral administration was shown to be superior to intragastric administration in terms of tolerance induction, suggesting that the oral immune system contributes to the induction of immunological tolerance. Therefore, the significant efficacy of sublingual immunotherapy using a peptide on allergen-specific T-cells was demonstrated in animals, and this may be potentiated by the oral mucosal immune system. Copyright (c) 2007 European Peptide Society and John Wiley & Sons, Ltd.

  14. ATTACK, a novel bispecific T cell-recruiting antibody with trivalent EGFR binding and monovalent CD3 binding for cancer immunotherapy

    DEFF Research Database (Denmark)

    Harwood, Seandean Lykke; Alvarez-Cienfuegos, Ana; Alanes, Natalia Nuñez del Prado

    2018-01-01

    (scFv; clone OKT3) in an intermediate molecular weight package. The two specificities are oriented in opposite directions in order to simultaneously engage cancer cells and T cell effectors, and thereby promote immunological synapse formation. EgA1 ATTACK was expressed as a homogenous, non...

  15. Role of neuron-glia interactions in developmental synapse elimination.

    Science.gov (United States)

    Terni, Beatrice; López-Murcia, Francisco José; Llobet, Artur

    2017-03-01

    During the embryonic development of the nervous system there is a massive formation of synapses. However, the exuberant connectivity present after birth must be pruned during postnatal growth to optimize the function of neuronal circuits. Whilst glial cells play a fundamental role in the formation of early synaptic contacts, their contribution to developmental modifications of established synapses is not well understood. The present review aims to highlight the various roles of glia in the developmental refinement of embryonic synaptic connectivity. We summarize recent evidences linking secretory abilities of glial cells to the disassembly of synaptic contacts that are complementary of a well-established phagocytic role. Considering a theoretical framework, it is discussed how release of glial molecules could be relevant to the developmental refinement of synaptic connectivity. Finally, we propose a three-stage model of synapse elimination in which neurons and glia are functionally associated to timely eliminate synapses. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. The Clinical Potential of Circulating Tumor Cells; The Need to Incorporate a Modern “Immunological Cocktail” in the Assay

    Energy Technology Data Exchange (ETDEWEB)

    Uhr, Jonathan W. [Cancer Immunobiology Center, University Texas Southwestern Medical Center, Dallas, TX 75390 (United States)

    2013-12-13

    The accepted clinical assay, CellSearch{sup ®}, and lab-on-a-chip tests for capturing circulating tumor cells are antibody-mediated. Attempts to improve their sensitivity have relied upon physical changes in the instruments. There have been no significant advances in improving the antibody-mediated portion of the capture. Modern immunologic engineering offers major possibilities for improving the sensitivity and other features of the assay. These include obtaining univalent antibody fragments such as scFvs with picomolar binding affinity and sufficient specificity; altering them to enhance their range of potential contact with target antigens; using antibodies directed against different epitopes on epithelial, mesenchymal or organ-specific cell surface markers to allow simultaneous binding and investigating non-antibody binding molecules as substitutes for antibody. These maneuvers could markedly improve the ability of current assays to improve patient care and might result in an acceptable test for detecting cancer earlier in high risk patients.

  17. The Clinical Potential of Circulating Tumor Cells; The Need to Incorporate a Modern “Immunological Cocktail” in the Assay

    Directory of Open Access Journals (Sweden)

    Jonathan W. Uhr

    2013-12-01

    Full Text Available The accepted clinical assay, CellSearch®, and lab-on-a-chip tests for capturing circulating tumor cells are antibody-mediated. Attempts to improve their sensitivity have relied upon physical changes in the instruments. There have been no significant advances in improving the antibody-mediated portion of the capture. Modern immunologic engineering offers major possibilities for improving the sensitivity and other features of the assay. These include obtaining univalent antibody fragments such as scFvs with picomolar binding affinity and sufficient specificity; altering them to enhance their range of potential contact with target antigens; using antibodies directed against different epitopes on epithelial, mesenchymal or organ-specific cell surface markers to allow simultaneous binding and investigating non-antibody binding molecules as substitutes for antibody. These maneuvers could markedly improve the ability of current assays to improve patient care and might result in an acceptable test for detecting cancer earlier in high risk patients.

  18. Rac1-Rab11-FIP3 regulatory hub coordinates vesicle traffic with actin remodeling and T-cell activation.

    Science.gov (United States)

    Bouchet, Jérôme; Del Río-Iñiguez, Iratxe; Lasserre, Rémi; Agüera-Gonzalez, Sonia; Cuche, Céline; Danckaert, Anne; McCaffrey, Mary W; Di Bartolo, Vincenzo; Alcover, Andrés

    2016-06-01

    The immunological synapse generation and function is the result of a T-cell polarization process that depends on the orchestrated action of the actin and microtubule cytoskeleton and of intracellular vesicle traffic. However, how these events are coordinated is ill defined. Since Rab and Rho families of GTPases control intracellular vesicle traffic and cytoskeleton reorganization, respectively, we investigated their possible interplay. We show here that a significant fraction of Rac1 is associated with Rab11-positive recycling endosomes. Moreover, the Rab11 effector FIP3 controls Rac1 intracellular localization and Rac1 targeting to the immunological synapse. FIP3 regulates, in a Rac1-dependent manner, key morphological events, like T-cell spreading and synapse symmetry. Finally, Rab11-/FIP3-mediated regulation is necessary for T-cell activation leading to cytokine production. Therefore, Rac1 endosomal traffic is key to regulate T-cell activation. © 2016 The Authors.

  19. Role of actin cytoskeleton at multiple levels of T cell activation

    Czech Academy of Sciences Publication Activity Database

    Huranová, Martina; Štěpánek, Ondřej

    2016-01-01

    Roč. 3, č. 4 (2016), s. 585-596 ISSN 2372-0301 R&D Projects: GA ČR GJ16-09208Y Institutional support: RVO:68378050 Keywords : T cell * actin * cytoskeleton * TCR * signal transduction * antigen recognition * antigen affinity threshold * immunological synapse Subject RIV: EB - Genetics ; Molecular Biology

  20. Burst activity and ultrafast activation kinetics of CaV1.3 Ca²⁺ channels support presynaptic activity in adult gerbil hair cell ribbon synapses.

    Science.gov (United States)

    Zampini, Valeria; Johnson, Stuart L; Franz, Christoph; Knipper, Marlies; Holley, Matthew C; Magistretti, Jacopo; Masetto, Sergio; Marcotti, Walter

    2013-08-15

    Auditory information transfer to afferent neurons relies on precise triggering of neurotransmitter release at the inner hair cell (IHC) ribbon synapses by Ca²⁺ entry through CaV1.3 Ca²⁺ channels. Despite the crucial role of CaV1.3 Ca²⁺ channels in governing synaptic vesicle fusion, their elementary properties in adult mammals remain unknown. Using near-physiological recording conditions we investigated Ca²⁺ channel activity in adult gerbil IHCs. We found that Ca²⁺ channels are partially active at the IHC resting membrane potential (-60 mV). At -20 mV, the large majority (>70%) of Ca²⁺ channel first openings occurred with an estimated delay of about 50 μs in physiological conditions, with a mean open time of 0.5 ms. Similar to other ribbon synapses, Ca²⁺ channels in IHCs showed a low mean open probability (0.21 at -20 mV), but this increased significantly (up to 0.91) when Ca²⁺ channel activity switched to a bursting modality. We propose that IHC Ca²⁺ channels are sufficiently rapid to transmit fast signals of sound onset and support phase-locking. Short-latency Ca²⁺ channel opening coupled to multivesicular release would ensure precise and reliable signal transmission at the IHC ribbon synapse.

  1. The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial

    NARCIS (Netherlands)

    Hunt, P.W.; Shulman, N.S.; Hayes, T.L.; Dahl, V.; Somsouk, M.; Funderburg, N.T.; McLaughlin, B.; Landay, A.L.; Adeyemi, O.; Gilman, L.E.; Clagett, B.; Rodriguez, B.; Martin, J.N.; Schacker, T.W.; Shacklett, B.L.; Palmer, S.; Lederman, M.M.; Deeks, S.G.

    2013-01-01

    The CCR5 inhibitor maraviroc has been hypothesized to decrease T-cell activation in HIV-infected individuals, but its independent immunologic effects have not been established in a placebo-controlled trial. We randomized 45 HIV-infected subjects with CD4 counts <350 cells per mm(3) and plasma HIV

  2. Immunologic proof of DNS irradiation damages and their repair in stationary yeast cells

    International Nuclear Information System (INIS)

    Waller, H.

    1980-08-01

    In rabbits an antiserum was produced by injecting UV-irradiated denaturated calf-thymus DNS; after inhibiting unspecific bindings, a specific serological reaction with UV-induced irradiation damages could be taken as present in this antiserum. By the ammonium sulphate precipitation as immunologic method of detection, after UV-irradiation the genesis of damages at certain sites in the DNS of different yeast lineages and their repair was observed. The elemination of UV-induced DNS damages was observed after an incubation in a nutrien medium, after photo-reactivation and after combining both therapeutic treatments. The following results were obtained: the detected DNS damage (number of induced dimeres/yeast genomes) had the same degree in the four yeast lineages. Apart from the excision-negative mutante 2094 for all yeast lineages a repair efficiency of 60% could be detected. All yeast lineages presented themselves as photographically to be reactivated; however, in all cases a DNS damage of 40 to 50% remained. The examinations for the specificity of antiserum against roentgenologically irradiated DNS led to the conclusion that the antibody population of the serum consisted mainly of immunoglobulines against unchanged DNS areas. A specific immunological reaction of only about 10% could be achieved. (orig./MG) [de

  3. Reproductive immunology

    DEFF Research Database (Denmark)

    Christiansen, Ole B

    2013-01-01

    pathological pregnancy are suggested to predispose to adaptive immunological processes against alloantigens on the trophoblast that may further increase the risk of pathological pregnancy outcome. The best documented adaptive immune reaction against fetal alloantigens is directed against male-specific minor...

  4. Immunology studies

    International Nuclear Information System (INIS)

    Smith, D.M.; Baron, P.A.; Drake, G.A.; LaBauve, P.M.; London, J.E.; Wilson, J.S.

    1977-01-01

    The following studies were conducted in the field of immunology; a model system to determine toxic effects on the immune system using 3 H-uridine uptake by Feells of rats; and survival in lethally irradiatd mice receiving allogenic fetal liver and thymus

  5. Hematopoietic stem cell transplantation induces immunologic tolerance in renal transplant patients via modulation of inflammatory and repair processes

    Directory of Open Access Journals (Sweden)

    Wu Duojiao

    2012-08-01

    Full Text Available Abstract Background Inducing donor-specific tolerance in renal transplant patients could potentially prevent allograft rejection and calcineurin inhibitor nephrotoxicity. Combined kidney and hematopoietic stem cell transplant from an HLA-matched donor is an exploratory and promising therapy to induce immune tolerance. Investigtion of molecular mechanisms involved in the disease is needed to understand the potential process of cell therapy and develop strategies to prevent this immunologic rejection. Methods We enrolled nine patients in a clinical study in which cryopreserved donor hematopoietic stem cells were infused on days 2, 4, and 6 after kidney transplantation. One month post-transplant, 4 plasma samples were collected from combined transplants (C + Tx, and 8 plasma samples from patients with kidney transplantation alone (Tx. High abundance proteins in plasma were depleted and the two-dimensional liquid chromatography-tandem mass spectrometry coupled with iTRAQ labeling was utilized to identify the protein profiling between the two groups. Clusters of up- and down-regulated protein profiles were submitted to MetaCore for the construction of transcriptional factors and regulation networks. Results and Discussion Among the 179 identified proteins, 65 proteins were found in C + Tx with at least a 2-fold change as compared with Tx. A subset of proteins related to the complement and coagulation cascade, including complement C3a,complement C5a, precrusors to fibrinogen alpha and beta chains,was significantly downregulated in C + Tx. Meanwhile, Apolipoprotein-A1(ApoA1, ApoC1, ApoA2, ApoE, and ApoB were significantly lower in Tx compared to C + Tx. Gene ontology analysis showed that the dominant processes of differentially expressed proteins were associated with the inflammatory response and positive regulation of plasma lipoprotein particle remodeling. Conclusions Thus, our study provides new insight into the molecular events in

  6. Basic and clinical immunology

    Science.gov (United States)

    Chinen, Javier; Shearer, William T.

    2003-01-01

    Progress in immunology continues to grow exponentially every year. New applications of this knowledge are being developed for a broad range of clinical conditions. Conversely, the study of primary and secondary immunodeficiencies is helping to elucidate the intricate mechanisms of the immune system. We have selected a few of the most significant contributions to the fields of basic and clinical immunology published between October 2001 and October 2002. Our choice of topics in basic immunology included the description of T-bet as a determinant factor for T(H)1 differentiation, the role of the activation-induced cytosine deaminase gene in B-cell development, the characterization of CD4(+)CD25(+) regulatory T cells, and the use of dynamic imaging to study MHC class II transport and T-cell and dendritic cell membrane interactions. Articles related to clinical immunology that were selected for review include the description of immunodeficiency caused by caspase 8 deficiency; a case series report on X-linked agammaglobulinemia; the mechanism of action, efficacy, and complications of intravenous immunoglobulin; mechanisms of autoimmunity diseases; and advances in HIV pathogenesis and vaccine development. We also reviewed two articles that explore the possible alterations of the immune system caused by spaceflights, a new field with increasing importance as human space expeditions become a reality in the 21st century.

  7. Alzheimer's disease: synapses gone cold

    Directory of Open Access Journals (Sweden)

    Hyman Bradley T

    2011-08-01

    Full Text Available Abstract Alzheimer's disease (AD is a progressive neurodegenerative disease characterized by insidious cognitive decline and memory dysfunction. Synapse loss is the best pathological correlate of cognitive decline in AD and mounting evidence suggests that AD is primarily a disease of synaptic dysfunction. Soluble oligomeric forms of amyloid beta (Aβ, the peptide that aggregates to form senile plaques in the brain of AD patients, have been shown to be toxic to neuronal synapses both in vitro and in vivo. Aβ oligomers inhibit long-term potentiation (LTP and facilitate long-term depression (LTD, electrophysiological correlates of memory formation. Furthermore, oligomeric Aβ has also been shown to induce synapse loss and cognitive impairment in animals. The molecular underpinnings of these observations are now being elucidated, and may provide clear therapeutic targets for effectively treating the disease. Here, we review recent findings concerning AD pathogenesis with a particular focus on how Aβ impacts synapses.

  8. The role of T-regulatory cells in the pathogenesis of immunological disturbances accompanying obesity and atherosclerosis

    Directory of Open Access Journals (Sweden)

    Włodzimierz Łuczyński

    2010-03-01

    Full Text Available Obesity and atherosclerosis, and their consequences, including cardiovascular disease, are plagues of the 21st century. Chronic inflammation, whose mechanism is not well understood, underlies the pathophysiological bases of both processes. T lymphocytes, macrophages, and the proinflammatory cytokines produced by these cells play key roles in the immunological disturbances accompanying obesity and atherosclerosis. It was recently shown that T-regulatory cells can play a role in these processes. T-regulatory cells are a small subpopulation of T cells which are responsible for inhibition of the immune response. In this review, experiments conducted in mice and human models on the role of diminished number and/or function of T-regulatory lymphocytes in the pathogenesis of immune disturbances accompanying obesity and atherosclerosis are discussed. The results of studies using T-regulatory cells to stabilize and decrease atherosclerotic lesions in blood vessel walls are also summarized. The results of experiments performed so far are encouraging and give some hope for the future use of T-regulatory cells in the therapy of obesity and atherosclerosis.

  9. Immunological Aspects of Cryoablation of Non-Small Cell Lung Cancer: A Comprehensive Review.

    Science.gov (United States)

    Katzman, Daniel; Wu, Shirley; Sterman, Daniel H

    2018-01-31

    In cryoimmunotherapy, target tumors are treated with cryoablation to generate antitumor immune responses. Because immune checkpoint inhibitors have demonstrated that lung cancer can be an immunotherapy-responsive disease, there has been renewed interest in the immunological aspects of cryoablation of lung cancer. Herein, we review preclinical and clinical trials of cryoablation of primary lung tumors. We examine the magnitude of cryoablation-induced antitumor immune responses and the synergy between cryoablation and either other immunotherapies or molecular targeted therapies to improve treatment responses in advanced lung cancer. We further discuss a rationale for the addition of cryoablation to immune checkpoint inhibitors for the treatment of advanced lung cancer, which is currently under clinical investigation. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  10. Synaptic Homeostasis and Its Immunological Disturbance in Neuromuscular Junction Disorders

    Directory of Open Access Journals (Sweden)

    Masaharu Takamori

    2017-04-01

    Full Text Available In the neuromuscular junction, postsynaptic nicotinic acetylcholine receptor (nAChR clustering, trans-synaptic communication and synaptic stabilization are modulated by the molecular mechanisms underlying synaptic plasticity. The synaptic functions are based presynaptically on the active zone architecture, synaptic vesicle proteins, Ca2+ channels and synaptic vesicle recycling. Postsynaptically, they are based on rapsyn-anchored nAChR clusters, localized sensitivity to ACh, and synaptic stabilization via linkage to the extracellular matrix so as to be precisely opposed to the nerve terminal. Focusing on neural agrin, Wnts, muscle-specific tyrosine kinase (a mediator of agrin and Wnts signalings and regulator of trans-synaptic communication, low-density lipoprotein receptor-related protein 4 (the receptor of agrin and Wnts and participant in retrograde signaling, laminin-network (including muscle-derived agrin, extracellular matrix proteins (participating in the synaptic stabilization and presynaptic receptors (including muscarinic and adenosine receptors, we review the functional structures of the synapse by making reference to immunological pathogenecities in postsynaptic disease, myasthenia gravis. The synapse-related proteins including cortactin, coronin-6, caveolin-3, doublecortin, R-spondin 2, amyloid precursor family proteins, glia cell-derived neurotrophic factor and neurexins are also discussed in terms of their possible contribution to efficient synaptic transmission at the neuromuscular junction.

  11. Immunology of Bee Venom.

    Science.gov (United States)

    Elieh Ali Komi, Daniel; Shafaghat, Farzaneh; Zwiener, Ricardo D

    2017-01-20

    Bee venom is a blend of biochemicals ranging from small peptides and enzymes to biogenic amines. It is capable of triggering severe immunologic reactions owing to its allergenic fraction. Venom components are presented to the T cells by antigen-presenting cells within the skin. These Th2 type T cells then release IL-4 and IL-13 which subsequently direct B cells to class switch to production of IgE. Generating venom-specific IgE and crosslinking FcεR1(s) on the surface of mast cells complete the sensitizing stage in allergic individuals who are most likely to experience severe and even fatal allergic reactions after being stung. Specific IgE for bee venom is a double-edged sword as it is a powerful mediator in triggering allergic events but is also applied successfully in diagnosis of the venom allergic patient. The healing capacity of bee venom has been rediscovered under laboratory-controlled conditions using animal models and cell cultures. The potential role of enzymatic fraction of bee venom including phospholipase A2 in the initiation and development of immune responses also has been studied in numerous research settings. Undoubtedly, having insights into immunologic interactions between bee venom components and innate/specific immune cells both locally and systematically will contribute to the development of immunologic strategies in specific and epitope-based immunotherapy especially in individuals with Hymenoptera venom allergy.

  12. HIV Molecular Immunology 2015

    Energy Technology Data Exchange (ETDEWEB)

    Yusim, Karina [Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Division; Korber, Bette Tina [Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Division; Brander, Christian [Institucio Catalana de Recerca i Estudis Avancats (ICREA), Barcelona (Spain); Barouch, Dan [Beth Israel Deaconess Medical Center, Boston, MA (United States). Division of Vaccine Research; de Boer, Rob [Utrecht University, Utrecht (Netherlands). Faculty of Biology; Haynes, Barton F. [Duke Univ., Durham, NC (United States). Duke Human Vaccine Institute and Departments of Medicine, Surgery and Immunology; Koup, Richard [National Inst. of Health (NIH), Bethesda, MD (United States). Vaccine Research Center; Moore, John P. [Cornell Univ., Ithaca, NY (United States). Weill Medical College; Walker, Bruce D. [Ragon Institute, Cambridge, MA (United States); Watkins, David [Wisconsin Regional Primate Research Center, Madison, WI (United States)

    2016-04-05

    The scope and purpose of the HIV molecular immunology database: HIV Molecular Immunology is a companion volume to HIV Sequence Compendium. This publication, the 2015 edition, is the PDF version of the web-based HIV Immunology Database (http://www.hiv.lanl.gov/ content/immunology/). The web interface for this relational database has many search options, as well as interactive tools to help immunologists design reagents and interpret their results. In the HIV Immunology Database, HIV-specific B-cell and T-cell responses are summarized and annotated. Immunological responses are divided into three parts, CTL, T helper, and antibody. Within these parts, defined epitopes are organized by protein and binding sites within each protein, moving from left to right through the coding regions spanning the HIV genome. We include human responses to natural HIV infections, as well as vaccine studies in a range of animal models and human trials. Responses that are not specifically defined, such as responses to whole proteins or monoclonal antibody responses to discontinuous epitopes, are summarized at the end of each protein section. Studies describing general HIV responses to the virus, but not to any specific protein, are included at the end of each part. The annotation includes information such as cross-reactivity, escape mutations, antibody sequence, TCR usage, functional domains that overlap with an epitope, immune response associations with rates of progression and therapy, and how specific epitopes were experimentally defined. Basic information such as HLA specificities for T-cell epitopes, isotypes of monoclonal antibodies, and epitope sequences are included whenever possible. All studies that we can find that incorporate the use of a specific monoclonal antibody are included in the entry for that antibody. A single T-cell epitope can have multiple entries, generally one entry per study. Finally, maps of all defined linear epitopes relative to the HXB2 reference proteins

  13. HIV Molecular Immunology 2014

    Energy Technology Data Exchange (ETDEWEB)

    Yusim, Karina [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Korber, Bette Tina Marie [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Barouch, Dan [Beth Israel Deaconess Medical Center, Boston, MA (United States); Koup, Richard [Vaccine Research Center National Institutes of Health (United States); de Boer, Rob [Utrecht Univ. (Netherlands). Dept. of Biology; Moore, John P. [Cornell Univ., Ithaca, NY (United States). Weill Medical College; Brander, Christian [Institucioi Catalana de Recerca i Estudis Avancats (ICREA), Barcelona (Spain); Haynes, Barton F. [Duke Univ., Durham, NC (United States). Duke Human Vaccine Institute and Departments of Medicine, Surgery and Immunology; Walker, Bruce D. [Ragon Institute of Massachusetts General Hospital, Cambridge, MA (United States); Harvard Univ., Cambridge, MA (United States); Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)

    2015-02-03

    HIV Molecular Immunology is a companion volume to HIV Sequence Compendium. This publication, the 2014 edition, is the PDF version of the web-based HIV Immunology Database (http://www.hiv.lanl.gov/content/immunology/). The web interface for this relational database has many search options, as well as interactive tools to help immunologists design reagents and interpret their results. In the HIV Immunology Database, HIV-specific B-cell and T-cell responses are summarized and annotated. Immunological responses are divided into three parts, CTL, T helper, and antibody. Within these parts, defined epitopes are organized by protein and binding sites within each protein, moving from left to right through the coding regions spanning the HIV genome. We include human responses to natural HIV infections, as well as vaccine studies in a range of animal models and human trials. Responses that are not specifically defined, such as responses to whole proteins or monoclonal antibody responses to discontinuous epitopes, are summarized at the end of each protein section. Studies describing general HIV responses to the virus, but not to any specific protein, are included at the end of each part. The annotation includes information such as crossreactivity, escape mutations, antibody sequence, TCR usage, functional domains that overlap with an epitope, immune response associations with rates of progression and therapy, and how specific epitopes were experimentally defined. Basic information such as HLA specificities for T-cell epitopes, isotypes of monoclonal antibodies, and epitope sequences are included whenever possible. All studies that we can find that incorporate the use of a specific monoclonal antibody are included in the entry for that antibody. A single T-cell epitope can have multiple entries, generally one entry per study. Finally, maps of all defined linear epitopes relative to the HXB2 reference proteins are provided.

  14. Brain RNA synthesis, long-term potentiation and depression at the perforant path-granule cell synapse in the guinea pig.

    Science.gov (United States)

    Sadile, A G; Neugebauer, A; Gessi, T; Marchionni, S; Giuditta, A

    1995-01-01

    The effects of long-term changes in synaptic efficacy at the perforant path-granule cell synapse on the de-novo synthesis of ribonucleic acid (RNA) were investigated in hippocampal and cortical areas in anaesthetized Guinea pig preparations. Two experiments were run with stimulating and recording microelectrodes aimed at the perforant bundle and dentate gyrus hilus on both sides. In Experiment 1, a low-frequency (LFS; 0.02 Hz, 3 h) or high-frequency stimulation (HFS; 400 Hz, 250 ms) was delivered to the left perforant bundle with the contralateral side as control. In Experiment 2, animals received LFS or HFS trains with implanted nonstimulated animals used as controls. The latency and amplitude of the field postsynaptic potentials (FPSP) and population spike (POPS) were monitored under baseline conditions and following stimulation over a 3 h period. In addition, two HFS groups were tested with few (HFS-F: every 15 min) or several test stimuli (HFS-S: every 3 min). In both experiments RNA synthesis was determined by measuring the amount of 3H-5,6-uridine incorporated into the RNA 3 h after bilateral intraventricular injection. In Exp. 1 the LFS group showed a higher synthesis of RNA than both HFS groups. The rate of RNA synthesis did not differ between the stimulated and nonstimulated side. In Exp. 2 the HFS groups showed a decreased RNA synthesis. In the HFS-F group, it pertained to the dorsal dentate area, CA1, subiculum, cingulate and dorsal cortices bilaterally, and to the ventral dentate area and CA3 on the nonstimulated side. In contrast, the HFS-S group showed decreased RNA synthesis at the dorsal dentate area and dorsal cortex on the stimulated side, and at CA1, subiculum, and cingulate cortex bilaterally. The decrease was stronger in the HFS-F than in the HFS-S group. Moreover, the subgroup with a low (0-60%) and that with a high (61-240%) level of long-term potentiation of FPSP revealed lower and higher RNA synthesis, respectively, both in homosynaptic

  15. Distributed changes in rat brain DNA synthesis with long-term habituation and potentiation of the perforant path-granule cell synapse.

    Science.gov (United States)

    Sadile, A G; Neugebauer, A; Morelli, F; Horvath, Z; Buzsàki, G; Giuditta, A

    1991-12-13

    The involvement of brain deoxyribonucleic acid (DNA) synthesis in adaptive neural events was studied in the adult rat during long-term habituation (LTH) or potentiation (LTP) of the perforant path-granule cell synapse. Male Long-Evans rats were given 50 muCi [3H]thymidine intraventricularly under urethane anesthesia. Soon thereafter, field excitatory postsynaptic potential (EPSP) slope and population spike were monitored from the right dentate gyrus before and at various times (5, 10, 15, 60 min) following the delivery to the ipsilateral perforant bundle of a low frequency (LFS: 1.0 Hz, 160 s) or a high-frequency train (HFS: 400 Hz, 200 ms), repeated once after 5 min. Unstimulated implanted rats served as controls. DNA synthesis was evaluated by the incorporation of the radioactive precursor into DNA of several brain areas at the end of a 1 h incorporation period. In CA1, LTH and LTP increased DNA synthesis by 30% on the stimulated side. In the entorhinal cortex, LTH but not LTP increased DNA synthesis (by 30%) on the stimulated side. Conversely, in the frontal cortex, LTP but not LTH increased DNA synthesis (by 100%) on both sides. Long-lasting changes in synaptic efficacy covaried non-linearly with DNA synthesis in mono- and polysynaptically stimulated hippocampal regions, and in functionally associated neocortical areas. The co-variations of population spike amplitude were positive for LTH and negative for LTP in the dentate gyrus and frontal cortex of both sides, and in CA3/CA1 of the stimulated side, indicating higher DNA synthesis at lower values of LTH and LTP, and viceversa. Further, regional cross-correlation analyses revealed a high degree of synchronization among brain sites, following low- or high-frequency train pulses, indicating that (i) extra-target sites participate on the stimulated and on the contralateral side, and (ii) small distributed changes take place across the sampled neural networks. A modulatory role of information flow on brain DNA

  16. Assessment of centrifugation using for accelerated immunological microarray analysis for blood cells investigation

    Directory of Open Access Journals (Sweden)

    A. V. Shishkin

    2011-01-01

    Full Text Available Phase of incubation microarray with cell suspension is prolonged when cells are investigated. It takes from 20 to 60 min if cell sedimentation on the surface of microarray is the result of gravity . Decrease of this stage duration is possible due to centrifugation. In th is article influence of centrifugation on results of analysis is considered. Changes of morphological description of cells are estimated when they a re precipitatedwith different acceleration. Also availability of centrifugation using when it is necessary to obtain the high density of cell binding in test regions of microarray if cells concentration in sample is small is demonstrated.

  17. Immunological and molecular biological identification of a true case of T-hairy cell leukaemia

    DEFF Research Database (Denmark)

    Demeter, J; Pálóczi, K; Földi, J

    1990-01-01

    A hairy cell leukaemia (HCL) patient is presented in whom the peripheral blood mononuclear cells (PBMCs) carried suppressor T-cell markers (CD3+, CD2+, CD8+/CD4-, CD38+). Analysis of genomic DNA of PBMNC showed the presence of a monoclonal population of T cells, the T-cell receptor (TCR) beta......-chain gene being rearranged on both alleles (DR/DR), while the immunoglobulin (Ig) heavy chain-genes were in germline configuration. The neoplastic cells were found to react with the monoclonal antibody RAB-1 - originally described as belonging to the B lineage-restricted monoclonal antibodies - and to carry...

  18. Immunological circumvention of multiple organ metastases of multidrug resistant human small cell lung cancer cells by mouse-human chimeric anti-ganglioside GM2 antibody KM966.

    Science.gov (United States)

    Hanibuchi, M; Yano, S; Nishioka, Y; Yanagawa, H; Miki, T; Sone, S

    2000-01-01

    serum against SBC-3/DOX cells to a similar extent compared with parental SBC-3 cells. Pretreatment of human effector cells with various cytokines induced further enhancement of the KM966-dependent ADCC against SBC-3/DOX cells. Intravenous injection of SBC-3 or SBC-3/DOX cells into natural killer (NK) cell-depleted severe combined immunodeficient (SCID) mice developed metastases in multiple organs (liver, kidneys and lymph nodes). Interestingly, SBC-3/DOX cells produced metastases more rapidly than SBC-3 cells, suggesting more aggressive phenotype of SBC-3/DOX cells than their parental cells in vivo. Systemic treatment with KM966, given on days 2 and 7, drastically inhibited the formation of multiple-organ metastases produced by both SBC-3 and SBC-3/DOX cells, indicating that KM966 can eradicate metastasis by SCLC cells irrespective of MDR phenotype. These findings suggest that the mouse-human chimeric KM966 targets the GM2 antigen, and might be useful for the immunological circumvention of multiple-organ metastases of refractory SCLC.

  19. Studying the Dynamics of TCR Internalization at the Immune Synapse.

    Science.gov (United States)

    Calleja, Enrique; Alarcón, Balbino; Oeste, Clara L

    2017-01-01

    Establishing a stable interaction between a T cell and an antigen presenting cell (APC) involves the formation of an immune synapse (IS). It is through this structure that the T cell can integrate all the signals provided by the APC. The IS also serves as a mechanism for TCR downregulation through internalization. Here, we describe methods for visualizing MHC-engaged T cell receptor (TCR) internalization from the IS in human cell lines and mouse primary T cells by confocal fluorescence microscopy techniques.

  20. Immunological Characterization of Whole Tumour Lysate-Loaded Dendritic Cells for Cancer Immunotherapy.

    Directory of Open Access Journals (Sweden)

    Veronica Rainone

    Full Text Available Dendritic cells play a key role as initiators of T-cell responses, and even if tumour antigen-loaded dendritic cells can induce anti-tumour responses, their efficacy has been questioned, suggesting a need to enhance immunization strategies.We focused on the characterization of bone marrow-derived dendritic cells pulsed with whole tumour lysate (TAA-DC, as a source of known and unknown antigens, in a mouse model of breast cancer (MMTV-Ras. Dendritic cells were evaluated for antigen uptake and for the expression of MHC class I/II and costimulatory molecules and markers associated with maturation.Results showed that antigen-loaded dendritic cells are characterized by a phenotypically semi-mature/mature profile and by the upregulation of genes involved in antigen presentation and T-cell priming. Activated dendritic cells stimulated T-cell proliferation and induced the production of high concentrations of IL-12p70 and IFN-γ but only low levels of IL-10, indicating their ability to elicit a TH1-immune response. Furthermore, administration of Antigen loaded-Dendritic Cells in MMTV-Ras mice evoked a strong anti-tumour response in vivo as demonstrated by a general activation of immunocompetent cells and the release of TH1 cytokines.Data herein could be useful in the design of antitumoral DC-based therapies, showing a specific activation of immune system against breast cancer.

  1. Immunologic Considerations for Generating Memory CD8 T Cells through Vaccination

    Science.gov (United States)

    Butler, Noah S.; Nolz, Jeffrey C.; Harty, John T.

    2011-01-01

    SUMMARY Following infection or vaccination, naïve CD8 T cells that receive the appropriate integration of antigenic, co-stimulatory, and inflammatory signals undergo a programmed series of biological changes that ultimately results in the generation of memory cells. Memory CD8 T cells, in contrast to naïve cells, more effectively limit or prevent pathogen re-infection due to both qualitative and quantitative changes that occur following their induction. Unlike vaccination strategies aimed at generating antibody production, the ability to generate protective memory CD8 T cells has proven more complicated and problematic. However, recent experimental results have revealed important principles regarding the molecular and genetic basis for memory CD8 T cell formation, as well as identified ways to manipulate their development through vaccination, resulting in potential new avenues to enhance protective immunity. PMID:21501363

  2. Immunologic considerations for generating memory CD8 T cells through vaccination.

    Science.gov (United States)

    Butler, Noah S; Nolz, Jeffrey C; Harty, John T

    2011-07-01

    Following infection or vaccination, naïve CD8 T cells that receive the appropriate integration of antigenic, co-stimulatory and inflammatory signals undergo a programmed series of biological changes that ultimately results in the generation of memory cells. Memory CD8 T cells, in contrast to naïve cells, more effectively limit or prevent pathogen re-infection because of both qualitative and quantitative changes that occur following their induction. Unlike vaccination strategies aimed at generating antibody production, the ability to generate protective memory CD8 T cells has proven more complicated and problematic. However, recent experimental results have revealed important principles regarding the molecular and genetic basis for memory CD8 T cell formation, as well as identified ways to manipulate their development through vaccination, resulting in potential new avenues to enhance protective immunity. © 2011 Blackwell Publishing Ltd.

  3. Psoralen/UV inactivation of HIV-1-infected cells for use in cytologic and immunologic procedures

    International Nuclear Information System (INIS)

    Watson, A.J.; Klaniecki, J.; Hanson, C.V.

    1990-01-01

    A rapid procedure for the inactivation of HIV-1-infected cells using psoralen and ultraviolet (UV) light is described. Exposure of HIV-1-infected cells to 5 micrograms/ml psoralen followed by UV irradiation (320-380 nm) for 5 minutes yields cells that are noninfectious as assessed by extended infectivity assays. The psoralen/UV inactivation procedure described is effective with cells chronically or acutely infected with HIV-1 and is unaffected by cell densities up to 12 x 10(6)/ml. At 5 micrograms/ml psoralen does little damage to cellular permeability as shown by the ability of treated cells to exclude trypan blue and propidium iodide. Psoralen/UV treatment of HIV-1-infected cells does not cause a significant decrease in the reactivity of HIV-1 core and envelope antigens or cellular antigens to monoclonal antibodies. Experiments are presented demonstrating the use of these cells for flow cytometry studies and for cell surface labeling using the lactoperoxidase 125 I iodination procedure

  4. Immunological control of a murine gammaherpesvirus independent of CD8+ T cells

    DEFF Research Database (Denmark)

    Stevenson, P G; Cardin, R D; Christensen, Jan Pravsgaard

    1999-01-01

    Adult thymectomized C57 BL/6J mice were depleted of T cell subsets by MAb treatment either prior to, or after, respiratory challenge with murine gammaherpesvirus-68. Protection against acute infection was maintained when either the CD4+ or the CD8+ T cell population was greatly diminished, whereas...... the concurrent removal of both T cell subsets proved invariably fatal. The same depletions had little effect on mice with established infection. The results indicate firstly that both CD4+ and CD8+ T cells play a significant part in dealing with the acute infection, and secondly that virus-specific antibody...

  5. Membrane prteins of herpes simplex infected cells. Immunological and biochemical studies

    NARCIS (Netherlands)

    Welling-Wester, Sijtske

    1981-01-01

    As a consequence of infection with herpes simplex virus (HSV), cells exhibit a number of alterations. One of these is expressed as a change in the polypeptide composition of the surface of the infected cells. In this study several methods used for the isolation of these polypeptides expressed on the

  6. Solution blow spinning fibres: New immunologically inert substrates for the analysis of cell adhesion and motility.

    Science.gov (United States)

    Paschoalin, Rafaella T; Traldi, Bruna; Aydin, Gülcan; Oliveira, Juliano E; Rütten, Stephan; Mattoso, Luiz H C; Zenke, Martin; Sechi, Antonio

    2017-03-15

    The control of cell behaviour through material geometry is appealing as it avoids the requirement for complex chemical surface modifications. Significant advances in new technologies have been made to the development of polymeric biomaterials with controlled geometry and physico-chemical properties. Solution blow spinning technique has the advantage of ease of use allowing the production of nano or microfibres and the direct fibre deposition on any surface in situ. Yet, in spite of these advantages, very little is known about the influence of such fibres on biological functions such as immune response and cell migration. In this work, we engineered polymeric fibres composed of either pure poly(lactic acid) (PLA) or blends of PLA and polyethylene glycol (PEG) by solution blow spinning and determined their impact on dendritic cells, highly specialised cells essential for immunity and tolerance. We also determined the influence of fibres on cell adhesion and motility. Cells readily interacted with fibres resulting in an intimate contact characterised by accumulation of actin filaments and focal adhesion components at sites of cell-fibre interactions. Moreover, cells were guided along the fibres and actin and focal adhesion components showed a highly dynamic behaviour at cell-fibre interface. Remarkably, fibres did not elicit any substantial increase of activation markers and inflammatory cytokines in dendritic cells, which remained in their immature (inactive) state. Taken together, these findings will be useful for developing new biomaterials for applications in tissue engineering and regenerative medicine. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  7. Detection of the immunologic rejection after xeno-islet transplantation: a study by MR imaging enhanced with superparamagnetic iron oxide marking CD4+ T cell antibody

    International Nuclear Information System (INIS)

    Nie Wei; Tang Yiya; Rong Pengfei; Ye Bin; Ye Zheng; Tong Qiongjuan; Wang Wei

    2008-01-01

    Objective: To evaluate the feasibility of the diagnosis of the early immunologic rejection after xeno-islet transplantation by MR imaging enhanced with superparamagnetic iron oxide (SPIO) marking CD4 + T cell antibody. Methods: Two thousand neonatal porcine islets (NPI)were transplanted under the left renal capsule of BALB/C nude mice. When the grafts could be observed by MRI, 10 7 human PBMC was intraperitoneal injected to nude mouse models to reconstitute the human immunologic system, 20 mice were reconstituted. Before and 3,7,14 days after reconstitution of human immunologic system on BALB/C nude mice, MRI imaging was performed half an hour after intravenous injection of nano-immunomagnetic beads via vena caudatis to observe the grafts' MRI signal. BALB/C nude mice were sacrificed after MRI scanning immediately, the histopathologic examination was assessed on grafts, the results were compared with MRI results. And calculate the sensitivity, specificity, Youden index number and coincidence of the MRI for immunologic rejection. Results: Grafts can be observed by MRI 3 weeks after islet cell transplantation (before immunologic rejection modeling), there is no abnormal MRI signal detected in nude mice' graft region after microbeads injected. Seven days after building of immunologic rejection model, MRI hypo-signal in graft site is shown in the T 2 WI sequence after nano-bioprober injected. Histopathologic assessments were employed on grafts in nude mice immediately (HE and immunohistochemistry staining), the results shown that there are a lot of T lymphocyts infiltrated in graft region, implying the occurrence of immunologic rejection. And the sensitivity, specificity, Youden index number and coincidence is: (72.96±0.24)%, 100%, 0.73±0.24, (88.46±0.13)% respectively. The correct Kappa between the MRI and the imunohistochemistry staining was 0.76. Conclusion: The cellular immunological rejection to xeno-islet grarts can be assessed with nano-bioprobe with anti-CD4

  8. Immunological challenges associated with artificial skin grafts: available solutions and stem cells in future design of synthetic skin.

    Science.gov (United States)

    Dixit, Saurabh; Baganizi, Dieudonné R; Sahu, Rajnish; Dosunmu, Ejowke; Chaudhari, Atul; Vig, Komal; Pillai, Shreekumar R; Singh, Shree R; Dennis, Vida A

    2017-01-01

    The repair or replacement of damaged skins is still an important, challenging public health problem. Immune acceptance and long-term survival of skin grafts represent the major problem to overcome in grafting given that in most situations autografts cannot be used. The emergence of artificial skin substitutes provides alternative treatment with the capacity to reduce the dependency on the increasing demand of cadaver skin grafts. Over the years, considerable research efforts have focused on strategies for skin repair or permanent skin graft transplantations. Available skin substitutes include pre- or post-transplantation treatments of donor cells, stem cell-based therapies, and skin equivalents composed of bio-engineered acellular or cellular skin substitutes. However, skin substitutes are still prone to immunological rejection, and as such, there is currently no skin substitute available to overcome this phenomenon. This review focuses on the mechanisms of skin rejection and tolerance induction and outlines in detail current available strategies and alternatives that may allow achieving full-thickness skin replacement and repair.

  9. On the resemblance of synapse formation and CNS myelination.

    Science.gov (United States)

    Almeida, R G; Lyons, D A

    2014-09-12

    The myelination of axons in the central nervous system (CNS) is essential for nervous system formation, function and health. CNS myelination continues well into adulthood, but not all axons become myelinated. Unlike the peripheral nervous system, where we know of numerous axon-glial signals required for myelination, we have a poor understanding of the nature or identity of such molecules that regulate which axons are myelinated in the CNS. Recent studies have started to elucidate cell behavior during myelination in vivo and indicate that the choice of which axons are myelinated is made prior to myelin sheath generation. Here we propose that interactions between axons and the exploratory processes of oligodendrocyte precursor cells (OPCs) lead to myelination and may be similar to those between dendrites and axons that prefigure and lead to synapse formation. Indeed axons and OPCs form synapses with striking resemblance to those of neurons, suggesting a similar mode of formation. We discuss families of molecules with specific functions at different stages of synapse formation and address studies that implicate the same factors during axon-OPC synapse formation and myelination. We also address the possibility that the function of such synapses might directly regulate the myelinating behavior of oligodendrocyte processes in vivo. In the future it may be of benefit to consider these similarities when taking a candidate-based approach to dissect mechanisms of CNS myelination. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Synapse Pathology in Psychiatric and Neurologic Disease

    NARCIS (Netherlands)

    M. van Spronsen (Myrrhe); C.C. Hoogenraad (Casper)

    2010-01-01

    textabstractInhibitory and excitatory synapses play a fundamental role in information processing in the brain. Excitatory synapses usually are situated on dendritic spines, small membrane protrusions that harbor glutamate receptors and postsynaptic density components and help transmit electrical

  11. Skin manifestations of adult T-cell leukemia/lymphoma: clinical, cytological and immunological features.

    Science.gov (United States)

    Tokura, Yoshiki; Sawada, Yu; Shimauchi, Takatoshi

    2014-01-01

    Adult T-cell leukemia/lymphoma (ATLL) is a malignancy of mature T cells caused by human T-cell leukemia virus type I. The endemic areas include Japan, especially in Kyushu, the Caribbean, Papua New Guinea, South America and Africa. Approximately 50% of ATLL patients exhibit skin manifestations. Cytologically, ATLL tumor cells are characterized by CD4(+) CD25(+) regulatory T-cell phenotype, high expressions of CCR4, and programmed cell death (PD)-1 and PD-ligand 1. The skin eruptions are categorized into six types: patch, plaque, multipapular, nodulotumoral, erythrodermic and purpuric. The overall survival of the eruption-bearing patients was poorer than that of the non-eruption-bearing patients in acute, chronic and smoldering types, but the survival levels of both groups were comparable in lymphoma type. The prognosis was poor in the order of: erythrodermic, nodulotumoral, multipapular/purpuric, plaque, then patch. Multivariate analysis revealed that the eruption type is an independent prognostic factor for ATLL. Patients may have other skin manifestations, secondary and infective lesions. © 2014 Japanese Dermatological Association.

  12. Unwanted Immunology

    Directory of Open Access Journals (Sweden)

    M.V. Supotnytskyi

    2016-04-01

    Full Text Available The paper considers the role of antigenic imprin­ting phenomena and antibody-dependent enhancement of infection in epidemic, infectious and postvaccinal processes. Based on published experimental data, it is shown that both phenomena are directly related to the laws of development and course of epide­mics, the pathogenesis of infectious diseases and safe use of vaccines. Their ignoring by researchers has led to failures in the design of vaccines against HIV/AIDS, dengue fever, influenza, malaria, hemorrhagic fever and encephalitis. These data show that, without taking into account the two phenomena, the further development of immunology and epidemiology in the direction of breakthrough discoveries in there areas of science are impossible.

  13. Hematology and immunology studies

    Science.gov (United States)

    Kimzey, S. L.

    1977-01-01

    A coordinated series of experiments were conducted to evaluate immunologic and hemotologic system responses of Skylab crewmen to prolonged space flights. A reduced PHA responsiveness was observed on recovery, together with a reduced number of T-cells, with both values returning to normal 3 to 5 days postflight. Subnormal red cell count, hemoglobin concentration, and hematocrit values also returned gradually to preflight limits. Most pronounced changes were found in the shape of red blood cells during extended space missions with a rapid reversal of these changes upon reentry into a normal gravitational environment.

  14. The gametic synapse

    DEFF Research Database (Denmark)

    Macaulay, Angus D.; Gilbert, Isabelle; Caballero, Julieta

    2014-01-01

    the gamete and the surrounding cells that is limited to paracrine signaling and direct transfer of small molecules via gap junctions existing at the end of the somatic cells' projections that are in contact with the oolemma. The purpose of this work was to explore the role of cumulus cell projections......, the delivery of which is supported by a remarkable synapselike vesicular trafficking connection between the cumulus cells and the gamete. This unexpected exogenous contribution to the maternal stores offers a new perspective on the determinants of female fertility....

  15. Post-Synapse Model Cell for Synaptic Glutamate Receptor (GluR-Based Biosensing: Strategy and Engineering to Maximize Ligand-Gated Ion-Flux Achieving High Signal-to-Noise Ratio

    Directory of Open Access Journals (Sweden)

    Tetsuya Haruyama

    2012-01-01

    Full Text Available Cell-based biosensing is a “smart” way to obtain efficacy-information on the effect of applied chemical on cellular biological cascade. We have proposed an engineered post-synapse model cell-based biosensors to investigate the effects of chemicals on ionotropic glutamate receptor (GluR, which is a focus of attention as a molecular target for clinical neural drug discovery. The engineered model cell has several advantages over native cells, including improved ease of handling and better reproducibility in the application of cell-based biosensors. However, in general, cell-based biosensors often have low signal-to-noise (S/N ratios due to the low level of cellular responses. In order to obtain a higher S/N ratio in model cells, we have attempted to design a tactic model cell with elevated cellular response. We have revealed that the increase GluR expression level is not directly connected to the amplification of cellular responses because the saturation of surface expression of GluR, leading to a limit on the total ion influx. Furthermore, coexpression of GluR with a voltage-gated potassium channel increased Ca2+ ion influx beyond levels obtained with saturating amounts of GluR alone. The construction of model cells based on strategy of amplifying ion flux per individual receptors can be used to perform smart cell-based biosensing with an improved S/N ratio.

  16. Post-synapse model cell for synaptic glutamate receptor (GluR)-based biosensing: strategy and engineering to maximize ligand-gated ion-flux achieving high signal-to-noise ratio.

    Science.gov (United States)

    Tateishi, Akito; Coleman, Sarah K; Migita, Satoshi; Keinänen, Kari; Haruyama, Tetsuya

    2012-01-01

    Cell-based biosensing is a "smart" way to obtain efficacy-information on the effect of applied chemical on cellular biological cascade. We have proposed an engineered post-synapse model cell-based biosensors to investigate the effects of chemicals on ionotropic glutamate receptor (GluR), which is a focus of attention as a molecular target for clinical neural drug discovery. The engineered model cell has several advantages over native cells, including improved ease of handling and better reproducibility in the application of cell-based biosensors. However, in general, cell-based biosensors often have low signal-to-noise (S/N) ratios due to the low level of cellular responses. In order to obtain a higher S/N ratio in model cells, we have attempted to design a tactic model cell with elevated cellular response. We have revealed that the increase GluR expression level is not directly connected to the amplification of cellular responses because the saturation of surface expression of GluR, leading to a limit on the total ion influx. Furthermore, coexpression of GluR with a voltage-gated potassium channel increased Ca(2+) ion influx beyond levels obtained with saturating amounts of GluR alone. The construction of model cells based on strategy of amplifying ion flux per individual receptors can be used to perform smart cell-based biosensing with an improved S/N ratio.

  17. Make immunological peace not war: Potential applications of tolerogenic dendritic cells

    Directory of Open Access Journals (Sweden)

    Emma Louise Walton

    2017-04-01

    Full Text Available In this issue of the Biomedical Journal, we explore the powerful immunosuppressive properties of tolerogenic dendritic cells and discuss their potential to bring about lifelong tolerance in transplantation and autoimmune disease. We also highlight an exciting new development in the field of malaria diagnosis that could facilitate early detection of the disease.

  18. Although Abundant in Tumor Tissue, Mast Cells Have No Effect on Immunological Micro-milieu or Growth of HPV-Induced or Transplanted Tumors

    Directory of Open Access Journals (Sweden)

    Shanawaz Mohammed Ghouse

    2018-01-01

    Full Text Available Summary: High numbers of mast cells populate the stroma of many types of neoplasms, including human papilloma virus-induced benign and malignant tumors in man and mouse. Equipped with numerous pattern recognition receptors and capable of executing important pro-inflammatory responses, mast cells are considered innate sentinels that significantly impact tumor biology. Mast cells were reported to promote human papilloma virus (HPV-induced epithelial hyperproliferation and neo-angiogenesis in an HPV-driven mouse model of skin cancer. We analyzed HPV-induced epithelial hyperplasia and squamous cell carcinoma formation, as well as growth of tumors inoculated into the dermis, in mice lacking skin mast cells. Unexpectedly, the absence of mast cells had no effect on HPV-induced epithelial growth or angiogenesis, on growth kinetics of inoculated tumors, or on the immunological tumor micro-milieu. Thus, the conspicuous recruitment of mast cells into tumor tissues cannot necessarily be equated with important mast cell functions in tumor growth. : Mast cells accumulate in high numbers in many human tumors, and they are widely viewed as important promoters of tumor growth. Ghouse et al. show that growth, angiogenesis, and the immunological micro-milieu of tumors growing in mice genetically deficient for mast cells are unchanged compared to control tumors. Keywords: mast cells, HPV-induced skin cancer, tumor angiogenesis, tumor micro-milieu

  19. Targeting dendritic cells through gold nanoparticles: A review on the cellular uptake and subsequent immunological properties.

    Science.gov (United States)

    Ahmad, Suhana; Zamry, Anes Ateqah; Tan, Hern-Tze Tina; Wong, Kah Keng; Lim, JitKang; Mohamud, Rohimah

    2017-11-01

    Gold nanoparticles (NPs) have been proposed as a highly potential tool in immunotherapies due to its advantageous properties including customizable size and shapes, surface functionality and biocompatibility. Dendritic cells (DCs), the sentinels of immune response, have been of interest to be manipulated by using gold NPs for targeted delivery of immunotherapeutic agent. Researches done especially in human DCs showed a variation of gold NPs effects on cellular uptake and internalization, DC maturation and subsequent T cells priming as well as cytotoxicity. In this review, we describe the synthesis and physiochemical properties of gold NPs as well as the importance of gold NPs in immunotherapies through their actions on human DCs. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. Make immunological peace not war: Potential applications of tolerogenic dendritic cells.

    Science.gov (United States)

    Walton, Emma Louise

    2017-04-01

    In this issue of the Biomedical Journal, we explore the powerful immunosuppressive properties of tolerogenic dendritic cells and discuss their potential to bring about lifelong tolerance in transplantation and autoimmune disease. We also highlight an exciting new development in the field of malaria diagnosis that could facilitate early detection of the disease. Copyright © 2017 Chang Gung University. Published by Elsevier B.V. All rights reserved.

  1. Polyactin A increases CD4(+) T-cell counts in HIV-infected individuals with insufficient immunologic response to highly active antiretroviral therapy.

    Science.gov (United States)

    Su, Qi-jian; Li, Yi-zhong; Liang, Fei-li; Xiao, Jian; Deng, Xin

    2014-01-01

    We conducted a study to determine whether an immunomodulator, polyactin A, is able to enhance the immunologic response in patients with insufficient immunologic response to highly active antiretroviral therapy. From 783 patients, 48 were eligible and were randomly assigned to an experimental group receiving polyactin A for 3 months or a control group. CD4(+) T-cell counts in the experimental group increased from 201 ± 31 to 228 ± 38 cells/µl after treatment (p counts in the control group and CD8(+) T-cell counts and CD4(+)/CD8(+) ratios in both groups did not differ significantly between baseline and month 3. The experimental group had a higher CD4(+) T-cell count than the control group at month 3 (228 ± 38 versus 205 ± 35, p counts in patients with insufficient immunologic response to highly active antiretroviral therapy, but further studies are required to determine its clinical benefits.

  2. Regenerative immunology: the immunological reaction to biomaterials.

    Science.gov (United States)

    Cravedi, Paolo; Farouk, Samira; Angeletti, Andrea; Edgar, Lauren; Tamburrini, Riccardo; Duisit, Jerome; Perin, Laura; Orlando, Giuseppe

    2017-12-01

    Regenerative medicine promises to meet two of the most urgent needs of modern organ transplantation, namely immunosuppression-free transplantation and an inexhaustible source of organs. Ideally, bioengineered organs would be manufactured from a patient's own biomaterials-both cells and the supporting scaffolding materials in which cells would be embedded and allowed to mature to eventually regenerate the organ in question. While some groups are focusing on the feasibility of this approach, few are focusing on the immunogenicity of the scaffolds that are being developed for organ bioengineering purposes. This review will succinctly discuss progress in the understanding of immunological characteristics and behavior of different scaffolds currently under development, with emphasis on the extracellular matrix scaffolds obtained decellularized animal or human organs which seem to provide the ideal template for bioengineering purposes. © 2017 Steunstichting ESOT.

  3. Metabolomics in Immunology Research.

    Science.gov (United States)

    Everts, Bart

    2018-01-01

    There is a growing appreciation that metabolic processes and individual metabolites can shape the function of immune cells and thereby play important roles in the outcome of immune responses. In this respect, the use of MS- and NMR spectroscopy-based platforms to characterize and quantify metabolites in biological samples has recently yielded important novel insights into how our immune system functions and has contributed to the identification of biomarkers for immune-mediated diseases. Here, these recent immunological studies in which metabolomics has been used and made significant contributions to these fields will be discussed. In particular the role of metabolomics to the rapidly advancing field of cellular immunometabolism will be highlighted as well as the future prospects of such metabolomic tools in immunology.

  4. The debate on the kiss-and-run fusion at synapses.

    Science.gov (United States)

    He, Liming; Wu, Ling-Gang

    2007-09-01

    It has long been proposed that following vesicle fusion, a small pore might open and close rapidly without full dilation. Such 'kiss-and-run' vesicle fusion can in principle result in rapid vesicle recycling and influence the size and the kinetics of the resulting synaptic current. However, the existence of kiss-and-run remains highly controversial, as revealed by recent imaging and electrophysiological studies at several synapses, including hippocampal synapses, neuromuscular junctions and retinal bipolar synapses. Only a minor fraction of fusion events has been shown to be kiss-and-run, as determined using cell-attached capacitance recordings in endocrine cells, pituitary nerve terminals and calyx-type synapses. Further work is needed to determine whether kiss-and-run is a major mode of fusion and has a major role in controlling synaptic strength at synapses.

  5. Dynamic mobility of functional GABAA receptors at inhibitory synapses.

    Science.gov (United States)

    Thomas, Philip; Mortensen, Martin; Hosie, Alastair M; Smart, Trevor G

    2005-07-01

    Importing functional GABAA receptors into synapses is fundamental for establishing and maintaining inhibitory transmission and for controlling neuronal excitability. By introducing a binding site for an irreversible inhibitor into the GABAA receptor alpha1 subunit channel lining region that can be accessed only when the receptor is activated, we have determined the dynamics of receptor mobility between synaptic and extrasynaptic locations in hippocampal pyramidal neurons. We demonstrate that the cell surface GABAA receptor population shows no fast recovery after irreversible inhibition. In contrast, after selective inhibition, the synaptic receptor population rapidly recovers by the import of new functional entities within minutes. The trafficking pathways that promote rapid importation of synaptic receptors do not involve insertion from intracellular pools, but reflect receptor diffusion within the plane of the membrane. This process offers the synapse a rapid mechanism to replenish functional GABAA receptors at inhibitory synapses and a means to control synaptic efficacy.

  6. A new Purkinje cell antibody (anti-Ca associated with subacute cerebellar ataxia: immunological characterization

    Directory of Open Access Journals (Sweden)

    Horn Sigrun

    2010-03-01

    Full Text Available Abstract We report on a newly discovered serum and cerebrospinal fluid (CSF reactivity to Purkinje cells (PCs associated with subacute inflammatory cerebellar ataxia. The patient, a previously healthy 33-year-old lady, presented with severe limb and gait ataxia, dysarthria, and diplopia two weeks after she had recovered from a common cold. Immunohistochemical studies on mouse, rat, and monkey brain sections revealed binding of a high-titer (up to 1:10,000 IgG antibody to the cerebellar molecular layer, Purkinje cell (PC layer, and white matter. The antibody is highly specific for PCs and binds to the cytoplasm as well as to the inner side of the membrane of PC somata, dendrites and axons. It is produced by B cell clones within the CNS, belongs to the IgG1 subclass, and activates complement in vitro. Western blotting of primate cerebellum extract revealed binding of CSF and serum IgG to an 80-97 kDa protein. Extensive control studies were performed to rule out a broad panel of previously described paraneoplastic and non-paraneoplastic antibodies known to be associated with cerebellar ataxia. Screening of >9000 human full length proteins by means of a protein array and additional confirmatory experiments revealed Rho GTPase activating protein 26 (ARHGAP26, GRAF, oligophrenin-1-like protein as the target antigen. Preadsorption of the patient's serum with human ARHGAP26 but not preadsorption with other proteins resulted in complete loss of PC staining. Our findings suggest a role of autoimmunity against ARHGAP26 in the pathogenesis of subacute inflammatory cerebellar ataxia, and extend the panel of diagnostic markers for this devastating disease.

  7. TFH-derived dopamine accelerates productive synapses in germinal centres.

    Science.gov (United States)

    Papa, Ilenia; Saliba, David; Ponzoni, Maurilio; Bustamante, Sonia; Canete, Pablo F; Gonzalez-Figueroa, Paula; McNamara, Hayley A; Valvo, Salvatore; Grimbaldeston, Michele; Sweet, Rebecca A; Vohra, Harpreet; Cockburn, Ian A; Meyer-Hermann, Michael; Dustin, Michael L; Doglioni, Claudio; Vinuesa, Carola G

    2017-07-20

    Protective high-affinity antibody responses depend on competitive selection of B cells carrying somatically mutated B-cell receptors by follicular helper T (T FH ) cells in germinal centres. The rapid T-B-cell interactions that occur during this process are reminiscent of neural synaptic transmission pathways. Here we show that a proportion of human T FH cells contain dense-core granules marked by chromogranin B, which are normally found in neuronal presynaptic terminals storing catecholamines such as dopamine. T FH cells produce high amounts of dopamine and release it upon cognate interaction with B cells. Dopamine causes rapid translocation of intracellular ICOSL (inducible T-cell co-stimulator ligand, also known as ICOSLG) to the B-cell surface, which enhances accumulation of CD40L and chromogranin B granules at the human T FH cell synapse and increases the synapse area. Mathematical modelling suggests that faster dopamine-induced T-B-cell interactions increase total germinal centre output and accelerate it by days. Delivery of neurotransmitters across the T-B-cell synapse may be advantageous in the face of infection.

  8. Immunology of endometriosis.

    Science.gov (United States)

    Riccio, Luiza da Gama Coelho; Santulli, Pietro; Marcellin, Louis; Abrão, Mauricio Simões; Batteux, Frederic; Chapron, Charles

    2018-02-08

    The pathophysiology of endometriosis is not completely understood, but an aberrant immune response in the peritoneal environment seems to be crucial for the proliferation of ectopic endometrial cells - as those cells escape apoptosis and peritoneal cavity immunosurveillance. The growth of endometrial implants leads to the recruitment of a large number and diversity of immune cells and intense inflammation with increased pro-inflammatory cytokines, growth factors, and angiogenesis. There is substantial evidence of aberrant function of almost all types of immune cells in women with endometriosis: decreased T cell reactivity and NK cytotoxicity, polyclonal activation of B cells and increased antibody production, increased number and activation of peritoneal macrophages, and changes in inflammatory mediators. New clinical treatments for endometriosis are an urgent need, especially nonhormonal drugs. The study of immunology may clarify its role in the pathogenesis of endometriosis and contribute to the development of new therapeutic strategies. Copyright © 2018 Elsevier Ltd. All rights reserved.

  9. Clinical and Immunological Features of Opsoclonus-Myoclonus Syndrome in the Era of Neuronal Cell Surface Antibodies.

    Science.gov (United States)

    Armangué, Thaís; Sabater, Lidia; Torres-Vega, Estefanía; Martínez-Hernández, Eugenia; Ariño, Helena; Petit-Pedrol, Mar; Planagumà, Jesús; Bataller, Luis; Dalmau, Josep; Graus, Francesc

    2016-04-01

    Most studies on opsoclonus-myoclonus syndrome (OMS) in adults are based on small case series before the era of neuronal cell surface antibody discovery. To report the clinical and immunological features of idiopathic OMS (I-OMS) and paraneoplastic OMS (P-OMS), the occurrence of antibodies to cell surface antigens, and the discovery of a novel cell surface epitope. Retrospective cohort study and laboratory investigations of 114 adult patients with OMS at a center for autoimmune neurological disorders done between January 2013 and September 2015. Review of clinical records. Immunohistochemistry on rat brain and cultured neurons as well as cell-based assays were used to identify known autoantibodies. Immunoprecipitation and mass spectrometry were used to characterize novel antigens. Of the 114 patients (62 [54%] female; median age, 45 years; interquartile range, 32-60 years), 45 (39%) had P-OMS and 69 (61%) had I-OMS. In patients with P-OMS, the associated tumors included lung cancer (n = 19), breast cancer (n = 10), other cancers (n = 5), and ovarian teratoma (n = 8); 3 additional patients without detectable cancer were considered to have P-OMS because they had positive results for onconeuronal antibodies. Patients with I-OMS, compared with those who had P-OMS, were younger (median age, 38 [interquartile range, 31-50] vs 54 [interquartile range, 45-65] years; P OMS with lung cancer (21% vs 5% in patients with OMS without lung cancer; P = .02); however, a similar frequency of glycine receptor antibodies was found in patients with lung cancer without OMS (13 of 65 patients [20%]). A novel cell surface epitope, human natural killer 1 (HNK-1), was the target of the antibodies in 3 patients with lung cancer and P-OMS. Patients with I-OMS responded better to treatment and had fewer relapses than those with P-OMS. Older age and encephalopathy, significantly associated with P-OMS, are clinical clues suggesting an underlying tumor. Glycine receptor antibodies occur

  10. Physiological Role of TNF in MucosalImmunology: Regulation of Macrophage/Dendritic Cell Function

    DEFF Research Database (Denmark)

    Rivollier, Aymeric Marie Christian; Marsal, J.; Agace, William Winston

    2015-01-01

    to the pathogenesis of inflammatory bowel disease. In this review, we discuss the role of tumor necrosis factor-α (TNF) in regulating multiple aspects of intestinal Mϕ and DC physiology, including their differentiation, migration, maturation, survival and effector functions. In inflammatory bowel disease, TNF...... signaling has been implicated in reprogramming monocyte differentiation from the anti-inflammatory Mϕ lineage towards the pro-inflammatory mononuclear phagocyte lineage.These cells become a major source of TNF and, thus,may contribute to the chronic inflammatory process. Finally,we highlight some...... of the important gaps in our current knowledge regarding the role of TNF in Mϕ and DCphysiology and suggest important directions for future research in this field....

  11. A review on tumor immunology

    Directory of Open Access Journals (Sweden)

    Sri Lalitha Kaja

    2017-01-01

    Full Text Available The ability of immune system to detect and destroy the altered/abnormal cells may inhibit the development of various cancers. The immune system had been proposed as a tactic in sustaining nonneoplastic state and also for the development of immunotherapy against cancer. Although the immune system exerts a protective role, under certain circumstances, it could be damaging in terms of modulating the oncogenic process. The failure of host's immunological responses against tumor growth and dissemination implicated that both immunologic and nonimmunologic factors may work together to affect tumorigenesis. Hence, understanding the aspects pertaining to tumor immunology which deals with the complex interactions between the host's immune system and neoplasm is essential. The current review focuses on the aspects concerned with tumor immunology, steps involved, and cancer immunotherapy as a probable therapeutic tool.

  12. Radiotherapy as an immunological booster in patients with metastatic melanoma or renal cell carcinoma treated with high-dose Interleukin-2: evaluation of biomarkers of immunologic and therapeutic response.

    Science.gov (United States)

    Ridolfi, Laura; de Rosa, Francesco; Ridolfi, Ruggero; Gentili, Giorgia; Valmorri, Linda; Scarpi, Emanuela; Parisi, Elisabetta; Romeo, Antonino; Guidoboni, Massimo

    2014-09-23

    Tumor cells killed by radiation therapy (RT) are a potentially good source of antigens for dendritic cell (DC) uptake and presentation to T-cells. RT upregulates cell death receptors such as Fas/CD95 and MHC-I, induces the expression of co-stimulatory molecules on tumor cells, and promotes production of pro-inflammatory cytokines. High-dose interleukin-2 (HD-IL-2) bolus has been shown to obtain objective response rates ranging from 15% to 17% in patients with metastatic melanoma or renal cell carcinoma (RCC), with 6% to 8% of cases experiencing a durable complete response. However, HD-IL-2 is also associated with severe side-effects; if it is to remain a component of the curative treatment strategy in patients with metastatic melanoma or RCC, its therapeutic efficacy must be improved and patients who are most likely to benefit from treatment must be identified a priori. We designed a clinical study combining immunomodulating RT and HD-IL-2 to evaluate their clinical and immunological efficacy and to explore the predictive and prognostic value of 1) tumor-specific immune response and 2) serum levels of proangiogenic cytokines. The primary endpoint of this proof-of-principle phase II study is immune response. Secondary endpoints are the identification of biomarkers potentially predictive of response, toxicity, response rate and overall survival. Three daily doses of booster radiotherapy (XRT) at 6-12 Gy will be administered to at least one metastatic field on days -3 to -1 before the first and third cycle. Treatment with IL-2 (dose 18 MIU/m2/day by continuous IV infusion for 72 hours) will start on day +1 and will be repeated every 3 weeks for up to 4 cycles and then every 4 weeks for a further 2 cycles. Immune response against tumor antigens expressed by melanoma and/or RCC will be evaluated during treatment. Circulating immune effectors and regulators, e.g. cytotoxic T lymphocytes and regulatory T cells, as well as serum levels of proangiogenic

  13. Immunological aspects of adult T-cell leukemia/lymphoma (ATLL), a possible neoplasm of regulatory T-cells

    OpenAIRE

    Yamada, Yasuaki; Kamihira, Shimeru

    2008-01-01

    Adult T-cell leukemia/lymphoma (ATLL) is a distinct disease caused by the first discovered human oncogenic retrovirus, human T-cell leukemia virus type-1 (HTLV-1). The peculiarity of this disease is not only in its causative agent HTLV-1 but also in the character of leukemia cells. ATLL cells express the mature helper/inducer T-cell antigens, CD2, CD3, CD4 and CD5 but usually lacking CD8. Despite CD4 expression, it has long been known that ATLL cells exhibit strong immunosuppressive activity ...

  14. [Bilharzial granuloma - immunological aspects (author's transl)].

    Science.gov (United States)

    Nozais, J P

    1981-01-01

    Living eggs of schistosoma are responsible for the tissular granulomatous reactions of the parasitized organism. It has been demonstrated that this process resorts to a reaction of delayed hypersensitivity related to the complex immunologic mechanisms involving egg specific antigens and immunocompetent cells (lympho-plasmocytic cells). In long duration infections, the granulomatous reaction disappears (endogenic desensitization by immunological processes).

  15. Segregation of receptor-ligand complexes in cell adhesion zones: Phase diagrams and role of thermal membrane roughness

    OpenAIRE

    Rozycki, Bartosz; Lipowsky, Reinhard; Weikl, Thomas R.

    2010-01-01

    The adhesion zone of immune cells, the 'immunological synapse', exhibits characteristic domains of receptor-ligand complexes. The domain formation is likely caused by a length difference of the receptor-ligand complexes, and has been investigated in experiments in which T cells adhere to supported membranes with anchored ligands. For supported membranes with two types of anchored ligands, MHCp and ICAM1, that bind to the receptors TCR and LFA1 in the cell membrane, the coexistence of domains ...

  16. Immunology in Pittsburgh.

    Science.gov (United States)

    Finn, Olivera J; Salter, Russell D

    2006-01-01

    The University of Pittsburgh School of Medicine has a long tradition of excellence in immunology research and training. Faculty, students, and postdoctoral fellows walk through hallways that are pictorial reminders of the days when Dr. Jonas Salk worked here to develop the polio vaccine, or when Dr. Niels Jerne chaired the Microbiology Department and worked on perfecting the Jerne Plaque Assay for antibody-producing cells. Colleagues and postdoctoral fellows of Professor Salk are still on the faculty of the University of Pittsburgh Medical School as are graduate students of Professor Jerne. A modern research building, the 17 story high Biomedical Science Tower, is a vivid reminder of the day when Dr. Thomas Starzl arrived in Pittsburgh and started building the most prominent solid-organ-transplant program in the world. The immunology research that developed around the problem of graft rejection and tolerance induction trained numerous outstanding students and fellows. Almost 20 yr ago, the University of Pittsburgh founded the University of Pittsburgh Cancer Institute (UPCI) with the renowned immunologist Dr. Ronald Herberman at its helm. This started a number of new research initiatives in cancer immunology and immunotherapy. A large number of outstanding young investigators, as well as several well-established tumor immunologists, were recruited to Pittsburgh at that time.

  17. Antibody response against Betaferon® in immune tolerant mice: involvement of marginal zone B-cells and CD4+ T-cells and apparent lack of immunological memory.

    Science.gov (United States)

    Sauerborn, Melody; van Beers, Miranda M C; Jiskoot, Wim; Kijanka, Grzegorz M; Boon, Louis; Schellekens, Huub; Brinks, Vera

    2013-01-01

    The immunological processes underlying immunogenicity of recombinant human therapeutics are poorly understood. Using an immune tolerant mouse model we previously demonstrated that aggregates are a major trigger of the antidrug antibody (ADA) response against recombinant human interferon beta (rhIFNβ) products including Betaferon®, and that immunological memory seems to be lacking after a rechallenge with non-aggregated rhIFNβ. The apparent absence of immunological memory indicates a CD4+ T-cell independent (Tind) immune response underlying ADA formation against Betaferon®. This hypothesis was tested. Using the immune tolerant mouse model we first validated that rechallenge with highly aggregated rhIFNβ (Betaferon®) does not lead to a subsequent fast increase in ADA titers, suggesting a lack of immunological memory. Next we assessed whether Betaferon® could act as Tind antigen by inactivation of marginal zone (MZ) B-cells during treatment. MZ B-cells are major effector cells involved in a Tind immune response. In a following experiment we depleted the mice from CD4+ T-cells to test their involvement in the ADA response against Betaferon®. Inactivation of MZ B-cells at the start of Betaferon® treatment drastically lowered ADA levels, suggesting a Tind immune response. However, persistent depletion of CD4+ T-cells before and during Betaferon® treatment abolished the ADA response in almost all mice. The immune response against rhIFNβ in immune tolerant mice is neither a T-cell independent nor a classical T-cell dependent immune response. Further studies are needed to confirm absence of immunological memory (cells).

  18. Distribution and structure of efferent synapses in the chicken retina

    Science.gov (United States)

    Lindstrom, SH; Nacsa, N; Blankenship, T; Fitzgerald, PG; Weller, C; Vaney, DI; Wilson, M

    2012-01-01

    The visual system of birds includes an efferent projection from a visual area, the isthmooptic nucleus in the midbrain, back to the retina. Using a combination of anterograde labeling of efferent fibers, reconstruction of dye-filled neurons, NADPH-diaphorase staining, and transmission electron microscopy we have examined the distribution of efferent fibers and their synaptic structures in the chicken retina. We show that efferent fibers terminate strictly within the ventral retina. In 2 completely mapped retinas, only 2 fibers from a total of 15,359 terminated in the dorsal retina. The major synapse made by each efferent fiber is with a single Efferent Target Amacrine Cell (TC). This synapse consists of 5-25 boutons of 2μm diameter, each with multiple active zones, pressed into the TC soma or synapsing with a basketwork of rudimentary TC dendrites in the inner nuclear layer (INL). This basketwork, which is sheathed by Muller cells processes, defines a private neuropil in the INL within which TCs were also seen to receive input from retinal neurons. In addition to the major synapse, efferent fibers typically produce several very thin processes that terminate nearby in single small boutons and for which the soma of a local amacrine cell is one of the likely postsynaptic partners. A minority of efferent fibers also give rise to a thicker process terminating in a strongly diaphorase positive ball about 5μm in diameter. PMID:19439107

  19. N-CADHERIN PRODOMAIN CLEAVAGE REGULATES SYNAPSE FORMATION IN VIVO

    Science.gov (United States)

    Latefi, Nazlie S.; Pedraza, Liliana; Schohl, Anne; Li, Ziwei; Ruthazer, Edward S.

    2009-01-01

    Cadherins are initially synthesized bearing a prodomain that is thought to limit adhesion during early stages of biosynthesis. Functional cadherins lack this prodomain, raising the intriguing possibility that cells may utilize prodomain cleavage as a means to temporally or spatially regulate adhesion after delivery of cadherin to the cell surface. In support of this idea, immunostaining for the prodomain of zebrafish N-cadherin revealed enriched labeling at neuronal surfaces at the soma and along axonal processes. To determine whether post-translational cleavage of the prodomain affects synapse formation, we imaged Rohon-Beard cells in zebrafish embryos expressing GFP-tagged wild-type N-cadherin (NCAD-GFP) or a GFP-tagged N-cadherin mutant expressing an uncleavable prodomain (PRON-GFP) rendering it non-adhesive. NCAD-GFP accumulated at synaptic microdomains in a developmentally regulated manner, and its overexpression transiently accelerated synapse formation. PRON-GFP was much more diffusely distributed along the axon and its overexpression delayed synapse formation. Our results support the notion that N-cadherin serves to stabilize pre- to postsynaptic contacts early in synapse development and suggests that regulated cleavage of the N-cadherin prodomain may be a mechanism by which the kinetics of synaptogenesis are regulated. PMID:19365814

  20. Microglial interactions with synapses are modulated by visual experience.

    Directory of Open Access Journals (Sweden)

    Marie-Ève Tremblay

    2010-11-01

    Full Text Available Microglia are the immune cells of the brain. In the absence of pathological insult, their highly motile processes continually survey the brain parenchyma and transiently contact synaptic elements. Aside from monitoring, their physiological roles at synapses are not known. To gain insight into possible roles of microglia in the modification of synaptic structures, we used immunocytochemical electron microscopy, serial section electron microscopy with three-dimensional reconstructions, and two-photon in vivo imaging to characterize microglial interactions with synapses during normal and altered sensory experience, in the visual cortex of juvenile mice. During normal visual experience, most microglial processes displayed direct apposition with multiple synapse-associated elements, including synaptic clefts. Microglial processes were also distinctively surrounded by pockets of extracellular space. In terms of dynamics, microglial processes localized to the vicinity of small and transiently growing dendritic spines, which were typically lost over 2 d. When experience was manipulated through light deprivation and reexposure, microglial processes changed their morphology, showed altered distributions of extracellular space, displayed phagocytic structures, apposed synaptic clefts more frequently, and enveloped synapse-associated elements more extensively. While light deprivation induced microglia to become less motile and changed their preference of localization to the vicinity of a subset of larger dendritic spines that persistently shrank, light reexposure reversed these behaviors. Taken together, these findings reveal different modalities of microglial interactions with synapses that are subtly altered by sensory experience. These findings suggest that microglia may actively contribute to the experience-dependent modification or elimination of a specific subset of synapses in the healthy brain.

  1. Peripheral synapses and giant neurons in whip spiders.

    Science.gov (United States)

    Foelix, Rainer; Troyer, David; Igelmund, Peter

    2002-08-15

    Among invertebrates the synapses between neurons are generally restricted to ganglia, i.e., to the central nervous system (CNS). As an exception, synapses occur in the sensory nerves of arachnid legs, indicating that some nervous integration is already taking place far out in the periphery. In the antenniform legs of whip spiders (Amblypygi), a very special synaptic circuit is present. These highly modified legs contain several large interneurons (giant neurons) that receive mechanosensory input from 700-1,500 tarsal bristles. Some of the sensory cell axons contact a giant neuron at its short, branched dendrite, a few at the soma, but most synapse onto the long giant axon. The fine structure of these synapses resembles that of typical chemical synapses in other arthropods. Although thousands of sensory fibers converge on a single giant neuron, there is no reduction in the actual number of sensory fibers, because these afferent fibers continue their course to the CNS after having made several en passant synapses onto the giant neuron. Touching a single tarsal bristle is sufficient to elicit action potentials in a giant neuron. Owing to the large diameter of the giant axon (10-20 microm), the action potentials reach the CNS within 55 ms, at conduction velocities of up to 7 m/s. However, mechanical stimulation of the tarsal bristles does not elicit a fast escape response, in contrast to giant fiber systems in earthworms, certain insects, and crayfishes. A quick escape is observed in whip spiders, but only after stimulation of the filiform hairs (trichobothria) on the regular walking legs. Although the giant fiber system in the antenniform legs undoubtedly provides a fast sensory pathway, its biological significance is not clearly understood at the moment. Copyright 2002 Wiley-Liss, Inc.

  2. N-cadherin relocalizes from the periphery to the center of the synapse after transient synaptic stimulation in hippocampal neurons.

    Directory of Open Access Journals (Sweden)

    Patricia T Yam

    Full Text Available N-cadherin is a cell adhesion molecule which is enriched at synapses. Binding of N-cadherin molecules to each other across the synaptic cleft has been postulated to stabilize adhesion between the presynaptic bouton and the postsynaptic terminal. N-cadherin is also required for activity-induced changes at synapses, including hippocampal long term potentiation and activity-induced spine expansion and stabilization. We hypothesized that these activity-dependent changes might involve changes in N-cadherin localization within synapses. To determine whether synaptic activity changes the localization of N-cadherin, we used structured illumination microscopy, a super-resolution approach which overcomes the conventional resolution limits of light microscopy, to visualize the localization of N-cadherin within synapses of hippocampal neurons. We found that synaptic N-cadherin exhibits a spectrum of localization patterns, ranging from puncta at the periphery of the synapse adjacent to the active zone to an even distribution along the synaptic cleft. Furthermore, the N-cadherin localization pattern within synapses changes during KCl depolarization and after transient synaptic stimulation. During KCl depolarization, N-cadherin relocalizes away from the central region of the synaptic cleft to the periphery of the synapse. In contrast, after transient synaptic stimulation with KCl followed by a period of rest in normal media, fewer synapses have N-cadherin present as puncta at the periphery and more synapses have N-cadherin present more centrally and uniformly along the synapse compared to unstimulated cells. This indicates that transient synaptic stimulation modulates N-cadherin localization within the synapse. These results bring new information to the structural organization and activity-induced changes occurring at synapses, and suggest that N-cadherin relocalization may contribute to activity dependent changes at synapses.

  3. Non-immunological activation of peritoneal mast cells of rats by means of mast cell degranulating peptide from bee toxic

    International Nuclear Information System (INIS)

    Martin, W.

    1982-01-01

    The subject of this dissertation is the interaction of MCD-peptide with the mast cell with regard to binding properties and histamine-liberating activity. The peptide is labelled with Na 125 I, its binding characteristics on degranulating and deactivating mast cells recorded and compared to binding on periteneal macrophages and neutrophilic granulocytes. Further, the non-lytic mode of action of MCD-peptide is pointed out, whereby the surface-active toxic peptide of the bee, melittin, finds application in parallel studies. In order to establish to what extent the binding property of the peptide to the mast cell is inhibited by IgE-antibodies charged on the later, rats are immunized with dead Bordetella pertussis microorganisms as adjuvant and ovalbumin as antigen. The induced IgE specific immune response provides active sensitized mast cells and enriches reagin antibodies in the sera of immunized animals. The binding of peptides is studied on active and passive sensitized mast cells and compared to the situation found with normal mast cells. A further section of work deals with the question whether an altered binding pattern is caused by enzymatic treatment of the cell surface. A possible interference of the MCD-peptide with the IgE-receptor could thus be indicated or other types of binding position demonstrated. The influence of granular secretion on mast cell binding is illustrated by means of studies on isolated mast cell granula. (orig./MG) [de

  4. T cell differentiation stages identified by molecular and immunologic analysis of the T cell receptor complex in childhood lymphoblastic leukemia.

    Science.gov (United States)

    Mirro, J; Kitchingman, G; Behm, F G; Murphy, S B; Goorha, R M

    1987-03-01

    T cell differentiation was investigated by determining the relationship of T cell receptor (Ti) gene rearrangement and transcription to the expression of surface and cytoplasmic T3 antigen using blast cells from five children with acute lymphoblastic leukemia of thymic origin. Patterns of monoclonal antibody (MoAb) reactivity indicated that these cases were representative of the three recognized stages (I, II, III) of human thymocyte development. The T3 antigen, which becomes linked to the Ti to form a functional T cell receptor complex on mature thymocytes, was expressed on the cell surface in two cases (stage III). However, in the remaining three cases that were surface T3 negative (stages I and II), large amounts of T3 were identified in the cytoplasm by immunoperoxidase staining and flow cytometry. Leukemic blasts from all five patients showed rearranged genes encoding the beta-chain portion of the Ti heterodimer. RNA transcripts of Ti beta-chain genes were also evident in lymphoblasts from all five cases, but transcripts coding for the alpha-chain portion of Ti were found only in cases that expressed T3 on the cell surface. Thus the absence of surface T3 (and presumably Ti) coincides with the absence of Ti alpha-chain RNA, suggesting that transcription of alpha-chain genes is a critical regulatory event in the surface expression of the Ti-T3 complex. Leukemic T cells that rearrange and express Ti beta-chain genes but lack Ti alpha-chain messenger RNA (mRNA) may represent a stage of differentiation analogous to pre-B cells, where heavy-chain immunoglobulin (Ig) genes are rearranged and expressed but light-chain Ig genes are not expressed.

  5. Organization of central synapses by adhesion molecules

    OpenAIRE

    Tallafuss, Alexandra; Constable, John R.L.; Washbourne, Philip

    2010-01-01

    Synapses are the primary means for transmitting information from one neuron to the next. They are formed during development of the nervous system, and formation of appropriate synapses is crucial for establishment of neuronal circuits that underlie behavior and cognition. Understanding how synapses form and are maintained will allow us to address developmental disorders such as autism, mental retardation and possibly also psychological disorders. A number of biochemical and proteomic studies ...

  6. Fundamentals of vaccine immunology

    Directory of Open Access Journals (Sweden)

    Angela S Clem

    2011-01-01

    Full Text Available From a literature review of the current literature, this article provides an introduction to vaccine immunology including a primer on the components of the immune system, passive vs. active immunization, the mechanism(s by which immunizations stimulate(s immunity, and the types of vaccines available. Both the innate and adaptive immune subsystems are necessary to provide an effective immune response to an immunization. Further, effective immunizations must induce long-term stimulation of both the humoral and cell-mediated arms of the adaptive system by the production of effector cells and memory cells. At least seven different types of vaccines are currently in use or in development that produce this effective immunity and have contributed greatly to the prevention of infectious disease around the world.

  7. Shaping inhibition: activity dependent structural plasticity of GABAergic synapses

    Directory of Open Access Journals (Sweden)

    Carmen E Flores

    2014-10-01

    Full Text Available Inhibitory transmission through the neurotransmitter Ɣ-aminobutyric acid (GABA shapes network activity in the mammalian cerebral cortex by filtering synaptic incoming information and dictating the activity of principal cells. The incredibly diverse population of cortical neurons that use GABA as neurotransmitter shows an equally diverse range of mechanisms that regulate changes in the strength of GABAergic synaptic transmission and allow them to dynamically follow and command the activity of neuronal ensembles. Similarly to glutamatergic synaptic transmission, activity-dependent functional changes in inhibitory neurotransmission are accompanied by alterations in GABAergic synapse structure that range from morphological reorganization of postsynaptic density to de novo formation and elimination of inhibitory contacts. Here we review several aspects of structural plasticity of inhibitory synapses, including its induction by different forms of neuronal activity, behavioral and sensory experience and the molecular mechanisms and signaling pathways involved. We discuss the functional consequences of GABAergic synapse structural plasticity for information processing and memory formation in view of the heterogenous nature of the structural plasticity phenomena affecting inhibitory synapses impinging on somatic and dendritic compartments of cortical and hippocampal neurons.

  8. Virtual Immunology: Software for Teaching Basic Immunology

    Science.gov (United States)

    Berçot, Filipe Faria; Fidalgo-Neto, Antônio Augusto; Lopes, Renato Matos; Faggioni, Thais; Alves, Luiz Anastácio

    2013-01-01

    As immunology continues to evolve, many educational methods have found difficulty in conveying the degree of complexity inherent in its basic principles. Today, the teaching-learning process in such areas has been improved with tools such as educational software. This article introduces "Virtual Immunology," a software program available…

  9. Microorganism and Fungi Drive Evolution of Plant Synapses

    Directory of Open Access Journals (Sweden)

    Frantisek eBaluska

    2013-08-01

    Full Text Available In the course of plant evolution, there is an obvious trend toward an increased complexity of plant bodies, as well as an increased sophistication of plant behavior and communication. Phenotypic plasticity of plants is based on the polar auxin transport machinery that is directly linked with plant sensory systems impinging on plant behavior and adaptive responses. Similar to the emergence and evolution of eukaryotic cells, evolution of land plants was also shaped and driven by infective and symbiotic microorganisms. These microorganisms are the driving force behind the evolution of plant synapses and other neuronal aspects of higher plants; this is especially pronounced in the root apices. Plant synapses allow synaptic cell-cell communication and coordination in plants, as well as sensory-motor integration in root apices searching for water and mineral nutrition. These neuronal aspects of higher plants are closely linked with their unique ability to adapt to environmental changes.

  10. Microorganism and filamentous fungi drive evolution of plant synapses.

    Science.gov (United States)

    Baluška, František; Mancuso, Stefano

    2013-01-01

    In the course of plant evolution, there is an obvious trend toward an increased complexity of plant bodies, as well as an increased sophistication of plant behavior and communication. Phenotypic plasticity of plants is based on the polar auxin transport machinery that is directly linked with plant sensory systems impinging on plant behavior and adaptive responses. Similar to the emergence and evolution of eukaryotic cells, evolution of land plants was also shaped and driven by infective and symbiotic microorganisms. These microorganisms are the driving force behind the evolution of plant synapses and other neuronal aspects of higher plants; this is especially pronounced in the root apices. Plant synapses allow synaptic cell-cell communication and coordination in plants, as well as sensory-motor integration in root apices searching for water and mineral nutrition. These neuronal aspects of higher plants are closely linked with their unique ability to adapt to environmental changes.

  11. CCL8 BASED IMMUNOLOGICAL MONITORING

    DEFF Research Database (Denmark)

    2008-01-01

    The present invention relates to an immunological method and, more particularly, a method for measuring cell-mediated immune reactivity (CMI) in mammals based on the production of CCL8.The invention further discloses an assay and a kit for measuring CMI to an antigen using whole blood or other...

  12. Limited impact of the thymus on immunological recovery during and after chemotherapy in patients with diffuse large B-cell lymphoma

    DEFF Research Database (Denmark)

    Vedel, S J; Tholstrup, D; Kolte, L

    2009-01-01

    To investigate the impact of thymus on immunological recovery after dose-dense chemotherapy a prospective study of 17 patients diagnosed with diffuse large B-cell lymphoma (DLBCL) was conducted. Patients were monitored before, during and until 3 months after chemotherapy. The thymus was visualized...... using computer tomographic scans. Patients were divided into two groups according to thymic size, one group comprising of patients without detectable thymus and one group of patients with detectable thymus. Naïve CD4 and CD8 counts were measured by flow cytometry, and to measure thymic output...

  13. Paul Ehrlich: pathfinder in cell biology. 1. Chronicle of his life and accomplishments in immunology, cancer research, and chemotherapy.

    Science.gov (United States)

    Kasten, F H

    1996-01-01

    The paper reviews the life of Paul Ehrlich and his biomedical accomplishments in immunology, cancer research, and chemotherapy. Ehrlich achieved renown as an organic chemist, histologist, hematologist, immunologist, and pharmacologist. He disliked the formality of school but managed to excel in Latin and mathematics. His role model was an older cousin, Carl Weigert, who became a lifelong friend. Ehrlich studied medicine at Breslau, Strasbourg, Freiburg, and Leipzig, coming under the influence of Wilhelm Waldeyer, Julius Cohnheim, Rudolf Heidenhein, and Ferdinand Cohn. As a medical student, Ehrlich was captivated by structural organic chemistry and dyes. When he was 23, his first paper was published on selective staining. His doctoral thesis, "Contribution to the Theory and Practice of Histological Staining" contained most of the germinal ideas that would guide his future career. Most of his early work was centered in Berlin at Charite Hospital, where he did pioneering studies on blood and intravital staining, and at Robert Koch's Institute for Infectious Diseases, where he undertook important investigations in immunology. Ehrlich became an authority on antitoxin standardization and developed the "side-chain theory" of antibody formation for which he was later awarded the Nobel Prize. He became director of an Institute for Experimental Therapy in Frankfurt where he continued research in immunology and carried out routine serum testing. He developed new lines of investigation in cancer research and originated the field of chemotherapy. Using principles developed in his early work with dyes, he successfully treated certain experimental trypanosomal infections with azo dyes. His crowning accomplishment was discovering that the compound Salvarsan could control human syphilis. Ehrlich's legacy in immunology and chemotherapy is discussed and an intimate portrait is drawn of Ehrlich the person.

  14. [Immunological theory of senescence].

    Science.gov (United States)

    Drela, Nadzieja

    2014-01-01

    Senescence can result from decreased potential of the immune system to respond to foreign and self antigens. The most common effect is the inhibition to destroy dying and cancer cells and the decrease of the immune response to pathogens. Aging is closely related to inflammatory phenotype, which facilitate the development of age-related diseases. The mammal immune system is highly organized and adapted to react to a wide range of antigens. According to the immunological theory, the causative agents of senescence are multilevel changes of development and functions of immune cells. Some of changes can be beneficial for the maintenance of homeostasis and lifespan in continuously changing endogenous environment and immune history of the organism.

  15. A history of pediatric immunology.

    Science.gov (United States)

    Stiehm, E Richard; Johnston, Richard B

    2005-03-01

    Immunology has played a prominent role in the history of medicine. Pediatric immunologists have focused on immune aberrations in pediatric disorders, particularly those involving host defense mechanisms. These efforts have paid rich dividends in terms of fundamental knowledge of the immune system and major therapeutic advances, including 1) i.v. immunoglobulin therapy, 2) hematopoietic stem cell transplantation, and 3) gene therapy. Pediatric immunology as an organized discipline emerged in the early 1950s, when pediatricians and their basic scientist colleagues began to focus on clinical and basic research related to immunodeficiency. Since then, key organizations and infrastructure have been developed to support this research and the clinical care of immunodeficient patients. We review here the evolution of contemporary pediatric immunology, particularly in North America, from its roots in 19th-century Europe to its current expression as one of the fundamental scientific and clinical disciplines of pediatrics.

  16. Immunological consideration for some aspects of radiology

    International Nuclear Information System (INIS)

    Makidono, Atsushi; Makidono, Tohoru; Yoshimoto, Kiichiro.

    1978-01-01

    What immunology should be in radiology was considered from the modern immunological and radioimmunological point of view. In order to evaluate an immunological response to radiation at a cellular level, radiosensitivities of macrophage, T-cell, and B-cell were selectively described from a modern immunological stand point. On the basis of this knowledge, radioimmunology was explained; and in clinical field, diagnosis and treatment of malignant tumor, radiotherapy for suppressing immuno-lymphatic system, and reactivators for making the treatment effective were described. Immunoreaction in homo-transplantation of organs, relationship between radiation and auto-immunization, and relationship between carcinogenesis of radiation and immunity were explained so that the way of considering immunology in radiology will be summarized. (Ueda, J.)

  17. Triple Function of Synaptotagmin 7 Ensures Efficiency of High-Frequency Transmission at Central GABAergic Synapses

    Directory of Open Access Journals (Sweden)

    Chong Chen

    2017-11-01

    Full Text Available Synaptotagmin 7 (Syt7 is thought to be a Ca2+ sensor that mediates asynchronous transmitter release and facilitation at synapses. However, Syt7 is strongly expressed in fast-spiking, parvalbumin-expressing GABAergic interneurons, and the output synapses of these neurons produce only minimal asynchronous release and show depression rather than facilitation. To resolve this apparent contradiction, we examined the effects of genetic elimination of Syt7 on synaptic transmission at the GABAergic basket cell (BC-Purkinje cell (PC synapse in cerebellum. Our results indicate that at the BC-PC synapse, Syt7 contributes to asynchronous release, pool replenishment, and facilitation. In combination, these three effects ensure efficient transmitter release during high-frequency activity and guarantee frequency independence of inhibition. Our results identify a distinct function of Syt7: ensuring the efficiency of high-frequency inhibitory synaptic transmission.

  18. Weighted Synapses Without Carry Operations for RRAM-Based Neuromorphic Systems

    Science.gov (United States)

    Liao, Yan; Deng, Ning; Wu, Huaqiang; Gao, Bin; Zhang, Qingtian; Qian, He

    2018-01-01

    The parallel updating scheme of RRAM-based analog neuromorphic systems based on sign stochastic gradient descent (SGD) can dramatically accelerate the training of neural networks. However, sign SGD can decrease accuracy. Also, some non-ideal factors of RRAM devices, such as intrinsic variations and the quantity of intermediate states, may significantly damage their convergence. In this paper, we analyzed the effects of these issues on the parallel updating scheme and found that it performed poorly on the task of MNIST recognition when the number of intermediate states was limited or the variation was too large. Thus, we propose a weighted synapse method to optimize the parallel updating scheme. Weighted synapses consist of major and minor synapses with different gain factors. Such a method can be widely used in RRAM-based analog neuromorphic systems to increase the number of equivalent intermediate states exponentially. The proposed method also generates a more suitable ΔW, diminishing the distortion caused by sign SGD. Unlike when several RRAM cells are combined to achieve higher resolution, there are no carry operations for weighted synapses, even if a saturation on the minor synapses occurs. The proposed method also simplifies the circuit overhead, rendering it highly suitable to the parallel updating scheme. With the aid of weighted synapses, convergence is highly optimized, and the error rate decreases significantly. Weighted synapses are also robust against the intrinsic variations of RRAM devices.

  19. Immunological mechanisms of sublingual immunotherapy.

    Science.gov (United States)

    Allam, Jean-Pierre; Novak, Natalija

    2014-12-01

    This review aims to recap recent published data on immunological mechanisms underlying sublingual immunotherapy (SLIT). Although several alternative noninvasive allergen application strategies have been investigated in allergen-specific immunotherapy, local intraoral allergen application to sublingual mucosa has been proven to be safe and effective. To date, SLIT is widely accepted by most allergists, especially in Europe as an alternative to subcutaneous immunotherapy. Within the recent decades, much scientific effort focused on local and systemic immunological responses to SLIT in mice as well as humans. Among these studies, several investigated detailed mechanisms following allergen application to the oral mucosa as part of the sophisticated mucosal immunological network in which the protolerogenic character of local antigen-presenting cells such as dendritic cells play a central role. Moreover, immune responses to SLIT have also been studied in nasal and bronchial mucosa as well as on the systemic T cell immune alterations. Altogether, exiting data have been published providing a better understanding of immunological features of SLIT but far more basic research is necessary to further uncover key mechanisms of SLIT.

  20. Astrocytosis in parkinsonism: considering tripartite striatal synapses in physiopathology?

    OpenAIRE

    Charron, Giselle; Doudnikoff, Evelyne; Canron, Marie-Helene; Li, Qin; Véga, Céline; Marais, Sebastien; Baufreton, Jérôme; Vital, Anne; Oliet, Stéphane H. R.; Bezard, Erwan

    2014-01-01

    International audience; The current concept of basal ganglia organization and function in physiological and pathophysiological conditions excludes the most numerous cells in the brain, i.e., the astrocytes, present with a ratio of 10:1 neuron. Their role in neurodegenerative condition such as Parkinson's disease (PD) remains to be elucidated. Before embarking into physiological investigations of the yet-to-be-identified " tripartite " synapses in the basal ganglia in general and the striatum ...

  1. Neuronal death and synapse elimination in the olivocerebellar system. II. Cell counts in the inferior olive of adult x-irradiated rats and weaver and reeler mutant mice

    International Nuclear Information System (INIS)

    Shojaeian, H.; Delhaye-Bouchaud, N.; Mariani, J.

    1985-01-01

    Cell death in the developing rat inferior olive precedes the regression of the polyneuronal innervation of Purkinje cells by olivary axons (i.e., climbing fibers), suggesting that the involution of the redundant olivocerebellar contacts is caused by a withdrawal of supernumerary axonal collaterals rather than by degeneration of the parent cell. However, a subsequent apparent increase of the olivary population occurs, which could eventually mask a residual presynaptic cell death taking place at the same time. Therefore, cell counts were performed in the inferior olive of adult rodents in which the multiple innervation of Purkinje cells by olivary axons is maintained, with the idea that if cell death plays a role in the regression of supernumerary climbing fibers, the number of olivary cells should be higher in these animals than in their controls. The results show that the size of the cell population in the inferior olive of weaver and reeler mutant mice and rats degranulated by early postnatal x-irradiation does not differ significantly from that of their controls. Similarly, the distribution of the cells in the four main olivary subnuclei is not modified in weaver mice and x-irradiated rats. The present data further support the assumption that the regression of the polyneuronal innervation of Purkinje cells occurs independently of cell death in the presynaptic population

  2. Immunological quality and performance of tumor vessel-targeting CAR-T cells prepared by mRNA-EP for clinical research.

    Science.gov (United States)

    Inoo, Kanako; Inagaki, Ryo; Fujiwara, Kento; Sasawatari, Shigemi; Kamigaki, Takashi; Nakagawa, Shinsaku; Okada, Naoki

    2016-01-01

    We previously reported that tumor vessel-redirected T cells, which were genetically engineered with chimeric antigen receptor (CAR) specific for vascular endothelial growth factor receptor 2 (VEGFR2), demonstrated significant antitumor effects in various murine solid tumor models. In the present study, we prepared anti-VEGFR2 CAR-T cells by CAR-coding mRNA electroporation (mRNA-EP) and analyzed their immunological characteristics and functions for use in clinical research. The expression of anti-VEGFR2 CAR on murine and human T cells was detected with approximately 100% efficiency for a few days, after peaking 6-12 hours after mRNA-EP. Triple transfer of murine anti-VEGFR2 CAR-T cells into B16BL6 tumor-bearing mice demonstrated an antitumor effect comparable to that for the single transfer of CAR-T cells engineered with retroviral vector. The mRNA-EP did not cause any damage or defects to human T-cell characteristics, as determined by viability, growth, and phenotypic parameters. Additionally, two kinds of human anti-VEGFR2 CAR-T cells, which expressed different CAR construction, differentiated to effector phase with cytokine secretion and cytotoxic activity in antigen-specific manner. These results indicate that our anti-VEGFR2 CAR-T cells prepared by mRNA-EP have the potential in terms of quality and performance to offer the prospect of safety and efficacy in clinical research as cellular medicine.

  3. Comparison of immunological characteristics of peripheral, splenic and tonsilar naïve B cells by differential gene expression meta-analyses.

    Science.gov (United States)

    Chokeshai-u-saha, Kaj; Lepoivre, Cyrille; Grieco, Luca; Nguyen, Catherine; Ruxrungtham, Kiat

    2012-12-01

    Naïve B cells isolated from peripheral blood, spleen and tonsil are commonly used in human B cell studies. However, little has been written about their possible variations in immunological properties. This study compared differential gene expression in human naive B subsets by meta-analysis using expression data available in Gene Expression Onimbus (GEO). Gene expression files of the Affymetrix Human Genome U133A Array (Affymetrix) were downloaded to collect 21 total array data samples of peripheral naïve B cells (n=10), splenic naïve B cells (n=2), tonsilar naïve B cells (n=3), peripheral memory B cells (n=4) and splenic memory B cells (n=2). Prior to differential gene expression analyses, data were normalized in order to reduce non-biological variation among the datasets. Comparisons of peripheral naive B cells with their splenic and tonsilar counterparts showed remarkable differences in terms of gene expression (29 and 202 genes, respectively). However, only minor differences were detected between splenic and tonsilar naive B cells (10 genes), consistent with the clustering results classifying both of them as lymphoid naive B cells. Differential gene expression results also implied higher stimulating states of lymphoid naive B cells when compared with peripheral blood naive B cells. These included enhanced expressions of CD27, CR2, EGR1, GADD45B, ICAM1, ICOSLG, IGHA, IL6, MMP9, SAMSN1, SMAD7, TNFAIP3, but reduced HLA-DOB expression. Our findings suggest that results generated from peripheral naive B cells may not always be applicable to the biological activities of other lymphoid naïve B cells. Nonetheless, further biological study is warranted.

  4. γ-Radiation promotes immunological recognition of cancer cells through increased expression of cancer-testis antigens in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Anu Sharma

    Full Text Available BACKGROUND: γ-radiation is an effective treatment for cancer. There is evidence that radiotherapy supports tumor-specific immunity. It was described that irradiation induces de novo protein synthesis and enhances antigen presentation, we therefore investigated whether γ-radiation results in increased expression of cancer-testis (CT antigens and MHC-I, thus allowing efficient immunological control. This is relevant because the expression of CT-antigens and MHC-I on tumor cells is often heterogeneous. We found that the changes induced by γ-radiation promote the immunological recognition of the tumor, which is illustrated by the increased infiltration by lymphocytes after radiotherapy. METHODS/FINDINGS: We compared the expression of CT-antigens and MHC-I in various cancer cell lines and fresh biopsies before and after in vitro irradiation (20 Gy. Furthermore, we compared paired biopsies that were taken before and after radiotherapy from sarcoma patients. To investigate whether the changed expression of CT-antigens and MHC-I is specific for γ-radiation or is part of a generalized stress response, we analyzed the effect of hypoxia, hyperthermia and genotoxic stress on the expression of CT-antigens and MHC-I. In vitro irradiation of cancer cell lines and of fresh tumor biopsies induced a higher or de novo expression of different CT-antigens and a higher expression of MHC-I in a time- and dose-dependent fashion. Importantly, we show that irradiation of cancer cells enhances their recognition by tumor-specific CD8+ T cells. The analysis of paired biopsies taken from a cohort of sarcoma patients before and after radiotherapy confirmed our findings and, in addition showed that irradiation resulted in higher infiltration by lymphocytes. Other forms of stress did not have an impact on the expression of CT-antigens or MHC-I. CONCLUSIONS: Our findings suggest that γ-radiation promotes the immunological recognition of the tumor. We therefore propose that

  5. Neuronal death and synapse elimination in the olivocerebellar system: III. Cell counts in the inferior olive of developing rats X-irradiated from birth

    International Nuclear Information System (INIS)

    Geoffroy, B.; Shojaeian, H.; Delhaye-Bouchaud, N.; Mariani, J.

    1988-01-01

    The change with age of cell number in the developing inferior olivary nucleus (ION) of the normal rat, compared to the time course of the regression of the polyneuronal innervation of Purkinje cells by olivary axons (i.e., the climbing fibers), suggests that the involution of the redundant olivocerebellar contacts is caused by a reduction of axonal branching rather than by degeneration of the parent cells, this being also suggested by the normal size of the olivary population in adult rodents whose Purkinje cells retain polyneuronal innervation. However, the similar size of the adult ION population does not necessarily imply that the development history is the same in normal and multiply innervated adult rodents. Therefore, cell counts were performed in developing rats which had been repeatedly X-irradiated from birth until postnatal day 14 and which retained polyneuronal innervation. The results show that, although less marked than during normal development, the evolution of the ION population is also characterized by a phase of cell loss followed by a slow increase. However, the number of cells in X-irradiated rats is higher than in their controls from birth to postnatal day 15 but becomes identical at 20 days and later. These data confirm that cell death in the ION does not play a major role in the shaping of olivocerebellar connections

  6. Selective pre-priming of HA-specific CD4 T cells restores immunological reactivity to HA on heterosubtypic influenza infection.

    Science.gov (United States)

    Alam, Shabnam; Chan, Cory; Qiu, Xing; Shannon, Ian; White, Chantelle L; Sant, Andrea J; Nayak, Jennifer L

    2017-01-01

    A hallmark of the immune response to influenza is repeated encounters with proteins containing both genetically conserved and variable components. Therefore, the B and T cell repertoire is continually being remodeled, with competition between memory and naïve lymphocytes. Our previous work using a mouse model of secondary heterosubtypic influenza infection has shown that this competition results in a focusing of CD4 T cell response specificity towards internal virion proteins with a selective decrease in CD4 T cell reactivity to the novel HA epitopes. Strikingly, this shift in CD4 T cell specificity was associated with a diminished anti-HA antibody response. Here, we sought to determine whether the loss in HA-specific reactivity that occurs as a consequence of immunological memory could be reversed by selectively priming HA-specific CD4 T cells prior to secondary infection. Using a peptide-based priming strategy, we found that selective expansion of the anti-HA CD4 T cell memory repertoire enhanced HA-specific antibody production upon heterosubtypic infection. These results suggest that the potentially deleterious consequences of repeated exposure to conserved influenza internal virion proteins could be reversed by vaccination strategies that selectively arm the HA-specific CD4 T cell compartment. This could be a potentially useful pre-pandemic vaccination strategy to promote accelerated neutralizing antibody production on challenge with a pandemic influenza strain that contains few conserved HA epitopes.

  7. Astrocytosis in parkinsonism: considering tripartite striatal synapses in physiopathology?

    Science.gov (United States)

    Charron, Giselle; Doudnikoff, Evelyne; Canron, Marie-Helene; Li, Qin; Véga, Céline; Marais, Sebastien; Baufreton, Jérôme; Vital, Anne; Oliet, Stéphane H R; Bezard, Erwan

    2014-01-01

    The current concept of basal ganglia organization and function in physiological and pathophysiological conditions excludes the most numerous cells in the brain, i.e., the astrocytes, present with a ratio of 10:1 neuron. Their role in neurodegenerative condition such as Parkinson's disease (PD) remains to be elucidated. Before embarking into physiological investigations of the yet-to-be-identified "tripartite" synapses in the basal ganglia in general and the striatum in particular, we therefore characterized anatomically the PD-related modifications in astrocytic morphology, the changes in astrocytic network connections and the consequences on the spatial relationship between astrocytic processes and asymmetric synapses in normal and PD-like conditions in experimental and human PD. Our results unravel a dramatic regulation of striatal astrocytosis supporting the hypothesis of a key role in (dys) regulating corticostriatal transmission. Astrocytes and their various properties might thus represent a therapeutic target in PD.

  8. Astrocytosis in parkinsonism: considering tripartite striatal synapses in physiopathology?

    Directory of Open Access Journals (Sweden)

    Giselle eCharron

    2014-09-01

    Full Text Available The current concept of basal ganglia organization and function in physiological and pathophysiological conditions excludes the most numerous cells in the brain, i.e. the astrocytes, present with a ratio of 10:1 neuron. Their role in neurodegenerative condition such as Parkinson’s disease (PD remains to be elucidated. Before embarking into physiological investigations of the yet-to-be-identified tripartite synapses in the basal ganglia in general and the striatum in particular, we therefore characterized anatomically the PD-related modifications in astrocytic morphology, the changes in astrocytic network connections and the consequences on the spatial relationship between astrocytic processes and asymmetric synapses in normal and PD-like conditions in experimental and human PD. Our results unravel a dramatic regulation of striatal astrocytosis supporting the hypothesis of a key role in (dysregulating corticostriatal transmission. Astrocytes and their various properties might thus represent a therapeutic target in PD.

  9. A new measure for the strength of electrical synapses

    Directory of Open Access Journals (Sweden)

    Julie S Haas

    2015-09-01

    Full Text Available Electrical synapses, like chemical synapses, mediate intraneuronal communication. Electrical synapses are typically quantified by subthreshold measurements of coupling, which fall short in describing their impact on spiking activity in coupled neighbors. Here we describe a novel measurement for electrical synapse strength that directly evaluates the effect of synaptically transmitted activity on spike timing. This method, also applicable to neurotransmitter-based synapses, communicates the considerable strength of electrical synapses. For electrical synapses measured in rodent slices of the thalamic reticular nucleus, spike timing is modulated by tens of ms by activity in a coupled neighbor.

  10. Crosstalk between T lymphocytes and dendritic cells.

    Science.gov (United States)

    Hivroz, Claire; Chemin, Karine; Tourret, Marie; Bohineust, Armelle

    2012-01-01

    Dendritic cells (DCs) are professional antigen-presenting cells (APCs) with the unique property of inducing priming and differentiation of naïve CD4+ and CD8+ T cells into helper and cytotoxic effectors. Their efficiency is due to their unique ability to process antigen, express costimulatory molecules, secrete cytokines, and migrate to tissues or lymphoid organs to prime T cells. DCs also play an important role in T-cell peripheral tolerance. There is ample evidence that the DC ability to present antigens is regulated by CD4+ helper T cells. Indeed, interactions between surface receptors and ligands expressed respectively by T cells and DCs, as well as T-cell-derived cytokines modify DC functions. This T-cell-induced modification of DCs has been called "education" or "licensing." This intimate crosstalk between DCs and T lymphocytes is key in establishing appropriate adaptive immune responses. It requires cognate interactions between T lymphocytes and DCs, which are organized in time and space by structures called immunological synapses. Here we discuss the particular aspects of immunological synapses formed between T cells and DCs and the role these organized interactions have in T-cell-DC crosstalk.

  11. Piccolo Promotes Vesicle Replenishment at a Fast Central Auditory Synapse

    Directory of Open Access Journals (Sweden)

    Tanvi Butola

    2017-10-01

    Full Text Available Piccolo and Bassoon are the two largest cytomatrix of the active zone (CAZ proteins involved in scaffolding and regulating neurotransmitter release at presynaptic active zones (AZs, but have long been discussed as being functionally redundant. We employed genetic manipulation to bring forth and segregate the role of Piccolo from that of Bassoon at central auditory synapses of the cochlear nucleus—the endbulbs of Held. These synapses specialize in high frequency synaptic transmission, ideally poised to reveal even subtle deficits in the regulation of neurotransmitter release upon molecular perturbation. Combining semi-quantitative immunohistochemistry, electron microscopy, and in vitro and in vivo electrophysiology we first studied signal transmission in Piccolo-deficient mice. Our analysis was not confounded by a cochlear deficit, as a short isoform of Piccolo (“Piccolino” present at the upstream ribbon synapses of cochlear inner hair cells (IHC, is unaffected by the mutation. Disruption of Piccolo increased the abundance of Bassoon at the AZs of endbulbs, while that of RIM1 was reduced and other CAZ proteins remained unaltered. Presynaptic fiber stimulation revealed smaller amplitude of the evoked excitatory postsynaptic currents (eEPSC, while eEPSC kinetics as well as miniature EPSCs (mEPSCs remained unchanged. Cumulative analysis of eEPSC trains indicated that the reduced eEPSC amplitude of Piccolo-deficient endbulb synapses is primarily due to a reduced readily releasable pool (RRP of synaptic vesicles (SV, as was corroborated by a reduction of vesicles at the AZ found on an ultrastructural level. Release probability seemed largely unaltered. Recovery from short-term depression was slowed. We then performed a physiological analysis of endbulb synapses from mice which, in addition to Piccolo deficiency, lacked one functional allele of the Bassoon gene. Analysis of the double-mutant endbulbs revealed an increase in release probability

  12. Neurobeachin regulates neurotransmitter receptor trafficking to synapses

    NARCIS (Netherlands)

    Nair, R.; Lauks, J.; Jung, S; Cooke, N.E.; de Wit, H.; Brose, N.; Kilimann, M.W.; Verhage, M.; Rhee, J.

    2013-01-01

    The surface density of neurotransmitter receptors at synapses is a key determinant of synaptic efficacy. Synaptic receptor accumulation is regulated by the transport, postsynaptic anchoring, and turnover of receptors, involving multiple trafficking, sorting, motor, and scaffold proteins. We found

  13. Synapse proteomics: current status and quantitative applications

    NARCIS (Netherlands)

    Li, K.W.; Jimenez, C.R.

    2008-01-01

    Chemical synapses are key organelles for neurotransmission. The coordinated actions of protein networks in diverse synaptic subdomains drive the sequential molecular events of transmitter release from the presynaptic bouton, activation of transmitter receptors located in the postsynaptic density and

  14. PKCtheta and HIV-1 transcriptional regulator Tat co-exist at the LTR promoter in CD4+ T cells

    OpenAIRE

    Maria Rosa eLopez-Huertas; Jasmine eLi; Anjum eZafar; Sara eRodriguez-Mora; Carlota eGarcía-Domínguez; Elena eMateos; Jose eAlcami; Sudha eRao; Mayte eCoiras

    2016-01-01

    PKCtheta is essential for the activation of CD4+ T cells. Upon TCR/CD28 stimulation, PKCtheta is phosphorylated and migrates to the immunological synapse, inducing the activation of cellular transcription factors such as NF-kB and kinases as ERK that are critical for HIV-1 replication. We previously demonstrated that PKCtheta is also necessary for HIV-1 replication but the precise mechanism is unknown. Efficient HIV-1 transcription and elongation is absolutely dependent on the synergy between...

  15. HIV-infected viremic long-term non-progressors and controllers display different immunological mechanisms for preserved CD4+cell counts

    DEFF Research Database (Denmark)

    Gaardbo, J; Ronit, A; Hartling, H

    2012-01-01

    (viral load, VL>5000 copies/ml, CD4+ cell count>350 cells/ul, infected>10 years), 30 VC (VL350 cells/ul), and 25 progressors (PR) (VL>5.000 copies/ml, CD4 count>350 cells/ul) were included. Immune activation (CD4+ and CD8+cells co-expressing CD38+HLA-DR+), apoptosis (CD8+CD28-CD95+), Th17 cells (CD4+CD......Purpose: Most HIV-infected patients develop immunodeficiency without treatment. However, Long-Term Non Progressors (LTNP) and Viremic Controllers (VC) maintain normal CD4 counts and do not progress in the absence of treatment. While VC are able to control viral replication LTNP are not. Thus, lack...... of viral replication cannot explain non-progression in LTNP. Therefore we hypothesized that the immunological mechanism responsible for preserved CD4 counts in LTNP is different from that in VC. Methods: 69 treatment naïve HIV-infected patients were included in a cross-sectional study. A total of 14 LTNP...

  16. Prevention of Noise Damage to Cochlear Synapses

    Science.gov (United States)

    2016-10-01

    neurotrophic factor CNTF in promoting synapse regeneration. KEYWORDS Anandamide Auditory Brainstem Response Calcium Ion Calcium-Permeable AMPA Receptors...excitotoxic trauma (kainic acid) in vitro? f) Does CNTF promote synapse regeneration in vitro as does NT-3? W81XWH-14-1-0494 Annual Progress Report 29... CNTF ) is expressed in the organ of Corti at high levels, comparable to NT-3. We have also found that CNTF is approximately as effective as NT-3 in

  17. Defects of the Glycinergic Synapse in Zebrafish

    OpenAIRE

    Ogino, Kazutoyo; Hirata, Hiromi

    2016-01-01

    Glycine mediates fast inhibitory synaptic transmission. Physiological importance of the glycinergic synapse is well established in the brainstem and the spinal cord. In humans, the loss of glycinergic function in the spinal cord and brainstem leads to hyperekplexia, which is characterized by an excess startle reflex to sudden acoustic or tactile stimulation. In addition, glycinergic synapses in this region are also involved in the regulation of respiration and locomotion, and in the nocicepti...

  18. The artificial synapse chip: From proteins to prostheses

    Science.gov (United States)

    Peterman, Mark Charles

    Most retinal prostheses use an electric field to stimulate retinal circuitry, yet information transfer in the retina is primarily through neurotransmitters. To address this difference, this thesis describes a proof of concept retinal interface based on localized chemical delivery. This system, the Artificial Synapse Chip, is based on a 5 mum aperture in a silicon nitride membrane overlying a microfluidic channel. The effectiveness of this interface is demonstrated by ejecting bradykinin on cultured excitable cells. Even with manual fluidic control, the relationship between the extent of stimulation and concentration is linear, providing enough control to limit stimulation to individual cells. A neurotransmitter-based prosthesis will require advanced fluidic control. This thesis reports the use of electroosmosis to eject or withdraw fluid from an aperture in a channel wall. This effect is demonstrated experimentally, and numerically, using a finite-element method. Our primary device is a prototype interface with four individually addressable apertures in a 2 x 2 array. Using this array, we demonstrate stimulation of both PC12 and retinal ganglion cells. This demonstration of localized chemical stimulation of excitable cells illustrates the potential of this technology for retinal prostheses. As a final application of the Artificial Synapse Chip, we applied the concept to lipid bilayer membranes and membrane-bound proteins. Not only are membrane-bound proteins crucial to the function of biological synapses, but also are important from a technological point of view. In this thesis, we use a Langmuir-Blodgett technique to producing lipid bilayers across apertures in a modified version of the Artificial Synapse Chip. These bilayers display many of the same properties as bilayers across apertures in Teflon films. In addition, these bilayers remain unbroken at transmembrane potentials over +/-400 mV, higher than Teflon-supported bilayers. We also demonstrate single

  19. Spiking Neural P Systems With Scheduled Synapses.

    Science.gov (United States)

    Cabarle, Francis George C; Adorna, Henry N; Jiang, Min; Zeng, Xiangxiang

    2017-12-01

    Spiking neural P systems (SN P systems) are models of computation inspired by biological spiking neurons. SN P systems have neurons as spike processors, which are placed on the nodes of a directed and static graph (the edges in the graph are the synapses). In this paper, we introduce a variant called SN P systems with scheduled synapses (SSN P systems). SSN P systems are inspired and motivated by the structural dynamism of biological synapses, while incorporating ideas from nonstatic (i.e., dynamic) graphs and networks. In particular, synapses in SSN P systems are available only at specific durations according to their schedules. The SSN P systems model is a response to the problem of introducing durations to synapses of SN P systems. Since SN P systems are in essence static graphs, it is natural to consider them for dynamic graphs also. We introduce local and global schedule types, also taking inspiration from the above-mentioned sources. We prove that SSN P systems are computationally universal as number generators and acceptors for both schedule types, under a normal form (i.e., a simplifying set of restrictions). The introduction of synapse schedules for either schedule type proves useful in programming the system, despite restrictions in the normal form.

  20. The space where aging acts: focus on the GABAergic synapse.

    Science.gov (United States)

    Rozycka, Aleksandra; Liguz-Lecznar, Monika

    2017-08-01

    As it was established that aging is not associated with massive neuronal loss, as was believed in the mid-20th Century, scientific interest has addressed the influence of aging on particular neuronal subpopulations and their synaptic contacts, which constitute the substrate for neural plasticity. Inhibitory neurons represent the most complex and diverse group of neurons, showing distinct molecular and physiological characteristics and possessing a compelling ability to control the physiology of neural circuits. This review focuses on the aging of GABAergic neurons and synapses. Understanding how aging affects synapses of particular neuronal subpopulations may help explain the heterogeneity of aging-related effects. We reviewed the literature concerning the effects of aging on the numbers of GABAergic neurons and synapses as well as aging-related alterations in their presynaptic and postsynaptic components. Finally, we discussed the influence of those changes on the plasticity of the GABAergic system, highlighting our results concerning aging in mouse somatosensory cortex and linking them to plasticity impairments and brain disorders. We posit that aging-induced impairments of the GABAergic system lead to an inhibitory/excitatory imbalance, thereby decreasing neuron's ability to respond with plastic changes to environmental and cellular challenges, leaving the brain more vulnerable to cognitive decline and damage by synaptopathic diseases. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  1. Microglia actively regulate the number of functional synapses.

    Directory of Open Access Journals (Sweden)

    Kyungmin Ji

    Full Text Available Microglia are the immunocompetent cells of the central nervous system. In the physiological setting, their highly motile processes continually survey the local brain parenchyma and transiently contact synaptic elements. Although recent work has shown that the interaction of microglia with synapses contributes to synaptic remodeling during development, the role of microglia in synaptic physiology is just starting to get explored. To assess this question, we employed an electrophysiological approach using two methods to manipulate microglia in culture: organotypic hippocampal brain slices in which microglia were depleted using clodronate liposomes, and cultured hippocampal neurons to which microglia were added. We show here that the frequency of excitatory postsynaptic current increases in microglia-depleted brain slices, consistent with a higher synaptic density, and that this enhancement ensures from the loss of microglia since it is reversed when the microglia are replenished. Conversely, the addition of microglia to neuronal cultures decreases synaptic activity and reduces the density of synapses, spine numbers, surface expression of AMPA receptor (GluA1, and levels of synaptic adhesion molecules. Taken together, our findings demonstrate that non-activated microglia acutely modulate synaptic activity by regulating the number of functional synapses in the central nervous system.

  2. Temporal coding at the immature depolarizing GABAergic synapse

    Directory of Open Access Journals (Sweden)

    Guzel Valeeva

    2010-07-01

    Full Text Available In the developing hippocampus, GABA exerts depolarizing and excitatory actions and contributes to the generation of neuronal network driven Giant Depolarizing Potentials (GDPs. Here, we studied spike time coding at immature GABAergic synapses and its impact on synchronization of the neuronal network during GDPs in the neonatal (postnatal days P2-6 rat hippocampal slices. Using extracellular recordings, we found that the delays of action potentials (APs evoked by synaptic activation of GABA(A receptors are long (mean, 65 ms and variable (within a time window of 10-200 ms. During patch-clamp recordings, depolarizing GABAergic responses were mainly subthreshold and their amplification by persistent sodium conductance was required to trigger APs. AP delays at GABAergic synapses shortened and their variability reduced with an increase in intracellular chloride concentration during whole-cell recordings. Negative shift of the GABA reversal potential (EGABA with low concentrations of bumetanide, or potentiation of GABA(A receptors with diazepam reduced GDPs amplitude, desynchronized neuronal firing during GDPs and slowed down GDPs propagation. Partial blockade of GABA(A receptors with bicuculline increased neuronal synchronization and accelerated GDPs propagation. We propose that spike-timing at depolarizing GABA synapses is determined by intracellular chloride concentration. At physiological levels of intracellular chloride GABAergic depolarization does not reach the action potential threshold and amplification of GABAergic responses by non-inactivating sodium conductance is required for postsynaptic AP initiation. Slow and variable excitation at GABAergic synapse determines the level of neuronal synchrony and the rate of GDPs propagation in the developing hippocampus.

  3. The New Cellular Immunology

    Science.gov (United States)

    Claman, Henry N.

    1973-01-01

    Discusses the nature of the immune response and traces many of the discoveries that have led to the present state of knowledge in immunology. The new cellular immunology is directing its efforts toward improving health by proper manipulation of the immune mechanisms of the body. (JR)

  4. Immunology Research in Israel.

    Science.gov (United States)

    1985-11-14

    leukemia virus transformation. lergic encephalomyelitis (EAE) is genet- Mozes et al. are studying interleukin- ically controlled, both in guinea pigs ... experimental autoimmune I. Pecht (Department of Chemical myasthenia gravis (EAMG). These anti- " Immunology, Weizmann Institute) and his bodies block...production and expansion; genetics of autoimmunity and cancer; lymphokines and comple- ment; autoiminunity; tumor immunology; transplantation and tissue

  5. Learning-guided automatic three dimensional synapse quantification for drosophila neurons.

    Science.gov (United States)

    Sanders, Jonathan; Singh, Anil; Sterne, Gabriella; Ye, Bing; Zhou, Jie

    2015-05-28

    The subcellular distribution of synapses is fundamentally important for the assembly, function, and plasticity of the nervous system. Automated and effective quantification tools are a prerequisite to large-scale studies of the molecular mechanisms of subcellular synapse distribution. Common practices for synapse quantification in neuroscience labs remain largely manual or semi-manual. This is mainly due to computational challenges in automatic quantification of synapses, including large volume, high dimensions and staining artifacts. In the case of confocal imaging, optical limit and xy-z resolution disparity also require special considerations to achieve the necessary robustness. A novel algorithm is presented in the paper for learning-guided automatic recognition and quantification of synaptic markers in 3D confocal images. The method developed a discriminative model based on 3D feature descriptors that detected the centers of synaptic markers. It made use of adaptive thresholding and multi-channel co-localization to improve the robustness. The detected markers then guided the splitting of synapse clumps, which further improved the precision and recall of the detected synapses. Algorithms were tested on lobula plate tangential cells (LPTCs) in the brain of Drosophila melanogaster, for GABAergic synaptic markers on axon terminals as well as dendrites. The presented method was able to overcome the staining artifacts and the fuzzy boundaries of synapse clumps in 3D confocal image, and automatically quantify synaptic markers in a complex neuron such as LPTC. Comparison with some existing tools used in automatic 3D synapse quantification also proved the effectiveness of the proposed method.

  6. Untangling the two-way signalling route from synapses to the nucleus, and from the nucleus back to the synapses.

    Science.gov (United States)

    Nonaka, Mio; Fujii, Hajime; Kim, Ryang; Kawashima, Takashi; Okuno, Hiroyuki; Bito, Haruhiko

    2014-01-05

    During learning and memory, it has been suggested that the coordinated electrical activity of hippocampal neurons translates information about the external environment into internal neuronal representations, which then are stored initially within the hippocampus and subsequently into other areas of the brain. A widely held hypothesis posits that synaptic plasticity is a key feature that critically modulates the triggering and the maintenance of such representations, some of which are thought to persist over time as traces or tags. However, the molecular and cell biological basis for these traces and tags has remained elusive. Here, we review recent findings that help clarify some of the molecular and cellular mechanisms critical for these events, by untangling a two-way signalling crosstalk route between the synapses and the neuronal soma. In particular, a detailed interrogation of the soma-to-synapse delivery of immediate early gene product Arc/Arg3.1, whose induction is triggered by heightened synaptic activity in many brain areas, teases apart an unsuspected 'inverse' synaptic tagging mechanism that likely contributes to maintaining the contrast of synaptic weight between strengthened and weak synapses within an active ensemble.

  7. Immunological quality and performance of tumor vessel-targeting CAR-T cells prepared by mRNA-EP for clinical research

    Directory of Open Access Journals (Sweden)

    Kanako Inoo

    2016-01-01

    Full Text Available We previously reported that tumor vessel-redirected T cells, which were genetically engineered with chimeric antigen receptor (CAR specific for vascular endothelial growth factor receptor 2 (VEGFR2, demonstrated significant antitumor effects in various murine solid tumor models. In the present study, we prepared anti-VEGFR2 CAR-T cells by CAR-coding mRNA electroporation (mRNA-EP and analyzed their immunological characteristics and functions for use in clinical research. The expression of anti-VEGFR2 CAR on murine and human T cells was detected with approximately 100% efficiency for a few days, after peaking 6–12 hours after mRNA-EP. Triple transfer of murine anti-VEGFR2 CAR-T cells into B16BL6 tumor-bearing mice demonstrated an antitumor effect comparable to that for the single transfer of CAR-T cells engineered with retroviral vector. The mRNA-EP did not cause any damage or defects to human T-cell characteristics, as determined by viability, growth, and phenotypic parameters. Additionally, two kinds of human anti-VEGFR2 CAR-T cells, which expressed different CAR construction, differentiated to effector phase with cytokine secretion and cytotoxic activity in antigen-specific manner. These results indicate that our anti-VEGFR2 CAR-T cells prepared by mRNA-EP have the potential in terms of quality and performance to offer the prospect of safety and efficacy in clinical research as cellular medicine.

  8. Immunology of root resorption: A literature review

    Directory of Open Access Journals (Sweden)

    Silva Luciano

    2008-01-01

    Full Text Available Root resorption seems to be related to a complex combination of mechanical factors and biological activity, which comprehends the role of immunologic structures including specialized cells. The aim of this research was to explain the development of the process - from mineralization to the destruction of hard tissues - and the possible relationship between root resorption and immunology, along with discussing current concepts described in the literature.

  9. The expression of the chemorepellent Semaphorin 3A is selectively induced in terminal Schwann cells of a subset of neuromuscular synapses that display limited anatomical plasticity and enhanced vulnerability in motor neuron disease

    NARCIS (Netherlands)

    De Winter, Fred; Vo, Tam; Stam, Floor J; Wisman, Liselijn A B; Bär, Peter R; Niclou, Simone P; van Muiswinkel, Freek L; Verhaagen, J.

    2006-01-01

    Neuromuscular synapses differ markedly in their plasticity. Motor nerve terminals innervating slow muscle fibers sprout vigorously following synaptic blockage, while those innervating fast-fatigable muscle fibers fail to exhibit any sprouting. Here, we show that the axon repellent Semaphorin 3A is

  10. Immunology of Gut Mucosal Vaccines

    Science.gov (United States)

    Pasetti, Marcela F.; Simon, Jakub K.; Sztein, Marcelo B.; Levine, Myron M.

    2011-01-01

    Summary Understanding the mechanisms underlying the induction of immunity in the gastrointestinal mucosa following oral immunization and the cross-talk between mucosal and systemic immunity should expedite the development of vaccines to diminish the global burden caused by enteric pathogens. Identifying an immunological correlate of protection in the course of field trials of efficacy, animal models (when available), or human challenge studies is also invaluable. In industrialized country populations, live attenuated vaccines (e.g. polio, typhoid, and rotavirus) mimic natural infection and generate robust protective immune responses. In contrast, a major challenge is to understand and overcome the barriers responsible for the diminished immunogenicity and efficacy of the same enteric vaccines in underprivileged populations in developing countries. Success in developing vaccines against some enteric pathogens has heretofore been elusive (e.g. Shigella). Different types of oral vaccines can selectively or inclusively elicit mucosal secretory immunoglobulin A and serum immunoglobulin G antibodies and a variety of cell-mediated immune responses. Areas of research that require acceleration include interaction between the gut innate immune system and the stimulation of adaptive immunity, development of safe yet effective mucosal adjuvants, better understanding of homing to the mucosa of immunologically relevant cells, and elicitation of mucosal immunologic memory. This review dissects the immune responses elicited in humans by enteric vaccines. PMID:21198669

  11. Immunology of gut mucosal vaccines.

    Science.gov (United States)

    Pasetti, Marcela F; Simon, Jakub K; Sztein, Marcelo B; Levine, Myron M

    2011-01-01

    Understanding the mechanisms underlying the induction of immunity in the gastrointestinal mucosa following oral immunization and the cross-talk between mucosal and systemic immunity should expedite the development of vaccines to diminish the global burden caused by enteric pathogens. Identifying an immunological correlate of protection in the course of field trials of efficacy, animal models (when available), or human challenge studies is also invaluable. In industrialized country populations, live attenuated vaccines (e.g. polio, typhoid, and rotavirus) mimic natural infection and generate robust protective immune responses. In contrast, a major challenge is to understand and overcome the barriers responsible for the diminished immunogenicity and efficacy of the same enteric vaccines in underprivileged populations in developing countries. Success in developing vaccines against some enteric pathogens has heretofore been elusive (e.g. Shigella). Different types of oral vaccines can selectively or inclusively elicit mucosal secretory immunoglobulin A and serum immunoglobulin G antibodies and a variety of cell-mediated immune responses. Areas of research that require acceleration include interaction between the gut innate immune system and the stimulation of adaptive immunity, development of safe yet effective mucosal adjuvants, better understanding of homing to the mucosa of immunologically relevant cells, and elicitation of mucosal immunologic memory. This review dissects the immune responses elicited in humans by enteric vaccines. © 2010 John Wiley & Sons A/S.

  12. Multiassociative Memory: Recurrent Synapses Increase Storage Capacity.

    Science.gov (United States)

    Gauy, Marcelo Matheus; Meier, Florian; Steger, Angelika

    2017-05-01

    The connection density of nearby neurons in the cortex has been observed to be around 0.1, whereas the longer-range connections are present with much sparser density (Kalisman, Silberberg, & Markram, 2005 ). We propose a memory association model that qualitatively explains these empirical observations. The model we consider is a multiassociative, sparse, Willshaw-like model consisting of binary threshold neurons and binary synapses. It uses recurrent synapses for iterative retrieval of stored memories. We quantify the usefulness of recurrent synapses by simulating the model for small network sizes and by doing a precise mathematical analysis for large network sizes. Given the network parameters, we can determine the precise values of recurrent and afferent synapse densities that optimize the storage capacity of the network. If the network size is like that of a cortical column, then the predicted optimal recurrent density lies in a range that is compatible with biological measurements. Furthermore, we show that our model is able to surpass the standard Willshaw model in the multiassociative case if the information capacity is normalized per strong synapse or per bits required to store the model, as considered in Knoblauch, Palm, and Sommer ( 2010 ).

  13. Glutamate synapses in human cognitive disorders.

    Science.gov (United States)

    Volk, Lenora; Chiu, Shu-Ling; Sharma, Kamal; Huganir, Richard L

    2015-07-08

    Accumulating data, including those from large genetic association studies, indicate that alterations in glutamatergic synapse structure and function represent a common underlying pathology in many symptomatically distinct cognitive disorders. In this review, we discuss evidence from human genetic studies and data from animal models supporting a role for aberrant glutamatergic synapse function in the etiology of intellectual disability (ID), autism spectrum disorder (ASD), and schizophrenia (SCZ), neurodevelopmental disorders that comprise a significant proportion of human cognitive disease and exact a substantial financial and social burden. The varied manifestations of impaired perceptual processing, executive function, social interaction, communication, and/or intellectual ability in ID, ASD, and SCZ appear to emerge from altered neural microstructure, function, and/or wiring rather than gross changes in neuron number or morphology. Here, we review evidence that these disorders may share a common underlying neuropathy: altered excitatory synapse function. We focus on the most promising candidate genes affecting glutamatergic synapse function, highlighting the likely disease-relevant functional consequences of each. We first present a brief overview of glutamatergic synapses and then explore the genetic and phenotypic evidence for altered glutamate signaling in ID, ASD, and SCZ.

  14. [Medical knowledge in immunological security of red blood cells transfusion in Tunisia: evaluation of a CD-ROM of auto-learning].

    Science.gov (United States)

    Ben Salah, N; El Borgi, W; Aounallah Skhiri, H; Ben Lakhal, F; Mouelhi, H; Zoueri, B; Gouider, E; Hafsia, R

    2013-09-01

    In Tunisia, red blood cells (RBC) transfusion joins in a statutory frame but remains subject to failures because of the misunderstanding of legislation and regulations. Our purpose is to estimate the knowledge of the medical staff in the immunological safety of RBC transfusion before and after reading an auto-education CD-ROM. It is a study of evaluation of an intervention. Eighty physicians participated to the study. The evaluation was done using an anonymous questionnaire, containing seven questions with multiple choices (QMC) relating to several items. The rate of good answers (RGA) calculated by questions and by items took into account the impact of the CD-ROM on the improvement of the answers after reading. The global average mark is 2.9/7. The RGA to questions varies from 22.5 % to 76.3%. All participants answered correctly to more than 50% of all items. Two answered correctly to all items. Among the participants, 31.3% answered to all "important" items, concerning ABO blood groups compatibility and ultimate bedside test. The rate of participation to the final evaluation was 83%. The impact of the CD-ROM was important and statistically significant. In the final evaluation, the global mark raised from 2.9 to 5.8/7, 31.5% (vs 2%) answered correctly all the questions and 95.5% (vs 31.3%) answered correctly all "important" items. This study revealed a misunderstanding of the doctors in immunological safety of RBC transfusions. Auto-teaching by CD-ROM was efficient. An improvement of the knowledge by continuous training is necessary in our country. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  15. Tools for cellular immunology and vaccine research the in the guinea pig: Monoclonal antibodies to cell surface antigens and cell lines

    OpenAIRE

    Schäfer, Hubert; Burger, Reinhard

    2012-01-01

    The use of monoclonal antibodies directed against membrane proteins of leukocytes has greatly contributed to our understanding of the function and development of the immune system. Meanwhile these reagents provide valuable tools in many fields of research, stretching far beyond immunology and hematology. For guinea pigs only a limited number of such reagents have been described, and the information about availability and specificity is scattered over many years and journals. We provide an ove...

  16. Development of radiation immunology

    International Nuclear Information System (INIS)

    Xie Yi; Dang Bingrong; Bing Tao; Zhang Hong; Li Wenjian; Liu Bing

    2005-01-01

    Radiation immunology as a new subject has made a great progress in recent years, especially in the radiation hormesis. At the same time, the research of radiobiological effect on heavy ions has played an important role in the cancer therapy, especially on the radiation immunology of heavy ions in the outer space. In this review, the authors summarized the status and development of radiation-immunology, and try to find out some better ways which can increase efficient killing on tumours, but reduce the damages on normal tissues. (authors)

  17. Long-term depression-associated signaling is required for an in vitro model of NMDA receptor-dependent synapse pruning.

    Science.gov (United States)

    Henson, Maile A; Tucker, Charles J; Zhao, Meilan; Dudek, Serena M

    2017-02-01

    Activity-dependent pruning of synaptic contacts plays a critical role in shaping neuronal circuitry in response to the environment during postnatal brain development. Although there is compelling evidence that shrinkage of dendritic spines coincides with synaptic long-term depression (LTD), and that LTD is accompanied by synapse loss, whether NMDA receptor (NMDAR)-dependent LTD is a required step in the progression toward synapse pruning is still unknown. Using repeated applications of NMDA to induce LTD in dissociated rat neuronal cultures, we found that synapse density, as measured by colocalization of fluorescent markers for pre- and postsynaptic structures, was decreased irrespective of the presynaptic marker used, post-treatment recovery time, and the dendritic location of synapses. Consistent with previous studies, we found that synapse loss could occur without apparent net spine loss or cell death. Furthermore, synapse loss was unlikely to require direct contact with microglia, as the number of these cells was minimal in our culture preparations. Supporting a model by which NMDAR-LTD is required for synapse loss, the effect of NMDA on fluorescence colocalization was prevented by phosphatase and caspase inhibitors. In addition, gene transcription and protein translation also appeared to be required for loss of putative synapses. These data support the idea that NMDAR-dependent LTD is a required step in synapse pruning and contribute to our understanding of the basic mechanisms of this developmental process. Published by Elsevier Inc.

  18. Essential Neuroscience in Immunology.

    Science.gov (United States)

    Chavan, Sangeeta S; Tracey, Kevin J

    2017-05-01

    The field of immunology is principally focused on the molecular mechanisms by which hematopoietic cells initiate and maintain innate and adaptive immunity. That cornerstone of attention has been expanded by recent discoveries that neuronal signals occupy a critical regulatory niche in immunity. The discovery is that neuronal circuits operating reflexively regulate innate and adaptive immunity. One particularly well-characterized circuit regulating innate immunity, the inflammatory reflex, is dependent upon action potentials transmitted to the reticuloendothelial system via the vagus and splenic nerves. This field has grown significantly with the identification of several other reflexes regulating discrete immune functions. As outlined in this review, the delineation of these mechanisms revealed a new understanding of immunity, enabled a first-in-class clinical trial using bioelectronic devices to inhibit cytokines and inflammation in rheumatoid arthritis patients, and provided a mosaic view of immunity as the integration of hematopoietic and neural responses to infection and injury. Copyright © 2017 by The American Association of Immunologists, Inc.

  19. Roitt's essential immunology

    National Research Council Canada - National Science Library

    Delves, Peter J; Roitt, Ivan M

    2011-01-01

    ... of the immune system, the hallmark easy-reading style of Roitt's Essential Immunology clearly explains the key principles needed by medical and health sciences students, from the basis of immunity to clinical applications...

  20. Molecular mechanisms underlying activity-dependent GABAergic synapse development and plasticity and its implications for neurodevelopmental disorders.

    Science.gov (United States)

    Chattopadhyaya, Bidisha

    2011-01-01

    GABAergic interneurons are critical for the normal function and development of neural circuits, and their dysfunction is implicated in a large number of neurodevelopmental disorders. Experience and activity-dependent mechanisms play an important role in GABAergic circuit development, also recent studies involve a number of molecular players involved in the process. Emphasizing the molecular mechanisms of GABAergic synapse formation, in particular basket cell perisomatic synapses, this paper draws attention to the links between critical period plasticity, GABAergic synapse maturation, and the consequences of its dysfunction on the development of the nervous system.

  1. Molecular Mechanisms Underlying Activity-Dependent GABAergic Synapse Development and Plasticity and Its Implications for Neurodevelopmental Disorders

    Directory of Open Access Journals (Sweden)

    Bidisha Chattopadhyaya

    2011-01-01

    Full Text Available GABAergic interneurons are critical for the normal function and development of neural circuits, and their dysfunction is implicated in a large number of neurodevelopmental disorders. Experience and activity-dependent mechanisms play an important role in GABAergic circuit development, also recent studies involve a number of molecular players involved in the process. Emphasizing the molecular mechanisms of GABAergic synapse formation, in particular basket cell perisomatic synapses, this paper draws attention to the links between critical period plasticity, GABAergic synapse maturation, and the consequences of its dysfunction on the development of the nervous system.

  2. ASIC-dependent LTP at multiple glutamatergic synapses in amygdala network is required for fear memory.

    Science.gov (United States)

    Chiang, Po-Han; Chien, Ta-Chun; Chen, Chih-Cheng; Yanagawa, Yuchio; Lien, Cheng-Chang

    2015-05-19

    Genetic variants in the human ortholog of acid-sensing ion channel-1a subunit (ASIC1a) gene are associated with panic disorder and amygdala dysfunction. Both fear learning and activity-induced long-term potentiation (LTP) of cortico-basolateral amygdala (BLA) synapses are impaired in ASIC1a-null mice, suggesting a critical role of ASICs in fear memory formation. In this study, we found that ASICs were differentially expressed within the amygdala neuronal population, and the extent of LTP at various glutamatergic synapses correlated with the level of ASIC expression in postsynaptic neurons. Importantly, selective deletion of ASIC1a in GABAergic cells, including amygdala output neurons, eliminated LTP in these cells and reduced fear learning to the same extent as that found when ASIC1a was selectively abolished in BLA glutamatergic neurons. Thus, fear learning requires ASIC-dependent LTP at multiple amygdala synapses, including both cortico-BLA input synapses and intra-amygdala synapses on output neurons.

  3. Specific immunologic recognition of the tumor-specific E2A-PBX1 fusion-point antigen in t(1;19)-positive pre-B cells.

    Science.gov (United States)

    Berendes, P; Hoogeveen, A; van Dijk, M; van Denderen, J; van Ewijk, W

    1995-08-01

    The t(1;19) translocation is the most commonly observed chromosomal translocation in childhood acute lymphoblastic leukemia (ALL). Its presence among pre-B cell ALL cases, has been associated with a poor prognosis. Two genes, E2A and PBX1, are involved in this t(1;19) translocation. As a consequence, parts of the E2A and PBX1 genes are fused, resulting in a chimeric E2A-PBX1 gene, encoding chimeric E2A-PBX1 proteins. As such, the amino acid sequence at the fusion site represents a unique tumor-specific determinant. We report on the generation of a polyclonal antiserum, termed BP 1/19, raised against the tumor-specific E2A-PBX1 junction of E2A-PBX1 proteins. The specificity of antiserum BP 1/19 for the E2A-PBX1 fusion-point is demonstrated at the peptide and at the protein level. Furthermore, specific binding of antiserum BP 1/19 to t(1;19) positive cells was shown using immunofluorescence techniques. The study shows that: (1) the tumor-specific fusion-point epitope on E2A-PBX1 proteins is presented in an antigenic fashion, and (2) this particular fusion-point epitope can be used in immunological marker analysis using fluorescence microscopy.

  4. Local immunological mechanisms of sublingual immunotherapy.

    Science.gov (United States)

    Allam, Jean-Pierre; Novak, Natalija

    2011-12-01

    To summarize novel insights into the immunological mechanisms of sublingual immunotherapy (SLIT). Within the recent decades, several alternative noninvasive allergen application strategies have been investigated in allergen-specific immunotherapy (AIT), of which intra-oral allergen application to sublingual mucosa has been proven to be well tolerated and effective. To date, SLIT is widely accepted by most allergists as an alternative option to conventional subcutaneous immunotherapy (SCIT). Although detailed immunological mechanisms remain to be elucidated, much scientific effort has been made to shed some light on local and systemic immunological responses to SLIT in mice as well as humans. Only a few studies focused on the detailed mechanisms following allergen application to the oral mucosa as part of the sophisticated mucosal immunological network. Within this network, the pro-tolerogenic properties of local antigen-presenting cells (APCs) such as dendritic cells - which are able to enforce tolerogenic mechanisms and to induce T-cell immune responses - play a central role. Further on, basic research focused not only on the immune response in nasal and bronchial mucosa but also on the systemic T-cell immune response. Thus, much exiting data have been published providing a better understanding of immunological features of SLIT but far more investigations are necessary to uncover further exciting details on the key mechanisms of SLIT.

  5. Neuroligin-1 loss is associated with reduced tenacity of excitatory synapses.

    Directory of Open Access Journals (Sweden)

    Adel Zeidan

    Full Text Available Neuroligins (Nlgns are postsynaptic, integral membrane cell adhesion molecules that play important roles in the formation, validation, and maturation of synapses in the mammalian central nervous system. Given their prominent roles in the life cycle of synapses, it might be expected that the loss of neuroligin family members would affect the stability of synaptic organization, and ultimately, affect the tenacity and persistence of individual synaptic junctions. Here we examined whether and to what extent the loss of Nlgn-1 affects the dynamics of several key synaptic molecules and the constancy of their contents at individual synapses over time. Fluorescently tagged versions of the postsynaptic scaffold molecule PSD-95, the AMPA-type glutamate receptor subunit GluA2 and the presynaptic vesicle molecule SV2A were expressed in primary cortical cultures from Nlgn-1 KO mice and wild-type (WT littermates, and live imaging was used to follow the constancy of their contents at individual synapses over periods of 8-12 hours. We found that the loss of Nlgn-1 was associated with larger fluctuations in the synaptic contents of these molecules and a poorer preservation of their contents at individual synapses. Furthermore, rates of synaptic turnover were somewhat greater in neurons from Nlgn-1 knockout mice. Finally, the increased GluA2 redistribution rates observed in neurons from Nlgn-1 knockout mice were negated by suppressing spontaneous network activity. These findings suggest that the loss of Nlgn-1 is associated with some use-dependent destabilization of excitatory synapse organization, and indicate that in the absence of Nlgn-1, the tenacity of excitatory synapses might be somewhat impaired.

  6. T Cell Epitope-Containing Domains of Ragweed Amb a 1 and Mugwort Art v 6 Modulate Immunologic Responses in Humans and Mice.

    Science.gov (United States)

    Sancho, Ana I; Wallner, Michael; Hauser, Michael; Nagl, Birgit; Himly, Martin; Asam, Claudia; Ebner, Christof; Jahn-Schmid, Beatrice; Bohle, Barbara; Ferreira, Fatima

    2017-01-01

    Ragweed (Ambrosia artemisiifolia) and mugwort (Artemisia vulgaris) are the major cause of pollen allergy in late summer. Allergen-specific lymphocytes are crucial for immune modulation during immunotherapy. We sought to generate and pre-clinically characterise highly immunogenic domains of the homologous pectate lyases in ragweed (Amb a 1) and mugwort pollen (Art v 6) for immunotherapy. Domains of Amb a 1 (Amb a 1α) and Art v 6 (Art v 6α) and a hybrid molecule, consisting of both domains, were designed, expressed in E. coli and purified. Human IgE reactivity and allergenicity were assessed by ELISA and mediator release experiments using ragweed and mugwort allergic patients. Moreover, T cell proliferation was determined. Blocking IgG antibodies and cytokine production in BALB/c mice were studied by ELISA and ELISPOT. The IgE binding capacity and in vitro allergenic activity of the Amb a 1 and Art v 6 domains and the hybrid were either greatly reduced or abolished. The recombinant proteins induced T cell proliferative responses comparable to those of the natural allergens, indicative of retained allergen-specific T cell response. Mice immunisation with the hypoallergens induced IL-4, IL-5, IL-13 and IFN-γ production after antigen-specific in vitro re-stimulation of splenocytes. Moreover, murine IgG antibodies that inhibited specific IgE binding of ragweed and mugwort pollen allergic patients were detected. Accumulation of T cell epitopes and deletion of IgE reactive areas of Amb a 1 and Art v 6, modulated the immunologic properties of the allergen immuno-domains, leading to promising novel candidates for therapeutic approach.

  7. T Cell Epitope-Containing Domains of Ragweed Amb a 1 and Mugwort Art v 6 Modulate Immunologic Responses in Humans and Mice.

    Directory of Open Access Journals (Sweden)

    Ana I Sancho

    Full Text Available Ragweed (Ambrosia artemisiifolia and mugwort (Artemisia vulgaris are the major cause of pollen allergy in late summer. Allergen-specific lymphocytes are crucial for immune modulation during immunotherapy. We sought to generate and pre-clinically characterise highly immunogenic domains of the homologous pectate lyases in ragweed (Amb a 1 and mugwort pollen (Art v 6 for immunotherapy.Domains of Amb a 1 (Amb a 1α and Art v 6 (Art v 6α and a hybrid molecule, consisting of both domains, were designed, expressed in E. coli and purified. Human IgE reactivity and allergenicity were assessed by ELISA and mediator release experiments using ragweed and mugwort allergic patients. Moreover, T cell proliferation was determined. Blocking IgG antibodies and cytokine production in BALB/c mice were studied by ELISA and ELISPOT.The IgE binding capacity and in vitro allergenic activity of the Amb a 1 and Art v 6 domains and the hybrid were either greatly reduced or abolished. The recombinant proteins induced T cell proliferative responses comparable to those of the natural allergens, indicative of retained allergen-specific T cell response. Mice immunisation with the hypoallergens induced IL-4, IL-5, IL-13 and IFN-γ production after antigen-specific in vitro re-stimulation of splenocytes. Moreover, murine IgG antibodies that inhibited specific IgE binding of ragweed and mugwort pollen allergic patients were detected.Accumulation of T cell epitopes and deletion of IgE reactive areas of Amb a 1 and Art v 6, modulated the immunologic properties of the allergen immuno-domains, leading to promising novel candidates for therapeutic approach.

  8. Localization of mineralocorticoid receptors at mammalian synapses.

    Directory of Open Access Journals (Sweden)

    Eric M Prager

    Full Text Available In the brain, membrane associated nongenomic steroid receptors can induce fast-acting responses to ion conductance and second messenger systems of neurons. Emerging data suggest that membrane associated glucocorticoid and mineralocorticoid receptors may directly regulate synaptic excitability during times of stress when adrenal hormones are elevated. As the key neuron signaling interface, the synapse is involved in learning and memory, including traumatic memories during times of stress. The lateral amygdala is a key site for synaptic plasticity underlying conditioned fear, which can both trigger and be coincident with the stress response. A large body of electrophysiological data shows rapid regulation of neuronal excitability by steroid hormone receptors. Despite the importance of these receptors, to date, only the glucocorticoid receptor has been anatomically localized to the membrane. We investigated the subcellular sites of mineralocorticoid receptors in the lateral amygdala of the Sprague-Dawley rat. Immunoblot analysis revealed the presence of mineralocorticoid receptors in the amygdala. Using electron microscopy, we found mineralocorticoid receptors expressed at both nuclear including: glutamatergic and GABAergic neurons and extra nuclear sites including: presynaptic terminals, neuronal dendrites, and dendritic spines. Importantly we also observed mineralocorticoid receptors at postsynaptic membrane densities of excitatory synapses. These data provide direct anatomical evidence supporting the concept that, at some synapses, synaptic transmission is regulated by mineralocorticoid receptors. Thus part of the stress signaling response in the brain is a direct modulation of the synapse itself by adrenal steroids.

  9. Otanps synapse linear relation multiplier circuit

    International Nuclear Information System (INIS)

    Chible, H.

    2008-01-01

    In this paper, a four quadrant VLSI analog multiplier will be proposed, in order to be used in the implementation of the neurons and synapses modules of the artificial neural networks. The main characteristics of this multiplier are the small silicon area and the low power consumption and the high value of the weight input voltage. (author)

  10. Localization of functional memory B cells at sites of antigen localization and its relationship to local aspects of immunological memory

    International Nuclear Information System (INIS)

    Ponzio, N.M.; Baine, Y.; Thorbecke, G.J.

    1980-01-01

    Experiments are described which have been designed to test whether antigen in a draining lymph node can mediate local accumulation of passively transferred antigen-specific memory B cells, using recipients whose own immune response is inhibited via γ-irradiation or by injection of cyclophosphamide. (Auth.)

  11. Defects of the Glycinergic Synapse in Zebrafish

    Science.gov (United States)

    Ogino, Kazutoyo; Hirata, Hiromi

    2016-01-01

    Glycine mediates fast inhibitory synaptic transmission. Physiological importance of the glycinergic synapse is well established in the brainstem and the spinal cord. In humans, the loss of glycinergic function in the spinal cord and brainstem leads to hyperekplexia, which is characterized by an excess startle reflex to sudden acoustic or tactile stimulation. In addition, glycinergic synapses in this region are also involved in the regulation of respiration and locomotion, and in the nociceptive processing. The importance of the glycinergic synapse is conserved across vertebrate species. A teleost fish, the zebrafish, offers several advantages as a vertebrate model for research of glycinergic synapse. Mutagenesis screens in zebrafish have isolated two motor defective mutants that have pathogenic mutations in glycinergic synaptic transmission: bandoneon (beo) and shocked (sho). Beo mutants have a loss-of-function mutation of glycine receptor (GlyR) β-subunit b, alternatively, sho mutant is a glycinergic transporter 1 (GlyT1) defective mutant. These mutants are useful animal models for understanding of glycinergic synaptic transmission and for identification of novel therapeutic agents for human diseases arising from defect in glycinergic transmission, such as hyperekplexia or glycine encephalopathy. Recent advances in techniques for genome editing and for imaging and manipulating of a molecule or a physiological process make zebrafish more attractive model. In this review, we describe the glycinergic defective zebrafish mutants and the technical advances in both forward and reverse genetic approaches as well as in vivo visualization and manipulation approaches for the study of the glycinergic synapse in zebrafish. PMID:27445686

  12. Visualizing the distribution of synapses from individual neurons in the mouse brain.

    Directory of Open Access Journals (Sweden)

    Ling Li

    2010-07-01

    Full Text Available Proper function of the mammalian brain relies on the establishment of highly specific synaptic connections among billions of neurons. To understand how complex neural circuits function, it is crucial to precisely describe neuronal connectivity and the distributions of synapses to and from individual neurons.In this study, we present a new genetic synaptic labeling method that relies on expression of a presynaptic marker, synaptophysin-GFP (Syp-GFP in individual neurons in vivo. We assess the reliability of this method and use it to analyze the spatial patterning of synapses in developing and mature cerebellar granule cells (GCs. In immature GCs, Syp-GFP is distributed in both axonal and dendritic regions. Upon maturation, it becomes strongly enriched in axons. In mature GCs, we analyzed synapses along their ascending segments and parallel fibers. We observe no differences in presynaptic distribution between GCs born at different developmental time points and thus having varied depths of projections in the molecular layer. We found that the mean densities of synapses along the parallel fiber and the ascending segment above the Purkinje cell (PC layer are statistically indistinguishable, and higher than previous estimates. Interestingly, presynaptic terminals were also found in the ascending segments of GCs below and within the PC layer, with the mean densities two-fold lower than that above the PC layer. The difference in the density of synapses in these parts of the ascending segment likely reflects the regional differences in postsynaptic target cells of GCs.The ability to visualize synapses of single neurons in vivo is valuable for studying synaptogenesis and synaptic plasticity within individual neurons as well as information flow in neural circuits.

  13. The interplay between surfaces and soluble factors define the immunologic and angiogenic properties of myeloid dendritic cells

    Directory of Open Access Journals (Sweden)

    Mansfield Kristen

    2011-06-01

    Full Text Available Abstract Background Dendritic cells (DCs are antigen presenting cells capable of inducing specific immune responses against microbial infections, transplant antigens, or tumors. Interestingly, microenvironment conditions such as those present in tumor settings might induce a DC phenotype that is poorly immunogenic and with the capability of promoting angiogenesis. We hypothesize that this plasticity may be caused not only by the action of specific cytokines or growth factors but also by the properties of the surfaces with which they interact, such as extracellular matrix (ECM components. Results Herewith we studied the effect of different surfaces and soluble factors on the biology of DCs. To accomplish this, we cultured murine myeloid(m DCs on surfaces coated with fibronectin, collagen I, gelatin, and Matrigel using poly-D-lysine and polystyrene as non-biological surfaces. Further, we cultured these cells in the presence of regular DC medium (RPMI 10% FBS or commercially available endothelial medium (EGM-2. We determined that mDCs could be kept in culture up to 3 weeks in these conditions, but only in the presence of GM-CSF. We were able to determine that long-term DC cultures produce an array of angiogenic factors, and that some of these cultures still retain the capability to induce T cell responses. Conclusions Altogether these data indicate that in order to design DC-based vaccines or treatments focused on changing the phenotype of DCs associated with diseases such as cancer or atherosclerosis, it becomes necessary to fully investigate the microenvironment in which these cells are present or will be delivered.

  14. Rebooting Human Immunology.

    Science.gov (United States)

    Davis, Mark M; Brodin, Petter

    2018-02-28

    Recent progress in both conceptual and technological approaches to human immunology have rejuvenated a field that has long been dominated by the inbred mouse model. This is a healthy development both for the clinical relevance of immunology and for the fact that it is a way to gain access to the wealth of phenomenology in the many human diseases that involve the immune system. This is where we are likely to discover new immunological mechanisms and principals, especially those involving genetic heterogeneity or environmental influences that are difficult to model effectively in inbred mice. We also suggest that there are likely to be novel immunological mechanisms in long-lived, less fecund mammals such as human beings since they must remain healthy far longer than short-lived rodents in order for the species to survive. Expected final online publication date for the Annual Review of Immunology Volume 36 is April 26, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  15. Extracellular proteolysis in structural and functional plasticity of mossy fiber synapses in hippocampus

    Directory of Open Access Journals (Sweden)

    Grzegorz eWiera

    2015-11-01

    Full Text Available Brain is continuously altered in response to experience and environmental changes. One of the underlying mechanisms is synaptic plasticity, which is manifested by modification of synapse structure and function. It is becoming clear that regulated extracellular proteolysis plays a pivotal role in the structural and functional remodeling of synapses during brain development, learning and memory formation. Clearly, plasticity mechanisms may substantially differ between projections. Mossy fiber synapses onto CA3 pyramidal cells display several unique functional features, including pronounced short-term facilitation, a presynaptically expressed LTP that is independent of NMDAR activation, and NMDA-dependent metaplasticity. Moreover, structural plasticity at mossy fiber synapses ranges from the reorganization of projection topology after hippocampus-dependent learning, through intrinsically different dynamic properties of synaptic boutons to pre- and postsynaptic structural changes accompanying LTP induction. Although concomitant functional and structural plasticity in this pathway strongly suggests a role of extracellular proteolysis, its impact only starts to be investigated in this projection. In the present report, we review the role of extracellular proteolysis in various aspects of synaptic plasticity in hippocampal mossy fiber synapses. A growing body of evidence demonstrates that among perisynaptic proteases, tPA/plasmin system, β-site amyloid precursor protein-cleaving enzyme 1 (BACE1 and metalloproteinases play a crucial role in shaping plastic changes in this projection. We discuss recent advances and emerging hypotheses on the roles of proteases in mechanisms underlying mossy fiber target specific synaptic plasticity and memory formation.

  16. Effects of Trace Metal Profiles Characteristic for Autism on Synapses in Cultured Neurons

    Directory of Open Access Journals (Sweden)

    Simone Hagmeyer

    2015-01-01

    Full Text Available Various recent studies revealed that biometal dyshomeostasis plays a crucial role in the pathogenesis of neurological disorders such as autism spectrum disorders (ASD. Substantial evidence indicates that disrupted neuronal homeostasis of different metal ions such as Fe, Cu, Pb, Hg, Se, and Zn may mediate synaptic dysfunction and impair synapse formation and maturation. Here, we performed in vitro studies investigating the consequences of an imbalance of transition metals on glutamatergic synapses of hippocampal neurons. We analyzed whether an imbalance of any one metal ion alters cell health and synapse numbers. Moreover, we evaluated whether a biometal profile characteristic for ASD patients influences synapse formation, maturation, and composition regarding NMDA receptor subunits and Shank proteins. Our results show that an ASD like biometal profile leads to a reduction of NMDAR (NR/Grin/GluN subunit 1 and 2a, as well as Shank gene expression along with a reduction of synapse density. Additionally, synaptic protein levels of GluN2a and Shanks are reduced. Although Zn supplementation is able to rescue the aforementioned alterations, Zn deficiency is not solely responsible as causative factor. Thus, we conclude that balancing Zn levels in ASD might be a prime target to normalize synaptic alterations caused by biometal dyshomeostasis.

  17. Morphological and immunological criteria of minimal residual disease detection in children with B-cell precursors acute lymphoblastic leukemia

    Science.gov (United States)

    Beznos, O. A.; Grivtsova, L. Yu; Popa, A. V.; Shervashidze, M. A.; Serebtyakova, I. N.; Tupitsyn, N. N.; Selchuk, V. U.; Grebennikova, O. P.; Titova, G. V.

    2018-01-01

    One of the key factors of prognosis and risk stratification in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is minimal residual disease (MRD). Identification of MRD on the day 15th is one of the most significant in prognosis of the disease. We compared data of a morphological and flow cytometry results of assessment of a bone marrow (BM) at the day 15th of induction chemotherapy in children with BCP-ALL.

  18. Systems Theory in Immunology

    CERN Document Server

    Doria, Gino; Koch, Giorgio; Strom, Roberto

    1979-01-01

    This volume collects the contributions presented at the "Working Conference on System Theory in Immunology", held in Rome, May 1978. The aim of the Conference was to bring together immunologists on one side and experts in system theory and applied mathematics on the other, in order to identify problems of common interest and to establish a network of joint effort toward their solution. The methodologies of system theory for processing experimental data and for describing dynamical phenomena could indeed contribute significantly to the under­ standing of basic immunological facts. Conversely, the complexity of experimental results and of interpretative models should stimulate mathematicians to formulate new problems and to design appropriate procedures of analysis. The multitude of scientific publications in theoretical biology, appeared in recent years, confirms this trend and calls for extensive interaction between mat- matics and immunology. The material of this volume is divided into five sections, along ...

  19. Immunological memory is associative

    Energy Technology Data Exchange (ETDEWEB)

    Smith, D.J.; Forrest, S. [New Mexico Univ., Albuquerque, NM (United States). Dept. of Computer Science; Perelson, A.S. [Los Alamos National Lab., NM (United States)

    1996-12-31

    The purpose of this paper is to show that immunological memory is an associative and robust memory that belongs to the class of sparse distributed memories. This class of memories derives its associative and robust nature by sparsely sampling the input space and distributing the data among many independent agents. Other members of this class include a model of the cerebellar cortex and Sparse Distributed Memory (SDM). First we present a simplified account of the immune response and immunological memory. Next we present SDM, and then we show the correlations between immunological memory and SDM. Finally, we show how associative recall in the immune response can be both beneficial and detrimental to the fitness of an individual.

  20. Long-term potentiation expands information content of hippocampal dentate gyrus synapses.

    Science.gov (United States)

    Bromer, Cailey; Bartol, Thomas M; Bowden, Jared B; Hubbard, Dusten D; Hanka, Dakota C; Gonzalez, Paola V; Kuwajima, Masaaki; Mendenhall, John M; Parker, Patrick H; Abraham, Wickliffe C; Sejnowski, Terrence J; Harris, Kristen M

    2018-03-06

    An approach combining signal detection theory and precise 3D reconstructions from serial section electron microscopy (3DEM) was used to investigate synaptic plasticity and information storage capacity at medial perforant path synapses in adult hippocampal dentate gyrus in vivo. Induction of long-term potentiation (LTP) markedly increased the frequencies of both small and large spines measured 30 minutes later. This bidirectional expansion resulted in heterosynaptic counterbalancing of total synaptic area per unit length of granule cell dendrite. Control hemispheres exhibited 6.5 distinct spine sizes for 2.7 bits of storage capacity while LTP resulted in 12.9 distinct spine sizes (3.7 bits). In contrast, control hippocampal CA1 synapses exhibited 4.7 bits with much greater synaptic precision than either control or potentiated dentate gyrus synapses. Thus, synaptic plasticity altered total capacity, yet hippocampal subregions differed dramatically in their synaptic information storage capacity, reflecting their diverse functions and activation histories.

  1. Eph receptors and ephrins in neuron-astrocyte communication at synapses.

    Science.gov (United States)

    Murai, Keith K; Pasquale, Elena B

    2011-11-01

    Neuron-glia communication is essential for regulating the properties of synaptic connections in the brain. Astrocytes, in particular, play a critical and complex role in synapse development, maintenance, and plasticity. Likewise, neurons reciprocally influence astrocyte physiology. However, the molecular signaling events that enable astrocytes and neurons to effectively communicate with each other are only partially defined. Recent findings have revealed that Eph receptor tyrosine kinases and ephrins play an important role in contact-dependent neuron-glia communication at synapses. Upon binding, these two families of cell surface-associated proteins trigger bidirectional signaling events that regulate the structural and physiological properties of both neurons and astrocytes. This review will focus on the emerging role of Eph receptors and ephrins in neuron-astrocyte interaction at synapses and discuss implications for synaptic plasticity, behavior, and disease. Copyright © 2011 Wiley-Liss, Inc.

  2. PKC-theta in regulatory and effector T-cell functions

    Directory of Open Access Journals (Sweden)

    Vedran eBrezar

    2015-10-01

    Full Text Available One of the major goals in immunology research is to understand the regulatory mechanisms that underpin the rapid switch on/off of robust and efficient effector (Teff or regulatory (Tregs T-cell responses. Understanding the molecular mechanisms underlying the regulation of such responses is critical for the development of effective therapies. T-cell activation involves the engagement of T-cell receptor and co-stimulatory signals, but the subsequent recruitment of serine/threonine-specific protein Kinase C-theta (PKC-θ to the immunological synapse is instrumental for the formation of signalling complexes, that ultimately lead to a transcriptional network in T cells. Recent studies demonstrated that major differences between Teffs and Tregs occurred at the immunological synapse where its formation induces altered signalling pathways in Tregs. These pathways are characterized by reduced recruitment of PKC-θ, suggesting that PKC-θ inhibits Tregs suppressive function in a negative feedback loop. As the balance of Teffs and Tregs has been shown to be central in several diseases, it was not surprising that some studies revealed that PKC-θ plays a major role in the regulation of this balance.This review will examine recent knowledge on the role of PKC-θ in T-cell transcriptional responses and how this protein can impact on the function of both Tregs and Teffs.

  3. Coordinated Feeding Behavior in Trichoplax, an Animal without Synapses.

    Directory of Open Access Journals (Sweden)

    Carolyn L Smith

    Full Text Available Trichoplax is a small disk-shaped marine metazoan that adheres to substrates and locomotes by ciliary gliding. Despite having only six cell types and lacking synapses Trichoplax coordinates a complex sequence of behaviors culminating in external digestion of algae. We combine live cell imaging with electron microscopy to show how this is accomplished. When Trichoplax glides over a patch of algae, its cilia stop beating so it ceases moving. A subset of one of the cell types, lipophils, simultaneously secretes granules whose content rapidly lyses algae. This secretion is accurately targeted, as only lipophils located near algae release granules. The animal pauses while the algal content is ingested, and then resumes gliding. Global control of gliding is coordinated with precise local control of lipophil secretion suggesting the presence of mechanisms for cellular communication and integration.

  4. Optimal and Local Connectivity Between Neuron and Synapse Array in the Quantum Dot/Silicon Brain

    Science.gov (United States)

    Duong, Tuan A.; Assad, Christopher; Thakoor, Anikumar P.

    2010-01-01

    This innovation is used to connect between synapse and neuron arrays using nanowire in quantum dot and metal in CMOS (complementary metal oxide semiconductor) technology to enable the density of a brain-like connection in hardware. The hardware implementation combines three technologies: 1. Quantum dot and nanowire-based compact synaptic cell (50x50 sq nm) with inherently low parasitic capacitance (hence, low dynamic power approx.l0(exp -11) watts/synapse), 2. Neuron and learning circuits implemented in 50-nm CMOS technology, to be integrated with quantum dot and nanowire synapse, and 3. 3D stacking approach to achieve the overall numbers of high density O(10(exp 12)) synapses and O(10(exp 8)) neurons in the overall system. In a 1-sq cm of quantum dot layer sitting on a 50-nm CMOS layer, innovators were able to pack a 10(exp 6)-neuron and 10(exp 10)-synapse array; however, the constraint for the connection scheme is that each neuron will receive a non-identical 10(exp 4)-synapse set, including itself, via its efficacy of the connection. This is not a fully connected system where the 100x100 synapse array only has a 100-input data bus and 100-output data bus. Due to the data bus sharing, it poses a great challenge to have a complete connected system, and its constraint within the quantum dot and silicon wafer layer. For an effective connection scheme, there are three conditions to be met: 1. Local connection. 2. The nanowire should be connected locally, not globally from which it helps to maximize the data flow by sharing the same wire space location. 3. Each synapse can have an alternate summation line if needed (this option is doable based on the simple mask creation). The 10(exp 3)x10(exp 3)-neuron array was partitioned into a 10-block, 10(exp 2)x10(exp 3)-neuron array. This building block can be completely mapped within itself (10,000 synapses to a neuron).

  5. Immunologic lung disease

    International Nuclear Information System (INIS)

    Harman, E.M.

    1985-01-01

    The term immunologic lung disease comprises a broad spectrum of disease. The authors have covered a few entities in which recent studies have been particularly helpful in elucidating pathophysiology though not in uncovering the inciting cause. Common to all of these entities is the problem of finding appropriate methods of defining disease activity and response to treatment. As exemplified by the improved outlook for Goodpasture's syndrome with elucidation of its underlying immunopathology, it is likely that better understanding of the immunologic basis of sarcoid and interstitial disease may be helpful in planning more effective treatment strategies. 44 references

  6. A Combined Nutritional and Immunological Intervention to Activate Natural Cytotoxicity Against Breast Cancer Cells In Vitro and In Vivo

    Science.gov (United States)

    2011-09-01

    canola oil), RA, α-GalCer, or both. All- trans-RA, 37.5 µg per mouse in canola oil, was given orally once a day for 10 days. α-GalCer, 2 µg per mouse in...null strains. Treatments with all-trans-RA, 37 µg per mouse in canola oil, were given orally once a day for 10-14 days (monitoring animal weight as...the spread of tumor cells (30). Twenty-four h later, mice were randomized to receive control (vehicle as Canola oil), RA, αGalCer, or both. All-trans-RA

  7. Generation of functional inhibitory synapses incorporating defined combinations of GABA(A or glycine receptor subunits

    Directory of Open Access Journals (Sweden)

    Christine Laura Dixon

    2015-12-01

    Full Text Available Fast inhibitory neurotransmission in the brain is mediated by wide range of GABAA receptor (GABAAR and glycine receptor (GlyR isoforms, each with different physiological and pharmacological properties. Because multiple isoforms are expressed simultaneously in most neurons, it is difficult to define the properties of inhibitory postsynaptic currents mediated by individual isoforms in vivo. Although recombinant expression systems permit the expression of individual isoforms in isolation, they require exogenous agonist application which cannot mimic the dynamic neurotransmitter profile characteristic of native synapses. We describe a neuron-HEK293 cell co-culture technique for generating inhibitory synapses incorporating defined combinations of GABAAR or GlyR subunits. Primary neuronal cultures, prepared from embryonic rat cerebral cortex or spinal cord, are used to provide presynaptic GABAergic and glycinergic terminals, respectively. When the cultures are mature, HEK293 cells expressing the subunits of interest plus neuroligin 2A are plated onto the neurons, which rapidly form synapses onto HEK293 cells. Patch clamp electrophysiology is then used to analyze the physiological and pharmacological properties of the inhibitory postsynaptic currents mediated by the recombinant receptors. The method is suitable for investigating the kinetic properties or the effects of drugs on inhibitory postsynaptic currents mediated by defined GABAAR or GlyR isoforms of interest, the effects of hereditary disease mutations on the formation and function of both types of synapses, and synaptogenesis and synaptic clustering mechanisms. The entire cell preparation procedure takes 2 – 5 weeks.

  8. Tools for cellular immunology and vaccine research the in the guinea pig: monoclonal antibodies to cell surface antigens and cell lines.

    Science.gov (United States)

    Schäfer, Hubert; Burger, Reinhard

    2012-08-31

    The use of monoclonal antibodies directed against membrane proteins of leukocytes has greatly contributed to our understanding of the function and development of the immune system. Meanwhile these reagents provide valuable tools in many fields of research, stretching far beyond immunology and hematology. For guinea pigs only a limited number of such reagents have been described, and the information about availability and specificity is scattered over many years and journals. We provide an overview on the monoclonal antibodies produced since the technique was applied first in this species, with a focus on those reagents which have been characterized in more detail, and which should still be available either commercially or directly from the labs that created them. Copyright © 2012 Elsevier Ltd. All rights reserved.

  9. G-CSF-primed autologous and allogeneic bone marrow for transplantation in clinical oncology. Cell content and immunological characteristics

    Science.gov (United States)

    Grivtsova, L. Yu; Melkova, K. N.; Kupryshkina, N. A.; Vorotnikov, I. K.; Grigoryeva, T. A.; Selchuk, V. Yu; Grebennikova, O. P.; Titova, G. V.; Tupitsyn, N. N.

    2018-01-01

    60 samples of G-CSF-primed bone marrow (39 cancer patients and 21 healthy donors) to be used for transplantation to cancer patients were analyzed and compared by main characteristics with historical control and 13 bone marrow samples from control patient with mastopathy. Basing on morphological and multicolor flow cytometry findings certain characteristics of G-CSF-primed bone marrow were discovered, such as a significant increase in blast count in cancer patients as compared to donors and control patients (p<0.037), a higher neutrophil maturation index (p<0.001) and a lower percentage of mature lymphocytes (p<0.008) as compared to the control group. Among lymphocyte populations G-CSF-priming was associated with a significant increase in the total of mature CD3+ T-cells and CD8+ T-killers (p<0.0001) and a decrease in CD56+CD3- and/or CD16+CD3- NK-cells (p<0.006) both in cancer patients and healthy donors in comparison with the controls.

  10. The critical roles of activated stellate cells-mediated paracrine signaling, metabolism and onco-immunology in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Fu, Yaojie; Liu, Shanshan; Zeng, Shan; Shen, Hong

    2018-02-19

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant diseases worldwide. It is refractory to conventional treatments, and consequently has a documented 5-year survival rate as low as 7%. Increasing evidence indicates that activated pancreatic stellate cells (PSCs), one of the stromal components in tumor microenvironment (TME), play a crucial part in the desmoplasia, carcinogenesis, aggressiveness, metastasis associated with PDAC. Despite the current understanding of PSCs as a "partner in crime" to PDAC, detailed regulatory roles of PSCs and related microenvironment remain obscure. In addition to multiple paracrine signaling pathways, recent research has confirmed that PSCs-mediated tumor microenvironment may influence behaviors of PDAC via diverse mechanisms, such as rewiring metabolic networks, suppressing immune responses. These new activities are closely linked with treatment and prognosis of PDAC. In this review, we discuss the recent advances regarding new functions of activated PSCs, including PSCs-cancer cells interaction, mechanisms involved in immunosuppressive regulation, and metabolic reprogramming. It's clear that these updated experimental or clinical studies of PSCs may provide a promising approach for PDAC treatment in the near future.

  11. Cell envelope of Bordetella pertussis: immunological and biochemical analyses and characterization of a major outer membrane porin protein

    International Nuclear Information System (INIS)

    Armstrong, S.K.

    1986-01-01

    Surface molecules of Bordetella pertussis which may be important in metabolism, pathogenesis, and immunity to whooping cough were examined using cell fractionation and 125 I cell surface labeling. Antigenic envelope proteins were examined by immunofluorescence microscopy and Western blotting procedures using monoclonal antibodies and convalescent sera. A surface protein with a high M/sub r/, missing in a mutant lacking the filamentous hemagglutinin, was identified in virulent Bordetella pertussis but was absent in virulent B. pertussis strains. At least three envelope proteins were found only in virulent B. pertussis strains and were absent or diminished in avirulent and most phenotypically modulated strains. Transposon-induced mutants unable to produce hemolysin, dermonecrotic toxin, pertussis toxin, and filamentous hemagglutinin also lacked these three envelope proteins, confirming that virulence-associated envelope proteins were genetically regulated with other virulence-associated traits. Two dimensional gel electrophoresis revealed at least five heat modifiable proteins which migrated as higher or lower M/sub r/ moieties if solubilized at 25 0 C instead of 100 0 C

  12. T cell antigen receptor activation and actin cytoskeleton remodeling

    Science.gov (United States)

    Kumari, Sudha; Curado, Silvia; Mayya, Viveka

    2013-01-01

    T cells constitute a crucial arm of the adaptive immune system and their optimal function is required for a healthy immune response. After the initial step of T cell-receptor (TCR) triggering by antigenic peptide complexes on antigen presenting cell (APC), the T cell exhibits extensive cytoskeletal remodeling. This cytoskeletal remodeling leads to formation of an “immunological synapse” [1] characterized by regulated clustering, segregation and movement of receptors at the interface. Synapse formation regulates T cell activation and response to antigenic peptides and proceeds via feedback between actin cytoskeleton and TCR signaling. Actin polymerization participates in various events during the synapse formation, maturation, and eventually its disassembly. There is increasing knowledge about the actin effectors that couple TCR activation to actin rearrangements [2, 3], and how defects in these effectors translate into impairment of T cell activation. In this review we aim to summarize and integrate parts of what is currently known about this feedback process. In addition, in light of recent advancements in our understanding of TCR triggering and translocation at the synapse, we speculate on the organizational and functional diversity of microfilament architecture in the T cell. PMID:23680625

  13. Impact of the B Cell Growth Factor APRIL on the Qualitative and Immunological Characteristics of Atherosclerotic Plaques.

    Science.gov (United States)

    Bernelot Moens, Sophie J; van Leuven, Sander I; Zheng, Kang H; Havik, Stefan R; Versloot, Miranda V; van Duivenvoorde, Leonie M; Hahne, Michael; Stroes, Erik S G; Baeten, Dominique L; Hamers, Anouk A J

    2016-01-01

    Studies on the role of B lymphocytes in atherosclerosis development, have yielded contradictory results. Whereas B lymphocyte-deficiency aggravates atherosclerosis in mice; depletion of mature B lymphocytes reduces atherosclerosis. These observations led to the notion that distinct B lymphocyte subsets have different roles. B1a lymphocytes exert an atheroprotective effect, which has been attributed to secretion of IgM, which can be deposited in atherosclerotic lesions thereby reducing necrotic core formation. Tumor necrosis factor (TNF)-family member 'A Proliferation-Inducing Ligand' (APRIL, also known as TNFSF13) was previously shown to increase serum IgM levels in a murine model. In this study, we investigated the effect of APRIL overexpression on advanced lesion formation and composition, IgM production and B cell phenotype. We crossed APRIL transgenic (APRIL-Tg) mice with ApoE knockout (ApoE-/-) mice. After a 12-week Western Type Diet, ApoE-/-APRIL-Tg mice and ApoE-/- littermates showed similar increases in body weight and lipid levels. Histologic evaluation showed no differences in lesion size, stage or necrotic area. However, smooth muscle cell (α-actin stain) content was increased in ApoE-/-APRIL-Tg mice, implying more stable lesions. In addition, increases in both plaque IgM deposition and plasma IgM levels were found in ApoE-/-APRIL-Tg mice compared with ApoE-/- mice. Flow cytometry revealed a concomitant increase in peritoneal B1a lymphocytes in ApoE-/-APRIL-Tg mice. This study shows that ApoE-/-APRIL-Tg mice have increased oxLDL-specific serum IgM levels, potentially mediated via an increase in B1a lymphocytes. Although no differences in lesion size were found, transgenic ApoE-/-APRIL-Tg mice do show potential plaque stabilizing features in advanced atherosclerotic lesions.

  14. Reciprocal synapses between mushroom body and dopamine neurons form a positive feedback loop required for learning.

    Science.gov (United States)

    Cervantes-Sandoval, Isaac; Phan, Anna; Chakraborty, Molee; Davis, Ronald L

    2017-05-10

    Current thought envisions dopamine neurons conveying the reinforcing effect of the unconditioned stimulus during associative learning to the axons of Drosophila mushroom body Kenyon cells for normal olfactory learning. Here, we show using functional GFP reconstitution experiments that Kenyon cells and dopamine neurons from axoaxonic reciprocal synapses. The dopamine neurons receive cholinergic input via nicotinic acetylcholine receptors from the Kenyon cells; knocking down these receptors impairs olfactory learning revealing the importance of these receptors at the synapse. Blocking the synaptic output of Kenyon cells during olfactory conditioning reduces presynaptic calcium transients in dopamine neurons, a finding consistent with reciprocal communication. Moreover, silencing Kenyon cells decreases the normal chronic activity of the dopamine neurons. Our results reveal a new and critical role for positive feedback onto dopamine neurons through reciprocal connections with Kenyon cells for normal olfactory learning.

  15. Immunological Approaches to Biomass Characterization and Utilization.

    Science.gov (United States)

    Pattathil, Sivakumar; Avci, Utku; Zhang, Tiantian; Cardenas, Claudia L; Hahn, Michael G

    2015-01-01

    Plant biomass is the major renewable feedstock resource for sustainable generation of alternative transportation fuels to replace fossil carbon-derived fuels. Lignocellulosic cell walls are the principal component of plant biomass. Hence, a detailed understanding of plant cell wall structure and biosynthesis is an important aspect of bioenergy research. Cell walls are dynamic in their composition and structure, varying considerably among different organs, cells, and developmental stages of plants. Hence, tools are needed that are highly efficient and broadly applicable at various levels of plant biomass-based bioenergy research. The use of plant cell wall glycan-directed probes has seen increasing use over the past decade as an excellent approach for the detailed characterization of cell walls. Large collections of such probes directed against most major cell wall glycans are currently available worldwide. The largest and most diverse set of such probes consists of cell wall glycan-directed monoclonal antibodies (McAbs). These McAbs can be used as immunological probes to comprehensively monitor the overall presence, extractability, and distribution patterns among cell types of most major cell wall glycan epitopes using two mutually complementary immunological approaches, glycome profiling (an in vitro platform) and immunolocalization (an in situ platform). Significant progress has been made recently in the overall understanding of plant biomass structure, composition, and modifications with the application of these immunological approaches. This review focuses on such advances made in plant biomass analyses across diverse areas of bioenergy research.

  16. Immunology & Human Health.

    Science.gov (United States)

    Dawson, Jeffrey R.; And Others

    This monograph was designed for the high school biology curriculum. The first section reviews the major areas of importance in immunology. Section three contains six instructional activities for the high school classroom and the second section contains teacher's materials for those activities. The activities address for students some of the major…

  17. Oral Microbiology and Immunology

    DEFF Research Database (Denmark)

    Dahlén, Gunnar; Fiehn, Nils-Erik; Olsen, Ingar

    , dental assistants and trainees may find it a useful source of reference. The contents are based on general microbiology and immunology. Oral microbiology is given particular attention, with examples relevant to oral infectious diseases. Each chapter opens with a relatively short pre-reading section...

  18. Refresher Course in Immunology

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 7; Issue 7. Refresher Course in Immunology. Information and Announcements Volume 7 Issue 7 July 2002 pp 92-92. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/007/07/0092-0092. Resonance – Journal ...

  19. Boltzmann energy-based image analysis demonstrates that extracellular domain size differences explain protein segregation at immune synapses.

    Directory of Open Access Journals (Sweden)

    Nigel J Burroughs

    2011-08-01

    Full Text Available Immune synapses formed by T and NK cells both show segregation of the integrin ICAM1 from other proteins such as CD2 (T cell or KIR (NK cell. However, the mechanism by which these proteins segregate remains unclear; one key hypothesis is a redistribution based on protein size. Simulations of this mechanism qualitatively reproduce observed segregation patterns, but only in certain parameter regimes. Verifying that these parameter constraints in fact hold has not been possible to date, this requiring a quantitative coupling of theory to experimental data. Here, we address this challenge, developing a new methodology for analysing and quantifying image data and its integration with biophysical models. Specifically we fit a binding kinetics model to 2 colour fluorescence data for cytoskeleton independent synapses (2 and 3D and test whether the observed inverse correlation between fluorophores conforms to size dependent exclusion, and further, whether patterned states are predicted when model parameters are estimated on individual synapses. All synapses analysed satisfy these conditions demonstrating that the mechanisms of protein redistribution have identifiable signatures in their spatial patterns. We conclude that energy processes implicit in protein size based segregation can drive the patternation observed in individual synapses, at least for the specific examples tested, such that no additional processes need to be invoked. This implies that biophysical processes within the membrane interface have a crucial impact on cell:cell communication and cell signalling, governing protein interactions and protein aggregation.

  20. Positioning of AMPA Receptor-Containing Endosomes Regulates Synapse Architecture

    Directory of Open Access Journals (Sweden)

    Marta Esteves da Silva

    2015-11-01

    Full Text Available Lateral diffusion in the membrane and endosomal trafficking both contribute to the addition and removal of AMPA receptors (AMPARs at postsynaptic sites. However, the spatial coordination between these mechanisms has remained unclear, because little is known about the dynamics of AMPAR-containing endosomes. In addition, how the positioning of AMPAR-containing endosomes affects synapse organization and functioning has never been directly explored. Here, we used live-cell imaging in hippocampal neuron cultures to show that intracellular AMPARs are transported in Rab11-positive recycling endosomes, which frequently enter dendritic spines and depend on the microtubule and actin cytoskeleton. By using chemically induced dimerization systems to recruit kinesin (KIF1C or myosin (MyosinV/VI motors to Rab11-positive recycling endosomes, we controlled their trafficking and found that induced removal of recycling endosomes from spines decreases surface AMPAR expression and PSD-95 clusters at synapses. Our data suggest a mechanistic link between endosome positioning and postsynaptic structure and composition.

  1. Prevention of Noise Damage to Cochlear Synapses

    Science.gov (United States)

    2017-10-01

    difference We therefore conclude that it is more likely that female hormones are protecting against susceptibility as opposed to male hormones...of synapse counts among all experimental conditions, those in A as well as saline/vehicle and systemic 4 mg/Kg IEM-1460 (IEMs4mg). There is no... animals at the approximate level of the animals ’ ears. The variation of the noise level across the animals ’ ears and across time is ə dB

  2. Specific recycling receptors are targeted to the immune synapse by the intraflagellar transport system

    Science.gov (United States)

    Finetti, Francesca; Patrussi, Laura; Masi, Giulia; Onnis, Anna; Galgano, Donatella; Lucherini, Orso Maria; Pazour, Gregory J.; Baldari, Cosima T.

    2014-01-01

    ABSTRACT T cell activation requires sustained signaling at the immune synapse, a specialized interface with the antigen-presenting cell (APC) that assembles following T cell antigen receptor (TCR) engagement by major histocompatibility complex (MHC)-bound peptide. Central to sustained signaling is the continuous recruitment of TCRs to the immune synapse. These TCRs are partly mobilized from an endosomal pool by polarized recycling. We have identified IFT20, a component of the intraflagellar transport (IFT) system that controls ciliogenesis, as a central regulator of TCR recycling to the immune synapse. Here, we have investigated the interplay of IFT20 with the Rab GTPase network that controls recycling. We found that IFT20 forms a complex with Rab5 and the TCR on early endosomes. IFT20 knockdown (IFT20KD) resulted in a block in the recycling pathway, leading to a build-up of recycling TCRs in Rab5+ endosomes. Recycling of the transferrin receptor (TfR), but not of CXCR4, was disrupted by IFT20 deficiency. The IFT components IFT52 and IFT57 were found to act together with IFT20 to regulate TCR and TfR recycling. The results provide novel insights into the mechanisms that control TCR recycling and immune synapse assembly, and underscore the trafficking-related function of the IFT system beyond ciliogenesis. PMID:24554435

  3. Modulation of Immunological Pathways in Autistic and Neurotypical Lymphoblastoid Cell Lines by the Enteric Microbiome Metabolite Propionic Acid.

    Science.gov (United States)

    Frye, Richard E; Nankova, Bistra; Bhattacharyya, Sudeepa; Rose, Shannon; Bennuri, Sirish C; MacFabe, Derrick F

    2017-01-01

    Propionic acid (PPA) is a ubiquitous short-chain fatty acid which is a fermentation product of the enteric microbiome and present or added to many foods. While PPA has beneficial effects, it is also associated with human disorders, including autism spectrum disorders (ASDs). We previously demonstrated that PPA modulates mitochondrial dysfunction differentially in subsets of lymphoblastoid cell lines (LCLs) derived from patients with ASD. Specifically, PPA significantly increases mitochondrial function in LCLs that have mitochondrial dysfunction at baseline [individuals with autistic disorder with atypical mitochondrial function (AD-A) LCLs] as compared to ASD LCLs with normal mitochondrial function [individuals with autistic disorder with normal mitochondrial function (AD-N) LCLs] and control (CNT) LCLs. PPA at 1 mM was found to have a minimal effect on expression of immune genes in CNT and AD-N LCLs. However, as hypothesized, Panther analysis demonstrated that 1 mM PPA exposure at 24 or 48 h resulted in significant activation of the immune system genes in AD-A LCLs. When the effect of PPA on ASD LCLs were compared to the CNT LCLs, both ASD groups demonstrated immune pathway activation, although the AD-A LCLs demonstrate a wider activation of immune genes. Ingenuity Pathway Analysis identified several immune-related pathways as key Canonical Pathways that were differentially regulated, specifically human leukocyte antigen expression and immunoglobulin production genes were upregulated. These data demonstrate that the enteric microbiome metabolite PPA can evoke atypical immune activation in LCLs with an underlying abnormal metabolic state. As PPA, as well as enteric bacteria which produce PPA, have been implicated in a wide variety of diseases which have components of immune dysfunction, including ASD, diabetes, obesity, and inflammatory diseases, insight into this metabolic modulator may have wide applications for both health and disease.

  4. IP-I0 BASED IMMUNOLOGICAL MONITORING

    DEFF Research Database (Denmark)

    2008-01-01

    The present invention relates to an immunological method and, more particularly, a method for measuring cell-mediated immune reactivity (CMI) in mammals based on the production of IP-10.The invention further discloses an assay and a kit for measuring CMI to an antigen using whole blood or other s...

  5. IP-I0 BASED IMMUNOLOGICAL MONITORING

    DEFF Research Database (Denmark)

    2008-01-01

    The present invention relates to an immunological method and, more particularly, a method for measuring cell-mediated immune reactivity (CMI) in mammals based on the production of IP-10.The invention further discloses an assay and a kit for measuring CMI to an antigen using whole blood or other...

  6. Haematological and immunological effect of coadministration of ...

    African Journals Online (AJOL)

    This study evaluated the effect of co-administration of extracts of Vernonia amygdalina Del. (VA) and Azadirachta indica Linn.(AI) on haemapoietic and immunological indices of normal and diabetic rats. White blood cells which were non-significantly decreased (p>0.05) in diabetic control rats relative to the normal control, ...

  7. Preferential loss of dorsal-hippocampus synapses underlies memory impairments provoked by short, multimodal stress.

    Science.gov (United States)

    Maras, P M; Molet, J; Chen, Y; Rice, C; Ji, S G; Solodkin, A; Baram, T Z

    2014-07-01

    The cognitive effects of stress are profound, yet it is unknown if the consequences of concurrent multiple stresses on learning and memory differ from those of a single stress of equal intensity and duration. We compared the effects on hippocampus-dependent memory of concurrent, hours-long light, loud noise, jostling and restraint (multimodal stress) with those of restraint or of loud noise alone. We then examined if differences in memory impairment following these two stress types might derive from their differential impact on hippocampal synapses, distinguishing dorsal and ventral hippocampus. Mice exposed to hours-long restraint or loud noise were modestly or minimally impaired in novel object recognition, whereas similar-duration multimodal stress provoked severe deficits. Differences in memory were not explained by differences in plasma corticosterone levels or numbers of Fos-labeled neurons in stress-sensitive hypothalamic neurons. However, although synapses in hippocampal CA3 were impacted by both restraint and multimodal stress, multimodal stress alone reduced synapse numbers severely in dorsal CA1, a region crucial for hippocampus-dependent memory. Ventral CA1 synapses were not significantly affected by either stress modality. Probing the basis of the preferential loss of dorsal synapses after multimodal stress, we found differential patterns of neuronal activation by the two stress types. Cross-correlation matrices, reflecting functional connectivity among activated regions, demonstrated that multimodal stress reduced hippocampal correlations with septum and thalamus and increased correlations with amygdala and BST. Thus, despite similar effects on plasma corticosterone and on hypothalamic stress-sensitive cells, multimodal and restraint stress differ in their activation of brain networks and in their impact on hippocampal synapses. Both of these processes might contribute to amplified memory impairments following short, multimodal stress.

  8. Preferential loss of dorsal-hippocampus synapses underlies memory impairments provoked by short, multimodal stress

    Science.gov (United States)

    Maras, P M; Molet, J; Chen, Y; Rice, C; Ji, S G; Solodkin, A; Baram, T Z

    2014-01-01

    The cognitive effects of stress are profound, yet it is unknown if the consequences of concurrent multiple stresses on learning and memory differ from those of a single stress of equal intensity and duration. We compared the effects on hippocampus-dependent memory of concurrent, hours-long light, loud noise, jostling and restraint (multimodal stress) with those of restraint or of loud noise alone. We then examined if differences in memory impairment following these two stress types might derive from their differential impact on hippocampal synapses, distinguishing dorsal and ventral hippocampus. Mice exposed to hours-long restraint or loud noise were modestly or minimally impaired in novel object recognition, whereas similar-duration multimodal stress provoked severe deficits. Differences in memory were not explained by differences in plasma corticosterone levels or numbers of Fos-labeled neurons in stress-sensitive hypothalamic neurons. However, although synapses in hippocampal CA3 were impacted by both restraint and multimodal stress, multimodal stress alone reduced synapse numbers severely in dorsal CA1, a region crucial for hippocampus-dependent memory. Ventral CA1 synapses were not significantly affected by either stress modality. Probing the basis of the preferential loss of dorsal synapses after multimodal stress, we found differential patterns of neuronal activation by the two stress types. Cross-correlation matrices, reflecting functional connectivity among activated regions, demonstrated that multimodal stress reduced hippocampal correlations with septum and thalamus and increased correlations with amygdala and BST. Thus, despite similar effects on plasma corticosterone and on hypothalamic stress-sensitive cells, multimodal and restraint stress differ in their activation of brain networks and in their impact on hippocampal synapses. Both of these processes might contribute to amplified memory impairments following short, multimodal stress. PMID:24589888

  9. CNS Neurons Deposit Laminin α5 to Stabilize Synapses

    Directory of Open Access Journals (Sweden)

    Mitchell H. Omar

    2017-10-01

    Full Text Available Summary: Synapses in the developing brain are structurally dynamic but become stable by early adulthood. We demonstrate here that an α5-subunit-containing laminin stabilizes synapses during this developmental transition. Hippocampal neurons deposit laminin α5 at synapses during adolescence as connections stabilize. Disruption of laminin α5 in neurons causes dramatic fluctuations in dendritic spine head size that can be rescued by exogenous α5-containing laminin. Conditional deletion of laminin α5 in vivo increases dendritic spine size and leads to an age-dependent loss of synapses accompanied by behavioral defects. Remaining synapses have larger postsynaptic densities and enhanced neurotransmission. Finally, we provide evidence that laminin α5 acts through an integrin α3β1-Abl2 kinase-p190RhoGAP signaling cascade and partners with laminin β2 to regulate dendritic spine density and behavior. Together, our results identify laminin α5 as a stabilizer of dendritic spines and synapses in the brain and elucidate key cellular and molecular mechanisms by which it acts. : In the developing brain, synaptic structure transitions from dynamic to stable by early adulthood. Omar et al. identify a laminin molecule deposited at synapses in the brain that is essential for dendritic spine structural regulation and synapse stability between early postnatal development and adulthood. Keywords: extracellular matrix, ECM, synapse maturation, adhesion, Lama5, Lamb2, synapse loss, stability, structural plasticity, motility

  10. [Immunological background and pathomechanisms of food allergies].

    Science.gov (United States)

    Schülke, Stefan; Scheurer, Stephan

    2016-06-01

    Recent advances in immunology have greatly improved our understanding of the pathomechanisms of food allergies. Food allergies are caused and maintained by complex interactions of the innate and adaptive immune system involving antigen-presenting cells (APC), T cells, group 2 innate lymphoid cells (ILC2), epithelial cells (EC) and effectors cells. Additionally, epigenetic factors, the intestinal microbiome and nutritional factors modulating the gastrointestinal lymphatic tissue probably have a significant impact on allergy development. However, why certain individuals develop tolerance while others mount allergic responses, the factors defining the allergenicity of food proteins, as well as the immunological mechanisms triggering allergy development have yet to be analyzed in detail.

  11. A roadmap towards personalized immunology.

    Science.gov (United States)

    Delhalle, Sylvie; Bode, Sebastian F N; Balling, Rudi; Ollert, Markus; He, Feng Q

    2018-01-01

    Big data generation and computational processing will enable medicine to evolve from a "one-size-fits-all" approach to precise patient stratification and treatment. Significant achievements using "Omics" data have been made especially in personalized oncology. However, immune cells relative to tumor cells show a much higher degree of complexity in heterogeneity, dynamics, memory-capability, plasticity and "social" interactions. There is still a long way ahead on translating our capability to identify potentially targetable personalized biomarkers into effective personalized therapy in immune-centralized diseases. Here, we discuss the recent advances and successful applications in "Omics" data utilization and network analysis on patients' samples of clinical trials and studies, as well as the major challenges and strategies towards personalized stratification and treatment for infectious or non-communicable inflammatory diseases such as autoimmune diseases or allergies. We provide a roadmap and highlight experimental, clinical, computational analysis, data management, ethical and regulatory issues to accelerate the implementation of personalized immunology.

  12. The immunology of hepatocellular carcinoma.

    Science.gov (United States)

    Ringelhan, Marc; Pfister, Dominik; O'Connor, Tracy; Pikarsky, Eli; Heikenwalder, Mathias

    2018-03-01

    In contrast to most other malignancies, hepatocellular carcinoma (HCC), which accounts for approximately 90% of primary liver cancers, arises almost exclusively in the setting of chronic inflammation. Irrespective of etiology, a typical sequence of chronic necroinflammation, compensatory liver regeneration, induction of liver fibrosis and subsequent cirrhosis often precedes hepatocarcinogenesis. The liver is a central immunomodulator that ensures organ and systemic protection while maintaining immunotolerance. Deregulation of this tightly controlled liver immunological network is a hallmark of chronic liver disease and HCC. Notably, immunotherapies have raised hope for the successful treatment of advanced HCC. Here we summarize the roles of specific immune cell subsets in chronic liver disease, with a focus on non-alcoholic steatohepatitis and HCC. We review new advances in immunotherapeutic approaches for the treatment of HCC and discuss the challenges posed by the immunotolerant hepatic environment and the dual roles of adaptive and innate immune cells in HCC.

  13. High Throughput Method to Quantify Anterior-Posterior Polarity of T-Cells and Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Susan J. Marriott

    2011-11-01

    Full Text Available The virologic synapse (VS, which is formed between a virus-infected and uninfected cell, plays a central role in the transmission of certain viruses, such as HIV and HTLV-1. During VS formation, HTLV-1-infected T-cells polarize cellular and viral proteins toward the uninfected T-cell. This polarization resembles anterior-posterior cell polarity induced by immunological synapse (IS formation, which is more extensively characterized than VS formation and occurs when a T-cell interacts with an antigen-presenting cell. One measure of cell polarity induced by both IS or VS formation is the repositioning of the microtubule organizing center (MTOC relative to the contact point with the interacting cell. Here we describe an automated, high throughput system to score repositioning of the MTOC and thereby cell polarity establishment. The method rapidly and accurately calculates the angle between the MTOC and the IS for thousands of cells. We also show that the system can be adapted to score anterior-posterior polarity establishment of epithelial cells. This general approach represents a significant advancement over manual cell polarity scoring, which is subject to experimenter bias and requires more time and effort to evaluate large numbers of cells.

  14. Monoacylated Cellular Prion Proteins Reduce Amyloid-β-Induced Activation of Cytoplasmic Phospholipase A2 and Synapse Damage

    Directory of Open Access Journals (Sweden)

    Ewan West

    2015-06-01

    Full Text Available Alzheimer’s disease (AD is a progressive neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ and the loss of synapses. Aggregation of the cellular prion protein (PrPC by Aβ oligomers induced synapse damage in cultured neurons. PrPC is attached to membranes via a glycosylphosphatidylinositol (GPI anchor, the composition of which affects protein targeting and cell signaling. Monoacylated PrPC incorporated into neurons bound “natural Aβ”, sequestering Aβ outside lipid rafts and preventing its accumulation at synapses. The presence of monoacylated PrPC reduced the Aβ-induced activation of cytoplasmic phospholipase A2 (cPLA2 and Aβ-induced synapse damage. This protective effect was stimulus specific, as treated neurons remained sensitive to α-synuclein, a protein associated with synapse damage in Parkinson’s disease. In synaptosomes, the aggregation of PrPC by Aβ oligomers triggered the formation of a signaling complex containing the cPLA2.a process, disrupted by monoacylated PrPC. We propose that monoacylated PrPC acts as a molecular sponge, binding Aβ oligomers at the neuronal perikarya without activating cPLA2 or triggering synapse damage.

  15. Immunological Deregulation in Classic Hodgkin Lymphoma

    Science.gov (United States)

    Romano, Alessandra; Vetro, Calogero; Caocci, Giovanni; Greco, Marianna; Parrinello, Nunziatina Laura; Di Raimondo, Francesco; La Nasa, Giorgio

    2014-01-01

    Classic Hodgkin Lymphoma (cHL) has a unique histology since only a few neoplastic cells are surrounded by inflammatory accessory cells that in the last years have emerged as crucial players in sustaining the course of disease. In addition, recent studies suggest that the abnormal activity of these inflammatory cells (such as deregulation in regulatory T cells signaling, expansion of myeloid derived suppressor cells, HLA-G signaling and natural killer cells dysfunction) may have prognostic significance. This review is focused on summarizing recent advanced in immunological defects in cHL with translational implications. PMID:24959336

  16. Synaptotagmin 2 Is the Fast Ca2+ Sensor at a Central Inhibitory Synapse

    Directory of Open Access Journals (Sweden)

    Chong Chen

    2017-01-01

    Full Text Available GABAergic synapses in brain circuits generate inhibitory output signals with submillisecond latency and temporal precision. Whether the molecular identity of the release sensor contributes to these signaling properties remains unclear. Here, we examined the Ca2+ sensor of exocytosis at GABAergic basket cell (BC to Purkinje cell (PC synapses in cerebellum. Immunolabeling suggested that BC terminals selectively expressed synaptotagmin 2 (Syt2, whereas synaptotagmin 1 (Syt1 was enriched in excitatory terminals. Genetic elimination of Syt2 reduced action potential-evoked release to ∼10%, identifying Syt2 as the major Ca2+ sensor at BC-PC synapses. Differential adenovirus-mediated rescue revealed that Syt2 triggered release with shorter latency and higher temporal precision and mediated faster vesicle pool replenishment than Syt1. Furthermore, deletion of Syt2 severely reduced and delayed disynaptic inhibition following parallel fiber stimulation. Thus, the selective use of Syt2 as release sensor at BC-PC synapses ensures fast and efficient feedforward inhibition in cerebellar microcircuits.

  17. The role of neurexins and neuroligins in the formation, maturation, and function of vertebrate synapses.

    Science.gov (United States)

    Krueger, Dilja D; Tuffy, Liam P; Papadopoulos, Theofilos; Brose, Nils

    2012-06-01

    Neurexins (NXs) and neuroligins (NLs) are transsynaptically interacting cell adhesion proteins that play a key role in the formation, maturation, activity-dependent validation, and maintenance of synapses. As complex alternative splicing processes in nerve cells generate a large number of NX and NLs variants, it has been proposed that a combinatorial interaction code generated by these variants may determine synapse identity and network connectivity during brain development. The functional importance of NXs and NLs is exemplified by the fact that mutations in NX and NL genes are associated with several neuropsychiatric disorders, most notably with autism. Accordingly, major research efforts have focused on the molecular mechanisms by which NXs and NLs operate at synapses. In this review, we summarize recent progress in this field and discuss emerging topics, such as the role of alternative interaction partners of NXs and NLs in synapse formation and function, and their relevance for synaptic plasticity in the mature brain. The novel findings highlight the fundamental importance of NX-NL interactions in a wide range of synaptic functions. Copyright © 2012 Elsevier Ltd. All rights reserved.

  18. Overview of spaceflight immunology studies

    Science.gov (United States)

    Taylor, G. R.

    1993-01-01

    The effects of spaceflight and analogues of spaceflight are discussed here and in nine accompanying articles. In this summary we present spaceflight studies with human subjects, animal subjects, and cell cultures and we review ground-based systems used to model the observed effects of spaceflight on the immune system. Human paradigms include bed rest, academic or psychological stress, physical stress, hypobaric or high altitude stress, and confinement. Animal models include antiorthostatic and orthostatic suspension, hypobarism, and confinement. The ten manuscripts in this collection were selected to provide a summary that should give the reader an overview of the various activities of spaceflight immunology researchers throughout the history of space travel. This manuscript identifies the major contributors to the study of spaceflight immunology, explains what types of studies have been conducted, and how they have changed over the years. Also presented is a discussion of the unusual limitations associated with spaceflight research and the efforts to develop appropriate ground-based surrogate model systems. Specific details, data, and mechanistic speculations will be held to a minimum, because they will be discussed in depth in the other articles in the collection.

  19. Helminths and immunological tolerance

    OpenAIRE

    Johnston, Chris J C; McSorley, Henry J; Anderton, Stephen M; Wigmore, Stephen J; Maizels, Rick M

    2014-01-01

    Current immunosuppression regimens for solid-organ transplantation have shown disappointing efficacy in the prevention of chronic allograft rejection and carry unacceptable risks including toxicity, neoplasia, and life-threatening infection. Achievement of immunological tolerance (long-term antigen unresponsiveness in an immunocompetent host) presents the exciting prospect of freedom from immunosuppression for transplant recipients. It is now 60 years since the first demonstration of immunolo...

  20. Immunology and Epidemiology

    CERN Document Server

    Hraba, Tomáš

    1986-01-01

    In February 1985 a small international meeting of scientists took place at the recreation resort of the Polish Academy of Sci­ ences in Mogilany, near Cracow, Poland. The initiative for holding the workshop came from a working meeting on mathematical immunology and related topics at the International Institute for Applied Sys­ tems Analysis in Laxenburg, Austria, in November 1983. In addition to representatives of IIASA, delegates of the IIASA National Member Organizations (NMO) of Czechoslovakia, Italy, and the soviet Union took part in that working meeting. The participants came to the conclusion that IIASA could play an important role in facilitating the development of research in this field. The first step that they recommended to I IASA was to organize a workshop on mathematical immunology. The purpose of the workshop was to review the progress that has been made in applying mathematics to problems in immunology and to explore ways in which further progress might be achieved, especially by more efficie...

  1. 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.

  2. Differences in immunological susceptibility to cadmium toxicity between two rat strains as demonstrated with cell biological methods. Effect of cadmium on DNA synthesis of thymus lymphocytes

    NARCIS (Netherlands)

    Morselt, A. F.; Leene, W.; de Groot, C.; Kipp, J. B.; Evers, M.; Roelofsen, A. M.; Bosch, K. S.

    1988-01-01

    When 2 inbred rat strains, the Brown-Norway rat and the Lewis rat were exposed to the same amount of CdCl2 for 15 days, a completely different immunological reaction pattern could be demonstrated. Despite the same amount of intrathymic cadmium in both strains, the Brown-Norway rat showed a

  3. Microglia-Synapse Pathways: Promising Therapeutic Strategy for Alzheimer's Disease

    Science.gov (United States)

    Xie, Jingdun; Wang, Haitao

    2017-01-01

    The main hallmarks of Alzheimer's disease (AD) are extracellular deposits of amyloid plaques and intracellular accumulation of hyperphosphorylated neurofibrillary tangles (tau). However, the mechanisms underlying these neuropathological changes remain largely unclear. To date, plenty of studies have shown that microglia-mediated neuroinflammation contributes to the pathogenesis of AD, and the microglia-synapse pathways have been repeatedly identified as the crucial factor in the disease process. In this review, evidences from microglia and synapse studies are presented, and the role of microglia in the pathogenesis of AD, the contributing factors to synapse dysfunction, and the role and mechanisms of microglia-synapse pathways will be discussed. PMID:28473983

  4. How synapses can enhance sensibility of a neural network

    Science.gov (United States)

    Protachevicz, P. R.; Borges, F. S.; Iarosz, K. C.; Caldas, I. L.; Baptista, M. S.; Viana, R. L.; Lameu, E. L.; Macau, E. E. N.; Batista, A. M.

    2018-02-01

    In this work, we study the dynamic range in a neural network modelled by cellular automaton. We consider deterministic and non-deterministic rules to simulate electrical and chemical synapses. Chemical synapses have an intrinsic time-delay and are susceptible to parameter variations guided by learning Hebbian rules of behaviour. The learning rules are related to neuroplasticity that describes change to the neural connections in the brain. Our results show that chemical synapses can abruptly enhance sensibility of the neural network, a manifestation that can become even more predominant if learning rules of evolution are applied to the chemical synapses.

  5. Neuromuscular NMDA Receptors Modulate Developmental Synapse Elimination.

    Science.gov (United States)

    Personius, Kirkwood E; Slusher, Barbara S; Udin, Susan B

    2016-08-24

    At birth, each mammalian skeletal muscle fiber is innervated by multiple motor neurons, but in a few weeks, all but one of those axons retracts (Redfern, 1970) and differential activity between inputs controls this phenomenon (Personius and Balice-Gordon, 2001; Sanes and Lichtman, 2001; Personius et al., 2007; Favero et al., 2012). Acetylcholine, the primary neuromuscular transmitter, has long been presumed to mediate this activity-dependent process (O'Brien et al., 1978), but glutamatergic transmission also occurs at the neuromuscular junction (Berger et al., 1995; Grozdanovic and Gossrau, 1998; Mays et al., 2009). To test the role of neuromuscular NMDA receptors, we assessed their contribution to muscle calcium fluxes in mice and tested whether they influence removal of excess innervation at the end plate. Developmental synapse pruning was slowed by reduction of NMDA receptor activation or expression and by reduction of glutamate production. Conversely, pruning is accelerated by application of exogenous NMDA. We also found that NMDA induced increased muscle calcium only during the first 2 postnatal weeks. Therefore, neuromuscular NMDA receptors play previously unsuspected roles in neuromuscular activity and synaptic pruning during development. In normal adult muscle, each muscle fiber is innervated by a single axon, but at birth, fibers are multiply innervated. Elimination of excess connections requires neural activity; because the neuromuscular junction (NMJ) is a cholinergic synapse, acetylcholine has been assumed to be the critical mediator of activity. However, glutamate receptors are also expressed at the NMJ. We found that axon removal in mice is slowed by pharmacological and molecular manipulations that decrease signaling through neuromuscular NMDA receptors, whereas application of exogenous NMDA at the NMJ accelerates synapse elimination and increases muscle calcium levels during the first 2 postnatal weeks. Therefore, neuromuscular NMDA receptors play

  6. Triheteromeric NMDA Receptors at Hippocampal Synapses

    Science.gov (United States)

    Tovar, Kenneth R.; McGinley, Matthew J.; Westbrook, Gary L.

    2013-01-01

    NMDA receptors are composed of two GluN1 (N1) and two GluN2 (N2) subunits. Constituent N2 subunits control the pharmacological and kinetic characteristics of the receptor. NMDA receptors in hippocampal or cortical neurons are often thought of as diheteromeric, i.e., containing only one type of N2 subunit. However, triheteromeric receptors with more than one type of N2 subunit also have been reported and the relative contribution of di- and triheteromeric NMDA receptors at synapses has been difficult to assess. Because wild-type hippocampal principal neurons express N1, N2A and N2B, we used cultured hippocampal principal neurons from N2A and N2B-knockout mice as templates for diheteromeric synaptic receptors. Summation of N1/N2B and N1/N2A excitatory postsynaptic currents could not account for the deactivation kinetics of wild-type excitatory postsynaptic currents (EPSCs) however. To make a quantitative estimate of NMDA receptor subtypes at wild-type synapses, we used the deactivation kinetics, as well as the effects of the competitive antagonist NVP-AAM077. Our results indicate that three types of NMDA receptors contribute to the wild-type EPSC, with at least two-thirds being triheteromeric receptors. Functional isolation of synaptic triheteromeric receptors revealed deactivation kinetics and pharmacology distinct from either diheteromeric receptor subtype. Because of differences in open probability, synaptic triheteromeric receptors outnumbered N1/N2A receptors by 5.8 to 1 and N1/N2B receptors by 3.2 to 1. Our results suggest that triheteromeric NMDA receptors must be either preferentially assembled or preferentially localized at synapses. PMID:23699525

  7. Independent origins of neurons and synapses: insights from ctenophores.

    Science.gov (United States)

    Moroz, Leonid L; Kohn, Andrea B

    2016-01-05

    There is more than one way to develop neuronal complexity, and animals frequently use different molecular toolkits to achieve similar functional outcomes. Genomics and metabolomics data from basal metazoans suggest that neural signalling evolved independently in ctenophores and cnidarians/bilaterians. This polygenesis hypothesis explains the lack of pan-neuronal and pan-synaptic genes across metazoans, including remarkable examples of lineage-specific evolution of neurogenic and signalling molecules as well as synaptic components. Sponges and placozoans are two lineages without neural and muscular systems. The possibility of secondary loss of neurons and synapses in the Porifera/Placozoa clades is a highly unlikely and less parsimonious scenario. We conclude that acetylcholine, serotonin, histamine, dopamine, octopamine and gamma-aminobutyric acid (GABA) were recruited as transmitters in the neural systems in cnidarian and bilaterian lineages. By contrast, ctenophores independently evolved numerous secretory peptides, indicating extensive adaptations within the clade and suggesting that early neural systems might be peptidergic. Comparative analysis of glutamate signalling also shows numerous lineage-specific innovations, implying the extensive use of this ubiquitous metabolite and intercellular messenger over the course of convergent and parallel evolution of mechanisms of intercellular communication. Therefore: (i) we view a neuron as a functional character but not a genetic character, and (ii) any given neural system cannot be considered as a single character because it is composed of different cell lineages with distinct genealogies, origins and evolutionary histories. Thus, when reconstructing the evolution of nervous systems, we ought to start with the identification of particular cell lineages by establishing distant neural homologies or examples of convergent evolution. In a corollary of the hypothesis of the independent origins of neurons, our analyses

  8. 21 CFR 866.5160 - Beta-globulin immunolog-ical test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Beta-globulin immunolog-ical test system. 866.5160... (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Immunological Test Systems § 866.5160 Beta-globulin immunolog-ical test system. (a) Identification. A beta-globulin immunological test system is a...

  9. Recurrent synapses and circuits in the CA3 region of the hippocampus: an associative network.

    Directory of Open Access Journals (Sweden)

    Richard eMiles

    2014-01-01

    Full Text Available In the CA3 region of the hippocampus, pyramidal cells excite other pyramidal cells and interneurons. The axons of CA3 pyramidal cells spread throughout most of the region to form an associative network. These connections were first drawn by Cajal and Lorente de No. Their physiological properties were explored to understand epileptiform discharges generated in the region. Synapses between pairs of pyramidal cells involve one or few release sites and are weaker than connections made by mossy fibres on CA3 pyramidal cells. Synapses with interneurons are rather effective, as needed to control unchecked excitation. We examine contributions of recurrent synapses to epileptiform synchrony, to the genesis of sharp waves in the CA3 region and to population oscillations at theta and gamma frequencies. Recurrent connections in CA3, as other associative cortices, have a lower connectivity spread over a larger area than in primary sensory cortices. This sparse, but wide-ranging connectivity serves the functions of an associative network, including acquisition of neuronal representations as activity in groups of CA3 cells and completion involving the recall from partial cues of these ensemble firing patterns.

  10. A roadmap towards personalized immunology

    DEFF Research Database (Denmark)

    Delhalle, Sylvie; Bode, Sebastian F N; Balling, Rudi

    2018-01-01

    Big data generation and computational processing will enable medicine to evolve from a "one-size-fits-all" approach to precise patient stratification and treatment. Significant achievements using "Omics" data have been made especially in personalized oncology. However, immune cells relative......-centralized diseases. Here, we discuss the recent advances and successful applications in "Omics" data utilization and network analysis on patients' samples of clinical trials and studies, as well as the major challenges and strategies towards personalized stratification and treatment for infectious or non......-communicable inflammatory diseases such as autoimmune diseases or allergies. We provide a roadmap and highlight experimental, clinical, computational analysis, data management, ethical and regulatory issues to accelerate the implementation of personalized immunology....

  11. New players tip the scales in the balance between excitatory and inhibitory synapses

    Directory of Open Access Journals (Sweden)

    El-Husseini Alaa

    2005-03-01

    Full Text Available Abstract Synaptogenesis is a highly controlled process, involving a vast array of players which include cell adhesion molecules, scaffolding and signaling proteins, neurotransmitter receptors and proteins associated with the synaptic vesicle machinery. These molecules cooperate in an intricate manner on both the pre- and postsynaptic sides to orchestrate the precise assembly of neuronal contacts. This is an amazing feat considering that a single neuron receives tens of thousands of synaptic inputs but virtually no mismatch between pre- and postsynaptic components occur in vivo. One crucial aspect of synapse formation is whether a nascent synapse will develop into an excitatory or inhibitory contact. The tight control of a balance between the types of synapses formed regulates the overall neuronal excitability, and is thus critical for normal brain function and plasticity. However, little is known about how this balance is achieved. This review discusses recent findings which provide clues to how neurons may control excitatory and inhibitory synapse formation, with focus on the involvement of the neuroligin family and PSD-95 in this process.

  12. Mixed electrical-chemical synapses in adult rat hippocampus are primarily glutamatergic and coupled by connexin-36

    Directory of Open Access Journals (Sweden)

    Farid eHamzei-Sichani

    2012-05-01

    Full Text Available Dendrodendritic electrical signaling via gap junctions is now an accepted feature of neuronal communication in the mammalian brain, whereas axodendritic and axosomatic gap junctions have rarely been described. We present ultrastructural, immunocytochemical, and dye-coupling evidence for mixed (electrical/chemical synapses in adult rat hippocampus on both principal cells and interneurons. Thin-section electron microscopic images of small gap junction-like appositions were found at mossy fiber (MF terminals on thorny excrescences of CA3 pyramidal neurons (CA3pyr, apparently forming glutamatergic mixed synapses. Lucifer Yellow injected into four weakly-fixed CA3pyr was detected in MF axons that contacted the injected CA3pyr, supporting gap junction-mediated coupling between those two types of principal cells. Freeze-fracture replica immunogold-labeling revealed diverse sizes and morphologies of connexin36-containing gap junctions throughout hippocampus. Of 20 immunogold-labeled gap junctions, seven were large (328-1140 connexons, three of which were consistent with electrical synapses between interneurons; but nine were at axon terminal synapses, three of which were immediately adjacent to distinctive glutamate receptor-containing postsynaptic densities, forming mixed glutamatergic synapses. Four others were adjacent to small clusters of immunogold-labeled 10-nm E-face intramembrane particles, apparently representing extrasynaptic glutamate receptor particles. Gap junctions also were on spines in stratum lucidum, stratum oriens, dentate gyrus, and hilus, on both interneurons and unidentified neurons. In addition, one putative GABAergic mixed synapse was found in thin section images of a CA3pyr, but none found by immunogold-labeling were at GABAergic mixed synapses, suggesting their rarity. Cx36-containing gap junctions throughout hippocampus suggest the possibility of reciprocal modulation of electrical and chemical signals in diverse hippocampal

  13. Immunological studies in the acquired immunodeficiency syndrome. II. Active suppression or intrinsic defect--investigated by mixing AIDS cells with HLA-DR identical normal cells

    DEFF Research Database (Denmark)

    Hofmann, B; Ødum, Niels; Jakobsen, B K

    1986-01-01

    The lymphocyte transformation responses to mitogens (phytohaemagglutinin (PHA), concanavalin A (Con A), and pokeweed mitogen (PWM)), allogeneic cells, and the antigen-purified protein derivative (PPD) were studied in six acquired immunodeficiency syndrome (AIDS) patients and in six healthy controls......, each of whom was HLA-DR- and mixed lymphocyte culture (MLC)-identical with one of the AIDS patients. No evidence of suppression was observed when irradiated or non-irradiated AIDS peripheral blood mononuclear cells (PBMC) were added to cultures of HLA-DR-identical PMBC from healthy controls stimulated...... with the strong mitogens PHA and Con A or with allogeneic cells, but suppression may be involved in the decreased responses in cultures stimulated with PWM or PPD. Addition of supernatants from macrocultures of AIDS cells did not suppress responses of control PBMC. Thus, suppression by any lymphocyte subset...

  14. Combinatorial detection of autoreactive CD8+T cells with HLA-A2 multimers: a multi-centre study by the Immunology of Diabetes Society T Cell Workshop.

    Science.gov (United States)

    James, Eddie A; Abreu, Joana R F; McGinty, John W; Odegard, Jared M; Fillié, Yvonne E; Hocter, Claire N; Culina, Slobodan; Ladell, Kristin; Price, David A; Alkanani, Aimon; Rihanek, Marynette; Fitzgerald-Miller, Lisa; Skowera, Ania; Speake, Cate; Gottlieb, Peter; Davidson, Howard W; Wong, F Susan; Roep, Bart; Mallone, Roberto

    2018-03-01

    Validated biomarkers are needed to monitor the effects of immune intervention in individuals with type 1 diabetes. Despite their importance, few options exist for monitoring antigen-specific T cells. Previous reports described a combinatorial approach that enables the simultaneous detection and quantification of multiple islet-specific CD8 + T cell populations. Here, we set out to evaluate the performance of a combinatorial HLA-A2 multimer assay in a multi-centre setting. The combinatorial HLA-A2 multimer assay was applied in five participating centres using centralised reagents and blinded replicate samples. In preliminary experiments, samples from healthy donors were analysed using recall antigen multimers. In subsequent experiments, samples from healthy donors and individuals with type 1 diabetes were analysed using beta cell antigen and recall antigen multimers. The combinatorial assay was successfully implemented in each participating centre, with CVs between replicate samples that indicated good reproducibility for viral epitopes (mean %CV = 33.8). For beta cell epitopes, the assay was very effective in a single-centre setting (mean %CV = 18.4), but showed sixfold greater variability across multi-centre replicates (mean %CV = 119). In general, beta cell antigen-specific CD8 + T cells were detected more commonly in individuals with type 1 diabetes than in healthy donors. Furthermore, CD8 + T cells recognising HLA-A2-restricted insulin and glutamate decarboxylase epitopes were found to occur at higher frequencies in individuals with type 1 diabetes than in healthy donors. Our results suggest that, although combinatorial multimer assays are challenging, they can be implemented in multiple laboratories, providing relevant T cell frequency measurements. Assay reproducibility was notably higher in the single-centre setting, suggesting that biomarker analysis of clinical trial samples would be most successful when assays are performed in a single laboratory

  15. Mucosal immunology and virology

    National Research Council Canada - National Science Library

    Tyring, Stephen

    2006-01-01

    .... A third chapter focuses on the proximal end of the gastrointestinal tract (i.e. the oral cavity). The mucosal immunology and virology of the distal end of the gastrointestinal tract is covered in the chapter on the anogenital mucosa. Mucosa-associated lymphoid tissue (MALT) plays a role in protection against all viral (and other) infections except those that enter the body via a bite (e.g. yellow fever or dengue from a mosquito or rabies from a dog) or an injection or transfusion (e.g. HIV, Hepatitis B). ...

  16. Oral Microbiology and Immunology

    DEFF Research Database (Denmark)

    Dahlén, Gunnar; Fiehn, Nils-Erik; Olsen, Ingar

    , dental assistants and trainees may find it a useful source of reference. The contents are based on general microbiology and immunology. Oral microbiology is given particular attention, with examples relevant to oral infectious diseases. Each chapter opens with a relatively short pre-reading section......This textbook is based on the curricula for dental students in the Nordic countries, and the authors teach the subject at three universities in Denmark, Norway and Sweden. Although primarily for undergraduates, the book may also appeal to Ph.D. students and general practitioners. In addition...

  17. Rhythmic changes in synapse numbers in Drosophila melanogaster motor terminals.

    Directory of Open Access Journals (Sweden)

    Santiago Ruiz

    Full Text Available Previous studies have shown that the morphology of the neuromuscular junction of the flight motor neuron MN5 in Drosophila melanogaster undergoes daily rhythmical changes, with smaller synaptic boutons during the night, when the fly is resting, than during the day, when the fly is active. With electron microscopy and laser confocal microscopy, we searched for a rhythmic change in synapse numbers in this neuron, both under light:darkness (LD cycles and constant darkness (DD. We expected the number of synapses to increase during the morning, when the fly has an intense phase of locomotion activity under LD and DD. Surprisingly, only our DD data were consistent with this hypothesis. In LD, we found more synapses at midnight than at midday. We propose that under LD conditions, there is a daily rhythm of formation of new synapses in the dark phase, when the fly is resting, and disassembly over the light phase, when the fly is active. Several parameters appeared to be light dependent, since they were affected differently under LD or DD. The great majority of boutons containing synapses had only one and very few had either two or more, with a 70∶25∶5 ratio (one, two and three or more synapses in LD and 75∶20∶5 in DD. Given the maintenance of this proportion even when both bouton and synapse numbers changed with time, we suggest that there is a homeostatic mechanism regulating synapse distribution among MN5 boutons.

  18. Clinical effect and immunological response in patients with advanced malignant glioma treated with WT1-pulsed dendritic cell-based immunotherapy: A report of two cases

    Directory of Open Access Journals (Sweden)

    Keiichi Sakai, MD, PhD

    2017-09-01

    Conclusions: WT1-pulsed DC-based vaccination for two patients with advanced malignant glioma demonstrated the safety and immunogenicity. The present cases provide clinical evidence and an immunological response that DC vaccination induces tumor regression and improves neurological findings. Prospective clinical trials are required to evaluate the efficacy of acquired immunity in response to DC vaccination in improving the prognosis of advanced malignant glioma.

  19. Helminths and immunological tolerance.

    Science.gov (United States)

    Johnston, Chris J C; McSorley, Henry J; Anderton, Stephen M; Wigmore, Stephen J; Maizels, Rick M

    2014-01-27

    Current immunosuppression regimens for solid-organ transplantation have shown disappointing efficacy in the prevention of chronic allograft rejection and carry unacceptable risks including toxicity, neoplasia, and life-threatening infection. Achievement of immunological tolerance (long-term antigen unresponsiveness in an immunocompetent host) presents the exciting prospect of freedom from immunosuppression for transplant recipients. It is now 60 years since the first demonstration of immunological tolerance in animal models of transplantation, but translation into routine clinical practice remains elusive. Helminth parasites may provide novel strategies toward achieving this goal. Helminths are remarkably successful parasites: they currently infect more than one quarter of the world's population. It is now well established that the parasites' success is the result of active immunomodulation of their hosts' immune response. Although this primarily secures ongoing survival of the parasites, helminth-induced immunomodulation can also have a number of benefits for the host. Significant reductions in the prevalence of allergy and autoimmune conditions among helminth-infected populations are well recognized and there is now a significant body of evidence to suggest that harmful immune responses to alloantigens may be abrogated as well. Here, we review all existing studies of helminth infection and transplantation, explore the mechanisms involved, and discuss possible avenues for future translation to clinical practice.

  20. Sequences Flanking the Gephyrin-Binding Site of GlyRβ Tune Receptor Stabilization at Synapses.

    Science.gov (United States)

    Grünewald, Nora; Jan, Audric; Salvatico, Charlotte; Kress, Vanessa; Renner, Marianne; Triller, Antoine; Specht, Christian G; Schwarz, Guenter

    2018-01-01

    The efficacy of synaptic transmission is determined by the number of neurotransmitter receptors at synapses. Their recruitment depends upon the availability of postsynaptic scaffolding molecules that interact with specific binding sequences of the receptor. At inhibitory synapses, gephyrin is the major scaffold protein that mediates the accumulation of heteromeric glycine receptors (GlyRs) via the cytoplasmic loop in the β-subunit (β-loop). This binding involves high- and low-affinity interactions, but the molecular mechanism of this bimodal binding and its implication in GlyR stabilization at synapses remain unknown. We have approached this question using a combination of quantitative biochemical tools and high-density single molecule tracking in cultured rat spinal cord neurons. The high-affinity binding site could be identified and was shown to rely on the formation of a 3 10 -helix C-terminal to the β-loop core gephyrin-binding motif. This site plays a structural role in shaping the core motif and represents the major contributor to the synaptic confinement of GlyRs by gephyrin. The N-terminal flanking sequence promotes lower affinity interactions by occupying newly identified binding sites on gephyrin. Despite its low affinity, this binding site plays a modulatory role in tuning the mobility of the receptor. Together, the GlyR β-loop sequences flanking the core-binding site differentially regulate the affinity of the receptor for gephyrin and its trapping at synapses. Our experimental approach thus bridges the gap between thermodynamic aspects of receptor-scaffold interactions and functional receptor stabilization at synapses in living cells.

  1. Flotillins are involved in the polarization of primitive and mature hematopoietic cells.

    Directory of Open Access Journals (Sweden)

    Lawrence Rajendran

    Full Text Available BACKGROUND: Migration of mature and immature leukocytes in response to chemokines is not only essential during inflammation and host defense, but also during development of the hematopoietic system. Many molecules implicated in migratory polarity show uniform cellular distribution under non-activated conditions, but acquire a polarized localization upon exposure to migratory cues. METHODOLOGY/PRINCIPAL FINDINGS: Here, we present evidence that raft-associated endocytic proteins (flotillins are pre-assembled in lymphoid, myeloid and primitive hematopoietic cells and accumulate in the uropod during migration. Furthermore, flotillins display a polarized distribution during immunological synapse formation. Employing the membrane lipid-order sensitive probe Laurdan, we show that flotillin accumulation in the immunological synapse is concomittant with membrane ordering in these regions. CONCLUSIONS: Together with the observation that flotillin polarization does not occur in other polarized cell types such as polarized epithelial cells, our results suggest a specific role for flotillins in hematopoietic cell polarization. Based on our results, we propose that in hematopoietic cells, flotillins provide intrinsic cues that govern segregation of certain microdomain-associated molecules during immune cell polarization.

  2. Cortical Actin Flow in T Cells Quantified by Spatio-temporal Image Correlation Spectroscopy of Structured Illumination Microscopy Data.

    Science.gov (United States)

    Ashdown, George; Pandžić, Elvis; Cope, Andrew; Wiseman, Paul; Owen, Dylan

    2015-12-17

    Filamentous-actin plays a crucial role in a majority of cell processes including motility and, in immune cells, the formation of a key cell-cell interaction known as the immunological synapse. F-actin is also speculated to play a role in regulating molecular distributions at the membrane of cells including sub-membranous vesicle dynamics and protein clustering. While standard light microscope techniques allow generalized and diffraction-limited observations to be made, many cellular and molecular events including clustering and molecular flow occur in populations at length-scales far below the resolving power of standard light microscopy. By combining total internal reflection fluorescence with the super resolution imaging method structured illumination microscopy, the two-dimensional molecular flow of F-actin at the immune synapse of T cells was recorded. Spatio-temporal image correlation spectroscopy (STICS) was then applied, which generates quantifiable results in the form of velocity histograms and vector maps representing flow directionality and magnitude. This protocol describes the combination of super-resolution imaging and STICS techniques to generate flow vectors at sub-diffraction levels of detail. This technique was used to confirm an actin flow that is symmetrically retrograde and centripetal throughout the periphery of T cells upon synapse formation.

  3. Immune dysregulation in patients with PTEN hamartoma tumor syndrome: Analysis of FOXP3 regulatory T cells.

    Science.gov (United States)

    Chen, Hannah H; Händel, Norman; Ngeow, Joanne; Muller, James; Hühn, Michael; Yang, Huei-Ting; Heindl, Mario; Berbers, Roos-Marijn; Hegazy, Ahmed N; Kionke, Janina; Yehia, Lamis; Sack, Ulrich; Bläser, Frank; Rensing-Ehl, Anne; Reifenberger, Julia; Keith, Julia; Travis, Simon; Merkenschlager, Andreas; Kiess, Wieland; Wittekind, Christian; Walker, Lisa; Ehl, Stephan; Aretz, Stefan; Dustin, Michael L; Eng, Charis; Powrie, Fiona; Uhlig, Holm H

    2017-02-01

    Patients with heterozygous germline mutations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) experience autoimmunity and lymphoid hyperplasia. Because regulation of the phosphoinositide 3-kinase (PI3K) pathway is critical for maintaining regulatory T (Treg) cell functions, we investigate Treg cells in patients with heterozygous germline PTEN mutations (PTEN hamartoma tumor syndrome [PHTS]). Patients with PHTS were assessed for immunologic conditions, lymphocyte subsets, forkhead box P3 (FOXP3) + Treg cell levels, and phenotype. To determine the functional importance of phosphatases that control the PI3K pathway, we assessed Treg cell induction in vitro, mitochondrial depolarization, and recruitment of PTEN to the immunologic synapse. Autoimmunity and peripheral lymphoid hyperplasia were found in 43% of 79 patients with PHTS. Immune dysregulation in patients with PHTS included lymphopenia, CD4 + T-cell reduction, and changes in T- and B-cell subsets. Although total CD4 + FOXP3 + Treg cell numbers are reduced, frequencies are maintained in the blood and intestine. Despite pathogenic PTEN mutations, the FOXP3 + T cells are phenotypically normal. We show that the phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP) downstream of PTEN is highly expressed in normal human Treg cells and provides complementary phosphatase activity. PHLPP is indispensable for the differentiation of induced Treg cells in vitro and Treg cell mitochondrial fitness. PTEN and PHLPP form a phosphatase network that is polarized at the immunologic synapse. Heterozygous loss of function of PTEN in human subjects has a significant effect on T- and B-cell immunity. Assembly of the PTEN-PHLPP phosphatase network allows coordinated phosphatase activities at the site of T-cell receptor activation, which is important for limiting PI3K hyperactivation in Treg cells despite PTEN haploinsufficiency. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights

  4. Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit

    Directory of Open Access Journals (Sweden)

    Lisa eMapelli

    2015-05-01

    Full Text Available The way long-term potentiation (LTP and depression (LTD are integrated within the different synapses of brain neuronal circuits is poorly understood. In order to progress beyond the identification of specific molecular mechanisms, a system in which multiple forms of plasticity can be correlated with large-scale neural processing is required. In this paper we take as an example the cerebellar network , in which extensive investigations have revealed LTP and LTD at several excitatory and inhibitory synapses. Cerebellar LTP and LTD occur in all three main cerebellar subcircuits (granular layer, molecular layer, deep cerebellar nuclei and correspondingly regulate the function of their three main neurons: granule cells (GrCs, Purkinje cells (PCs and deep cerebellar nuclear (DCN cells. All these neurons, in addition to be excited, are reached by feed-forward and feed-back inhibitory connections, in which LTP and LTD may either operate synergistically or homeostatically in order to control information flow through the circuit. Although the investigation of individual synaptic plasticities in vitro is essential to prove their existence and mechanisms, it is insufficient to generate a coherent view of their impact on network functioning in vivo. Recent computational models and cell-specific genetic mutations in mice are shedding light on how plasticity at multiple excitatory and inhibitory synapses might regulate neuronal activities in the cerebellar circuit and contribute to learning and memory and behavioral control.

  5. Immunology of Yersinia pestis Infection.

    Science.gov (United States)

    Bi, Yujing

    2016-01-01

    As a pathogen of plague, Yersinia pestis caused three massive pandemics in history that killed hundreds of millions of people. Yersinia pestis is highly invasive, causing severe septicemia which, if untreated, is usually fatal to its host. To survive in the host and maintain a persistent infection, Yersinia pestis uses several stratagems to evade the innate and the adaptive immune responses. For example, infections with this organism are biphasic, involving an initial "noninflammatory" phase where bacterial replication occurs initially with little inflammation and following by extensive phagocyte influx, inflammatory cytokine production, and considerable tissue destruction, which is called "proinflammatory" phase. In contrast, the host also utilizes its immune system to eliminate the invading bacteria. Neutrophil and macrophage are the first defense against Yersinia pestis invading through phagocytosis and killing. Other innate immune cells also play different roles, such as dendritic cells which help to generate more T helper cells. After several days post infection, the adaptive immune response begins to provide organism-specific protection and has a long-lasting immunological memory. Thus, with the cooperation and collaboration of innate and acquired immunity, the bacterium may be eliminated from the host. The research of Yersinia pestis and host immune systems provides an important topic to understand pathogen-host interaction and consequently develop effective countermeasures.

  6. TPM analyses reveal that FtsK contributes both to the assembly and the activation of the XerCD-dif recombination synapse.

    Science.gov (United States)

    Diagne, Cheikh Tidiane; Salhi, Maya; Crozat, Estelle; Salomé, Laurence; Cornet, Francois; Rousseau, Philippe; Tardin, Catherine

    2014-02-01

    Circular chromosomes can form dimers during replication and failure to resolve those into monomers prevents chromosome segregation, which leads to cell death. Dimer resolution is catalysed by a highly conserved site-specific recombination system, called XerCD-dif in Escherichia coli. Recombination is activated by the DNA translocase FtsK, which is associated with the division septum, and is thought to contribute to the assembly of the XerCD-dif synapse. In our study, direct observation of the assembly of the XerCD-dif synapse, which had previously eluded other methods, was made possible by the use of Tethered Particle Motion, a single molecule approach. We show that XerC, XerD and two dif sites suffice for the assembly of XerCD-dif synapses in absence of FtsK, but lead to inactive XerCD-dif synapses. We also show that the presence of the γ domain of FtsK increases the rate of synapse formation and convert them into active synapses where recombination occurs. Our results represent the first direct observation of the formation of the XerCD-dif recombination synapse and its activation by FtsK.

  7. Nonlinear Synapses for Large-Scale Models: An Efficient Representation Enables Complex Synapse Dynamics Modeling in Large-Scale Simulations

    Directory of Open Access Journals (Sweden)

    Eric eHu

    2015-09-01

    Full Text Available Chemical synapses are comprised of a wide collection of intricate signaling pathways involving complex dynamics. These mechanisms are often reduced to simple spikes or exponential representations in order to enable computer simulations at higher spatial levels of complexity. However, these representations cannot capture important nonlinear dynamics found in synaptic transmission. Here, we propose an input-output (IO synapse model capable of generating complex nonlinear dynamics while maintaining low computational complexity. This IO synapse model is an extension of a detailed mechanistic glutamatergic synapse model capable of capturing the input-output relationships of the mechanistic model using the Volterra functional power series. We demonstrate that the IO synapse model is able to successfully track the nonlinear dynamics of the synapse up to the third order with high accuracy. We also evaluate the accuracy of the IO synapse model at different input frequencies and compared its performance with that of kinetic models in compartmental neuron models. Our results demonstrate that the IO synapse model is capable of efficiently replicating complex nonlinear dynamics that were represented in the original mechanistic model and provide a method to replicate complex and diverse synaptic transmission within neuron network simulations.

  8. Ideernes epidemiologi og kulturens immunologi

    DEFF Research Database (Denmark)

    Sørensen, Jesper

    2007-01-01

    , suggested by Sperber, is extended by an ‘immunology of cultural systems’. In addition to the selective forces described by Sperber and Boyer, the immunological approach argues that the relative success of new representations is largely dependent on how well they fit already existing cultural models...

  9. Enhancement of immunological activity after mild hyperthermia

    International Nuclear Information System (INIS)

    Noguchi, Kenichi; Hasegawa, Takeo; Takahashi, Tohru

    2002-01-01

    At present, hyperthermia is clinically very important as interdisciplinary therapeutic method, and studies are being performed on combined effects with surgical treatment, radiotherapy, chemotherapy and gene therapy for the treatment of malignant tumors. We evaluated the effects of hyperthermia under temperature of 42.5C and demonstrated that the activation of immunological response is increased and anti-tumor effect cabn be obtained in this studies. We used animals were C3H mice (male,7W) bearing SCC-VII tumor on femur skin. Then, the mice were divided to 10 mice in each group, and only femur region was immersed in warm water for thermal treatment. Also we measured the tumor growth, changes of blood cell fraction and NK cell activity. The results of the present study confirmed: (1) Anti-tumor effect can be given by thermal treatment at relatively mild temperature (mild temperature at 39C-42C); (2) The increase of neutrophils is dependent on the quantity of heat added; (3) Immunological response of monocytes and lymphocytes is associated with it; (4) Activity of the immunological potency as a whole such as activation of NK cells was also confirmed

  10. Immunological properties of gold nanoparticles.

    Science.gov (United States)

    Dykman, Lev A; Khlebtsov, Nikolai G

    2017-03-01

    In the past decade, gold nanoparticles have attracted strong interest from the nanobiotechnological community owing to the significant progress made in robust and easy-to-make synthesis technologies, in surface functionalization, and in promising biomedical applications. These include bioimaging, gene diagnostics, analytical sensing, photothermal treatment of tumors, and targeted delivery of various biomolecular and chemical cargos. For the last-named application, gold nanoparticles should be properly fabricated to deliver the cargo into the targeted cells through effective endocytosis. In this review, we discuss recent progress in understanding the selective penetration of gold nanoparticles into immune cells. The interaction of gold nanoparticles with immune cell receptors is discussed. As distinct from other published reviews, we present a summary of the immunological properties of gold nanoparticles. This review also summarizes what is known about the application of gold nanoparticles as an antigen carrier and adjuvant in immunization for the preparation of antibodies in vivo . For each of the above topics, the basic principles, recent advances, and current challenges are discussed. Thus, this review presents a detailed analysis of data on interaction of gold nanoparticles with immune cells. Emphasis is placed on the systematization of data over production of antibodies by using gold nanoparticles and adjuvant properties of gold nanoparticles. Specifically, we start our discussion with current data on interaction of various gold nanoparticles with immune cells. The next section describes existing technologies to improve production of antibodies in vivo by using gold nanoparticles conjugated with specific ligands. Finally, we describe what is known about adjuvant properties of bare gold or functionalized nanoparticles. In the Conclusion section, we present a short summary of reported data and some challenges and perspectives.

  11. A shared synapse architecture for efficient FPGA implementation of autoencoders.

    Science.gov (United States)

    Suzuki, Akihiro; Morie, Takashi; Tamukoh, Hakaru

    2018-01-01

    This paper proposes a shared synapse architecture for autoencoders (AEs), and implements an AE with the proposed architecture as a digital circuit on a field-programmable gate array (FPGA). In the proposed architecture, the values of the synapse weights are shared between the synapses of an input and a hidden layer, and between the synapses of a hidden and an output layer. This architecture utilizes less of the limited resources of an FPGA than an architecture which does not share the synapse weights, and reduces the amount of synapse modules used by half. For the proposed circuit to be implemented into various types of AEs, it utilizes three kinds of parameters; one to change the number of layers' units, one to change the bit width of an internal value, and a learning rate. By altering a network configuration using these parameters, the proposed architecture can be used to construct a stacked AE. The proposed circuits are logically synthesized, and the number of their resources is determined. Our experimental results show that single and stacked AE circuits utilizing the proposed shared synapse architecture operate as regular AEs and as regular stacked AEs. The scalability of the proposed circuit and the relationship between the bit widths and the learning results are also determined. The clock cycles of the proposed circuits are formulated, and this formula is used to estimate the theoretical performance of the circuit when the circuit is used to construct arbitrary networks.

  12. Polyribosomes at the base of dendritic spines of central nervous system neurons - their possible role in synapse construction and modification

    International Nuclear Information System (INIS)

    Steward, O.

    1983-01-01

    The selective localization of polyribosomes at the base of dendritic spines in granule cells of the dentate gyrus was studied. These polyribosomes seem optimally situated to produce proteins for the postsynaptic membrane specialization or the spine and to have their synthetic activity regulated by functional activity over the synapse. The present work will summarize observations on the polyribosome clusters that were found to be ubiquitous in spines throughout the vertebrate CNS. Evidence will be presented that suggests a role for the polyribosomes in synapse construction and modification. 42 refs., 8 figs., 2 tabs

  13. Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by hepatitis C virus.

    Science.gov (United States)

    Horner, Stacy M; Liu, Helene Minyi; Park, Hae Soo; Briley, Jessica; Gale, Michael

    2011-08-30

    RIG-I is a cytosolic pathogen recognition receptor that engages viral RNA in infected cells to trigger innate immune defenses through its adaptor protein MAVS. MAVS resides on mitochondria and peroxisomes, but how its signaling is coordinated among these organelles has not been defined. Here we show that a major site of MAVS signaling is the mitochondrial-associated membrane (MAM), a distinct membrane compartment that links the endoplasmic reticulum to mitochondria. During RNA virus infection, RIG-I is recruited to the MAM to bind MAVS. Dynamic MAM tethering to mitochondria and peroxisomes then coordinates MAVS localization to form a signaling synapse between membranes. Importantly, the hepatitis C virus NS3/4A protease, which cleaves MAVS to support persistent infection, targets this synapse for MAVS proteolysis from the MAM, but not from mitochondria, to ablate RIG-I signaling of immune defenses. Thus, the MAM mediates an intracellular immune synapse that directs antiviral innate immunity.

  14. Unique immunologic patterns in fibromyalgia.

    Science.gov (United States)

    Behm, Frederick G; Gavin, Igor M; Karpenko, Oleksiy; Lindgren, Valerie; Gaitonde, Sujata; Gashkoff, Peter A; Gillis, Bruce S

    2012-12-17

    Fibromyalgia (FM) is a clinical syndrome characterized by chronic pain and allodynia. The diagnosis of FM has been one of exclusion as a test to confirm the diagnosis is lacking. Recent data highlight the role of the immune system in FM. Aberrant expressions of immune mediators, such as cytokines, have been linked to the pathogenesis and traits of FM. We therefore determined whether cytokine production by immune cells is altered in FM patients by comparing the cellular responses to mitogenic activators of stimulated blood mononuclear cells of a large number of patients with FM to those of healthy matched individuals. Plasma and peripheral blood mononuclear cells (PBMC) were collected from 110 patients with the clinical diagnosis of FM and 91 healthy donors. Parallel samples of PBMC were cultured overnight in medium alone or in the presence of mitogenic activators; PHA or PMA in combination with ionomycin. The cytokine concentrations of IFN-γ, IL-5, IL-6, IL-8, IL-10, MIP-1β , MCP-1, and MIP1-α in plasma as well as in cultured supernatants were determined using a multiplex immunoassay using bead array technology. Cytokine levels of stimulated PBMC cultures of healthy control subjects were significantly increased as compared to matched non-stimulated PBMC cultures. In contrast, the concentrations of most cytokines were lower in stimulated samples from patients with FM compared to controls. The decreases of cytokine concentrations in patients samples ranged from 1.5-fold for MIP-1β to 10.2-fold for IL-6 in PHA challenges. In PMA challenges, we observed 1.8 to 4-fold decreases in the concentrations of cytokines in patient samples. The cytokine responses to mitogenic activators of PBMC isolated from patients with FM were significantly lower than those of healthy individuals, implying that cell-mediated immunity is impaired in FM patients. This novel cytokine assay reveals unique and valuable immunologic traits, which, when combined with clinical patterns, can offer

  15. Can myofascial techniques modify immunological parameters?

    Science.gov (United States)

    Fernández-Pérez, Antonio Manuel; Peralta-Ramírez, Maria Isabel; Pilat, Andrzej; Moreno-Lorenzo, Carmen; Villaverde-Gutiérrez, Carmen; Arroyo-Morales, Manuel

    2013-01-01

    The objective was to determine the effect of myofascial techniques on the modulation of immunological variables. Thirty-nine healthy male volunteers were randomly assigned to an experimental or control group. The experimental group underwent three manual therapy modalities: suboccipital muscle release, so-called fourth intracranial ventricle compression, and deep cervical fascia release. The control group remained in a resting position for the same time period under the same environmental conditions. Changes in counts of CD3, CD4, CD8, CD19, and natural killer (NK) cells (as immunological markers) between baseline and 20 minutes post-intervention. Repeated-measures ANOVA revealed a significant time × groups interaction (F(1,35)=9.33; p=0.004) for CD19. There were no significant time × group interaction effects on CD3, CD4, CD8, or NK cell counts. Intrasubject analyses showed a higher CD19 count in the experimental group post-intervention versus baseline (t=-4.02; p=0.001), with no changes in the control group (t=0.526; p=0.608). A major immunological modulation, with an increased B lymphocyte count, was observed at 20 minutes after the application of craniocervical myofascial induction techniques.

  16. Array tomography: characterizing FAC-sorted populations of zebrafish immune cells by their 3D ultrastructure.

    Science.gov (United States)

    Wacker, Irene; Chockley, Peter; Bartels, Carolin; Spomer, Waldemar; Hofmann, Andreas; Gengenbach, Ulrich; Singh, Sachin; Thaler, Marlene; Grabher, Clemens; Schröder, Rasmus R

    2015-08-01

    For 3D reconstructions of whole immune cells from zebrafish, isolated from adult animals by FAC-sorting we employed array tomography on hundreds of serial sections deposited on silicon wafers. Image stacks were either recorded manually or automatically with the newly released ZEISS Atlas 5 Array Tomography platform on a Zeiss FEGSEM. To characterize different populations of immune cells, organelle inventories were created by segmenting individual cells. In addition, arrays were used for quantification of cell populations with respect to the various cell types they contained. The detection of immunological synapses in cocultures of cell populations from thymus or WKM with cancer cells helped to identify the cytotoxic nature of these cells. Our results demonstrate the practicality and benefit of AT for high-throughput ultrastructural imaging of substantial volumes. © 2015 The Authors Journal of Microscopy © 2015 Royal Microscopical Society.

  17. Astrocytic Gliotransmitter: Diffusion Dynamics and Induction of Information Processing on Tripartite Synapses

    Science.gov (United States)

    Li, Jia-Jia; Du, Meng-Meng; Wang, Rong; Lei, Jin-Zhi; Wu, Ying

    Astrocytes have important functions in the central nervous system (CNS) and are significant in our understanding of the neuronal network. Astrocytes modulate neuronal firings at both single cell level of tripartite synapses and the neuron-glial network level. Astrocytes release adenosine triphosphate (ATP) and glutamate into the neuron-glial network. These gliotransmitters diffuse over the network to form long distance signals to regulate neuron firings. In this paper, we study a neuron-glial network model that includes a diffusion of astrocytic ATP and glutamate to investigate how long distance diffusion of the gliotransmitters affects the information processing in a neuronal network. We find that gliotransmitters diffusion can compensate for the failure of information processing of interneuron network firings induced by defectively coupled synapses. Moreover, we find that calcium waves in astrocyte network and firings in interneuron network are both sensitive to the glutamate diffusion rate and feedback intensities of astrocytes on interneurons.

  18. Engineering antigen-specific immunological tolerance.

    Energy Technology Data Exchange (ETDEWEB)

    Kontos, Stephan; Grimm, Alizee J.; Hubbell, Jeffrey A.

    2015-05-01

    Unwanted immunity develops in response to many protein drugs, in autoimmunity, in allergy, and in transplantation. Approaches to induce immunological tolerance aim to either prevent these responses or reverse them after they have already taken place. We present here recent developments in approaches, based on engineered peptides, proteins and biomaterials, that harness mechanisms of peripheral tolerance both prophylactically and therapeutically to induce antigenspecific immunological tolerance. These mechanisms are based on responses of B and T lymphocytes to other cells in their immune environment that result in cellular deletion or ignorance to particular antigens, or in development of active immune regulatory responses. Several of these approaches are moving toward clinical development, and some are already in early stages of clinical testing.

  19. Immunologic reaction and viability of cryopreserved homografts.

    Science.gov (United States)

    Fischlein, T; Schütz, A; Haushofer, M; Frey, R; Uhlig, A; Detter, C; Reichart, B

    1995-08-01

    Homograft cell viability after cryopreservation was investigated and cytoimmunologic monitoring was performed during the early postoperative course to research possible immunologic reactions after allograft aortic valve replacement. After cryopreservation, morphologic observations were made, a nonradioactive cell proliferation assay was used, and prostaglandin I2 secretion of the remaining endothelial cells was determined. Cytoimmunologic monitoring was performed daily within the first 3 weeks postoperatively. An increase of the activation index greater than 1 was rated as an immunologic reaction. Maintained metabolic activity of graft endothelial cells after cryopreservation was confirmed by prostaglandin I2 release (9.24 +/- 3.48 ng/cm2 basic release and 20.1 +/- 5.76 ng/cm2 when stimulated with 25 mumol/L Na arachidonic acid). Cell proliferation was indicated after graft incubation with the nonradioactive viability kit (0.27 +/- 0.9 at 450 nm). Cytoimmunologic examinations (n = 861) after homograft implantation showed a more intense activation in patients with ABO-incompatible grafts (activation index 2.1 +/- 1.6, n = 16) than in those with ABO-compatible grafts (activation index 1.3 +/- 0.8, n = 17). In these groups, the duration of activation by cytoimmunologic monitoring was 2.8 +/- 1.5 days and 1.3 +/- 0.6 days, respectively (p < 0.041). No activation was observed in 8 patients after xenograft valve replacement (p < 0.01). Our data indicate that cryopreservation of homograft valves represents a cell- and tissue-protective preservation method. Postoperatively, all homograft valves caused immunologic reactions, which were reversible without immunosuppression treatment.

  20. Systems immunology: just getting started.

    Science.gov (United States)

    Davis, Mark M; Tato, Cristina M; Furman, David

    2017-06-20

    Systems-biology approaches in immunology take various forms, but here we review strategies for measuring a broad swath of immunological functions as a means of discovering previously unknown relationships and phenomena and as a powerful way of understanding the immune system as a whole. This approach has rejuvenated the field of vaccine development and has fostered hope that new ways will be found to combat infectious diseases that have proven refractory to classical approaches. Systems immunology also presents an important new strategy for understanding human immunity directly, taking advantage of the many ways the immune system of humans can be manipulated.

  1. Immunological methods for gentamicin determination

    International Nuclear Information System (INIS)

    Krugers Dagneauz, P.G.L.C.; Olthuis, F.M.F.G.

    1979-01-01

    For immunoassay, an antibody against the substance to the determined, the pure substance itself, and a labelled form or derivative of the substance are required. The principles and problems of the preparation of antibodies are discussed, some methods for the preparation of derivatives labelled with radioactive tracers or enzymes are reviewed, and homologous enzyme-immunological determination of gentamicin is discussed in detail. A comparison is mae of three radio-immunological determination methods, and the most suitable radio-immunological method is compared with two microbiological techniques. The results are found to be comparable. (Auth.)

  2. PKC? and HIV-1 Transcriptional Regulator Tat Co-exist at the LTR Promoter in CD4+ T Cells

    OpenAIRE

    L?pez-Huertas, Mar?a Rosa; Li, Jasmine; Zafar, Anjum; Rodr?guez-Mora, Sara; Garc?a-Dom?nguez, Carlota; Mateos, Elena; Alcam?, Jos?; Rao, Sudha; Coiras, Mayte

    2016-01-01

    PKCθ is essential for the activation of CD4+ T cells. Upon TCR/CD28 stimulation, PKCθ is phosphorylated and migrates to the immunological synapse, inducing the activation of cellular transcription factors such as NF-κB and kinases as ERK that are critical for HIV-1 replication. We previously demonstrated that PKCθ is also necessary for HIV-1 replication but the precise mechanism is unknown. Efficient HIV-1 transcription and elongation are absolutely dependent on the synergy between NF-κB and ...

  3. Silent Synapse-Based Circuitry Remodeling in Drug Addiction.

    Science.gov (United States)

    Dong, Yan

    2016-05-01

    Exposure to cocaine, and likely other drugs of abuse, generates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-silent glutamatergic synapses in the nucleus accumbens. These immature synaptic contacts evolve after drug withdrawal to redefine the neurocircuital properties. These results raise at least three critical questions: (1) what are the molecular and cellular mechanisms that mediate drug-induced generation of silent synapses; (2) how are neurocircuits remodeled upon generation and evolution of drug-generated silent synapses; and (3) what behavioral consequences are produced by silent synapse-based circuitry remodeling? This short review analyzes related experimental results, and extends them to some speculations. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  4. The immunology of animal papillomaviruses.

    Science.gov (United States)

    Nicholls, P K; Stanley, M A

    2000-02-25

    Papillomaviruses are species- and tissue-specific double-stranded DNA viruses. These viruses cause epithelial tumours in many animals, including man. Typically, the benign warts undergo spontaneous, immune-mediated regression, most likely effected by T-cells (especially CD4, but also CD8 subsets), whereas humoral immunity can prevent new infections. Some papillomavirus infections fail to regress spontaneously and others progress to malignant epithelial tumours. Additionally, the impact of these lesions is greater in immunosuppressed individuals. Many therapies are ineffective, and there is much interest in the potential for immunological intervention in papillomavirus infections of man and animals. Vaccination can be achieved with 'live' virus, formalin-inactivated virus, synthetic virus-like particles, and DNA vaccination. There has been much recent progress in the development of such vaccines for papillomavirus infections in the rabbit, ox and dog. Success in these animal models suggests that similar approaches may prove useful for prophylactic or therapeutic vaccination against the important human papillomaviruses involved in the development of cutaneous and anogenital warts, laryngeal papillomatosis, and cervical cancer.

  5. Changes in rat hippocampal CA1 synapses following imipramine treatment

    DEFF Research Database (Denmark)

    Chen, Fenghua; Madsen, Torsten M; Wegener, Gregers

    2008-01-01

    Neuronal plasticity in hippocampus is hypothesized to play an important role in both the pathophysiology of depressive disorders and the treatment. In this study, we investigated the consequences of imipramine treatment on neuroplasticity (including neurogenesis, synaptogenesis, and remodelling...... and number of neurons of hippocampal subregions following imipramine treatment were found. However, the number and percentage of CA1 asymmetric spine synapses increased significantly and, conversely, the percentage of asymmetric shaft synapses significantly decreased in the imipramine treated group. Our...

  6. Immunology and immunity against infection: General rules

    Science.gov (United States)

    Zinkernagel, Rolf M.

    2005-12-01

    Simplified and generalizable rules of immune responses against infections or vaccines have been summarized into 20 statements previously (Scand. J. Immunol. 60 (2004) 9-13) and are restated in a slightly different form here. The key terms of immunology (e.g. specificity, tolerance and memory) are explained in terms of their co-evolutionary importance in the equilibrium between infectious agents and diseases with higher vertebrate hosts. Specificity is best defined by protective antibodies or protective activated T cells; e.g. serotype specific neutralizing antibodies against polio viruses represent the discriminatory power of an immune response very well indeed. Tolerance is reviewed in terms of reactivity rather than self-nonself discrimination. Immune respones are deleted against antigens expressed at sufficient levels within the lymphoheamopoetic system, but may well exist at both, the T and the B cell level against antigens strictly outside of secondary lymphatic organs. In this respect the immune system behaves identically against virus infections and against self antigens. Persistent virus infections delete responsive T cells, once eliminated immune T cell responses wane, if a virus keeps outside of secondary lymphatic tissues no immune response is induced. Immunological memory is usually defined as earlier and greater responses but this does not correlate with protective immunity stringently. It is summarized here that pre-existing titers of protective neutralizing antibodies or pre-existence of activated T cells are the correlates of protection acute cytopathic lethal infections and toxins or against intracellular parasites. It is concluded that many discrepancies and uncertainties in immunological research derive from model situations and experimental results that are correctly measured but cannot be related to co-evolutionary contexts, i.e. survival.

  7. Calcium channel-dependent molecular maturation of photoreceptor synapses.

    Directory of Open Access Journals (Sweden)

    Nawal Zabouri

    Full Text Available Several studies have shown the importance of calcium channels in the development and/or maturation of synapses. The Ca(V1.4(α(1F knockout mouse is a unique model to study the role of calcium channels in photoreceptor synapse formation. It features abnormal ribbon synapses and aberrant cone morphology. We investigated the expression and targeting of several key elements of ribbon synapses and analyzed the cone morphology in the Ca(V1.4(α(1F knockout retina. Our data demonstrate that most abnormalities occur after eye opening. Indeed, scaffolding proteins such as Bassoon and RIM2 are properly targeted at first, but their expression and localization are not maintained in adulthood. This indicates that either calcium or the Ca(V1.4 channel, or both are necessary for the maintenance of their normal expression and distribution in photoreceptors. Other proteins, such as Veli3 and PSD-95, also display abnormal expression in rods prior to eye opening. Conversely, vesicle related proteins appear normal. Our data demonstrate that the Ca(V1.4 channel is important for maintaining scaffolding proteins in the ribbon synapse but less vital for proteins related to vesicular release. This study also confirms that in adult retinae, cones show developmental features such as sprouting and synaptogenesis. Overall we present evidence that in the absence of the Ca(V1.4 channel, photoreceptor synapses remain immature and are unable to stabilize.

  8. Persistent long-term facilitation at an identified synapse becomes labile with activation of short-term heterosynaptic plasticity.

    Science.gov (United States)

    Hu, Jiang-Yuan; Schacher, Samuel

    2014-04-02

    Short-term and long-term synaptic plasticity are cellular correlates of learning and memory of different durations. Little is known, however, how these two forms of plasticity interact at the same synaptic connection. We examined the reciprocal impact of short-term heterosynaptic or homosynaptic plasticity at sensorimotor synapses of Aplysia in cell culture when expressing persistent long-term facilitation (P-LTF) evoked by serotonin [5-hydroxytryptamine (5-HT)]. Short-term heterosynaptic plasticity induced by 5-HT (facilitation) or the neuropeptide FMRFa (depression) and short-term homosynaptic plasticity induced by tetanus [post-tetanic potentiation (PTP)] or low-frequency stimulation [homosynaptic depression (HSD)] of the sensory neuron were expressed in both control synapses and synapses expressing P-LTF in the absence or presence of protein synthesis inhibitors. All forms of short-term plasticity failed to significantly affect ongoing P-LTF in the absence of protein synthesis inhibitors. However, P-LTF reversed to control levels when either 5-HT or FMRFa was applied in the presence of rapamycin. In contrast, P-LTF was unaffected when either PTP or HSD was evoked in the presence of either rapamycin or anisomycin. These results indicate that synapses expressing persistent plasticity acquire a "new" baseline and functionally express short-term changes as naive synapses, but the new baseline becomes labile following selective activations-heterosynaptic stimuli that evoke opposite forms of plasticity-such that when presented in the presence of protein synthesis inhibitors produce a rapid reversal of the persistent plasticity. Activity-selective induction of a labile state at synapses expressing persistent plasticity may facilitate the development of therapies for reversing inappropriate memories.

  9. Panel 5: Microbiology and immunology panel.

    Science.gov (United States)

    Murphy, Timothy F; Chonmaitree, Tasnee; Barenkamp, Stephen; Kyd, Jennelle; Nokso-Koivisto, Johanna; Patel, Janak A; Heikkinen, Terho; Yamanaka, Noboru; Ogra, Pearay; Swords, W Edward; Sih, Tania; Pettigrew, Melinda M

    2013-04-01

    The objective is to perform a comprehensive review of the literature from January 2007 through June 2011 on the virology, bacteriology, and immunology related to otitis media. PubMed database of the National Library of Medicine. Three subpanels with co-chairs comprising experts in the virology, bacteriology, and immunology of otitis media were formed. Each of the panels reviewed the literature in their respective fields and wrote draft reviews. The reviews were shared with all panel members, and a second draft was created. The entire panel met at the 10th International Symposium on Recent Advances in Otitis Media in June 2011 and discussed the review and refined the content further. A final draft was created, circulated, and approved by the panel. Excellent progress has been made in the past 4 years in advancing an understanding of the microbiology and immunology of otitis media. Advances include laboratory-based basic studies, cell-based assays, work in animal models, and clinical studies. The advances of the past 4 years formed the basis of a series of short-term and long-term research goals in an effort to guide the field. Accomplishing these goals will provide opportunities for the development of novel interventions, including new ways to better treat and prevent otitis media.

  10. Panel 5: Microbiology and Immunology Panel

    Science.gov (United States)

    Murphy, Timothy F.; Chonmaitree, Tasnee; Barenkamp, Stephen; Kyd, Jennelle; Nokso-Koivisto, Johanna; Patel, Janak A.; Heikkinen, Terho; Yamanaka, Noboru; Ogra, Pearay; Swords, W. Edward; Sih, Tania; Pettigrew, Melinda M.

    2014-01-01

    Objective The objective is to perform a comprehensive review of the literature from January 2007 through June 2011 on the virology, bacteriology, and immunology related to otitis media. Data Sources PubMed database of the National Library of Medicine. Review Methods Three subpanels with co-chairs comprising experts in the virology, bacteriology, and immunology of otitis media were formed. Each of the panels reviewed the literature in their respective fields and wrote draft reviews. The reviews were shared with all panel members, and a second draft was created. The entire panel met at the 10th International Symposium on Recent Advances in Otitis Media in June 2011 and discussed the review and refined the content further. A final draft was created, circulated, and approved by the panel. Conclusion Excellent progress has been made in the past 4 years in advancing an understanding of the microbiology and immunology of otitis media. Advances include laboratory-based basic studies, cell-based assays, work in animal models, and clinical studies. Implications for Practice The advances of the past 4 years formed the basis of a series of short-term and long-term research goals in an effort to guide the field. Accomplishing these goals will provide opportunities for the development of novel interventions, including new ways to better treat and prevent otitis media. PMID:23536533

  11. Immunological studies relating to the climate

    International Nuclear Information System (INIS)

    Ballester, J.M.; Cruz, C.; Inclan, G.; Maclas, C.; Suarez, L.; Rivero, R.; Borres, I.M.; Ustariz, C.; Del Valle, L.; Villegas, R.; Martinez, E.; Rorrajero, I.; Guevara, V.; Leon, A.; Paz, L.; Pelaez, J.C.; Roque, M.C.

    1993-01-01

    In order to know the effects of ultra-violet radiations on the integrity of their immunological system, a hematologic and immunological study was carried out in 30 clinically healthy children aged between 10 and 15; 15 of each sex, who come from a region in Bielorussia that was affected by the Chernobyl nuclear accident, and who received medical and recreational services at the 'Jose Marti' Pioneers'City, located Tarara Beach (Havana, Cuba) from July 9,1990 to August 27,1990. Data from the initial evaluations upon their arrival in Cuba were compared whit the final results before their return to Bielorussia, in the following variables: haemoglobin, leucocytes, platelets, absolute counts of lymphocytes and neutrophylous polymorphonuclears, levels of sericeus of Igs G, A, M, and E sericas and (CH50), as well as the presence of circulating immuno complexes; besides spot-forming cellular clusters (spontaneous, active, and medial by the receptor Fc in neutrophylous) and the cells identified with monoclonal antibodies against CD2, CD3, CD8 and CD4/CD8 quotient. Cutaneous response to antigen and lymphoblastic transformation in the presence of PHA and PwN were also assessed. Results of this research allow to infer that the adequate and monitored position against ultra-violet rays from the solar radiation in children exposed to low doses of ionizing irradiation does not deteriorate the human immunological system, and do favor its regulation and normal performance

  12. Monitoring single-synapse glutamate release and presynaptic calcium concentration in organised brain tissue.

    Science.gov (United States)

    Jensen, Thomas P; Zheng, Kaiyu; Tyurikova, Olga; Reynolds, James P; Rusakov, Dmitri A

    2017-06-01

    Brain function relies in large part on Ca 2+ -dependent release of the excitatory neurotransmitter glutamate from neuronal axons. Establishing the causal relationship between presynaptic Ca 2+ dynamics and probabilistic glutamate release is therefore a fundamental quest across neurosciences. Its progress, however, has hitherto depended primarily on the exploration of either cultured nerve cells or giant central synapses accessible to direct experimental probing in situ. Here we show that combining patch-clamp with time-resolved imaging of Ca 2+ -sensitive fluorescence lifetime of Oregon Green BAPTA-1 (Tornado-FLIM) enables readout of single spike-evoked presynaptic Ca 2+ concentration dynamics, with nanomolar sensitivity, in individual neuronal axons in acute brain slices. In parallel, intensity Tornado imaging of a locally expressed extracellular optical glutamate sensor iGluSnFr provides direct monitoring of single-quantum, single-synapse glutamate releases in situ. These two methods pave the way for simultaneous registration of presynaptic Ca 2+ dynamics and transmitter release in an intact brain at the level of individual synapses. Copyright © 2017. Published by Elsevier Ltd.

  13. Automated detection of synapses in serial section transmission electron microscopy image stacks.

    Directory of Open Access Journals (Sweden)

    Anna Kreshuk

    Full Text Available We describe a method for fully automated detection of chemical synapses in serial electron microscopy images with highly anisotropic axial and lateral resolution, such as images taken on transmission electron microscopes. Our pipeline starts from classification of the pixels based on 3D pixel features, which is followed by segmentation with an Ising model MRF and another classification step, based on object-level features. Classifiers are learned on sparse user labels; a fully annotated data subvolume is not required for training. The algorithm was validated on a set of 238 synapses in 20 serial 7197×7351 pixel images (4.5×4.5×45 nm resolution of mouse visual cortex, manually labeled by three independent human annotators and additionally re-verified by an expert neuroscientist. The error rate of the algorithm (12% false negative, 7% false positive detections is better than state-of-the-art, even though, unlike the state-of-the-art method, our algorithm does not require a prior segmentation of the image volume into cells. The software is based on the ilastik learning and segmentation toolkit and the vigra image processing library and is freely available on our website, along with the test data and gold standard annotations (http://www.ilastik.org/synapse-detection/sstem.

  14. (Na+ + K+)-ATPase and plasma membrane polarity of intestinal epithelial cells: Presence of a brush border antigen in the distal large intestine that is immunologically related to beta subunit

    Energy Technology Data Exchange (ETDEWEB)

    Marxer, A.; Stieger, B.; Quaroni, A.; Kashgarian, M.; Hauri, H.P. (Univ. of Basel (Switzerland))

    1989-09-01

    The previously produced monoclonal antibody IEC 1/48 against cultured rat intestinal crypt cells was extensively characterized and found to be directed against the beta subunit of (Na+ + K+)-ATPase as assessed by immunological and enzymatic criteria. Under nondenaturing conditions the antibody precipitated the alpha-beta enzyme complex (98,000 and 48,000 Mr). This probe, together with the monoclonal antibody C 62.4 against the alpha subunit was used to localize (Na+ + K+)-ATPase in epithelial cells along the rat intestinal tract by immunofluorescence and immunoelectron microscopy. Both antibodies exclusively labeled the basolateral membrane of small intestine and proximal colon epithelial cells. However, in the distal colon, IEC 1/48, but not C 62.4, also labeled the brush border membrane. The cross-reacting beta-subunit-like antigen on the apical cell pole was tightly associated with isolated brush borders but was apparently devoid of (Na+ + K+)-ATPase activity. Subcellular fractionation of colonocytes in conjunction with limited proteolysis and surface radioiodination of intestinal segments suggested that the cross-reacting antigen in the brush border may be very similar to the beta subunit. The results support the notion that in the small intestine and proximal colon the enzyme subunits are exclusively targeted to the basolateral membrane while in the distal colon nonassembled beta subunit or a beta-subunit-like protein is also transported to the apical cell pole.

  15. Calcium signaling in synapse-to-nucleus communication.

    Science.gov (United States)

    Hagenston, Anna M; Bading, Hilmar

    2011-11-01

    Changes in the intracellular concentration of calcium ions in neurons are involved in neurite growth, development, and remodeling, regulation of neuronal excitability, increases and decreases in the strength of synaptic connections, and the activation of survival and programmed cell death pathways. An important aspect of the signals that trigger these processes is that they are frequently initiated in the form of glutamatergic neurotransmission within dendritic trees, while their completion involves specific changes in the patterns of genes expressed within neuronal nuclei. Accordingly, two prominent aims of research concerned with calcium signaling in neurons are determination of the mechanisms governing information conveyance between synapse and nucleus, and discovery of the rules dictating translation of specific patterns of inputs into appropriate and specific transcriptional responses. In this article, we present an overview of the avenues by which glutamatergic excitation of dendrites may be communicated to the neuronal nucleus and the primary calcium-dependent signaling pathways by which synaptic activity can invoke changes in neuronal gene expression programs.

  16. GABAA Receptor Activity Shapes the Formation of Inhibitory Synapses between Developing Medium Spiny Neurons

    Directory of Open Access Journals (Sweden)

    Jessica eArama

    2015-08-01

    Full Text Available Basal ganglia play an essential role in motor coordination and cognitive functions. The GABAergic medium spiny neurons (MSNs account for ~95 % of all the neurons in this brain region. Central to the normal functioning of MSNs is integration of synaptic activity arriving from the glutamatergic corticostriatal and thalamostriatal afferents, with synaptic inhibition mediated by local interneurons and MSN axon collaterals. In this study we have investigated how the specific types of GABAergic synapses between the MSNs develop over time, and how the activity of GABAA receptors (GABAARs influences this development. Isolated embryonic (E17 MSNs form a homogenous population in vitro and display spontaneous synaptic activity and functional properties similar to their in vivo counterparts. In dual whole-cell recordings of synaptically connected pairs of MSNs, action potential-activated synaptic events were detected between 7 and 14 days in vitro (DIV, which coincided with the shift in GABAAR operation from depolarization to hyperpolarization, as detected indirectly by intracellular calcium imaging. In parallel, the predominant subtypes of inhibitory synapses, which innervate dendrites of MSNs and contain GABAAR α1 or α2 subunits, underwent distinct changes in the size of postsynaptic clusters, with α1 becoming smaller and α2 larger over time, while both the percentage and the size of mixed α1/α2-postsynaptic clusters were increased. When activity of GABAARs was under chronic blockade between 4-7 DIV, the structural properties of these synapses remained unchanged. In contrast, chronic inhibition of GABAARs between7-14 DIV led to reduction in size of α1- and α1/α2-postsynaptic clusters and a concomitant increase in number and size of α2-postsynaptic clusters. Thus, the main subtypes of GABAergic synapses formed by MSNs are regulated by GABAAR activity, but in opposite directions, and thus appear to be driven by different molecular mechanisms.

  17. Influence of gut microbiota on immunological maturation in infancy

    DEFF Research Database (Denmark)

    Sørensen, Rikke Brandt; Pedersen, Susanne Brix; Frøkiær, Hanne

    8+ T-cells as well as NK-cells similar to those found in adult mice, while splenocytes expressed severely reduced levels of these markers and were impaired in their ability to proliferate in response to anti-CD3/anti-CD28. To further characterize the development of immunological maturation...

  18. Role of immunological surveillance in radiation carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Sado, Toshihiko [National Inst. of Radiological Sciences, Chiba (Japan)

    2003-07-01

    The immune system is known to be highly susceptible to various physical, chemical, and biological insults. The studies on the immediate and long-term effects of radiation on immune system of mice indicated very clearly that there was a dose-dependent reduction in the number of T and B cells, depression of antibody and cytotoxic T cell responses as well as proliferative responses of spleen cells to T and B cell mitogens shortly after irradiation, but they all recovered to the control level within a few months. Immunosuppression observed shortly after irradiation had little influence on the development of radiogenic tumors. The effects of radiation on the incidence of Friend leukemia virus (FLV)-induced leukemias are examined by using young adult B6C3F{sub 1} male mice which are normally resistant to FLV-induced leukemogenesis. There was a clear threshold dose of 2 Gy below which the development of FLV induced leukemias was not observed but after exposure to >3 Gy high incidence of leukemias was observed. Fractionated, weekly exposure of young C57BL strain mice to 1.6 Gy of X-rays for four successive weeks causes most of the exposed mice to develop thymic lymphomas between 3 and 10 months. However, when the exposed mice are grafted with bone marrow cells from normal donors, the development of thymic lymphomas on the exposed mice is greatly inhibited. There was a clear dose response relationship between the number of bone marrow cells injected and the inhibition of the development of thymic lymphomas. It now appears clear that T cell-mediated immunological surveillance against newly arising neoplasms conceived by Thomas and Burnet does not hold true anymore in the original form, although virus-infected host cells and other host cells expressing altered-self' markers on their cell surfaces are constantly monitored by the immunological surveillance mechanism. A surveillance function against newly arising neoplasms may be a property of surrounding normal tissue

  19. Immunological recovery and dose evaluation in IFN-alpha treatment of hairy cell leukemia: analysis of leukocyte differentiation antigens, NK and 2',5'-oligoadenylate synthetase activity

    DEFF Research Database (Denmark)

    Nielsen, B; Hokland, M; Justesen, J

    1989-01-01

    , the number of NK cells normalized in 90 to 180 d, whereas normalization of B cell number was seen only after 180 to 360 d of treatment. Mean pretreatment 2-5A synthetase activity was normal or low, but upon treatment the levels rose immediately to higher than normal values and remained high throughout......A low-dose interferon (IFN)-alpha regimen for the treatment of hairy cell leukemia (HCL) was evaluated by following changes in leukocyte differentiation antigens (LDA), natural killer cell (NK) and 2',5'-oligoadenylate (2-5A) synthetase activities. Due to hairy cells' (HC) weak expression...... of several antigens positive for T cells, B cells, NK cells and monocytes, the use of a double marker specific for hairy cells was needed to distinguish the different subpopulations. Analysis of LDA in peripheral blood (PB) showed a total normalization of the T cell and monocyte numbers within 90 days...

  20. Unique immunologic patterns in fibromyalgia

    Directory of Open Access Journals (Sweden)

    Behm Frederick G

    2012-12-01

    Full Text Available Abstract Background Fibromyalgia (FM is a clinical syndrome characterized by chronic pain and allodynia. The diagnosis of FM has been one of exclusion as a test to confirm the diagnosis is lacking. Recent data highlight the role of the immune system in FM. Aberrant expressions of immune mediators, such as cytokines, have been linked to the pathogenesis and traits of FM. We therefore determined whether cytokine production by immune cells is altered in FM patients by comparing the cellular responses to mitogenic activators of stimulated blood mononuclear cells of a large number of patients with FM to those of healthy matched individuals. Methods Plasma and peripheral blood mononuclear cells (PBMC were collected from 110 patients with the clinical diagnosis of FM and 91 healthy donors. Parallel samples of PBMC were cultured overnight in medium alone or in the presence of mitogenic activators; PHA or PMA in combination with ionomycin. The cytokine concentrations of IFN-γ, IL-5, IL-6, IL-8, IL-10, MIP-1β , MCP-1, and MIP1-α in plasma as well as in cultured supernatants were determined using a multiplex immunoassay using bead array technology. Results Cytokine levels of stimulated PBMC cultures of healthy control subjects were significantly increased as compared to matched non-stimulated PBMC cultures. In contrast, the concentrations of most cytokines were lower in stimulated samples from patients with FM compared to controls. The decreases of cytokine concentrations in patients samples ranged from 1.5-fold for MIP-1β to 10.2-fold for IL-6 in PHA challenges. In PMA challenges, we observed 1.8 to 4-fold decreases in the concentrations of cytokines in patient samples. Conclusion The cytokine responses to mitogenic activators of PBMC isolated from patients with FM were significantly lower than those of healthy individuals, implying that cell-mediated immunity is impaired in FM patients. This novel cytokine assay reveals unique and valuable

  1. Changes in Properties of Auditory Nerve Synapses following Conductive Hearing Loss.

    Science.gov (United States)

    Zhuang, Xiaowen; Sun, Wei; Xu-Friedman, Matthew A

    2017-01-11

    Auditory activity plays an important role in the development of the auditory system. Decreased activity can result from conductive hearing loss (CHL) associated with otitis media, which may lead to long-term perceptual deficits. The effects of CHL have been mainly studied at later stages of the auditory pathway, but early stages remain less examined. However, changes in early stages could be important because they would affect how information about sounds is conveyed to higher-order areas for further processing and localization. We examined the effects of CHL at auditory nerve synapses onto bushy cells in the mouse anteroventral cochlear nucleus following occlusion of the ear canal. These synapses, called endbulbs of Held, normally show strong depression in voltage-clamp recordings in brain slices. After 1 week of CHL, endbulbs showed even greater depression, reflecting higher release probability. We observed no differences in quantal size between control and occluded mice. We confirmed these observations using mean-variance analysis and the integration method, which also revealed that the number of release sites decreased after occlusion. Consistent with this, synaptic puncta immunopositive for VGLUT1 decreased in area after occlusion. The level of depression and number of release sites both showed recovery after returning to normal conditions. Finally, bushy cells fired fewer action potentials in response to evoked synaptic activity after occlusion, likely because of increased depression and decreased input resistance. These effects appear to reflect a homeostatic, adaptive response of auditory nerve synapses to reduced activity. These effects may have important implications for perceptual changes following CHL. Normal hearing is important to everyday life, but abnormal auditory experience during development can lead to processing disorders. For example, otitis media reduces sound to the ear, which can cause long-lasting deficits in language skills and verbal

  2. Immunology of the Uterine and Vaginal Mucosae.

    Science.gov (United States)

    Zhou, Jordan Z; Way, Sing Sing; Chen, Kang

    2018-04-01

    Along with the maintenance of symbiotic mutualism with commensal microbes and protection against invasive infections common to all mucosal barrier tissues, female reproductive tissues have additional, unique tasks that include dynamic cyclic cellular turnover in menstruation and immunological tolerance to genetically foreign fetal antigens in pregnancy. Here we review current knowledge on distinct features of the immune cells in female reproductive tissue with regard to antimicrobial host defense and adaptations to accommodate the fetus during pregnancy. Outstanding areas for future research to obtain new functional insights on this enigmatic mucosal barrier are also highlighted. Copyright © 2018 Elsevier Ltd. All rights reserved.

  3. Immunology of Psoriasis

    Science.gov (United States)

    Lowes, Michelle A.; Suárez-Fariñas, Mayte; Krueger, James G.

    2014-01-01

    The skin is the front line of defense against insult and injury and contains many epidermal and immune elements that comprise the skin-associated lymphoid tissue (SALT). The reaction of these components to injury allows an effective cutaneous response to restore homeostasis. Psoriasis vulgaris is the best-understood and most accessible human disease that is mediated by T cells and dendritic cells. Inflammatory myeloid dendritic cells release IL-23 and IL-12 to activate IL-17-producing T cells, Th1 cells, and Th22 cells to produce abundant psoriatic cytokines IL-17, IFN-γ, TNF, and IL-22. These cytokines mediate effects on keratinocytes to amplify psoriatic inflammation. Therapeutic studies with anticytokine antibodies have shown the importance of the key cytokines IL-23, TNF, and IL-17 in this process. We discuss the genetic background of psoriasis and its relationship to immune function, specifically genetic mutations, key PSORS loci, single nucleotide polymorphisms, and the skin transcriptome. The association between comorbidities and psoriasis is reviewed by correlating the skin transcriptome and serum proteins. Psoriasis-related cytokine-response pathways are considered in the context of the transcriptome of different mouse models. This approach offers a model for other inflammatory skin and autoimmune diseases. PMID:24655295

  4. Fundamental Molecules and Mechanisms for Forming and Maintaining Neuromuscular Synapses

    Science.gov (United States)

    Huijbers, Maartje G.; Remedio, Leonor

    2018-01-01

    The neuromuscular synapse is a relatively large synapse with hundreds of active zones in presynaptic motor nerve terminals and more than ten million acetylcholine receptors (AChRs) in the postsynaptic membrane. The enrichment of proteins in presynaptic and postsynaptic membranes ensures a rapid, robust, and reliable synaptic transmission. Over fifty years ago, classic studies of the neuromuscular synapse led to a comprehensive understanding of how a synapse looks and works, but these landmark studies did not reveal the molecular mechanisms responsible for building and maintaining a synapse. During the past two-dozen years, the critical molecular players, responsible for assembling the specialized postsynaptic membrane and regulating nerve terminal differentiation, have begun to be identified and their mechanism of action better understood. Here, we describe and discuss five of these key molecular players, paying heed to their discovery as well as describing their currently understood mechanisms of action. In addition, we discuss the important gaps that remain to better understand how these proteins act to control synaptic differentiation and maintenance. PMID:29415504

  5. The presynaptic machinery at the synapse of C. elegans.

    Science.gov (United States)

    Calahorro, Fernando; Izquierdo, Patricia G

    2018-03-12

    Synapses are specialized contact sites that mediate information flow between neurons and their targets. Important physical interactions across the synapse are mediated by synaptic adhesion molecules. These adhesions regulate formation of synapses during development and play a role during mature synaptic function. Importantly, genes regulating synaptogenesis and axon regeneration are conserved across the animal phyla. Genetic screens in the nematode Caenorhabditis elegans have identified a number of molecules required for synapse patterning and assembly. C. elegans is able to survive even with its neuronal function severely compromised. This is in comparison with Drosophila and mice where increased complexity makes them less tolerant to impaired function. Although this fact may reflect differences in the function of the homologous proteins in the synapses between these organisms, the most likely interpretation is that many of these components are equally important, but not absolutely essential, for synaptic transmission to support the relatively undemanding life style of laboratory maintained C. elegans. Here, we review research on the major group of synaptic proteins, involved in the presynaptic machinery in C. elegans, showing a strong conservation between higher organisms and highlight how C. elegans can be used as an informative tool for dissecting synaptic components, based on a simple nervous system organization.

  6. The immunology of hypertension.

    Science.gov (United States)

    Norlander, Allison E; Madhur, Meena S; Harrison, David G

    2018-01-02

    Although systemic hypertension affects a large proportion of the population, its etiology remains poorly defined. Emerging evidence supports the concept that immune cells become activated and enter target organs, including the vasculature and the kidney, in this disease. Mediators released by these cells, including reactive oxygen species, metalloproteinases, cytokines, and antibodies promote dysfunction of the target organs and cause damage. In vessels, these factors enhance constriction, remodeling, and rarefaction. In the kidney, these mediators increase expression and activation of sodium transporters, and cause interstitial fibrosis and glomerular injury. Factors common to hypertension, including oxidative stress, increased interstitial sodium, cytokine production, and inflammasome activation promote immune activation in hypertension. Recent data suggest that isolevuglandin-modified self-proteins in antigen-presenting cells are immunogenic, promoting cytokine production by the cells in which they are formed and T cell activation. Efforts to prevent and reverse immune activation may prove beneficial in preventing the long-term sequelae of hypertension and its related cardiovascular diseases. © 2018 Norlander et al.

  7. Sensory experience shapes the development of the visual system's first synapse.

    Science.gov (United States)

    Dunn, Felice A; Della Santina, Luca; Parker, Edward D; Wong, Rachel O L

    2013-12-04

    Specific connectivity patterns among neurons create the basic architecture underlying parallel processing in our nervous system. Here we focus on the visual system's first synapse to examine the structural and functional consequences of sensory deprivation on the establishment of parallel circuits. Dark rearing reduces synaptic strength between cones and cone bipolar cells, a previously unappreciated effect of sensory deprivation. In contrast, rod bipolar cells, which utilize the same glutamate receptor to contact rods, are unaffected by dark rearing. Underlying the physiological changes, we find the localization of metabotropic glutamate receptors within cone bipolar, but not rod bipolar, cell dendrites is a light-dependent process. Furthermore, although cone bipolar cells share common cone partners, each bipolar cell type that we examined depends differentially on sensory input to achieve mature connectivity. Thus, visual experience differentially affects maturation of rod versus cone pathways and of cell types within the cone pathway. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. VLA-4 integrin concentrates at the peripheral supramolecular activation complex of the immune synapse and drives T helper 1 responses

    Science.gov (United States)

    Mittelbrunn, María; Molina, Ana; Escribese, María M.; Yáñez-Mó, María; Escudero, Ester; Ursa, Ángeles; Tejedor, Reyes; Mampaso, Francisco; Sánchez-Madrid, Francisco

    2004-07-01

    The integrin 41 (VLA-4) not only mediates the adhesion and transendothelial migration of leukocytes, but also provides costimulatory signals that contribute to the activation of T lymphocytes. However, the behavior of 41 during the formation of the immune synapse is currently unknown. Here, we show that 41 is recruited to both human and murine antigen-dependent immune synapses, when the antigen-presenting cell is a B lymphocyte or a dendritic cell, colocalizing with LFA-1 at the peripheral supramolecular activation complex. However, when conjugates are formed in the presence of anti-4 antibodies, VLA-4 colocalizes with the CD3- chain at the center of the synapse. In addition, antibody engagement of 4 integrin promotes polarization toward a T helper 1 (Th1) response in human in vitro models of CD4+ T cell differentiation and naïve T cell priming by dendritic cells. The in vivo administration of anti-4 integrin antibodies also induces an immune deviation to Th1 response that dampens a Th2-driven autoimmune nephritis in Brown Norway rats. These data reveal a regulatory role of 4 integrins on T lymphocyte-antigen presenting cell cognate immune interactions.

  9. Lichen planus: immunologic and morphologic identification of the submucosal infiltrate.

    Science.gov (United States)

    Regezi, J A; Deegan, M J; Hayward, J R

    1978-07-01

    The purpose of this investigation was to specifically identify T cells, B cells, and histiocytes in the infiltrate typically seen in lichen planus. In frozen tissue sections, AET-treated sheep erythrocytes formed immunologic rosettes with the lymphocytes in the infiltrate, designating them as T cells. Rosette assays with reagent erythrocytes, IgGEA, IgMEA, IgMEAC, and E resulted in nonadherence, indicating a lack of B cells and macrophages, and indirectly implicating them as T cells. Scanning electron microscopy of the cellular infiltrate, in situ, showed that the cells had smooth, nonvillous surfaces. These observations were consistent with a T cell origin and were considered supportive of the immunologic data. The results of this investigation support the hypothesis that lichen planus is a disease mediated by thymus-dependent lymphocytes.

  10. Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity.

    Science.gov (United States)

    Pérez de Diego, Rebeca; Sánchez-Ramón, Silvia; López-Collazo, Eduardo; Martínez-Barricarte, Rubén; Cubillos-Zapata, Carolina; Ferreira Cerdán, Antonio; Casanova, Jean-Laurent; Puel, Anne

    2015-11-01

    Three members of the caspase recruitment domain (CARD) family of adaptors (CARD9, CARD10, and CARD11) are known to form heterotrimers with B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1). These 3 CARD-BCL10-MALT1 (CBM) complexes activate nuclear factor κB in both the innate and adaptive arms of immunity. Human inherited defects of the 3 components of the CBM complex, including the 2 adaptors CARD9 and CARD11 and the 2 core components BCL10 and MALT1, have recently been reported. Biallelic loss-of-function mutant alleles underlie several different immunologic and clinical phenotypes, which can be assigned to 2 distinct categories. Isolated invasive fungal infections of unclear cellular basis are associated with CARD9 deficiency, whereas a broad range of clinical manifestations, including those characteristic of T- and B-lymphocyte defects, are associated with CARD11, MALT1, and BCL10 deficiencies. Interestingly, human subjects with these mutations have some features in common with the corresponding knockout mice, but other features are different between human subjects and mice. Moreover, germline and somatic gain-of-function mutations of MALT1, BCL10, and CARD11 have also been found in patients with other lymphoproliferative disorders. This broad range of germline and somatic CBM lesions, including loss-of-function and gain-of-function mutations, highlights the contribution of each of the components of the CBM complex to human immunity. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  11. Coding deficits in noise-induced hidden hearing loss may stem from incomplete repair of ribbon synapses in the cochlea

    Directory of Open Access Journals (Sweden)

    Lijuan eShi

    2016-05-01

    Full Text Available Recent evidence has shown that noise-induced damage to the synapse between inner hair cells (IHCs and type I afferent auditory nerve fibers (ANFs may occur in the absence of permanent threshold shift (PTS, and that synapses connecting IHCs with low spontaneous rate (SR ANFs are disproportionately affected. Due to the functional importance of low-SR ANF units for temporal processing and signal coding in noisy backgrounds, deficits in cochlear coding associated with noise-induced damage may result in significant difficulties with temporal processing and hearing in noise (i.e., hidden hearing loss. However, significant noise-induced coding deficits have not been reported at the single unit level following the loss of low-SR units. We have found evidence to suggest that some aspects of neural coding are not significantly changed with the initial loss of low-SR ANFs, and that further coding deficits arise in association with the subsequent reestablishment of the synapses. This suggests that synaptopathy in hidden hearing loss may be the result of insufficient repair of disrupted synapses, and not simply due to the loss of low-SR units. These coding deficits include decreases in driven spike rate for intensity coding as well as several aspects of temporal coding: spike latency, peak-to-sustained spike ratio and the recovery of spike rate as a function of click-interval.

  12. Journal of Immunology

    OpenAIRE

    Probst, Peter; Stromberg, Erika J.; Ghalib, Hashim W.; Mozel, Michelle; Badaró, Roberto José da Silva; Reed, Steven G.; Webb, John R.

    2001-01-01

    Texto completo: acesso restrito. p. 498-505 Persistent immunity against Leishmania infections in humans is mediated predominantly by CD4+ T cells of the Th1 phenotype. Herein we report the expression cloning of eight Leishmania Ags using parasite-specific T cell lines derived from an immune donor. The Ags identified by this technique include the flagellar proteins α- and β-tubulin, histone H2b, ribosomal protein S4, malate dehydrogenase, and elongation factor 2, as well as two novel parasi...

  13. Mechanisms of immunological eradication of a syngeneic guinea pig tumor. II. Effect of methotrexate treatment and T cell depletion of the recipient on adoptive immunity

    Energy Technology Data Exchange (ETDEWEB)

    Shu, S.; Fonseca, L.S.; Hunter, J.T.; Rapp, H.J.

    1983-01-01

    The influence of methotrexate on the development of immunity to the line 10 hepatoma was studied in guinea pigs. Chronic methotrexate treatment had no apparent effect on the ability of immune guinea pigs to suppress the growth of inoculated tumor cells. In contrast, the same methotrexate regimen inhibited the development of tumor immunity if started before the 8th day after immunization with a vaccine containing viable line 10 cells admixed with Bacillus Calmette-Guerin (BCG) cell walls. Thus, methotrexate selectively inhibited the afferent limb of the immune response. In adoptive transfer experiments, methotrexate-treated recipient guinea pigs were capable of being passively sensitized with immune spleen cells, indicating that the primary cell-mediated immune response of the recipient was not required for adoptive immunity. The contribution of recipient T cells in adoptive immunity was further investigated in guinea pigs deleted of T cells by thymectomy, irradiation, and bone marrow reconstitution. Despite demonstrable deficiency in T lymphocyte reactions, B animals were fully capable of rejecting tumors after transfer of immune cells. These results suggest that the expression of adoptive immunity was independent of recipient T cell participation. In addition, sublethal irradiation of immune spleen cells prior to adoptive transfer abolished their efficacy. Proliferation of transferred immune cells in the recipient may be essential for expression of adoptive immunity.

  14. Mechanisms of immunological eradication of a syngeneic guinea pig tumor. II. Effect of methotrexate treatment and T cell depletion of the recipient on adoptive immunity

    International Nuclear Information System (INIS)

    Shu, S.; Fonseca, L.S.; Hunter, J.T.; Rapp, H.J.

    1983-01-01

    The influence of methotrexate on the development of immunity to the line 10 hepatoma was studied in guinea pigs. Chronic methotrexate treatment had no apparent effect on the ability of immune guinea pigs to suppress the growth of inoculated tumor cells. In contrast, the same methotrexate regimen inhibited the development of tumor immunity if started before the 8th day after immunization with a vaccine containing viable line 10 cells admixed with Bacillus Calmette-Guerin (BCG) cell walls. Thus, methotrexate selectively inhibited the afferent limb of the immune response. In adoptive transfer experiments, methotrexate-treated recipient guinea pigs were capable of being passively sensitized with immune spleen cells, indicating that the primary cell-mediated immune response of the recipient was not required for adoptive immunity. The contribution of recipient T cells in adoptive immunity was further investigated in guinea pigs deleted of T cells by thymectomy, irradiation, and bone marrow reconstitution. Despite demonstrable deficiency in T lymphocyte reactions, B animals were fully capable of rejecting tumors after transfer of immune cells. These results suggest that the expression of adoptive immunity was independent of recipient T cell participation. In addition, sublethal irradiation of immune spleen cells prior to adoptive transfer abolished their efficacy. Proliferation of transferred immune cells in the recipient may be essential for expression of adoptive immunity

  15. Beneficial effects of dietary probiotics mixture on hemato-immunology and cell apoptosis of Labeo rohita fingerlings reared at higher water temperatures.

    Science.gov (United States)

    Mohapatra, Sipra; Chakraborty, Tapas; Prusty, Ashisa K; PaniPrasad, Kurchetti; Mohanta, Kedar N

    2014-01-01

    Probiotics play an important role in growth increment, immune enhancement and stress mitigation in fish. Increasing temperature is a major concern in present aquaculture practices as it markedly deteriorates the health condition and reduces the growth in fish. In order to explore the possibilities of using probiotics as a counter measure for temperature associated problems, a 30 days feeding trial was conducted to study the hemato-immunological and apoptosis response of Labeo rohita (8.3±0.4 g) reared at different water temperatures, fed with or without dietary supplementation of a probiotic mixture (PM) consisting of Bacillus subtilis, Lactococcus lactis and Saccharomyces cerevisiae) (1011 cfu kg(-1)). Three hundred and sixty fish were randomly distributed into eight treatment groups in triplicates, namely, T1(28°C+BF(Basal feed)+PM), T2(31°C+BF+PM), T3(34°C+BF+PM), T4(37°C+BF+PM), T5(28°C+BF), T6(31°C+BF), T7(34°C+BF) and T8(37°C+BF). A significant increase (Palkaline phosphatase and acid phosphatase were significantly higher (Peffect of rearing temperature and dietary probiotic mixture on serum myeloperoxidase activity, HSP70 level and immunoglobulin production was observed. Degree of apoptosis in different tissues was also significantly reduced in probiotic-supplemented groups. Hence, the present results show that a dietary PM could be beneficial in enhancing the immune status of the fish and also help in combating the stress caused to the organism by higher rearing water temperature.

  16. Remodelling at the calyx of Held-MNTB synapse in mice developing with unilateral conductive hearing loss.

    Science.gov (United States)

    Grande, Giovanbattista; Negandhi, Jaina; Harrison, Robert V; Wang, Lu-Yang

    2014-04-01

    Structure and function of central synapses are profoundly influenced by experience during developmental sensitive periods. Sensory synapses, which are the indispensable interface for the developing brain to interact with its environment, are particularly plastic. In the auditory system, moderate forms of unilateral hearing loss during development are prevalent but the pre- and postsynaptic modifications that occur when hearing symmetry is perturbed are not well understood. We investigated this issue by performing experiments at the large calyx of Held synapse. Principal neurons of the medial nucleus of the trapezoid body (MNTB) are innervated by calyx of Held terminals that originate from the axons of globular bushy cells located in the contralateral ventral cochlear nucleus. We compared populations of synapses in the same animal that were either sound deprived (SD) or sound experienced (SE) after unilateral conductive hearing loss (CHL). Middle ear ossicles were removed 1 week prior to hearing onset (approx. postnatal day (P) 12) and morphological and electrophysiological approaches were applied to auditory brainstem slices taken from these mice at P17-19. Calyces in the SD and SE MNTB acquired their mature digitated morphology but these were structurally more complex than those in normal hearing mice. This was accompanied by bilateral decreases in initial EPSC amplitude and synaptic conductance despite the CHL being unilateral. During high-frequency stimulation, some SD synapses displayed short-term depression whereas others displayed short-term facilitation followed by slow depression similar to the heterogeneities observed in normal hearing mice. However SE synapses predominantly displayed short-term facilitation followed by slow depression which could be explained in part by the decrease in release probability. Furthermore, the excitability of principal cells in the SD MNTB had increased significantly. Despite these unilateral changes in short-term plasticity

  17. Citizens unite for computational immunology!

    Science.gov (United States)

    Belden, Orrin S; Baker, Sarah Catherine; Baker, Brian M

    2015-07-01

    Recruiting volunteers who can provide computational time, programming expertise, or puzzle-solving talent has emerged as a powerful tool for biomedical research. Recent projects demonstrate the potential for such 'crowdsourcing' efforts in immunology. Tools for developing applications, new funding opportunities, and an eager public make crowdsourcing a serious option for creative solutions for computationally-challenging problems. Expanded uses of crowdsourcing in immunology will allow for more efficient large-scale data collection and analysis. It will also involve, inspire, educate, and engage the public in a variety of meaningful ways. The benefits are real - it is time to jump in! Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. An actin cytoskeletal barrier inhibits lytic granule release from natural killer cells in patients with Chediak-Higashi syndrome.

    Science.gov (United States)

    Gil-Krzewska, Aleksandra; Saeed, Mezida B; Oszmiana, Anna; Fischer, Elizabeth R; Lagrue, Kathryn; Gahl, William A; Introne, Wendy J; Coligan, John E; Davis, Daniel M; Krzewski, Konrad

    2017-12-11

    Chediak-Higashi syndrome (CHS) is a rare disorder caused by biallelic mutations in the lysosomal trafficking regulator gene (LYST), resulting in formation of giant lysosomes or lysosome-related organelles in several cell types. The disease is characterized by immunodeficiency and a fatal hemophagocytic lymphohistiocytosis caused by impaired function of cytotoxic lymphocytes, including natural killer (NK) cells. We sought to determine the underlying biochemical cause of the impaired cytotoxicity of NK cells in patients with CHS. We generated a human cell model of CHS using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology. We used a combination of classical techniques to evaluate lysosomal function and cell activity in the model system and super-resolution microscopy to visualize F-actin and lytic granules in normal and LYST-deficient NK cells. Loss of LYST function in a human NK cell line, NK92mi, resulted in inhibition of NK cell cytotoxicity and reproduced other aspects of the CHS cellular phenotype, including the presence of significantly enlarged lytic granules with defective exocytosis and impaired integrity of endolysosomal compartments. The large granules had an acidic pH and normal activity of lysosomal enzymes and were positive for the proteins essential for lytic granule exocytosis. Visualization of the actin meshwork openings at the immunologic synapse revealed that the cortical actin acts as a barrier for secretion of such large granules at the cell-cell contact site. Decreasing the cortical actin density at the immunologic synapse or decreasing the lytic granule size restored the ability of LYST-deficient NK cells to degranulate and kill target cells. The cortical actin and granule size play significant roles in NK cell cytotoxic function. We present evidence that the periodicity of subsynaptic actin is an important factor limiting the release of large lytic granules from NK cells from patients with CHS and could be a novel

  19. Immunological self, nonself discrimination

    DEFF Research Database (Denmark)

    Guillet, J G; Lai, M Z; Briner, T J

    1987-01-01

    The ability of immunodominant peptides derived from several antigen systems to compete with each other for T cell activation was studied. Only peptides restricted by a given transplantation antigen are mutually competitive. There is a correlation between haplotype restriction, ability to bind to ...... that provides a basis for explaining self, nonself discrimination as well as alloreactivity....

  20. Immunological self, nonself discrimination

    DEFF Research Database (Denmark)

    Guillet, J G; Lai, M Z; Briner, T J

    1987-01-01

    The ability of immunodominant peptides derived from several antigen systems to compete with each other for T cell activation was studied. Only peptides restricted by a given transplantation antigen are mutually competitive. There is a correlation between haplotype restriction, ability to bind to ...

  1. Spatially restricted actin-regulatory signaling contributes to synapse morphology

    Science.gov (United States)

    Nicholson, Daniel A.; Cahill, Michael E.; Tulisiak, Christopher T.; Geinisman, Yuri; Penzes, Peter

    2012-01-01

    The actin cytoskeleton in dendritic spines is organized into microdomains, but how signaling molecules that regulate actin are spatially governed is incompletely understood. Here we examine how the localization of the RacGEF kalirin-7, a well-characterized regulator of actin in spines, varies as a function of postsynaptic density (PSD) area and spine volume. Using serial section electron microscopy (EM), we find that extrasynaptic, but not synaptic, expression of kalirin-7 varies directly with synapse size and spine volume. Moreover, we find that overall expression levels of kalirin-7 differ in spines bearing perforated and non-perforated synapses, due primarily to extrasynaptic pools of kalirin-7 expression in the former. Overall, our findings indicate that kalirin-7 is differentially compartmentalized in spines as a function of both synapse morphology and spine size. PMID:22458534

  2. An NMDA Receptor-Dependent Mechanism Underlies Inhibitory Synapse Development

    Directory of Open Access Journals (Sweden)

    Xinglong Gu

    2016-01-01

    Full Text Available In the mammalian brain, GABAergic synaptic transmission provides inhibitory balance to glutamatergic excitatory drive and controls neuronal output. The molecular mechanisms underlying the development of GABAergic synapses remain largely unclear. Here, we report that NMDA-type ionotropic glutamate receptors (NMDARs in individual immature neurons are the upstream signaling molecules essential for GABAergic synapse development, which requires signaling via Calmodulin binding motif in the C0 domain of the NMDAR GluN1 subunit. Interestingly, in neurons lacking NMDARs, whereas GABAergic synaptic transmission is strongly reduced, the tonic inhibition mediated by extrasynaptic GABAA receptors is increased, suggesting a compensatory mechanism for the lack of synaptic inhibition. These results demonstrate a crucial role for NMDARs in specifying the development of inhibitory synapses, and suggest an important mechanism for controlling the establishment of the balance between synaptic excitation and inhibition in the developing brain.

  3. Learning through ferroelectric domain dynamics in solid-state synapses

    Science.gov (United States)

    Boyn, Sören; Grollier, Julie; Lecerf, Gwendal; Xu, Bin; Locatelli, Nicolas; Fusil, Stéphane; Girod, Stéphanie; Carrétéro, Cécile; Garcia, Karin; Xavier, Stéphane; Tomas, Jean; Bellaiche, Laurent; Bibes, Manuel; Barthélémy, Agnès; Saïghi, Sylvain; Garcia, Vincent

    2017-04-01

    In the brain, learning is achieved through the ability of synapses to reconfigure the strength by which they connect neurons (synaptic plasticity). In promising solid-state synapses called memristors, conductance can be finely tuned by voltage pulses and set to evolve according to a biological learning rule called spike-timing-dependent plasticity (STDP). Future neuromorphic architectures will comprise billions of such nanosynapses, which require a clear understanding of the physical mechanisms responsible for plasticity. Here we report on synapses based on ferroelectric tunnel junctions and show that STDP can be harnessed from inhomogeneous polarization switching. Through combined scanning probe imaging, electrical transport and atomic-scale molecular dynamics, we demonstrate that conductance variations can be modelled by the nucleation-dominated reversal of domains. Based on this physical model, our simulations show that arrays of ferroelectric nanosynapses can autonomously learn to recognize patterns in a predictable way, opening the path towards unsupervised learning in spiking neural networks.

  4. Neuromorphic function learning with carbon nanotube based synapses

    International Nuclear Information System (INIS)

    Gacem, Karim; Filoramo, Arianna; Derycke, Vincent; Retrouvey, Jean-Marie; Chabi, Djaafar; Zhao, Weisheng; Klein, Jacques-Olivier

    2013-01-01

    The principle of using nanoscale memory devices as artificial synapses in neuromorphic circuits is recognized as a promising way to build ground-breaking circuit architectures tolerant to defects and variability. Yet, actual experimental demonstrations of the neural network type of circuits based on non-conventional/non-CMOS memory devices and displaying function learning capabilities remain very scarce. We show here that carbon-nanotube-based memory elements can be used as artificial synapses, combined with conventional neurons and trained to perform functions through the application of a supervised learning algorithm. The same ensemble of eight devices can notably be trained multiple times to code successively any three-input linearly separable Boolean logic function despite device-to-device variability. This work thus represents one of the very few demonstrations of actual function learning with synapses based on nanoscale building blocks. The potential of such an approach for the parallel learning of multiple and more complex functions is also evaluated. (paper)

  5. Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease.

    Science.gov (United States)

    Brand, S

    2009-08-01

    Traditionally, Crohn's disease has been associated with a Th1 cytokine profile, while Th2 cytokines are modulators of ulcerative colitis. This concept has been challenged by the description of tolerising regulatory T cells (Treg) and by proinflammatory Th17 cells, a novel T cell population characterised by the master transcription factor RORgammat, the surface markers IL23R and CCR6, and by production of the proinflammatory cytokines IL17A, IL17F, IL21, IL22 and IL26, and the chemokine CCL20. Th17 cells differentiate under the influence of IL1beta, IL6, IL21 and IL23. Recent studies indicate that TGFbeta is essential not only for the development of murine Th17 cells but also for differentiation of human Th17 cells. TGFbeta reciprocally regulates the differentiation of inflammatory Th17 cells and suppressive Treg subsets, with the concomitant presence of proinflammatory cytokines favouring Th17 cell differentiation. Several studies demonstrated an important role of Th17 cells in intestinal inflammation, particularly in Crohn's disease. Genome-wide association studies indicate that IL23R and five additional genes involved in Th17 differentiation (IL12B, JAK2, STAT3, CCR6 and TNFSF15) are associated with susceptibility to Crohn's disease and partly also to ulcerative colitis. Taken together, both Th1 and Th17 cells are important mediators of inflammation in Crohn's disease, although activities previously ascribed to IL12 may be mediated by IL23. Anti-IL12/IL23p40 antibody therapy, which targets both Th1 and Th17 cells, is effective in Crohn's disease. However, the complex relationship between Th1 and Th17 cells has not been completely analysed. This will be of great importance to delineate the specific contributions of these cells to Crohn's disease and other autoimmune diseases.

  6. Maximal frustration as an immunological principle.

    Science.gov (United States)

    de Abreu, F Vistulo; Mostardinha, P

    2009-03-06

    A fundamental problem in immunology is that of understanding how the immune system selects promptly which cells to kill without harming the body. This problem poses an apparent paradox. Strong reactivity against pathogens seems incompatible with perfect tolerance towards self. We propose a different view on cellular reactivity to overcome this paradox: effector functions should be seen as the outcome of cellular decisions which can be in conflict with other cells' decisions. We argue that if cellular systems are frustrated, then extensive cross-reactivity among the elements in the system can decrease the reactivity of the system as a whole and induce perfect tolerance. Using numerical and mathematical analyses, we discuss two simple models that perform optimal pathogenic detection with no autoimmunity if cells are maximally frustrated. This study strongly suggests that a principle of maximal frustration could be used to build artificial immune systems. It would be interesting to test this principle in the real adaptive immune system.

  7. Immunologic Regulation in Pregnancy: From Mechanism to Therapeutic Strategy for Immunomodulation

    Directory of Open Access Journals (Sweden)

    Shyi-Jou Chen

    2012-01-01

    Full Text Available The immunologic interaction between the fetus and the mother is a paradoxical communication that is regulated by fetal antigen presentation and/or by recognition of and reaction to these antigens by the maternal immune system. There have been significant advances in understanding of abnormalities in the maternal-fetal immunologic relationship in the placental bed that can lead to pregnancy disorders. Moreover, immunologic recognition of pregnancy is vital for the maintenance of gestation, and inadequate recognition of fetal antigens may cause abortion. In this paper, we illustrate the complex immunologic aspects of human reproduction in terms of the role of human leukocyte antigen (HLA, immune cells, cytokines and chemokines, and the balance of immunity in pregnancy. In addition, we review the immunologic processes of human reproduction and the current immunologic therapeutic strategies for pathological disorders of pregnancy.

  8. Neuroglial plasticity at striatal glutamatergic synapses in Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Rosa M Villalba

    2011-08-01

    Full Text Available Striatal dopamine denervation is the pathological hallmark of Parkinson’s disease (PD. Another major pathological change described in animal models and PD patients is a significant reduction in the density of dendritic spines on medium spiny striatal projection neurons. Simultaneously, the ultrastructural features of the neuronal synaptic elements at the remaining corticostriatal and thalamostriatal glutamatergic axo-spinous synapses undergo complex ultrastructural remodeling consistent with increased synaptic activity (Villalba et al., 2011. The concept of tripartite synapses (TS was introduced a decade ago, according to which astrocytes process and exchange information with neuronal synaptic elements at glutamatergic synapses (Araque et al., 1999a. Although there has been compelling evidence that astrocytes are integral functional elements of tripartite glutamatergic synaptic complexes in the cerebral cortex and hippocampus, their exact functional role, degree of plasticity and preponderance in other CNS regions remain poorly understood. In this review, we discuss our recent findings showing that neuronal elements at cortical and thalamic glutamatergic synapses undergo significant plastic changes in the striatum of MPTP-treated parkinsonian monkeys. We also present new ultrastructural data that demonstrate a significant expansion of the astrocytic coverage of striatal TS synapses in the parkinsonian state, providing further evidence for ultrastructural compensatory changes that affect both neuronal and glial elements at TS. Together with our limited understanding of the mechanisms by which astrocytes respond to changes in neuronal activity and extracellular transmitter homeostasis, the role of both neuronal and glial components of excitatory synapses must be considered, if one hopes to take advantage of glia-neuronal communication knowledge to better understand the pathophysiology of striatal processing in parkinsonism, and develop new PD

  9. Identification of CD8(+) T Cell Epitopes in the West Nile Virus Polyprotein by Reverse-Immunology Using NetCTL

    DEFF Research Database (Denmark)

    Larsen, Mette Voldby; Lelic, A.; Parsons, R.

    2010-01-01

    bioinformatics methods to predict WNV-specific CD8(+) T cell epitopes and selected a set of peptides that constitutes maximum coverage of 20 fully-sequenced WNV strains. We then tested these putative epitopes for cellular reactivity in a cohort of WNV-infected patients. We identified 26 new CD8(+) T cell...... identified CD8(+) T cell epitopes contribute to our knowledge of the immune response against WNV infection and greatly extend the list of known WNV CD8(+) T cell epitopes. A polytope incorporating these and other epitopes could possibly serve as the basis for a WNV vaccine....

  10. [Method for concentrating marrow stem cells using the IBM 2991 washer. Necessary preparation before in vitro treatment of bone marrow by pharmacologic or immunologic means].

    Science.gov (United States)

    Hervé, P; Coffe, C; Peters, A

    1983-04-01

    The technique using the IBM 2991 blood cell processor is an effective technique for the concentration of mononuclear cells from large volumes of bone marrow. The marrow cells are layered on to Ficoll Metrizoate using the IBM processing set. The mononuclear cells and CFU-GM recoveries are in close relationship with the hematocrit of the cell suspension processed. Twenty two bone marrows have been collected and purified according to this protocol. The mononuclear cell recovery is an average of 78,3% (range: 44-92%) and the CFU-GM recovery is in average of 67,5% (range: 40-89%). At the end of the procedure the cell viability is satisfying (97,1% +/- 1,7 are trypan blue negatives). When it is necessary to remove from the bone marrow collected either malignant cells prior autologous bone marrow graft or T lymphocytes in an attempt to prevent GVHD in allogeneic BMT, the purity of marrow cell suspension become a fundamental parameter.

  11. The Immunology of Melanoma.

    Science.gov (United States)

    Ko, Jennifer S

    2017-09-01

    The relatively high DNA mutational burden in melanoma allows for the creation of potentially "foreign," immune-stimulating neoantigens, and leads to its exceptional immunogenicity. Brisk tumor-infiltrating lymphocytes, a marker of immune editing, confer improved overall survival in melanoma, possibly due to reduced sentinel lymph node spread. Meanwhile, T-cell-stimulating drugs, so-called T-cell checkpoint inhibitors, which reverse peripheral tolerance-dependent tumor escape, have demonstrated unparalleled clinical success in metastatic melanoma. Markers to predict response to immunotherapy are currently imperfect, and the subject of intense research, which will guide the future of ancillary pathologic testing in this setting. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Immunology of BVDV vaccines.

    Science.gov (United States)

    Ridpath, Julia F

    2013-01-01

    Providing acquired immune protection against infection with bovine viral diarrhea viruses (BVDV) is challenging due to the heterogeneity that exists among BVDV strains and the ability of the virus to infect the fetus and establish persistent infections. Both modified live and killed vaccines have been shown to be efficacious under controlled conditions. Both humoral and cellular immune responses are protective. Following natural infection or vaccination with a modified live vaccine, the majority of the B cell response (as measured by serum antibodies) is directed against the viral proteins E2 and NS2/3, with minor responses against the Erns and E1 proteins. Vaccination with killed vaccines results in serum antibodies directed mainly at the E2 protein. It appears that the major neutralizing epitopes are conformational and are located within the N-terminal half of the E2 protein. While it is thought that the E2 and NS2/3 proteins induce protective T cell responses, these epitopes have not been mapped. Prevention of fetal infections requires T and B cell response levels that approach sterilizing immunity. The heterogeneity that exists among circulating BVDV strains, works against establishing such immunity. Vaccination, while not 100% effective in every individual animal, is effective at the herd level. Copyright © 2012. Published by Elsevier Ltd.

  13. Modulation of Central Synapses by Astrocyte-Released ATP and Postsynaptic P2X Receptors

    Science.gov (United States)

    Pankratov, Yuriy

    2017-01-01

    Communication between neuronal and glial cells is important for neural plasticity. P2X receptors are ATP-gated cation channels widely expressed in the brain where they mediate action of extracellular ATP released by neurons and/or glia. Recent data show that postsynaptic P2X receptors underlie slow neuromodulatory actions rather than fast synaptic transmission at brain synapses. Here, we review these findings with a particular focus on the release of ATP by astrocytes and the diversity of postsynaptic P2X-mediated modulation of synaptic strength and plasticity in the CNS. PMID:28845311

  14. Modulation of Central Synapses by Astrocyte-Released ATP and Postsynaptic P2X Receptors

    Directory of Open Access Journals (Sweden)

    Eric Boué-Grabot

    2017-01-01

    Full Text Available Communication between neuronal and glial cells is important for neural plasticity. P2X receptors are ATP-gated cation channels widely expressed in the brain where they mediate action of extracellular ATP released by neurons and/or glia. Recent data show that postsynaptic P2X receptors underlie slow neuromodulatory actions rather than fast synaptic transmission at brain synapses. Here, we review these findings with a particular focus on the release of ATP by astrocytes and the diversity of postsynaptic P2X-mediated modulation of synaptic strength and plasticity in the CNS.

  15. Advances in mechanisms of asthma, allergy, and immunology in 2010.

    Science.gov (United States)

    Broide, David H; Finkelman, Fred; Bochner, Bruce S; Rothenberg, Marc E

    2011-03-01

    2010 was marked by rapid progress in our understanding of the cellular and molecular mechanisms involved in the pathogenesis of allergic inflammation and asthma. Studies published in the Journal of Allergy and Clinical Immunology described advances in our knowledge of cells associated with allergic inflammation (mast cells, eosinophils, dendritic cells, and T cells), as well as IgE, cytokines, receptors, signaling molecules, and pathways. Studies used animal models, as well as human cells and tissues, to advance our understanding of mechanisms of asthma, eosinophilic esophagitis, food allergy, anaphylaxis and immediate hypersensitivity, mast cells and their disorders, atopic dermatitis, nasal polyposis, and hypereosinophilic syndromes. Additional studies provided novel information about the induction and regulation of allergic inflammation and the genetic contribution to allergic inflammation. Critical features of these studies and their potential effects on human atopic disorders are summarized here. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  16. Restoration of the CD4 T cell compartment after long-term highly active antiretroviral therapy without phenotypical signs of accelerated immunological aging

    NARCIS (Netherlands)

    Vrisekoop, Nienke; van Gent, Rogier; de Boer, Anne Bregje; Otto, Sigrid A.; Borleffs, Jan C. C.; Steingrover, Radjin; Prins, Jan M.; Kuijpers, Taco W.; Wolfs, Tom F. W.; Geelen, Sibyl P. M.; Vulto, Irma; Lansdorp, Peter; Tesselaar, Kiki; Borghans, José A. M.; Miedema, Frank

    2008-01-01

    It remains uncertain whether full T cell reconstitution can be established in HIV-infected children and adults with long-term sustained virological control by highly active antiretroviral therapy (HAART). In this study, we comprehensively analyzed various phenotypical markers of CD4 T cell recovery.

  17. Restoration of the CD4 T cell compartment after long-term highly active Antiretroviral therapy without phenotypical signs of accelerated immunological aging

    NARCIS (Netherlands)

    Vrisekoop, Nienke; van Gent, Rogier; de Boer, Anne Bregje; Otto, Sigrid A.; Borleffs, Jan C. C.; Stemgrover, Radjin; Prins, Jan M.; Kuijpers, Taco W.; Wolfs, Tom F. W.; Geelen, Sibyl P. M.; Vulto, Irma; Lansdorp, Peter; Tesselaar, Kiki; Borghans, Jose A. M.; Miedema, Frank

    2008-01-01

    It remains uncertain whether full T cell reconstitution can be established in HIV-infected children and adults with long-term sustained virological control by highly active antiretroviral therapy (HAART). In this study, we comprehensively analyzed various phenotypical markers of CD4 T cell recovery.

  18. Aire Inhibits the Generation of a Perinatal Population of Interleukin-17A-Producing γδ T Cells to Promote Immunologic Tolerance.

    Science.gov (United States)

    Fujikado, Noriyuki; Mann, Alexander O; Bansal, Kushagra; Romito, Kimberly R; Ferre, Elise M N; Rosenzweig, Sergio D; Lionakis, Michail S; Benoist, Christophe; Mathis, Diane

    2016-11-15

    Aire's primary mechanism of action is to regulate transcription of a battery of genes in medullary thymic epithelial cells (mTECs) and, consequently, negative selection of effector T cells and positive selection of regulatory T cells. We found that Aire-deficient mice had expanded thymic and peripheral populations of perinatally generated IL-17A + Vγ6 + Vδ1 + T cells, considered to be "early responders" to tissue stress and drivers of inflammatory reactions. Aire-dependent control of Il7 expression in mTECs regulated the size of thymic IL-17A + Vγ6 + Vδ1 + compartments. In mice lacking Aire and γδ T cells, certain tissues typically targeted in the "Aire-less" disease, notably the retina, were only minimally infiltrated. IL-17A + Vγ6 + Vδ1 + cells were present in the retina of wild-type mice and expanded very early in Aire-deficient mice. A putatively parallel population of IL-17A + Vγ9 + Vδ2 + T cells was increased in humans lacking Aire. Thus, Aire exerts multi-faceted autoimmune control that extends to a population of innate-like T cells. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. A role for dendritic mGluR5-mediated local translation of Arc/Arg3.1 in MEF2-dependent synapse elimination.

    Science.gov (United States)

    Wilkerson, Julia R; Tsai, Nien-Pei; Maksimova, Marina A; Wu, Hao; Cabalo, Nicole P; Loerwald, Kristofer W; Dictenberg, Jason B; Gibson, Jay R; Huber, Kimberly M

    2014-06-12

    Experience refines synaptic connectivity through neural activity-dependent regulation of transcription factors. Although activity-dependent regulation of transcription factors has been well described, it is unknown whether synaptic activity and local, dendritic regulation of the induced transcripts are necessary for mammalian synaptic plasticity in response to transcription factor activation. Neuronal depolarization activates the myocyte enhancer factor 2 (MEF2) family of transcription factors that suppresses excitatory synapse number. We report that activation of metabotropic glutamate receptor 5 (mGluR5) on the dendrites, but not cell soma, of hippocampal CA1 neurons is required for MEF2-induced functional and structural synapse elimination. We present evidence that mGluR5 is necessary for synapse elimination to stimulate dendritic translation of the MEF2 target gene Arc/Arg3.1. Activity-regulated cytoskeletal-associated protein (Arc) is required for MEF2-induced synapse elimination, where it plays an acute, cell-autonomous, and postsynaptic role. This work reveals a role for dendritic activity in local translation of specific transcripts in synapse refinement. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  20. A Role for Dendritic mGluR5-Mediated Local Translation of Arc/Arg3.1 in MEF2-Dependent Synapse Elimination

    Directory of Open Access Journals (Sweden)

    Julia R. Wilkerson

    2014-06-01

    Full Text Available Experience refines synaptic connectivity through neural activity-dependent regulation of transcription factors. Although activity-dependent regulation of transcription factors has been well described, it is unknown whether synaptic activity and local, dendritic regulation of the induced transcripts are necessary for mammalian synaptic plasticity in response to transcription factor activation. Neuronal depolarization activates the myocyte enhancer factor 2 (MEF2 family of transcription factors that suppresses excitatory synapse number. We report that activation of metabotropic glutamate receptor 5 (mGluR5 on the dendrites, but not cell soma, of hippocampal CA1 neurons is required for MEF2-induced functional and structural synapse elimination. We present evidence that mGluR5 is necessary for synapse elimination to stimulate dendritic translation of the MEF2 target gene Arc/Arg3.1. Activity-regulated cytoskeletal-associated protein (Arc is required for MEF2-induced synapse elimination, where it plays an acute, cell-autonomous, and postsynaptic role. This work reveals a role for dendritic activity in local translation of specific transcripts in synapse refinement.

  1. The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome.

    Directory of Open Access Journals (Sweden)

    Hongen Wei

    Full Text Available Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs from Fmr1 knockout (KO mice, a mouse model for fragile X syndrome (FXS and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs.

  2. The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome.

    Science.gov (United States)

    Wei, Hongen; Dobkin, Carl; Sheikh, Ashfaq M; Malik, Mazhar; Brown, W Ted; Li, Xiaohong

    2012-01-01

    Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs) from Fmr1 knockout (KO) mice, a mouse model for fragile X syndrome (FXS) and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs.

  3. Beneficial effects of dietary probiotics mixture on hemato-immunology and cell apoptosis of Labeo rohita fingerlings reared at higher water temperatures.

    Directory of Open Access Journals (Sweden)

    Sipra Mohapatra

    Full Text Available Probiotics play an important role in growth increment, immune enhancement and stress mitigation in fish. Increasing temperature is a major concern in present aquaculture practices as it markedly deteriorates the health condition and reduces the growth in fish. In order to explore the possibilities of using probiotics as a counter measure for temperature associated problems, a 30 days feeding trial was conducted to study the hemato-immunological and apoptosis response of Labeo rohita (8.3±0.4 g reared at different water temperatures, fed with or without dietary supplementation of a probiotic mixture (PM consisting of Bacillus subtilis, Lactococcus lactis and Saccharomyces cerevisiae (1011 cfu kg(-1. Three hundred and sixty fish were randomly distributed into eight treatment groups in triplicates, namely, T1(28°C+BF(Basal feed+PM, T2(31°C+BF+PM, T3(34°C+BF+PM, T4(37°C+BF+PM, T5(28°C+BF, T6(31°C+BF, T7(34°C+BF and T8(37°C+BF. A significant increase (P<0.01 in weight gain percentage was observed in the probiotic fed fish even when reared at higher water temperature (34-37°C. Respiratory burst assay, blood glucose, erythrocyte count, total serum protein, albumin, alkaline phosphatase and acid phosphatase were significantly higher (P<0.01 in the probiotic fed groups compared to the non-probiotic fed groups. A significant (P<0.01 effect of rearing temperature and dietary probiotic mixture on serum myeloperoxidase activity, HSP70 level and immunoglobulin production was observed. Degree of apoptosis in different tissues was also significantly reduced in probiotic-supplemented groups. Hence, the present results show that a dietary PM could be beneficial in enhancing the immune status of the fish and also help in combating the stress caused to the organism by higher rearing water temperature.

  4. Immunological aspects of Graves' disease

    NARCIS (Netherlands)

    B.M. van Ouwerkerk (Marcel)

    1986-01-01

    textabstractAssuming an autoimmune interested to know whether apart from restoring the immunologic parameters. Freshly diagnosed hyperthyroid patients with Graves' disease were all similarly treated with MMI 10 mg t.i.d. and when euthyroidism was achieved, with substitution of thyroid hormone. At

  5. Npas4 Is a Critical Regulator of Learning-Induced Plasticity at Mossy Fiber-CA3 Synapses during Contextual Memory Formation

    DEFF Research Database (Denmark)

    Weng, Feng-Ju; Garcia, Rodrigo I; Lutzu, Stefano

    2018-01-01

    pyramidal cells that were activated by contextual learning and found that MF inputs on these cells were selectively strengthened. Deletion of Npas4 prevented both contextual memory formation and this learning-induced synaptic modification. We further show that Npas4 regulates MF-CA3 synapses by controlling......Synaptic connections between hippocampal mossy fibers (MFs) and CA3 pyramidal neurons are essential for contextual memory encoding, but the molecular mechanisms regulating MF-CA3 synapses during memory formation and the exact nature of this regulation are poorly understood. Here we report...... the expression of the polo-like kinase Plk2. Thus, Npas4 is a critical regulator of experience-dependent, structural, and functional plasticity at MF-CA3 synapses during contextual memory formation....

  6. Synaptically Driven Phosphorylation of Ribosomal Protein S6 Is Differentially Regulated at Active Synapses versus Dendrites and Cell Bodies by MAPK and PI3K/mTOR Signaling Pathways

    Science.gov (United States)

    Pirbhoy, Patricia Salgado; Farris, Shannon; Steward, Oswald

    2017-01-01

    High-frequency stimulation of the medial perforant path triggers robust phosphorylation of ribosomal protein S6 (rpS6) in activated dendritic domains and granule cell bodies. Here we dissect the signaling pathways responsible for synaptically driven rpS6 phosphorylation in the dentate gyrus using pharmacological agents to inhibit PI3-kinase/mTOR…

  7. In vitro formation and activity-dependent plasticity of synapses between Helix neurons involved in the neural control of feeding and withdrawal behaviors.

    Science.gov (United States)

    Fiumara, F; Leitinger, G; Milanese, C; Montarolo, P G; Ghirardi, M

    2005-01-01

    Short-term activity-dependent synaptic plasticity has a fundamental role in short-term memory and information processing in the nervous system. Although the neuronal circuitry controlling different behaviors of land snails of the genus Helix has been characterized in some detail, little is known about the activity-dependent plasticity of synapses between identified neurons regulating specific behavioral acts. In order to study homosynaptic activity-dependent plasticity of behaviorally relevant Helix synapses independently of heterosynaptic influences, we sought to reconstruct them in cell culture. To this aim, we first investigated in culture the factors regulating synapse formation between Helix neurons, and then we studied the short-term plasticity of in vitro-reconstructed monosynaptic connections involved in the neural control of salivary secretion and whole-body withdrawal. We found that independently of extrinsic factors, cell-cell interactions are seemingly sufficient to trigger the formation of electrical and chemical synapses, although mostly inappropriate--in their type or association--with respect to the in vivo synaptic connectivity. The presence of ganglia-derived factors in the culture medium was required for the in vitro reestablishment of the appropriate in vivo-like connectivity, by reducing the occurrence of electrical connections and promoting the formation of chemical excitatory synapses, while apparently not influencing the formation of inhibitory connections. These heat-labile factors modulated electrical and chemical synaptogenesis through distinct protein tyrosine kinase signal transduction pathways. Taking advantage of in vitro-reconstructed synapses, we have found that feeding interneuron-efferent neuron synapses and mechanosensory neuron-withdrawal interneuron synapses display multiple forms of short-term enhancement-like facilitation, augmentation and posttetanic potentiation as well as homosynaptic depression. These forms of plasticity

  8. American Academy of Allergy, Asthma, and Immunology

    Science.gov (United States)

    ... Joint Congress Mark your calendars and head to Orlando for the premier event in allergy/immunology. You ... Of Allergy, Asthma & Immunology Life Spectrum of Asthma Meeting School-based Asthma Management Program – (SAMPRO TM ) This ...

  9. Intensive educational course in allergy and immunology.

    Science.gov (United States)

    Elizalde, A; Perez, E E; Sriaroon, P; Nguyen, D; Lockey, R F; Dorsey, M J

    2012-09-01

    A one-day intensive educational course on allergy and immunology theory and diagnostic procedure significantly increased the competency of allergy and immunology fellows-in-training. © 2012 John Wiley & Sons A/S.

  10. Experimental photoimmunology: immunologic ramifications of UV-induced carcinogenesis

    International Nuclear Information System (INIS)

    Daynes, R.A.; Bernhard, E.J.; Gurish, M.F.; Lynch, D.H.

    1981-01-01

    The use of animal model systems to investigate the sequence of events which lead to the induction and progression of skin tumors following chronic ultraviolet light (UVL) exposure has clearly shown that the direct mutagenic effects of UVL is only one of the components involved in this process. In spite of the fact that overt carcinogenesis is only one of the many effects produced by UV light, most hypotheses as to the mechanism by which UVL can cause the mutations necessary to achieve the transformed phenotype have focused on the direct effects of UVL on DNA and the generation of carcinogenic compounds. Investigations during the last 5 yr, however, have clearly demonstrated that immunologic factors are also critically important in the pathogenesis of UV-induced skin cancers. A complete understanding of UV-carcinogenesis must therefore consider the mechanisms which allow the transformed cell to evade immunologic rejection by the host in addition to those aspects which deal with conversion of a normal cell to a cancer cell. It is the object of this review to provide both a historical account of the work which established the immunologic consequences of chronic UVL exposure and the results of recent experiments designed to investigate the kinetics and mechanisms by which UVL affects the immunologic apparatus. In addition, a hypothetical model is presented to explain the sequence of events which ultimately lead to the emergence of the suppressor T-cells which regulate antitumor immune responses

  11. Polish scientists in fish immunology: a short history : review

    NARCIS (Netherlands)

    Muiswinkel, van W.B.; Pilarczyk, A.

    2015-01-01

    This review describes the role played by Polish scientists in the field of fish immunology and vaccination starting around 1900. In the early days, most publications were dealing with a description of relevant cells and organs in fish. Functional studies (phagocytosis, antibody response) came later

  12. A Yin and Yang in Epithelial Immunology: The Roles of the αE(CD103)β7Integrin in T Cells.

    Science.gov (United States)

    Hardenberg, Jan-Hendrik B; Braun, Andrea; Schön, Michael P

    2018-01-01

    The proper function(s) of cell-surface receptors is crucial for the regulation of adaptive immune responses. One such receptor is the α E (CD103)β 7 integrin, whose history in science is closely linked with the evolution of our knowledge of immune regulation. Initially described as a marker of intraepithelial T-lymphocytes, this leukocyte integrin is now seen as a dynamically regulated receptor involved in the functional differentiation of some cytotoxic T cells as well as regulatory T cells, thus presumably contributing to the fine-tuning of immune reactions in epithelial compartments. In this brief overview, we delineate our current view on α E (CD103)β 7 in T-cell-mediated immune responses. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Ratio of Circulating IFNγ+ “Th17 Cells” in Memory Th Cells Is Inversely Correlated with the Titer of Anti-CCP Antibodies in Early-Onset Rheumatoid Arthritis Patients Based on Flow Cytometry Methods of the Human Immunology Project

    Directory of Open Access Journals (Sweden)

    Shigeru Kotake

    2016-01-01

    Full Text Available Rheumatoid arthritis (RA is a systemic autoimmune disease with chronic joint inflammation characterized by activated T cells. IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. However, it remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we validated the methods of the Human Immunology Project using only the cell-surface marker through measuring the actual expression of IL-17 and IFNγ. We also evaluated the expression of CD161 in human Th17 cells. We then tried to identify Th17 cells, IL-17+Th17 cells, and IFNγ+Th17 cells in the peripheral blood of early-onset RA patients using the standardized method of the Human Immunology Project. Our findings validated the method and the expression of CD161. The ratio of IFNγ+Th17 cells in memory T cells was inversely correlated to the titers of anti-CCP antibodies in the early-onset RA patients. These findings suggest that Th17 cells play important roles in the early phase of RA and that anti-IL-17 antibodies should be administered to patients with early phase RA, especially those with high titers of CCP antibodies.

  14. Characterization of a new cell-bound alpha-amylase in Bacillus subtilis 168 Marburg that is only immunologically related to the exocellular alpha-amylase.

    OpenAIRE

    Haddaoui, E; Petit-Glatron, M F; Chambert, R

    1995-01-01

    Immunoblot analysis of Bacillus subtilis cell extracts with polyclonal antibodies, raised against purified exocellular alpha-amylase, revealed one protein species of 82,000 Da. This protein was found even in cells in which the amyE gene, encoding exocellular alpha-amylase, was disrupted. Isolated from the membrane fraction, the 82,000-M(r) protein displayed an alpha-amylase activity in vitro.

  15. Characterization of a new cell-bound alpha-amylase in Bacillus subtilis 168 Marburg that is only immunologically related to the exocellular alpha-amylase.

    Science.gov (United States)

    Haddaoui, E; Petit-Glatron, M F; Chambert, R

    1995-01-01

    Immunoblot analysis of Bacillus subtilis cell extracts with polyclonal antibodies, raised against purified exocellular alpha-amylase, revealed one protein species of 82,000 Da. This protein was found even in cells in which the amyE gene, encoding exocellular alpha-amylase, was disrupted. Isolated from the membrane fraction, the 82,000-M(r) protein displayed an alpha-amylase activity in vitro. PMID:7665495

  16. [Allergology and clinical immunology].

    Science.gov (United States)

    Coattrenec, Yann; Harr, Thomas; Chizzolini, Carlo; Jandus, Peter

    2018-01-10

    Hereditary angioedema (HA) is a disabling and potentially fatal condition. The management of HA includes treatment of acute attacks, short-term prophylaxis to prevent an attack, and long-term prophylaxis to minimize the frequency and severity of recurrent attacks. In this article, we will present new therapeutic alternatives for long term prophylaxis. Glucocorticoids (GC) usage leads to a number of severe side-effects. In giant cell arteritis, the use of tocilizumab in conjunction with low doses of GC reduces the number of relapses. In ANCA-associated vasculitis the use of an anti-C5R (avacopan) alone or in conjunction with low doses of GC results in similar remission rates to those induced by high dose GC.

  17. A new era in veterinary immunology

    NARCIS (Netherlands)

    Halliwell, R.E.W.; Goudswaard, J.

    1979-01-01

    The importance of the creation of a new international journal of “Veterinary Immunology and Immunopathology” is apparent following the emergence of veterinary immunology as an identifiable discipline and the vital part played by investigations of animal models of immunological diseases of

  18. 42 CFR 493.921 - Diagnostic immunology.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 5 2010-10-01 2010-10-01 false Diagnostic immunology. 493.921 Section 493.921... Testing Proficiency Testing Programs by Specialty and Subspecialty § 493.921 Diagnostic immunology. The subspecialties under the specialty of immunology for which a program may offer proficiency testing are syphilis...

  19. The Immunological Basis of Inflammatory Bowel Disease

    Directory of Open Access Journals (Sweden)

    Francesca A. R. Silva

    2016-01-01

    Full Text Available Inflammatory bowel diseases (IBDs are chronic ailments, Crohn’s disease and ulcerative colitis being the most important. These diseases present an inflammatory profile and they differ according to pathophysiology, the affected area in the gastrointestinal tract, and the depth of the inflammation in the intestinal wall. The immune characteristics of IBD arise from abnormal responses of the innate and adaptive immune system. The number of Th17 cells increases in the peripheral blood of IBD patients, while Treg cells decrease, suggesting that the Th17/Treg proportion plays an important role in the development and maintenance of inflammation. The purpose of this review was to determine the current state of knowledge on the immunological basis of IBD. Many studies have shown the need for further explanation of the development and maintenance of the inflammatory process.

  20. Micro–adhesion rings surrounding TCR microclusters are essential for T cell activation

    Science.gov (United States)

    Sakuma, Machie; Yokosuka, Tadashi

    2016-01-01

    The immunological synapse (IS) formed at the interface between T cells and antigen-presenting cells represents a hallmark of initiation of acquired immunity. T cell activation is initiated at T cell receptor (TCR) microclusters (MCs), in which TCRs and signaling molecules assemble at the interface before IS formation. We found that each TCR-MC was transiently bordered by a ring structure made of integrin and focal adhesion molecules in the early phase of activation, which is similar in structure to the IS in microscale. The micro–adhesion ring is composed of LFA-1, focal adhesion molecules paxillin and Pyk2, and myosin II (MyoII) and is supported by F-actin core and MyoII activity through LFA-1 outside-in signals. The formation of the micro–adhesion ring was transient but especially sustained upon weak TCR stimulation to recruit linker for activation of T cells (LAT) and SLP76. Perturbation of the micro–adhesion ring induced impairment of TCR-MC development and resulted in impaired cellular signaling and cell functions. Thus, the synapse-like structure composed of the core TCR-MC and surrounding micro–adhesion ring is a critical structure for initial T cell activation through integrin outside-in signals. PMID:27354546

  1. Remodeling of Hippocampal Synapses After Hippocampus-Dependent Associative Learning

    NARCIS (Netherlands)

    Geinisman, Yuri; Disterhoft, John F.; Gundersen, Hans Jørgen G.; McEchron, Matthew D.; Persina, Inna S.; Power, John M.; Zee, Eddy A. van der; West, Mark J.

    2000-01-01

    The aim of this study was to determine whether hippocampus-dependent associative learning involves changes in the number and/or structure of hippocampal synapses. A behavioral paradigm of trace eyeblink conditioning was used. Young adult rabbits were given daily 80 trial sessions to a criterion of

  2. Ultralow power artificial synapses using nanotextured magnetic Josephson junctions

    Science.gov (United States)

    Schneider, Michael L.; Donnelly, Christine A.; Russek, Stephen E.; Baek, Burm; Pufall, Matthew R.; Hopkins, Peter F.; Dresselhaus, Paul D.; Benz, Samuel P.; Rippard, William H.

    2018-01-01

    Neuromorphic computing promises to markedly improve the efficiency of certain computational tasks, such as perception and decision-making. Although software and specialized hardware implementations of neural networks have made tremendous accomplishments, both implementations are still many orders of magnitude less energy efficient than the human brain. We demonstrate a new form of artificial synapse based on dynamically reconfigurable superconducting Josephson junctions with magnetic nanoclusters in the barrier. The spiking energy per pulse varies with the magnetic configuration, but in our demonstration devices, the spiking energy is always less than 1 aJ. This compares very favorably with the roughly 10 fJ per synaptic event in the human brain. Each artificial synapse is composed of a Si barrier containing Mn nanoclusters with superconducting Nb electrodes. The critical current of each synapse junction, which is analogous to the synaptic weight, can be tuned using input voltage spikes that change the spin alignment of Mn nanoclusters. We demonstrate synaptic weight training with electrical pulses as small as 3 aJ. Further, the Josephson plasma frequencies of the devices, which determine the dynamical time scales, all exceed 100 GHz. These new artificial synapses provide a significant step toward a neuromorphic platform that is faster, more energy-efficient, and thus can attain far greater complexity than has been demonstrated with other technologies. PMID:29387787

  3. A recipe for ridding synapses of the ubiquitous AMPA receptor.

    Science.gov (United States)

    Turrigiano, Gina G

    2002-12-01

    Getting AMPA receptors into and out of synapses represents an important mechanism for changing synaptic strength, but the signals that target AMPA receptors for removal from the synaptic membrane are incompletely understood. A recent study in Ceanorhabditis elegans suggests that ubiquitination of AMPA receptors is one important signal that targets these receptors for endocytosis.

  4. Sleep: The hebbian reinforcement of the local inhibitory synapses.

    Science.gov (United States)

    Touzet, Claude

    2015-09-01

    Sleep is ubiquitous among the animal realm, and represents about 30% of our lives. Despite numerous efforts, the reason behind our need for sleep is still unknown. The Theory of neuronal Cognition (TnC) proposes that sleep is the period of time during which the local inhibitory synapses (in particular the cortical ones) are replenished. Indeed, as long as the active brain stays awake, hebbian learning guarantees that efficient inhibitory synapses lose their efficiency – just because they are efficient at avoiding the activation of the targeted neurons. Since hebbian learning is the only known mechanism of synapse modification, it follows that to replenish the inhibitory synapses' efficiency, source and targeted neurons must be activated together. This is achieved by a local depolarization that may travel (wave). The period of time during which such slow waves are experienced has been named the "slow-wave sleep" (SWS). It is cut into several pieces by shorter periods of paradoxical sleep (REM) which activity resembles that of the awake state. Indeed, SWS – because it only allows local neural activation – decreases the excitatory long distance connections strength. To avoid losing the associations built during the awake state, these long distance activations are played again during the REM sleep. REM and SWS sleeps act together to guarantee that when the subject awakes again, his inhibitory synaptic efficiency is restored and his (excitatory) long distance associations are still there. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Psychological status and immunological parameters of institutionalized aged.

    Science.gov (United States)

    Bartoloni, C; Guidi, L; Antico, L; Pariante, C M; Di Giovanni, A; Pili, R; Cursi, F; Tricerri, A; Tempesta, E; Frasca, D

    1991-01-01

    In the elderly, an impairment of the immune system could lead to increased incidence of infectious, neoplastic and autoimmune diseases; on the other hand, depression, which is the most common psychiatric problem in aged people, seems to be linked with alterations in immunological function. Thirteen institutionalized elderly subjects were studied to investigate the relationship between depression and immunological parameters. These subjects were selected as "healthy" according to the SENIEUR-EURAGE protocol and they belonged to a population already evaluated by our group--one year before--for psychological, endocrinological and immunological parameters. The lymphocyte mitotic response to PHA was greatly diminished in aged subjects, when compared to the adult controls. Depressed elderly showed impaired immunological function as compared with nondepressed ones, either "in vitro" or "in vivo". Lymphocyte stimulation with phytohemagglutinin (PHA), T cell growth factor (TCGF) production (induced by stimulation with PHA) and cutaneous delayed hypersensitivity (CDH) were reduced in depressed aged subjects. As far as lymphocyte proliferation with PHA in the whole group were concerned, no differences were found comparing the present results with those obtained in a former study. Although it is difficult to understand the significance of the immune imbalance associated with depression in the elderly, our results suggest that psychological status could influence the immunological functions in old people.

  6. Immunological condition in population living near Semipalatinsk tests site

    International Nuclear Information System (INIS)

    Satow, Yukio; Ueda, Masafumi.

    1992-01-01

    This is the brief introduction of the immunological survey at Pavlodar, Kazakhstan SSR, a 300 km away from the Semipalatinsk test site, originally reported by Beysembaev E.A.,Valivach M.N. (Course of Clinical Immunology in Pavlodar Dzerzhynsky str., 166), Molochanov N.E. (Pavlodar Regional Hospital), Kazakav, V.M. (Radiologist Lab. of Regional Sanitary and Epidemiology Station), Ounusov B.A. and Osorodnikova O.P. (Clinical Immunology Centre in Pavlodar). The comparative investigations on (1) 150 preschool age children in Pavlodar before and 6 months after the cessation of nuclear tests, (2) 25 children suffering from frequent respiratory infections before the cessation and 25 analogous children after the cessation, and (3) 69 children (age 1 - 7) and 70 adults (age 28 - 58) inhabitants of Maysky district, where radioactivity is especially high, and 50 children and 50 adults of Pavlodar inhabitants, are reported. Erythrocyte rosette-forming cells, immunoglobulins G, A, and M, etc. are tested. (A.Y.)

  7. Clinical aspects and distribution of immunologically active cells in the nasal mucosa of patients with nasal polyps after endoscopic sinus surgery and treatment with topical corticosteroids.

    Science.gov (United States)

    Stoop, A E; van der Heijden, H A; Biewenga, J; van der Baan, S

    1992-01-01

    Clinical parameters of 72 patients who were operated upon for nasal polyps were evaluated as well as biopsy specimens of the mucosa of the middle and inferior turbinates of 41 of these patients. Biopsies were taken at the time of endoscopic sinus surgery (ESS), after 6 months and after 1 year in 23 patients. During the follow-up period the patients were treated with topical corticosteroids (budesonide). At the time of ESS significantly more CD8+ (suppressor/cytotoxic) cells than CD4+ (helper/inducer) cells were found in the middle and inferior turbinates. At 6 months significantly more CD4+ cells were found than at the time of ESS, whereas at 1 year the number of CD4+ cells had decreased and was lower than at 6 months. These data support the theory that the occurrence of nasal polyps is associated with T-cell-dependent disturbances. Clinical evaluation revealed that most of the patients with chronic airway obstruction had better pulmonary functions postoperatively or required less medication for lung disease. These findings show that ESS combined with topical corticosteroids has a positive effect on upper and lower respiratory tract pathology.

  8. Cerebellar Shank2 Regulates Excitatory Synapse Density, Motor Coordination, and Specific Repetitive and Anxiety-Like Behaviors.

    Science.gov (United States)

    Ha, Seungmin; Lee, Dongwon; Cho, Yi Sul; Chung, Changuk; Yoo, Ye-Eun; Kim, Jihye; Lee, Jiseok; Kim, Woohyun; Kim, Hyosang; Bae, Yong Chul; Tanaka-Yamamoto, Keiko; Kim, Eunjoon

    2016-11-30

    Shank2 is a multidomain scaffolding protein implicated in the structural and functional coordination of multiprotein complexes at excitatory postsynaptic sites as well as in psychiatric disorders, including autism spectrum disorders. While Shank2 is strongly expressed in the cerebellum, whether Shank2 regulates cerebellar excitatory synapses, or contributes to the behavioral abnormalities observed in Shank2 -/- mice, remains unexplored. Here we show that Shank2 -/- mice show reduced excitatory synapse density in cerebellar Purkinje cells in association with reduced levels of excitatory postsynaptic proteins, including GluD2 and PSD-93, and impaired motor coordination in the Erasmus test. Shank2 deletion restricted to Purkinje cells (Pcp2-Cre;Shank2 fl/fl mice) leads to similar reductions in excitatory synapse density, synaptic protein levels, and motor coordination. Pcp2-Cre;Shank2 fl/fl mice do not recapitulate autistic-like behaviors observed in Shank2 -/- mice, such as social interaction deficits, altered ultrasonic vocalizations, repetitive behaviors, and hyperactivity. However, Pcp2-Cre;Shank2 fl/fl mice display enhanced repetitive behavior in the hole-board test and anxiety-like behavior in the light-dark test, which are not observed in Shank2 -/- mice. These results implicate Shank2 in the regulation of cerebellar excitatory synapse density, motor coordination, and specific repetitive and anxiety-like behaviors. The postsynaptic side of excitatory synapses contains multiprotein complexes, termed the postsynaptic density, which contains receptors, scaffolding/adaptor proteins, and signaling molecules. Shank2 is an excitatory postsynaptic scaffolding protein implicated in the formation and functional coordination of the postsynaptic density and has been linked to autism spectrum disorders. Using Shank2-null mice and Shank2-conditional knock-out mice with a gene deletion restricted to cerebellar Purkinje cells, we explored functions of Shank2 in the cerebellum

  9. Effects of hypergravity on immunologic function

    Science.gov (United States)

    Sonnenfeld, G.; Koebel, D. A.; Davis, S.

    1995-01-01

    The purpose of this study was to compare the effects of hypergravity exposure (2g) with those of exposure to space flight in the Cosmos 2044 flight. To do so, rats were centrifuged continuously for 14 days. Two different experiments were carried out on tissue obtained from the centrifuged rats. In the first experiment, rat bone marrow cells were examined for their response to recombinant murine colony stimulating factor-granulocyte/monocyte (GM-CSF). In the second experiment, rat spleen and bone marrow cells were stained in with a variety of antibodies directed against cell surface antigenic markers. These cells were preserved and analyzed on a flow cytometer. The results of the studies indicated that bone marrow cells from centrifuged rats showed no significant change in response to GM-CSF as compared to bone marrow cells from control rats. Spleen cells from flown rats showed some statistically significant changes in leukocytes subset distribution, but no differences that appeared to be of biological significance. These results indicate that hypergravity did not greatly affect the same immunological parameters affected by space flight in the Cosmos 2044 mission.

  10. Phosphatidylinositol 4-phosphate 5-kinases in the regulation of T cell activation

    Directory of Open Access Journals (Sweden)

    Loretta eTuosto

    2016-05-01

    Full Text Available Phosphatidylinositol 4,5-biphosphate kinases (PIP5K are critical regulators of T cell activation being the main enzymes involved in the synthesis of phosphatidylinositol 4,5-biphosphate (PIP2. PIP2 is indeed a pivotal regulator of the actin cytoskeleton, thus controlling T cell polarization and migration, stable adhesion to antigen presenting cells (APC, spatial organization of the immunological synapse (IS, and costimulation. Moreover, PIP2 serves also as a precursor for the second messengers inositol triphosphate (IP3, diacylglycerol (DAG and phosphatidylinositol 3,4,5-triphosphate (PIP3, which are essential for the activation of signalling pathways regulating cytokine production, cell cycle progression, survival, metabolism and differentiation. Here, we discuss the impact of PIP5Ks on several T lymphocyte functions with a specific focus on the role of CD28 co-stimulation in PIP5K compartimentalization and activation.

  11. Analog Memristive Synapse in Spiking Networks Implementing Unsupervised Learning

    Science.gov (United States)

    Covi, Erika; Brivio, Stefano; Serb, Alexander; Prodromakis, Themis; Fanciulli, Marco; Spiga, Sabina

    2016-01-01

    Emerging brain-inspired architectures call for devices that can emulate the functionality of biological synapses in order to implement new efficient computational schemes able to solve ill-posed problems. Various devices and solutions are still under investigation and, in this respect, a challenge is opened to the researchers in the field. Indeed, the optimal candidate is a device able to reproduce the complete functionality of a synapse, i.e., the typical synaptic process underlying learning in biological systems (activity-dependent synaptic plasticity). This implies a device able to change its resistance (synaptic strength, or weight) upon proper electrical stimuli (synaptic activity) and showing several stable resistive states throughout its dynamic range (analog behavior). Moreover, it should be able to perform spike timing dependent plasticity (STDP), an associative homosynaptic plasticity learning rule based on the delay time between the two firing neurons the synapse is connected to. This rule is a fundamental learning protocol in state-of-art networks, because it allows unsupervised learning. Notwithstanding this fact, STDP-based unsupervised learning has been proposed several times mainly for binary synapses rather than multilevel synapses composed of many binary memristors. This paper proposes an HfO2-based analog memristor as a synaptic element which performs STDP within a small spiking neuromorphic network operating unsupervised learning for character recognition. The trained network is able to recognize five characters even in case incomplete or noisy images are displayed and it is robust to a device-to-device variability of up to ±30%. PMID:27826226

  12. Emerging immunological drugs for chronic lymphocytic leukemia.

    Science.gov (United States)

    Robak, Pawel; Smolewski, Piotr; Robak, Tadeusz

    2015-09-01

    Over the last few years, several new immunological drugs, particularly monoclonal antibodies (mAbs), immunomodulatory drugs and B-cell receptor (BCR) pathway inhibitors have been developed and investigated in chronic lymphocytic leukemia (CLL). This article summarizes recent discoveries regarding their mechanism of action, pharmacological properties, clinical activity and toxicity, as well as the emerging role of these agents in CLL. A literature review of mAbs, BCR pathway inhibitors and immunomodulating drugs was conducted of the MEDLINE database via PubMed for articles in English. Publications from 2000 through February 2015 were scrutinized. The search terms used were alemtuzumab, BI 836826, duvelisib ibrutinib, idelalisib, lenalidomide, monoclonal antibodies, MEDI-551, MOR208, obinutuzumab, ocaratuzumab, ofatumumab, ONO-4059, otlertuzumab, spebrutinib, veltuzumab and XmAb5574 in conjunction with CLL. Conference proceedings from the previous 5 years of the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, and ACR/ARHP Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. The use of mAbs, BCR inhibitors and immunomodulating drugs is a promising new strategy for chemotherapy-free treatment of CLL. However, definitive data from ongoing and future clinical trials will aid in better defining the status of immunological drugs in the treatment of this disease.

  13. Blockade of IDO-kynurenine-AhR metabolic circuitry abrogates IFN-γ-induced immunologic dormancy of tumor-repopulating cells

    Science.gov (United States)

    Liu, Yuying; Liang, Xiaoyu; Yin, Xiaonan; Lv, Jiadi; Tang, Ke; Ma, Jingwei; Ji, Tiantian; Zhang, Huafeng; Dong, Wenqian; Jin, Xun; Chen, Degao; Li, Yanchun; Zhang, Songyan; Xie, Heidi Q.; Zhao, Bin; Zhao, Tong; Lu, Jinzhi; Hu, Zhuo-Wei; Cao, Xuetao; Qin, F. Xiao-Feng; Huang, Bo

    2017-01-01

    Interactions with the immune system may lead tumorigenic cells into dormancy. However, the underlying molecular mechanism is poorly understood. Using a 3D fibrin gel model, we show that IFN-γ induces tumour-repopulating cells (TRCs) to enter dormancy through an indolamine 2,3-dioxygenase 1 (IDO1)-kynurenine (Kyn)-aryl hydrocarbon receptor (AhR)-p27 dependent pathway. Mechanistically, IFN-γ signalling triggers differentiated tumour cell apoptosis via STAT1; however, when IDO1 and AhR are highly expressed as in TRCs, IFN-γ results in IDO1/AhR-dependent p27 induction that prevents STAT1 signalling, thus suppressing the process of cell death and activating the dormancy program. Blocking the IDO/AhR metabolic circuitry not only abrogates IFN-γ-induced dormancy but also results in enhanced repression of tumour growth by IFN-γ-induced apoptosis of TRCs both in vitro and in vivo. These data present a previously unrecognized mechanism of inducing TRC dormancy by IFN-γ, suggesting a potential effective cancer immunotherapeutic modality through the combination of IFN-γ and IDO/AhR inhibitors. PMID:28488695

  14. Current status of immunologic studies in human lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Gross, R.L.

    1978-06-01

    Several aspects of the immunology of human malignancy are reviewed, with particular emphasis on relevant findings in lung cancer. The existence of tumor-specific cell-mediated immune responses in patients with cancer has been demonstrated in numerous tumor types. Of more relevance in clinical situations is the association of generalized immunologic depression with malignancy. In the vast majority of cases, progressive declines in both tumor-specific and nonspecific immunologic parameters are observed with advancing disease. The approach to the immunologic evaluation of cancer patients and the potential usefulness of this approach to the diagnosis, prognosis, management, and assessment of therapeutic response are discussed. Evidence aimed at elucidating the mechanism of immunosuppression in malignancy, such as serum-blocking factors, immunoregulatory alpha globulins, and suppressor cells, is presented. Finally, emphasis is placed on the various forms of immunotherapy, including both specific active methods such as tumor cell or tumor antigen vaccines and nonspecific active immunotherapy involving agents like Bacillus Calmette-Guerin and levamisole. Early results from clinical immunotherapeutic trials are discussed.

  15. Immunologic assessment of patients with pulmonary metaplasia and neoplasia

    International Nuclear Information System (INIS)

    Gross, R.L.; Saccomanno, G.; Smith, D.M.; Saunders, R.; Thomas, R.G.

    1979-01-01

    Immune profiles have been obtained on 206 individuals including 57 controls, 50 lung cancer patients, and 99 uranium miners with well-defined sputum cytologies ranging from normal to carcinoma in situ. Little effect of smoking, uranium mining or a combination of mining plus smoking on immune function was observed if sputum cytology was normal. In heavy smokers there was a suggestion that total T cells are increased while T cell function is slightly depressed. Immunologic abnormalities were noted in the moderate atypia group where 40% had one or more abnormal immunologic parameters. Immunologic abnormalities were detected in 68 to 70 patients with marked atypia, carcinoma in situ, or invasive carcinoma. Further sequential study of the uranium miner population is necessary to define more precisely the predictive value of immunologic testing, and the role of early identification of high risk individuals in the early institution of definitive therapy, such as surgery or immunotherapy. Long-term prospective analysis of this population may also provide the answer to the question of whether alterations in immune function precede, or result from the appearance of cells committed to the development of neoplasia

  16. IMMUNOLOGICAL ASPECTS OF OBESITY

    Directory of Open Access Journals (Sweden)

    Z. R. Gusova

    2015-01-01

    Full Text Available Background: At present, convincing data on the role of immune system in pathophysiology of obesity are lacking, which makes it necessary to investigate this issue. Aim: To assess metabolic status and characteristics of immune system in patients with overweight and morbid obesity.Materials and methods: One hundred and ninety two patients with overweight and advanced obesity (mean body mass index (BMI 36.8 ± 7.3 kg/m. aged from 19 to 55 years were recruited in to the study. Depending on the grade of obesity, the patients