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Sample records for lymphocyte function-associated antigen-1

  1. Involvement of lymphocyte function-associated antigen-1 (LFA-1) in HIV infection: inhibition by monoclonal antibody

    DEFF Research Database (Denmark)

    Hansen, J E; Nielsen, C; Mathiesen, Lars Reinhardt

    1991-01-01

    Monoclonal antibodies (MAbs) against the alpha- and beta-chain of lymphocyte-associated antigen-1 (LFA-1) were examined for inhibition of HIV-1 infection in vitro. Infection of the T cell line MT4 and the monocytic cell line U937 by isolates HTLVIIIB and SSI-002, respectively was inhibited...

  2. Involvement of lymphocyte function-associated antigen-1 (LFA-1) in HIV infection: inhibition by monoclonal antibody

    DEFF Research Database (Denmark)

    Hansen, J E; Nielsen, C; Mathiesen, Lars Reinhardt

    1991-01-01

    Monoclonal antibodies (MAbs) against the alpha- and beta-chain of lymphocyte-associated antigen-1 (LFA-1) were examined for inhibition of HIV-1 infection in vitro. Infection of the T cell line MT4 and the monocytic cell line U937 by isolates HTLVIIIB and SSI-002, respectively was inhibited...

  3. Involvement of lymphocyte function-associated antigen-1 (LFA-1) in HIV infection: inhibition by monoclonal antibody

    DEFF Research Database (Denmark)

    Hansen, J E; Nielsen, C; Mathiesen, Lars Reinhardt;

    1991-01-01

    Monoclonal antibodies (MAbs) against the alpha- and beta-chain of lymphocyte-associated antigen-1 (LFA-1) were examined for inhibition of HIV-1 infection in vitro. Infection of the T cell line MT4 and the monocytic cell line U937 by isolates HTLVIIIB and SSI-002, respectively was inhibited...... in a concentration dependent manner by MAb against the beta-chain but not against the alpha-chain. No cross-reactivity was found between MAb against LFA-1 and against the CD4 receptor (MAb Leu3a). MAbs against the beta-chain and the CD4 receptor were found to act synergistically in inhibiting HIV infection....... These data indicate that the beta-chain of LFA-1 in addition to the CD4 receptor may be involved in HIV infection in vitro....

  4. The wild boar (Sus scrofa Lymphocyte function-associated antigen-1 (CD11a/CD18 receptor: cDNA sequencing, structure analysis and comparison with homologues

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    Bergh Philippe

    2007-10-01

    Full Text Available Abstract Background The most predominant beta2-integrin lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18, alphaLbeta2, expressed on all leukocytes, is essential for many adhesive functions of the immune system. Interestingly, RTX toxin-producing bacteria specifically target this leukocyte beta2-integrin which exacerbates lesions and disease development. Results This study reports the sequencing of the wild boar beta2-integrin CD11a and CD18 cDNAs. Predicted CD11a and CD18 subunits share all the main structural characteristics of their mammalian homologues, with a larger interspecies conservation for the CD18 than the CD11a. Besides these strong overall similarities, wild boar and domestic pig LFA-1 differ by 2 (CD18 and 1 or 3 (CD11a substitutions, of which one is located in the crucial I-domain (CD11a, E168D. Conclusion As most wild boars are seropositive to the RTX toxin-producing bacterium Actinobacillus pleuropneumoniae and because they have sustained continuous natural selection, future studies addressing the functional impact of these polymorphisms could bring interesting new information on the physiopathology of Actinobacillus pleuropneumoniae-associated pneumonia in domestic pigs.

  5. The CD11a partner in Sus scrofa lymphocyte function-associated antigen-1 (LFA-1: mRNA cloning, structure analysis and comparison with mammalian homologues

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    Thomas Anne VT

    2005-10-01

    Full Text Available Abstract Background Lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18, alphaLbeta2, the most abundant and widely expressed beta2-integrin, is required for many cellular adhesive interactions during the immune response. Many studies have shown that LFA-1 is centrally involved in the pathogenesis of several diseases caused by Repeats-in-toxin (RTX -producing bacteria. Results The porcine-LFA-1 CD11a (alpha subunit coding sequence was cloned, sequenced and compared with the available mammalian homologues in this study. Despite some focal differences, it shares all the main characteristics of these latter. Interestingly, as in sheep and humans, an allelic variant with a triplet insertion resulting in an additional Gln-744 was consistently identified, which suggests an allelic polymorphism that might be biologically relevant. Conclusion Together with the pig CD18-encoding cDNA, which has been available for a long time, the sequence data provided here will allow the successful expression of porcine CD11a, thus giving the first opportunity to express the Sus scrofa beta2-integrin LFA-1 in vitro as a tool to examine the specificities of inflammation in the porcine species.

  6. CD226 (DNAM-1) is involved in lymphocyte function-associated antigen 1 costimulatory signal for naive T cell differentiation and proliferation.

    Science.gov (United States)

    Shibuya, Kazuko; Shirakawa, Jun; Kameyama, Tomie; Honda, Shin-Ichiro; Tahara-Hanaoka, Satoko; Miyamoto, Akitomo; Onodera, Masafumi; Sumida, Takayuki; Nakauchi, Hiromitsu; Miyoshi, Hiroyuki; Shibuya, Akira

    2003-12-15

    Upon antigen recognition by the T cell receptor, lymphocyte function-associated antigen 1 (LFA-1) physically associates with the leukocyte adhesion molecule CD226 (DNAM-1) and the protein tyrosine kinase Fyn. We show that lentiviral vector-mediated mutant (Y-F322) CD226 transferred into naive CD4+ helper T cells (Ths) inhibited interleukin (IL)-12-independent Th1 development initiated by CD3 and LFA-1 ligations. Moreover, proliferation induced by LFA-1 costimulatory signal was suppressed in mutant (Y-F322) CD226-transduced naive CD4+ and CD8+ T cells in the absence of IL-2. These results suggest that CD226 is involved in LFA-1-mediated costimulatory signals for triggering naive T cell differentiation and proliferation. We also demonstrate that although LFA-1, CD226, and Fyn are polarized at the immunological synapse upon stimulation with anti-CD3 in CD4+ and CD8+ T cells, lipid rafts are polarized in CD4+, but not CD8+, T cells. Moreover, proliferation initiated by LFA-1 costimulatory signal is suppressed by lipid raft disruption in CD4+, but not CD8+, T cells, suggesting that the LFA-1 costimulatory signal is independent of lipid rafts in CD8+ T cells.

  7. The CC chemokine thymus-derived chemotactic agent 4 (TCA-4, secondary lymphoid tissue chemokine, 6Ckine, exodus-2) triggers lymphocyte function-associated antigen 1-mediated arrest of rolling T lymphocytes in peripheral lymph node high endothelial venules.

    Science.gov (United States)

    Stein, J V; Rot, A; Luo, Y; Narasimhaswamy, M; Nakano, H; Gunn, M D; Matsuzawa, A; Quackenbush, E J; Dorf, M E; von Andrian, U H

    2000-01-03

    T cell homing to peripheral lymph nodes (PLNs) is defined by a multistep sequence of interactions between lymphocytes and endothelial cells in high endothelial venules (HEVs). After initial tethering and rolling via L-selectin, firm adhesion of T cells requires rapid upregulation of lymphocyte function-associated antigen 1 (LFA-1) adhesiveness by a previously unknown pathway that activates a Galpha(i)-linked receptor. Here, we used intravital microscopy of murine PLNs to study the role of thymus-derived chemotactic agent (TCA)-4 (secondary lymphoid tissue chemokine, 6Ckine, Exodus-2) in homing of adoptively transferred T cells from T-GFP mice, a transgenic strain that expresses green fluorescent protein (GFP) selectively in naive T lymphocytes (T(GFP) cells). TCA-4 was constitutively presented on the luminal surface of HEVs, where it was required for LFA-1 activation on rolling T(GFP) cells. Desensitization of the TCA-4 receptor, CC chemokine receptor 7 (CCR7), blocked T(GFP) cell adherence in wild-type HEVs, whereas desensitization to stromal cell-derived factor (SDF)-1alpha (the ligand for CXC chemokine receptor 4 [CXCR4]) did not affect T(GFP) cell behavior. TCA-4 protein was not detected on the luminal surface of PLN HEVs in plt/plt mice, which have a congenital defect in T cell homing to PLNs. Accordingly, T(GFP) cells rolled but did not arrest in plt/plt HEVs. When TCA-4 was injected intracutaneously into plt/plt mice, the chemokine entered afferent lymph vessels and accumulated in draining PLNs. 2 h after intracutaneous injection, luminal presentation of TCA-4 was detectable in a subset of HEVs, and LFA-1-mediated T(GFP) cell adhesion was restored in these vessels. We conclude that TCA-4 is both required and sufficient for LFA-1 activation on rolling T cells in PLN HEVs. This study also highlights a hitherto undocumented role for chemokines contained in afferent lymph, which may modulate leukocyte recruitment in draining PLNs.

  8. Physical and functional association between thymic shared antigen-1/stem cell antigen-2 and the T cell receptor complex.

    Science.gov (United States)

    Kosugi, A; Saitoh, S; Noda, S; Miyake, K; Yamashita, Y; Kimoto, M; Ogata, M; Hamaoka, T

    1998-05-15

    Thymic shared antigen-1 (TSA-1)/stem cell Ag-2 (Sca-2) is a glycosylphosphatidylinositol (GPI)-anchored antigen expressed on lymphocytes. We have previously demonstrated that a signal via TSA-1/Sca-2 inhibits T cell receptor (TCR)-mediated T cell activation and apoptosis. To elucidate a molecular mechanism for TSA-1-mediated modulation of the TCR-signaling pathway, we examined whether TSA-1 is physically coupled to the TCR in the present study. TSA-1 was clearly associated with CD3zeta chains in T cell hybridomas, activated T cells, and COS-7 cells transfected with TSA-1 and CD3zeta cDNA. The physical association was confirmed on the surface of T cells in immunoprecipitation and confocal microscopy. The analysis using stable and transient transfectants expressing a transmembrane form of TSA-1 revealed that the association of CD3zeta did not require the GPI anchor of TSA-1. Finally, tyrosine phosphorylation of CD3zeta chains was induced after stimulation with anti-TSA-1, suggesting that a functional association between these two molecules also exists. These results imply that the physical association to CD3zeta underlies a regulatory role of TSA-1/Sca-2 in the TCR-signaling pathway.

  9. Stereoselectivity of isoflurane in adhesion molecule leukocyte function-associated antigen-1.

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    Weiming Bu

    Full Text Available BACKGROUND: Isoflurane in clinical use is a racemate of S- and R-isoflurane. Previous studies have demonstrated that the effects of S-isoflurane on relevant anesthetic targets might be modestly stronger (less than 2-fold than R-isoflurane. The X-ray crystallographic structure of the immunological target, leukocyte function-associated antigen-1 (LFA-1 with racemic isoflurane suggested that only S-isoflurane bound specifically to this protein. If so, the use of specific isoflurane enantiomers may have advantage in the surgical settings where a wide range of inflammatory responses is expected to occur. Here, we have further tested the hypothesis that isoflurane enantioselectivity is apparent in solution binding and functional studies. METHODS: First, binding of isoflurane enantiomers to LFA-1 was studied using 1-aminoanthracene (1-AMA displacement assays. The binding site of each enantiomer on LFA-1 was studied using the docking program GLIDE. Functional studies employed the flow-cytometry based ICAM binding assay. RESULTS: Both enantiomers decreased 1-AMA fluorescence signal (at 520 nm, indicating that both competed with 1-AMA and bound to the αL I domain. The docking simulation demonstrated that both enantiomers bound to the LFA-1 "lovastatin site." ICAM binding assays showed that S-isoflurane inhibited more potently than R-isoflurane, consistent with the result of 1-AMA competition assay. CONCLUSIONS: In contrast with the x-ray crystallography, both enantiomers bound to and inhibited LFA-1. S-isoflurane showed slight preference over R-isoflurane.

  10. 淋巴细胞功能相关抗原-1调节Treg细胞对炎症性肠病的影响%Effect of Lymphocyte Function-associated Antigen-1 on Inflammatory Bowel Disease by Regulating Treg Cells

    Institute of Scientific and Technical Information of China (English)

    姚仁玲; 邹晓平; 于成功

    2013-01-01

    背景:Treg细胞在炎症性肠病(IBD)中主要发挥免疫保护作用,淋巴细胞功能相关抗原-1(LFA-1)参与了Treg细胞的分化和功能发挥.目的:探讨LFA-1调节Treg细胞对IBD的影响,明确LFA-1在IBD发生中的作用.方法:将LFA-1基因缺失小鼠和相同遗传背景野生型小鼠各20只分别随机分为对照组和炎症组,炎症组以饮用4.5%DSS溶液诱导结肠炎模型.观察各组小鼠一般情况和结肠组织学表现,流式细胞术检测外周血CD4+、Treg细胞比例,real time PCR检测结肠组织Foxp3 mRNA表达,ELISA法检测血清IL-17A、TGF-β1、IL-10水平.结果:LFA-1缺失炎症组实验过程中有2只小鼠死于消化道出血,体质量下降较野生型炎症组显著.LFA-1基因缺失小鼠外周血CD4+、Treg细胞比例低于野生型小鼠,其中LFA-1缺失炎症组伴TGF-β1、IL-10分泌减少;LFA-1缺失炎症组与野生型炎症组间外周血Treg细胞比例无明显差异.野生型和LFA-1缺失炎症组血清IL-17A、TGF-β1、IL-10水平和结肠组织Foxp3 mRNA表达均高于相应对照组.结论:LFA-1参与了IBD时Treg细胞的分化和迁移.LFA-1基因缺失小鼠对DSS结肠炎的耐受性差于野生型小鼠,可能与其Treg细胞分化和相关细胞因子分泌受到影响有关.%Background:It has been widely accepted that Treg cells exert an immunoprotective effect in inflammatory bowel disease (IBD),and lymphocyte function-associated antigen-1 (LFA-1) is involved in the differentiation and suppressor function of Treg cells.Aims:To investigate the effect of LFA-1 on IBD by regulating Treg cells and verify the role of LFA1 in the pathogenesis of IBD.Methods:Twenty LFA-1 gene knockout (LFA-1-/-) mice and 20 wild type mice with same genetic background were randomly divided into control group and colitis group,respectively.Colitis model was induced by drinking 4.5 % DSS solution.General condition and histology of the colon were observed in each group.Percentages of CD4 + and

  11. 肾移植受者外周血白细胞淋巴细胞功能相关抗原-1表达的意义%Clinical significance of peripheral blood leukocyte and lymphocyte function-associated antigen-1 expression in renal allograft recipients

    Institute of Scientific and Technical Information of China (English)

    白寒; 潘光辉; 蒋立城

    2000-01-01

    目的 监测肾移植前、后外周血白细胞淋巴细胞功能相关抗原-1(LFA-1)的表达水平,了解其变化规律,探讨其在肾移植排斥反应中的意义.方法 应用单克隆抗体-流式细胞仪荧光抗体技术监测肾移植受者外周血白细胞的LFA-1表达水平.结果 肾移植术后LFA-1表达水平较术前显著降低,并维持在低水平,发生排斥反应时显著升高;排斥时的LFA-1表达水平与术后无排斥时及排斥反应控制后比较,差异有显著性,与术前比较,差异无显著性.结论 LFA-1在白细胞上的表达与排斥反应密切相关;监测LFA-1的表达水平有助于肾移植排斥反应的诊断.%Objectives To inspect the levels of peripheral blood leukocyte and lymphocyte functionassociated antigen-1(LFA-1)expression in renaI allograft recipients before and after renal transplantation.Methods Using monoclonal antibody-flow cytometer fluorescence technique,the expression of LFA-1 in lymphocytes of 33 patients with renal transplantation was detected at 1 day before operation and 3,6,9,15 days after operation by flow cytometric immunological technique,Results The level of LFA-1 expression after transplantation was significantly decreased and maintained at a low level.and ascended suddenly during the course of graft rejection.The level of LFA-1 expression in rejection was obviously higher than in non-rejection and after the eontrollring of rejection.Conclusions LFA-1 might Dlay an important role in graft rejection.Monitoring of the expression of LFA-1 is helpful for the diagnosis of the graft rejection.

  12. Propofol Shares the Binding Site with Isoflurane and Sevoflurane on Leukocyte Function-Associated Antigen-1

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    Yuki, Koichi; Bu, Weiming; Xi, Jin; Shimaoka, Motomu; Eckenhoff, Roderic

    2013-01-01

    Background We previously demonstrated that propofol interacted with the leukocyte adhesion molecule leukocyte function–associated antigen-1 (LFA-1) and inhibited the production of interleukin-2 via LFA-1 in a dependent manner. However, the binding site(s) of propofol on LFA-1 remains unknown. Methods First, the inhibition of LFA-1's ligand binding by propofol was confirmed in an ELISA-type assay. The binding site of propofol on LFA-1 was probed with a photolabeling experiment using a photoactivatable propofol analog called azi-propofol-m. The adducted residues of LFA-1 by this compound were determined using liquid chromatography–mass spectrometry. In addition, the binding of propofol to the ligand-binding domain of LFA-1 was examined using 1-aminoanthracene (1-AMA) displacement assay. Furthermore, the binding site(s) of 1-AMA and propofol on LFA-1 was studied using the docking program GLIDE. Results We demonstrated that propofol impaired the binding of LFA-1 to its ligand intercellular adhesion molecule-1. The photolabeling experiment demonstrated that the adducted residues were localized in the allosteric cavity of the ligand-binding domain of LFA-1 called “lovastatin site. ” The shift of fluorescence spectra was observed when 1-AMA was coincubated with the low-affinity conformer of LFA-1 ligand-binding domain (wild-type [WT] αL I domain), not with the high-affinity conformer, suggesting that 1-AMA bound only to WT αL I domain. In the 1-AMA displacement assay, propofol decreased 1-AMA fluorescence signal (at 520 nm), suggesting that propofol competed with 1-AMA and bound to the WT αL I domain. The docking simulation demonstrated that both 1-AMA and propofol bound to the lovastatin site, which agreed with the photolabeling experiment. Conclusions We demonstrated that propofol bound to the lovastatin site in LFA-1. Previously we showed that the volatile anesthetics isoflurane and sevoflurane bound to this site. Taken together, the lovastatin site is an

  13. FRET based quantification and screening technology platform for the interactions of leukocyte function-associated antigen-1 (LFA-1 with intercellular adhesion molecule-1 (ICAM-1.

    Directory of Open Access Journals (Sweden)

    Sandeep Chakraborty

    Full Text Available The interaction between leukocyte function-associated antigen-1(LFA-1 and intercellular adhesion molecule-1 (ICAM-1 plays a pivotal role in cellular adhesion including the extravasation and inflammatory response of leukocytes, and also in the formation of immunological synapse. However, irregular expressions of LFA-1 or ICAM-1 or both may lead to autoimmune diseases, metastasis cancer, etc. Thus, the LFA-1/ICAM-1 interaction may serve as a potential therapeutic target for the treatment of these diseases. Here, we developed one simple 'in solution' steady state fluorescence resonance energy transfer (FRET technique to obtain the dissociation constant (Kd of the interaction between LFA-1 and ICAM-1. Moreover, we developed the assay into a screening platform to identify peptides and small molecules that inhibit the LFA-1/ICAM-1 interaction. For the FRET pair, we used Alexa Fluor 488-LFA-1 conjugate as donor and Alexa Fluor 555-human recombinant ICAM-1 (D1-D2-Fc as acceptor. From our quantitative FRET analysis, the Kd between LFA-1 and D1-D2-Fc was determined to be 17.93±1.34 nM. Both the Kd determination and screening assay were performed in a 96-well plate platform, providing the opportunity to develop it into a high-throughput assay. This is the first reported work which applies FRET based technique to determine Kd as well as classifying inhibitors of the LFA-1/ICAM-1 interaction.

  14. SHARPIN Regulates Uropod Detachment in Migrating Lymphocytes

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    Jeroen Pouwels

    2013-11-01

    Full Text Available SHARPIN-deficient mice display a multiorgan chronic inflammatory phenotype suggestive of altered leukocyte migration. We therefore studied the role of SHARPIN in lymphocyte adhesion, polarization, and migration. We found that SHARPIN localizes to the trailing edges (uropods of both mouse and human chemokine-activated lymphocytes migrating on intercellular adhesion molecule-1 (ICAM-1, which is one of the major endothelial ligands for migrating leukocytes. SHARPIN-deficient cells adhere better to ICAM-1 and show highly elongated tails when migrating. The increased tail lifetime in SHARPIN-deficient lymphocytes decreases the migration velocity. The adhesion, migration, and uropod defects in SHARPIN-deficient lymphocytes were rescued by reintroducing SHARPIN into the cells. Mechanistically, we show that SHARPIN interacts directly with lymphocyte-function-associated antigen-1 (LFA-1, a leukocyte counterreceptor for ICAM-1, and inhibits the expression of intermediate and high-affinity forms of LFA-1. Thus, SHARPIN controls lymphocyte migration by endogenously maintaining LFA-1 inactive to allow adjustable detachment of the uropods in polarized cells.

  15. Vaccination with Trypomastigote Surface Antigen 1-Encoding Plasmid DNA Confers Protection against Lethal Trypanosoma cruzi Infection

    OpenAIRE

    1998-01-01

    DNA vaccination was evaluated with the experimental murine model of Trypanosoma cruzi infection as a means to induce antiparasite protective immunity, and the trypomastigote surface antigen 1 (TSA-1), a target of anti-T. cruzi antibody and major histocompatibility complex (MHC) class I-restricted CD8+ cytotoxic T-lymphocyte (CTL) responses, was used as the model antigen. Following the intramuscular immunization of H-2b and H-2d mice with a plasmid DNA encoding an N-terminally truncated TSA-1 ...

  16. Specific T-cell recognition of the merozoite proteins rhoptry-associated protein 1 and erythrocyte-binding antigen 1 of Plasmodium falciparum

    DEFF Research Database (Denmark)

    Jakobsen, P H; Hviid, L; Theander, T G;

    1993-01-01

    The merozoite proteins merozoite surface protein 1 (MSP-1) and rhoptry-associated protein 1 (RAP-1) and synthetic peptides containing sequences of MSP-1, RAP-1, and erythrocyte-binding antigen 1, induced in vitro proliferative responses of lymphocytes collected from Ghanaian blood donors living...

  17. Role of very late antigen-1 in T-cell-mediated immunity to systemic viral infection

    DEFF Research Database (Denmark)

    Ørding Kauffmann, Susanne; Thomsen, Allan Randrup; Christensen, Jan Pravsgaard

    2006-01-01

    The T-cell response to lymphocytic choriomeningitis virus was studied in mice lacking very late antigen-1 (VLA-1). The generation of virus-specific effector T cells was unimpaired in VLA-1(-/-) mice. In the memory phase, VLA-1 deficiency did not influence the number of memory CD8(+) T cells or th......, the current findings indicate that the expression of VLA-1 is not pivotal for T-cell-mediated antiviral immunity to a systemic infection.......-cell-mediated inflammation, no significant influence of VLA-1 was found either in the primary response or in the memory phase. However, alpha-VLA-4 antibody reduced the DTH-like reaction in VLA-1(-/-) mice to a higher degree than in wt mice, suggesting a synergistic effect of blocking both integrins. Taken together...

  18. A talin-dependent LFA-1 focal zone is formed by rapidly migrating T lymphocytes.

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    Smith, Andrew; Carrasco, Yolanda R; Stanley, Paula; Kieffer, Nelly; Batista, Facundo D; Hogg, Nancy

    2005-07-01

    Cells such as fibroblasts and endothelial cells migrate through the coordinated responses of discrete integrin-containing focal adhesions and complexes. In contrast, little is known about the organization of integrins on the highly motile T lymphocyte. We have investigated the distribution, activity, and cytoskeletal linkage of the integrin lymphocyte function associated antigen-1 (LFA-1) on human T lymphocytes migrating on endothelial cells and on ligand intercellular adhesion molecule-1 (ICAM-1). The pattern of total LFA-1 varies from low expression in the lamellipodia to high expression in the uropod. However, high affinity, clustered LFA-1 is restricted to a mid-cell zone that remains stable over time and over a range of ICAM-1 densities. Talin is essential for the stability and formation of the LFA-1 zone. Disruption of the talin-integrin link leads to loss of zone integrity and a substantial decrease in speed of migration on ICAM-1. This adhesive structure, which differs from the previously described integrin-containing attachments displayed by many other cell types, we have termed the "focal zone."

  19. Characterization of a novel inhibitory human monoclonal antibody directed against Plasmodium falciparum Apical Membrane Antigen 1.

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    Maskus, Dominika J; Królik, Michał; Bethke, Susanne; Spiegel, Holger; Kapelski, Stephanie; Seidel, Melanie; Addai-Mensah, Otchere; Reimann, Andreas; Klockenbring, Torsten; Barth, Stefan; Fischer, Rainer; Fendel, Rolf

    2016-12-21

    Malaria remains a major challenge to global health causing extensive morbidity and mortality. Yet, there is no efficient vaccine and the immune response remains incompletely understood. Apical Membrane Antigen 1 (AMA1), a leading vaccine candidate, plays a key role during merozoite invasion into erythrocytes by interacting with Rhoptry Neck Protein 2 (RON2). We generated a human anti-AMA1-antibody (humAbAMA1) by EBV-transformation of sorted B-lymphocytes from a Ghanaian donor and subsequent rescue of antibody variable regions. The antibody was expressed in Nicotiana benthamiana and in HEK239-6E, characterized for binding specificity and epitope, and analyzed for its inhibitory effect on Plasmodium falciparum. The generated humAbAMA1 shows an affinity of 106-135 pM. It inhibits the parasite strain 3D7A growth in vitro with an expression system-independent IC50-value of 35 μg/ml (95% confidence interval: 33 μg/ml-37 μg/ml), which is three to eight times lower than the IC50-values of inhibitory antibodies 4G2 and 1F9. The epitope was mapped to the close proximity of the RON2-peptide binding groove. Competition for binding between the RON2-peptide and humAbAMA1 was confirmed by surface plasmon resonance spectroscopy measurements. The particularly advantageous inhibitory activity of this fully human antibody might provide a basis for future therapeutic applications.

  20. Vaccination with trypomastigote surface antigen 1-encoding plasmid DNA confers protection against lethal Trypanosoma cruzi infection.

    Science.gov (United States)

    Wizel, B; Garg, N; Tarleton, R L

    1998-11-01

    DNA vaccination was evaluated with the experimental murine model of Trypanosoma cruzi infection as a means to induce antiparasite protective immunity, and the trypomastigote surface antigen 1 (TSA-1), a target of anti-T. cruzi antibody and major histocompatibility complex (MHC) class I-restricted CD8(+) cytotoxic T-lymphocyte (CTL) responses, was used as the model antigen. Following the intramuscular immunization of H-2(b) and H-2(d) mice with a plasmid DNA encoding an N-terminally truncated TSA-1 lacking or containing the C-terminal nonapeptide tandem repeats, the antibody level, CTL response, and protection against challenge with T. cruzi were assessed. In H-2(b) mice, antiparasite antibodies were induced only by immunization with the DNA construct encoding TSA-1 containing the C-terminal repeats. However, both DNA constructs were efficient in eliciting long-lasting CTL responses against the protective H-2Kb-restricted TSA-1515-522 epitope. In H-2(d) mice, inoculation with either of the two TSA-1-expressing vectors effectively generated antiparasite antibodies and primed CTLs that lysed T. cruzi-infected cells in an antigen-specific, MHC class I-restricted, and CD8(+)-T-cell-dependent manner. When TSA-1 DNA-vaccinated animals were challenged with T. cruzi, 14 of 22 (64%) H-2(b) and 16 of 18 (89%) H-2(d) mice survived the infection. The ability to induce significant murine anti-T. cruzi protective immunity by immunization with plasmid DNA expressing TSA-1 provides the basis for the application of this technology in the design of optimal DNA multicomponent anti-T. cruzi vaccines which may ultimately be used for the prevention or treatment of Chagas' disease.

  1. Tumor microenvironment contributes to Epstein-Barr virus anti-nuclear antigen-1 antibody production in nasopharyngeal carcinoma.

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    Ai, Ping; Li, Zhiping; Jiang, Yong; Song, Changping; Zhang, Lin; Hu, Huaizhong; Wang, Tao

    2017-08-01

    Nuclear antigen-1 (NA1) protein of Epstein-Barr virus (EBV) is expressed in EBV-infected cells in the microenvironment of cancer. Since immune cells infiltrate abundantly in nasopharyngeal carcinoma (NPC) tumor tissues, we hypothesized that the local tumor microenvironment may perform an important role in the production of antibodies directed at NA1. Furthermore, we hypothesized that anti-NA1 antibody originating in the local microenvironment could be secreted into the saliva of patients with NPC. In the present study, 20 healthy controls and 39 patients with NPC treated with intensity-modulated radiation therapy were recruited for the study. Saliva and serum samples were collected from the NPC patients, and nasopharyngeal tissue samples from the patients with NPC. The titers of anti-NA1 antibody [immunoglobulin A (IgA)] were determined by ELISA. Expression of NA1, human leukocyte antigen-antigen D related (HLA-DR), cluster of differentiation (CD)80, CD86, CD3, CD4, CD19 and IgA was detected by immunohistochemical staining on paraffin-embedded nasopharyngeal tissue sections. Anti-NA1 antibodies were detected in the serum and saliva samples of the patients with NPC. In infiltrating cells, expression of HLA-DR, CD80, CD86, CD3, CD4, CD19 and IgA was detected, indicating that dendritic cells, T lymphocytes and B lymphocytes were all present in the local tumor tissues. Furthermore, expression of EBNA1 protein was detected on the membrane of the NPC tumor cells. Therefore, the NPC tumor microenvironment has the potential to initiate a humoral response to EBNA1 by producing IgA antibodies.

  2. Fetal antigen 1 in healthy adults and patients with pituitary disease

    DEFF Research Database (Denmark)

    Andersen, M; Jensen, Charlotte Harken; Støving, René Klinkby;

    2001-01-01

    Immunohistochemical analysis of the distribution of human fetal antigen 1 (FA1) in adult human tissues has demonstrated a strong association between FA1 and (neuro)endocrine structures. In the anterior pituitary gland FA1 was colocalized with GH, and the present study was performed to evaluate a ...

  3. Modulation of TCR-mediated signaling pathway by thymic shared antigen-1 (TSA-1)/stem cell antigen-2 (Sca-2).

    Science.gov (United States)

    Saitoh, S; Kosugi, A; Noda, S; Yamamoto, N; Ogata, M; Minami, Y; Miyake, K; Hamaoka, T

    1995-12-15

    Thymic shared antigen-1 (TSA-1) is a glycosyl-phosphatidylinositol (GPI)-anchored differentiation Ag expressed on murine lymphocytes, and is identical to stem cell Ag-2 (Sca-2). Using newly established mAb against TSA-1/Sca-2, we have previously shown that surface TSA-1 expression is induced upon activation in T cells, and that anti-TSA-1 inhibits IL-2 production induced by anti-CD3 stimulation in T cell hybridomas. In the present study, we have analyzed the functional role of TSA-1 during T cell activation using normal T cells, T cell hybridomas, and transfected Jurkat cell lines that expressed either GPI-anchored or transmembrane form of TSA-1. Anti-TSA-1 inhibited IL-2 production from normal T cells stimulated with soluble anti-CD3 plus accessory cells. Anti-TSA-1 exhibited the inhibitory effect on T cells, but not on accessory cells, because anti-TSA-1 inhibited IL-2 production in Jurkat cells transfected with TSA-1 cDNA, but not in control transfectant. A transmembrane form of TSA-1 was expressed in Jurkat cells by fusing the extracellular portion of TSA-1 to the transmembrane and cytoplasmic regions of the class 1 Db. The analysis using this transfectant revealed that anti-TSA-1-mediated inhibition of IL-2 production did not require the GPI anchor of TSA-1. Finally, in addition to the inhibition of IL-2 production, tyrosine phosphorylation of CD3 zeta-chains observed following TCR stimulation, one of the important early activation events, was markedly reduced by anti-TSA-1. These results imply that TSA-1/Sca-2 plays an important regulatory role in the TCR signaling pathway of activated T cells in addition to its role in T cell differentiation.

  4. Genome-wide analysis of host-chromosome binding sites for Epstein-Barr Virus Nuclear Antigen 1 (EBNA1

    Directory of Open Access Journals (Sweden)

    Wang Pu

    2010-10-01

    Full Text Available Abstract The Epstein-Barr Virus (EBV Nuclear Antigen 1 (EBNA1 protein is required for the establishment of EBV latent infection in proliferating B-lymphocytes. EBNA1 is a multifunctional DNA-binding protein that stimulates DNA replication at the viral origin of plasmid replication (OriP, regulates transcription of viral and cellular genes, and tethers the viral episome to the cellular chromosome. EBNA1 also provides a survival function to B-lymphocytes, potentially through its ability to alter cellular gene expression. To better understand these various functions of EBNA1, we performed a genome-wide analysis of the viral and cellular DNA sites associated with EBNA1 protein in a latently infected Burkitt lymphoma B-cell line. Chromatin-immunoprecipitation (ChIP combined with massively parallel deep-sequencing (ChIP-Seq was used to identify cellular sites bound by EBNA1. Sites identified by ChIP-Seq were validated by conventional real-time PCR, and ChIP-Seq provided quantitative, high-resolution detection of the known EBNA1 binding sites on the EBV genome at OriP and Qp. We identified at least one cluster of unusually high-affinity EBNA1 binding sites on chromosome 11, between the divergent FAM55 D and FAM55B genes. A consensus for all cellular EBNA1 binding sites is distinct from those derived from the known viral binding sites, suggesting that some of these sites are indirectly bound by EBNA1. EBNA1 also bound close to the transcriptional start sites of a large number of cellular genes, including HDAC3, CDC7, and MAP3K1, which we show are positively regulated by EBNA1. EBNA1 binding sites were enriched in some repetitive elements, especially LINE 1 retrotransposons, and had weak correlations with histone modifications and ORC binding. We conclude that EBNA1 can interact with a large number of cellular genes and chromosomal loci in latently infected cells, but that these sites are likely to represent a complex ensemble of direct and indirect EBNA

  5. Fetal antigen 1 (FA1), a circulating member of the epidermal growth factor (EGF) superfamily

    DEFF Research Database (Denmark)

    Jensen, Charlotte Harken; Krogh, T N; Støving, René Klinkby;

    1997-01-01

    We describe an ELISA technique for quantification of fetal antigen 1 (FA1), a glycoprotein belonging to the EGF-superfamily. The ELISA is based on immunospecifically purified polyclonal antibodies and has a dynamic range of 0.7-5.3 ng/ml, intra- and inter-assay C.V.s of less than 3.2% and an aver......We describe an ELISA technique for quantification of fetal antigen 1 (FA1), a glycoprotein belonging to the EGF-superfamily. The ELISA is based on immunospecifically purified polyclonal antibodies and has a dynamic range of 0.7-5.3 ng/ml, intra- and inter-assay C.V.s of less than 3...

  6. Multiple elliptic gamma functions associated to cones

    CERN Document Server

    Winding, Jacob

    2016-01-01

    We define generalizations of the multiple elliptic gamma functions and the multiple sine functions, associated to good rational cones. We explain how good cones are related to collections of $SL_r(\\mathbb{Z})$-elements and prove that the generalized multiple sine and multiple elliptic gamma functions enjoy infinite product representations and modular properties determined by the cone. This generalizes the modular properties of the elliptic gamma function studied by Felder and Varchenko, and the results about the usual multiple sine and elliptic gamma functions found by Narukawa.

  7. Lung ICAM-1 and ICAM-2 support spontaneous intravascular effector lymphocyte entrapment but are not required for neutrophil entrapment or emigration inside endotoxin-inflamed lungs.

    Science.gov (United States)

    Petrovich, Ekaterina; Feigelson, Sara W; Stoler-Barak, Liat; Hatzav, Miki; Solomon, Adam; Bar-Shai, Amir; Ilan, Neta; Li, Jin-Ping; Engelhardt, Britta; Vlodavsky, Israel; Alon, Ronen

    2016-05-01

    The pulmonary vasculature constitutively expresses the integrin lymphocyte function-associated antigen-1 ligands intercellular adhesion molecule (ICAM)-1 and -2. In this study, effector T cells were temporarily entrapped by the lung vasculature on their way to inflamed lymph nodes, and this entrapment was strongly reduced in ICAM-1 and -2 double-deficient mice (79 and 86% reduction for CD8(+) and CD4(+) effectors, respectively, compared with wild-type mice). Although the pulmonary vasculature has been suggested to be masked by the heparan sulfate-containing glycocalyx, which is susceptible to heparanase-mediated shedding, lung and lymphocyte heparanase have been found to be unnecessary for this entrapment. Systemic LPS induced rapid neutrophil entrapment in the lung vasculature, but in contrast to T-cell entrapment, this sequestration was ICAM-1, ICAM-2, and heparanase independent. Furthermore, neutrophil migration into the bronchoalveolar space induced by LPS inhalation and LPS-induced leakage of red blood cells into this space were not dependent on lung ICAMs or heparanase activity. Nevertheless, heparanase was critical for neutrophil accumulation in smoke-exposed lungs. Our results indicate that, whereas T cells use ICAM-1 and -2 for temporary pulmonary entrapment, neutrophils get sequestered and extravasate into inflamed lungs independent of ICAMs. This is the first demonstration that the pulmonary vasculature is differentially recognized by T cells and neutrophils.-Petrovich, E., Feigelson, S. W., Stoler-Barak, L., Hatzav, M., Solomon, A., Bar-Shai, A., Ilan, N., Li, J.-P., Engelhardt, B., Vlodavsky, I., Alon, R. Lung ICAM-1 and ICAM-2 support spontaneous intravascular effector lymphocyte entrapment but are not required for neutrophil entrapment or emigration inside endotoxin-inflamed lungs.

  8. Fetal antigen 1 in healthy adults and patients with pituitary disease

    DEFF Research Database (Denmark)

    Andersen, M; Jensen, Charlotte Harken; Støving, René Klinkby

    2001-01-01

    Immunohistochemical analysis of the distribution of human fetal antigen 1 (FA1) in adult human tissues has demonstrated a strong association between FA1 and (neuro)endocrine structures. In the anterior pituitary gland FA1 was colocalized with GH, and the present study was performed to evaluate a ...... during weeks to months had a corresponding direct or indirect effect on FA1 levels in patients with GH deficiency or acromegaly. However, a direct effect of octreotide on FA1 levels, independent of GH levels, has not been ruled out. Udgivelsesdato: Nov...

  9. Transcription factor Fos-related antigen 1 is an effective target for a breast cancer vaccine

    Science.gov (United States)

    Luo, Yunping; Zhou, He; Mizutani, Masato; Mizutani, Noriko; Reisfeld, Ralph A.; Xiang, Rong

    2003-07-01

    Protection against breast cancer was achieved with a DNA vaccine against murine transcription factor Fos-related antigen 1, which is overexpressed in aggressively proliferating D2F2 murine breast carcinoma. Growth of primary s.c. tumor and dissemination of pulmonary metastases was markedly suppressed by this oral DNA vaccine, carried by attenuated Salmonella typhimurium, encoding murine Fos-related antigen 1, fused with mutant polyubiquitin, and cotransformed with secretory murine IL-18. The life span of 60% of vaccinated mice was tripled in the absence of detectable tumor growth after lethal tumor cell challenge. Immunological mechanisms involved activation of T, natural killer, and dendritic cells, as indicated by up-regulation of their activation markers and costimulatory molecules. Markedly increased specific target cell lysis was mediated by both MHC class I-restricted CD8+ T cells and natural killer cells isolated from splenocytes of vaccinated mice, including a significant release of proinflammatory cytokines IFN- and IL-2. Importantly, fluorescence analysis of fibroblast growth factor 2 and tumor cell-induced vessel growth in Matrigel plugs demonstrated marked suppression of angiogenesis only in vaccinated animals. Taken together, this multifunctional DNA vaccine proved effective in protecting against growth and metastases of breast cancer by combining the action of immune effector cells with suppression of tumor angiogenesis. vaccine | tumor | metastases | antiangiogenesis

  10. Immunolocalization of the Epstein-Barr nuclear antigen-1 in conjunctival squamous carcinomas and dysplasias.

    Science.gov (United States)

    Restelli, Marcela; Grinstein, Saul; Gattuso, Paolo; Preciado, M Victoria; Brunzini, Mario A; Zarate, Jorge; Mosquera, Juan-Miguel; Gould, Victor E

    2005-04-01

    Epstein-Barr virus (EBV) has been linked etiologically to infectious mononucleosis, some non-Hodgkin as well as Hodgkin lymphomas, and lymphoepithelioma-like carcinomas. Moreover, various EBV antigens have been identified by a variety of techniques in a number of visceral carcinomas including breast, prostate, colon and lung primaries. We have now demonstrated by immunohistochemistry the presence of EBV nuclear antigen-1 (EBNA-1) in 4 of 15 cases of conjuntival squamous carcinomas and related dysplasias. At present, there is no significant evidence linking etiologically EVB to this type of tumor and dysplasia. However, our findings merit further investigation given the growing evidence that EBV may enhance proliferation and aggressiveness of tumor systems as well as the immortalization of non-neoplastic cells.

  11. Ofatumumab, Pentostatin, and Cyclophosphamide in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2014-10-30

    Hematopoietic/Lymphoid Cancer; B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Small Lymphocytic Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  12. Thymic-shared antigen-1 (TSA-1). A lymphostromal cell membrane Ly-6 superfamily molecule with a putative role in cellular adhesion.

    Science.gov (United States)

    Classon, B J; Boyd, R L

    1998-01-01

    The seeding and colonization of the thymus by bone marrow stem cells and the maturation of these cells into mature T lymphocytes are dependent on cell-surface recognition events between different cell lineages within the thymic microenvironment. Positive and negative selection processes within the thymus produce a peripheral T-cell repertoire capable of recognizing peptides derived from foreign antigen bound to self MHCmolecules. In addition to the TCR/MHC-peptide interaction, many other cell-surface molecules act in concert to regulate the kinetics of cellular interactions and intracellular signaling events during thymopoiesis. We have investigated the complexity of the thymic stroma by using monoclonal antibodies to clone cell-membrane molecules of thymic stromal cells. Thymic-shared antigen-1 (TSA-1) is a molecule of interest because it is expressed by both immature thymocytes and stromal cells. We report herein the structural and evolutionary relationships between TSA-1 and molecules of the Ly-6 superfamily (Ly-6SF), and present evidence that TSA-1 functions as a cell-surface receptor by binding a cognate cell target molecule on the surface of a subset of thymocytes.

  13. Bendamustine Plus Alemtuzumab for Refractory Chronic Lymphocytic Leukemia (CLL)

    Science.gov (United States)

    2013-08-20

    Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  14. Expression, biosynthesis and release of preadipocyte factor-1/ delta-like protein/fetal antigen-1 in pancreatic -cells

    DEFF Research Database (Denmark)

    Friedrichsen, B N; Carlsson, C; Møldrup, A

    2003-01-01

    Preadipocyte factor-1 (Pref-1)/delta-like protein/fetal antigen-1 (FA1) is a member of the epidermal growth factor-like family. It is widely expressed in embryonic tissues, whereas in adults it is confined to the adrenal gland, the anterior pituitary, the endocrine pancreas, the testis and the ov......Preadipocyte factor-1 (Pref-1)/delta-like protein/fetal antigen-1 (FA1) is a member of the epidermal growth factor-like family. It is widely expressed in embryonic tissues, whereas in adults it is confined to the adrenal gland, the anterior pituitary, the endocrine pancreas, the testis...

  15. What Is Chronic Lymphocytic Leukemia?

    Science.gov (United States)

    ... Chronic Lymphocytic Leukemia (CLL) About Chronic Lymphocytic Leukemia What Is Chronic Lymphocytic Leukemia? Cancer starts when cells ... body, including the lymph nodes, liver, and spleen. What is leukemia? Leukemia is a cancer that starts ...

  16. Alvocidib in Treating Patients With B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2013-07-01

    B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Small Lymphocytic Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  17. Detection of Pancreatic Ductal Adenocarcinoma in Mice by Ultrasound Imaging of Thymocyte Differentiation Antigen 1

    Science.gov (United States)

    Foygel, Kira; Wang, Huaijun; Machtaler, Steven; Lutz, Amelie M.; Chen, Ru; Pysz, Marybeth; Lowe, Anson W.; Tian, Lu; Carrigan, Tricia; Brentnall, Teresa A.; Willmann, Jürgen K.

    2013-01-01

    BACKGROUND & AIMS Early detection of pancreatic ductal adenocarcinoma (PDAC) allows for surgical resection and increases patient survival times. Imaging agents that bind and amplify the signal of neovascular proteins in neoplasms can be detected by ultrasound, enabling accurate detection of small lesions. We searched for new markers of neovasculature in PDAC and assessed their potential for tumor detection by ultrasound molecular imaging. METHODS Thymocyte Differentiation Antigen 1 (Thy1) was identified as a specific biomarker of PDAC neovasculature by proteomic analysis. Upregulation in PDAC was validated by immunohistochemical analysis of pancreatic tissue samples from 28 healthy individuals, 15 with primary chronic pancreatitis tissues, and 196 with PDAC. Binding of Thy1-targeted contrast microbubbles was assessed in cultured cells, in mice with orthotopic PDAC xenograft tumors expressing human Thy1 on the neovasculature, and on the neovasculature of a genetic mouse model of PDAC. RESULTS Based on immunohistochemical analyses, levels of Thy1 were significantly higher in the vascular of human PDAC than chronic pancreatitis (P=.007) or normal tissue samples (P<.0001). In mice, ultrasound imaging accurately detected human Thy1-positive PDAC xenografts, as well as PDACs that express endogenous Thy1 in genetic mouse models of PDAC. CONCLUSION We have identified and validated Thy1 as a marker of PDAC that can be detected by ultrasound molecular imaging in mice. The development of a specific imaging agent and identification of Thy1 as a new biomarker could aid in the diagnosis of this cancer and management of patients. PMID:23791701

  18. Identification and characterization of Eimeria tenella apical membrane antigen-1 (AMA1.

    Directory of Open Access Journals (Sweden)

    Lianlian Jiang

    Full Text Available Apical membrane antigen-1 (AMA1 is a micronemal protein of apicomplexan parasites that appears to be essential during the invasion of host cells. In this study, a full-length cDNA of AMA1 was identified from Eimeria tenella (Et using expressed sequence tag and the rapid amplification of cDNA ends technique. EtAMA1 had an open reading frame of 1608 bp encoding a protein of 535 amino acids. Quantitative real-time PCR analysis revealed that EtAMA1 was expressed at higher levels in sporozoites than in the other developmental stages (unsporulated oocysts, sporulated oocysts and second-generation merozoites. The ectodomain sequence was expressed as recombinant EtAMA1 (rEtAMA1 and rabbit polyclonal antibodies raised against the rEtAMA1 recognized a 58-kDa native parasite protein by Western Blotting and had a potent inhibitory effect on parasite invasion, decreasing it by approximately 70%. Immunofluorescence analysis and immunohistochemistry analysis showed EtAMA1 might play an important role in sporozoite invasion and development.

  19. Alanine mutagenesis of the primary antigenic escape residue cluster, c1, of apical membrane antigen 1.

    Science.gov (United States)

    Dutta, Sheetij; Dlugosz, Lisa S; Clayton, Joshua W; Pool, Christopher D; Haynes, J David; Gasser, Robert A; Batchelor, Adrian H

    2010-02-01

    Antibodies against apical membrane antigen 1 (AMA1) inhibit invasion of Plasmodium merozoites into red cells, and a large number of single nucleotide polymorphisms on AMA1 allow the parasite to escape inhibitory antibodies. The availability of a crystal structure makes it possible to test protein engineering strategies to develop a monovalent broadly reactive vaccine. Previously, we showed that a linear stretch of polymorphic residues (amino acids 187 to 207), localized within the C1 cluster on domain 1, conferred the highest level of escape from inhibitory antibodies, and these were termed antigenic escape residues (AER). Here we test the hypothesis that immunodampening the C1 AER will divert the immune system toward more conserved regions. We substituted seven C1 AER of the FVO strain Plasmodium falciparum AMA1 with alanine residues (ALA). The resulting ALA protein was less immunogenic than the native protein in rabbits. Anti-ALA antibodies contained a higher proportion of cross-reactive domain 2 and domain 3 antibodies and had higher avidity than anti-FVO. No overall enhancement of cross-reactive inhibitory activity was observed when anti-FVO and anti-ALA sera were compared for their ability to inhibit invasion. Alanine mutations at the C1 AER had shifted the immune response toward cross-strain-reactive epitopes that were noninhibitory, refuting the hypothesis but confirming the importance of the C1 cluster as an inhibitory epitope. We further demonstrate that naturally occurring polymorphisms that fall within the C1 cluster can predict escape from cross-strain invasion inhibition, reinforcing the importance of the C1 cluster genotype for antigenic categorization and allelic shift analyses in future phase 2b trials.

  20. Kloning Gen Melanoma Antigen 1 (Mage-1 dari Jaringan Testis untuk mendapatkan Plasmid Rekombinan Mage-1

    Directory of Open Access Journals (Sweden)

    Gondo Mastutik

    2015-12-01

    Full Text Available Melanoma antigen-1 (Mage-1 is expressed by spermatogonia cells of normal testicular tissue and 60−80% is expressed by the liver of hepatocellular carcinoma (HC patients. Mage-1 expression is a marker for diagnosing HC and predicting gastric and colorectal cancers. Isolation of messenger ribonucleid acid (mRNA Mage-1 from the liver tissue of HC patients is difficult; therefore, Mage-1 mRNA isolates can be obtained from tissues that express Mage-1 such as normal testicular tissues . This is an explorative research that was conducted at the Institute of Tropical Diseases of Airlangga University during August 2006–August 2008. The aim was to clone the coding sequence of Mage-1 gene from testicular tissues into a vector and to get recombinant plasmid Mage-1. Isolation of the full-length Mage-1 was performed using semi-nested polymerase chain reaction (PCR which was then cloned into plasmid pET101/D-TOPO and transformed into Escherichia coli (E. coli Top10 to get recombinant plasmid Mage-1. The length of pET101/D-TOPO was 5,753 bp and Mage-1 was 927 bp. The length of recombinant plasmid was 6,680 bp (5,753+927. Restriction analysis using EcoRV showed 4,230 and 2,450 bp bands (4,230+2,450=6,680. Sequence analyses showed that Mage-1 was 100% homologous with M77481 and NM_004988, 99% homologous with BC01755. In conclusion, according to the results of the restriction and sequences analysis, the recombinant plasmid pETGM/MAGE1-Testis contains the full length coding region of Mage-1 and is useful for developing the hepatocellular carcinoma diagnostic kits.

  1. Genetic diversity and antigenicity variation of Babesia bovis merozoite surface antigen-1 (MSA-1) in Thailand.

    Science.gov (United States)

    Tattiyapong, Muncharee; Sivakumar, Thillaiampalam; Takemae, Hitoshi; Simking, Pacharathon; Jittapalapong, Sathaporn; Igarashi, Ikuo; Yokoyama, Naoaki

    2016-07-01

    Babesia bovis, an intraerythrocytic protozoan parasite, causes severe clinical disease in cattle worldwide. The genetic diversity of parasite antigens often results in different immune profiles in infected animals, hindering efforts to develop immune control methodologies against the B. bovis infection. In this study, we analyzed the genetic diversity of the merozoite surface antigen-1 (msa-1) gene using 162 B. bovis-positive blood DNA samples sourced from cattle populations reared in different geographical regions of Thailand. The identity scores shared among 93 msa-1 gene sequences isolated by PCR amplification were 43.5-100%, and the similarity values among the translated amino acid sequences were 42.8-100%. Of 23 total clades detected in our phylogenetic analysis, Thai msa-1 gene sequences occurred in 18 clades; seven among them were composed of sequences exclusively from Thailand. To investigate differential antigenicity of isolated MSA-1 proteins, we expressed and purified eight recombinant MSA-1 (rMSA-1) proteins, including an rMSA-1 from B. bovis Texas (T2Bo) strain and seven rMSA-1 proteins based on the Thai msa-1 sequences. When these antigens were analyzed in a western blot assay, anti-T2Bo cattle serum strongly reacted with the rMSA-1 from T2Bo, as well as with three other rMSA-1 proteins that shared 54.9-68.4% sequence similarity with T2Bo MSA-1. In contrast, no or weak reactivity was observed for the remaining rMSA-1 proteins, which shared low sequence similarity (35.0-39.7%) with T2Bo MSA-1. While demonstrating the high genetic diversity of the B. bovis msa-1 gene in Thailand, the present findings suggest that the genetic diversity results in antigenicity variations among the MSA-1 antigens of B. bovis in Thailand.

  2. Acute Lymphocytic Leukemia

    Science.gov (United States)

    ... for information in your local library and on the Internet. Good sources include the National Cancer Institute, the ... mayoclinic.org/diseases-conditions/acute-lymphocytic-leukemia/basics/definition/CON-20042915 . Mayo Clinic Footer Legal Conditions and ...

  3. HPK1 associates with SKAP-HOM to negatively regulate Rap1-mediated B-lymphocyte adhesion.

    Directory of Open Access Journals (Sweden)

    Sebastian Königsberger

    Full Text Available BACKGROUND: Hematopoietic progenitor kinase 1 (HPK1 is a Ste20-related serine/threonine kinase activated by a range of environmental stimuli including genotoxic stress, growth factors, inflammatory cytokines and antigen receptor triggering. Being inducibly recruited to membrane-proximal signalling scaffolds to regulate NFAT, AP-1 and NFkappaB-mediated gene transcription in T-cells, the function of HPK1 in B-cells to date remains rather ill-defined. METHODOLOGY/PRINCIPAL FINDINGS: By using two loss of function models, we show that HPK1 displays a novel function in regulating B-cell integrin activity. Wehi 231 lymphoma cells lacking HPK1 after shRNA mediated knockdown exhibit increased basic activation levels of Ras-related protein 1 (Rap1, accompanied by a severe lymphocyte function-associated antigen-1 (LFA-1 dependent homotypic aggregation and increased adhesion to intercellular adhesion molecule 1 (ICAM-1. The observed phenotype of enhanced integrin activity is caused downstream of Src, by a signalling module independent of PI3K and PLC, involving HPK1, SKAP55 homologue (SKAP-HOM and Rap1-GTP-interacting adaptor molecule (RIAM. This alters actin dynamics and renders focal adhesion kinase (FAK constitutively phosphorylated. Bone marrow and splenic B-cell development of HPK1(-/- mice are largely unaffected, except age-related tendencies for increased splenic cellularity and BCR downregulation. In addition, naïve splenic knockout B-cells appear hyperresponsive to a range of stimuli applied ex vivo as recently demonstrated by others for T-cells. CONCLUSIONS/SIGNIFICANCE: We therefore conclude that HPK1 exhibits a dual function in B-cells by negatively regulating integrin activity and controlling cellular activation, which makes it an interesting candidate to study in pathological settings like autoimmunity and cancer.

  4. Activation-induced expression of thymic shared antigen-1 on T lymphocytes and its inhibitory role for TCR-mediated IL-2 production.

    Science.gov (United States)

    Kosugi, A; Saitoh, S; Narumiya, S; Miyake, K; Hamaoka, T

    1994-12-01

    We have produced a hamster mAb, PRST1, which reacts with thymic shared Ag-1 (TSA-1), a product of the Ly6 gene family. By cross-blocking experiments, we found that TSA-1 is identical to stem cell Ag-2 (Sca-2). Using PRST1, the changes of TSA-1/Sca-2 expression on mature T cells during the activation process were analyzed. Although freshly isolated T cells did not express detectable TSA-1 on their cell surface, in vitro stimulation of T cells with concanavalin A induced a marked increase of surface TSA-1 expression. The increased expression of TSA-1 on T cells was detected from 12 h after stimulation and was associated with the increase of TSA-1 mRNA. In vivo injection of mice with staphylococcal enterotoxin B (SEB) resulted in the enhanced TSA-1 expression in splenic V beta 8+ T cells. This antigen-specific induction of TSA-1 expression in vivo preceded a detectable increase in numbers of V beta 8- T cells after SEB injection. Functionally, whereas anti-TSA-1 mAb was not mitogenic to T cells, it inhibited anti-CD3-induced IL-2 production by T cell hybridomas. These results indicate that TSA-1/Sca-2 is a unique marker for T cell activation and a signal through this molecule may have a negative feedback role to limit IL-2 production from activated T cells stimulated through the TCR.

  5. Plasmodium falciparum liver stage antigen-1 is cross-linked by tissue transglutaminase

    Directory of Open Access Journals (Sweden)

    Doerig Christian

    2011-01-01

    Full Text Available Abstract Background Plasmodium falciparum sporozoites injected by mosquitoes into the blood rapidly enter liver hepatocytes and undergo pre-erythrocytic developmental schizogony forming tens of thousands of merozoites per hepatocyte. Shortly after hepatocyte invasion, the parasite starts to produce Liver Stage Antigen-1 (LSA-1, which accumulates within the parasitophorous vacuole surrounding the mass of developing merozoites. The LSA-1 protein has been described as a flocculent mass, but its role in parasite development has not been determined. Methods Recombinant N-terminal, C-terminal or a construct containing both the N- and C- terminal regions flanking two 17 amino acid residue central repeat sequences (LSA-NRC were subjected to in vitro modification by tissue transglutaminase-2 (TG2 to determine if cross-linking occurred. In addition, tissue sections of P. falciparum-infected human hepatocytes were probed with monoclonal antibodies to the isopeptide ε-(γ-glutamyllysine cross-bridge formed by TG2 enzymatic activity to determine if these antibodies co-localized with antibodies to LSA-1 in the growing liver schizonts. Results This study identified a substrate motif for (TG2 and a putative casein kinase 2 phosphorylation site within the central repeat region of LSA-1. The function of TG2 is the post-translational modification of proteins by the formation of a unique isopeptide ε-(γ-glutamyllysine cross-bridge between glutamine and lysine residues. When recombinant LSA-1 protein was crosslinked in vitro by purified TG2 in a calcium dependent reaction, a flocculent mass of protein was formed that was highly resistant to degradation. The cross-linking was not detectably affected by phosphorylation with plasmodial CK2 in vitro. Monoclonal antibodies specific to the very unique TG2 catalyzed ε- lysine cross-bridge co-localized with antibodies to LSA-1 in infected human hepatocytes providing visual evidence that LSA-1 was cross-linked in vivo

  6. Small molecule and peptide-mediated inhibition of Epstein-Barr virus nuclear antigen 1 dimerization

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sun Young; Song, Kyung-A [Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Samsung Biomedical Research Institute (SBRI), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Kieff, Elliott [Department of Medicine, Brigham and Women' s Hospital and Harvard Medical School, Boston, MA 02115 (United States); Kang, Myung-Soo, E-mail: mkang@skku.edu [Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Samsung Biomedical Research Institute (SBRI), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Department of Medicine, Brigham and Women' s Hospital and Harvard Medical School, Boston, MA 02115 (United States)

    2012-07-27

    Highlights: Black-Right-Pointing-Pointer Evidence that targeting EBNA1 dimer, an EBV onco-antigen, can be achievable. Black-Right-Pointing-Pointer A small molecule and a peptide as EBNA1 dimerization inhibitors identified. Black-Right-Pointing-Pointer Both inhibitors associated with EBNA1 and blocked EBNA1 DNA binding activity. Black-Right-Pointing-Pointer Also, prevented its dimerization, and repressed viral gene transcription. -- Abstract: Latent Epstein-Barr virus (EBV) infection is associated with human B cell lymphomas and certain carcinomas. EBV episome persistence, replication, and gene expression are dependent on EBV-encoded nuclear antigen 1 (EBNA1)'s DNA binding domain (DBD)/dimerization domain (DD)-mediated sequence-specific DNA binding activity. Homodimerization of EBNA1 is essential for EBNA1 DNA binding and transactivation. In this study, we characterized a novel small molecule EBNA1 inhibitor EiK1, screened from the previous high throughput screening (HTS). The EiK1 compound specifically inhibited the EBNA1-dependent, OriP-enhanced transcription, but not EBNA1-independent transcription. A Surface Plasmon Resonance Biacore assay revealed that EiK1 associates with EBNA1 amino acid 459-607 DBD/DD. Consistent with the SPR data, in vitro gel shift assays showed that EiK1 suppressed the activity of EBNA1 binding to the cognate familial repeats (FR) sequence, but not control RBP-J{kappa} binding to the J{kappa} site. Subsequently, a cross-linker-mediated in vitro multimerization assay and EBNA1 homodimerization-dependent yeast two-hybrid assay showed that EiK1 significantly inhibited EBNA1 dimerization. In an attempt to identify more highly specific peptide inhibitors, small peptides encompassing the EBNA1 DBD/DD were screened for inhibition of EBNA1 DBD-mediated DNA binding function. The small peptide P85, covering EBNA1 a.a. 560-574, significantly blocked EBNA1 DNA binding activity in vitro, prevented dimerization in vitro and in vivo, associated

  7. Hierarchical phosphorylation of apical membrane antigen 1 is required for efficient red blood cell invasion by malaria parasites

    OpenAIRE

    Boris Prinz; Katherine L. Harvey; Louisa Wilcke; Ulrike Ruch; Klemens Engelberg; Laura Biller; Isabelle Lucet; Steffen Erkelenz; Dorothee Heincke; Tobias Spielmann; Christian Doerig; Conrad Kunick; Brendan S Crabb; Gilson, Paul R.; Gilberger, Tim W

    2016-01-01

    Central to the pathogenesis of malaria is the proliferation of Plasmodium falciparum parasites within human erythrocytes. Parasites invade erythrocytes via a coordinated sequence of receptor-ligand interactions between the parasite and host cell. One key ligand, Apical Membrane Antigen 1 (AMA1), is a leading blood-stage vaccine and previous work indicates that phosphorylation of its cytoplasmic domain (CPD) is important to its function during invasion. Here we investigate the significance of ...

  8. Chemokines, lymphocytes, and HIV

    Directory of Open Access Journals (Sweden)

    Farber J.M.

    1998-01-01

    Full Text Available Chemokines are members of a family of more than 30 human cytokines whose best-described activities are as chemotactic factors for leukocytes and that are presumed to be important in leukocyte recruitment and trafficking. While many chemokines can act on lymphocytes, the roles of chemokines and their receptors in lymphocyte biology are poorly understood. The recent discoveries that chemokines can suppress infection by HIV-1 and that chemokine receptors serve, along with CD4, as obligate co-receptors for HIV-1 entry have lent urgency to studies on the relationships between chemokines and lymphocytes. My laboratory has characterized Mig and Crg-2/IP-10, chemokines that are induced by IFN-g and that specifically target lymphocytes, particularly activated T cells. We have demonstrated that the genes for these chemokines are widely expressed during experimental infections in mice with protozoan and viral pathogens, but that the patterns of mig and crg-2 expression differed, suggesting non-redundant roles in vivo. Our related studies to identify new chemokine receptors from activated lymphocytes resulted in the cloning of STRL22 and STRL33. We and others have shown that STRL22 is a receptor for the CC chemokine MIP-3a, and STRL22 has been re-named CCR6. Although STRL33 remains an orphan receptor, we have shown that it can function as a co-receptor for HIV-1 envelope glycoproteins, and that it is active with a broader range of HIV-1 envelope glycoproteins than the major co-receptors described to date. The ability of STRL33 to function with a wide variety of envelope glycoproteins may become particularly important if therapies are instituted to block other specific co-receptors. We presume that investigations into the roles of chemokines and their receptors in lymphocyte biology will provide information important for understanding the pathogenesis of AIDS and for manipulating immune and inflammatory responses for clinical benefit

  9. The power of operon rearrangements for predicting functional associations

    Directory of Open Access Journals (Sweden)

    Gabriel Moreno-Hagelsieb

    2015-01-01

    Full Text Available In this mini-review I aim to make the case that operons might be the most powerful source for predicted associations among gene products. Such associations can help identify potential processes where the products of unannotated genes might play a role. The power of the operon for providing insight into functional associations stems from four features: (1 on average, around 60% of the genes in prokaryotes are associated into operons; (2 the functional associations between genes in operons tend to be highly conserved; (3 operons can be predicted with high accuracy by conservation of gene order and by the distances between adjacent genes in the same DNA strand; and (4 operons frequently reorganize, providing further insight into functional associations that would not be evident without these reorganization events.

  10. Cyclophosphamide, Alvocidib, and Rituximab in Treating Patients With High Risk B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2015-11-10

    Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  11. Thymic shared antigen-1. A novel thymocyte marker discriminating immature from mature thymocyte subsets.

    Science.gov (United States)

    Godfrey, D I; Masciantonio, M; Tucek, C L; Malin, M A; Boyd, R L; Hugo, P

    1992-04-01

    In a previous study, we raised a mAb (MTS 35) reacting with a plasma membrane Ag expressed on both cortical thymocytes and a subset of thymic medullary epithelial cells. In view of the shared expression of this molecule, we have defined it as thymic shared Ag-1 (TSA-1). Considering its selective reactivity with cortical, but not medullary thymocytes, the relevance of TSA-1 as a marker of immature T cells was investigated in detail in this study, using multicolor flow cytometric analysis. TSA-1 was found on all immature thymocyte subsets (CD3-4-8-, CD3-4+8-, CD3-4-8+, CD3-4+8+, CD3low4+8+). Conversely, CD3high4+8- and CD3high4-8+ thymocytes, early thymic migrants and peripheral T cells were TSA-1-. More refined gating and analysis of the transitional CD3intermediate/high4+8+ thymocytes, proposed candidates for negative selection, demonstrated that approximately one half were TSA-1-. In fact, there was a directly inverse relationship between TSA-1 and CD3 expression on thymocytes. In the periphery, TSA-1 was detected on B lymphocytes. TSA-1 is PI-linked and has a molecular mass of 17 kDa nonreduced, or 12 to 13 kDa reduced. Through cross-correlation analysis, this molecule was distinct from H-2K, PNA-R, CD5, CD11a/18, Thy-1, HSA, Ly6A/E, Ly6C, ThB, CD25, CD44. Hence TSA-1 appears to be a unique marker which exquisitely separates mature from immature thymocytes.

  12. LYMPHOCYTE APOPTOSIS IN PSORIASIS

    Directory of Open Access Journals (Sweden)

    О. M. Kapuler

    2006-01-01

    Full Text Available Abstract. Forty-two patients with progressive vulgar psoriasis (PASI = 19.7 ± 1.5 and 40 healthy volunteers were under investigation. Psoriatic patients were characterized by increased number of CD4+ CD95+ peripheral blood T lymphocytes, which correlates with clinical psoriatic score, and by increased levels of soluble Fas (sFas in serum, as compared to controls (resp., 1868.1 ± 186.8 pg/ml vs. 1281.4 ± 142.5 pg/ml, PLSD = 0.019. The levels of spontaneous lymphocyte apoptosis and anti-Fas (Mab-induced apoptosis in psoriatic patients did not differ from the controls. However, apoptosis induced by “oxidative stress” (50 M Н202, 4 hrs was depressed in the patients. Moreover, a simultaneous assessment of cell cycle structure (metachromatic staining with Acridine Orange, apoptosis and Fas receptor expression (AnnV-FITC/antiFas mAbs-PE staining following a short-term mitogenic stimulation (PHA-P, 5 µg/ml, 24 hrs were performed. We found no marked differences in mitogenic reactivity, activation-induced apoptosis, and activation-induced Fas receptor expression when studying lymphocytes from healthy donors and psoriatic patients. However, PHA-activated lymphocytes from psoriatic patients displayed a significantly decreased ratio of AnnV+CD95+ to the total AnnV+ subpopulation, thus suggesting a decreased role of Fas-dependent mechanisms of apoptosis during the cell activation. The data obtained confirm a view, that an abnormal lymphocyte “apoptotic reactivity”, which plays a crucial role in the mechanisms of autoimmunity, may also of importance in the pathogenesis of psoriasis.

  13. ON WEIGHTED GENERALIZED FUNCTIONS ASSOCIATED WITH QUADRATIC FORMS

    Directory of Open Access Journals (Sweden)

    E. L. Shishkina

    2016-12-01

    Full Text Available In this article we consider certain types of weighted generalized functions associated with nondegenerate quadratic forms. Such functions and their derivatives are used for constructing fundamental solutions of iterated ultra-hyperbolic equations with the Bessel operator and for constructing negative real powers of ultra-hyperbolic operators with the Bessel operator.

  14. Higher Genus Abelian Functions Associated with Cyclic Trigonal Curves

    Directory of Open Access Journals (Sweden)

    Matthew England

    2010-03-01

    Full Text Available We develop the theory of Abelian functions associated with cyclic trigonal curves by considering two new cases. We investigate curves of genus six and seven and consider whether it is the trigonal nature or the genus which dictates certain areas of the theory. We present solutions to the Jacobi inversion problem, sets of relations between the Abelian function, links to the Boussinesq equation and a new addition formula.

  15. Curcumin and Cholecalciferol in Treating Patients With Previously Untreated Stage 0-II Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2016-10-04

    Contiguous Stage II Small Lymphocytic Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia

  16. Nonmuscle myosin heavy chain IIA mediates integrin LFA-1 de-adhesion during T lymphocyte migration.

    Science.gov (United States)

    Morin, Nicole A; Oakes, Patrick W; Hyun, Young-Min; Lee, Dooyoung; Chin, Y Eugene; Chin, Eugene Y; King, Michael R; Springer, Timothy A; Shimaoka, Motomu; Tang, Jay X; Reichner, Jonathan S; Kim, Minsoo

    2008-01-21

    Precise spatial and temporal regulation of cell adhesion and de-adhesion is critical for dynamic lymphocyte migration. Although a great deal of information has been learned about integrin lymphocyte function-associated antigen (LFA)-1 adhesion, the mechanism that regulates efficient LFA-1 de-adhesion from intercellular adhesion molecule (ICAM)-1 during T lymphocyte migration is unknown. Here, we show that nonmuscle myosin heavy chain IIA (MyH9) is recruited to LFA-1 at the uropod of migrating T lymphocytes, and inhibition of the association of MyH9 with LFA-1 results in extreme uropod elongation, defective tail detachment, and decreased lymphocyte migration on ICAM-1, without affecting LFA-1 activation by chemokine CXCL-12. This defect was reversed by a small molecule antagonist that inhibits both LFA-1 affinity and avidity regulation, but not by an antagonist that inhibits only affinity regulation. Total internal reflection fluorescence microscopy of the contact zone between migrating T lymphocytes and ICAM-1 substrate revealed that inactive LFA-1 is selectively localized to the posterior of polarized T lymphocytes, whereas active LFA-1 is localized to their anterior. Thus, during T lymphocyte migration, uropodal adhesion depends on LFA-1 avidity, where MyH9 serves as a key mechanical link between LFA-1 and the cytoskeleton that is critical for LFA-1 de-adhesion.

  17. Lymphocyte 'homing' and chronic inflammation.

    Science.gov (United States)

    Sakai, Yasuhiro; Kobayashi, Motohiro

    2015-07-01

    Chronic inflammation is a response to prolonged exposure to injurious stimuli that harm and destroy tissues and promote lymphocyte infiltration into inflamed sites. Following progressive accumulation of lymphocytes, the histology of inflamed tissue begins to resemble that of peripheral lymphoid organs, which can be referred to as lymphoid neogenesis or formation of tertiary lymphoid tissues. Lymphocyte recruitment to inflamed tissues is also reminiscent of lymphocyte homing to peripheral lymphoid organs. In the latter, under physiological conditions, homing receptors expressed on lymphocytes adhere to vascular addressin expressed on high endothelial venules (HEVs), initiating a lymphocyte migration process composed of sequential adhesive interactions. Intriguingly, in chronic inflammation, HEV-like vessels are induced de novo, despite the fact that the inflamed site is not originally lymphoid tissue, and these vessels contribute to lymphocyte recruitment in a manner similar to physiological lymphocyte homing. In this review, we first describe physiological lymphocyte homing mechanisms focusing on vascular addressins. We then describe HEV-like vessel-mediated pathogenesis seen in various chronic inflammatory disorders such as Helicobacter pylori gastritis, inflammatory bowel disease (IBD), autoimmune pancreatitis and sclerosing sialadenitis, as well as chronic inflammatory cell neoplasm MALT lymphoma, with reference to our work and that of others.

  18. Lymphocyte Trafficking to Mucosal Tissues

    DEFF Research Database (Denmark)

    Mikhak, Zamaneh; Agace, William Winston; Luster, Andrew D.

    2015-01-01

    Lymphocytes are the key cells of the adaptive immune system that provide antigen-specific responses tailored to the context of antigen exposure. Through cytokine release and antibody production, lymphocytes orchestrate and amplify the recruitment and function of other immune cells and contribute...... to host defense against invading pathogens and the pathogenesis of many inflammatory diseases. Lymphocyte function is critically dependent on their ability to traffic into the correct anatomic locations at the appropriate times. This process is highly regulated and requires that lymphocytes interact...

  19. Lymphocytic Interstitial Pneumonia.

    Science.gov (United States)

    Panchabhai, Tanmay S; Farver, Carol; Highland, Kristin B

    2016-09-01

    Lymphocytic interstitial pneumonia (LIP) is a rare lung disease on the spectrum of benign pulmonary lymphoproliferative disorders. LIP is frequently associated with connective tissue diseases or infections. Idiopathic LIP is rare; every attempt must be made to diagnose underlying conditions when LIP is diagnosed. Computed tomography of the chest in patients with LIP may reveal ground-glass opacities, centrilobular and subpleural nodules, and randomly distributed thin-walled cysts. Demonstrating polyclonality with immunohistochemistry is the key to differentiating LIP from lymphoma. The 5-year mortality remains between 33% and 50% and is likely to vary based on the underlying disease process.

  20. Identification of Protective B-Cell Epitopes within the Novel Malaria Vaccine Candidate Plasmodium falciparum Schizont Egress Antigen 1.

    Science.gov (United States)

    Nixon, Christina E; Park, Sangshin; Pond-Tor, Sunthorn; Raj, Dipak; Lambert, Lynn E; Orr-Gonzalez, Sachy; Barnafo, Emma K; Rausch, Kelly M; Friedman, Jennifer F; Fried, Michal; Duffy, Patrick E; Kurtis, Jonathan D

    2017-07-01

    Naturally acquired antibodies to Plasmodium falciparum schizont egress antigen 1 (PfSEA-1A) are associated with protection against severe malaria in children. Vaccination of mice with SEA-1A from Plasmodium berghei (PbSEA-1A) decreases parasitemia and prolongs survival following P. berghei ANKA challenge. To enhance the immunogenicity of PfSEA-1A, we identified five linear B-cell epitopes using peptide microarrays probed with antisera from nonhuman primates vaccinated with recombinant PfSEA-1A (rPfSEA-1A). We evaluated the relationship between epitope-specific antibody levels and protection from parasitemia in a longitudinal treatment-reinfection cohort in western Kenya. Antibodies to three epitopes were associated with 16 to 17% decreased parasitemia over an 18-week high transmission season. We are currently designing immunogens to enhance antibody responses to these three epitopes. Copyright © 2017 American Society for Microbiology.

  1. Chronic lymphocytic leukaemia

    Science.gov (United States)

    Kipps, Thomas J.; Stevenson, Freda K.; Wu, Catherine J.; Croce, Carlo M.; Packham, Graham; Wierda, William G.; O’Brien, Susan; Gribben, John; Rai, Kanti

    2017-01-01

    Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5+ B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow and lymphoid tissues. Signalling via surface immunoglobulin, which constitutes the major part of the B cell receptor, and several genetic alterations play a part in CLL pathogenesis, in addition to interactions between CLL cells and other cell types, such as stromal cells, T cells and nurse-like cells in the lymph nodes. The clinical progression of CLL is heterogeneous and ranges from patients who require treatment soon after diagnosis to others who do not require therapy for many years, if at all. Several factors, including the immunoglobulin heavy-chain variable region gene (IGHV) mutational status, genomic changes, patient age and the presence of comorbidities, should be considered when defining the optimal management strategies, which include chemotherapy, chemoimmunotherapy and/or drugs targeting B cell receptor signalling or inhibitors of apoptosis, such as BCL-2. Research on the biology of CLL has profoundly enhanced our ability to identify patients who are at higher risk for disease progression and our capacity to treat patients with drugs that selectively target distinctive phenotypic or physiological features of CLL. How these and other advances have shaped our current understanding and treatment of patients with CLL is the subject of this Primer. PMID:28102226

  2. Decreased deformability of lymphocytes in chronic lymphocytic leukemia

    Science.gov (United States)

    Zheng, Yi; Wen, Jun; Nguyen, John; Cachia, Mark A.; Wang, Chen; Sun, Yu

    2015-01-01

    This paper reports the first study of stiffness/deformability changes of lymphocytes in chronic lymphocytic leukemia (CLL) patients, demonstrating that at the single cell level, leukemic metastasis progresses are accompanied by biophysical property alterations. A microfluidic device was utilized to electrically measure cell volume and transit time of single lymphocytes from healthy and CLL patients. The results from testing thousands of cells reveal that lymphocytes from CLL patients have higher stiffness (i.e., lower deformability), as compared to lymphocytes in healthy samples, which was also confirmed by AFM indentation tests. This observation is in sharp contrast to the known knowledge on other types of metastatic cells (e.g., breast and lung cancer cells) whose stiffness becomes lower as metastasis progresses.

  3. The function of platelet and T cell activation antigen 1 (PTA1) on NK cells%血小板T细胞活化抗原1分子在NK细胞上的作用研究

    Institute of Scientific and Technical Information of China (English)

    张贇; 金伯泉; 欧阳为明; 李林; 李德敏; 朱勇; 贾卫; 刘雪松; 李琦; 张新海

    2001-01-01

    目的研究血小板T细胞活化抗原1(PTA1)分子在NK细胞杀伤过程中的作用。方法应用重导向细胞毒实验,探讨了PTA1分子对混合淋巴细胞反应中活化的NK细胞杀伤作用的影响。结果在重导向细胞毒实验中,PTA1 McAb能明显上调NK细胞及CTL的杀伤活性。结论 PTA1分子在NK细胞上具有刺激性受体的功能。%Objective To study the function of platelet and T cell activation antigen 1(PTA1) in cytotoxicity of human NK cells. Methods Redirected cytotoxicity assay (RCA) was used to detect the effect of PTA1 on cytotoxicity of NK cells generated from mixed lymphocyte culture (MLC). Results In RCA, PTA1 McAb upregulated the cytotoxicity of NK cells and CTLs. Conclusion PTA1 functions as an activation receptor/membrane molecule on killer cells including NK and CTLs.

  4. Obinutuzumab in chronic lymphocytic leukemia.

    Science.gov (United States)

    Dupuis, Jehan

    2015-09-01

    Obinutuzumab is the second next-generation monoclonal anti-CD20 antibody (after ofatumumab) to enter clinical practice in chronic lymphocytic leukemia. Its superiority in association with chlorambucil as compared with chlorambucil alone has led to its approval as a first-line treatment for chronic lymphocytic leukemia, for patients who are not candidates for a more intensive treatment.

  5. Expression, biosynthesis and release of preadipocyte factor-1/ delta-like protein/fetal antigen-1 in pancreatic beta-cells

    DEFF Research Database (Denmark)

    Friedrichsen, B N; Carlsson, C; Møldrup, Annette

    2003-01-01

    Preadipocyte factor-1 (Pref-1)/delta-like protein/fetal antigen-1 (FA1) is a member of the epidermal growth factor-like family. It is widely expressed in embryonic tissues, whereas in adults it is confined to the adrenal gland, the anterior pituitary, the endocrine pancreas, the testis and the ov......Preadipocyte factor-1 (Pref-1)/delta-like protein/fetal antigen-1 (FA1) is a member of the epidermal growth factor-like family. It is widely expressed in embryonic tissues, whereas in adults it is confined to the adrenal gland, the anterior pituitary, the endocrine pancreas, the testis...

  6. Decitabine enhances stem cell antigen-1 expression in cigarette smoke extract-induced emphysema in animal model.

    Science.gov (United States)

    He, Zhi-Hui; Chen, Yan; Chen, Ping; He, Sheng-Dong; Ye, Ji-Ru; Liu, Da

    2016-01-01

    Stem cell antigen-1 (Sca-1) is a mouse glycosyl phosphatidylinositol-anchored protein and a cell surface marker found on hematopoietic stem cells (HSCs). Despite decades of study, its biological functions remain little known. Sca-1 is a typical marker of bone marrow-derived HSCs, it is also expressed by a mixture of tissue-resident stem, progenitor cells in nonhematopoietic organs. Endothelial progenitor cell (EPC) is a subtype of HSC and contributes to endothelial repair by homing in on locations of injury. Abnormal genetic methylation has been detected in smoking-related diseases. The present study aimed to investigate the lung function and histomorphology, the expression of Sca-1 gene in lung tissues, and bone marrow-derived EPCs in cigarette smoke extract (CSE)-induced emphysema mice, and to further determine whether Decitabine (Dec), the most widely used inhibitor of DNA methylation, could protect against the damages caused by CSE. The results of the present study demonstrated that Dec could partly protect against CSE-induced emphysema in mice, enhance Sca-1 expression in lung tissue, and bone marrow-derived EPCs. The results suggested that the depletion of the progenitor cell pool and DNA methylation of Sca-1 gene may be involved in the progression of emphysema in mice. © 2015 by the Society for Experimental Biology and Medicine.

  7. Molecular insights into the interaction between Plasmodium falciparum apical membrane antigen 1 and an invasion-inhibitory peptide.

    Directory of Open Access Journals (Sweden)

    Geqing Wang

    Full Text Available Apical membrane antigen 1 (AMA1 of the human malaria parasite Plasmodium falciparum has been implicated in invasion of the host erythrocyte. It interacts with malarial rhoptry neck (RON proteins in the moving junction that forms between the host cell and the invading parasite. Agents that block this interaction inhibit invasion and may serve as promising leads for anti-malarial drug development. The invasion-inhibitory peptide R1 binds to a hydrophobic cleft on AMA1, which is an attractive target site for small molecules that block parasite invasion. In this work, truncation and mutational analyses show that Phe5-Phe9, Phe12 and Arg15 in R1 are the most important residues for high affinity binding to AMA1. These residues interact with two well-defined binding hot spots on AMA1. Computational solvent mapping reveals that one of these hot spots is suitable for small molecule targeting. We also confirm that R1 in solution binds to AMA1 with 1:1 stoichiometry and adopts a secondary structure consistent with the major form of R1 observed in the crystal structure of the complex. Our results provide a basis for designing high affinity inhibitors of the AMA1-RON2 interaction.

  8. Genetic polymorphism in domain I of the apical membrane antigen-1 among Plasmodium knowlesi clinical isolates from Peninsular Malaysia.

    Science.gov (United States)

    Fong, Mun Yik; Wong, Shen Siang; Silva, Jeremy Ryan De; Lau, Yee Ling

    2015-12-01

    The simian malaria parasite Plasmodium knowlesi is now recognized as a species that can cause human malaria. The first report of large scale human knowlesi malaria was in 2004 in Malaysia Borneo. Since then, hundreds of human knowlesi malaria cases have been reported in Southeast Asia. The present study investigates the genetic polymorphism of P. knowlesi DI domain of the apical membrane antigen-1 (AMA-1), a protein considered as a promising vaccine candidate for malaria. The DI domain of AMA-1 gene of P. knowlesi clinical isolates from Peninsular Malaysia was amplified by PCR, cloned into Escherichia coli, then sequenced and analysed. Ninety-seven DI domain sequences were obtained. Comparison at the nucleotide level against P. knowlesi strain H as reference sequence showed 21 synonymous and 25 nonsynonymous mutations. Nonetheless, nucleotide sequence analysis revealed low genetic diversity of the DI domain, and it was under purifying (negative) selection. At the amino acid level, 26 different haplotypes were identified and 2 were predominant haplotypes (H1, H2) with high frequencies. Phylogenetic analysis revealed that the 26 haplotypes could be clustered into 2 distinct groups (I and II). Members of the groups were basically derived from haplotypes H1 and H2, respectively.

  9. Plasmodium falciparum apical membrane antigen 1 vaccine elicits multifunctional CD4 cytokine-producing and memory T cells.

    Science.gov (United States)

    Huaman, Maria Cecilia; Mullen, Gregory E D; Long, Carole A; Mahanty, Siddhartha

    2009-08-20

    The Plasmodium falciparum apical membrane antigen 1 (AMA1) is a leading vaccine candidate and was tested for safety and immunogenicity in human Phase I Clinical Trials. PBMC from vaccine recipients were analyzed by flow cytometric methods to determine the nature of T-cell responses and AMA1-reactive memory T cells. Both CD4 and CD8 T cells produced a number of cytokines following AMA1 re-stimulation, with IL-5-producing cells at the highest frequency, consistent with a Th2 bias. The relative frequency of multifunctional cells synthesizing Th1 cytokines IFN-gamma, IL-2 and TNF-alpha changed after each vaccination. Interestingly, median fluorescence intensity measurements revealed that cells producing more than one cytokine contributed greater quantities of each cytokine than cell populations that produced each of the cytokines alone. AMA1 vaccination also elicited the development of memory cell populations, and both central and effector memory T cells were identified concurrently after the AMA1 vaccination. The detailed profile of multifunctional T-cell responses to AMA1 presented here will advance our ability to assess the immunogenicity of human malarial vaccines.

  10. Comparative sequence analysis of domain I of Plasmodium falciparum apical membrane antigen 1 from Saudi Arabia and worldwide isolates.

    Science.gov (United States)

    Al-Qahtani, Ahmed A; Abdel-Muhsin, Abdel-Muhsin A; Bin Dajem, Saad M; AlSheikh, Adel Ali H; Bohol, Marie Fe F; Al-Ahdal, Mohammed N; Putaporntip, Chaturong; Jongwutiwes, Somchai

    2016-04-01

    The apical membrane antigen 1 of Plasmodium falciparum (PfAMA1) plays a crucial role in erythrocyte invasion and is a target of protective antibodies. Although domain I of PfAMA1 has been considered a promising vaccine component, extensive sequence diversity in this domain could compromise an effective vaccine design. To explore the extent of sequence diversity in domain I of PfAMA1, P. falciparum-infected blood samples from Saudi Arabia collected between 2007 and 2009 were analyzed and compared with those from worldwide parasite populations. Forty-six haplotypes and a novel codon change (M190V) were found among Saudi Arabian isolates. The haplotype diversity (0.948±0.004) and nucleotide diversity (0.0191±0.0008) were comparable to those from African hyperendemic countries. Positive selection in domain I of PfAMA1 among Saudi Arabian parasite population was observed because nonsynonymous nucleotide substitutions per nonsynonymous site (dN) significantly exceeded synonymous nucleotide substitutions per synonymous site (dS) and Tajima's D and its related statistics significantly deviated from neutrality in the positive direction. Despite a relatively low prevalence of malaria in Saudi Arabia, a minimum of 17 recombination events occurred in domain I. Genetic differentiation was significant between P. falciparum in Saudi Arabia and parasites from other geographic origins. Several shared or closely related haplotypes were found among parasites from different geographic areas, suggesting that vaccine derived from multiple shared epitopes could be effective across endemic countries.

  11. Characterization of Fetal Antigen 1/Delta-Like 1 Homologue Expressing Cells in the Rat Nigrostriatal System

    DEFF Research Database (Denmark)

    Liechti, Rémy; Ducray, Angélique D; Jensen, Pia;

    2015-01-01

    Fetal antigen 1/delta-like 1 homologue (FA1/dlk1) belongs to the epidermal growth factor superfamily and is considered to be a non-canonical ligand for the Notch receptor. Interactions between Notch and its ligands are crucial for the development of various tissues. Moreover, FA1/dlk1 has been su...... adult rats. FA1/dlk1-ir cells were predominantly distributed in the substantia nigra (SN) pars compacta (SNc) and in the ventral tegmental area. Interestingly, the expression of FA1/dlk1 significantly increased in tyrosine hydroxylase (TH)-ir cells during early postnatal development. Co......-localization and tracing studies demonstrated that FA1/dlk1-ir cells in the SNc were nigrostriatal dopaminergic neurons, and unilateral 6-OHDA lesions resulted in loss of both FA1/dlk1-ir and TH-ir cells in the SNc. Surprisingly, increased numbers of FA1/dlk1-ir cells (by 70%) were detected in dopamine-depleted striata...... as compared to unlesioned controls. The higher number of FA1/dlk1-ir cells was likely not due to neurogenesis as colocalization studies for proliferation markers were negative. This suggests that FA1/dlk1 was up-regulated in intrinsic cells in response to the 6-OHDA-mediated loss of FA1/dlk1-expressing SNc...

  12. Laboratorial diagnosis of lymphocytic meningitis

    Directory of Open Access Journals (Sweden)

    Sérgio Monteiro de Almeida

    Full Text Available Meningitis is the main infectious central nervous system (CNS syndrome. Viruses or bacteria can cause acute meningitis of infectious etiology. The term "Aseptic Meningitis" denotes a clinical syndrome with a predominance of lymphocytes in the cerebrospinal fluid (CSF, with no common bacterial agents identified in the CSF. Viral meningitis is considered the main cause of lymphocyte meningitis. There are other etiologies of an infectious nature. CSF examination is essential to establish the diagnosis and to identify the etiological agent of lymphocytic meningitis. We examined CSF characteristics and the differential diagnosis of the main types of meningitis.

  13. Laboratorial diagnosis of lymphocytic meningitis

    Directory of Open Access Journals (Sweden)

    Sérgio Monteiro de Almeida

    2007-10-01

    Full Text Available Meningitis is the main infectious central nervous system (CNS syndrome. Viruses or bacteria can cause acute meningitis of infectious etiology. The term "Aseptic Meningitis" denotes a clinical syndrome with a predominance of lymphocytes in the cerebrospinal fluid (CSF, with no common bacterial agents identified in the CSF. Viral meningitis is considered the main cause of lymphocyte meningitis. There are other etiologies of an infectious nature. CSF examination is essential to establish the diagnosis and to identify the etiological agent of lymphocytic meningitis. We examined CSF characteristics and the differential diagnosis of the main types of meningitis.

  14. Genes2FANs: connecting genes through functional association networks

    Directory of Open Access Journals (Sweden)

    Dannenfelser Ruth

    2012-07-01

    Full Text Available Abstract Background Protein-protein, cell signaling, metabolic, and transcriptional interaction networks are useful for identifying connections between lists of experimentally identified genes/proteins. However, besides physical or co-expression interactions there are many ways in which pairs of genes, or their protein products, can be associated. By systematically incorporating knowledge on shared properties of genes from diverse sources to build functional association networks (FANs, researchers may be able to identify additional functional interactions between groups of genes that are not readily apparent. Results Genes2FANs is a web based tool and a database that utilizes 14 carefully constructed FANs and a large-scale protein-protein interaction (PPI network to build subnetworks that connect lists of human and mouse genes. The FANs are created from mammalian gene set libraries where mouse genes are converted to their human orthologs. The tool takes as input a list of human or mouse Entrez gene symbols to produce a subnetwork and a ranked list of intermediate genes that are used to connect the query input list. In addition, users can enter any PubMed search term and then the system automatically converts the returned results to gene lists using GeneRIF. This gene list is then used as input to generate a subnetwork from the user’s PubMed query. As a case study, we applied Genes2FANs to connect disease genes from 90 well-studied disorders. We find an inverse correlation between the counts of links connecting disease genes through PPI and links connecting diseases genes through FANs, separating diseases into two categories. Conclusions Genes2FANs is a useful tool for interpreting the relationships between gene/protein lists in the context of their various functions and networks. Combining functional association interactions with physical PPIs can be useful for revealing new biology and help form hypotheses for further experimentation. Our

  15. Fetal antigen 1, an EGF multidomain protein in the sex hormone-producing cells of the gonads and the microenvironment of germ cells

    DEFF Research Database (Denmark)

    Jensen, Charlotte Harken; Erb, K; Westergaard, L G

    1999-01-01

    Fetal antigen 1 (FA1), an epidermal growth factor (EGF) multidomain glycoprotein, was investigated in the human reproductive system. Immunohistochemical analysis of the male reproductive system revealed staining for FA1 in the Leydig cells only. Concentrations of FA1 in seminal plasma and serum w...

  16. Mouse fetal antigen 1 (mFA1), the circulating gene product of mdlk, pref-1 and SCP-1: isolation, characterization and biology

    DEFF Research Database (Denmark)

    Bachmann, E; Krogh, T N; Højrup, P

    1996-01-01

    The mouse homologue to human fetal antigen 1 (hFA1) was purified from mouse amniotic fluid by cation exchange chromatography and immunospecific affinity chromatography. Mouse FA1 (mFA1) is a single chain glycoprotein with an M(r) of 42-50 kDa (SDS-PAGE). The N-terminal amino acid sequence (39 res...

  17. Delta-like 1/fetal antigen 1(DLK1/FA1) inhibits BMP2 induced osteoblast differentiation through modulation of NFκB signaling pathway

    DEFF Research Database (Denmark)

    Qiu, Weimin; Abdallah, Basem; Kassem, Moustapha

    DLK1/FA1 (delta-like 1/fetal antigen-1) is a negative regulator of bone mass that acts to inhibit osteoblast differentiation and stimulate osteoclast differentiation. However, the molecular mechanisms underlying these effects are not known. Thus, we studied the effect of DLK1/FA1 on different...

  18. Initiation of lymphocyte DNA synthesis.

    Science.gov (United States)

    Coffman, F D; Fresa, K L; Cohen, S

    1991-01-01

    The initiation of DNA replication in T lymphocytes appears to be regulated by two distinct activities: one associated with proliferation which mediates initiation, and another associated with quiescence which blocks initiation. Activated lymphocytes and proliferating lymphoid cell lines produce an activity, termed ADR, which can initiate DNA replication in isolated, quiescent nuclei. ADR is heat-labile, has protease activity or interacts closely with a protease, and is distinct from the DNA polymerases. ADR activity is absent in quiescent lymphocytes and appears in mitogen-stimulated lymphocytes after IL-2 binding. The generation of active ADR appears to be mediated by phosphorylation of a precursor which is present in resting cells. Nuclei from mitogen-unresponsive lymphocytes fail to initiate DNA replication in response to ADR, of potential importance in the age-related decline of immunity. Quiescent lymphocytes lack ADR and synthesize an ADR-inhibitory activity. The ADR inhibitor is a heat-stable protein which suppresses the initiation of DNA synthesis, but is ineffective at suppressing elongation once DNA strand replication has begun. Nuclei from several neoplastic cell lines fail to respond to the ADR inhibitor, which may play a role in the continuous proliferation of these cells. At least one of these neoplastic cell lines produces both ADR and an inhibitory factor. These findings suggest that the regulation of proliferation is dependent on the balance between activating and inhibitory pathways.

  19. Markers of T cell infiltration and function associate with favorable outcome in vascularized high-grade serous ovarian carcinoma.

    Directory of Open Access Journals (Sweden)

    Katelin N Townsend

    Full Text Available BACKGROUND: When T cells infiltrate the tumor environment they encounter a myriad of metabolic stressors including hypoxia. Overcoming the limitations imposed by an inadequate tumor vasculature that contributes to these stressors may be a crucial step to immune cells mounting an effective anti-tumor response. We sought to determine whether the functional capacity of tumor infiltrating lymphocytes (TIL could be influenced by the tumor vasculature and correlated this with survival in patients with ovarian cancer. METHODOLOGY AND PRINCIPAL FINDINGS: In 196 high-grade serous ovarian tumors, we confirmed that the tumor vascularity as measured by the marker CD31 was associated with improved patient disease-specific survival. We also found that tumors positive for markers of TIL (CD8, CD4 and forkhead box P3 (FoxP3 and T cell function (granzyme B and T-cell restricted intracellular antigen-1 (TIA-1 correlated significantly with elevated vascularity. In vitro, hypoxic CD8 T cells showed reduced cytolytic activity, secreted less effector cytokines and upregulated autophagy. Survival analysis revealed that patients had a significant improvement in disease-specific survival when FoxP3 expressing cells were present in CD31-high tumors compared to patients with FoxP3 expressing cells in CD31-low tumors [HR: 2.314 (95% CI 1.049-5.106; p = 0.0377]. Patients with high vascular endothelial growth factor (VEGF expressing tumors containing granzyme B positive cells had improved survival compared to patients with granzyme B positive cells in VEGF-low tumors [HR: 2.522 (95% CI 1.097-5.799; p = 0.0294]. SIGNIFICANCE: Overall, this data provides a rationale for developing strategies aimed at improving the adaptability and function of TIL to hypoxic tumor conditions.

  20. Natural selection and population genetic structure of domain-I of Plasmodium falciparum apical membrane antigen-1 in India.

    Science.gov (United States)

    Basu, Madhumita; Maji, Ardhendu Kumar; Mitra, Mitashree; Sengupta, Sanghamitra

    2013-08-01

    Development of a vaccine against Plasmodium falciparum infection is an urgent priority particularly because of widespread resistance to most traditionally used drugs. Multiple evidences point to apical membrane antigen-1(AMA-1) as a prime vaccine candidate directed against P. falciparum asexual blood-stages. To gain understanding of the genetic and demographic forces shaping the parasite sequence diversity in Kolkata, a part of Pfama-1 gene covering domain-I was sequenced from 100 blood samples of malaria patients. Statistical and phylogenetic analyses of the sequences were performed using DnaSP and MEGA. Very high haplotype diversity was detected both at nucleotide (0.998±0.002) and amino-acid (0.996±0.001) levels. An abundance of low frequency polymorphisms (Tajima's D=-1.190, Fu & Li's D(∗) and F(∗)=-3.068 and -2.722), unimodal mismatch distribution and a star-like median-joining network of ama-1 haplotypes indicated a recent population expansion among Kolkata parasites. The high minimum number of recombination events (Rm=26) and a significantly high dN/dS of 3.705 (PIgNAR. Alterations in the desolvation and global energies of PfAMA-1-PfRON2 interaction complexes at the hotspot contact residues were observed together with redistribution of surface electrostatic potentials at the variant alleles with respect to referent Pf3D7 sequence. Finally, a comparison of P. falciparum subpopulations in five Indian regional isolates retrieved from GenBank revealed a significant level of genetic differentiation (FST=0.084-0.129) with respect to Kolkata sequences. Collectively, our results indicated a very high allelic and haplotype diversity, a high recombination rate and a signature of natural selection favoring accumulation of non-synonymous substitutions that facilitated PfAMA-1-PfRON2 interaction and hence parasite growth in Kolkata clinical isolates.

  1. Identification of a highly antigenic linear B cell epitope within Plasmodium vivax apical membrane antigen 1 (AMA-1.

    Directory of Open Access Journals (Sweden)

    Lilian Lacerda Bueno

    Full Text Available Apical membrane antigen 1 (AMA-1 is considered to be a major candidate antigen for a malaria vaccine. Previous immunoepidemiological studies of naturally acquired immunity to Plasmodium vivax AMA-1 (PvAMA-1 have shown a higher prevalence of specific antibodies to domain II (DII of AMA-1. In the present study, we confirmed that specific antibody responses from naturally infected individuals were highly reactive to both full-length AMA-1 and DII. Also, we demonstrated a strong association between AMA-1 and DII IgG and IgG subclass responses. We analyzed the primary sequence of PvAMA-1 for B cell linear epitopes co-occurring with intrinsically unstructured/disordered regions (IURs. The B cell epitope comprising the amino acid sequence 290-307 of PvAMA-1 (SASDQPTQYEEEMTDYQK, with the highest prediction scores, was identified in domain II and further selected for chemical synthesis and immunological testing. The antigenicity of the synthetic peptide was identified by serological analysis using sera from P. vivax-infected individuals who were knowingly reactive to the PvAMA-1 ectodomain only, domain II only, or reactive to both antigens. Although the synthetic peptide was recognized by all serum samples specific to domain II, serum with reactivity only to the full-length protein presented 58.3% positivity. Moreover, IgG reactivity against PvAMA-1 and domain II after depletion of specific synthetic peptide antibodies was reduced by 18% and 33% (P = 0.0001 for both, respectively. These results suggest that the linear epitope SASDQPTQYEEEMTDYQK is highly antigenic during natural human infections and is an important antigenic region of the domain II of PvAMA-1, suggesting its possible future use in pre-clinical studies.

  2. Differentiation of bone marrow-derived stage-specific embryonic antigen 1 positive pluripotent stem cells into male germ cells.

    Science.gov (United States)

    Shirazi, Reza; Zarnani, Amir Hassan; Soleimani, Masoud; Nayernia, Karim; Ragerdi Kashani, Iraj

    2017-04-01

    Studies published in recent years have changed the outlook on sterility and germ cell development by producing gametes from stem cells. In present study, a novel approach on differentiation of bone marrow-derived stage-specific embryonic antigen 1 positive (SSEA-1(+) ) pluripotent stem cells into male germ cells has been addressed. SSEA-1(+) stem cells were separated from murine bone marrow using magnetic-activated cell sorting (MACS) system and propagated on a feeder layer cells. To evaluate the pluripotency characteristic of the purified cells, they were differentiated toward cells of three germ layers. Later the SSEA-1(+) stem cells were induced to differentiate along male germ cell lineage with retinoic acid. Flowcytometric analysis of SSEA-1(+) stem cells revealed purity of about 62% which increased to 91% after cultivation over feeder cells. Expression of specific transcripts of Oct4, SSEA-1, Nanog, Dppa3, fragilis, Rex-1, SOX-2, and alkaline-phosphatase and immunofluorescence evaluation of Oct4 and SSEA-1 expression showed the differentiation of purified stem cells toward the cells of three germ layers. Differentiation potential of purified cells was positively evidenced by expression markers specific for primordial germ cells, spermatogonial stem cells and spermatogonia including Mvh, fragilis, Dppa3, Stra8, DAZL, Piwil2, β1, and α6-integrins as well as meiotic-specific marker SYCP3. Our results showed that SSEA-1(+) pluripotent stem cells are able to differentiate into male germ cells. The results of the present study are encouraging enough to merit further investigation, provide a new hope for those suffering from infertility and introduce a novel platform for research on germ cell development. © 2016 Wiley Periodicals, Inc.

  3. Epstein-Barr virus nuclear antigen 1 interacts with regulator of chromosome condensation 1 dynamically throughout the cell cycle.

    Science.gov (United States)

    Deschamps, Thibaut; Bazot, Quentin; Leske, Derek M; MacLeod, Ruth; Mompelat, Dimitri; Tafforeau, Lionel; Lotteau, Vincent; Maréchal, Vincent; Baillie, George S; Gruffat, Henri; Wilson, Joanna B; Manet, Evelyne

    2017-02-01

    The Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is a sequence-specific DNA-binding protein that plays an essential role in viral episome replication and segregation, by recruiting the cellular complex of DNA replication onto the origin (oriP) and by tethering the viral DNA onto the mitotic chromosomes. Whereas the mechanisms of viral DNA replication are well documented, those involved in tethering EBNA1 to the cellular chromatin are far from being understood. Here, we have identified regulator of chromosome condensation 1 (RCC1) as a novel cellular partner for EBNA1. RCC1 is the major nuclear guanine nucleotide exchange factor for the small GTPase Ran enzyme. RCC1, associated with chromatin, is involved in the formation of RanGTP gradients critical for nucleo-cytoplasmic transport, mitotic spindle formation and nuclear envelope reassembly following mitosis. Using several approaches, we have demonstrated a direct interaction between these two proteins and found that the EBNA1 domains responsible for EBNA1 tethering to the mitotic chromosomes are also involved in the interaction with RCC1. The use of an EBNA1 peptide array confirmed the interaction of RCC1 with these regions and also the importance of the N-terminal region of RCC1 in this interaction. Finally, using confocal microscopy and Förster resonance energy transfer analysis to follow the dynamics of interaction between the two proteins throughout the cell cycle, we have demonstrated that EBNA1 and RCC1 closely associate on the chromosomes during metaphase, suggesting an essential role for the interaction during this phase, perhaps in tethering EBNA1 to mitotic chromosomes.

  4. High antibody titer against apical membrane antigen-1 is required to protect against malaria in the Aotus model.

    Directory of Open Access Journals (Sweden)

    Sheetij Dutta

    Full Text Available A Plasmodium falciparum 3D7 strain Apical Membrane Antigen-1 (AMA1 vaccine, formulated with AS02(A adjuvant, slowed parasite growth in a recent Phase 1/2a trial, however sterile protection was not observed. We tested this AS02(A, and a Montanide ISA720 (ISA formulation of 3D7 AMA1 in Aotus monkeys. The 3D7 parasite does not invade Aotus erythrocytes, hence two heterologous strains, FCH/4 and FVO, were used for challenge, FCH/4 AMA1 being more homologous to 3D7 than FVO AMA1. Following three vaccinations, the monkeys were challenged with 50,000 FCH/4 or 10,000 FVO parasites. Three of the six animals in the AMA+ISA group were protected against FCH/4 challenge. One monkey did not become parasitemic, another showed only a short period of low level parasitemia that self-cured, and a third animal showed a delay before exhibiting its parasitemic phase. This is the first protection shown in primates with a recombinant P. falciparum AMA1 without formulation in Freund's complete adjuvant. No animals in the AMA+AS02(A group were protected, but this group exhibited a trend towards reduced growth rate. A second group of monkeys vaccinated with AMA+ISA vaccine was not protected against FVO challenge, suggesting strain-specificity of AMA1-based protection. Protection against FCH/4 strain correlated with the quantity of induced antibodies, as the protected animals were the only ones to have in vitro parasite growth inhibitory activity of >70% at 1:10 serum dilution; immuno-fluorescence titers >8,000; ELISA titers against full-length AMA1 >300,000 and ELISA titer against AMA1 domains1+2 >100,000. A negative correlation between log ELISA titer and day 11 cumulative parasitemia (Spearman rank r = -0.780, p value = 0.0001, further confirmed the relationship between antibody titer and protection. High titers of cross-strain inhibitory antibodies against AMA1 are therefore critical to confer solid protection, and the Aotus model can be used to down-select future AMA1

  5. Essential Role for the Lymphostromal Plasma Membrane Ly-6 Superfamily Molecule Thymic Shared Antigen 1 in Development of the Embryonic Adrenal Gland

    OpenAIRE

    2002-01-01

    Thymic shared antigen 1 (TSA-1) is a plasma membrane protein of the Ly-6 superfamily expressed on thymocytes, thymic stromal cells, and other cells of the hematopoietic system. TSA-1 is also expressed in other nonhematopoietic tissues, in particular, embryonic and adult adrenal glands. To address the function of TSA-1, we generated mutant mice in which TSA-1 expression was inactivated by gene targeting. Here we show that deletion of both TSA-1 alleles results in abnormal adrenal gland develop...

  6. Studies on rabbit lymphocytes in vitro

    Science.gov (United States)

    Sell, S.; Gell, P. G. H.

    1969-01-01

    Anti-allotypic sera that have no known allotypic determinants other than those also present in the genotype of the lymphocyte donor are as able to induce lymphocyte `blast' transformation in vitro as are anti-allotypic sera that do have allotypic determinants that are not present in the lymphocyte donor. Therefore, anti-allotypic sera do not appear to function in the stimulation of blast transformation by providing access for any of the known allotypic determinants into lymphocytes. PMID:5769980

  7. Rapid exacerbation of lymphocytic infundibuloneurohypophysitis

    Science.gov (United States)

    Shibue, Kimitaka; Fujii, Toshihito; Goto, Hisanori; Yamashita, Yui; Sugimura, Yoshihisa; Tanji, Masahiro; Yasoda, Akihiro; Inagaki, Nobuya

    2017-01-01

    Abstract Rationale: Lymphocytic hypophysitis is a relatively rare autoimmune disease defined by lymphocytic infiltration to the pituitary. Its rarity and wide spectrum of clinical manifestations make clarification of the pathology difficult. Here, we describe a case we examined from the primary diagnosis to final discharge, showing the serial progression of lymphocytic infundibuloneurohypophysitis (LINH) to panhypopituitarism with extrapituitary inflammatory invasion in a short period, and responding favorably to high-dose glucocorticoid treatment. Patient concerns: Polyuria, General fatigue and Nausea/Vomiting. Diagnoses: Central diabetes insipidus (CDI), Lymphocytic infundibuloneurohypophysitis (LINH). Interventions: Desmopressin acetate, High-dose glucocorticoid (GC) treatment. Outcomes: He was prescribed desmopressin acetate and subsequently discharged. A month later, he revisited our hospital with general fatigue and nausea/vomiting. A screening test disclosed hypopituitarism with adrenal insufficiency. MRI revealed expanded contrast enhancement to the peripheral extrapituitary lesion. He received high-dose GC treatment and the affected lesion exhibited marked improvement on MRI, along with the recovery of the anterior pituitary function. Lessons: This case demonstrates the potential for classical LINH to develop into panhypopituitarsim. We consider this is the first documentation of approaching the cause of atypical LINH with progressive clinical course from the pathological viewpoint. PMID:28248860

  8. Treatment of chronic lymphocytic leukemia.

    Science.gov (United States)

    Ferrajoli, Alessandra; O'Brien, Susan M

    2004-04-01

    Treatment options for patients with chronic lymphocytic leukemia have changed over the past two decades. This article reviews the experience accumulated with the use of alkylating agents alone and in combination; purine analogues alone and in combination and monoclonal antibodies such as rituximab, and alemtuzumab alone and in combination. The results obtained with different treatment strategies are summarized, compared, and reviewed.

  9. Fludarabine Phosphate, Radiation Therapy, and Rituximab in Treating Patients Who Are Undergoing Donor Stem Cell Transplant Followed by Rituximab for High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2017-03-27

    Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma; T-Cell Large Granular Lymphocyte Leukemia

  10. Fludarabine Phosphate and Total-Body Irradiation Before Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia

    Science.gov (United States)

    2016-07-18

    B-Cell Prolymphocytic Leukemia; Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; T-Cell Prolymphocytic Leukemia

  11. Protection from anti-TCR/CD3-induced apoptosis in immature thymocytes by a signal through thymic shared antigen-1/stem cell antigen-2

    OpenAIRE

    1996-01-01

    During T cell development in the thymus, the expression of thymic shared antigen-1 (TSA-1)/stem cell antigen-2 (Sca-2), a glycosylphosphatidylinositol (GPI)-anchored differentiation antigen, is developmentally regulated. The expression level of TSA-1 is the highest in most immature CD4- CD8- thymocytes, high in CD4+ CD8+ thymocytes, but barely detectable in mature CD4+ CD8- or CD4- CD8- thymocytes and peripheral T cells. We have previously shown that surface TSA-1 expression in peripheral T c...

  12. Fetal antigen 1, an EGF multidomain protein in the sex hormone-producing cells of the gonads and the microenvironment of germ cells

    DEFF Research Database (Denmark)

    Jensen, Charlotte Harken; Erb, K; Westergaard, L G

    1999-01-01

    Fetal antigen 1 (FA1), an epidermal growth factor (EGF) multidomain glycoprotein, was investigated in the human reproductive system. Immunohistochemical analysis of the male reproductive system revealed staining for FA1 in the Leydig cells only. Concentrations of FA1 in seminal plasma and serum...... were similar and significantly correlated in weekly samples from three men (P men (n = 4) were not significantly different from those of normal men (n = 187). The concentration of FA1 in seminal plasma was significantly correlated...... with the sperm counts of normozoospermic men (P men with sperm counts > 20 x 10(6)/ml, compared with those with counts Udgivelsesdato: 1999-Oct...

  13. Opinion: Interactions of innate and adaptive lymphocytes

    Science.gov (United States)

    Gasteiger, Georg; Rudensky, Alexander Y.

    2015-01-01

    Innate lymphocytes, including natural killer (NK) cells and the recently discovered innate lymphoid cells (ILCs) have crucial roles during infection, tissue injury and inflammation. Innate signals regulate the activation and homeostasis of innate lymphocytes. Less well understood is the contribution of the adaptive immune system to the orchestration of innate lymphocyte responses. We review our current understanding of the interactions between adaptive and innate lymphocytes, and propose a model in which adaptive T cells function as antigen-specific sensors for the activation of innate lymphocytes to amplify and instruct local immune responses. We highlight the potential role of regulatory and helper T cells in these processes and discuss major questions in the emerging area of crosstalk between adaptive and innate lymphocytes. PMID:25132095

  14. [Adoptive transfer of T lymphocytes].

    Science.gov (United States)

    Vié, H; Clémenceau, B

    2017-09-01

    Within a few years, the success of treatments based on the use of T-cells armed with a chimeric T-receptor for the CD19 molecule (CAR-T CD19) has revolutionized the perception of adoptive transfer approaches. The levels of responses observed in acute leukemias, of the order of 70-90 % are indeed unprecedented. The medical and financial enthusiasm aroused by these results has led to the current situation where more than 300 clinical trials are under way, against some thirty different antigens. This enthusiasm, well justified by the first successes, must however be tempered by the difficulties associated with the use of these cells. Indeed, the management of patients is made very complex both for medical reasons, because the toxicities associated with these treatments are important, and for technical reasons, because the preparation of T lymphocytes for therapeutic use requires dedicated structures. During this same period, knowledge of the mechanisms of regulation of T lymphocytes and the possibilities offered by synthetic biology and techniques of genome engineering have progressed considerably. Combined, they allow envisaging a true "programming" of the T lymphocytes, intended to improve the efficiency of the treatments and the safety of the patients. Medical and industrial perspectives and the role of these approaches in the arsenal of cancer therapies will depend largely on two conditions: the emergence of a robust demonstration of their effectiveness in solid tumors, and the establishment of an acceptable production and distribution model 1. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  15. Lymphocyte subpopulations in Sheehan's syndrome.

    Science.gov (United States)

    Atmaca, Hulusi; Araslı, Mehmet; Yazıcı, Zihni Acar; Armutçu, Ferah; Tekin, Ishak Özel

    2013-06-01

    The role of autoimmunity in the development of Sheehan's syndrome is obscure. There are a limited number of studies investigating the immunological alterations accompanying Sheehan's Syndrome. Our objective was to evaluate lymphocyte subsets in these patients. We conducted a cross-sectional clinical study. Cytofluorometry was used for the immunophenotyping of peripheral blood leukocytes from patients with Sheehan's syndrome followed up in the endocrine clinic during 2005-2009. Fifteen consecutive patients (mean age 61.6 ± 11.3, range 34-75 years) and 25 healthy controls (mean age 56.7 ± 10.6, range 34-80 years) were included. There was no statistically significant difference between the groups in terms of mean age. The percentages of CD19(+), CD16(+)/56(+), CD8(+)28(-), γδTCR(+), CD8(+); the total lymphocyte counts; and the ratio of CD8(+)28(-)/CD8(+)28(+) were similar (p > 0.05) between patients and controls. Whereas the leucocyte counts (p = 0.003), the percentage of CD3 (+) DR (+) (p Sheehan's syndrome compared to healthy controls. There was a positive correlation between the duration of illness and the percentage of CD3(+)DR(+) (r = 0.53, p = 0.03) expression. Some peripheral lymphocyte cell subsets show marked variation in patients with Sheehan's syndrome in comparison to matched healthy subjects, which may have implications for altered immune regulation in these patients. High CD3 (+) DR (+) expression that correlates with the duration of illness in Sheehan's patients is suggestive of an ongoing inflammation accompanying the slow progression of pituitary dysfunction in Sheehan's syndrome. It is not clear if these cellular alterations contribute to the cause or consequence of pituitary deficiency in Sheehan's syndrome.

  16. Adipose tissue lymphocytes: types and roles.

    Science.gov (United States)

    Caspar-Bauguil, S; Cousin, B; Bour, S; Casteilla, L; Castiella, L; Penicaud, L; Carpéné, C

    2009-12-01

    Besides adipocytes, specialized in lipid handling and involved in energy balance regulation, white adipose tissue (WAT) is mainly composed of other cell types among which lymphocytes represent a non-negligible proportion. Different types of lymphocytes (B, alphabetaT, gammadeltaT, NK and NKT) have been detected in WAT of rodents or humans, and vary in their relative proportion according to the fat pad anatomical location. The lymphocytes found in intra-abdominal, visceral fat pads seem representative of innate immunity, while those present in subcutaneous fat depots are part of adaptive immunity, at least in mice. Both the number and the activity of the different lymphocyte classes, except B lymphocytes, are modified in obesity. Several of these modifications in the relative proportions of the lymphocyte classes depend on the degree of obesity, or on leptin concentration, or even fat depot anatomical location. Recent studies suggest that alterations of lymphocyte number and composition precede the macrophage increase and the enhanced inflammatory state of WAT found in obesity. Lymphocytes express receptors to adipokines while several proinflammatory chemokines are produced in WAT, rendering intricate crosstalk between fat and immune cells. However, the evidences and controversies available so far are in favour of an involvement of lymphocytes in the control of the number of other cells in WAT, either adipocytes or immune cells and of their secretory and metabolic activities. Therefore, immunotherapy deserves to be considered as a promising approach to treat the endocrino-metabolic disorders associated to excessive fat mass development.

  17. Autoimmune hepatitis in association with lymphocytic colitis.

    LENUS (Irish Health Repository)

    Cronin, Edmond M

    2012-02-03

    Autoimmune hepatitis is a rare, chronic inflammatory disorder which has been associated with a number of other auto-immune conditions. However, there are no reports in the medical literature of an association with microscopic (lymphocytic) colitis. We report the case of a 53-year-old woman with several autoimmune conditions, including lymphocytic colitis, who presented with an acute hepatitis. On the basis of the clinical features, serology, and histopathology, we diagnosed autoimmune hepatitis. To our knowledge, this is the first report of autoimmune hepatitis in association with lymphocytic colitis, and lends support to the theory of an autoimmune etiology for lymphocytic colitis.

  18. Lymphocyte-platelet crosstalk in Graves' disease.

    Science.gov (United States)

    Kuznik, Boris I; Vitkovsky, Yuri A; Gvozdeva, Olga V; Solpov, Alexey V; Magen, Eli

    2014-03-01

    Platelets can modulate lymphocytes' role in the pathophysiology of thyroid autoimmune diseases. The present study was performed to clarify the status of platelet-lymphocyte subpopulations aggregation in circulating blood in patients with Graves' disease (GD). One hundred and fifty patients with GD (GD group) and 45 hyperthyroid patients with toxic multinodular goiter (TMG group) were recruited in the study. Control group consisted 150 healthy subjects. Immunophenotyping of lymphocytes was performed by flow cytometry. Detection of lymphocyte-platelet aggregates (LPAs) was done using light microscope after Ficoll-gradient centrifugation. The group of GD patients exhibited reduced CD8 lymphocyte and higher CD19 cell counts compared with TMG group and healthy controls. A greater number of activated CD3, HLA-DR+ lymphocytes were observed in GD than in TMG group and control group. GD group was characterized by lower blood platelet count (232 ± 89 × 10 cells/µL) than TMG group (251 ± 97 × 10 cells/µL; P < 0.05) and control group (262 ± 95 × 10 cells/µL; P < 0.05). In GD group, more platelet-bound lymphocytes (332 ± 91 /µL) were found than that in TMG group (116 ± 67/µL, P < 0.005) and control group (104 ± 58 /µL; P < 0.001). GD is associated with higher levels of activated lymphocytes and lymphocyte-platelet aggregates.

  19. Changes of lymphocyte kinetics in the normal rat, induced by the lymphocyte mobilizing agent polymethacrylic acid

    NARCIS (Netherlands)

    Ormai, S.; Hagenbeek, A.; Palkovits, M.; Bekkum, D.W. van

    1973-01-01

    The changes in lymphocyte kinetics induced by the lymphocyte mobilizing agent polymethacrylic acid (PMAA) were studied in the normal rat. Quantitative data are presented concerning the degree of lymphocyte mobilization in the spleen and in various lymph nodes at different times after PMAA administra

  20. Interpretation of NCCN Guideline: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Version 1, 2017

    Directory of Open Access Journals (Sweden)

    Lei XIA

    2016-12-01

    Full Text Available Chronic lymphocytic leukemia (CLL is a kind of chronic lymphocyte proliferative disease with corresponding clinical symptoms caused by the accumulation of mature B lymphocytes in peripheral blood, bone marrow and lymphatic tissues. In recent years, great achievements have been reached on the basic research, new prognostic markers, diagnostic criteria and therapeutic methods in CLL. This study mainly interpreted the corresponding diagnosis and treatment of CLL in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Version 1, 2017.

  1. Essential role for the lymphostromal plasma membrane Ly-6 superfamily molecule thymic shared antigen 1 in development of the embryonic adrenal gland.

    Science.gov (United States)

    Zammit, David J; Berzins, Stuart P; Gill, Jason W; Randle-Barrett, Elise S; Barnett, Louise; Koentgen, Frank; Lambert, Gavin W; Harvey, Richard P; Boyd, Richard L; Classon, Brendan J

    2002-02-01

    Thymic shared antigen 1 (TSA-1) is a plasma membrane protein of the Ly-6 superfamily expressed on thymocytes, thymic stromal cells, and other cells of the hematopoietic system. TSA-1 is also expressed in other nonhematopoietic tissues, in particular, embryonic and adult adrenal glands. To address the function of TSA-1, we generated mutant mice in which TSA-1 expression was inactivated by gene targeting. Here we show that deletion of both TSA-1 alleles results in abnormal adrenal gland development and midgestational lethality due to cardiac abnormalities. We also report that TSA-1-deficient adrenal glands have significantly reduced levels of the catecholamines noradrenaline and adrenaline. We conclude that TSA-1 is required for normal embryonic development but that deletion of its expression does not obviously impair lymphoid development.

  2. Delta-like 1/fetal antigen-1 (Dlk1/FA1) is a novel regulator of chondrogenic cell differentiation via inhibition of the Akt kinase-dependent pathway

    DEFF Research Database (Denmark)

    Chen, Li; Qanie, Diyako; Jafari, Abbas

    2011-01-01

    Delta-like 1 (Dlk1, also known as fetal antigen-1, FA1) is a member of Notch/Delta family that inhibits adipocyte and osteoblast differentiation; however, its role in chondrogenesis is still not clear. Thus, we overexpressed Dlk1/FA1 in mouse embryonic ATDC5 cells and tested its effects...... on chondrogenic differentiation. Dlk1/FA1 inhibited insulin-induced chondrogenic differentiation as evidenced by reduction of cartilage nodule formation and gene expression of aggrecan, collagen Type II and X. Similar effects were obtained either by using Dlk1/FA1-conditioned medium or by addition of a purified......, secreted, form of Dlk1 (FA1) directly to the induction medium. The inhibitory effects of Dlk1/FA1 were dose-dependent and occurred irrespective of the chondrogenic differentiation stage: proliferation, differentiation, maturation, or hypertrophic conversion. Overexpression or addition of the Dlk1/FA1...

  3. Genetics Home Reference: bare lymphocyte syndrome type I

    Science.gov (United States)

    ... Home Health Conditions bare lymphocyte syndrome type I bare lymphocyte syndrome type I Enable Javascript to view ... boxes. Download PDF Open All Close All Description Bare lymphocyte syndrome type I (BLS I) is an ...

  4. The Danish National Chronic Lymphocytic Leukemia Registry

    DEFF Research Database (Denmark)

    da Cunha-Bang, Caspar; Geisler, Christian Hartmann; Enggaard, Lisbeth

    2016-01-01

    AIM: In 2008, the Danish National Chronic Lymphocytic Leukemia Registry was founded within the Danish National Hematology Database. The primary aim of the registry is to assure quality of diagnosis and care of patients with chronic lymphocytic leukemia (CLL) in Denmark. Secondarily, to evaluate...

  5. In Vitro Differentiation of Insulin Secreting Cells from Mouse Bone Marrow Derived Stage-Specific Embryonic Antigen 1 Positive Stem Cells

    Directory of Open Access Journals (Sweden)

    Morteza Abouzaripour

    2016-02-01

    Full Text Available Objective: Bone marrow has recently been recognized as a novel source of stem cells for the treatment of wide range of diseases. A number of studies on murine bone marrow have shown a homogenous population of rare stage-specific embryonic antigen 1 (SSEA-1 positive cells that express markers of pluripotent stem cells. This study focuses on SSEA-1 positive cells isolated from murine bone marrow in an attempt to differentiate them into insulin-secreting cells (ISCs in order to investigate their differentiation potential for future use in cell therapy. Materials and Methods: This study is an experimental research. Mouse SSEA-1 positive cells were isolated by Magnetic-activated cell sorting (MACS followed by characterization with flow cytometry. Induced SSEA-1 positive cells were differentiated into ISCs with specific differentiation media. In order to evaluate differentiation quality and analysis, dithizone (DTZ staining was use, followed by reverse transcription polymerase chain reaction (RT-PCR, immunocytochemistry and insulin secretion assay. Statistical results were analyzed by one-way ANOVA. Results: The results achieved in this study reveal that mouse bone marrow contains a population of SSEA-1 positive cells that expresses pluripotent stem cells markers such as SSEA-1, octamer-binding transcription factor 4 (OCT-4 detected by immunocytochemistry and C-X-C chemokine receptor type 4 (CXCR4 and stem cell antigen-1 (SCA-1 detected by flow cytometric analysis. SSEA-1 positive cells can differentiate into ISCs cell clusters as evidenced by their DTZ positive staining and expression of genes such as Pdx1 (pancreatic transcription factors, Ngn3 (endocrine progenitor marker, Insulin1 and Insulin2 (pancreaticβ-cell markers. Additionally, our results demonstrate expression of PDX1 and GLUT2 protein and insulin secretion in response to a glucose challenge in the differentiated cells. Conclusion: Our study clearly demonstrates the potential of SSEA-1

  6. Lenalidomide and Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Ana Pilar González-Rodríguez

    2013-01-01

    Full Text Available Lenalidomide is an oral immunomodulatory drug used in multiple myeloma and myelodysplastic syndrome and most recently it has shown to be effective in the treatment of various lymphoproliferative disorders such as chronic lymphocytic leukemia (CLL and non-Hodgkin lymphoma. The mechanism of action of lenalidomide varies depending on the pathology, and in the case of CLL, it appears to primarily act by restoring the damaged mechanisms of tumour immunosurveillance. This review discusses the potential mechanism of action and efficacy of lenalidomide, alone or in combination, in treatment of CLL and its toxic effects such as tumor lysis syndrome (TLS and tumor flare reaction (TFR, that make its management different from other hematologic malignancies.

  7. Enhancement of lytic activity of leukemic cells by CD8+ cytotoxic T lymphocytes generated against a WT1 peptide analogue.

    Science.gov (United States)

    Al Qudaihi, Ghofran; Lehe, Cynthia; Negash, Muna; Al-Alwan, Monther; Ghebeh, Hazem; Mohamed, Said Yousuf; Saleh, Abu-Jafar Mohammed; Al-Humaidan, Hind; Tbakhi, Abdelghani; Dickinson, Anne; Aljurf, Mahmoud; Dermime, Said

    2009-02-01

    The Wilms tumor antigen 1 (WT1) antigen is over-expressed in human leukemias, making it an attractive target for immunotherapy. Most WT1-specific Cytotoxic T Lymphocytes (CTLs) described so far displayed low avidity, limiting its function. To improve the immunogenicity of CTL epitopes, we replaced the first-amino-acid of two known immunogenic WT1-peptides (126 and 187) with a tyrosine. This modification enhances 126Y analogue-binding ability, triggers significant number of IFN-gamma-producing T cells (P = 0.0003), induces CTL that cross-react with the wild-type peptide, exerts a significant lytic activity against peptide-loaded-targets (P = 0.0006) and HLA-A0201-matched-leukemic cells (P = 0.0014). These data support peptide modification as a feasible approach for the development of a leukemia-vaccine.

  8. M-Finder: Uncovering functionally associated proteins from interactome data integrated with GO annotations

    Science.gov (United States)

    2013-01-01

    Background Protein-protein interactions (PPIs) play a key role in understanding the mechanisms of cellular processes. The availability of interactome data has catalyzed the development of computational approaches to elucidate functional behaviors of proteins on a system level. Gene Ontology (GO) and its annotations are a significant resource for functional characterization of proteins. Because of wide coverage, GO data have often been adopted as a benchmark for protein function prediction on the genomic scale. Results We propose a computational approach, called M-Finder, for functional association pattern mining. This method employs semantic analytics to integrate the genome-wide PPIs with GO data. We also introduce an interactive web application tool that visualizes a functional association network linked to a protein specified by a user. The proposed approach comprises two major components. First, the PPIs that have been generated by high-throughput methods are weighted in terms of their functional consistency using GO and its annotations. We assess two advanced semantic similarity metrics which quantify the functional association level of each interacting protein pair. We demonstrate that these measures outperform the other existing methods by evaluating their agreement to other biological features, such as sequence similarity, the presence of common Pfam domains, and core PPIs. Second, the information flow-based algorithm is employed to discover a set of proteins functionally associated with the protein in a query and their links efficiently. This algorithm reconstructs a functional association network of the query protein. The output network size can be flexibly determined by parameters. Conclusions M-Finder provides a useful framework to investigate functional association patterns with any protein. This software will also allow users to perform further systematic analysis of a set of proteins for any specific function. It is available online at http

  9. [Evolution and phylogeny of B lymphocytes].

    Science.gov (United States)

    Claudio-Piedras, Fabiola; Lanz-Mendoza, Humberto

    2016-01-01

    B lymphocytes are one of the most important cell types involved in the immune response of mammals. The origin and evolution of this cellular type is unknown, but the B lymphocyte bona fide appeared first in fish. In this review we analize the principal components of the immune response of invertebrates, their phylogenetic distribution and the permancence of some properties that allowed the emergence of the B lymphocyte. We started from the idea that many of the components that characterize the B lymphocyte are found distributed among the invertebrates, however, it is in the B lymphocyte, where all these components that give this type of cell its identity, converged. The actual knowledge we have in regards of the lymphocytes comes, in the most part, from physiological studies in mammals, being the mice the more representative. The origin of the B lymphocyte, its alternative mechanisms for generating receptor diversity, its immune effector response, and the generation of memory, require an evolutionary and multidisiplinary approach for its study.

  10. Metabolism of peripheral lymphocytes, interleukin-2-activated lymphocytes and tumor-infiltrating lymphocytes from sup 31 P NMR studies

    Energy Technology Data Exchange (ETDEWEB)

    Kaplan, O.; Cohen, J.S.; Aebersold, P.

    1989-11-20

    {sup 31}O NMR spectra of tumor-infiltrating lymphocytes (TILs) were found to be significantly diefferent form those of normal peripheral lymphocytes. The greatest difference was in the phosphodiester (PDE) region, mainly in the glycerophosphocholine (GPC) signal. Short-term activation of peripheral lymphocytes with interleukin-2 induced a small increase in ATP levels. In all lumphocytes the phosphomonoester (PME) region is dominated by phosphoethanolamine (PE), while there is an unusual absence of phosphocholine (PC). Perfusion of these cells with high concentrations of choline caused only a minimal increase in PC, indicating that choline kinase is not the rate limiting step of lecithin synthesis in lymphocytes. (author). 13 refs.; 3 figs.; 1 tab.

  11. Studies on the isolation, structural analysis and tissue localization of fetal antigen 1 and its relation to a human adrenal-specific cDNA, pG2

    DEFF Research Database (Denmark)

    Jensen, Charlotte Harken; Teisner, Børge; Højrup, Peter

    1993-01-01

    , prolines and amino acids (aa) with acidic side-chains indicating that fetal antigen 1 is a compactly folded, strongly hydrophilic molecule. The N-terminal amino acid sequence (37 aa) revealed no homology to other known protein sequences, implying that fetal antigen 1 is a 'novel' human protein. When the aa...... is encoded by the mRNA defined by the cDNA clone pG2, but definitive sequencing and expression studies of this mRNA have not been achieved. Udgivelsesdato: 1993-Apr...

  12. Linear Fractional Transformations of Nevanlinna Functions Associated with a Nonnegative Operator

    NARCIS (Netherlands)

    Behrndt, Jussi; Hassi, Seppo; de Snoo, Henk; Wietsma, Rudi; Winkler, Henrik

    2013-01-01

    In the present paper a subclass of scalar Nevanlinna functions is studied, which coincides with the class of Weyl functions associated to a nonnegative symmetric operator of defect one in a Hilbert space. This class consists of all Nevanlinna functions that are holomorphic on (-a, 0) and all those N

  13. Whittaker functions associated to newforms for GL(n) over p-adic fields

    CERN Document Server

    Miyauchi, Michitaka

    2012-01-01

    Let F be a non-archimedean local field of characteristic zero. Jacquet, Piatetski-Shapiro and Shalika introduced the notion of newforms for irreducible generic representations of GL_n(F). In this paper, we give an explicit formula for Whittaker functions associated to newforms on the diagonal matrices in GL_n(F).

  14. Monoclonal antibodies in chronic lymphocytic leukemia.

    Science.gov (United States)

    Ferrajoli, Alessandra; Faderl, Stefan; Keating, Michael J

    2006-09-01

    Multiple options are now available for the treatment of chronic lymphocytic leukemia. Over the last 10 years, monoclonal antibodies have become an integral part of the management of this disease. Alemtuzumab has received approval for use in patients with fludarabine-refractory chronic lymphocytic leukemia. Rituximab has been investigated extensively in chronic lymphocytic leukemia both as a single agent and in combination with chemotherapy and other monoclonal antibodies. Epratuzumab and lumiliximab are newer monoclonal antibodies in the early phase of clinical development. This article will review the monoclonal antibodies more commonly used to treat chronic lymphocytic leukemia, the results obtained with monoclonal antibodies as single agents and in combination with chemotherapy, and other biological agents and newer compounds undergoing clinical trials.

  15. Chronic lymphocytic leukemia: present status.

    Science.gov (United States)

    Montserrat, E; Rozman, C

    1995-03-01

    Chronic lymphocytic leukemia (CLL) is the form of leukemia which occurs most frequently in Western countries. Its etiology is unknown, and no relationship with viruses or genes has been demonstrated. Epidemiological data suggest that genetic and ambiental factors might be of some significance. Clinical features of CLL are due to the accumulation of leukemic cells in bone marrow and lymphoid organs as well as the immune disturbances that accompany the disease. The prognosis of patients with CLL varies. Treatment is usually indicated by the risk of the individual patient, which is clearly reflected by the stage of the disease. In the early stage (Binet A, Rai O) it is reasonable to defer therapy until disease progression is observed. By contrast, because their median survival is less than five years, patients with more advanced stages require therapy. For almost 50 years, no major advances in the management of CLL, which has revolved around the use of alkylating agents, have been made. In recent years, the therapeutic approach in patients with CLL has changed as a result of the introduction of combination chemotherapy regimens and, in particular, purine analogues. The latter are already the treatment of choice for patients not responding to standard therapies, and their role as front-line therapy is being investigated. Bone marrow transplants are also being increasingly used. It is to be hoped that in years to come the outcome of patients with CLL will be improved by these advances.

  16. Lymphocyte subsets in pediatric migraine.

    Science.gov (United States)

    Cseh, Aron; Farkas, Kristof Mark; Derzbach, Laszlo; Muller, Katalin; Vasarhelyi, Barna; Szalay, Balazs; Treszl, Andras; Farkas, Viktor

    2013-07-01

    Aseptic inflammation due to activated immune cells has been implicated in the pathomechanism of migraine. We measured the prevalence of regulatory T cells (Tregs), along with that of CD4(+)/CD8(+) lymphocytes and their Th1/Th2 commitment in pediatric migraine. Children and adolescents suffering from migraine without aura, migraine with aura and hemiplegic migraine ictally (n = 53, 27, and 20, respectively), also interictally (n = 33) were recruited and compared to 24 healthy children. Our results indicated comparable prevalence of Tregs, CD4(+) and Th1/Th2 committed cells. CD8(+) prevalence was lower, and CD4(+)/CD8(+) ratio was higher in ictal phase irrespective of the subtype of migraine. No association between CD8(+) prevalence and gender, body weight, disease onset and attack duration in migraine subtypes was found. CD8(+) prevalence was normal in patients in interictal phase. These results suggest the absence of major systemic alteration of adaptive immunity in children and adolescents suffering from migraine; however, a transient decrease of CD8(+) prevalence during the ictal phase was detected irrespective of the subtype of migraine.

  17. Obinutuzumab for chronic lymphocytic leukemia.

    Science.gov (United States)

    Rioufol, Catherine; Salles, Gilles

    2014-10-01

    Chronic lymphocytic leukemia (CLL) is a frequent hematological malignancy that is incurable using standard approaches. Two anti-CD20 monoclonal antibodies (mAb), rituximab and ofatumumab, have been approved for CLL treatment. A new glycoengineered type II humanized anti-CD20 mAb, obinutuzumab (GA101), has been developed and demonstrates increased activity against B-cell malignancies by inducing direct cell death and better antibody-dependent cellular cytotoxicity. In a recent randomized Phase III study in patients with newly diagnosed CLL and coexisting conditions, obinutuzumab plus chlorambucil demonstrated significant improvement in progression-free survival and several other outcome parameters, in contrast to rituximab plus chlorambucil. Grade 3-4 infusion-related reactions and neutropenia occurred more frequently in patients who received obinutuzumab compared with those who received rituximab; however, the rate of serious infections was similar. Obinutuzumab represents a promising new option for patients with CLL and must be investigated with other chemotherapy regimens or with new targeted agents.

  18. How T lymphocytes see antigen

    Science.gov (United States)

    Chakraborty, Arup K.

    2009-03-01

    Complex organisms, like humans, have an adaptive immune system that enables us to do battle with diverse pathogens. This flexible system can also go awry, and many diseases are the direct consequence of the adaptive immune system failing to discriminate between markers of self and non-self. The orchestrators of adaptive immunity are a class of cells called T lymphocytes (T cells). T cells recognize minute numbers of molecular signatures of pathogens, and T cell recognition of these molecular markers of non-self is both specific and degenerate. The specific (yet, cross-reactive), diverse, and self-tolerant T cell repertoire is designed in the thymus. I will describe how an approach that brings together theoretical and computational studies (rooted in statistical physics) with experiments (carried out by key collaborators) has allowed us to shed light on the mechanistic principles underlying how T cells respond to pathogens in a digital fashion (``on'' or ``off''), and how this molecular machinery coupled with frustration (a la spin glasses) plays a key role in designing the special properties of the T cell repertoire during development in the thymus.

  19. Bilateral dacryoadenitis complicated by lymphocytic hypophysitis.

    Science.gov (United States)

    Baoke, Hou; Shihui, Wei; Maonian, Zhang; Zhaohui, Li; Zhitong, Zou; Zhigang, Song; Yan, Hei

    2009-09-01

    Three patients developed dacryoadenitis (DA) or lymphocytic pneumonitis before the diagnosis of lymphocytic hypophysitis (LyH). There were two previous reports of concurrence of DA and LyH. Our patients add support to the idea that DA and LyH are manifestations of a systemic autoimmune disease. We suggest that the discovery of DA should prompt imaging and endocrine investigation of LyH.

  20. Expression of tenascin in lymphocytic autoimmune thyroiditis.

    OpenAIRE

    Back, W; Heubner, C; Winter, J.; Bleyl, U

    1997-01-01

    AIMS: To study the distribution of tenascin by immunocytochemistry in autoimmune diseases of the thyroid. METHODS: Thyroids from patients with inflammatory lesions of the thyroid (lymphocytic thyroiditis Hashimoto, Grave's disease, thyroiditis DeQuervain) were studied by immunocytochemistry using antibodies against tenascin, collagen III, and collagen IV. RESULTS: In autoimmune lymphocytic thyroiditis Hashimoto there was a characteristic corona-like staining pattern of tenascin around all act...

  1. Effects of Intermittent Administration of Parathyroid Hormone (1-34 on Bone Differentiation in Stromal Precursor Antigen-1 Positive Human Periodontal Ligament Stem Cells

    Directory of Open Access Journals (Sweden)

    Xiaoxiao Wang

    2016-01-01

    Full Text Available Periodontitis is the most common cause of tooth loss and bone destruction in adults worldwide. Human periodontal ligament stem cells (hPDLSCs may represent promising new therapeutic biomaterials for tissue engineering applications. Stromal precursor antigen-1 (STRO-1 has been shown to have roles in adherence, proliferation, and multipotency. Parathyroid hormone (PTH has been shown to enhance proliferation in osteoblasts. Therefore, in this study, we aimed to compare the functions of STRO-1(+ and STRO-1(− hPDLSCs and to investigate the effects of PTH on the osteogenic capacity of STRO-1(+ hPDLSCs in order to evaluate their potential applications in the treatment of periodontitis. Our data showed that STRO-1(+ hPDLSCs expressed higher levels of the PTH-1 receptor (PTH1R than STRO-1(− hPDLSCs. In addition, intermittent PTH treatment enhanced the expression of PTH1R and osteogenesis-related genes in STRO-1(+ hPDLSCs. PTH-treated cells also exhibited increased alkaline phosphatase activity and mineralization ability. Therefore, STRO-1(+ hPDLSCs represented a more promising cell resource for biomaterials and tissue engineering applications. Intermittent PTH treatment improved the capacity for STRO-1(+ hPDLSCs to repair damaged tissue and ameliorate the symptoms of periodontitis.

  2. Inhibition of the function of the FcgammaRIIB by a monoclonal antibody to thymic shared antigen-1, a Ly-6 family antigen.

    Science.gov (United States)

    Ding, L; Shevach, E M

    2001-09-01

    Thymic shared antigen-1 (TSA-1) is a member of the Ly-6 family of glycosyl-phosphatidylinositol (GPI)-linked proteins. While it has been proposed that TSA-1 may play a role in thymic development, a physiological ligand for this antigen has not been identified. Here we report that a monoclonal antibody (mAb) to TSA-1, generated by immunizing a hamster with CD40 ligand (CD40L)-activated B cells, interferes with the function of FcgammaRIIB on splenic B cells and the B-cell lymphoma cell line, M12, by binding to TSA on the same cells. The interaction of anti-TSA with FcgammaRIIB resulted in an inhibition of the ability of the FcgammaRIIB to cross-link and/or aggregate soluble anti-CD3 or soluble anti-Cbeta T-cell receptor (TCR), leading to an inhibition of induction of expression of CD25 and CD69, interleukin (IL)-2 production and proliferation of naive T cells. Cross-blocking studies with mAbs strongly suggested that a physical association exists between TSA-1 and the FcgammaRIIB on the surface of activated B cells and favour the view that a functional intermolecular association exists between these two distinct membrane antigens.

  3. Heat shock factor 1 upregulates transcription of Epstein-Barr Virus nuclear antigen 1 by binding to a heat shock element within the BamHI-Q promoter

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Feng-Wei [The State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou (China); Wu, Xian-Rui [Department of Surgery, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou (China); Liu, Wen-Ju; Liao, Yi-Ji [The State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou (China); Lin, Sheng [Laboratory of Integrated Biosciences, School of Life Science, Sun Yat-sen University, Guangzhou (China); Zong, Yong-Sheng; Zeng, Mu-Sheng; Zeng, Yi-Xin [The State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou (China); Mai, Shi-Juan, E-mail: maishj@sysucc.org.cn [The State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou (China); Xie, Dan, E-mail: xied@mail.sysu.edu.cn [The State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou (China)

    2011-12-20

    Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is essential for maintenance of the episome and establishment of latency. In this study, we observed that heat treatment effectively induced EBNA1 transcription in EBV-transformed B95-8 and human LCL cell lines. Although Cp is considered as the sole promoter used for the expression of EBNA1 transcripts in the lymphoblastoid cell lines, the RT-PCR results showed that the EBNA1 transcripts induced by heat treatment arise from Qp-initiated transcripts. Using bioinformatics, a high affinity and functional heat shock factor 1 (HSF1)-binding element within the - 17/+4 oligonucleotide of the Qp was found, and was determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Moreover, heat shock and exogenous HSF1 expression induced Qp activity in reporter assays. Further, RNA interference-mediated HSF1 gene silencing attenuated heat-induced EBNA1 expression in B95-8 cells. These results provide evidence that EBNA1 is a new target for the transcription factor HSF1.

  4. Structural basis for the regulation of nuclear import of Epstein-Barr virus nuclear antigen 1 (EBNA1) by phosphorylation of the nuclear localization signal.

    Science.gov (United States)

    Nakada, Ryohei; Hirano, Hidemi; Matsuura, Yoshiyuki

    2017-02-26

    Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is expressed in every EBV-positive tumor and is essential for the maintenance, replication, and transcription of the EBV genome in the nucleus of host cells. EBNA1 is a serine phosphoprotein, and it has been shown that phosphorylation of S385 in the nuclear localization signal (NLS) of EBNA1 increases the binding affinity to the nuclear import adaptor importin-α1 as well as importin-α5, and stimulates nuclear import of EBNA1. To gain insights into how phosphorylation of the EBNA1 NLS regulates nuclear import, we have determined the crystal structures of two peptide complexes of importin-α1: one with S385-phosphorylated EBNA1 NLS peptide, determined at 2.0 Å resolution, and one with non-phosphorylated EBNA1 NLS peptide, determined at 2.2 Å resolution. The structures show that EBNA1 NLS binds to the major and minor NLS-binding sites of importin-α1, and indicate that the binding affinity of the EBNA1 NLS to the minor NLS-binding site could be enhanced by phosphorylation of S385 through electrostatic interaction between the phosphate group of phospho-S385 and K392 of importin-α1 (corresponding to R395 of importin-α5) on armadillo repeat 8.

  5. Multilevel Precision-Based Rational Design of Chemical Inhibitors Targeting the Hydrophobic Cleft of Toxoplasma gondii Apical Membrane Antigen 1 (AMA1)

    Science.gov (United States)

    Muralikumar, Shalini; Mahalakshmi, B; Lily Therese, K; Madhavan, HN; Alameen, Mohamed; Thirumudi, Indhuja

    2016-01-01

    Toxoplasma gondii is an intracellular Apicomplexan parasite and a causative agent of toxoplasmosis in human. It causes encephalitis, uveitis, chorioretinitis, and congenital infection. T. gondii invades the host cell by forming a moving junction (MJ) complex. This complex formation is initiated by intermolecular interactions between the two secretory parasitic proteins—namely, apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2) and is critically essential for the host invasion process. By this study, we propose two potential leads, NSC95522 and NSC179676 that can efficiently target the AMA1 hydrophobic cleft, which is a hotspot for targeting MJ complex formation. The proposed leads are the result of an exhaustive conformational search-based virtual screen with multilevel precision scoring of the docking affinities. These two compounds surpassed all the precision levels of docking and also the stringent post docking and cumulative molecular dynamics evaluations. Moreover, the backbone flexibility of hotspot residues in the hydrophobic cleft, which has been previously reported to be essential for accommodative binding of RON2 to AMA1, was also highly perturbed by these compounds. Furthermore, binding free energy calculations of these two compounds also revealed a significant affinity to AMA1. Machine learning approaches also predicted these two compounds to possess more relevant activities. Hence, these two leads, NSC95522 and NSC179676, may prove to be potential inhibitors targeting AMA1-RON2 complex formation towards combating toxoplasmosis. PMID:27445648

  6. Protein kinase a dependent phosphorylation of apical membrane antigen 1 plays an important role in erythrocyte invasion by the malaria parasite.

    Directory of Open Access Journals (Sweden)

    Kerstin Leykauf

    2010-06-01

    Full Text Available Apicomplexan parasites are obligate intracellular parasites that infect a variety of hosts, causing significant diseases in livestock and humans. The invasive forms of the parasites invade their host cells by gliding motility, an active process driven by parasite adhesion proteins and molecular motors. A crucial point during host cell invasion is the formation of a ring-shaped area of intimate contact between the parasite and the host known as a tight junction. As the invasive zoite propels itself into the host-cell, the junction moves down the length of the parasite. This process must be tightly regulated and signalling is likely to play a role in this event. One crucial protein for tight-junction formation is the apical membrane antigen 1 (AMA1. Here we have investigated the phosphorylation status of this key player in the invasion process in the human malaria parasite Plasmodium falciparum. We show that the cytoplasmic tail of P. falciparum AMA1 is phosphorylated at serine 610. We provide evidence that the enzyme responsible for serine 610 phosphorylation is the cAMP regulated protein kinase A (PfPKA. Importantly, mutation of AMA1 serine 610 to alanine abrogates phosphorylation of AMA1 in vivo and dramatically impedes invasion. In addition to shedding unexpected new light on AMA1 function, this work represents the first time PKA has been implicated in merozoite invasion.

  7. Multilevel Precision-Based Rational Design of Chemical Inhibitors Targeting the Hydrophobic Cleft of Toxoplasma gondii Apical Membrane Antigen 1 (AMA1).

    Science.gov (United States)

    Vetrivel, Umashankar; Muralikumar, Shalini; Mahalakshmi, B; Lily Therese, K; Madhavan, H N; Alameen, Mohamed; Thirumudi, Indhuja

    2016-06-01

    Toxoplasma gondii is an intracellular Apicomplexan parasite and a causative agent of toxoplasmosis in human. It causes encephalitis, uveitis, chorioretinitis, and congenital infection. T. gondii invades the host cell by forming a moving junction (MJ) complex. This complex formation is initiated by intermolecular interactions between the two secretory parasitic proteins-namely, apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2) and is critically essential for the host invasion process. By this study, we propose two potential leads, NSC95522 and NSC179676 that can efficiently target the AMA1 hydrophobic cleft, which is a hotspot for targeting MJ complex formation. The proposed leads are the result of an exhaustive conformational search-based virtual screen with multilevel precision scoring of the docking affinities. These two compounds surpassed all the precision levels of docking and also the stringent post docking and cumulative molecular dynamics evaluations. Moreover, the backbone flexibility of hotspot residues in the hydrophobic cleft, which has been previously reported to be essential for accommodative binding of RON2 to AMA1, was also highly perturbed by these compounds. Furthermore, binding free energy calculations of these two compounds also revealed a significant affinity to AMA1. Machine learning approaches also predicted these two compounds to possess more relevant activities. Hence, these two leads, NSC95522 and NSC179676, may prove to be potential inhibitors targeting AMA1-RON2 complex formation towards combating toxoplasmosis.

  8. Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization.

    Science.gov (United States)

    Saridakis, Vivian; Sheng, Yi; Sarkari, Feroz; Holowaty, Melissa N; Shire, Kathy; Nguyen, Tin; Zhang, Rongguang G; Liao, Jack; Lee, Weontae; Edwards, Aled M; Arrowsmith, Cheryl H; Frappier, Lori

    2005-04-01

    USP7/HAUSP is a key regulator of p53 and Mdm2 and is targeted by the Epstein-Barr nuclear antigen 1 (EBNA1) protein of Epstein-Barr virus (EBV). We have determined the crystal structure of the p53 binding domain of USP7 alone and bound to an EBNA1 peptide. This domain is an eight-stranded beta sandwich similar to the TRAF-C domains of TNF-receptor associated factors, although the mode of peptide binding differs significantly from previously observed TRAF-peptide interactions in the sequence (DPGEGPS) and the conformation of the bound peptide. NMR chemical shift analyses of USP7 bound by EBNA1 and p53 indicated that p53 binds the same pocket as EBNA1 but makes less extensive contacts with USP7. Functional studies indicated that EBNA1 binding to USP7 can protect cells from apoptotic challenge by lowering p53 levels. The data provide a structural and conceptual framework for understanding how EBNA1 might contribute to the survival of Epstein-Barr virus-infected cells.

  9. Small molecule inhibition of Epstein-Barr virus nuclear antigen-1 DNA binding activity interferes with replication and persistence of the viral genome.

    Science.gov (United States)

    Lee, Eun Kyung; Kim, Sun Young; Noh, Ka-Won; Joo, Eun Hye; Zhao, Bo; Kieff, Elliott; Kang, Myung-Soo

    2014-04-01

    The replication and persistence of extra chromosomal Epstein-Barr virus (EBV) episome in latently infected cells are primarily dependent on the binding of EBV-encoded nuclear antigen 1 (EBNA1) to the cognate EBV oriP element. In continuation of the previous study, herein we characterized EBNA1 small molecule inhibitors (H20, H31) and their underlying inhibitory mechanisms. In silico docking analyses predicted that H20 fits into a pocket in the EBNA1 DNA binding domain (DBD). However, H20 did not significantly affect EBNA1 binding to its cognate sequence. A limited structure-relationship study of H20 identified a hydrophobic compound H31, as an EBNA1 inhibitor. An in vitro EBNA1 EMSA and in vivo EGFP-EBNA1 confocal microscopy analysis showed that H31 inhibited EBNA1-dependent oriP sequence-specific DNA binding activity, but not sequence-nonspecific chromosomal association. Consistent with this, H31 repressed the EBNA1-dependent transcription, replication, and persistence of an EBV oriP plasmid. Furthermore, H31 induced progressive loss of EBV episome. In addition, H31 selectively retarded the growth of EBV-infected LCL or Burkitt's lymphoma cells. These data indicate that H31 inhibition of EBNA1-dependent DNA binding decreases transcription from and persistence of EBV episome in EBV-infected cells. These new compounds might be useful probes for dissecting EBNA1 functions in vitro and in vivo.

  10. Overexpression of Hepatitis B Virus-binding Protein, Squamous Cell Carcinoma Antigen 1, Extends Retention of Hepatitis B Virus in Mouse Liver

    Institute of Scientific and Technical Information of China (English)

    Hong-Bin XIA; Xi-Gu CHEN

    2006-01-01

    How receptors mediate the entry of hepatitis B virus (HBV) into the target liver cells is poorly understood. Recently, human squamous cell carcinoma antigen 1 (SCCA1) has been found to mediate binding and internalization of HBV to liver-derived cell lines in vitro. In this report, we investigate if SCCA1 is able to function as an HBV receptor and mediate HBV entry into mouse liver. SCCA1 transgene under the control of Rous sarcoma virus promoter was constructed in a minicircle DNA vector that was delivered to NOD/SCID mouse liver using the hydrodynamic technique. Subsequently, HBV-positive human serum was injected intravenously. We demonstrated that approximately 30% of the mouse liver cells expressed a high level of recombined SCCA1 protein for at least 37 d. The HBV surface antigen was found to persist in mouse liver for up to 17 d. Furthermore, HBV genome also persisted in mouse liver, as determined by polymerase chain reaction, for up to 17 d, and in mouse circulation for 7 d. These results suggest that SCAA1 might serve as an HBV receptor or co-receptor and play an important role in mediating HBV entry into hepatocytes, although its role in human HBV infection remains to be determined.

  11. Tumor-promoting function and prognostic significance of the RNA-binding protein T-cell intracellular antigen-1 in esophageal squamous cell carcinoma.

    Science.gov (United States)

    Hamada, Junichi; Shoda, Katsutoshi; Masuda, Kiyoshi; Fujita, Yuji; Naruto, Takuya; Kohmoto, Tomohiro; Miyakami, Yuko; Watanabe, Miki; Kudo, Yasusei; Fujiwara, Hitoshi; Ichikawa, Daisuke; Otsuji, Eigo; Imoto, Issei

    2016-03-29

    T-cell intracellular antigen-1 (TIA1) is an RNA-binding protein involved in many regulatory aspects of mRNA metabolism. Here, we report previously unknown tumor-promoting activity of TIA1, which seems to be associated with its isoform-specific molecular distribution and regulation of a set of cancer-related transcripts, in esophageal squamous cell carcinoma (ESCC). Immunohistochemical overexpression of TIA1 ectopically localized in the cytoplasm of tumor cells was an independent prognosticator for worse overall survival in a cohort of 143 ESCC patients. Knockdown of TIA1 inhibited proliferation of ESCC cells. By exogenously introducing each of two major isoforms, TIA1a and TIA1b, only TIA1a, which was localized to both the nucleus and cytoplasm, promoted anchorage-dependent and anchorage-independent ESCC cell proliferation. Ribonucleoprotein immunoprecipitation, followed by microarray analysis or massive-parallel sequencing, identified a set of TIA1-binding mRNAs, including SKP2 and CCNA2. TIA1 increased SKP2 and CCNA2 protein levels through the suppression of mRNA decay and translational induction, respectively. Our findings uncover a novel oncogenic function of TIA1 in esophageal tumorigenesis, and implicate its use as a marker for prognostic evaluation and as a therapeutic target in ESCC.

  12. The genetic diversity of merozoite surface antigen 1 (MSA-1) among Babesia bovis detected from cattle populations in Thailand, Brazil and Ghana.

    Science.gov (United States)

    Nagano, Daisuke; Sivakumar, Thillaiampalam; De De Macedo, Alane Caine Costa; Inpankaew, Tawin; Alhassan, Andy; Igarashi, Ikuo; Yokoyama, Naoaki

    2013-11-01

    In the present study, we screened blood DNA samples obtained from cattle bred in Brazil (n=164) and Ghana (n=80) for Babesia bovis using a diagnostic PCR assay and found prevalences of 14.6% and 46.3%, respectively. Subsequently, the genetic diversity of B. bovis in Thailand, Brazil and Ghana was analyzed, based on the DNA sequence of merozoite surface antigen-1 (MSA-1). In Thailand, MSA-1 sequences were relatively conserved and found in a single clade of the phylogram, while Brazilian MSA-1 sequences showed high genetic diversity and were dispersed across three different clades. In contrast, the sequences from Ghanaian samples were detected in two different clades, one of which contained only a single Ghanaian sequence. The identities among the MSA-1 sequences from Thailand, Brazil and Ghana were 99.0-100%, 57.5-99.4% and 60.3-100%, respectively, while the similarities among the deduced MSA-1 amino acid sequences within the respective countries were 98.4-100%, 59.4-99.7% and 58.7-100%, respectively. These observations suggested that the genetic diversity of B. bovis based on MSA-1 sequences was higher in Brazil and Ghana than in Thailand. The current data highlight the importance of conducting extensive studies on the genetic diversity of B. bovis before designing immune control strategies in each surveyed country.

  13. Lymphocyte migration into syngeneic implanted lymph nodes

    Energy Technology Data Exchange (ETDEWEB)

    Gordeeva, M.S.

    1986-03-01

    To judge the functional activity of lymphocytes of an implanted lymph node (LN), the proliferative response of lymphocytes of the implanted organ in the blast-transformation reaction in vitro and their ability to induce a local graft versus host reaction (GVHR) were determined. The lymphocyte suspension for labeling with /sup 51/Cr was obtained from peripheral LN in different situations from syngeneic mice. The resulting lymphocyte suspension was labeled with a solution of sodium chromate-/sup 51/Cr in a concentration of 20-40 microCi/100.10/sup 6/ cells in 1 ml for 40 min at 37/sup 0/C. The proliferative activity of a suspension of lymphocytes was estimated as incorporation of /sup 3/H-thymidine into DNA during incubation of the cell suspension for 3 days. Data on migration of /sup 51/Cr-labeled cells and the results of the morphological observations revealed marked ability of lymphocytes of the peripheral pool to colonize the regenerating stroma.

  14. Prenatal ontogeny of lymphocyte subpopulations in pigs.

    Science.gov (United States)

    Sinkora, M; Sinkora, J; Reháková, Z; Splíchal, I; Yang, H; Parkhouse, R M; Trebichavsk, I

    1998-12-01

    Although porcine lymphocytes have been classified into numerous subpopulations in postnatal animals, little is known about the ontogeny of these complex cell subsets. Using double- and triple-colour flow cytometry (FCM), we investigated the surface phenotype of fetal lymphoid cells in the thymus, cord blood, spleen and mesenteric lymph nodes at different stages of gestation. It was found that the major lymphocyte subpopulations started to appear at the beginning of the second third of the gestation period, with B cells being the earliest lymphocyte subpopulation to appear in the periphery. The T-cell receptor (TCR) gamma delta+ cells were the earliest detectable T-cell subset, developing first in the thymus and subsequently arriving in the periphery. Later in ontogeny, however, the number of TCRalpha beta+ lymphocytes rapidly increased, becoming the predominant T cells both in the thymus and in the periphery. Cells with the phenotype of adult natural killer cells were also identified in pig fetuses, though their nature and functional roles remain to be investigated. In addition, CD2 was expressed on most B cells whilst very few CD4+ TCRalpha beta+ cells or CD2+ TCRgamma delta+ cells expressed CD8, suggesting that the expression of CD2 and CD8 may reflect the functional status of the cells in postnatal animals. Taken together, this study has provided a systematic analysis of fetal porcine lymphocyte subpopulations and may provide the base for studies to establish the physiological roles of these lymphocyte subsets.

  15. Entospletinib and Obinutuzumab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Non-Hodgkin Lymphoma

    Science.gov (United States)

    2017-07-24

    Anemia; B-Cell Prolymphocytic Leukemia; Fatigue; Fever; Grade 1 Follicular Lymphoma; Grade 2 Follicular Lymphoma; Grade 3a Follicular Lymphoma; Hairy Cell Leukemia; Lymphadenopathy; Lymphocytosis; Lymphoplasmacytic Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Night Sweats; Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Small Lymphocytic Lymphoma; Richter Syndrome; Splenomegaly; Thrombocytopenia; Weight Loss

  16. Phase 1/2a study of the malaria vaccine candidate apical membrane antigen-1 (AMA-l) administered in adjuvant system AS01B or AS02A

    NARCIS (Netherlands)

    M.D. Spring (Michele Donna); J.F. Cummings (James); C.F. Ockenhouse (Christian); S. Dutta (Shantanu); R. Reidler (Randall); E. Angov (Evelina); E. Bergmann-Leitner (Elke); V.A. Stewart (Ann); S. Bittner (Stacey); L. Juompan (Laure); M.G. Kortepeter (Mark); R. Nielsen (Robin); U. Krzych (Urszula); E. Tierney (Ev); L.A. Ware (Lisa); M. Dowler (Megan); C.C. Hermsen (Cornelus); R.W. Sauerwein (Robert); S.J. de Vlas (Sake); O. Ofori-Anyinam (Opokua); D.E. Lanar (David); J.L. Williams (Jack); K.E. Kester (Kent); K. Tucker (Kathryn); M. Shi (Meng); E. Malkin (Elissa); C. Long (Carole); C.L. Diggs (Carter); L. Soisson (Lorraine Amory); M.C. Dubois; W.R. Ballou (Ripley); J. Cohen (Joe); D.G. Heppner (Gray)

    2009-01-01

    textabstractBackground: This Phase 1/2a study evaluated the safety, immunogenicity, and efficacy of an experimental malaria vaccine comprised of the recombinant Plasmodium falciparum protein apical membrane antigen-1 (AMA-1) representing the 3D7 allele formulated with either the AS01B or AS02A Adjuv

  17. Monoclonal Antibody Therapy in Treating Patients With Chronic Lymphocytic Leukemia, Lymphocytic Lymphoma, Acute Lymphoblastic Leukemia, or Acute Myeloid Leukemia

    Science.gov (United States)

    2013-06-03

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma

  18. Selective effects of alpha interferon on human T-lymphocyte subsets during mixed lymphocyte cultures

    DEFF Research Database (Denmark)

    Hokland, M; Hokland, P; Heron, I

    1983-01-01

    Mixed lymphocyte reaction (MLR) cultures of human lymphocyte subsets with or without the addition of physiological doses of human alpha interferon (IFN-alpha) were compared with respect to surface marker phenotypes and proliferative capacities of the responder cells. A selective depression on the T...

  19. Association analysis of anti-Epstein-Barr nuclear antigen-1 antibodies, anti-cyclic citrullinated peptide antibodies, the shared epitope and smoking status in Brazilian patients with rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    Michel Alexandre Yazbek

    2011-01-01

    Full Text Available INTRODUCTION: Epstein-Barr virus exposure appears to be an environmental trigger for rheumatoid arthritis that interacts with other risk factors. Relationships among anti-cyclic citrullinated peptide antibodies, the shared epitope, and smoking status have been observed in patients with rheumatoid arthritis from different populations. OBJECTIVE: To perform an association analysis of anti-Epstein-Barr nuclear antigen-1 antibodies, anti-cyclic citrullinated peptide antibodies, the shared epitope, and smoking status in Brazilian patients with rheumatoid arthritis. METHODS: In a case-control study, 140 rheumatoid arthritis patients and 143 healthy volunteers who were matched for age, sex, and ethnicity were recruited. Anti-Epstein-Barr nuclear antigen-1 antibodies and anti-cyclic citrullinated peptide antibodies were examined using an enzyme-linked immunosorbent assay, and shared epitope alleles were identified by genotyping. Smoking information was collected from all subjects. A comparative analysis of anti-Epstein-Barr nuclear antigen-1 antibodies, anti-cyclic citrullinated peptide antibodies, the shared epitope, and smoking status was performed in the patient group. Logistic regression analysis models were used to analyze the risk of rheumatoid arthritis. RESULTS: Anti-Epstein-Barr nuclear antigen-1 antibodies were not associated with anti-cyclic citrullinated peptide antibodies, shared epitope alleles, or smoking status. Anti-cyclic citrullinated peptide antibody positivity was significantly higher in smoking patients with shared epitope alleles (OR = 3.82. In a multivariate logistic regression analysis using stepwise selection, only anti-cyclic citrullinated peptide antibodies were found to be independently associated with rheumatoid arthritis (OR = 247.9. CONCLUSION: Anti-Epstein-Barr nuclear antigen-1 antibodies did not increase the risk of rheumatoid arthritis and were not associated with the rheumatoid arthritis risk factors studied. Smoking

  20. Local network topology in human protein interaction data predicts functional association.

    Directory of Open Access Journals (Sweden)

    Hua Li

    Full Text Available The use of high-throughput techniques to generate large volumes of protein-protein interaction (PPI data has increased the need for methods that systematically and automatically suggest functional relationships among proteins. In a yeast PPI network, previous work has shown that the local connection topology, particularly for two proteins sharing an unusually large number of neighbors, can predict functional association. In this study we improved the prediction scheme by developing a new algorithm and applied it on a human PPI network to make a genome-wide functional inference. We used the new algorithm to measure and reduce the influence of hub proteins on detecting function-associated protein pairs. We used the annotations of the Gene Ontology (GO and the Kyoto Encyclopedia of Genes and Genomes (KEGG as benchmarks to compare and evaluate the function relevance. The application of our algorithms to human PPI data yielded 4,233 significant functional associations among 1,754 proteins. Further functional comparisons between them allowed us to assign 466 KEGG pathway annotations to 274 proteins and 123 GO annotations to 114 proteins with estimated false discovery rates of <21% for KEGG and <30% for GO. We clustered 1,729 proteins by their functional associations and made functional inferences from detailed analysis on one subcluster highly enriched in the TGF-beta signaling pathway (P<10(-50. Analysis of another four subclusters also suggested potential new players in six signaling pathways worthy of further experimental investigations. Our study gives clear insight into the common neighbor-based prediction scheme and provides a reliable method for large-scale functional annotation in this post-genomic era.

  1. The Work Function Associated with Ultra-relativistic Electron Emission from Strongly Magnetized Neutron Star Surface

    Indian Academy of Sciences (India)

    Arpita Ghosh; Somenath Chakrabarty

    2011-09-01

    Following an extremely interesting idea (Schieber 1984), published long ago, the work function associated with the emission of ultra-relativistic electrons from magnetically deformed metallic crystal (mainly iron) at the outer crust of a magnetar is obtained using relativistic version of Thomas–Fermi type model for electron distribution around the nuclei in this region. In the present scenario, surprisingly, the work function becomes anisotropic; the longitudinal part is an increasing function of magnetic field strength, whereas the transverse part diverges.

  2. Characterization of the atypical lymphocytes in African swine fever

    Directory of Open Access Journals (Sweden)

    Z. A. Karalyan

    2016-07-01

    Full Text Available Aim: Atypical lymphocytes usually described as lymphocytes with altered shape, increased DNA amount, and larger size. For analysis of cause of genesis and source of atypical lymphocytes during African swine fever virus (ASFV infection, bone marrow, peripheral blood, and in vitro model were investigated. Materials and Methods: Atypical lymphocytes under the influence of ASFV were studied for morphologic, cytophotometric, and membrane surface marker characteristics and were used in vivo and in vitro models. Results: This study indicated the increased size, high metabolic activity, and the presence of additional DNA amount in atypical lymphocytes caused by ASFV infection. Furthermore, in atypical lymphocytes, nuclear-cytoplasmic ratio usually decreased, compared to normal lymphocytes. In morphology, they looking like lymphocytes transformed into blasts by exposure to mitogens or antigens in vitro. They vary in morphologic detail, but most of them are CD2 positive. Conclusions: Our data suggest that atypical lymphocytes may represent an unusual and specific cellular response to ASFV infection.

  3. Characterization of the atypical lymphocytes in African swine fever

    Science.gov (United States)

    Karalyan, Z. A.; Ter-Pogossyan, Z. R.; Abroyan, L. O.; Hakobyan, L. H.; Avetisyan, A. S.; Karalyan, N. Yu; Karalova, E. M.

    2016-01-01

    Aim: Atypical lymphocytes usually described as lymphocytes with altered shape, increased DNA amount, and larger size. For analysis of cause of genesis and source of atypical lymphocytes during African swine fever virus (ASFV) infection, bone marrow, peripheral blood, and in vitro model were investigated. Materials and Methods: Atypical lymphocytes under the influence of ASFV were studied for morphologic, cytophotometric, and membrane surface marker characteristics and were used in vivo and in vitro models. Results: This study indicated the increased size, high metabolic activity, and the presence of additional DNA amount in atypical lymphocytes caused by ASFV infection. Furthermore, in atypical lymphocytes, nuclear-cytoplasmic ratio usually decreased, compared to normal lymphocytes. In morphology, they looking like lymphocytes transformed into blasts by exposure to mitogens or antigens in vitro. They vary in morphologic detail, but most of them are CD2 positive. Conclusions: Our data suggest that atypical lymphocytes may represent an unusual and specific cellular response to ASFV infection. PMID:27536044

  4. Protection from anti-TCR/CD3-induced apoptosis in immature thymocytes by a signal through thymic shared antigen-1/stem cell antigen-2.

    Science.gov (United States)

    Noda, S; Kosugi, A; Saitoh, S; Narumiya, S; Hamaoka, T

    1996-05-01

    During T cell development in the thymus, the expression of thymic shared antigen-1 (TSA-1)/stem cell antigen-2 (Sca-2), a glycosylphosphatidylinositol (GPI)-anchored differentiation antigen, is developmentally regulated. The expression level of TSA-1 is the highest in most immature CD4- CD8- thymocytes, high in CD4+ CD8+ thymocytes, but barely detectable in mature CD4+ CD8- or CD4- CD8- thymocytes and peripheral T cells. We have previously shown that surface TSA-1 expression in peripheral T cells is induced upon activation and that anti-TSA-1 mAb inhibits the T cell receptor (TCR) signaling pathway in activated T cells. In the present study, we have analyzed a role of TSA-1 in thymic selection events, especially in TCR-mediated apoptosis. In in vitro experiments, anti-TSA-1 blocked anti-CD3-induced cell death of T cell hybridomas. When anti-TSA-1 was injected into newborn mice in vivo together with anti-CD3 epsilon or anti-TCR-beta, TCR/CD3-mediated apoptosis of thymocytes was almost completely blocked. The blockade of apoptosis was defined by the inhibition of, first, the decrease in total number of thymocytes; second, the decrease in percentages of CD4+ CD8+ thymocytes; and third, the induction of DNA fragmentation. However, anti-TSA-1 did not block either steroid- or radiation-induced apoptosis, indicating that a signal via TSA-1 does not inhibit a common pathway of thymocyte apoptosis. Since TCR-mediated apoptosis is pivotal in thymic ontogeny, these results suggest that TSA-1/Sca-2 is an important cell surface molecule regulating the fate of a developing T cell.

  5. Defining the antigenic diversity of Plasmodium falciparum apical membrane antigen 1 and the requirements for a multi-allele vaccine against malaria.

    Directory of Open Access Journals (Sweden)

    Damien R Drew

    Full Text Available Apical Membrane Antigen 1 (AMA1 is a leading malaria vaccine candidate and a target of naturally-acquired human immunity. Plasmodium falciparum AMA1 is polymorphic and in vaccine trials it induces strain-specific protection. This antigenic diversity is a major roadblock to development of AMA1 as a malaria vaccine and understanding how to overcome it is essential. To assess how AMA1 antigenic diversity limits cross-strain growth inhibition, we assembled a panel of 18 different P. falciparum isolates which are broadly representative of global AMA1 sequence diversity. Antibodies raised against four well studied AMA1 alleles (W2Mef, 3D7, HB3 and FVO were tested for growth inhibition of the 18 different P. falciparum isolates in growth inhibition assays (GIA. All antibodies demonstrated substantial cross-inhibitory activity against different isolates and a mixture of the four different AMA1 antibodies inhibited all 18 isolates tested, suggesting significant antigenic overlap between AMA1 alleles and limited antigenic diversity of AMA1. Cross-strain inhibition by antibodies was only moderately and inconsistently correlated with the level of sequence diversity between AMA1 alleles, suggesting that sequence differences are not a strong predictor of antigenic differences or the cross-inhibitory activity of anti-allele antibodies. The importance of the highly polymorphic C1-L region for inhibitory antibodies and potential vaccine escape was assessed by generating novel transgenic P. falciparum lines for testing in GIA. While the polymorphic C1-L epitope was identified as a significant target of some growth-inhibitory antibodies, these antibodies only constituted a minor proportion of the total inhibitory antibody repertoire, suggesting that the antigenic diversity of inhibitory epitopes is limited. Our findings support the concept that a multi-allele AMA1 vaccine would give broad coverage against the diversity of AMA1 alleles and establish new tools to

  6. Genetic polymorphism and effect of natural selection at domain I of apical membrane antigen-1 (AMA-1) in Plasmodium vivax isolates from Myanmar.

    Science.gov (United States)

    Moon, Sung-Ung; Na, Byoung-Kuk; Kang, Jung-Mi; Kim, Jung-Yeon; Cho, Shin-Hyeong; Park, Yun-Kyu; Sohn, Woon-Mok; Lin, Khin; Kim, Tong-Soo

    2010-05-01

    Malaria is endemic or hypoendemic in Myanmar and the country still contributes to the high level of malaria deaths in South-East Asia. Although information on the nature and extent of population diversity within malaria parasites in the country is essential not only for understanding the epidemic situation but also to establish a proper control strategy, very little data is currently available on the extent of genetic polymorphisms of the malaria parasites in Myanmar. In this study, we analyzed the genetic polymorphism and natural selection at domain I of the apical membrane antigen-1 (AMA-1) among Plasmodium vivax Myanmar isolates. A total of 34 distinguishable haplotypes were identified among the 76 isolates sequenced. Comparison with the previously available PvAMA-1 sequences in the GenBank database revealed that 21 of them were new haplotypes that have never been reported till date. The difference between the rate of nonsynonymous (dN) and synonymous (dS) mutations was positive (dN-dS, 0.013+/-0.005), suggesting the domain I is under positive natural selection. The Tajima's D statistics was found to be -0.74652, suggesting that the gene has evolved under population size expansion and/or positive selection. The minimum recombination events were also high, indicating that recombination may occur within the domain I resulting in allelic diversity of PvAMA-1. Our results collectively suggest that PvAMA-1 displays high genetic polymorphism among Myanmar P. vivax isolates with highly diversifying selection at domain I. These results have significant implications in understanding the nature of P. vivax population circulating in Myanmar as well as providing useful information for malaria vaccine development based on this antigen.

  7. Epstein-Barr Virus Nuclear Antigen 1 (EBNA1) interacts with Regulator of Chromosome Condensation (RCC1) dynamically throughout the cell cycle.

    Science.gov (United States)

    Deschamps, Thibaut; Quentin, Bazot; Leske, Derek M; MacLeod, Ruth; Mompelat, Dimitri; Tafforeau, Lionel; Lotteau, Vincent; Maréchal, Vincent; Baillie, George S; Gruffat, Henri; Wilson, Joanna B; Manet, Evelyne

    2016-12-12

    The Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is a sequence-specific DNA binding protein which plays an essential role in viral episome replication and segregation, by recruiting the cellular complex of DNA replication onto the origin (oriP) and by tethering the viral DNA onto the mitotic chromosomes. Whereas the mechanisms of viral DNA replication are well documented, those involved in tethering EBNA1 to the cellular chromatin are far from being understood. Here, we have identified Regulator of Chromosome Condensation 1 (RCC1) as a novel cellular partner for EBNA1. RCC1 is the major nuclear guanine nucleotide exchange factor (RanGEF) for the small GTPase Ran enzyme. RCC1, associated with chromatin, is involved in the formation of RanGTP gradients critical for nucleo-cytoplasmic transport, mitotic spindle formation, and nuclear envelope reassembly following mitosis. Using several approaches, we have demonstrated a direct interaction between these two proteins and found that the EBNA1 domains responsible for EBNA1 tethering to the mitotic chromosomes are also involved in the interaction with RCC1. The use of an EBNA1 peptide array confirmed the interaction of RCC1 with these regions and also the importance of the N-terminal region of RCC1 in this interaction. Finally, using confocal microscopy and FRET analysis to follow the dynamics of interaction between the two proteins throughout the cell cycle, we have demonstrated that EBNA1 and RCC1 closely associate on the chromosomes during metaphase, suggesting an essential role for the interaction during this phase, perhaps in tethering EBNA1 to mitotic chromosomes.

  8. Identification and expression of Babesia ovis secreted antigen 1 and evaluation of its diagnostic potential in an enzyme-linked immunosorbent assay.

    Science.gov (United States)

    Sevinc, Ferda; Cao, Shinuo; Xuan, Xuenan; Sevinc, Mutlu; Ceylan, Onur

    2015-05-01

    In order to identify immunoreactive proteins that are usable for the immunological diagnosis of Babesia ovis infections, a phage lambda cDNA expression library was constructed and screened using parasite-specific immune serum. Immunoscreening resulted in the identification of a full-length cDNA clone encoding a secreted protein designated Babesia ovis secreted antigen 1 (BoSA1). The full-length BoSA1 cDNA contained a 1,137-bp open reading frame that encoded a protein of 378 amino acids, with a signal peptide and 2 internal repeat domains. The theoretical molecular mass of the mature protein was 42.5 kDa. Recombinant BoSA1 (rBoSA1) protein was expressed in Escherichia coli strain DH5α cells as a glutathione S-transferase (GST) fusion protein and was purified by affinity chromatography. Purified rBoSA1 was tested for reactivity with sera from animals experimentally or naturally infected with B. ovis, in an indirect enzyme-linked immunosorbent assay (ELISA). The results showed that specific antibodies against rBoSA1 were detectable on days 7 and 8 of the experimental infection and were maintained during the sampling period. Additionally, 38 field sera taken from sheep naturally infected with B. ovis gave strong positive reactions in the ELISA between day 20 and day 30 of treatment. As a result, the identified recombinant BoSA1 protein seems to be a promising diagnostic antigen that is usable for the development of serological assays for the diagnosis of ovine babesiosis. This is the first report on the molecular cloning, expression, and potential use of a recombinant antigen for the diagnosis of ovine babesiosis.

  9. Flow cytometric analysis of lymphocytes and lymphocyte subpopulations in induced sputum from patients with asthma

    Directory of Open Access Journals (Sweden)

    Yutaro Shiota

    2000-01-01

    Full Text Available Study objectives were to compare the numbers of lymphocytes and lymphocyte subpopulations in induced sputum from asthmatic patients and from healthy subjects, and to determine the effect of inhaled anti-asthmatic steroid therapy on these cell numbers. Hypertonic saline inhalation was used to non-invasively induce sputum samples in 34 patients with bronchial asthma and 21 healthy subjects. The sputum samples were reduced with dithioerythritol and absolute numbers of lymphocytes and lymphocyte subpopulations were assessed by direct immunofluorescence and flow cytometry. To assess the effect of beclomethasone dipropionate (BDP on induced sputum, numbers of lymphocytes and lymphocyte subpopulations in sputum also were evaluated after 4 weeks of BDP inhalation treatment in seven asthmatic patients. An adequate sample was obtained in 85.3% of patients with asthma and in 79.2% of the healthy subjects. Induced sputum from patients with asthma had increased numbers of lymphocytes (P = 0.009; CD4+ cells (P = 0.044; CD4+ cells-bearing interleukin-2 receptor (CD25; P = 0.016; and CD4+ cells bearing human histocompatibility leukocyte antigen (HLA-DR (P = 0.033. CD8+ cells were not increased in asthmatic patients. In patients treated with inhaled steroids, numbers of lymphocytes, CD4+ cells, CD25-bearing CD4+ cells and HLA-DR-bearing CD4+ cells in sputum decreased from pretreatment numbers (P = 0.016, 0.002, 0.003 and 0.002, respectively. Analysis of lymphocytes in induced sputum by flow cytometry is useful in assessing bronchial inflammation, and activated CD4+ lymphocytes may play a key role in the pathogenesis of airway inflammation in bronchial asthma.

  10. Nodular lymphocyte-predominant Hodgkin lymphoma.

    Science.gov (United States)

    Savage, Kerry J; Mottok, Anja; Fanale, Michelle

    2016-07-01

    Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma with distinct clinicopathologic features. It is typified by the presence of lymphocyte predominant (LP) cells, which are CD20(+) but CD15(-) and CD30(-) and are found scattered amongst small B lymphocytes arranged in a nodular pattern. Despite frequent and often late or multiple relapses, the prognosis of NLPHL is very favorable. There is an inherent risk of secondary aggressive non-Hodgkin lymphoma (NHL) and studies support that risk is highest in those with splenic involvement at presentation. Given disease rarity, the optimal management is unclear and opinions differ as to whether treatment paradigms should be similar to or differ from those for classical Hodgkin lymphoma (CHL). This review provides an overview of the existing literature describing pathological subtypes, outcome and treatment approaches for NLPHL.

  11. T cell immunity using transgenic B lymphocytes

    Science.gov (United States)

    Gerloni, Mara; Rizzi, Marta; Castiglioni, Paola; Zanetti, Maurizio

    2004-03-01

    Adaptive immunity exists in all vertebrates and plays a defense role against microbial pathogens and tumors. T cell responses begin when precursor T cells recognize antigen on specialized antigen-presenting cells and differentiate into effector cells. Currently, dendritic cells are considered the only cells capable of stimulating T lymphocytes. Here, we show that mature naïve B lymphocytes can be genetically programmed by using nonviral DNA and turned into powerful antigen-presenting cells with a dual capacity of synthesis and presentation of antigen to T cells in vivo. A single i.v. injection of transgenic lymphocytes activates T cell responses reproducibly and specifically even at very low cell doses (102). We also demonstrate that T cell priming can occur in the absence of dendritic cells and results in immunological memory with protective effector functions. These findings disclose aspects in the regulation of adaptive immunity and indicate possibilities for vaccination against viruses and cancer in humans.

  12. An intrinsic GABAergic system in human lymphocytes.

    Science.gov (United States)

    Dionisio, Leonardo; José De Rosa, María; Bouzat, Cecilia; Esandi, María Del Carmen

    2011-01-01

    γ-amino butyric acid (GABA) is an ubiquitous neurotransmitter in the central nervous system and it is also present in non-neuronal cells. In this study we investigated the presence of neuronal components of the GABAergic system in lymphocytes and its functional significance. By using RT-PCR we detected mRNA expression of different components of the GABAergic system in resting and mitogen-activated lymphocytes: i) GAD67, an isoform of the enzyme that synthetizes GABA; ii) VIAAT, the vesicular protein involved in GABA storage; iii) GABA transporters (GAT-1 and GAT-2); iv) GABA-T, the enzyme that catabolizes GABA; and v) subunits that conform ionotropic GABA receptors. The presence of VIAAT protein in resting and activated cells was confirmed by immunocytochemistry. The functionality of GABA transporters was evaluated by measuring the uptake of radioactive GABA. The results show that [(3)H]GABA uptake is 5-fold higher in activated than in resting lymphocytes. To determine if GABA subunits assemble into functional channels, we performed whole-cell recordings in activated lymphocytes. GABA and muscimol, a specific agonist of ionotropic GABA receptors, elicit macroscopic currents in about 10-15% of the cells. Finally, by using [(3)H]thymidine incorporation assays, we determined that the presence of agonists of GABA receptor during activation inhibits lymphocyte proliferation. Our results reveal that lymphocytes have a functional GABAergic system, similar to the neuronal one, which may operate as a modulator of T-cell activation. Pharmacological modulation of this system may provide new approaches for regulation of T-cell response. Copyright © 2010 Elsevier Ltd. All rights reserved.

  13. Lymphocytic adenohypophysitis: skull radiographs and MRI

    Energy Technology Data Exchange (ETDEWEB)

    Saiwai, S.; Miyamoto, T. [Department of Radiology, Kobe Central Municipal Hospital, Hyogo (Japan); Inoue, Y.; Nemoto, Y.; Tashiro, T. [Department of Radiology, Osaka City University Medical School (Japan); Ishihara, T. [Department of Endocrinology, Kobe Central Municipal Hospital, Hyogo (Japan); Matsumoto, S. [Department of Neurosurgery, Kobe Central Municipal Hospital, Hyogo (Japan); Hakuba, A. [Department of Neurosurgery, Osaka City University Medical School, 1-5-7 Asahimachi, Abeno, Osaka, 545 (Japan)

    1998-02-01

    We report the skull radiograph, CT and MRI findings in three patients with lymphocytic adenohypophysitis mimicking pituitary adenoma. All cases were associated with pregnancy. CT demonstrated a pituitary mass but did not differentiate lymphocytic adenohypophysitis from pituitary adenoma. The skull radiographs showed either a normal sella turcica or minimal abnormalities; they did not show ballooning or destruction. The MRI appearances were distinctive: relatively low signal on T1-weighted images; preservation of the bright posterior pituitary lobe despite the presence of a relatively large pituitary mass, less common in macroadenomas; marked contrast enhancement compared with pituitary macroadenomas; and dural enhancement adjacent to a pituitary mass. (orig.) With 3 figs., 1 tab., 40 refs.

  14. The Uptake and Utilization of Chlorambucil by Lymphocytes from Patients with Chronic Lymphocytic Leukaemia

    Science.gov (United States)

    Hill, Bridget T.; Harrap, K. R.

    1972-01-01

    It has been shown that lymphocytes isolated from the peripheral blood of patients with chronic lymphocytic leukaemia do not modify the mustard group of chlorambucil, as has been demonstrated previously in Yoshida ascites cells. However, lymphocytes from patients with an unsatisfactory clinical course or poor response to treatment were able to modify the aromatic region of the drug molecule; little change occurred in the aromatic absorption of intracellular chlorambucil in patients who responded to treatment. This simple test may provide a rapid assessment of a patient's potential response to chemotherapy. PMID:4647395

  15. Lymphocytic adrenal medullitis and lymphocytic thyroiditis in a laboratory beagle dog.

    Science.gov (United States)

    Doi, Takuya; Tomonari, Yuki; Kawasako, Kazufumi; Yamada, Naoaki; Tsuchitani, Minoru

    2017-02-04

    Lymphocytic adrenal medullitis characterized by inflammation and atrophy in the medulla of the bilateral adrenal glands was observed in an 18-month-old male laboratory beagle dog. It might be that the present lymphocytic adrenal medullitis is an autoimmune-mediated disease as the histological characteristics are consistent with an autoimmune pathogenesis. However, the actual cause remains unclear as the existence of serum autoantibodies against the adrenal medulla could not be confirmed. Although this dog also contracted lymphocytic thyroiditis along with serum thyroglobulin autoantibodies, indicating that the thyroiditis occurred with an autoimmune basis; the relation between the adrenal medullitis and thyroiditis is unknown.

  16. Phase 1/2a study of the malaria vaccine candidate apical membrane antigen-1 (AMA-1 administered in adjuvant system AS01B or AS02A.

    Directory of Open Access Journals (Sweden)

    Michele D Spring

    Full Text Available BACKGROUND: This Phase 1/2a study evaluated the safety, immunogenicity, and efficacy of an experimental malaria vaccine comprised of the recombinant Plasmodium falciparum protein apical membrane antigen-1 (AMA-1 representing the 3D7 allele formulated with either the AS01B or AS02A Adjuvant Systems. METHODOLOGY/PRINCIPAL FINDINGS: After a preliminary safety evaluation of low dose AMA-1/AS01B (10 microg/0.5 mL in 5 adults, 30 malaria-naïve adults were randomly allocated to receive full dose (50 microg/0.5 mL of AMA-1/AS01B (n = 15 or AMA-1/AS02A (n = 15, followed by a malaria challenge. All vaccinations were administered intramuscularly on a 0-, 1-, 2-month schedule. All volunteers experienced transient injection site erythema, swelling and pain. Two weeks post-third vaccination, anti-AMA-1 Geometric Mean Antibody Concentrations (GMCs with 95% Confidence Intervals (CIs were high: low dose AMA-1/AS01B 196 microg/mL (103-371 microg/mL, full dose AMA-1/AS01B 279 microg/mL (210-369 microg/mL and full dose AMA-1/AS02A 216 microg/mL (169-276 microg/mL with no significant difference among the 3 groups. The three vaccine formulations elicited equivalent functional antibody responses, as measured by growth inhibition assay (GIA, against homologous but not against heterologous (FVO parasites as well as demonstrable interferon-gamma (IFN-gamma responses. To assess efficacy, volunteers were challenged with P. falciparum-infected mosquitoes, and all became parasitemic, with no significant difference in the prepatent period by either light microscopy or quantitative polymerase chain reaction (qPCR. However, a small but significant reduction of parasitemia in the AMA-1/AS02A group was seen with a statistical model employing qPCR measurements. SIGNIFICANCE: All three vaccine formulations were found to be safe and highly immunogenic. These immune responses did not translate into significant vaccine efficacy in malaria-naïve adults employing a primary sporozoite

  17. Identifying Patient-Specific Epstein-Barr Nuclear Antigen-1 Genetic Variation and Potential Autoreactive Targets Relevant to Multiple Sclerosis Pathogenesis.

    Directory of Open Access Journals (Sweden)

    Monika Tschochner

    Full Text Available Epstein-Barr virus (EBV infection represents a major environmental risk factor for multiple sclerosis (MS, with evidence of selective expansion of Epstein-Barr Nuclear Antigen-1 (EBNA1-specific CD4+ T cells that cross-recognize MS-associated myelin antigens in MS patients. HLA-DRB1*15-restricted antigen presentation also appears to determine susceptibility given its role as a dominant risk allele. In this study, we have utilised standard and next-generation sequencing techniques to investigate EBNA-1 sequence variation and its relationship to HLA-DR15 binding affinity, as well as examining potential cross-reactive immune targets within the central nervous system proteome.Sanger sequencing was performed on DNA isolated from peripheral blood samples from 73 Western Australian MS cases, without requirement for primary culture, with additional FLX 454 Roche sequencing in 23 samples to identify low-frequency variants. Patient-derived viral sequences were used to predict HLA-DRB1*1501 epitopes (NetMHCII, NetMHCIIpan and candidates were evaluated for cross recognition with human brain proteins.EBNA-1 sequence variation was limited, with no evidence of multiple viral strains and only low levels of variation identified by FLX technology (8.3% nucleotide positions at a 1% cut-off. In silico epitope mapping revealed two known HLA-DRB1*1501-restricted epitopes ('AEG': aa 481-496 and 'MVF': aa 562-577, and two putative epitopes between positions 502-543. We identified potential cross-reactive targets involving a number of major myelin antigens including experimentally confirmed HLA-DRB1*15-restricted epitopes as well as novel candidate antigens within myelin and paranodal assembly proteins that may be relevant to MS pathogenesis.This study demonstrates the feasibility of obtaining autologous EBNA-1 sequences directly from buffy coat samples, and confirms divergence of these sequences from standard laboratory strains. This approach has identified a number of

  18. Predicting functional associations from metabolism using bi-partite network algorithms

    Directory of Open Access Journals (Sweden)

    Veeramani Balaji

    2010-07-01

    Full Text Available Abstract Background Metabolic reconstructions contain detailed information about metabolic enzymes and their reactants and products. These networks can be used to infer functional associations between metabolic enzymes. Many methods are based on the number of metabolites shared by two enzymes, or the shortest path between two enzymes. Metabolite sharing can miss associations between non-consecutive enzymes in a serial pathway, and shortest-path algorithms are sensitive to high-degree metabolites such as water and ATP that create connections between enzymes with little functional similarity. Results We present new, fast methods to infer functional associations in metabolic networks. A local method, the degree-corrected Poisson score, is based only on the metabolites shared by two enzymes, but uses the known metabolite degree distribution. A global method, based on graph diffusion kernels, predicts associations between enzymes that do not share metabolites. Both methods are robust to high-degree metabolites. They out-perform previous methods in predicting shared Gene Ontology (GO annotations and in predicting experimentally observed synthetic lethal genetic interactions. Including cellular compartment information improves GO annotation predictions but degrades synthetic lethal interaction prediction. These new methods perform nearly as well as computationally demanding methods based on flux balance analysis. Conclusions We present fast, accurate methods to predict functional associations from metabolic networks. Biological significance is demonstrated by identifying enzymes whose strong metabolic correlations are missed by conventional annotations in GO, most often enzymes involved in transport vs. synthesis of the same metabolite or other enzyme pairs that share a metabolite but are separated by conventional pathway boundaries. More generally, the methods described here may be valuable for analyzing other types of networks with long-tailed degree

  19. Predicting functional associations from metabolism using bi-partite network algorithms.

    Science.gov (United States)

    Veeramani, Balaji; Bader, Joel S

    2010-07-14

    Metabolic reconstructions contain detailed information about metabolic enzymes and their reactants and products. These networks can be used to infer functional associations between metabolic enzymes. Many methods are based on the number of metabolites shared by two enzymes, or the shortest path between two enzymes. Metabolite sharing can miss associations between non-consecutive enzymes in a serial pathway, and shortest-path algorithms are sensitive to high-degree metabolites such as water and ATP that create connections between enzymes with little functional similarity. We present new, fast methods to infer functional associations in metabolic networks. A local method, the degree-corrected Poisson score, is based only on the metabolites shared by two enzymes, but uses the known metabolite degree distribution. A global method, based on graph diffusion kernels, predicts associations between enzymes that do not share metabolites. Both methods are robust to high-degree metabolites. They out-perform previous methods in predicting shared Gene Ontology (GO) annotations and in predicting experimentally observed synthetic lethal genetic interactions. Including cellular compartment information improves GO annotation predictions but degrades synthetic lethal interaction prediction. These new methods perform nearly as well as computationally demanding methods based on flux balance analysis. We present fast, accurate methods to predict functional associations from metabolic networks. Biological significance is demonstrated by identifying enzymes whose strong metabolic correlations are missed by conventional annotations in GO, most often enzymes involved in transport vs. synthesis of the same metabolite or other enzyme pairs that share a metabolite but are separated by conventional pathway boundaries. More generally, the methods described here may be valuable for analyzing other types of networks with long-tailed degree distributions and high-degree hubs.

  20. SVD-phy: improved prediction of protein functional associations through singular value decomposition of phylogenetic profiles.

    Science.gov (United States)

    Franceschini, Andrea; Lin, Jianyi; von Mering, Christian; Jensen, Lars Juhl

    2016-04-01

    A successful approach for predicting functional associations between non-homologous genes is to compare their phylogenetic distributions. We have devised a phylogenetic profiling algorithm, SVD-Phy, which uses truncated singular value decomposition to address the problem of uninformative profiles giving rise to false positive predictions. Benchmarking the algorithm against the KEGG pathway database, we found that it has substantially improved performance over existing phylogenetic profiling methods. The software is available under the open-source BSD license at https://bitbucket.org/andrea/svd-phy lars.juhl.jensen@cpr.ku.dk Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press.

  1. LP BOUNDEDNESS OF AREA FUNCTION ASSOCIATED WITH OPERATORS ON PRODUCT SPACES

    Institute of Scientific and Technical Information of China (English)

    Liang Song; Chaoqiang Tan

    2006-01-01

    Let L be the infinitesimal generator of an analytic semigroup on L2 (Rn) with suitable upper bounds on its heat kernels. Assume that L has a bounded holomorphic functional calculus on L2(Rn). In this paper,we define the Littlewood- Paley g function associated with L on Rn × Rn, denoted by GL(f)(x1, x2), and decomposition, we prove that ‖SL(f)‖p ≈‖GL(f)‖p ≈‖f‖p for 1 < p <∞.

  2. Dual character of interaction between lymphocytes and allogeneic stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Petrov, R.V.; Dozmorov, I.M.; Kochetkova, M.O.; Nikolaeva, I.S.

    1986-10-01

    The mechanisms of stimulation of colony formation by small doses of allogeneic lymphocytes were studied in mice. When interaction of lymphocytes with allogeneic stem cells was studied, bone marrow cells of mice were injected into lethally irradiated recipients in the control, and mixtures of bone marrow cells with varied numbers of lymphocytes were injected in the experiment. Dependence of the inactivation indices on the number of lymphocytes injected, based on the results of counting macro- and microcolonies in the spleen, is shown.

  3. Morphometric Characterization of Small Cell Lymphocytic Lymphoma

    Directory of Open Access Journals (Sweden)

    Chisoi Anca

    2014-11-01

    Full Text Available The morphometry in histopathology is used to characterize cell populations belonging to different tissues and to identify differences in their parameters with prognostic implications. To achieve morphometric examination were selected 6 of 24 cases identified as small cell lymphocytic lymphoma. For each case analysis was done on five fields, for each field measuring the parameters of 20 cells. The studied parameters were for cytoplasm: cytoplasmic area, maximum and minimum cytoplasmic diameter, cytoplasmic perimeter; for nucleus were measured: nuclear area, minimum and maximum nuclear diameter, nuclear perimeter, nuclear contour index, nuclear ellipticity index, nuclear irregularity index. Also the nucleocytoplasmic ratio was calculated in all studied cases. Small cell lymphocytic lymphoma is characterized in morphometric terms having a small cytoplasmic area (average 29.206 and also a small nuclear area (mean 28.939 having a nucleo-cytoplasmic ratio appearance suggestive for adult lymphocyte. A nuclear contour index small value (3.946, ellipticity index value also small (3.521 and small nuclear irregularity index (3.965. Standard deviations, in any of the studied morphometric categories, is around or below 1 suggesting monomorphic cell appearance. These morphometric and microscopic features characterized mainly by a small population of adult lymphocytes, monomorphic, with rounded hipercromic nuclei, dense chromatin, support the framing into indolent lymphoma group in terms of clinical outcome.

  4. Targeting cytotoxic T lymphocytes for cancer immunotherapy

    OpenAIRE

    Maher, J; Davies, E. T.

    2004-01-01

    In light of their preeminent role in cellular immunity, there is considerable interest in targeting of cytotoxic T-lymphocytes to cancer. This review summarises the active and passive immunotherapeutic approaches under development to achieve this goal, emphasising how recent advances in tumour immunology and gene transfer have impacted upon this field.

  5. Immunophenotypic lymphocyte profiles in human african trypanosomiasis.

    Directory of Open Access Journals (Sweden)

    Caroline Boda

    Full Text Available Human African trypanosomiasis (HAT is a deadly vector-born disease caused by an extracellular parasite, the trypanosome. Little is known about the cellular immune responses elicited by this parasite in humans. We used multiparameter flow cytometry to characterize leukocyte immunophenotypes in the blood and cerebrospinal fluid (CSF of 33 HAT patients and 27 healthy controls identified during a screening campaign in Angola and Gabon. We evaluated the subsets and activation markers of B and T lymphocytes. Patients had a higher percentage of CD19+ B lymphocytes and activated B lymphocytes in the blood than did controls, but lacked activated CD4+ T lymphocytes (CD25+. Patients displayed no increase in the percentage of activated CD8+ T cells (HLA-DR+, CD69+ or CD25+, but memory CD8 T-cell levels (CD8+CD45RA2 were significantly lower in patients than in controls, as were effector CD8 T-cell levels (CD8+CD45RA+CD62L2. No relationship was found between these blood immunophenotypes and disease severity (stage 1 vs 2. However, CD19+ B-cell levels in the CSF increased with disease severity. The patterns of T and B cell activation in HAT patients suggest that immunomodulatory mechanisms may operate during infection. Determinations of CD19+ B-cell levels in the CSF could improve disease staging.

  6. SnapShot: chronic lymphocytic leukemia.

    Science.gov (United States)

    Ciccone, Maria; Ferrajoli, Alessandra; Keating, Michael J; Calin, George A

    2014-11-10

    Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in western countries. This SnapShot depicts the origins and evolution of this B cell malignancy, describes prognostic factors and CLL animal models, and illustrates therapies in preclinical and clinical development against CLL.

  7. Regulatory T-lymphocytes in asthma

    NARCIS (Netherlands)

    van Oosterhout, AJM; Bloksma, N

    2005-01-01

    T-helper cell type (Th)2 lymphocytes play an important role in the initiation, progression and persistence of allergic diseases, including asthma. However, little is known about immunoregulatory mechanisms that determine susceptibility to, severity of, or persistence of asthma. The concept of a dist

  8. Lymphocyte dynamics in health and disease

    NARCIS (Netherlands)

    van Gent, R.

    2009-01-01

    Following immune depletion, it is vital that the immune system recovers rapidly to avoid severe or life-threatening infections. In adults, full recovery of CD4+ and CD8+ T-cell counts, important cell types of the immune system, may take years. Similar to other lymphocytes, T cells start their develo

  9. Peripheral lymphocyte subpopulations in recurrent aphthous ulceration

    DEFF Research Database (Denmark)

    Pedersen, A; Klausen, B; Hougen, H P

    1991-01-01

    Peripheral lymphocyte subsets--T-helper (CD4+), T-suppressor/cytotoxic (CD8+), and naive/virgin T cells/natural killer cells (CD45RA)--were studied quantitatively in 30 patients with recurrent aphthous ulceration (RAU) and 29 sex- and age-matched RAU-free control donors. The CD4+ percentage was s...

  10. Effect of chloroquine on human lymphocyte proliferation

    DEFF Research Database (Denmark)

    Bygbjerg, Ib Christian; Flachs, H

    1986-01-01

    the response to pokeweed mitogen. The response to concanavalin A and to various antigens was suppressed, especially the response to large particulate antigens. Oral intake of 300 mg of chloroquine base/week did not affect the lymphocyte proliferative responses. 600 mg of base/week decreased the response...

  11. Rosette formation of pig T lymphocytes with sheep erythrocytes.

    Science.gov (United States)

    Escajadillo, C; Binns, R M

    1975-01-01

    The relationship of sheep RBC rosette formation to density of thymus and blood lymphocytes was investigated. Thymocyte density was unimodal and cells of all densities rosetted equally. Blood lymphocyte density was bimodal with most rosette-forming cells in the denser ficoll layers. Papain treatment of SRBC increases rosette formation with blood lymphocytes while apparently maintaining specificity of T cells.

  12. 21 CFR 864.8500 - Lymphocyte separation medium.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Lymphocyte separation medium. 864.8500 Section 864.8500 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... medium. (a) Identification. A lymphocyte separation medium is a device used to isolate lymphocytes from...

  13. DMPD: Developmental plasticity of lymphocytes. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18472258 Developmental plasticity of lymphocytes. Cobaleda C, Busslinger M. Curr Op...in Immunol. 2008 Apr;20(2):139-48. Epub 2008 May 9. (.png) (.svg) (.html) (.csml) Show Developmental plastic...ity of lymphocytes. PubmedID 18472258 Title Developmental plasticity of lymphocytes. Authors Cobaleda C, Bus

  14. Chronic lymphocytic leukemia/small lymphocytic lymphoma presenting as septic arthritis of the shoulder

    Energy Technology Data Exchange (ETDEWEB)

    Donovan, Andrea; Schweitzer, Mark E.; Nomikos, George [NYU Hospital for Joint Diseases, New York, NY (United States); Garcia, Roberto A. [Bellevue Hospital Center, New York, NY (United States)

    2008-11-15

    We report a case of a 53-year-old man presenting with shoulder pain mimicking septic arthritis. Laboratory findings were atypical. Biopsy performed to assess for possible osteomyelitis demonstrated chronic lymphocytic leukemia/small lymphocytic lymphoma. Intra-articular lymphoma is a rare but important consideration in patients with atypical clinical presentation. Imaging alone may be insufficient to render diagnosis as lymphoma can mimic infection, synovial hypertrophic processes, and depositional arthropathy. (orig.)

  15. NEUTROPHIL/LYMPHOCYTE RATIO AND PLATELET/LYMPHOCYTE RATIO IN PATIENTS WITH NSCLC

    OpenAIRE

    Cukic, Vesna

    2016-01-01

    Objective: to compare neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) in patients with NSCLC (Non- Small- Cell Lung Cancer): with and without metastases at the time of diagnosis to find out if there is the importance of these cell ratios in the assessment of severity NSCLC. Material and Methods: this is the retrospective analysis of NRL and PRL in patients with NSCLC at the time of the diagnosis of disease before any anti tumor treatment (chemotherapy, radiotherapy, surg...

  16. Lymphocytic colitis: A clue to bacterial etiology

    Institute of Scientific and Technical Information of China (English)

    Thanaa EA Helal; Naglaa S Ahmed; Osama Abo El Fotoh

    2005-01-01

    AIM: To find out the role of bacteria as a possible etiological factor in lymphocytic colitis.METHODS: Twenty patients with histopathological diagnosis of lymphocytic colitis and 10 normal controls were included in this study. Colonoscopic biopsies were obtained from three sites (hepatic and splenic flexures and rectosigmoid region). Each biopsy was divided into two parts. A fresh part was incubated on special cultures for bacterial growth. The other part was used for the preparation of histologic tissue sections that were examined for the presence of bacteria with the help of Giemsa stain.RESULTS: Culture of tissue biopsies revealed bacterial growth in 18 out of 20 patients with lymphocytic colitis mostly Escherichia coli(14/18), which was found in all rectosigmoid specimens (14/14), but only in 8/14 and 6/14 of splenic and hepatic flexure specimens respectively. In two of these cases, E coliwas associated with proteus. Proteus was found only in one case, Klebsiella in two cases, and Staphylococcus aureus in one case. In the control group, only 2 out of 10 controls showed the growth of E coliin their biopsy cultures.Histopathology showed rod-shaped bacilli in the tissue sections of 12 out of 14 cases with positive E coliin their specimen's culture. None of the controls showed these bacteria in histopathological sections.CONCLUSION: This preliminary study reports an association between E coliand lymphocytic colitis, based on histological and culture observations. Serotyping and molecular studies are in process to assess the role of E coliin the pathogenesis of lymphocytic colitis.

  17. Lymphocyte transformation studies in drug hypersensitivity.

    Science.gov (United States)

    Warrington, R J; Tse, K S

    1979-05-05

    In a group of patients with clinically diagnosed drug hypersensitivity the in vitro lymphocyte response to the suspected drug was assessed by the lymphocyte transformation test. The test gave positive results in all 15 patients with penicillin-induced immediate or accelerated allergic reactions and positive immediate skin-test reactivity to the major or the minor antigenic determinant of penicillin, or both, but in only 3 of the 12 patients with delayed-onset maculopapular rashes induced by penicillin, despite positive immediate reactivity to the skin-test reagents.Lymphocyte stimulation greater than five times the control level was demonstrated for five patients with penicillin-induced erythroderma, Stevens-Johnson syndrome or a serum-sickness-like illness, or with methicillin-induced interstitial nephritis, all of whom had negative reactions to the appropriate skin-test reagents. A low level of stimulation was seen in eight other skin-test-negative patients with possible allergic reactions induced by penicillins. However, in all subjects tested the stimulation was significantly greater than the mean for control subjects.For 9 of 11 patients with isoniazid-induced hepatitis or maculopapular rashes, but for only 8 of 31 patients with eruptions induced by a variety of drugs other than penicillins and isoniazid, significant stimulation occurred in the lymphocyte transformation test.It is concluded that the lymphocyte transformation test is useful in the detection of hypersensitivity to the penicillins (although in IgE-mediated reactions skin testing is clearly preferable) and isoniazid but is of limited value in the demonstration of hypersensitivity to other drugs.

  18. Epstein-Barr Virus nuclear antigen 1 (EBNA1) confers resistance to apoptosis in EBV-positive B-lymphoma cells through up-regulation of survivin.

    Science.gov (United States)

    Lu, Jie; Murakami, Masanao; Verma, Subhash C; Cai, Qiliang; Haldar, Sabyasachi; Kaul, Rajeev; Wasik, Mariusz A; Middeldorp, Jaap; Robertson, Erle S

    2011-02-05

    Resistance to apoptosis is an important component of the overall mechanism which drives the tumorigenic process. EBV is a ubiquitous human gamma-herpesvirus which preferentially establishes latent infection in viral infected B-lymphocytes. EBNA1 is typically expressed in most forms of EBV-positive malignancies and is important for replication of the latent episome in concert with replication of the host cells. Here, we investigate the effects of EBNA1 on survivin up-regulation in EBV-infected human B-lymphoma cells. We present evidence which demonstrates that EBNA1 forms a complex with Sp1 or Sp1-like proteins bound to their cis-element at the survivin promoter. This enhances the activity of the complex and up-regulates survivin. Knockdown of survivin and EBNA1 showed enhanced apoptosis in infected cells and thus supports a role for EBNA1 in suppressing apoptosis in EBV-infected cells. Here, we suggest that EBV encoded EBNA1 can contribute to the oncogenic process by up-regulating the apoptosis suppressor protein, survivin in EBV-associated B-lymphoma cells.

  19. Is lymphocytic (hashimoto) thyroiditis associated with suicide?

    Science.gov (United States)

    Cina, Stephen J; Perper, Joshua A

    2009-09-01

    The histologic diagnosis of lymphocytic (Hashimoto) thyroiditis requires lymphocytic inflammation of the thyroid gland in combination with Hourthle cell metaplasia of follicular epithelial cells. Clinically, this autoimmune process has been associated with hypothyroidism and psychiatric conditions including depression. This retrospective study was designed to quantify the incidence and severity of lymphocytic thyroiditis in a series of nonconsecutive suicides compared with a cohort of motor vehicle accident victim controls. Eighty-one suicide victims (61 male, 20 female; age range 13-79 years, average 43) were compared with 88 age and gender matched controls (64 males, 24 females; age range 19-85 years, average 36). The degree of lymphocytic inflammation of the thyroid gland was graded on a scale of 0 to 3 (0 = no inflammation, 1 = mild inflammation, 2-3 moderate-to-marked inflammation with Hourthle cell metaplasia). Slides from each case were reviewed while blinded to the cause and manner of death in each case. Of these 169 total cases, 8 (4.7%) received a score of 3, whereas additional 7 (4.1%) received a grade of 2. Eighty-six percent of all of the cases showed no significant inflammation and recorded a score of 0. Of the 81 suicides, 3 had a score of 3, and 3 had a score of 2 (combined incidence of 7.4%). Within the control group, 5 of 88 cases scored 3 and another 4 scored 2 (combined incidence = 10.2%). Three males and 5 females scored 3 with an age range of 23 to 63 years, average 42. Incidental data tabulated showed that 19% of suicide victims were on psychoactive medications compared with 6% in the motor vehicle accident control group. No one on this study was on thyroid hormone replacement therapy. Depression is strongly linked to suicide and lymphocytic thyroiditis may be a cause of depression. Based on this study, however, the presence of lymphocytic thyroiditis cannot be used as a histologic adjunct to discriminate between suicide and accident in

  20. Mean dose to lymphocytes during radiotherapy treatments

    Energy Technology Data Exchange (ETDEWEB)

    Brandan, M.E.; Perez-Pastenes, M.A. [Instituto de Fisica (Mexico); Ostrosky-Wegman, P.; Gonsebatt, M.E. [Instituto de Investigaciones Biomedicas (Mexico); Diaz-Perches, R. [Hospital General de Mexico (Mexico)

    1994-10-01

    Using a probabilistic model with parameters from four radiotherapy protocols used in Mexican hospitals for the treatment of cervical cancer, the authors have calculated the distribution of dose to cells in peripheral blood of patients. Values of the mean dose to the lymphocytes during and after a {sup 60}Co treatment are compared to estimates from an in vivo chromosome aberration study performed on five patients. Calculations indicate that the mean dose to the circulating blood is about 2% of the tumor dose, while the mean dose to recirculating lymphocytes may reach up to 7% of the tumor dose. Differences up to a factor of two in the dose to the blood are predicted for different protocols delivering equal tumor doses. The data suggest mean doses higher than the predictions of the model. 10 refs., 3 figs., 2 tabs.

  1. Cell Death Mechanisms Induced by Cytotoxic Lymphocytes

    Institute of Scientific and Technical Information of China (English)

    Ch(a)vez-Gal(a)n L; Arenas-Del Angel MC; Zenteno E; Ch(a)vez R; Lascurain R

    2009-01-01

    One of the functions of the immune system is to recognize and destroy abnormal or infected cells to maintain homeostasis. This is accomplished by cytotoxic lymphocytes. Cytotoxicity is a highly organized multifactor process. Here, we reviewed the apoptosis pathways induced by the two main cytotoxic lymphocyte subsets, natural killer (NK) cells and CD8+T cells. In base to recent experimental evidence, we reviewed NK receptors involved in recognition of target-cell, as well as lytic molecules such as perforin, granzymes-A and -B, and granulysin. In addition, we reviewed the Fas-FasL intercellular linkage mediated pathway, and briefly the cross-linking of tumor necrosis factor (TNF) and TNF receptor pathway. We discussed three models of possible molecular interaction between lyric molecules from effector cytotoxic cells and target-cell membrane to induction of apoptosis.

  2. Bioluminescent assay for human lymphocyte blast transformation.

    Science.gov (United States)

    Bulanova, E G; Budagyan, V M; Romanova, N A; Brovko LYu; Ugarova, N N

    1995-05-01

    One of the basic tests of in vitro evaluation of immune cell functional activity is a proliferative response of lymphocytes on the action of external stimuli such as mitogenic lectines, antigens, etc. We compared two methods used to assess the lymphocyte functional status. (1) [3H]thymidine incorporation and (2) bioluminescence for determination of intracellular ATP in blast cells. Comparison has been done for healthy donors and patients with proven low immunological status. The proposed bioluminescent method for evaluation of the proliferative response was shown to be sensitive enough for diagnostic purposes. This method allows one to process a large number of samples at the same time and correlates highly with the radionuclide test use hazardous radioactive materials.

  3. Lymphocyte transformation in presumed ocular histoplasmosis

    Energy Technology Data Exchange (ETDEWEB)

    Ganley, J.P.; Nemo, G.J.; Comstock, G.W.; Brody, J.A.

    1981-08-01

    Lymphocytes from individuals with inactive macular disciform lesions of presumed ocular histoplasmosis challenged with three histoplasmin antigens incorporated tritiated thymidine at a significantly higher rate than histoplasmin-stimulated lymphocytes of matched control and peripheral scar groups. This finding is consistent with the etiologic association of the disciform ocular syndrome and previous systemic infection with Histoplasma capsulatum. The disciform group had a higher mean response than the other two groups to pokeweed mitogen but not to phytohemagglutinin and had higher mean counts per minute to the specific antigens Toxoplasma gondii, Blastomyces dermatitidis, Cryptococcus neoformans, Mycobacterium tuberculosis, M battery, and M gaus, but not to Candida albicans. These data would suggest that individuals with the disciform lesion of presumed ocular histoplasmosis have a hyperreactive cellular immune response; this response may play an important role in the development of the disciform.

  4. Obinutuzumab for previously untreated chronic lymphocytic leukemia.

    Science.gov (United States)

    Abraham, Jame; Stegner, Mark

    2014-04-01

    Obinutuzumab was approved by the Food and Drug Administration in late 2013 for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). The approval was based on results of an open-label phase 3 trial that showed improved progression-free survival (PFS) with the combination of obinutuzumab plus chlorambucil compared with chlorambucil alone. Obinutuzumab is a monoclonal antibody that targets CD20 antigen expressed on the surface of pre B- and mature B-lymphocytes. After binding to CD20, obinutuzumab mediates B-cell lysis by engaging immune effector cells, directly activating intracellular death signaling pathways, and activating the complement cascade. Immune effector cell activities include antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.

  5. The Danish National Chronic Lymphocytic Leukemia Registry

    DEFF Research Database (Denmark)

    da Cunha-Bang, Caspar; Geisler, Christian Hartmann; Enggaard, Lisbeth;

    2016-01-01

    , and for decision on treatment initiation as well as characteristics included in the CLL International Prognostic Index are collected. DESCRIPTIVE DATA: To ensure full coverage of Danish CLL patients in the registry, both continuous queries in case of missing data, and cross-referencing with the Danish National......, 3,082 patients have been registered. CONCLUSION: The Danish National CLL Registry is based within the Danish National Hematology Database. The registry covers a cohort of all patients diagnosed with CLL in Denmark since 2008. It forms the basis for quality assessment of CLL treatment in Denmark......AIM: In 2008, the Danish National Chronic Lymphocytic Leukemia Registry was founded within the Danish National Hematology Database. The primary aim of the registry is to assure quality of diagnosis and care of patients with chronic lymphocytic leukemia (CLL) in Denmark. Secondarily, to evaluate...

  6. Metabolism pathways in chronic lymphocytic leukemia.

    Science.gov (United States)

    Rozovski, Uri; Hazan-Halevy, Inbal; Barzilai, Merav; Keating, Michael J; Estrov, Zeev

    2016-01-01

    Alterations in chronic lymphocytic leukemia (CLL) cell metabolism have been studied by several investigators. Unlike normal B lymphocytes or other leukemia cells, CLL cells, like adipocytes, store lipids and utilize free fatty acids (FFA) to produce chemical energy. None of the recently identified mutations in CLL directly affects metabolic pathways, suggesting that genetic alterations do not directly contribute to CLL cells' metabolic reprogramming. Conversely, recent data suggest that activation of STAT3 or downregulation of microRNA-125 levels plays a crucial role in the utilization of FFA to meet the CLL cells' metabolic needs. STAT3, known to be constitutively activated in CLL, increases the levels of lipoprotein lipase (LPL) that mediates lipoprotein uptake and shifts the CLL cells' metabolism towards utilization of FFA. Herein, we review the evidence for altered lipid metabolism, increased mitochondrial activity and formation of reactive oxygen species (ROS) in CLL cells, and discuss the possible therapeutic strategies to inhibit lipid metabolism pathways in patient with CLL.

  7. B cell acute lymphocytic leukemia in pregnancy.

    Science.gov (United States)

    Bottsford-Miller, Justin; Haeri, Sina; Baker, Arthur M; Boles, Jeremiah; Brown, Mark

    2011-08-01

    Acute lymphocytic leukemia (ALL) is a rare occurrence in pregnancy and can be rapidly fatal if left untreated. The need for immediate treatment of ALL, coupled with the maternal-fetal risks from the chemotherapy regimen render a therapeutic dilemma in pregnant women with ALL. We report a case of ALL diagnosed in the 24th week of pregnancy to outline our management strategy, to demonstrate the feasibility of treatment with multi-agent chemotherapy, and to provide a review of the literature.

  8. GABA, a natural immunomodulator of T lymphocytes

    DEFF Research Database (Denmark)

    Bjurstöm, Helen; Wang, Junyang; Ericsson, Ida

    2008-01-01

    gamma-aminobutyric acid (GABA) is the main neuroinhibitory transmitter in the brain. Here we show that GABA in the extracellular space may affect the fate of pathogenic T lymphocytes entering the brain. We examined in encephalitogenic T cells if they expressed functional GABA channels that could......M and higher GABA concentrations decreased T cell proliferation. The results are consistent with GABA being immunomodulatory....

  9. Lymphocytic hypophysitis masquerading as pituitary adenoma

    Directory of Open Access Journals (Sweden)

    Rajneesh Mittal

    2012-01-01

    Full Text Available Introduction: Pituitary hypophysitis (PH is characterized by pituitary infiltration of lymphocytes, macrophages, and plasma cells that could lead to loss of pituitary function. Hypophysitis may be autoimmune or secondary to systemic diseases or infections. Based on the histopathological findings PH is classified into lymphocytic, granulomatous, xanthomatous, mixed forms (lymphogranulomatous, xanthogranulomatous, necrotizing and Immunoglobulin- G4 (IgG4 plasmacytic types. Objective: To report a case of lymphocytic hypophysitis (LH. Case Report: A 15-year-old girl presented with history of headache, amenorrhea, and history of polyuria for past 4 months. Initial evaluation had suppressed follicular stimulating hormone (<0.01 mIU/ml, high prolactin levels (110.85 ng/ml and diabetes insipidus (DI. Magnetic resonance imaging of sella was suggestive of pituitary macroadenoma with partial compression over optic chiasma. Patient underwent surgical decompression. Yellowish firm tissue was evacuated and xanthochromic fluid was aspirated. Histopathology was suggestive of LH. She resumed her cycles postoperatively after 4 months, prolactin levels normalized, however, she continues to have DI and is on desmopressin spray. This case has been presented here for its rare presentation in an adolescent girl because it is mostly seen in young females and postpartum period and its unique presentation as an expanding pituitary mass with optic chiasma compression. Conclusion: Definitive diagnosis of LH is based on histopathological evaluation. Therapeutic approach should be based on the grade of suspicion and clinical manifestations of LH.

  10. [Circadian rhythm of human lymphocyte subpopulations].

    Science.gov (United States)

    Pasqualetti, P; Colantonio, D; Casale, R; Colangeli, S; Natali, G

    1988-01-01

    Circadian rhythm of lymphocyte subsets was investigated in four healthy subjects, males, aged 35-58 years old. After a period of ambiental synchronization, venous blood samples were taken during a span of a day at 0.00 a.m., 4.00 a.m., 8.00 a.m., noon, 4.00 p.m. and 8.00 p.m. Lymphocyte subsets (OKT3, OKT4, OKT8, OKB7, OKJa1) were determined by monoclonal antibodies method, and serum level of cortisol by radioimmunoassay method. The OKT4/OKT8 ratio was also calculated. Data were analyzed by chronograms (mean +/- 1SD) and by cosinor method. Results show a significant circadian rhythm for each lymphocyte subset and for serum cortisol levels. The lowest levels of all circulating subsets were seen between noon and 4.00 p.m. and the highest levels around midnight, inversely related with the circadian rhythm of serum cortisol. The OKT4/OKT8 ratio, on the contrary, was relatively constant during the day, without a significant circadian rhythm. These observations have laboratoristic, clinical, and therapeutic implications and should be considered in the course of immunological studies.

  11. Normal lymphocyte immunophenotype in an elderly population

    Directory of Open Access Journals (Sweden)

    Sâmia Macedo Queiroz Mota Castellão Tavares

    2014-06-01

    Full Text Available OBJECTIVE: The aim of this work was to evaluate the lymphocyte immunophenotype in an elderly population.METHODS: This study enrolled 35 over 60-year-old volunteers and a control group composed of 35 young adults. The study included elderly without diseases that might affect the functioning of the immune system. These individuals were consulted by doctors and after a physical examination, laboratory tests were performed using a Beckman Coulter (r flow cytometer. The GraphPad Prism computer program was employed for statistical analysis with the level of significance being set for p-values <0.05.RESULTS: There is a statistically significant reduction in the number of lymphocytes (CD8 +, CD2 + and CD3 + cells in the elderly compared to young adults. These low rates are explained by changes attributed to aging and may be partly responsible for the reduction in the cellular immune response, lower proliferative activity and the low cytotoxicity of lymphocytes.CONCLUSION: These parameters showed greater impairment of adaptive immunity in the elderly population and can therefore explain the greater fragility of the aged body to developing diseases.

  12. Sudden unexpected death associated with lymphocytic thyroiditis.

    Science.gov (United States)

    Vestergaard, Vibeke; Drostrup, Dorthe Høj; Thomsen, Jørgen L

    2007-04-01

    A forensic autopsy study comprising 125 cases was carried out retrospectively in order to evaluate pathological changes in the thyroid gland in different groups of death. The five groups selected consecutively were: (i) opiate addicts who died from an overdose, (ii) alcoholics who died as a result of their alcohol abuse, (iii) cases of fatal poisoning other than opiate addicts, (iv) unknown cause of death and (v) controls without prior disease. Tissue samples from the thyroid gland were cut and stained with haematoxylin and eosin and van Gieson. Histology examinations were subsequently performed blind with semiquantitative assessment of the following six parameters: (a) height of the follicular epithelium, (b) the amount of lymphocytes, (c) the presence of plasma cells, (d) hyperplastic follicular changes, (e) oxyphilic changes, and (f) fibrosis. The most striking result was the finding of extensive lymphocytic infiltration of the thyroid parenchyma in five of the 124 cases, of which four belonged in the group of 'unknown cause of death'. This discovery leads to reflections regarding lymphocytic thyroiditis as a cause of death, either by itself or in combination with other disorders. Silent (painless) thyroiditis, especially, is easily overlooked at autopsy as there are no macroscopic changes and often no prior symptoms or history of thyroid disease pointing towards this condition. Analyses of thyroid hormones are unreliable in predicting endocrine status in life. Routine microscopy of the thyroid gland is therefore advocated in cases of sudden unexpected death in order to diagnose thyroid disease, in particular silent (painless) thyroiditis.

  13. Transfer of cholesterol from macrophages to lymphocytes in culture.

    Science.gov (United States)

    de Bittencourt Júnior, P I; Curi, R

    1998-02-01

    A major feature of macrophage metabolism is its capacity to produce and export cholesterol. Several reports have shown that the manipulation of lymphocyte cholesterol content elicits important changes in lymphocyte proliferation. These findings lead to an inquiry as to whether macrophage-derived cholesterol released into the lymphocyte surroundings may be transferred to the latter thus affecting lymphocyte function. In this study, cholesterol transfer from macrophages to lymphocytes was examined in vitro using rat cells in culture. The findings indicate that there may be a significant transfer of cholesterol from [4-14C]cholesterol labeled resident peritoneal macrophages to mesenteric lymph node resting lymphocytes (up to 173.9 +/- 2.7 pmol/10(7) lymphocytes/10(7) macrophages when co-cultivated for 48 h), in a lipoprotein-dependent manner. This represents the mass transfer of ca. 17 nmoles of cholesterol molecules per 10(7) lymphocytes from 10(7) macrophages (calculated on the basis of specific radioactivity incorporated into macrophages after the pre-labelling period), which suggests that macrophages are capable of replacing the whole lymphocyte cholesterol pool every 21 h. Moreover, an 111%-increase in the total cholesterol content of lymphocytes was found after co-cultivation with macrophages for 48 h. When compared to peritoneal cells, monocytes/macrophages obtained from circulating blood leukocytes presented a much higher cholesterol transfer capacity to lymphocytes (3.06 +/- 0.10 nmol/10(7) lymphocytes/10(7) macrophages co-cultivated for 24 h). Interestingly, inflammatory macrophages dramatically reduced their cholesterol transfer ability (by up to 91%, as compared to resident macrophages). Cholesterol transfer may involve a humoral influence, since it is not only observed when cells are co-cultivated in a single-well chamber system (cells in direct contact), but also in a two-compartment system (where cells can communicate but not by direct contact). Co

  14. Alteration of peripheral blood lymphocyte subsets in acute pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Miroslawa Pietruczuk; Milena I Dabrowska; Urszula Wereszczynska-Siemiatkowska; Andrzej Dabrowski

    2006-01-01

    AIM: To evaluate peripheral blood lymphocyte subsets in patients with acute pancreatitis (AP).METHODS: Twenty patients with mild AP (M-AP) and 15 with severe AP (S-AP) were included in our study. Peripheral blood lymphocytes were examined at d 1-3, 5,10 and 30 by means of flow cytometry.RESULTS: A significant depletion of circulating lymphocytes was found in AP. In the early AP, the magnitude of depletion was similar for T- and B- lymphocytes. In the late course of S-AP, B-lymphocytes were much more depleted than T-lymphocytes. At d 10, strong shift in the CD7+/CD19+ ratio implicating predominance of Tover B-lymphocytes in S-AP was found. Among T-lymphocytes, the significant depletion of the CD4+ population was observed in M-AP and S-AP, while CD8+ cells were in the normal range. Lymphocytes were found to strongly express activation markers: CD69, CD25, CD28,CD38 and CD122. Serum interleukin-2 (IL-2), IL-4, IL-5,IL-10, interferon-γ (IFN-γ) and tumor necrosis factor-α(TNF-α) levels were significantly increased in both forms of AP. The magnitude of elevation of cytokines known to be produced by Th2 was much higher than cytokines produced by Th1 cells.CONCLUSION: AP in humans is characterized by significant reduction of peripheral blood T- and B-lymphocytes.

  15. C1-esterase inhibitor blocks T lymphocyte proliferation and cytotoxic T lymphocyte generation in vitro

    DEFF Research Database (Denmark)

    Nissen, Mogens Holst; Bregenholt, S; Nording, J A

    1998-01-01

    We have previously shown that activated C1s complement and activated T cells cleave beta2-microglobulin (beta2m) in vitro leading to the formation of desLys58 beta2m. This process can specifically be inhibited by C1-esterase inhibitor (C1-inh). Furthermore we showed that exogenously added desLys58...... beta2m in nanomolar amounts to a one-way allogenic mixed lymphocyte culture (MLC) increased the endogenous production of IL-2 and the generation of allo-specific cytotoxic T lymphocytes. C1-inh was purified from fresh human plasma and added to human or murine MLC and mitogen-stimulated lymphocyte...... of allospecific cytotoxic activity, and changed the endogenous production of IL-2, IL-4, IL-10, IL-12 and IFN-gamma. These data clearly demonstrate a regulatory function of C1-inh on T cell-mediated immune functions....

  16. Idelalisib for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma.

    Science.gov (United States)

    Barrientos, Jacqueline C

    2016-09-01

    Idelalisib is a first-in-class selective oral PI3Kδ inhibitor for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma, a predominantly elderly population with high comorbidity. The drug promotes apoptosis in primary CLL cells ex vivo, independent of common prognostic markers and inhibits CLL cell homing, migration and adhesion to cells in the microenvironment. Idelalisib has shown efficacy with acceptable safety as monotherapy and combination therapy in relapsed/refractory CLL. Idelalisib has clinical activity in patients with CLL with del(17p). The development of other novel B-cell-targeted agents provides the opportunity to evaluate additional idelalisib treatment combinations for their potential to further improve outcomes in CLL/small lymphocytic lymphoma.

  17. Suppressive effects of antigens on the activity of specific activated lymphocytes: A test to define the specificity of activated lymphocytes

    Institute of Scientific and Technical Information of China (English)

    HU Jun; PAN Sheng-jun; CAI Zhen-jie; GUAN De-lin; LIU Xiao-cheng

    2006-01-01

    Objective:With the regular mixed lymphocytes culture (MLC) to detect the allograft rejection, the reactivity of the activated lymphocytes (primed lymphocytes) of a recipient shows sometimes increase and sometimes decrease against the antigens from the donor, which is inconsistent with the clinical results. In order to establish a convenient method for testing the specificity of the activated lymphocytes in vitro, so as to know the rejection occurred or not by testing the existence of the specific activated lymphocytes against donor's HLA antigens in the recipient's peripheral blood. Methods: Anti-IL-2 neutralizing monoclonal antibody (anti-IL-2 N-mAb) and immunosuppressors were introduced in this test system in the presence of specific stimulators and activated lymphocytes. Results: When the activated lymphocytes were chosen from the one-way MLC 4 d to undergo re-stimulation by specific stimulators, the activity of activated lymphocytes in the treatment group was suppressed significantly compared with that in the control group. The result of this test method is consistent with the biopsy in the clinical diagnosis of rejection.Conclusion :It suggests that the activated lymphocytes can be inactivated by specific antigens in certain conditions. This can be a useful tool to define the specificity of the activated lymphocytes.

  18. Beneficial Roles of Emotion in Decision Making: Functional Association of Brain and Body

    Directory of Open Access Journals (Sweden)

    Hideki Ohira

    2011-12-01

    Full Text Available Though traditional microeconomics has supposed that human decisions are based on logical and exact computation of cost-benefit balances or efficacies, studies in behavioral economics have shown that humans sometimes make seemingly irrational decisions driven by emotions. In our everyday situations, factors related to decisions are complex and which alternative will be the most beneficial is uncertain. In such cases, emotions have been thought adaptive because they can quickly reduce negative alternatives and facilitate fast and effective decision making. Some theorists argued that one of important sources of such emotional drives affecting decision making is bodily responses that are represented in brain regions (Craig, 2009; Damasio, 1994. In this article, empirical evidence for the functional associations of the brain and body accompanying decision making will be shown as follows. (1 Heart rate responses and concentration of inflammatory cytokine (IL-6 can predict acceptance or rejection of an unfair offer in an economical negotiation game, the Ultimatum Game. Activation of the anterior insula mediates relationship between bodily states and decision making. (2 Sympathetic responses reflected by secretion of adrenaline are represented in brain regions such as the midbrain, anterior cingulate cortex, and anterior insula, and furthermore can determine exploration of decision making in a situation where an action-outcome contingency is stochastic and unstable. These findings suggest beneficial roles of emotion and bodily responses in decision making.

  19. Moments of zeta functions associated to hyperelliptic curves over finite fields.

    Science.gov (United States)

    Rubinstein, Michael O; Wu, Kaiyu

    2015-04-28

    Let q be an odd prime power, and Hq,d denote the set of square-free monic polynomials D(x)∈Fq[x] of degree d. Katz and Sarnak showed that the moments, over Hq,d, of the zeta functions associated to the curves y(2)=D(x), evaluated at the central point, tend, as q→∞, to the moments of characteristic polynomials, evaluated at the central point, of matrices in USp(2⌊(d-1)/2⌋). Using techniques that were originally developed for studying moments of L-functions over number fields, Andrade and Keating conjectured an asymptotic formula for the moments for q fixed and q→∞. We provide theoretical and numerical evidence in favour of their conjecture. In some cases, we are able to work out exact formulae for the moments and use these to precisely determine the size of the remainder term in the predicted moments. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

  20. Experimental evidence validating the computational inference of functional associations from gene fusion events: a critical survey.

    Science.gov (United States)

    Promponas, Vasilis J; Ouzounis, Christos A; Iliopoulos, Ioannis

    2014-05-01

    More than a decade ago, a number of methods were proposed for the inference of protein interactions, using whole-genome information from gene clusters, gene fusions and phylogenetic profiles. This structural and evolutionary view of entire genomes has provided a valuable approach for the functional characterization of proteins, especially those without sequence similarity to proteins of known function. Furthermore, this view has raised the real possibility to detect functional associations of genes and their corresponding proteins for any entire genome sequence. Yet, despite these exciting developments, there have been relatively few cases of real use of these methods outside the computational biology field, as reflected from citation analysis. These methods have the potential to be used in high-throughput experimental settings in functional genomics and proteomics to validate results with very high accuracy and good coverage. In this critical survey, we provide a comprehensive overview of 30 most prominent examples of single pairwise protein interaction cases in small-scale studies, where protein interactions have either been detected by gene fusion or yielded additional, corroborating evidence from biochemical observations. Our conclusion is that with the derivation of a validated gold-standard corpus and better data integration with big experiments, gene fusion detection can truly become a valuable tool for large-scale experimental biology.

  1. Aryl hydrocarbon mono-oxygenase activity in human lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Griffin, G.D.; Schuresko, D.D.

    1981-06-01

    Aryl hydrocarbon mono-oxygenase (AHM), an enzyme of key importance in metabolism of xenobiotic chemicals such as polynuclear aromatic hydrocarbons (PNA), is present in human lymphocytes. Studies investing the relation of activity of AHM in human lymphocytes to parameters such as disease state, PNA exposure, in vitro mitogen stimulation, etc. have been summarized in this report. Some studies have demonstrated increased AHM activity in lymphocytes from cigarette smokers (compared to nonsmokers), and in lung cancer patients when compared to appropriate control groups. These observations are confused by extreme variability in human lymphocyte AHM activities, such variability arising from factors such as genetic variation in AHM activity, variation in in vitro culture conditions which affect AHM activity, and the problematical relationship of common AHM assays to actual PNA metabolism taking place in lymphocytes. If some of the foregoing problems can be adequately addressed, lymphocyte AHM activity could hold the promise of being a useful biomarker system for human PNA exposure.

  2. The association between chronic lymphocytic thyroiditis and thyroid tumors.

    Science.gov (United States)

    Tamimi, Dalal M

    2002-04-01

    An association between lymphocytic thyroiditis and thyroid papillary carcinoma is still controversial. To assess the relationship, a histopathologic analysis of surgically resected thyroid tumors together with the frequency and severity of chronic lymphocytic infiltration of the thyroid among patients with follicular adenoma, follicular carcinoma, and papillary carcinoma was performed. The prevalence of lymphocytic infiltrate, which is indicative of autoimmune thyroiditis, was significantly higher in patients with papillary carcinoma (58%) than in patients with follicular carcinoma (20%) or follicular adenoma (14%). The lymphocytic infiltration within the tumor compared with the severity of thyroiditis in the nontumorous tissue. Therefore, the association between chronic lymphocytic thyroiditis and papillary carcinoma was confirmed. The possibility that an immunologic mechanism involved in the pathogenesis of papillary carcinoma stimulates lymphocytic infiltration in the thyroid tissue through an autoimmune mechanism is suggested.

  3. Signaling through intercellular adhesion molecule 1 (ICAM-1) in a B cell lymphoma line

    DEFF Research Database (Denmark)

    Holland, J; Owens, T

    1997-01-01

    Intercellular adhesion molecule 1 (ICAM-1) (CD54) is an adhesion molecule of the immunoglobulin superfamily. The interaction between ICAM-1 on B lymphocytes and leukocyte function-associated antigen 1 on T cells plays a major role in several aspects of the immune response, including T-dependent B...

  4. Chronic lymphocytic leukemia: case-based session.

    Science.gov (United States)

    Rai, K R; Döhner, H; Keating, M J; Montserrat, E

    2001-01-01

    Drs. Hartmut Döhner, Michael J. Keating, Kanti R. Rai and Emili Montserrat form the panel to review chronic lymphocytic leukemia (CLL) while focusing on the clinical features of a particular patient. The pace of progress in CLL has accelerated in the past decade. The pathophysiological nature of this disease, as had been known in the past, was based largely on the intuitive and empiric notions of two leaders in hematology, William Dameshek and David Galton. Now the works of a new generation of leaders are providing us with the scientific explanations of why CLL is a heterogeneous disease, perhaps consisting of at least two separate entities. In one form of CLL, the leukemic lymphocytes have a surface immunoglobulin (Ig) variable region gene that has undergone somatic mutations, with tell-tale markers suggesting that these cells had previously traversed the germinal centers. Such patients have a distinctly superior prognosis than their counterparts whose leukemic lymphocytes IgV genes have no mutations (these are indeed immunologically naive cells), who have a worse prognosis. The introduction of fluorescence in situ hybridization (FISH) technique has provided us with new insights into the diverse chromosomal abnormalities that can occur in CLL, and which have significant impact on the clinical behavior and prognosis of patients with this disease. Major advances in therapeutics of CLL also have occurred during the past decade. Two monoclonal antibodies, Campath-1H (anti-CD52) and rituximab (anti-CD20), and one nucleoside analogue, fludarabine, have emerged as three agents of most promise in the front-line treatment of this disease. Studies currently in progress reflect our attempts to find the most effective manner of combining these agents to improve the overall survival statistics for CLL patients. As in many other hematological malignancies, high dose chemotherapy followed by autologous or HLA-compatible allogeneic stem cells rescue strategies are under study as

  5. Natural History Study of Monoclonal B Cell Lymphocytosis (MBL), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Lymphoplasmacytic Lymphoma (LPL)/Waldenstrom Macroglobulinemia (WM), and Splenic Marginal Zone Lymphoma (SMZL)

    Science.gov (United States)

    2017-10-05

    B-Cell Chronic Lymphocytic Leukemia; Monoclonal B-Cell Lymphocytosis; Lymhoma, Small Lymphocytic; Chronic Lymphocytic Leukemia; Lymphoplasmacytic Lymphoma; Waldenstrom Macroglobulinemia; Splenic Marginal Zone Lymphoma

  6. Phenotypic and Functional Analysis of Porcine T Lymphocytes

    Institute of Scientific and Technical Information of China (English)

    李华; 陈应华

    2001-01-01

    Porcine and other higher mammals express clusters of differentiation (CD) antigens on the surface of T lymphocytes, such as CD2, CD3, CD4, CD8, etc. However, in porcine, a high percentage of the CD4+ CD8-T lymphocyte subpopulation exist in the peripheral blood and the ratio of the CD4+ and CD8+ T lymphocyte subpopulations is reversed. These differences bring new challenges to better understanding of the phenotype and function of porcine T lymphocytes in antigen recognition and immune response.

  7. Recent advances in chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    N Vyas

    2012-01-01

    Full Text Available Chronic lymphocytic leukemia (CLL was largely considered to be a disease of slow progression, standard treatment with Chlorambucil and having almost similar prognosis. With the introduction of molecular methods for understanding the disease pathophysiology in CLL there has been a remarkable change in the approach towards the disease. The variation in B-cell receptor response and immunoglobulin heavy chain variable region (IGHV mutation, genetic aberration and defect in apoptosis and proliferation has had an impact on therapy initiation and prognosis. Early diagnosis of molecular variant is therefore necessary in CLL.

  8. Chronic pain: cytokines, lymphocytes and chemokines.

    Science.gov (United States)

    de Miguel, Marcia; Kraychete, Durval Campos; Meyer Nascimento, Roberto Jose

    2014-01-01

    Chronic pain is a debilitating condition and, in most cases, difficult to treat. A prominent example of this is neuropathic pain. Understanding pathophysiological mechanisms of pain and, therefore, making this knowledge into an effective treatment is still a challenge to experts. Pain can now be considered as a neuro-immune disorder, since recent data indicate critical involvement of innate and adaptive immune responses following injury, and this interaction plays an important role in the onset and perpetuation of chronic pain. The aim of this article is to review the relationship between immune system and chronic pain, especially about neuropathic pain, and focusing on cytokines, chemokines and lymphocytes.

  9. Spinal epidural compression in chronic lymphocytic leukemia.

    Science.gov (United States)

    Michalevicz, R; Burstein, A; Razon, N; Reider, I; Ilie, B

    1989-11-01

    Spinal epidural compression is a rare neurologic complication in patients with lymphoma. It occurs mostly in those with intermediate-grade to high-grade malignancy disease. This type of neurologic involvement has not been described in chronic lymphocytic leukemia (CLL). A patient with a long, stable CLL course developed spinal epidural compression and consequently died. The frequency of spinal epidural compression in lymphoma, according to the histologic subtypes and the considerations in making the right choice of therapy are discussed in light of the presented case.

  10. HLA-DP related suppression of mixed lymphocyte reaction with alloactivated lymphocytes

    DEFF Research Database (Denmark)

    Ødum, Niels; Hofmann, B; Jakobsen, B K

    1986-01-01

    We studied the influence of HLA class I and class II antigens on the suppression of the MLR induced by primed lymphocytes (PLs) alloactivated in vitro. The suppression of 14 different PLs of 83 MLRs was analyzed. The PLs were primed against (i) HLA-DP (SB) (ii) HLA-DR/DQ or (iii) both HLA-DP and DR...

  11. Absolute Quantification of the Host-To-Parasite DNA Ratio in Theileria parva-Infected Lymphocyte Cell Lines.

    Directory of Open Access Journals (Sweden)

    Hanzel T Gotia

    Full Text Available Theileria parva is a tick-transmitted intracellular apicomplexan pathogen of cattle in sub-Saharan Africa that causes East Coast fever (ECF. ECF is an acute fatal disease that kills over one million cattle annually, imposing a tremendous burden on African small-holder cattle farmers. The pathology and level of T. parva infections in its wildlife host, African buffalo (Syncerus caffer, and in cattle are distinct. We have developed an absolute quantification method based on quantitative PCR (qPCR in which recombinant plasmids containing single copy genes specific to the parasite (apical membrane antigen 1 gene, ama1 or the host (hypoxanthine phosphoribosyltransferase 1, hprt1 are used as the quantification reference standards. Our study shows that T. parva and bovine cells are present in similar numbers in T. parva-infected lymphocyte cell lines and that consequently, due to its much smaller genome size, T. parva DNA comprises between 0.9% and 3% of the total DNA samples extracted from these lines. This absolute quantification assay of parasite and host genome copy number in a sample provides a simple and reliable method of assessing T. parva load in infected bovine lymphocytes, and is accurate over a wide range of host-to-parasite DNA ratios. Knowledge of the proportion of target DNA in a sample, as enabled by this method, is essential for efficient high-throughput genome sequencing applications for a variety of intracellular pathogens. This assay will also be very useful in future studies of interactions of distinct host-T. parva stocks and to fully characterize the dynamics of ECF infection in the field.

  12. Age-related decrease in an early step of DNA-repair of normal human lymphocytes exposed to ultraviolet-irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Roth, M.; Emmons, L.R.; Haener, M.M.; Mueller, H.J.B.; Boyle, J.M.

    1989-01-01

    A monoclonal antibody-based immunoassay has been used to detect age-related changes in the rate of loss of photoproduct antigenicity from the DNA of peripheral blood lymphocytes irradiated with 10 J m-2 uv-C. Lymphocytes were obtained from 75 healthy volunteers whose ages ranged from 14 months to 82 years. The samples were divided by age decades into groups of 10 individuals, except the first decade which contained only 5 individuals. The mean loss of antigenicity +/- 1 standard deviation was determined for each group at 10, 30, and 60 min after irradiation. The data were analyzed by Mann-Whitney U test and by the Kruskal-Wallis test. After a recovery period of 10 min the loss of antigenicity was most rapid in group I (0-9 years), less rapid in group II (10-19 years), and least rapid in all other groups. The differences between groups became less at 30 min and were not significant at 60 min incubation. These data obtained from normal cells concur with our previous conclusions, that reductions in the rate of loss of antigenicity in nondiseased cells isolated from patients with melanoma and dysplastic naevus syndrome reflect genetic abnormalities in these patients.

  13. Functional associations between the metabolome and manganese tolerance in Vigna unguiculata.

    Science.gov (United States)

    Führs, Hendrik; Specht, André; Erban, Alexander; Kopka, Joachim; Horst, Walter J

    2012-01-01

    Genotypic- and silicon (Si)-mediated differences in manganese (Mn) tolerance of cowpea (Vigna unguiculata) arise from a combination of symplastic and apoplastic traits. A detailed metabolomic inspection could help to identify functional associations between genotype- and Si-mediated Mn tolerance and metabolism. Two cowpea genotypes differing in Mn tolerance (TVu 91, Mn sensitive; TVu 1987, Mn tolerant) were subjected to differential Mn and Si treatments. Gas chromatography-mass spectrometry (GC-MS)-based metabolite profiling of leaf material was performed. Detailed evaluation of the response of metabolites was combined with gene expression and physiological analyses. After 2 d of 50 μM Mn supply TVu 91 expressed toxicity symptoms first in the form of brown spots on the second oldest trifoliate leaves. Silicon treatment suppressed symptom development in TVu 91. Despite higher concentrations of Mn in leaves of TVu 1987 compared with TVu 91, the tolerant genotype did not show symptoms. From sample cluster formation as identified by independent component analysis (ICA) of metabolite profiles it is concluded that genotypic differences accounted for the highest impact on variation in metabolite pools, followed by Mn and Si treatments in one of two experiments. Analysis of individual metabolites corroborated a comparable minor role for Mn and Si treatments in the modulation of individual metabolites. Mapping individual metabolites differing significantly between genotypes onto biosynthetic pathways and gene expression studies on the corresponding pathways suggest that genotypic Mn tolerance is a consequence of differences (i) in the apoplastic binding capacity; (ii) in the capability to maintain a high antioxidative state; and (iii) in the activity of shikimate and phenylpropanoid metabolism.

  14. Characterization of the lymphocyte substance P receptor

    Energy Technology Data Exchange (ETDEWEB)

    McGillis, J.P.; Organist, M.L.; Payan, D.G.

    1986-03-01

    Recent studies have provided evidence that tissues of the immune and reticuloendothelial systems are influenced by various hormones and neuropeptides. While the interrelationship between these peptides and the immune system, and the physiological relevance of their effects is not clear, a variety of highly specific, receptor-mediated effects has been demonstrated. One neuropeptide for which immunomodulatory effects have been identified is substance P (SP). SP acts as a potent T-cell mitogen, and enhances the mitogenic effects of PHA. Radioreceptor and FACS binding studies suggest that the SP receptor is present on a discrete population of T-cells and has a Kd of 0.87 nM and a density of 24,000. Studies have been initiated to biochemically characterize the lymphocyte SP receptor on IM-9 lymphoblasts. (/sup 125/I)-labeled SP was covalently crosslinked to the receptor using disuccinimidyl suberate and solubilized. Two radioactive bands of m.w. 55,000 and 33,000 were seen when the solubilized crosslinked receptor was electrophoresed on SDS gels. The authors are currently using a combination of HPLC immunoaffinity and reverse-phase chromatography to purify the receptor. The initial studies indicate that the receptor can be purified to homogeneity using this approach. The biochemical characterization of this receptor should provide a better understanding of its importance not only on lymphocytes, but in other tissues as well.

  15. Benzene metabolites induce apoptosis in lymphocytes.

    Science.gov (United States)

    Martínez-Velázquez, M; Maldonado, V; Ortega, A; Meléndez-Zajgla, J; Albores, A

    2006-08-01

    Benzene is an important environmental pollutant with important health implications. Exposure to this aromatic hydrocarbon is associated with hematotoxicity, and bone marrow carcinogenic effects. It has been shown that benzene induces oxidative stress, cell cycle alterations, and programmed cell death in cultured cells. Hepatic metabolism of benzene is thought to be a prerequisite for its bone marrow toxicity. Nevertheless, there are no reports on the cellular effects of reactive intermediates derived from hepatic metabolism of benzene. Thus, the goal of this project was to determine the cellular alterations of benzene metabolites produced by the cultured hepatic cell line HepG2. Supernatants collected from these cells were applied to a culture of freshly isolated lymphocytes. A higher decrease in cell viability was found in cells exposed to these supernatants than to unmetabolized benzene. This viability decrease was due to apoptosis, as determined by Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL) assay and internucleosomal fragmentation of DNA. When supernatants were analyzed by HPLC, we found that not all the hydrocarbon was biotransformed, since a 28 microM concentration (37%) remained. The only metabolite found in the culture medium was muconic acid. The present results show that muconic acid derived from benzene metabolism is able to cooperate with the pollutant for the induction of apoptosis in rat lymphocytes.

  16. Spondylarthritis in the absence of B lymphocytes.

    Science.gov (United States)

    Baeten, Dominique; Kruithof, Elli; Breban, Maxime; Tak, Paul P

    2008-03-01

    The highly effective treatment of rheumatoid arthritis by B cell depletion and the presence of B cells in the peripheral and axial lesions of patients with spondylarthritis (SpA) raise the question as to whether B lymphocytes could also be an appropriate therapeutic target in the latter disease. We describe 2 male HLA-B27-positive patients who had active SpA despite absence of B cells. One patient developed SpA with sacroiliitis and asymmetric oligoarthritis after having been diagnosed as having severe Bruton agammaglobulinemia. Since extensive investigations excluded an infectious origin of the SpA, this case illustrates that functional B cells and/or gamma globulins are not strictly required for SpA pathogenesis. The second patient had severe axial and peripheral SpA that was treated successfully with etanercept. After discontinuation of etanercept treatment because of non-Hodgkin's B cell lymphoma, both axial and peripheral SpA symptoms relapsed rapidly, and this exacerbation of articular disease activity was not modulated by successful B cell depletion therapy for the lymphoma. Although case reports have obvious limitations, our clinical observations provide evidence that active SpA can occur in the absence of functional mature B cells and thus emphasize the need for systematic studies of the exact role and function of B lymphocytes in this disease.

  17. Secondary autoimmune cytopenias in chronic lymphocytic leukemia.

    Science.gov (United States)

    Rogers, Kerry A; Woyach, Jennifer A

    2016-04-01

    Secondary autoimmune cytopenias in chronic lymphocytic leukemia are distinct clinical entities that require specific management. These autoimmune disorders have a complex pathogenesis that involves both the leukemic cells and the immune environment in which they exist. The mechanism is not the same in all cases, and to varying degrees involves the chronic lymphocytic leukemia (CLL) cells in antibody production, antigen presentation, and stimulation of T cells and bystander polyclonal B cells. Diagnosis of autoimmune cytopenias can be challenging as it is difficult to differentiate between autoimmunity and bone marrow failure due to disease progression. There is a need to distinguish these causes, as prognosis and treatment are not the same. Evidence regarding treatment of secondary autoimmune cytopenias is limited, but many effective options exist and treatment can be selected with severity of disease and patient factors in mind. With new agents to treat CLL coming into widespread clinical use, it will be important to understand how these will change the natural history and treatment of autoimmune cytopenias.

  18. The immunodeficiency of bone marrow-transplanted patients. II. CD8-related suppression by patient lymphocytes of the response of donor lymphocytes to mitogens, antigens, and allogeneic cells

    DEFF Research Database (Denmark)

    Ødum, Niels; Hofmann, B; Jacobsen, N

    1987-01-01

    Lymphocytes from 21 patients sampled 1-6 months after bone marrow transplantation (BMT) were tested for functional suppressor activity against marrow-donor lymphocytes in the lymphocyte transformation test. Suppression of donor responses to allogeneic (i.e. mixed lymphocyte reaction, MLR...

  19. Safety and Tolerability Study of PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia

    Science.gov (United States)

    2017-10-09

    B-cell Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Diffuse Well-differentiated Lymphocytic Lymphoma; B Cell Lymphoma; Follicular Lymphoma; Mantle Cell Lymphoma; Non-Hodgkin's Lymphoma; Waldenstrom Macroglobulinemia; Burkitt Lymphoma; B-Cell Diffuse Lymphoma

  20. 9 CFR 113.42 - Detection of lymphocytic choriomeningitis contamination.

    Science.gov (United States)

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Detection of lymphocytic choriomeningitis contamination. 113.42 Section 113.42 Animals and Animal Products ANIMAL AND PLANT HEALTH... contamination. The test for detection of lymphocytic choriomeningitis (LCM) virus provided in this section...

  1. Lymphocytes and liver fibrosis in HIV & HCV coinfection

    NARCIS (Netherlands)

    Feuth, M.|info:eu-repo/dai/nl/371501547

    2014-01-01

    Coinfection with HIV has an important impact on immunity against hepatitis C virus (HCV). In the present dissertation, phenotypes of lymphocytes derived from the peripheral blood of HCV-infected patients were studied into detail, with special attention to changes in phenotype of lymphocytes associat

  2. Lymphocyte apoptosis in the pathogenesis of type 1 diabetes mellitus

    African Journals Online (AJOL)

    EL-HAKIM

    is an emerging evidence that T cell-induced apoptosis is a dominant effector mechanism ... Patients were subjected to clinical evaluation with special ... The percentage of CD95 on T-lymphocytes could not be ..... Correlation between CD3 lymphocytes and CD95 antigen .... control.36 On the other hand, Tchórzewski et al.1.

  3. Effect of praziquantel on human lymphocyte proliferation in vitro

    DEFF Research Database (Denmark)

    Odum, Niels; Theander, T G; Bygbjerg, I C

    1984-01-01

    The antischistosomal drugs tartar emetic and niridazole exert immunosuppression both in vitro and in vivo. In the present study the influence of praziquantel (Biltricide), a potent schistosomicidal drug, on human lymphocyte proliferation in vitro was investigated. Praziquantel 80 micrograms...... no suppressive effect on human lymphocyte proliferation in vitro....

  4. Carotenoid levels in human lymphocytes, measured by Raman microspectroscopy

    NARCIS (Netherlands)

    Ramanauskaite, R B; SegersNolten, IGMJ; DeGrauw, K J; Sijtsema, N M; VanderMaas, L; Greve, J; Otto, C; Figdor, C G

    1997-01-01

    Carotenoid levels in lymphocytes obtained from peripheral blood of healthy people have been investigated by Raman microspectroscopy. We observed that carotenoids are concentrated in so-called ''Gall bodies''. The level of carotenoids in living human lymphocytes was found to be age-dependent and to d

  5. T-lymphocyte subsets in recurrent aphthous ulceration

    DEFF Research Database (Denmark)

    Pedersen, A; Klausen, B; Hougen, H P;

    1989-01-01

    Peripheral T-lymphocyte subsets: T-helper (OKT4) and T-suppressor (OKT8) cells were studied quantitatively in 20 patients with recurrent aphthous ulceration (RAU) in ulcerative, as well as inactive, stages of the disease. The figures were compared with T-lymphocyte subsets from matched control do...

  6. Lymphocytes and liver fibrosis in HIV & HCV coinfection

    NARCIS (Netherlands)

    Feuth, M.

    2014-01-01

    Coinfection with HIV has an important impact on immunity against hepatitis C virus (HCV). In the present dissertation, phenotypes of lymphocytes derived from the peripheral blood of HCV-infected patients were studied into detail, with special attention to changes in phenotype of lymphocytes associat

  7. Lymphocytes as a neural probe : potential for studying psychiatric disorders

    NARCIS (Netherlands)

    Gladkevich, A; Kauffman, HF; Korf, J

    There is an increasing body evidence pointing to a close integration between the central nervous system (CNS) and immunological functions with lymphocytes playing therein a central role. The authors provide arguments to consider blood lymphocytes as a convenient probe of-an albeit-limited number of

  8. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Herman, S E M; Niemann, C U; Farooqui, M

    2014-01-01

    Ibrutinib and other targeted inhibitors of B-cell receptor signaling achieve impressive clinical results for patients with chronic lymphocytic leukemia (CLL). A treatment-induced rise in absolute lymphocyte count (ALC) has emerged as a class effect of kinase inhibitors in CLL and warrants further...

  9. Endothelial PI 3-kinase activity regulates lymphocyte diapedesis.

    Science.gov (United States)

    Nakhaei-Nejad, Maryam; Hussain, Amer M; Zhang, Qiu-Xia; Murray, Allan G

    2007-12-01

    Lymphocyte recruitment to sites of inflammation involves a bidirectional series of cues between the endothelial cell (EC) and the leukocyte that culminate in lymphocyte migration into the tissue. Remodeling of the EC F-actin cytoskeleton has been observed after leukocyte adhesion, but the signals to the EC remain poorly defined. We studied the dependence of peripheral blood lymphocyte transendothelial migration (TEM) through an EC monolayer in vitro on EC phosphatidylinositol 3-kinase (PI 3-kinase) activity. Lymphocytes were perfused over cytokine-activated EC using a parallel-plate laminar flow chamber. Inhibition of EC PI 3-kinase activity using LY-294002 or wortmannin decreased lymphocyte TEM (48 +/- 6 or 34 +/- 7%, respectively, vs. control; mean +/- SE; P structure" after intercellular adhesion molecule-1 ligation, whereas this was inhibited by jasplakinolide treatment. A similar fraction of lymphocytes migrated on control or LY-294002-treated EC and localized to interendothelial junctions. However, lymphocytes failed to extend processes below the level of vascular endothelial (VE)-cadherin on LY-294002-treated EC. Together these observations indicate that EC PI 3-kinase activity and F-actin remodeling are required during lymphocyte diapedesis and identify a PI 3-kinase-dependent step following initial separation of the VE-cadherin barrier.

  10. Lymphocytes in patients with psoriasis promote proliferation of keratinocytes

    Institute of Scientific and Technical Information of China (English)

    DENG An-mei; ZHONG Ren-qian; CHEN Sun-xiao; ZHOU Ye; KONG Xian-tao

    2002-01-01

    Objective: To analyze the effect of lymphocytes on proliferation of keratinocytes in patients with psoriasis. Methods: Lymphocytes in lesion and peripheral blood were isolated and amplified, then cultured together with normal keratinocytes. By MTT method, the living cells were quantified in the mixed culture.Results: Compared with normal controls, lymphocytes from lesion and peripheral blood of psoriasis both promote the proliferation of keratinocytes (P<0. 01 and P<0. 05 respectively). The concentrations of IL-2 and IFN-γ in the mixture of lesion lymphocytes and keratinocytes were significantly higher than that of controls.Tripterygium glycosides inhibited this promotion. Conclusion: Lymphocytes in patients with psoriasis (mainly Thl cell) play an important role in proliferation of keratinocytes. This psoriasis cell model is useful for studies on signal transduction in psoriasis.

  11. Lymphocyte respiration in children with Trisomy 21

    Directory of Open Access Journals (Sweden)

    Aburawi Elhadi H

    2012-12-01

    Full Text Available Abstract Background This study measured lymphocyte mitochondrial O2 consumption (cellular respiration in children with trisomy 21. Methods Peripheral blood mononuclear cells were isolated from whole blood of trisomy 21 and control children and these cells were immediately used to measure cellular respiration rate. [O2] was determined as a function of time from the phosphorescence decay rates (1/τ of Pd (II-meso-tetra-(4-sulfonatophenyl-tetrabenzoporphyrin. In sealed vials containing lymphocytes and glucose as a respiratory substrate, [O2] declined linearly with time, confirming the zero-order kinetics of O2 conversion to H2O by cytochrome oxidase. The rate of respiration (k, in μM O2 min-1, thus, was the negative of the slope of [O2] vs. time. Cyanide inhibited O2 consumption, confirming that oxidation occurred in the mitochondrial respiratory chain. Results For control children (age = 8.8 ± 5.6 years, n = 26, the mean (± SD value of kc (in μM O2 per min per 107 cells was 1.36 ± 0.79 (coefficient of variation, Cv = 58%; median = 1.17; range = 0.60 to 3.12; -2SD = 0.61. For children with trisomy 21 (age = 7.2 ± 4.6 years, n = 26, the values of kc were 0.82 ± 0.62 (Cv = 76%; median = 0.60; range = 0.20 to 2.80, pp6.1 mU/L. Fourteen of 26 (54% children with trisomy 21 had kc values of 0.20 to 0.60 (i.e., kc positively correlated with body-mass index (BMI, R >0.302, serum creatinine (R >0.507, blood urea nitrogen (BUN, R >0.535 and albumin (R >0.446. Conclusions Children with trisomy 21 in this study have reduced lymphocyte bioenergetics. The clinical importance of this finding requires further studies.

  12. The Danish National Chronic Lymphocytic Leukemia Registry

    Directory of Open Access Journals (Sweden)

    da Cunha-Bang C

    2016-10-01

    Full Text Available Caspar da Cunha-Bang,1 Christian Hartmann Geisler,2 Lisbeth Enggaard,3 Christian Bjørn Poulsen,4 Peter de Nully Brown,2 Henrik Frederiksen,5 Olav Jonas Bergmann,6 Elisa Jacobsen Pulczynski,7 Robert Schou Pedersen,8 Linda Højberg Nielsen,9 Ilse Christiansen,10 Carsten Utoft Niemann2 1Department of Internal Medicine, Roskilde Hospital, Roskilde, Denmark; 2Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 3Department of Hematology, Herlev Hospital, Herlev, Denmark; 4Department of Hematology, Roskilde Hospital, Roskilde, Denmark; 5Department of Hematology, Odense University Hospital, Odense, Denmark; 6Department of Hematology, Vejle Hospital, Vejle, Denmark; 7Department of Hematology, Aarhus University Hospital, Aarhus, Denmark; 8Department of Hematology, Holstebro Hospital, Holstebro, Denmark; 9Department of Hematology, Esbjerg Hospital, Esbjerg, Denmark; 10Department of Hematology, Aalborg University Hospital, Aalborg, Denmark Aim: In 2008, the Danish National Chronic Lymphocytic Leukemia Registry was founded within the Danish National Hematology Database. The primary aim of the registry is to assure quality of diagnosis and care of patients with chronic lymphocytic leukemia (CLL in Denmark. Secondarily, to evaluate adherence to national guidelines and to provide source data for research purposes. Study population: All patients diagnosed with CLL in Denmark from 2008 onward are included in the registry. Patients are followed in one of nine hematology centers. All centers participate in the registry and are all obliged to collect data. Main variables: Predefined data are collected at the time of diagnosis, and follow-up at the time of significant events: treatment, progression, transplantation, and death. Parameters included in the International Workshop on Chronic Lymphocytic Leukaemia criteria for diagnosis, and for decision on treatment initiation as well as characteristics included in the CLL

  13. Mitochondrial apoptosis of lymphocyte is induced in type 2 diabetes

    Institute of Scientific and Technical Information of China (English)

    Xu Hui; Chen Yanbo; Li Yanxiang; Xia Fangzhen; Han Bing; Zhang Huixin; Zhai Hualing

    2014-01-01

    Background Lymphocyte function and homeostasis is associated with immune defence to infection.Apoptosis of lymphocytes might be a considerably important component which has an impact on immunity to infections in people with hyperglycemia.The aim of this study was to explore the mitochondrial apoptosis pathway of lymphocyte in diabetic patients.Methods Sixty patients with type 2 diabetes mellitus and fifty healthy volunteers were included in this study.Annexin V and propidiumiodide (Pl) were joined in the isolated lymphocytes and the rate of lymphocyte apoptosis was calculated with flow cytometry.Observation of the lymphocytes was done using transmission electron microscopy; mitochondria had been extracted and then mitochondrial membrane potential (MMP) was detected to assess mitochondrial function; the mRNA level of Bcl-2,cytochrome c (Cyt-C),caspase-9 and caspase-3 were analyzed by real-time reverse transcriptionpolymerase chain reaction (RT-PCR).Results Apoptosis rate of lymphocyte was significantly higher in diabetic group than that in normal control group (P <0.05).Transmission electron microscopy showed lymphocyte shrinkage and breakage,chromatin condensation and less mitochondria; a fall in MMP levels was also evident; Bcl-2 concentration was reduced and the expressions of caspase-9,caspase-3 and Cyt-C were elevated (P <0.05) in diabetic patients.Conclusions The rate of lymphocyte apoptosis was significantly higher in type 2 diabetic patients than that in normal population.Mitochondrial apoptosis pathway may play a very important role in decreasing function of lymphocyte in diabetes.

  14. Expression of protooncogenes during lymphocyte activation by growth factors.

    Science.gov (United States)

    Bulanova, E G; Budagyan, V M; Yarilin, A A; Mazurenko, N N

    1997-09-01

    Effects of growth factors of non-immune origin including somatotropin (ST) and platelet-derived growth factor (PDGF) on the expression of the proteins encoded by c-fos, c-myc, c-fun, and c-ets family protooncogenes were studied for the first time. The dynamics of the oncoprotein expression in activated CD(3+)-lymphocytes was investigated by immunoblotting. The accumulation of the Fos and Myc proteins was enhanced in T-lymphocytes treated with ST, PDGF, or phytohemagglutinin; the accumulation was maximum at 30-60 min and decreased in 2 h; the data indicate that the oncoproteins participate in the early lymphocyte activation by various growth factors. The Jun protein appears only in 3 h after the onset of lymphocyte activation; this suggests independent participation of Fos in the early stages of lymphocyte activation prior to the appearance of Jun, preceding the joint action of Fos and Jun within the AP-1 transcription complex. The products of the c-ets family are differentially activated by the studied growth factors. Resting lymphocytes actively accumulate the Ets-1 protein; ST and PDGF activation decreases Ets-1 expression in 2 h. The Ets-2 protein is not detected in resting cells and PDGF-activated lymphocytes, whereas lymphocyte activation by ST is associated with accumulation of Ets-2. The data suggest that the product of the c-ets-1 gene is more important in the regulation of resting cells and the product of the c-ets-2 gene is important during activation of lymphocytes by ST. The results indicate that activation of lymphocytes with growth factors of non-immune origin is mediated by several signal transduction pathways.

  15. Metal ion levels and lymphocyte counts

    DEFF Research Database (Denmark)

    Penny, Jeannette Ø; Varmarken, Jens-Erik; Ovesen, Ole

    2013-01-01

    . RESULTS: The T-lymphocyte counts for both implant types declined over the 2-year period. This decline was statistically significant for CD3(+)CD8(+) in the THA group, with a regression coefficient of -0.04 × 10(9)cells/year (95% CI: -0.08 to -0.01). Regression analysis indicated a depressive effect...... of cobalt ions in particular on T-cells with 2-year whole-blood cobalt regression coefficients for CD3+ of -0.10 (95% CI: -0.16 to -0.04) × 10(9) cells/parts per billion (ppb), for CD3+CD4+ of -0.06 (-0.09 to -0.03) × 10(9) cells/ppb, and for CD3(+)CD8(+) of -0.02 (-0.03 to -0.00) × 10(9) cells/ppb...

  16. Fungal natural products targeting chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Bladt, Tanja Thorskov; Kildgaard, Sara; Knudsen, Peter Boldsen

    2012-01-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults from the western world. No curative treatments of CLL are presently known so the treatment strategy today is primarily to prolong patient survival,1 why we have initiated new activities towards discovery of novel compounds...... with potential tumor specificity. Our starting point is a diverse fungal collection of thousands of Penicillium and Aspergillus species. These fungi have proven to be a very rich source of various bioactive compounds and yet our dereplication investigations have demonstrated that there are still numerous unknown...... compounds to be identified within these species. Until now we have found that 11 out of 289 fungal extracts are active against CLL cells. Using our established chemotaxonomic discovery approach we have dereplicated and fractionated these extracts to track the activity into single fractions/compounds.2...

  17. Molecular Mechanisms of Lymphocyte-Mediated Cytotoxicity

    Institute of Scientific and Technical Information of China (English)

    Zusen Fan; Qixiang Zhang

    2005-01-01

    Granule-mediated cytotoxicity is the major mechanism for lymphocytes to kill viruses, intracellular bacteria and tumors. The cytotoxic granules move to the immunological synapse by exocytosis after recognition of a killer cell.The contents of the granules are delivered into target cells with the help of perforin by endocytosis. A group of serine protease granzymes cleave their critical substrates to initiate DNA damage and cell death. The most abundant granzymes are granzyme A and B. They induce cell death through alternate and nonoverlapping pathways. The substrates and functions of the majority of the orphan granzymes have not yet been identified. It is possible that the diversity of granzymes provides fail-safe mechanisms for killing viruses and tumor cells.

  18. Role of angiogenesis in chronic lymphocytic leukemia.

    Science.gov (United States)

    Letilovic, Tomislav; Vrhovac, Radovan; Verstovsek, Srdan; Jaksic, Branimir; Ferrajoli, Alessandra

    2006-09-01

    Angiogenesis is a physiologic process of new blood vessels formation mediated by various cytokines called angiogenic and angiostatic factors. Although its potential pathophysiologic role in solid tumors has been extensively studied for more than 3 decades, enhancement of angiogenesis in chronic lymphocytic leukemia (CLL) and other malignant hematological disorders has been recognized more recently. An increased level of angiogenesis has been documented by various experimental methods both in bone marrow and lymph nodes of patients with CLL. Although the role of angiogenesis in the pathophysiology of this disease remains to be fully elucidated, experimental data suggest that several angiogenic factors play a role in the disease progression. Biologic markers of angiogenesis were also shown to be of prognostic relevance in CLL. The current findings provide the rationale for investigating antiangiogenic agents in CLL. In the current review angiogenesis in CLL is discussed and its potential diagnostic and therapeutic applications.

  19. Chronic lymphocytic leukemia in African Americans.

    Science.gov (United States)

    Coombs, Catherine C; Falchi, Lorenzo; Weinberg, J Brice; Ferrajoli, Alessandra; Lanasa, Mark C

    2012-11-01

    Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the United States with almost 4390 attributable deaths per year. Epidemiologic data compiled by the Surveillance, Epidemiology and End Results (SEER) program identifies important differences in incidence and survival for African Americans with CLL. Although the incidence of CLL is lower among African Americans than among Caucasians (4.6 and 6.2 per 100 000 men, respectively), age-adjusted survival is inferior. African American patients with CLL are almost twice as likely to die from a CLL-related complication in the first 5 years after diagnosis as are Caucasian patients with CLL. The biologic basis for these observations is almost entirely unexplored, and a comprehensive clinical analysis of African American patients with CLL is lacking. This is the subject of the present review.

  20. Thyroid carcinoma: immunology, irradiation, and lymphocytic infiltration

    Energy Technology Data Exchange (ETDEWEB)

    Shull, J.H.; Sharon, N.; Victor, T.A.; Scanlon, E.F.

    1979-06-01

    Patients undergoing thyroidectomies at Evanston (I11) Hospital, during a six-month period had immunological studies performed preoperatively. No differential could be found between those with carcinoma or benign pathologic findings. T- and B-cell distribution and lymphocytic response to mitogens varied widely. Quantitative immunoglobulins showed slightly increased levels of IgG in patients wih carcinoma and thyroiditis in comparison with those patients with adenomas. Antithyroglobulin antibodies were negative in all patients. Pathology slides from 107 patients with thyroid carcinoma between 1972 and 1978 at Evanston Hospital were reviewed for the presence of thyroiditis, either focal or diffuse. It was found that 50% of all carcinomas had either diffuse or focal thyroiditis. Diffuse thyroiditis was more common in patients with no history of irradiation and papillary carcinoma, and in younger age groups.

  1. Mediastinal irradiation for chronic lymphocytic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Sawitskii, A.; Rai, K.R.; Aral, I.; Silver, R.T.; Glicksman, A.S.; Carey, R.W.; Scialla, S.; Cornell, C.J. Jr.; Seligman, B.; Shapiro, L.

    1976-12-01

    Thirty-one patients with chronic lymphocytic leukemia were treated with mediastinal radiation. In none of the patients was complete remission achieved; either partial remission or clinical improvement was achieved in 52 percent, but the duration of response was short. The response rate was 77 percent for the patients receiving a total radiation dose greater than 3,000 rads and 45 percent for those receiving less than 3,000 rads. Severe life-threatening toxicity was noted in 11 patients and seven of these patients died; two patients died with progressive disease. Severe toxicity was manifested by one or more of the following: bone marrow aplasia, pancytopenia, gram-negative sepsis, generalized herpes zoster and severe esophagitis. Neither the total dose of radiation nor the dose per week correlated with the severity of reaction or death.

  2. Autoimmune Cytopenias in Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Giovanni D'Arena

    2013-01-01

    Full Text Available The clinical course of chronic lymphocytic leukemia (CLL may be complicated at any time by autoimmune phenomena.The most common ones are hematologic disorders, such as autoimmune hemolytic anemia (AIHA and immune thrombocytopenia (ITP. Pure red cell aplasia (PRCA and autoimmune agranulocytosis (AG are, indeed, more rarely seen. However, they are probably underestimated due to the possible misleading presence of cytopenias secondary to leukemic bone marrow involvement or to chemotherapy cytotoxicity. The source of autoantibodies is still uncertain, despite the most convincing data are in favor of the involvement of resting normal B-cells. In general, excluding the specific treatment of underlying CLL, the managementof these complications is not different from that of idiopathic autoimmune cytopenias or of those associated to other causes. Among different therapeutic approaches, monoclonal antibody rituximab, given alone or in combination, has shown to be very effective.

  3. Epigenetic repolarization of T lymphocytes from chronic lymphocytic leukemia patients using 5-aza-2'-deoxycytidine.

    Science.gov (United States)

    Dubovsky, Jason A; Powers, John J; Gao, Yang; Mariusso, Luis F; Sotomayor, Eduardo M; Pinilla-Ibarz, Javier A

    2011-09-01

    T cell immune dysfunction has an important role in the profound immune suppression that characterizes chronic lymphocytic leukemia (CLL). Improper polarization of T cells has been proposed as one of the mechanism involved. Mounting data implicates chromatin regulation, namely promoter methylation, in the plasticity of naïve human T cells. Recent in vitro evidence indicates that this plasticity may be phenotypically altered by using methylation inhibitors which are approved for clinical use in certain types of cancer. These results beg the question: can the ineffective polarization of T lymphocytes in the context of CLL be effectively modulated using methylation inhibitors in a sustainable therapeutic fashion? To answer this question our laboratory has studied the effects of 5-aza-2'-deoxycytidine (5A2) in helper and cytotoxic T lymphocytes from healthy donors and CLL patients in well characterized molecular and epigenetic signaling pathways involved in effective polarization. Moreover, we sought to investigate the consequences of methylation inhibitor treatment on lymphocyte survival, activation intensity, and naïve cell polarization. Our data indicates that 5A2 treatment can depolarize Th2 cells to effectively secrete interferon gamma, signal via T-bet, and achieve demethylation of critical Th1 specific promoters. Moreover, we demonstrate that 5A2 can force Th1 polarization of naïve T cells despite a strong IL-4 stimuli and a lack of IL-12. In conclusion our data seeks to define a modality in which improper or ineffective T cell polarization can be altered by 5AZA and could be incorporated in future therapeutic interventions.

  4. [Lymphocytic duodenosis: etiological study and clinical presentations].

    Science.gov (United States)

    Santolaria, Santos; Dominguez, Manuel; Alcedo, Javier; Abascal, Manuel; García-Prats, M Dolores; Marigil, Miguel; Vera, Jesus; Ferrer, Margarita; Montoro, Miguel

    2013-11-01

    Lymphocytic duodenosis (LD) is a characteristic lesion in the initial phases of celiac disease (CD) but can be associated with many other entities. The aim of this study was to evaluate the prevalence of distinct causes of LD and possible differences in clinical presentation according to etiology. A retrospective study was performed that included 194 patients diagnosed with LD (more than 25 intraepithelial lymphocytes per 100 epithelial cells). A preestablished strategy to evaluate the cause of the disease was followed that included celiac serology (antitransglutaminase antibodies), HLA-DQ2/DQ8 genotypes, diagnosis of Helicobacter pylori and small intestinal bacterial overgrowth (SIBO). Diagnosis of CD was established on the basis of clinical and histological response to a gluten-free diet in patients with positive serology or compatible findings on HLA-DQ2 (at least one of the alleles) or -DQ8 (both alleles) study. The most frequent cause of LD was CD (39%), followed by SBBO (22%), H.pylori (14%), CD and SIBO (12%), and other causes (13%). Most of the patients (83%) had a compatible HLA-DQ2 or -DQ8 genotype. In these patients, the most frequent diagnosis was CD (46%), while in the absence of HLA-DQ2/DQ8, the most frequent diagnoses were SIBO (44%) and H. pylori (22%). CD was the most frequent diagnosis in patients referred for dyspepsia, diarrhea and anemia, while H. pylori was the most frequent diagnosis in patients with abdominal pain. The most common causes of LD in our environment are CD, followed by SIBO and H. pylori infection. Copyright © 2013 Elsevier España, S.L. and AEEH y AEG. All rights reserved.

  5. Lymphocytes subsets in children with febrile convulsions.

    Science.gov (United States)

    Tuncer, Oğuz; Karaman, Sait; Caksen, Hüseyin; Oner, Ahmet Faik; Odabas, Dursun; Yilmaz, Cahide; Atas, Bülent

    2007-07-01

    In this study, lymphocytes subsets including blood CD3, CD4, CD8, CD16, CD19, and CD56 values were analyzed in children with febrile convulsion (FC) to determine whether there was the association of lymphocytes subsets in the pathogenesis of FC. The study includes 48 children with FC, and 55 healthy age matched control subjects, followed in Yüzüncü Yil University, Faculty of Medicine, Department of Pediatrics between October 2003 and June 2004. Blood CD3, CD4, CD8, CD16, CD19, and CD56 values were examined in the study and control groups. The analyses were performed in the Hematology Laboratory, Yüzüncü Yil University Faculty of Medicine, with flow cytometer device (Coulter Epics XL2, Flow Cytometer). A total of 48 children [17 girls (35.5%) and 31 boys (64.5%)], aged 6 months to 60 months (mean 22.20 +/- 13.75 months) with FC and 55 healthy children [28 girls (51%) and 27 boys (49%)], aged 6 months to 60 months (mean 28.87 +/- 17.04 months) were included in the study. When compared with the control group, the study found significantly decreased blood CD3 and CD4 values in the study group (p .05). When comparing the children with and without positive family history for FC, the study did not find any difference for all CD values between the groups (p >.05). Similarly, there was not significant difference in CD values between the children with simple and complex FC (p >.05). The findings suggested that decreased blood CD3 and CD4 values might be responsible for the infections connected with FC or that they might be related to the pathogenesis of FC in some children.

  6. Multiple dysfunctions in developmental and activational stages of T lymphocytes, B lymphocytes and monocytes in ARC and AIDS patients.

    Science.gov (United States)

    Sei, Y; Tsang, P H; Petrella, R J; Bekesi, J G

    1987-11-01

    Peripheral blood leukocytes from ARC and AIDS patients were examined before and after phytohemagglutinin (PHA) stimulation by dual color flow cytometry and monoclonal antibodies which identify developmental and activational stages of T lymphocytes, B cells and monocytes. There was a persistent elevation in the total number of circulating Ia+ lymphocytes with progressive selection for B1+ Ia+ lymphocytes and T suppressor cells and a concurrent reduction in the antigen-presenting monocytes. Following PHA stimulation there was a marked decrease in all subsets of Ia+ lymphocytes and monocytes. These results indicate (a) multicellular dysfunctions in the immunosurveillance mechanisms in AIDS, and (b) that many functional subsets of circulating lymphocytes and monocytes were already activated and therefore poorly responsive to additional antigenic or mitogenic stimuli.

  7. Lymphocyte Perturbations in Malawian Children with Severe and Uncomplicated Malaria.

    Science.gov (United States)

    Mandala, Wilson L; Msefula, Chisomo L; Gondwe, Esther N; Gilchrist, James J; Graham, Stephen M; Pensulo, Paul; Mwimaniwa, Grace; Banda, Meraby; Taylor, Terrie E; Molyneux, Elizabeth E; Drayson, Mark T; Ward, Steven A; Molyneux, Malcolm E; MacLennan, Calman A

    2015-11-18

    Lymphocytes are implicated in immunity and pathogenesis of severe malaria. Since lymphocyte subsets vary with age, assessment of their contribution to different etiologies can be difficult. We immunophenotyped peripheral blood from Malawian children presenting with cerebral malaria, severe malarial anemia, and uncomplicated malaria (n = 113) and healthy aparasitemic children (n = 42) in Blantyre, Malawi, and investigated lymphocyte subset counts, activation, and memory status. Children with cerebral malaria were older than those with severe malarial anemia. We found panlymphopenia in children presenting with cerebral malaria (median lymphocyte count, 2,100/μl) and uncomplicated malaria (3,700/μl), which was corrected in convalescence and was absent in severe malarial anemia (5,950/μl). Median percentages of activated CD69(+) NK (73%) and γδ T (60%) cells were higher in cerebral malaria than in other malaria types. Median ratios of memory to naive CD4(+) lymphocytes were higher in cerebral malaria than in uncomplicated malaria and low in severe malarial anemia. The polarized lymphocyte subset profiles of different forms of severe malaria are independent of age. In conclusion, among Malawian children cerebral malaria is characterized by lymphocyte activation and increased memory cells, consistent with immune priming. In contrast, there are reduced memory cells and less activation in severe malaria anemia. Further studies are required to understand whether these immunological profiles indicate predisposition of some children to one or another form of severe malaria. Copyright © 2016 Mandala et al.

  8. T- and B-lymphocyte chimerism in the marmoset

    Energy Technology Data Exchange (ETDEWEB)

    Niblack, G.D.; Kateley, J.R.; Gengozian, N.

    1977-01-01

    Marmosets are natural blood chimeras, this condition resulting from the high frequency of fraternal twinning and the consistent development of placental vascular anastomoses between the two embryos. Identification of chimerism by sex-chromosome analysis of cultured blood lymphocytes provided a means of determining the proportion of chimerism among T and B lymphocytes. Peripheral blood lymphocytes were enriched for T or B cells by filtration through a nylon column (yields >95% T-cells) or inactivation of T lymphocytes by treatment with a goat anti-marmoset thymocyte antiserum in the presence of complement (yields >95% B cells). Mitogenic stimulation of these separated, enriched cell populations yielded metaphase plates which could be scored for percentage male and female cells. Tests on five different blood chimeras showed the T- and B-lymphocyte chimerism to be the same. Stimulation of blood lymphocytes with cells from another species of marmoset in a mixed lymphocyte culture test revealed the chimeric T-cell response (i.e., host and co-twin cells) to be similar to that obtained with a mitogenic lectin. The demonstration of equivalent T- and B-cell chimerism in these animals suggests derivation of these cells from a common stem cell pool and the response of both T-cell populations to an antigenic stimulus in proportions similar to their percentage chimerism suggests complete immunologic tolerance exists in this species for co-twin histocompatibility antigens.

  9. Evaluation of lymphocyte subgroups in children with subacute sclerosing panencephalitis.

    Science.gov (United States)

    Yilmaz, C; Yuca, S A; Yilmaz, N; Oner, A F; Caksen, H

    2009-01-01

    The aetiology of subacute sclerosing panencephalitis (SSPE) remains to be fully elucidated, although it follows infection with a hypermutant defective M-protein measles virus. This study analysed peripheral blood lymphocyte subgroups to determine their role in the pathophysiology of SSPE. It included 22 children with SSPE aged 2 - 15 years (patient group) and 22 age- and gender-matched healthy children (control group). In children or= 6 years old, there were no significant differences in the lymphocyte subgroups. In conclusion, these findings suggest that a low CD4(+) lymphocyte count might be responsible for SSPE in younger children.

  10. CD3 immunohistochemical staining in diagnosis of lymphocytic colitis

    DEFF Research Database (Denmark)

    Fiehn, Anne-Marie Kanstrup; Engel, Ulla; Holck, Susanne

    2016-01-01

    Microscopic colitis (MC) is a common cause of chronic watery diarrhea. Traditionally, MC encompasses the 2 subgroups lymphocytic colitis (LC) and collagenous colitis, but recently, an additional subgroup, MC incomplete, has been introduced. Distinguishing between the subgroups relies exclusively...

  11. Prognostic significance of serum immunoglobulin pareprotein in chronic lymphocytic leukemia

    Institute of Scientific and Technical Information of China (English)

    杨舒

    2012-01-01

    Objective To investigate the incidence of serum immunoglobulin (Ig) paraprotein in chronic lymphocytic leukemia(CLL) ,and to explore its clinical associated laboratory features and prognostic implication. Methods Serum protein electrophoresis and immunofixation

  12. Lymphocyte apoptosis: role of uremia and permeability of dialysis membrane.

    Science.gov (United States)

    Soriano, Sagrario; Martín-Malo, Alejandro; Carracedo, Julia; Ramírez, Rafael; Rodríguez, Mariano; Aljama, Pedro

    2005-01-01

    Uremia is associated to host defense mechanism disorders. Lymphocyte apoptosis, which may cause alteration of the immune system, is increased in uremic patients. The aim of the present study was to determine if, in addition to uremia, dialysis membranes with different biocompatibility and permeability have an effect on lymphocyte apoptosis. Cell apoptosis and Fas expression were assessed using flow cytometry in four groups of patients: (1) uremic non-dialyzed (Non-D) patients; (2) hemodialysis (HD) patients on hemophan; (3) low-flux polysulfone, and (4) high-flux polysulfone membrane. Ten healthy volunteers were used as controls. At baseline, lymphocytes from patients on hemophan showed an increase in apoptosis (18.4 +/- 6.9%) as compared with Non-D (7.2 +/- 2.8%; p dialysis patients lymphocyte apoptosis is influenced not only by the biocompatibility but also by the permeability of the dialysis membrane.

  13. Chronic lymphocytic thyroiditis in a cynomolgus macaque (Macaca fascicularis).

    Science.gov (United States)

    Guzman, Roberto E; Radi, Zaher A

    2007-02-01

    Chronic lymphocytic thyroiditis characterized by multifocal follicular lymphoid cell infiltrates with germinal centers, thyroid acinar atrophy and pituitary cell hyperplasia/hypertrophy of the adenohypophysis was detected in a vehicle control, 4-year-old female Cynomolgus macaque in a routine toxicology study. Lymphoid cells of germinal centers were positive for the B-cell marker CD20 by immunohistochemistry (IHC), while remaining lymphocytes were positive for the T-cell marker CD3. Hypertrophied/hyperplastic pituitary cells were positive for thyroid stimulating hormone (TSH) by IHC, consistent with an adaptive response due to removal of hormonal negative feedback from the diseased thyroid gland. Features of this case are similar to chronic lymphocytic thyroiditis in humans, an autoimmune disorder also known as Hashimoto's disease. Chronic lymphocytic thyroiditis with compensatory pituitary changes may occur spontaneously in young, clinically normal cynomolgus macaques and its presence in drug treated animals should be interpreted with caution.

  14. The nature of the refractive granules in human lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Knowlton, N.P. Jr.; Hempelmann, L.H. [Los Alamos Scientific Lab., NM (United States)

    1949-04-19

    The number of refractive bodies in human lymphocytes increases in persons chronically exposed to low level doses of ionizing radiation. The observations of the optical properties, the histochemistry, and the method of formation of these bodies are described.

  15. Psychopatholgy, fundamental assumptions and CD-4 T lymphocyte ...

    African Journals Online (AJOL)

    in HIV-positive patients were associated with lower CD4 T-lymphocyte counts. Method: Self-rating .... depression) were excluded from participation. For comparison ... Examination (MMSE) and the HIV Dementia Scale (HDS). The. MMSE is the ...

  16. INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    AnnaMaria Nosari

    2012-01-01

    Full Text Available

    Infectious complications have been known to be a major cause of morbidity and mortality in CLL patients who are predisposed to infections because of both the humoral immunodepression inherent to hematologic disease, which is related to stage and duration of CLL, and to further immunosuppression related to therapy. The majority of infections in CLL patients treated with alkilating agents is of bacterial origin. The immunodeficiency and natural infectious history of alkylator-resistant, corticosteroid-treated patients appears to have changed with the administration of purine analogs, which has been complicated by very severe and unusual infections and also more viral infections due to sustained reduction of CD4-positive T lymphocytes. The following introduction of monoclonal antibody therapies, in particular alemtuzumab, further increased the immunodepression, increasing also infections which appeared more often in patients with recurrent neutropenia due to chemotherapy cycles.

    Epidemiological data regarding fungal infections in lymphoproliferative disorders are scarce. Italian SEIFEM group in a retrospective multicentre study regarding CLL patients reported an incidence of mycoses 0.5%; however, chronic lymphoproliferative disorders emerged as second haematological underlying disease after acute leukemia in a French study on aspergillosis; in particular CLL with aspergillosis accounted for a third of these chronic lymphoproliferative diseases presenting mould infection.

  17. INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    AnnaMaria Nosari

    2012-11-01

    Full Text Available Infectious complications have been known to be a major cause of morbidity and mortality in CLL patients who are predisposed to infections because of both the humoral immunodepression inherent to hematologic disease, which is related to stage and duration of CLL, and to further immunosuppression related to therapy. The majority of infections in CLL patients treated with alkilating agents is of bacterial origin. The immunodeficiency and natural infectious history of alkylator-resistant, corticosteroid-treated patients appears to have changed with the administration of purine analogs, which has been complicated by very severe and unusual infections and also more viral infections due to sustained reduction of CD4-positive T lymphocytes. The following introduction of monoclonal antibody therapies, in particular alemtuzumab, further increased the immunodepression, increasing also infections which appeared more often in patients with recurrent neutropenia due to chemotherapy cycles. Epidemiological data regarding fungal infections in lymphoproliferative disorders are scarce. Italian SEIFEM group in a retrospective multicentre study regarding CLL patients reported an incidence of mycoses 0.5%; however, chronic lymphoproliferative disorders emerged as second haematological underlying disease after acute leukemia in a French study on aspergillosis; in particular CLL with aspergillosis accounted for a third of these chronic lymphoproliferative diseases presenting mould infection.

  18. Leptomeningeal disease in chronic lymphocytic leukemia.

    Science.gov (United States)

    Lange, C P E; Brouwer, R E; Brooimans, R; Vecht, Ch J

    2007-12-01

    Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the western hemisphere, with an annual incidence of 3:100000. Commonly patients are asymptomatic but not rarely disease progression occurs in the setting of lymphadenopathy and extensive leukemic burden. Leptomeningeal involvement in patients with CLL is infrequent, with presenting symptoms of headache (23%), acute or chronic changes in mental status (28%), cranial nerve abnormalities (54%) including optic neuropathy (28%), weakness of lower extremities (23%) and cerebellar signs (18%). In this report, we discuss a CLL patient with leptomeningeal involvement, who presented with neurological symptoms as the first clinical sign, and a diagnosis of leptomeningeal was made based on CSF cytology and flow cytometry. Treatment consisted of radiation therapy and intrathecal chemotherapy with arabinoside-cytosine and systemic chemotherapy. On the basis of this patient-report together with 37 other previously reported cases, the clinical characteristics together with treatment options and outcome of leptomeningeal involvement in CLL are reviewed. Our case together with data from the literature indicate that a timely diagnosis and intensive treatment of leptomeningeal disease of CLL may lead to longstanding and complete resolution of neurological symptoms.

  19. Sampling site matters when counting lymphocyte subpopulations.

    Directory of Open Access Journals (Sweden)

    Benson Ogunjimi

    Full Text Available Clinical and scientific work routinely relies on antecubital venipunctures for hematological, immunological or other analyses on blood. This study tested the hypothesis that antecubital veins can be considered to be a good proxy for other sampling sites. Using a hematocytometer and a flow cytometer, we analyzed the cell counts from samples coming from the radial artery, the dorsal hand veins and the antecubital veins from 18 volunteers. Most surprisingly, we identified the greatest difference not to exist between arterial and venous circulation, but between the distal (radial artery & dorsal hand veins and proximal (antecubital veins sampling sites. Naïve T cells had a higher cell count distally compared to proximally and the reverse was true for effector memory T cells. Despite these differences there were high correlations between the different sampling sites, which partially supports our initial hypothesis. Our findings are crucial for the future design and interpretation of immunological research, and for clinical practice. Furthermore, our results suggest a role for interval lymph nodes in the trafficking of lymphocytes.

  20. Richter Syndrome in Chronic Lymphocytic Leukemia.

    Science.gov (United States)

    Vitale, Candida; Ferrajoli, Alessandra

    2016-02-01

    The term Richter syndrome (RS) indicates the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma. RS is a rare complication with an aggressive clinical course, bearing an unfavorable prognosis. In the majority of cases, CLL transforms into RS as diffuse large B cell lymphoma (DLBCL), and a clonal relation between the two processes can be found. However, clonally unrelated RS can occur and transformations to other histologies beside DLBCL have been described. Recent data have shed some light on genetic characteristics that can influence and drive the transformation from CLL to RS. This molecular information has not been translated yet into significant treatment advances, and currently the therapy regimens for RS continue to rely on intensive chemotherapy combinations followed by stem cell transplant in suitable candidates. Based on the rapid pace of discoveries in the field of hematological malignancies and on the recent revolution in the therapeutic landscape for CLL and B cell lymphomas, new therapeutic options for RS might be available in the upcoming years.

  1. Tumor infiltrating lymphocytes in ovarian cancer.

    Science.gov (United States)

    Santoiemma, Phillip P; Powell, Daniel J

    2015-01-01

    The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment.

  2. Isochromosome 17q in Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Eyad Alhourani

    2015-01-01

    Full Text Available In chronic lymphocytic leukemia (CLL, presence of acquired cytogenetic abnormalities may help to estimate prognosis. However, deletion of TP53 gene, which is associated with an aggressive course of the disease and poor prognosis along with a lack of response to treatment, is one of the alterations which may escape cytogenetic diagnoses in CLL. Thus, other techniques have emerged such as interphase fluorescence in situ hybridization (iFISH. Deletion of TP53 may but must not go together with the formation of an isochromosome i(17q; surprisingly this subgroup of patients was not in the focus of CLL studies yet. This study was about if presence of i(17q could be indicative for a new subgroup in CLL with more adverse prognosis. As a result, TP53 deletion was detected in 18 out of 150 (12% here studied CLL cases. Six of those cases (~33% had the TP53 deletion accompanied by an i(17q. Interestingly, the cases with i(17q showed a tendency towards more associated chromosomal aberrations. These findings may be the bases for follow-up studies in CLL patients with TP53 deletion with and without i(17q; it may be suggested that the i(17q presents an even more adverse prognostic marker than TP53 deletion alone.

  3. Targeting CD20 in chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Nahas MR

    2015-03-01

    Full Text Available Myrna R Nahas, Jon E ArnasonBeth Israel Deaconess Medical Center, Boston, MA, USAAbstract: Chronic lymphocytic leukemia (CLL, the most common leukemia in adults, is standardly managed with chemotherapy in combination with the anti-CD20 antibody rituximab. In this review, we discuss the history, use, and evolution of rituximab in the treatment of CLL and explore the next generation CD20 antibodies ofatumumab and obinutuzumab with a focus on recent clinical trials. Increased understanding of the importance of B cell receptor (BCR signaling in CLL has resulted in the development of several drugs with significant clinical activity that are ideally suited for combination with CD20 therapy as is being currently explored. Moving forward, these developments have the potential to result in treatment regimens that do not include traditional chemotherapeutic agents, which is of particular importance in CLL given the late onset of diagnosis and potential frailty of the patients.Keywords: CLL, monoclonal antibody, rituximab, ofatumumab, obinutuzumab

  4. SUBTYPES OF B LYMPHOCYTES IN PATIENTS WITH AUTOIMMUNE HEMOCYTOPENIA

    Institute of Scientific and Technical Information of China (English)

    Li-min Xing; Hai-rong Jia; Juan Sun; Chong-li Yang; Zong-hong Shao; Rong Fu; Hong Liu; Jun Shi; Lie Bai; Mei-feng Tu; Hua-quan Wang; Zhen-zhu Cui

    2007-01-01

    Objective To investigate the quantities of bone marrow CD5+ B lymphocytes in the patients with autoimmune hemocytopenia and the relationship between quantities of CD5+ B lymphocytes and clinical or laboratorial parameters.Methods Quantities of CD5+ B lymphocytes in the bone marrow of 14 patients with autoimmune hemolytic anemia (AIHA) or Evans syndrome, 22 immunorelated pancytopenia (IRP) patients, and 10 normal controls were assayed by flow cytometry. The correlation between their clinical or laboratorial parameters and CD5+ B lymphocytes was analyzed.Results The quantity of CD5+B lymphocytes of AIHA/Evans syndrome (34. 64% ± 19. 81% ) or IRP patients (35.81% ±16.83% ) was significantly higher than that of normal controls (12.00% ±1.97% , P<0. 05). However, there was no significant difference between AIHA/Evans syndrome and IRP patients (P > 0. 05). In all hemocytopenic patients, the quantity of bone marrow CD5+ B lymphocytes showed significantly negative correlation with serum complement C3 level (r = - 0. 416, P< 0. 05). In the patients with AIHA/Evans syndrome, the quantity of bone marrow CD5+ B lymphocytes showed significantly positive correlation with serum indirect bilirubin level (r = 1. 00, P<0. 05). In Evans syndrome patients, the quantity of CD5+ B lymphocytes in bone marrow showed significantly positive correlation with platelet-associated immunoglobulin G (r = 0. 761, P< 0. 05) and platelet-associated immunoglobulin M (r = 0. 925, P< 0. 05). The quantity of CD5+ B lymphocytes in bone marrow of all hemocytopenic patients showed significantly negative correlation with treatment response (tau-b = - 0. 289, P< 0. 05), but had no correlation with colony forming unit-erythroid ( r = - 0. 205, P > 0. 05 ) or colony forming unit-granulocyte-macrophage colonies ( r = -0.214, P>0.05).Conclusions The quantity of bone marrow CD5+ B lymphocytes in the patients with autoimmune hemocytopenia significantly increases and is correlated with disease

  5. Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio are Predictors of Heart Failure

    Directory of Open Access Journals (Sweden)

    Erdal Durmus

    2015-01-01

    Full Text Available AbstractBackground:Neutrophil-to-lymphocyte ratio (NLR and platelet-to-lymphocyte ratio (PLR are inflammatory markers used as prognostic factors in various diseases. The aims of this study were to compare the PLR and the NLR of heart failure (HF patients with those of age-sex matched controls, to evaluate the predictive value of those markers in detecting HF, and to demonstrate the effect of NLR and PLR on mortality in HF patients during follow-up.Methods:This study included 56 HF patients and 40 controls without HF. All subjects underwent transthoracic echocardiography to evaluate cardiac functions. The NLR and the PLR were calculated as the ratio of neutrophil count to lymphocyte count and as the ratio of platelet count to lymphocyte count, respectively. All HF patients were followed after their discharge from the hospital to evaluate mortality, cerebrovascular events, and re-hospitalization.Results:The NLR and the PLR of HF patients were significantly higher compared to those of the controls (p < 0.01. There was an inverse correlation between the NLR and the left ventricular ejection fraction of the study population (r: -0.409, p < 0.001. The best cut-off value of NLR to predict HF was 3.0, with 86.3% sensitivity and 77.5% specificity, and the best cut-off value of PLR to predict HF was 137.3, with 70% sensitivity and 60% specificity. Only NLR was an independent predictor of mortality in HF patients. A cut-off value of 5.1 for NLR can predict death in HF patients with 75% sensitivity and 62% specificity during a 12.8-month follow-up period on average.Conclusion:NLR and PLR were higher in HF patients than in age-sex matched controls. However, NLR and PLR were not sufficient to establish a diagnosis of HF. NLR can be used to predict mortality during the follow-up of HF patients.

  6. Regulatory B lymphocyte functions should be considered in chronic lymphocytic leukemia.

    Science.gov (United States)

    Mohr, Audrey; Renaudineau, Yves; Bagacean, Cristina; Pers, Jacques-Olivier; Jamin, Christophe; Bordron, Anne

    2016-05-01

    Chronic lymphocytic leukemia (CLL) is characterized by an abnormal expansion of mature B cells in the bone marrow and their accumulation in blood and secondary lymphoid organs. Tumor CLL cells share expression of various surface molecules with many subsets of B cells and have several common characteristics with regulatory B cells (B regs). However, the identification of B regs and their role in CLL remain elusive. The aim of this review is to summarize recent works regarding the regulatory and phenotypic characteristic of B regs and their associated effects on the immune system. It is also meant to highlight their potential importance with regards to the immunotherapeutic response.

  7. Concanavalin A-induced activation of lymphocytic choriomeningitis virus memory lymphocytes into specifically cytotoxic T cells

    DEFF Research Database (Denmark)

    Marker, O; Thomsen, Allan Randrup; Andersen, G T

    1977-01-01

    When spleen cells, which have been primed to Lymphocytic Choriomeningitis (LCM) virus during a primary infection several months previously, are stimulated in vitro with Con A. highly specific secondary cytotoxic effector cells are generated. The degree of cytotoxicity revealed by such Con A......-stimulated cells is higher than that of non-incubated spleen cells harvested nine days following the primary infection, and the effect is totally inhibited by anti-theta serum plus complement treatment of the effector cells immediately before the cytotoxic test....

  8. Chronic lymphocytic leukaemia: case control epidemiological study in Yorkshire.

    OpenAIRE

    Cartwright, R. A.; Bernard, S.M.; Bird, C. C.; Darwin, C. M.; O'Brien, C; Richards, I D; Roberts, B; McKinney, P A

    1987-01-01

    This is the second report of a large case control study of lymphoma/leukaemia occurring in Yorkshire during 1979-84, and deals with chronic lymphocytic leukaemia presenting either in its haematological (CLL) or more solid lymphomatous (malignant lymphoma-lymphocytic or MLL) forms. In all, 330 cases and 561 controls were interviewed. The results support the concept that CLL/MLL is a condition of multiple aetiologies with evidence for genetic predisposition through an excess of family cases, im...

  9. Genotoxicity of the herbicide butachlor in cultured human lymphocytes.

    Science.gov (United States)

    Sinha, S; Panneerselvam, N; Shanmugam, G

    1995-08-01

    Butachlor, a pre-emergence herbicide was investigated for its ability to induce sister chromatid exchanges (SCE) and chromosome aberrations (CA) in cultured human peripheral blood lymphocytes. Mitogen-stimulated lymphocytes were treated with three different concentrations (5, 10 and 20 micrograms/ml) of butachlor for 24, 48 and 72 h. Our results indicate a dose-dependent increase in the frequency of chromosomal aberrations at 24, 48 and 72 h of treatment with butachlor. No SCE was promoted by butachlor.

  10. Biophysical aspects of T lymphocyte activation at the immune synapse

    Directory of Open Access Journals (Sweden)

    Claire eHivroz

    2016-02-01

    Full Text Available T lymphocyte activation is a pivotal step of the adaptive immune response. It requires the recognition by T-cell receptors (TCR of peptides presented in the context of major histocompatibility complex molecules (pMHC present at the surface of antigen presenting cells (APCs. T lymphocyte activation also involves engagement of co-stimulatory receptors and adhesion molecules recognizing ligands on the APC. Integration of these different signals requires the formation of a specialized dynamic structure: the immune synapse. While the biochemical and molecular aspects of this cell-cell communication have been extensively studied, their mechanical features have only recently been addressed. Yet, the immune synapse is also the place of exchange of mechanical signals. Receptors engaged on the T lymphocyte surface are submitted to many tensile and traction forces. These forces are generated by various phenomena: membrane undulation/protrusion/retraction, cell mobility or spreading and dynamic remodeling of the actomyosin cytoskeleton inside the T lymphocyte. Moreover, the TCR can both induce force development, following triggering, and sense and convert forces into biochemical signals, as a bona fide mechanotransducer. Other co-stimulatory molecules such as LFA-1, engaged during immune synapse formation, also display these features. Moreover, T lymphocytes themselves are mechanosensitive, since substrate stiffness can modulate their response. In this review, we will summarize recent studies from a biophysical perspective to explain how mechanical cues can affect T lymphocyte activation. We will particularly discuss how forces are generated during immune synapse formation; how these forces affect various aspects of T lymphocyte biology; and what are the key features of T lymphocyte response to stiffness.

  11. Ivabradine Reduces Chemokine-Induced CD4-Positive Lymphocyte Migration

    OpenAIRE

    Thomas Walcher; Peter Bernhardt; Dusica Vasic; Helga Bach; Renate Durst; Wolfgang Rottbauer; Daniel Walcher

    2010-01-01

    Aims. Migration of CD4-positive lymphocytes into the vessel wall is a critical step in atherogenesis. Recent data suggest that ivabradine, a selective I(f)-channel blocker, reduces atherosclerotic plaque formation in apolipoprotein E-deficient mice, hitherto nothing is known about the mechanism by which ivabradine modulates plaque formation. Therefore, the present study investigated whether ivabradine regulates chemokine-induced migration of lymphocytes. Methods and results. Stimulation of CD...

  12. The lymphocyte transformation test in allergic contact dermatitis: New opportunities.

    Science.gov (United States)

    Popple, Amy; Williams, Jason; Maxwell, Gavin; Gellatly, Nichola; Dearman, Rebecca J; Kimber, Ian

    2016-01-01

    Allergic contact dermatitis (ACD) is driven by the activation and proliferation of allergen-specific memory T-lymphocytes and is currently diagnosed by patch testing with a selected panel of chemical allergens. The lymphocyte transformation test (LTT) can be used to monitor ex vivo T-lymphocyte responses to antigens, including contact allergens. The LTT is not viewed as being an alternative to patch testing, but it does seek to reflect experimentally skin sensitization to specific chemicals. The LTT is based on stimulation in vitro of antigen-driven T-lymphocyte proliferation. That is, exposure in culture of primed memory T-lymphocytes to the relevant antigen delivered in an appropriate configuration will provoke a secondary response that reflects the acquisition of skin sensitization. The technical aspects of this test and the utility of the approach for investigation of immune responses to contact allergens in humans are reviewed here, with particular emphasis on further development and refinement of the protocol. An important potential application is that it may provide a basis for characterizing those aspects of T-lymphocyte responses to contact allergens that have the greatest influence on skin sensitizing potency and this will be considered in some detail.

  13. Lymphocyte subset reference intervals in blood donors from northeastern Brazil

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    ALEX J.L. TORRES

    2015-06-01

    Full Text Available The reference intervals for leukocytes and lymphocytes currently used by most clinical laboratories present limitations as they are primarily derived from individuals of North American and European origin. The objective this study was to determine reference values for peripheral blood B lymphocytes, T lymphocyte subsets (CD4+, CD8+, naïve, memory, regulatory, TCRαβ and TCRγδ+ and NK cells from blood donors in Salvador-Bahia, Brazil. Results: The proportion of included male subjects was 73.7% and the median ages of males (34 and females (35 were found to be similar. Absolute counts total lymphocytes subsets to both gender was 1,956 (1,060-4,186 cells and relative values 34%. The T CD4+ and T CD8+ lymphocytes relative values was 51% (20-62 and 24% (9-28, respectively. The most statistically significant finding observed was a higher percentage of B lymphocytes (p=0.03 in females. Commonly cited subset reference intervals were found to be consistent with values in several populations from different geographic areas.

  14. Carbon nanotubes enhance cytotoxicity mediated by human lymphocytes in vitro.

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    Zhao Sun

    Full Text Available With the expansion of the potential applications of carbon nanotubes (CNT in biomedical fields, the toxicity and biocompatibility of CNT have become issues of growing concern. Since the immune system often mediates tissue damage during pathogenesis, it is important to explore whether CNT can trigger cytotoxicity through affecting the immune functions. In the current study, we evaluated the influence of CNT on the cytotoxicity mediated by human lymphocytes in vitro. The results showed that while CNT at low concentrations (0.001 to 0.1 µg/ml did not cause obvious cell death or apoptosis directly, it enhanced lymphocyte-mediated cytotoxicity against multiple human cell lines. In addition, CNT increased the secretion of IFN-γ and TNF-α by the lymphocytes. CNT also upregulated the NF-κB expression in lymphocytes, and the blockage of the NF-κB pathway reduced the lymphocyte-mediated cytotoxicity triggered by CNT. These results suggest that CNT at lower concentrations may prospectively initiate an indirect cytotoxicity through affecting the function of lymphocytes.

  15. Stressed to death: implication of lymphocyte apoptosis for psychoneuroimmunology

    Science.gov (United States)

    Shi, Yufang; Devadas, Satish; Greeneltch, Kristy M.; Yin, Deling; Allan Mufson, R.; Zhou, Jian-nian

    2003-01-01

    Psychological and physical stressors best exemplify the intercommunication of the immune and the nervous systems. It has been shown that stress significantly impacts leukocyte cellularity and immune responses and alters susceptibility to various diseases. While acute stress has been shown to enhance immune responses, chronic stress often leads to immunosuppression. Among many criteria examined upon exposure to chronic stress, the reduction in lymphocyte mitogenic response and lymphocyte cellularity are commonly assessed. We have reported that chronic restraint stress could induce lymphocyte reduction, an effect dependent on endogenous opioids. Interestingly, the effect of endogenous opioids was found to be exerted through increasing the expression of a cell death receptor, Fas, and an increased sensitivity of lymphocytes to apoptosis. Stress-induced lymphocyte reduction was not affected by adrenalectomy. In this review, based on available literature and our recent data, we will discuss the role of the hypothalamic-pituitary-adrenal axis and endogenous opioids and examine the mechanisms by which chronic stress modulates lymphocyte apoptosis.

  16. Presentation of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma in a Warthin Tumor: Case Report and Literature Review.

    Science.gov (United States)

    Jawad, Hadeel; McCarthy, Peter; O'Leary, Gerard; Heffron, Cynthia C

    2017-10-01

    Warthin tumor is the second most common salivary gland neoplasm. It occurs more commonly in males than in females. Malignant transformation in Warthin tumor is a rare but well-recognized phenomenon; however, the development or presentation of lymphoma in a Warthin tumor is rare. An 80-year-old man presented with painless mass of the right parotid gland of 2 years duration with recent ulceration of the overlying skin and right cervical lymphadenopathy underwent a surgical resection of parotid mass and biopsy of the periglandular lymph nodes. The histological diagnosis was malignant lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, present within the stroma of a Warthin tumor, and also present within the adjacent lymph node. This case is the third reported case describing a collision of Warthin tumor and chronic lymphocytic leukemia/small lymphocytic lymphoma. It also emphasizes the importance of careful examination of the lymphoid stroma of these tumors.

  17. MHC and non-MHC genes regulate elimination of lymphocytic choriomeningitis virus and antiviral cytotoxic T lymphocyte and delayed-type hypersensitivity mediating T lymphocyte activity in parallel

    DEFF Research Database (Denmark)

    Thomsen, Allan Randrup; Marker, O

    1989-01-01

    The course of systemic infection with lymphocytic choriomeningitis virus was studied in mouse strains differing in the MHC or non-MHC background. Virus clearance rates differed significantly between H-2 identical strains as well as between congenic strains differing in the H-2L subregion, indicat......The course of systemic infection with lymphocytic choriomeningitis virus was studied in mouse strains differing in the MHC or non-MHC background. Virus clearance rates differed significantly between H-2 identical strains as well as between congenic strains differing in the H-2L subregion...

  18. Synergistic Cytotoxicity of Melatonin and New-generation Anticancer Drugs Against Leukemia Lymphocytes But Not Normal Lymphocytes.

    Science.gov (United States)

    Zhelev, Zhivko; Ivanova, Donika; Bakalova, Rumiana; Aoki, Ichio; Higashi, Tatsuya

    2017-01-01

    The present study demonstrates specific sensitization of leukemia lymphocytes towards anticancer drugs using melatonin and clarifies the role of reactive oxygen species (ROS) for induction of apoptosis. The study covers four conventional and 11 new-generation anticancer drugs. Four parameters were analyzed simultaneously in leukemia and normal lymphocytes treated with drug, melatonin, or their combination: cell viability, induction of apoptosis, level of reactive oxygen species (ROS), and level of protein-carbonyl products. Almost all investigated combinations of melatonin with new-generation anticancer drugs were characterized by synergistic cytotoxicity towards leukemia lymphocytes, while the combinations with conventional drugs exhibited additive or antagonistic effects on cell viability. In leukemia lymphocytes, the additive cytotoxicity of doxorubicin plus melatonin was accompanied by low levels of ROS and protein-carbonyl products, as well as by suppression of apoptosis. In normal lymphocytes, none of the studied parameters changed significantly compared to cells treated with doxorubicin only. The combinations of everolimus plus melatonin and barasertib plus melatonin exhibited impressive synergistic cytotoxic effects on leukemia lymphocytes but did not affect the viability of normal lymphocytes. In leukemia cells, the synergistic cytotoxicity was accompanied by strong induction of apoptosis but a decrease of ROS to a level below that of the control. In normal lymphocytes, these combinations did not affect the level of ROS nor of protein-carbonyl products, and did not induce apoptosis. The data suggest that melatonin is a promising supplementary component in chemotherapy which allows the therapeutic doses of anticancer drugs to be reduced, minimizing their side-effects.

  19. Chronic lymphocytic leukemia/small lymphocytic lymphoma: another neoplasm related to the B-cell follicle?

    Science.gov (United States)

    Tandon, Bevan; Swerdlow, Steven H; Hasserjian, Robert P; Surti, Urvashi; Gibson, Sarah E

    2015-01-01

    Although there has been increased attention paid to the critical nature of nodal involvement in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the B-cell compartment it is most closely related to and its relationship to the follicle remain uncertain. A clinicopathologic investigation of 60 extramedullary biopsies of LEF1+ CLL/SLL, including 29 cases with perifollicular/follicular (PF/F) growth, was therefore performed. A subset of PF/F cases demonstrated inner mantle zone preservation or intra-mantle zone growth. All PF/F and 16/31 other cases contained CD21+ follicular dendritic cells. No cytogenetic, IGHV mutational or gene usage differences were seen between PF/F and diffuse cases. PF/F cases were more often kappa positive (p<0.03) and had fewer involved nodal sites (p=0.0004). These findings suggest that at least a subset of bona fide CLL/SLL is related to the follicle, most likely the outer mantle zone, and that at least a subset of the diffuse cases may represent "later" disease.

  20. Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma.

    Science.gov (United States)

    Nasr, Samih H; Shanafelt, Tait D; Hanson, Curtis A; Fidler, Mary E; Cornell, Lynn D; Sethi, Sanjeev; Chaffee, Kari G; Morris, Joseph; Leung, Nelson

    2015-06-01

    Granulomatous interstitial nephritis (GIN) is an uncommon pathologic lesion encountered in 0.5% to 5.9% of renal biopsies. Drugs, sarcoidosis, and infections are responsible for most cases of GIN. Malignancy is not an established cause of GIN. Here, we report a series of 5 patients with GIN secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients were mostly elderly white males with an established history of CLL/SLL who presented with severe renal impairment (median peak serum creatinine, 7.3 mg/dL), leukocyturia, and mild proteinuria. One had nephromegaly. In 2 patients, the development and relapse of renal insufficiency closely paralleled the level of lymphocytosis. Kidney biopsy in all patients showed GIN concomitant with CLL/SLL leukemic interstitial infiltration. Granulomas were nonnecrotizing and epithelioid and were associated with giant cells. One biopsy showed granulomatous arteritis. One patient had a granulomatous reaction in lymph nodes and skin. Steroids with/without CLL/SLL-directed chemotherapy led to partial improvement of kidney function in all patients except 1 who had advanced cortical scarring on biopsy. In conclusion, we report an association between CLL/SLL and GIN. Patients typically present with severe renal failure due to both GIN and leukemic interstitial infiltration, which tends to respond to steroids with/without CLL/SLL-directed chemotherapy. The pathogenesis of GIN in this clinical setting is unknown but may represent a local hypersensitivity reaction to the CLL/SLL tumor cells.

  1. Elutriated lymphocytes for manufacturing chimeric antigen receptor T cells.

    Science.gov (United States)

    Stroncek, David F; Lee, Daniel W; Ren, Jiaqiang; Sabatino, Marianna; Highfill, Steven; Khuu, Hanh; Shah, Nirali N; Kaplan, Rosandra N; Fry, Terry J; Mackall, Crystal L

    2017-03-16

    Clinical trials of Chimeric Antigen Receptor (CAR) T cells manufactured from autologous peripheral blood mononuclear cell (PBMC) concentrates for the treatment of hematologic malignancies have been promising, but CAR T cell yields have been variable. This variability is due in part to the contamination of the PBMC concentrates with monocytes and granulocytes. Counter-flow elutriation allows for the closed system separation of lymphocytes from monocytes and granulocytes. We investigated the use of PBMC concentrates enriched for lymphocytes using elutriation for manufacturing 8 CD19- and 5 GD2-CAR T cell products. When compared to PBMC concentrates, lymphocyte-enriched elutriation fractions contained greater proportions of CD3+ and CD56+ cells and reduced proportions of CD14+ and CD15+ cells. All 13 CAR T cell products manufactured using the elutriated lymphocytes yielded sufficient quantities of transduced CAR T cells to meet clinical dose criteria. The GD2-CAR T cell products contained significantly more T cells and transduced T cells than the CD19-CAR T cell products. A comparison of the yields of CAR T cells produced from elutriated lymphocytes with the yields of CAR T cells previous produced from cells isolated from PBMC concentrates by anti-CD3/CD28 bead selection or by anti-CD3/CD28 bead selection plus plastic adherence found that greater quantities of GD2-CAR T cells were produced from elutriated lymphocytes, but not CD19-CAR T cells. Enrichment of PBMC concentrates for lymphocytes using elutriation increased the quantity of GD2-CAR T cells produced. These results provide further evidence that CAR T cell expansion is inhibited by monocytes and granulocytes.

  2. Prognostic impact of lymphocytes in soft tissue sarcomas.

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    Sveinung W Sorbye

    Full Text Available PURPOSE: The purpose of this study was to clarify the prognostic significance of lymphocyte infiltration in soft tissue sarcomas (STS. Prognostic markers in potentially curable STS should guide therapy after surgical resection. The immune status at the time of resection may be important, but the prognostic significance of tumor infiltrating lymphocytes is controversial as the immune system has conflicting roles during cancer development. EXPERIMENTAL DESIGN: Tissue microarrays from 249 patients with STS were constructed from duplicate cores of viable and representative neoplastic tumor areas. Immunohistochemistry was used to evaluate the CD3+, CD4+, CD8+, CD20+ and CD45+ lymphocytes in tumors. RESULTS: In univariate analyses, increased numbers of CD4+ (P = 0.008 and CD20+ (P = 0.006 lymphocytes in tumor correlated significantly with an improved disease-specific survival (DSS in patients with wide resection margins (n = 108. In patients with non-wide resection margins (n = 141 increased numbers of CD3+ (P = 0.028 lymphocytes in tumor correlated significantly with shorter DSS. In multivariate analyses, a high number of CD20+ lymphocytes (HR = 5.5, CI 95%  = 1.6-18.6, P = 0.006 in the tumor was an independent positive prognostic factor for DSS in patients with wide resections margins. CONCLUSIONS: High density of CD20+ lymphocytes in STS with wide resection margins is an independent positive prognostic indicator for these patients. Further research is needed to define if CD20+ cells can modify tumors in a way that reduces disease progression and metastatic potential.

  3. Cloning and expression of recombinant human testis specific antigen - 1 related to infertility in E. coli%重组人睾丸特异性抗原-1(TSA-1)的基因克隆及原核表达

    Institute of Scientific and Technical Information of China (English)

    周晓宁; 武婕; 张宏斌; 王捷

    2008-01-01

    目的 为了阐明血清中存在的抗精子抗体引起不孕不育的原因,构建重组人睾丸特异性抗原-1(recombinanthuman testis specie antigen-1,rhTSA-1)的原核表达质粒并在大肠杆菌中诱导表达.方法 采用RT-PCR法,从人睾丸组织总RNA中扩增获得人TSA-1的cDNA,将其克隆入表达载体pGEX-4T-2,构建TSA-1的重组原核表达质粒pGEX/TSA-1.重组质粒经酶切和测序鉴定后,转化大肠杆菌JM109并在大肠杆菌中诱导表达目的 蛋白.结果 测序表明,重组基因序列与人TSA-1基因完全一致.SDS-PAGE电泳显示,表达产物的相对分子量与预期结果相符.结论 获得了人TSA-1的编码基因,并在大肠杆菌中可表达人TSA-1.

  4. Morphologic studies of lymphocyte nuclei in follicular and diffuse mixed small- and large-cell (lymphocytic-histiocytic) lymphoma.

    Science.gov (United States)

    Dardick, I; Caldwell, D R; Moher, D; Jabi, M

    1988-08-01

    Twelve examples of mixed small- and large-cell lymphoma (eight follicular, one follicular and diffuse, and three diffuse) were investigated morphometrically using plastic-embedded tissue in order to study nuclear characteristics of lymphocyte populations in this form of non-Hodgkin's lymphoma (NHL) and to test morphologic bases for current NHL classification systems. This study illustrates that there are many inaccuracies, illusions, and misconceptions in the morphologic criteria currently used to classify mixed small- and large-cell lymphoma. A principal finding was that lymphocyte nuclear profiles in mixed-cell lymphomas tend to be smaller in size (P less than .005) and more irregular in shape (P = .0001) than the morphologically similar counterparts in germinal centers of lymph nodes with reactive hyperplasia. Intercase comparison of mixed small- and large-cell lymphomas revealed a considerable range of mean nuclear area values, some of which were within the size range of normal, small lymphocytes. At the magnifications used for morphometric assessment, a high proportion of lymphocyte nuclear profiles had shallow invaginations, but only a limited number of profiles (4% to 14%) had deep (cleaved) indentations. Contrary to current definitions for this subtype of NHL, lymphocytes with "small" nuclei had the same proportion of the nuclear diameter occupied by nuclear invaginations as lymphocytes with "large" nuclei and, in fact, mean nuclear invagination depth was shallower in "small" nuclei than in "large" nuclei. Furthermore, regardless of whether it is nuclear area or shape that is evaluated, lymphocytes in mixed-cell lymphoma do not separate into two populations of small-cleaved and large noncleaved cells. Morphometry reveals that only four of the 12 examples of mixed small- and large-cell lymphoma had a proportion of the lymphocytes in the size range of fully transformed germinal center lymphocytes that exceeded 25%, and none of the cases approached 50% even

  5. Apoptosis of matured T lymphocytes induced by mouse sertoli cells in cocultures in vitro

    Institute of Scientific and Technical Information of China (English)

    LIU Yang; LIN Zi-hao; ZHU Xiao-hai; LIU Shan-rong

    2001-01-01

    Objective: To study whether mouse sertoli cells can induce the apoptosis of matured T lymphocytes in cocultures in vitro. Methods: With TUNEL, DNA electrophoresis, eleetro-mierography and flow cytometry, we examined the apoptosis and its rates of mouse matured T lymphocytes in control group (T lymphocytes only), group A (T lymphocytes + culture medium of sertoli cells), group B (T lymphocytes + sertoli cells). Results: Under electro-micrography, chromatin condensation, karyopyknosis, karyorhexis and apoptotic body were observed in some T lymphocytes in 3 groups; some nucleuses were stained dark blue with TUNEL; a typical DNA ladder was found with DNA electrophoresis. The apoptotic rates of T lymphocytes in group A and B were significantly higher than that in control group (P<0.01). The apoptotic rate of T lymphocytes in group B was significantly higher than that in group A (P<0.01). Conclusion: In coculture condition in vitro,mouse sertoli cells can induce the apoptosis of matured T lymphocytes.

  6. Effect of in vitro x-irradiation on human peripheral blood T and B lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Prusek, W. (Szpital Wojewodzki, Wroclaw (Poland)); Astaldi, G. (The Blood Research Foundation Centre, Tortona (Italy))

    1979-01-01

    The effect of in vitro irradiation with increasing in logarythmic progress X-ray doses on lymphocyte viability and on T and B lymphocyte populations was studied in normal adults, patients with myasthenia gravis and in patients undergoing long-term steroid therapy. Decrease in numbers of lymphocytes carrying T or B lymphocyte surface markers was higher than the viable cell loss. The decrease showed no linear correlation with X-ray doses applied, which might reflect the existence of radioresistant T and B lymphocytes. A higher so-called early radiosensitivity of B lymphocytes was demonstrated. In patients with myasthenia gravis early radioresistance of T lymphocytes was detected. In patients undergoing long-term steroid therapy, an increase in numbers of cells lacking markers of any of lymphocyte populations was found in parallel with a decrease in T lymphocyte number which, in these patients, showed a higher radiosensitivity.

  7. Cytotoxic T lymphocytes specific for the simian immunodeficiency virus.

    Science.gov (United States)

    Letvin, N L; Schmitz, J E; Jordan, H L; Seth, A; Hirsch, V M; Reimann, K A; Kuroda, M J

    1999-08-01

    A non-human primate model for acquired immunodeficiency syndrome (AIDS), the simian immunodeficiency virus (SIV)-infected rhesus monkey, was used to explore the role of the AIDS virus-specific cytotoxic T-lymphocyte (CTL) response in disease pathogenesis. This CTL response was measured using the major histocompatibility complex (MHC) class I/peptide tetramer technology. Large numbers of tetramer-binding CD8+ T lymphocytes were demonstrable not only in the peripheral blood, but in lymph nodes and even in semen of chronically SIV-infected monkeys. The central role of these effector T lymphocytes in containing SIV spread during primary infection was demonstrated by showing that early SIV clearance during primary infection correlated with the emergence of the tetramer binding CD8+ T lymphocytes and that in vivo depletion of CD8+ lymphocytes eliminated the ability of the infected monkeys to contain SIV replication. These observations suggest that an effective AIDS vaccine should elicit a potent virus-specific CTL response. In fact, a live, recombinant SIV vaccine constructed using the attenuated pox virus vector modified vaccinia Ankara (MVA) elicited a high-frequency CTL response, comparable in magnitude to that elicited by SIV infection itself. This suggests that vaccine modalities such as MVA may prove useful in creating an effective human immunodeficiency virus (HIV) vaccine. These studies also indicate the power of both the SIV/macaque model and MHC class I/peptide tetramers for assessing AIDS vaccine strategies.

  8. Antibody production in early life supported by maternal lymphocyte factors.

    Science.gov (United States)

    Shimamura, Michio; Huang, Yi-Ying; Goji, Hiroshi

    2003-01-20

    To examine the influence of maternal lymphocyte factors on the immune responses in offspring in early life, antibody production in neonates born to either normal or lymphocyte-deficient mothers was analyzed. Recombination activating gene (Rag)-2(+/-) mouse neonates born to Rag-2(+/+), Rag-2(+/-)or Rag-2(-/-)mothers were injected with goat anti-mouse IgD antiserum, and IgE and IgG(1) production was evaluated. The levels of IgE and IgG(1) were higher in the pups born to Rag-2(+/+)and Rag-2(+/-) dams than to lymphocyte-deficient Rag-2(-/-) dams. The enhanced antibody production in the former compared with the latter neonates was also found following immunization with ovalbumin or TNP-Ficoll. Thus, the presence of maternal lymphocyte factors was suggested in neonates that augmented antigen-specific antibody production in both T cell-dependent and -independent pathways. A reduction in antibody production was observed in normal neonates when they were foster-nursed by Rag-2(-/-) mothers. Thus, the maternal lymphocyte factors enhancing the immune responses in newborns were shown to be present in breast-milk.

  9. T lymphocyte insensitivity to corticosteroids in chronic obstructive pulmonary disease

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    Kaur Manminder

    2012-03-01

    Full Text Available Abstract Background There are increased numbers of activated lymphocytes in the lungs of chronic obstructive pulmonary disease (COPD patients. The clinical benefits of corticosteroids in COPD patients are limited. Our hypothesis is that lymphocytes play a role in this corticosteroid insensitivity. Objectives To investigate the effects of the corticosteroid dexamethasone on lung lymphocyte cytokine production from patients with COPD compared to controls. Methods Cultured airway lymphocytes obtained by bronchoscopy from healthy non-smokers (HNS, smokers (S and COPD patients were stimulated with phytohaemagglutinin (PHA & phorbol myristate acetate (PMA, +/- dexamethasone. Supernatants were assayed for interleukin (IL-2 and interferon (IFNγ. Immunofluoresence was used to analyse changes in CD8 glucocorticoid receptor (GRα and GRβ expression. Results The inhibition of PHA/PMA stimulated IFNγ production by dexamethasone was reduced in COPD patients compared to HNS (p p Conclusions IFNγ production from COPD airway lymphocytes is corticosteroid insensitive. This phenomenon may be important in the poor clinical response often observed with corticosteroids.

  10. T-lymphocyte and B-lymphocyte dichotomy in anuran amphibians: III. Assessment and identification of inducible killer T-lymphocytes (IKTL) and spontaneous killer T-lymphocytes (SKTL).

    Science.gov (United States)

    Klempau, A E; Cooper, E L

    1984-01-01

    We have established the existence of alloreactive inducible killer (IK) T-lymphocytes in Rana pipiens by injecting immunogenic concentrations of allogeneic frog erythrocytes (RBC). Assessment of specific IK activity was determined microscopically, observing effector-target conjugate formation, and spectrophotometrically as released hemoglobin (Hb) from lysed targets (RBC). The presence of spontaneous killer (SK) T-lymphocyte activity was also determined using unimmunized frogs and similar assay conditions. Assays using rabbit anti-frog Thy-1.1 antiserum inhibition, but not E-rosetted T-lymphocyte depletion, confirmed the T-lymphocyte category of both effector cell populations in Rana pipiens. For IK activity, we determined the 1) best priming doses, 2) best effector cell source (peripheral blood), 3) best priming route (intraperitoneal), 4) kinetics of immunity development, and 5) kinetics of lysis. Kinetics of lysis and organ distribution for spontaneous killer cells were also determined. Our results may assist 1) in establishing the evolutionary origin of cytotoxic T-lymphocytes (CTL) and natural killer (NK) cells, and 2) in predicting where the capacity of immuno-surveillance against modified-self appeared in phylogeny. The implications are important for understanding origins of mechanisms of resistance against neoplastic conditions.

  11. Ivabradine Reduces Chemokine-Induced CD4-Positive Lymphocyte Migration

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    Thomas Walcher

    2010-01-01

    Full Text Available Aims. Migration of CD4-positive lymphocytes into the vessel wall is a critical step in atherogenesis. Recent data suggest that ivabradine, a selective I(f-channel blocker, reduces atherosclerotic plaque formation in apolipoprotein E-deficient mice, hitherto nothing is known about the mechanism by which ivabradine modulates plaque formation. Therefore, the present study investigated whether ivabradine regulates chemokine-induced migration of lymphocytes. Methods and results. Stimulation of CD4-positive lymphocytes with SDF-1 leads to a 2.0±0.1 fold increase in cell migration (P<.01; n=7. Pretreatment of cells with ivabradine reduces this effect to a maximal 1.2±0.1 fold induction at 0.1 µmol/L ivabradine (P<.01 compared to SDF-1-treated cells, n=7. The effect of ivabradine on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity as determined by PI-3 kinase activity assays. Downstream, ivabradine inhibits activation of the small GTPase Rac and phosphorylation of the Myosin Light Chain (MLC. Moreover, ivabradine treatment reduces f-actin formation as well as ICAM3 translocation to the uropod of the cell, thus interfering with two important steps in T cell migration. Conclusion. Ivabradine inhibits chemokine-induced migration of CD4-positive lymphocytes. Given the crucial importance of chemokine-induced T-cell migration in early atherogenesis, ivabradine may be a promising tool to modulate this effect.

  12. Rituximab for the treatment of patients with chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    M Gentile

    2010-03-01

    Full Text Available M Gentile, E Vigna, C Mazzone, E Lucia, AG Recchia, L Morabito2, MG Bisconte, C Gentile, F Morabito1UOC di Ematologia, Azienda Ospedaliera di Cosenza, Italy; 2Servicio de Hematología y Hemoterapia, Hospital Universitario de Canarias, La Laguna, Tenerife, SpainAbstract: Chronic lymphocytic leukemia (CLL is a lymphoproliferative disorder that originates from antigen-experienced B lymphocytes that do not die and hence accumulate due to external survival signals or undergo apoptosis and are replenished by proliferating precursors. These neoplastic lymphocytes exhibit a characteristic immunophenotype of CD5+/CD19+/CD20+/HLA-DR+/CD23+/sIgdim. Thus, the CD20 antigen has been an appealing target for therapy. The introduction of the monoclonal antibody rituximab (anti-CD20 enabled an outstanding advance in CLL treatment. The introduction of this monoclonal antibody into chemotherapy regimens has dramatically improved complete response rates and progression-free survival in patients with both untreated and relapsed CLL. Although only preliminary data from phase III confirmatory trials have been reported, the FCR regimen, which combines fludarabine and cyclophosphamide with rituximab, is currently the most effective treatment regimen for CLL patients, and has also been demonstrated to significantly improve overall survival . The success of rituximab and the identification of other CLL lymphocyte surface antigens have spurred the development of a multitude of monoclonal antibodies targeting distinct proteins and epitopes in an attempt to target CLL cells more effectively.Keywords: rituximab, chronic lymphocytic leukemia, chemotherapy

  13. NEUTROPHIL/LYMPHOCYTE RATIO AND PLATELET/LYMPHOCYTE RATIO IN PATIENTS WITH NSCLC

    Science.gov (United States)

    Cukic, Vesna

    2016-01-01

    Objective: to compare neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) in patients with NSCLC (Non- Small- Cell Lung Cancer): with and without metastases at the time of diagnosis to find out if there is the importance of these cell ratios in the assessment of severity NSCLC. Material and Methods: this is the retrospective analysis of NRL and PRL in patients with NSCLC at the time of the diagnosis of disease before any anti tumor treatment (chemotherapy, radiotherapy, surgery). 57 of patients with NSCLC treated in the first three months of 2016. year were chosen at random regardless of sex and age. We examined full blood count cells (FBC), calculated NLR and PLR in every patient and compared obtained values in patients with and patients without metastases. Results: In 57 patients with NSCLC there were 15 males with metastases, 28 without metastases, and 8 females with metastases, 6 without metastases. Since there was no regularity in the distribution of obtained values of NLR and PLR we made the Mann-Whitney U test. Mean values are presented with a median and interquartile percentiles. There was no significant difference in NLR between patients without and with metastases (p = 0.614; p = NS) as well as in PLR (p=0,068; p=NS). Conclusion: There must be a link between the immune status of the organism and lung cancer development. Immune cells have become of interest in recent years and much work has been done to study their role in the genesis of cancer but it did not give satisfactory results. Further clinical studies on large number of patients and further laboratory examination of the role of immune cells in cancer development and suppression are required. PMID:27999489

  14. Glycosylation analysis and protein structure determination of murine fetal antigen 1 (mFA1)--the circulating gene product of the delta-like protein (dlk), preadipocyte factor 1 (Pref-1) and stromal-cell-derived protein 1 (SCP-1) cDNAs

    DEFF Research Database (Denmark)

    Krogh, T N; Bachmann, E; Teisner, B

    1997-01-01

    By means of sequence analysis, murine fetal antigen 1 (mFA1) isolated from Mus musculus amniotic fluid was shown to be the circulating protein of the delta-like protein, stromal-cell-derived protein 1 (SCP-1) and preadipocyte factor 1 (Pref-1) gene products. The protein contains 36 cysteine resid...

  15. Injurious effect on rat liver mitochondria by lymphocytes from patients with primary biliary cirrhosis.

    Science.gov (United States)

    Bootello, A; Fernandez-Cruz, E; Escartin, P; Blanco, M F; Gosalvez, M; Segovia De Arana, J M

    1976-01-01

    Lymphocytes from primary biliary cirrhosis (PBC) patients were shown to have an injurious effect on rat liver mitochondria, as was demonstrated by the inhibition of mitochondrial respiratory control by these cells. The incubation of the PBC patients' lymphocytes with isolated rat liver mitochondria produced a significant inhibition of mitochondrial respiration in the presence of ADP. However, no significant effect on respiration was seen with control lymphocytes of normal persons or with lymphocytes from patients with alcoholic cirrhosis and miscellaneous liver diseases. The results suggest that this injurious effect of PBC lymphocytes on mitochondria might be a consequence of sensitization in vivo of the PBC patients' lymphocytes by the mitochondrial antigens. PMID:1277585

  16. Resistance to Dasatinib in primary chronic lymphocytic leukemia lymphocytes involves AMPK-mediated energetic re-programming.

    Science.gov (United States)

    Martinez Marignac, Veronica L; Smith, Sarah; Toban, Nader; Bazile, Miguel; Aloyz, Raquel

    2013-12-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the western world. Although promising new therapies for this incurable disease are being tested in clinical trials, the therapeutic relevance of metabolic rewiring in chronic lymphocytic leukemia (CLL) is poorly understood. The aim of this study was to identify targetable metabolic differences in primary CLL lymphocytes by the use of Dasatinib. Dasatinib is a multi-tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML) and is being tested in clinical trials for several cancers including CLL. This drug has been shown to be beneficial to CML patients suffering from diabetes by reducing their glucose plasma levels. In keeping with this previous observation, we report that Dasatinib induced glucose use while reducing lactate production, suggesting that this tyrosine kinase inhibitor decreases aerobic glycolysis and shifts glucose use in primary CLL lymphocytes. Our results suggest that primary CLL lymphocytes (independently of traditional prognostic factors) can be stratified in two subsets by their sensitivity to Dasatinib in vitro. Increased glucose use induced by Dasatinib or by inhibition of mitochondrial respiration was not sufficient to sustain survival and ATP levels in CLL samples sensitive to Dasatinib. The two subsets of primary CLL lymphocytes are characterized as well by a differential dependency on mitochondrial respiration and the use of anabolic or catabolic processes to cope with induced metabolic/energetic stress. Differential metabolic reprogramming between subsets is supported by the contrasting effect on the survival of Dasatinib treated CLL lymphocytes with pharmacological inhibition of two master metabolic regulators (mTorc1 and AMPK) as well as induced autophagy. Alternative metabolic organization between subsets is further supported by the differential basal expression (freshly purified lymphocytes) of active AMPK, regulators of glucose metabolism and

  17. D-ribose inhibits DNA repair synthesis in human lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Zunica, G.; Marini, M.; Brunelli, M.A.; Chiricolo, M.; Franceschi, C.

    1986-07-31

    D-ribose is cytotoxic for quiescent human lymphocytes and severely inhibits their PHA-induced proliferation at concentrations (25-50 mM) at which other simple sugars are ineffective. In order to explain these effects, DNA repair synthesis was evaluated in PHA-stimulated human lymphocytes treated with hydroxyurea and irradiated. D-ribose, in contrast to other reducing sugars, did not induce repair synthesis and therefore did not apparently damage DNA in a direct way, although it markedly inhibited gamma ray-induced repair. Taking into account that lymphocytes must rejoin physiologically-formed DNA strand breaks in order to enter the cell cycle, we suggest that D-ribose exerts its cytotoxic activity by interfering with metabolic pathways critical for the repair of DNA breaks.

  18. Antigen-specific lymphocyte transformation in patients with recent yersiniosis.

    Science.gov (United States)

    Vuento, R

    1983-04-01

    Lymphocyte transformation in patients with recent yersiniosis was studied. A micromethod using washed blood cells and Yersinia enterocolitica antigen was employed. The washed blood cells were incubated in the presence of various dilutions of heat-treated whole bacteria; these proved as antigen superior to gentamicin- or formalin-treated bacteria. Patients with recent yersiniosis had a significantly higher response against Yersinia antigen as compared to 20 healthy controls, who had either no response or a low response. No difference could be observed in responses against PPD or streptokinase-streptodornase, or in the mitogen responses between these two groups. A marked cross-reaction was observed between Yersinia and Escherichia coli antigen. The results show that patients with recent yersiniosis develop lymphocyte transformation response against Yersinia. Lymphocyte transformation test can be used in the study of host responses against infecting Yersinia in patients with different clinical pictures of yersiniosis.

  19. Clonal expansion of renal cell carcinoma-infiltrating T lymphocytes

    DEFF Research Database (Denmark)

    Sittig, Simone; Køllgaard, Tania; Grønbæk, Kirsten

    2013-01-01

    T lymphocytes can mediate the destruction of cancer cells by virtue of their ability to recognize tumor-derived antigenic peptides that are presented on the cell surface in complex with HLA molecules and expand. Thus, the presence of clonally expanded T cells within neoplastic lesions...... is an indication of ongoing HLA-restricted T cell-mediated immune responses. Multiple tumors, including renal cell carcinomas (RCCs), are often infiltrated by significant amounts of T cells, the so-called tumor-infiltrating lymphocytes (TILs). In the present study, we analyzed RCC lesions (n = 13) for the presence...... of expanded T-cell clonotypes using T-cell receptor clonotype mapping. Surprisingly, we found that RCCs comprise relatively low numbers of distinct expanded T-cell clonotypes as compared with melanoma lesions. The numbers of different T-cell clonotypes detected among RCC-infiltrating lymphocytes were...

  20. Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes

    Science.gov (United States)

    Morgan, Richard A.; Dudley, Mark E.; Wunderlich, John R.; Hughes, Marybeth S.; Yang, James C.; Sherry, Richard M.; Royal, Richard E.; Topalian, Suzanne L.; Kammula, Udai S.; Restifo, Nicholas P.; Zheng, Zhili; Nahvi, Azam; de Vries, Christiaan R.; Rogers-Freezer, Linda J.; Mavroukakis, Sharon A.; Rosenberg, Steven A.

    2006-10-01

    Through the adoptive transfer of lymphocytes after host immunodepletion, it is possible to mediate objective cancer regression in human patients with metastatic melanoma. However, the generation of tumor-specific T cells in this mode of immunotherapy is often limiting. Here we report the ability to specifically confer tumor recognition by autologous lymphocytes from peripheral blood by using a retrovirus that encodes a T cell receptor. Adoptive transfer of these transduced cells in 15 patients resulted in durable engraftment at levels exceeding 10% of peripheral blood lymphocytes for at least 2 months after the infusion. We observed high sustained levels of circulating, engineered cells at 1 year after infusion in two patients who both demonstrated objective regression of metastatic melanoma lesions. This study suggests the therapeutic potential of genetically engineered cells for the biologic therapy of cancer.

  1. Serotonin Transporter Clustering in Blood Lymphocytes of Reeler Mice

    Directory of Open Access Journals (Sweden)

    Tania Rivera-Baltanas

    2010-01-01

    Full Text Available Serotonin transporter clustering is an important feature for regulation of this transporter activity. We used immunocytochemistry to analyze alterations in serotonin transporter clustering in blood lymphocytes of reeler mice. Serotonin transporter immunolabelling is observed mostly as a patchy staining in lymphocytes membranes. Comparison of the number and size of serotonin transporter clusters in wild-type mice, heterozygous reeler mice, and homozygous reeler mice showed an increase in the number and size of clusters in heterozygous reeler mice, but only an increase in clusters size in homozygous reeler mice. Reelin is down-regulated in the brain of schizophrenia, autism, and mood disorders, and is also expressed in blood plasma. There is the possibility therefore that alterations in serotonin transporter clustering in blood lymphocytes associated with a decrease in reelin expression may be operative in some cardiovascular or immune system alterations showing comorbidity with these mental disorders.

  2. Human lymphocyte sub-populations and K cells.

    Science.gov (United States)

    Sandilands, G; Gray, K; Cooney, A; Froebel, K; Anderson, J R

    1976-01-01

    Peripheral blood lymphocytes from 19 normal subjects were examined for surface Ig (SIg) and capacity to form rosettes with normal and neuraminidase-treated sheep erythrocytes and with chicken erythrocytes sensitised with IgG antibody. Information on the relationship between the presence of SIg and capacity to form rosettes was obtained by combined tests and depletion experiments. By these means, a population of lymphocytes with Fc receptors, but lacking SIg (mean 14.6%) was defined and shown to correlate closely with cytotoxic activity for antibody-sensitised target cells. Indirect evidence was also obtained that these lymphocytes, which are regarded as the major population of antibody-dependent cytotoxic cells, are capable of forming rosettes with normal and neuraminidase-treated sheep erythrocytes. The nature of these cells is briefly discussed.

  3. Cytotoxicity and genotoxicity of gliotoxin on human lymphocytes in vitro

    Directory of Open Access Journals (Sweden)

    Mohammed Adel Nouri

    2015-07-01

    Full Text Available The cytotoxic effects on human lymphocytes of two gliotoxin samples (one pure sample produced in the laboratory for this study, and one sample purchased from a standard source were assessed at four different concentrations (25, 50, 100 and 200 ng/ml using the methylthiazol tetrazolium (MTT bioassay. The results showed that growth was inhibited by 21, 39.10, 61.99 and 87.45% for each of the four concentrations of the pure sample, respectively, and by 17.89, 34.92, 58.34 and 85.22% respectively, in the case of the standard purchased sample. Deoxyribonucleic acid (DNA was extracted from the lymphocytes and analysed by electrophoresis on a 1% agarose gel. Gliotoxin appeared to have the ability to degrade or damage the DNA. The present study showed that both the growth inhibition and DNA damage experienced by the human lymphocytes increased linearly with increasing concentrations of toxin.

  4. Key role of mitochondria in apoptosis of lymphocytes.

    Science.gov (United States)

    Boichuk, S V; Minnebaev, M M; Mustafin, I G

    2001-12-01

    Changes in the mitochondrial potential, expression of phosphatidylserine, parameters of direct and lateral light scattering, and DNA fragmentation during spontaneous and induced apoptosis in peripheral blood lymphocytes were studied by flow cytofluorometry. Dexamethasone and Ca2+ ionophore A23187 served as inductors of apoptosis. A decrease in the mitochondrial potential is an early sign of spontaneous and induced apoptosis. Phosphatidylserine expression on the outer plasma membrane occurred later and inversely depended on the mitochondrial potential. Our results indicate that the involvement of mitochondria in spontaneous and induced apoptosis accompanied by a decrease in the mitochondrial potential is an early and key event of programmed lymphocyte death. The decrease in the mitochondrial potential of lymphocytes induced degradation of their nuclei (DNA fragmentation) and promoted elimination of apoptotic cells (phosphatidylserine expression).

  5. Herpesvirus sylvilagus infects both B and T lymphocytes in vivo.

    Science.gov (United States)

    Kramp, W J; Medveczky, P; Mulder, C; Hinze, H C; Sullivan, J L

    1985-01-01

    Herpesvirus sylvilagus infection of cottontail rabbits (Sylvilagus floridanus) was studied as a model of herpesvirus-induced lymphoproliferative disorders. Leukocytosis, splenomegaly, proliferation of T cells and virus production by lymphocytes characterized this infectious mononucleosis-like disease. Approximately two copies of circular herpesvirus sylvilagus genomes per cell were detected in spleen cells at 2 weeks postinfection, and circular genomes could still be observed after 4 months. Circular viral genomes were found in both B and T lymphocytes. Small amounts of linear viral DNA (0.1 to 0.3 copies per cell) were also detected in both B and T cells. These results indicated that the virus did not replicate in the majority of lymphocytes in vivo. Herpesvirus sylvilagus infection in cottontail rabbits could be useful as a model for studying the complex virus-host relationships of lymphotropic herpesviruses and perhaps as an animal model for Epstein-Barr virus infection in humans. Images PMID:2993667

  6. Kinetics of circulating B lymphocytes in human myeloma

    Energy Technology Data Exchange (ETDEWEB)

    Boccadoro, M.; Gavarotti, P.; Fossati, G.; Massaia, M.; Pileri, A.; Durie, B.G.

    1983-04-01

    The tritiated thymidine labeling index (LI%) of peripheral B lymphocytes was studied in eight myeloma patients using simultaneous immunofluorescence and autoradiography. The LI% values were low (0.3%-5.1%), but significantly increased as compared to normal controls. In addition, there was excellent correlation between the LI% values and myeloma disease activity: lowest LI% values were observed in remission patients and the highest at the time of relapse. Simultaneous LI% evaluation of bone marrow myeloma cells in five patients gave concordant results, indicating the same kinetic behavior in both these compartments, particularly in the relapse phase. These data indicate both that circulating B lymphocytes include the neoplastic clone and that these B lymphocytes and bone marrow myeloma cells have similar kinetics.

  7. MAJOR AND LYMPHOCYTE POPULATIONS OF HUMAN PERIPHERAL BLOOD LYMPHOCYTES AND THEIR REFERENCE VALUES, AS ASSAYED BY MULTI-COLOUR CYTOMETRY

    Directory of Open Access Journals (Sweden)

    S. V. Khaidukov

    2009-01-01

    Full Text Available Abstract. Determination of lymphocyte subpopulations and their phenotypes is an important diagnostic feature, in order to elucidate some disturbances connected with immune system functioning. However, insufficient data are obtained when analyzing only major populations of peripheral lymphocytes. In order to perform clinical diagnostics, the data about minor lymphocytic populations and activated cellular pools seem to be more pertinent.Studies of peripheral blood cell subpopulations of healthy donors performed in different Russian regions allowed to assess quantitative distribution intervals for both major and minor immune cell subpopulations in humans. The results obtained, as compared with data from literature, provide an evidence for similar reference intervals for main immune cell subpopulations in healthy donors, independent on their habitation area.Present work has resulted into development of algorithms for cytometric studies and generation of certain panels of monoclonal antibodies enabling evaluation of all main lymphocyte subpopulations, as well as their minor subsets participating in emerging immune response. The distribution intervals have been estimated for such minor subpopulations, as B1- and B2-lymphocytes, memory B-cells, γδ- and αβT-cells, regulatory and naїve T-cells, cytotoxic and secretory NK-cell polupations.The results of present study, while been performed with peripheral blood of healthy donors, may provide a basis of reference values when studying subpopulation profile of immune cells.

  8. Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis

    KAUST Repository

    Hill-Cawthorne, Grant A.

    2011-11-05

    Background: Alemtuzumab is a lymphocyte depleting monoclonal antibody that has demonstrated superior efficacy over interferon β-1a for relapsing-remitting multiple sclerosis (MS), and is currently under investigation in phase 3 trials. One unresolved issue is the duration and significance of the lymphopenia induced. The long term effects on lymphocyte reconstitution of a single course, and the consequences that this has on disability, morbidity, mortality and autoimmunity, were examined. Methods: The lymphocyte reconstitution (n=36; 384 person years) and crude safety data (n=37; 447 person years) are reported for the first patients with progressive MS to receive alemtuzumab (1991-1997). Reconstitution time was expressed as a geometric mean or, when a non-negligible number of individuals failed to recover, as a median using survival analysis. Results: Geometric mean recovery time (GMRT) of total lymphocyte counts to the lower limit of the normal range (LLN; ≥1.0×10 9 cells/l) was 12.7 months (95% CI 8.8 to 18.2 months). For B cells, GMRT to LLN (≥0.1×10 9/l) was 7.1 months (95% CI 5.3 to 9.5); median recovery times for CD8 (LLN ≥0.2×10 9 cells/l) and CD4 lymphocytes (LLN ≥0.4×10 9 cells/l) were 20 months and 35 months, respectively. However, CD8 and CD4 counts recovered to baseline levels in only 30% and 21% of patients, respectively. No infective safety concerns arose during 447 person years of follow-up. Conclusions: Lymphocyte counts recovered to LLN after a single course of alemtuzumab in approximately 8 months (B cells) and 3 years (T cell subsets), but usually did not recover to baseline values. However, this long lasting lymphopenia in patients with a previously normal immune system was not associated with an increased risk of serious opportunistic infection.

  9. Psychosocial factors and T lymphocyte counts in Brazilian peacekeepers.

    Science.gov (United States)

    Silva, Angela M Monteiro da; Speranza, Francisco A B; Ishii, Solange Kiyoko; Hirata Jr, Raphael; Mattos-Guaraldi, Ana Luíza; Milagres, Lucimar Gonçalves

    2015-02-01

    To investigate the associations between psychosocial factors and peripheral blood CD4 and CD8 T lymphocyte numbers in Brazilian peacekeepers. Venous blood was collected from 759 peacekeepers who had just returned from a peace mission in Haiti. Among the 759 soldiers, 642 individuals completed the psychosocial measures. CD4 and CD8 T lymphocyte counts were measured by flow cytometry using a commercially available kit. Psychosocial factors, including military peace force stressors, clinical stress, anxiety and depression, were recorded. As a reference for T lymphocyte numbers, we measured T lymphocyte counts in 75 blood donors from the Instituto de Biologia do Exército, Rio de Janeiro. The median numbers of CD4 and CD8 T lymphocytes in the blood donors were 819 cells/µl and 496 cells/µl, respectively, with a CD4:CD8 ratio of 1.6. Significantly (p<0.05) lower CD4 T cell counts (759 cells/µl) were recorded for peacekeepers, with similar CD8 levels (548 cells/µl) and smaller CD4:CD8 ratios (1.3, p<0.001) compared to blood donors. These differences were due to a group of 14 military personnel with CD4 and CD8 medians of 308 and 266 cells/µl, respectively. Only one (7.1%) of these 14 individuals was diagnosed with clinical stress compared with 13.5% of the individuals with normal levels of CD4 T lymphocytes. One individual out of 628 (0.16%) had a Lipp's Stress Symptom Inventory score of 3, indicating near exhaustion. The prevalence of psychological disorders was low and there were no associations with CD4 or CD8 T cell numbers.

  10. Chronic lymphocytic leukaemia: case control epidemiological study in Yorkshire.

    Science.gov (United States)

    Cartwright, R A; Bernard, S M; Bird, C C; Darwin, C M; O'Brien, C; Richards, I D; Roberts, B; McKinney, P A

    1987-07-01

    This is the second report of a large case control study of lymphoma/leukaemia occurring in Yorkshire during 1979-84, and deals with chronic lymphocytic leukaemia presenting either in its haematological (CLL) or more solid lymphomatous (malignant lymphoma-lymphocytic or MLL) forms. In all, 330 cases and 561 controls were interviewed. The results support the concept that CLL/MLL is a condition of multiple aetiologies with evidence for genetic predisposition through an excess of family cases, immune perturbation demonstrated by excessive previous skin diseases and phenylbutazone use, and viral involvement shown by links with infectious diseases and multiple sclerosis.

  11. Effects of cobalt and chromium ions on lymphocyte migration.

    Science.gov (United States)

    Baskey, Stephen J; Lehoux, Eric A; Catelas, Isabelle

    2017-04-01

    A T cell-mediated hypersensitivity reaction has been reported in some patients with CoCrMo-based implants. However, the role of cobalt and chromium ions in this reaction remains unclear. The objective of the present study was to analyze the effects of Co(2+) and Cr(3+) in culture medium, as well as the effects of culture supernatants of macrophages exposed to Co(2+) or Cr(3+) , on the migration of lymphocytes. The release of cytokines/chemokines by macrophages exposed to Co(2+) and Cr(3+) was also analyzed. The migration of murine lymphocytes was quantified using the Boyden chamber assay and flow cytometry, while cytokine/chemokine release by J774A.1 macrophages was measured by ELISA. Results showed an ion concentration-dependent increase in TNF-α and MIP-1α release and a decrease in MCP-1 and RANTES release. Migration analysis showed that the presence of Co(2+) (8 ppm) and Cr(3+) (100 ppm) in culture medium increased the migration of T lymphocytes, while it had little or no effect on the migration of B lymphocytes, suggesting that Co(2+) and Cr(3+) can stimulate the migration of T but not B lymphocytes. Levels of T lymphocyte migration in culture medium containing Co(2+) or Cr(3+) were not statistically different from those in culture supernatants of macrophages exposed to Co(2+) or Cr(3+) , suggesting that the effects of the ions and chemokines were not additive, possibly because of ion interference with the chemokines and/or their cognate receptors. Overall, results suggest that Co(2+) and Cr(3+) are capable of stimulating the migration of T (but not B) lymphocytes in the absence of cytokines/chemokines, and could thereby contribute to the accumulation of more T than B lymphocytes in periprosthetic tissues of some patients with CoCrMo-based implants. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:916-924, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  12. Polycyclic’ Aromatic Hydrocarbon Induced Intracellular Signaling and Lymphocyte Apoptosis

    DEFF Research Database (Denmark)

    Schneider, Alexander M.

    of this research indicate that the AhR is controlled by the cell progression through the cell cycle. This may imply differential cellular sensitivity to the toxins, and a role for the AhR in cell growth/differentiation. Previous PAH inununotoxicity research did not adequately address effects on immature...... lymphocytes. Our experiments on preB lymphocytes supported by stromal cells suggest that apoptosis is one of the mechanisms for PAH immunosuppression. It could be either due to direct effect of the PAH on the B cells, via stromal cell signaling. Ubiquitous PAH-like toxin, fluoranthene, was tested for it...

  13. Life and death of lymphocytes: a role in immunesenescence

    Directory of Open Access Journals (Sweden)

    Agrawal Sudhanshu

    2005-08-01

    Full Text Available Abstract Human aging is associated with progressive decline in immune functions, increased frequency of infections. Among immune functions, a decline in T cell functions during aging predominates. In this review, we will discuss the molecular signaling in two major pathways of apoptosis, namely death receptor pathway and mitochondrial pathway, and their alterations in both T and B lymphocytes in human aging with a special emphasis on naïve and different memory subsets of CD8+ T cells. We will also discuss a possible role of lymphocyte apoptosis in immune senescence.

  14. Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance

    DEFF Research Database (Denmark)

    Tenzer, Stefan; Wee, Edmund; Burgevin, Anne

    2009-01-01

    Although cytotoxic T lymphocytes (CTLs) in people infected with human immunodeficiency virus type 1 can potentially target multiple virus epitopes, the same few are recognized repeatedly. We show here that CTL immunodominance in regions of the human immunodeficiency virus type 1 group-associated ......Although cytotoxic T lymphocytes (CTLs) in people infected with human immunodeficiency virus type 1 can potentially target multiple virus epitopes, the same few are recognized repeatedly. We show here that CTL immunodominance in regions of the human immunodeficiency virus type 1 group...

  15. Effect of oral proguanil on human lymphocyte proliferation

    DEFF Research Database (Denmark)

    Bygbjerg, Ib Christian; Flachs, H

    1986-01-01

    In vitro studies have indicated that the antifolates pyrimethamine [4, 6] and cycloguanil (the active metabolite of proguanil) suppress the proliferation of stimulated human lymphocytes; proguanil has no effect [2]. During the early growth phase of the cells, 14C-thymidine (14C-TdR) incorporation...... on human lymphocytes, the present study was undertaken. Little information is available about the serum levels of proguanil and cycloguanil following ingestion of prophylactic doses [8]. Therefore, the serum concentrations of proguanil and cycloguanil were estimated, to allow comparison with previous...

  16. Lymphocyte fluorescent profiles (LFP): a possible screening technique in neoplasia.

    Science.gov (United States)

    Love, L A; Metcalf, N F; Metcalf, W K; Sharp, J G

    1979-05-01

    A technique involving fluorescent protein staining and microfluorometry has been developed for measuring the lymphocyte fluorescent profile (LFP) of peripheral blood lymphocytes. In contrast to normal humans who display a regular bell-shaped curve, the profile from patients with cancer is irregular, showing a bimodal distribution of fluorescence, with a significant population of cells fluorescing at a higher relative intensity. It is suggested that this elevation in protein concentration is due to an immune response to the presence of a neoplasm, and thus this technique may prove to be a useful indicator of malignancy.

  17. MG132 plus apoptosis antigen-1 (APO-1) antibody cooperate to restore p53 activity inducing autophagy and p53-dependent apoptosis in HPV16 E6-expressing keratinocytes.

    Science.gov (United States)

    Lagunas-Martínez, Alfredo; García-Villa, Enrique; Arellano-Gaytán, Magaly; Contreras-Ochoa, Carla O; Dimas-González, Jisela; López-Arellano, María E; Madrid-Marina, Vicente; Gariglio, Patricio

    2017-01-01

    The E6 oncoprotein can interfere with the ability of infected cells to undergo programmed cell death through the proteolytic degradation of proapoptotic proteins such as p53, employing the proteasome pathway. Therefore, inactivation of the proteasome through MG132 should restore the activity of several proapoptotic proteins. We investigated whether in HPV16 E6-expressing keratinocytes (KE6 cells), the restoration of p53 levels mediated by MG132 and/or activation of the CD95 pathway through apoptosis antigen-1 (APO-1) antibody are responsible for the induction of apoptosis. We found that KE6 cells underwent apoptosis mainly after incubation for 24 h with MG132 alone or APO-1 plus MG132. Both treatments activated the extrinsic and intrinsic apoptosis pathways. Autophagy was also activated, principally by APO-1 plus MG132. Inhibition of E6-mediated p53 proteasomal degradation by MG132 resulted in the elevation of p53 protein levels and its phosphorylation in Ser46 and Ser20; the p53 protein was localized mainly at nucleus after treatment with MG132 or APO-1 plus MG132. In addition, induction of its transcriptional target genes such as p21, Bax and TP53INP was observed 3 and 6 h after treatment. Also, LC3 mRNA was induced after 3 and 6 h, which correlates with lipidation of LC3B protein and induction of autophagy. Finally, using pifithrin alpha we observed a decrease in apoptosis induced by MG132, and by APO-1 plus MG132, suggesting that restoration of APO-1 sensitivity occurs in part through an increase in both the levels and the activity of p53. The use of small molecules to inhibit the proteasome pathway might permit the activation of cell death, providing new opportunities for CC treatment.

  18. Bombyx mori nucleopolyhedrovirus nucleic acid binding proteins BRO-B and BRO-E associate with host T-cell intracellular antigen 1 homologue BmTRN-1 to influence protein synthesis during infection.

    Science.gov (United States)

    Kotani, Eiji; Muto, Sayaka; Ijiri, Hiroshi; Mori, Hajime

    2015-07-01

    Previous reports have indicated that the Bombyx mori nucleopolyhedrovirus (BmNPV) nucleic acid binding proteins BRO-B and BRO-E are expressed during the early stage of infection and that the BRO family likely supports the regulation of mRNA; however, no study has directly examined the function of BRO family proteins in virus-permissive cells. Here, we show that BRO-B and BRO-E associate with cellular T-cell intracellular antigen 1 homologue (BmTRN-1), a translational regulator, and other cellular translation-related proteins in silkworm cells during viral infection. We created BM-N cells that expressed BRO-B/E to study molecular interactions between BmTRN-1 and BRO-B/E and how they influenced protein synthesis. Fluorescent microscopy revealed that BmTRN-1 was localized in cytoplasmic foci during BmNPV infection. Immunofluorescence studies confirmed that BmTRN-1 and BRO-B/E were colocalized in the amorphous conspicuous cytoplasmic foci. Reporter gene studies revealed that co-expression of BRO-B/E synergistically led to a significant decrease in protein synthesis from a designed transcript carrying the 5'untranslated region of a cellular mRNA with no significant change of transcript abundance. Additionally, RNA interference-mediated knockdown of BmTRN-1 resulted in a marked inhibition of the ability of BRO-B/E to regulate the transcript. These results suggested that the association of BmTRN-1 with BRO-B/E is responsible for the inhibitory regulation of certain mRNAs at the post-transcriptional level and add an additional mechanism for how baculoviruses control protein synthesis during infection.

  19. Fusion of Epstein-Barr virus nuclear antigen-1-derived glycine-alanine repeat to trans-dominant HIV-1 Gag increases inhibitory activities and survival of transduced cells in vivo.

    Science.gov (United States)

    Hammer, Diana; Wild, Jens; Ludwig, Christine; Asbach, Benedikt; Notka, Frank; Wagner, Ralf

    2008-06-01

    Trans-dominant human immunodeficiency virus type 1 (HIV-1) Gag derivatives have been shown to efficiently inhibit late steps of HIV-1 replication in vitro by interfering with Gag precursor assembly, thus ranking among the interesting candidates for gene therapy approaches. However, efficient antiviral activities of corresponding transgenes are likely to be counteracted in particular by cell-mediated host immune responses toward the transgene-expressing cells. To decrease this potential immunogenicity, a 24-amino acid Gly-Ala (GA) stretch derived from Epstein-Barr virus nuclear antigen-1 (EBNA1) and known to overcome proteasomal degradation was fused to a trans-dominant Gag variant (sgD1). To determine the capacity of this fusion polypeptide to repress viral replication, PM-1 cells were transduced with sgD1 and GAsgD1 transgenes, using retroviral gene transfer. Challenge of stably transfected permissive cell lines with various viral strains indicated that N-terminal GA fusion even enhanced the inhibitory properties of sgD1. Further studies revealed that the GA stretch increased protein stability by blocking proteasomal degradation of Gag proteins. Immunization of BALB/c mice with a DNA vaccine vector expressing sgD1 induced substantial Gag-specific immune responses that were, however, clearly diminished in the presence of GA. Furthermore, recognition of cells expressing the GA-fused transgene by CD8(+) T cells was drastically reduced, both in vitro and in vivo, resulting in prolonged survival of the transduced cells in recipient mice.

  20. Anti-apical-membrane-antigen-1 antibody is more effective than anti-42-kilodalton-merozoite-surface-protein-1 antibody in inhibiting plasmodium falciparum growth, as determined by the in vitro growth inhibition assay.

    Science.gov (United States)

    Miura, Kazutoyo; Zhou, Hong; Diouf, Ababacar; Moretz, Samuel E; Fay, Michael P; Miller, Louis H; Martin, Laura B; Pierce, Mark A; Ellis, Ruth D; Mullen, Gregory E D; Long, Carole A

    2009-07-01

    Apical membrane antigen 1 (AMA1) and the 42-kDa merozoite surface protein 1 (MSP1(42)) are leading malaria vaccine candidates. Several preclinical and clinical trials have been conducted, and an in vitro parasite growth inhibition assay has been used to evaluate the biological activities of the resulting antibodies. In a U.S. phase 1 trial with AMA1-C1/Alhydrogel plus CPG 7909, the vaccination elicited anti-AMA1 immunoglobulin G (IgG) which showed up to 96% inhibition. However, antibodies induced by MSP1(42)-C1/Alhydrogel plus CPG 7909 vaccine showed less than 32% inhibition in vitro. To determine whether anti-MSP1(42) IgG had less growth-inhibitory activity than anti-AMA1 IgG in vitro, the amounts of IgG that produced 50% inhibition of parasite growth (Ab(50)) were compared for rabbit and human antibodies. The Ab(50)s of rabbit and human anti-MSP1(42) IgGs were significantly higher (0.21 and 0.62 mg/ml, respectively) than those of anti-AMA1 IgGs (0.07 and 0.10 mg/ml, respectively) against 3D7 parasites. Ab(50) data against FVO parasites also demonstrated significant differences. We further investigated the Ab(50)s of mouse and monkey anti-AMA1 IgGs and showed that there were significant differences between the species (mouse, 0.28 mg/ml, and monkey, 0.14 mg/ml, against 3D7 parasites). Although it is unknown whether growth-inhibitory activity in vitro reflects protective immunity in vivo, this study showed that the Ab(50) varies with both antigen and species. Our data provide a benchmark for antibody levels for future AMA1- or MSP1(42)-based vaccine development efforts in preclinical and clinical trials.

  1. Chronic lymphocytic-leukemia with pleomorphic lymphocytes (cll-pleo) - a comparative-study with typical cll.

    Science.gov (United States)

    Batata, A; Shen, B; Batata, S

    1994-05-01

    Cell suspensions from the peripheral brood of 21 cases of chronic lymphocytic leukemia with pleomorphic lymphocytes (CLL-pleo) and 155 cases of typical CLL were analyzed to define the phenotype of the former and compare it with the phenotype of the latter. CLL-pleo was characterized by weak fluorescence intensity of surface immunoglobulin (mean channel number on flow cytometry <200), positive mouse rosettes and CD5, and negative CD22 and tartrate resistant acid phosphatase. Comparison of the positive rates of the markers and of the mean percentages of marker-expressing cells showed no statistical difference between CLL-pleo and typical CLL. CLL-pleo constitutes a morphological variant of typical CLL bearing the same membrane phenotype as typical CLL, although the mean absolute lymphocyte count in CLL-pleo was significantly higher than that of typical CLL.

  2. Stereological quantification of lymphocytes in skin biopsies from atopic dermatitis patients

    DEFF Research Database (Denmark)

    Ellingsen, A R; Sørensen, F B; Larsen, Jytte Overgaard

    2001-01-01

    Atopic dermatitis (AD) is histologically characterized by lymphocytic infiltration of the skin and quantitative assessment is required. This study introduces stereological techniques to quantify the number of lymphocytes in skin biopsies. Four-millimetre punch biopsies were taken from skin...

  3. Population Pharmacokinetics of Ofatumumab in Patients With Chronic Lymphocytic Leukemia, Follicular Lymphoma, and Rheumatoid Arthritis

    DEFF Research Database (Denmark)

    Struemper, Herbert; Sale, Mark; Patel, Bela R;

    2014-01-01

    Ofatumumab is a human monoclonal antibody directed at CD20 approved for treatment of chronic lymphocytic leukemia. The population pharmacokinetics of intravenous ofatumumab were characterized in patients with relapsed/refractory chronic lymphocytic leukemia, relapsed/refractory follicular lymphoma...

  4. B lymphocytes not required for progression from insulitis to diabetes in non-obese diabetic mice.

    Science.gov (United States)

    Charlton, B; Zhang, M D; Slattery, R M

    2001-12-01

    Previous studies have implicated B lymphocytes in the pathogenesis of diabetes in the non-obese diabetic (NOD) mouse. While it is clear that B lymphocytes are necessary, it has not been clear at which stage of disease they play a role; early, late or both. To clarify when B lymphocytes are needed, T lymphocytes were transferred from 5-week-old NOD female mice to age-matched NOD/severe combined immunodeficiency (SCID) recipient mice. NOD/SCID mice, which lack functionally mature T and B lymphocytes, do not normally develop insulitis or insulin-dependent diabetes melitus (IDDM). The NOD/SCID mice that received purified T lymphocytes from 5-week-old NOD mice subsequently developed insulitis and diabetes even though they did not have detectable B lymphocytes. This suggests that while B lymphocytes may be essential for an initial priming event they are not requisite for disease progression in the NOD mouse.

  5. Ibrutinib Improves Survival in Patients with Previously Treated Chronic Lymphocytic Leukemia

    Science.gov (United States)

    A summary of results from an international phase III trial that compared ibrutinib (Imbruvica®) and ofatumumab (Arzerra®) for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

  6. The imbalance of helper T lymphocytes and cytotoxic T lymphocytes in acute renal transplantation rejection

    Institute of Scientific and Technical Information of China (English)

    YAN JIANG; ZHI QIN TANG; LIN PENG; YU LIANG WANG; ZHI PING WANG

    2007-01-01

    To investigate the imbalance state of helper T lymphocytes (Th) and cytotoxic T lymphocytes (Tc) and the roles of Th1/Th2/Th3 and Tc1/Tc2 cells in renal transplantation rejection, the percentages of these cells in peripheral blood of 24 cases of renal transplantation recipients with acute rejection and the dynamic changes of the CD4/CD8 ratio were determined by flow cytometry analysis,while 30 cases of healthy individuals were set up as controls. In these healthy controls, the percentages of the Th1, Th2 and Th3 cells were (10.45±8.15)%, (5.05±4.15)% and (3.90±3.21)%,and those of Tc1 and Tc2 cells were (9.83±7.03)% and (4.51±2.17)%, respectively. However,the percentages of Th1 and Tc1 cells in peripheral blood of the stable recipients after transplantation were (7.29±5.62)% and (7.04±5.15)%, showing definite reduction, while those of Th2, Th3and Tc2 cells showed significant increase, (6.34±5.67)%, (4.94±4.14) % and ( 6.86 ±4.42) %, respectively. In case of recipients with acute rejection, the percentages of Th1 and Tc1 cells appeared to be (18.55±13.21)% and (15.84±11.72)%, also showing significant increase, but those of Th2,Th3 and Tc2 cells appeared to be reduced, (4.19±3.62)%, (3.02±2.83)% and (3.88±1.63) %, respectively. Significant differences could be detected among these three groups (P <0.05). The CD4/CD8 ratio in cases with acute rejection was higher than those of stable recipients (2.24±0.59 vs 1.95±0.45), but that of the stable recipients and healthy controls (1.98±0.31 )showed no any significant difference. From the above observation, it is evident that imbalance between Th1, Th2 and Th3 with Te1 and Tc2 cells may exist after renal transplantation and probably, the immune imbalance may be induced through the secretion of cytokines INF-γ by Th1 or Te1 cells , I1-4 by Th2 and Tc2 cells and TGF-β by Th3.

  7. The peripheral blood compartment in patients with Graves' disease: activated T lymphocytes and increased transitional and pre-naive mature B lymphocytes

    Science.gov (United States)

    Van der Weerd, K; Van Hagen, P M; Schrijver, B; Kwekkeboom, D J; De Herder, W W; Ten Broek, M R J; Postema, P T E; Van Dongen, J J M; Staal, F J T; Dik, W A

    2013-01-01

    Graves' disease (GD) is an autoimmune disease that involves aberrant B and T lymphocyte responses. Detailed knowledge about lymphocyte subpopulation composition will therefore enhance our understanding of the pathogenesis of GD and might support the development of new immunomodulatory treatment approaches. The aim of this study was to gain detailed insight into the composition of the peripheral blood lymphocyte compartment in GD before and during anti-thyroid drug therapy. Major B and T lymphocyte subpopulations were investigated by flow cytometry in peripheral blood from newly diagnosed GD patients (n = 5), GD patients treated with anti-thyroid drugs (n = 4), patients with recurrent GD (n = 7) and healthy controls (HC; n = 10). In GD patients, numbers of activated T lymphocytes [human leucocyte antigen D-related (HLA-DR)+ and CD25+] were increased. The B lymphocyte compartment in GD was characterized by significantly higher numbers of transitional (CD38highCD27−, P < 0·03) and pre-naive mature (CD38lowCD27−IgD+CD5+, P < 0·04) B lymphocytes, while memory populations were slightly decreased. The increased numbers of CD5+, transitional and pre-naive mature B lymphocytes correlated positively with fT4 plasma levels. GD is associated with increased numbers of activated T lymphocytes and transitional and pre-naive mature CD5+ B lymphocytes within the peripheral blood. The increase in CD5+ B lymphocytes was due mainly to an increase in transitional and pre-naive mature B lymphocytes. Increased fT4 plasma levels might be associated with this increase in transitional and pre-naive mature CD5+ B lymphocytes. PMID:23901889

  8. Lymphocyte subsets in healthy Malawians: implications for immunologic assessment of HIV infection in Africa.

    Science.gov (United States)

    Mandala, Wilson L; MacLennan, Jenny M; Gondwe, Esther N; Ward, Steven A; Molyneux, Malcolm E; MacLennan, Calman A

    2010-01-01

    CD4(+)T lymphocyte measurements are the most important indicator of mortality in HIV-infected individuals in resource-limited settings. There is currently a lack of comprehensive immunophenotyping data from African populations to guide the immunologic assessment of HIV infection. To quantify variation in absolute and relative lymphocyte subsets with age in healthy Malawians. Lymphocyte subsets in peripheral blood of 539 healthy HIV-uninfected Malawians stratified by age were enumerated by flow cytometry. B and T-lymphocyte and T-lymphocyte subset absolute concentrations peaked in early childhood then decreased to adult levels, whereas lymphocyte subset proportions demonstrated much less variation with age. Adult lymphocyte subsets were similar to those in developed countries. In contrast, high B-lymphocyte and CD8(+)T-lymphocyte levels among children under 2 years, relative to those in developed countries, resulted in low CD4(+)T-lymphocyte percentages that varied little between 0 and 5 years (35% to 39%). The CD4(+)T-lymphocyte percentages in 35% of healthy children under 1 year and 18% of children age 1 to 3 years were below the World Health Organization threshold defining immunodeficiency in HIV-infected children in resource-limited settings. Thirteen percent of healthy children under 18 months old had a CD4:CD8T-lymphocyte ratio <1.0, which is commonly associated with HIV infection. All immunologic parameters except absolute natural killer lymphocyte concentration varied significantly with age, and percentage and overall absolute CD4(+)T-lymphocyte counts were higher in females than males. Although lymphocyte subsets in Malawian adults are similar to those from developed countries, CD4(+)T-lymphocyte percentages in young children are comparatively low. These findings need to be considered when assessing the severity of HIV-related immunodeficiency in African children under 3 years. Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by

  9. Subacute lymphocytic thyroiditis after lobectomy in a patient with papillary thyroid carcinoma: a case report

    OpenAIRE

    Choi Young Sik; Han You Jin; Yeo Go Eun; Kwon Su Kyoung; Kim Bu Kyung; Park Yo-Han; Kim Sung Won; Chun Bong Kwon; Kong Eun Hee; Kim Jeong Hoon

    2013-01-01

    Abstract Introduction Subacute lymphocytic thyroiditis is anautoimmune thyroid disease presenting with transient thyrotoxicosis as well as transient hypothyroidism. Several factors have been thought to be the initiating event in subacute lymphocytic thyroiditis. However, subacute lymphocytic thyroiditis that develops after thyroid lobectomy has not yet been reported in the literature. We report a case of subacute lymphocytic thyroiditis after lobectomy in a patient with papillary thyroid carc...

  10. Radiosensitivity of peripheral blood lymphocytes in autoimmune disease

    Energy Technology Data Exchange (ETDEWEB)

    Harris, G. (Kennedy Inst. of Rheumatology, London (UK). Div. of Experimental Pathology); Cramp, W.A.; Edwards, J.C.; George, A.M.; Sabovljev, S.A.; Hart, L.; Hughes, G.R.V. (Hammersmith Hospital, London (UK)); Denman, A.M. (Northwich Park Hospital, Harrow (UK)); Yatvin, M.B. (Wisconsin Clinical Cancer Center, Madison (USA))

    1985-06-01

    The proliferation of peripheral blood lymphocytes, cultured with Con A, can be inhibited by ionizing radiation. Lymphocytes from patients with conditions associated with autoimmunity, such as rheumatoid arthritis, systemic lupus erythematosus and polymyositis, are more radiosensitive than those from healthy volunteers or patients with conditions not associated with autoimmunity. Nuclear material isolated from the lymphocytes of patients with autoimmune diseases is, on average, lighter in density than the nuclear material from most healthy controls. This difference in density is not related to increased sensitivity to ionizing radiation but the degree of post-irradiation change in density (lightening) is proportional to the initial density, i.e. more dense nuclear material always shows a greater upward shift after radiation. The recovery of pre-irradiation density of nuclear material, 1 h after radiation exposure, taken as an indication of DNA repair, correlates with the radiosensitivity of lymphocyte proliferation (Con A response); failure to return to pre-irradiation density being associated with increased sensitivity of proliferative response. These results require extension but, taken with previously reported studied of the effects of DNA methylating agents, support the idea that DNA damage and its defective repair could be important in the aetio-pathogenesis of autoimmune disease.

  11. Langerhans cells and subsets of lymphocytes in the nasal mucosa

    DEFF Research Database (Denmark)

    Hellquist-Dahl, B; Olsen, K E; Irander, K;

    1991-01-01

    Langerhans cells and different lymphocytes were studied in the nasal mucosa of 39 woodwork teachers and a control group of 14 healthy subjects. Ten of the woodwork teachers were sensitized as determined by skin prick test. A panel of different monoclonal antibodies was applied on the frozen nasal...

  12. Increased circulating apoptotic lymphocytes in children with Down syndrome

    NARCIS (Netherlands)

    Gemen, E.F.A.; Verstegen, R.H.J.; Leuvenink, J.; Vries, E. de

    2012-01-01

    Down syndrome (DS) resembles immunodeficiency with increased infections, auto-immune diseases, and hematological malignancies. Until now, immunological studies in DS mainly focused on T-lymphocytes. We recently described a profound B-lymphocytopenia in children with DS. This could be caused by incre

  13. FUNCTIONAL AORTIC STIFFNESS:ROLE OF CD4+ T LYMPHOCYTES

    Directory of Open Access Journals (Sweden)

    Beenish A. Majeed

    2015-08-01

    Full Text Available The immune system is suggested to be essential in vascular remodeling and stiffening. To study the dependence upon lymphocytes in vascular stiffening, we compared an angiotensin II-model of vascular stiffening in normal C57BL/6J mice with lymphocyte-deficient RAG 1-/- mice and additionally characterized the component of vascular stiffness due to vasoconstriction versus vascular remodeling. Chronic angiotensin II increased aortic pulse wave velocity, effective wall stiffness, and effective Young’s modulus in C57BL/6J mice by 3-fold but caused no change in the RAG 1-/- mice. These functional measurements were supported by aortic morphometric analysis. Adoptive transfer of CD4+ T helper lymphocytes restored the angiotensin II-mediated aortic stiffening in the RAG 1-/- mice. In order to account for the hydraulic versus material effects of angiotensin II on pulse wave velocity, subcutaneous osmotic pumps were removed after 21 days of angiotensin II-infusion in the WT mice to achieve normotensive values. The pulse wave velocity decreased from 3- to 2-fold above baseline values up to 7 days following pump removal. This study supports the pivotal role of the CD4+ T-lymphocytes in angiotensin II-mediated vascular stiffening and that angiotensin II-mediated aortic stiffening is due to the additive effect of active vascular smooth muscle vasoconstriction and vascular remodeling.

  14. Association of lymphocytic colitis and lactase deficiency in pediatric population.

    Science.gov (United States)

    Sun, Jihong; Lin, Jingmei; Parashette, Kalayan; Zhang, Jianjun; Fan, Rong

    2015-02-01

    Characterized by colonic mucosa intraepithelial lymphocytosis, lymphocytic colitis is primarily an entity presented in the middle-aged to elderly patient population. Very few large series of lymphocytic colitis of childhood occurrence are available in the medical literature. Ten cases each of lymphocytic colitis and of colonic lymphocytosis of other diagnosis, all with duodenal disaccharidases analysis data, were collected from the files of our institution. The electronic medical records were reviewed and multiple variables were analyzed. The ten patients with lymphocytic colitis presented with diarrhea. Of these, three had abdominal pain. The age range was 2-18 years. Nearly all patients were Caucasian (90%) and 70% were female. Endoscopically, most had normal appearing colonic mucosa. Significant past medical history, family medical history and associated comorbidities included celiac disease, Down syndrome, juvenile arthritis and other autoimmune diseases. Interestingly, the most revealing observation was that the majority of cases (80%) were associated with lactase deficiency and, for the most part, gastrointestinal symptoms improved simply by treatment with Lactaid or avoidance of dairy products. This association is statistically significant. Our clinicopathological study indicates that the typical pediatric patient is a female Caucasian. A large of portion of the patients had associated lactase deficiency and improved on Lactaid supplement alone.

  15. The antigen specific composition of melanoma tumor infiltrating lymphocytes?

    DEFF Research Database (Denmark)

    Hadrup, Sine Reker

    2012-01-01

    Large numbers of tumor associated antigens has been characterized, but only a minor fraction of these are recognized by tumor infiltrating lymphocytes of melanoma, although these have shown the ability to recognize tumor and provide tumor regression upon adoptive transfer. Thus the peptide...

  16. Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors

    DEFF Research Database (Denmark)

    Xochelli, Aliki; Baliakas, Panagiotis; Kavakiotis, Ioannis

    2017-01-01

    Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether...

  17. IAN family critically regulates survival and development of T lymphocytes.

    Directory of Open Access Journals (Sweden)

    Takeshi Nitta

    2006-04-01

    Full Text Available The IAN (immune-associated nucleotide-binding protein family is a family of functionally uncharacterized GTP-binding proteins expressed in vertebrate immune cells and in plant cells during antibacterial responses. Here we show that all eight IAN family genes encoded in a single cluster of mouse genome are predominantly expressed in lymphocytes, and that the expression of IAN1, IAN4, and IAN5 is significantly elevated upon thymic selection of T lymphocytes. Gain-of-function experiments show that the premature overexpression of IAN1 kills immature thymocytes, whereas short hairpin RNA-mediated loss-of-function studies show that IAN4 supports positive selection. The knockdown of IAN5 perturbs the optimal generation of CD4/CD8 double-positive thymocytes and reduces the survival of mature T lymphocytes. We also show evidence suggesting that IAN4 and IAN5 are associated with anti-apoptotic proteins Bcl-2 and Bcl-xL, whereas IAN1 is associated with pro-apoptotic Bax. Thus, the IAN family is a novel family of T cell-receptor-responsive proteins that critically regulate thymic development and survival of T lymphocytes and that potentially exert regulatory functions through the association with Bcl-2 family proteins.

  18. Iron Deficiency Impairs Intra-Hepatic Lymphocyte Mediated Immune Response.

    Directory of Open Access Journals (Sweden)

    Eliano Bonaccorsi-Riani

    Full Text Available Hepatic expression of iron homeostasis genes and serum iron parameters predict the success of immunosuppression withdrawal following clinical liver transplantation, a phenomenon known as spontaneous operational tolerance. In experimental animal models, spontaneous liver allograft tolerance is established through a process that requires intra-hepatic lymphocyte activation and deletion. Our aim was to determine if changes in systemic iron status regulate intra-hepatic lymphocyte responses. We used a murine model of lymphocyte-mediated acute liver inflammation induced by Concanavalin A (ConA injection employing mice fed with an iron-deficient (IrDef or an iron-balanced diet (IrRepl. While the mild iron deficiency induced by the IrDef diet did not significantly modify the steady state immune cell repertoire and systemic cytokine levels, it significantly dampened inflammatory liver damage after ConA challenge. These findings were associated with a marked decrease in T cell and NKT cell activation following ConA injection in IrDef mice. The decreased liver injury observed in IrDef mice was independent from changes in the gut microflora, and was replicated employing an iron specific chelator that did not modify intra-hepatic hepcidin secretion. Furthermore, low-dose iron chelation markedly impaired the activation of isolated T cells in vitro. All together, these results suggest that small changes in iron homeostasis can have a major effect in the regulation of intra-hepatic lymphocyte mediated responses.

  19. Signaling lymphocyte activating molecule (SLAM) expression in subacute sclerosing panencephalitis.

    Science.gov (United States)

    Piskin, A Kevser; Akpinar, Pinar; Muftuoglu, Sevda; Anlar, Banu

    2007-08-01

    Signaling lymphocyte activating molecule (SLAM) is a receptor for measles virus which also has immunomodulatory activity. We analyzed SLAM expression in mononuclear cells (MNC) of patients with SSPE (n=7) and control subjects (n=7) from the same population. Native 10% PAGE analysis in cell and brain tissue extracts followed by Western blotting using monoclonal anti-human SLAM showed four types of bands. Differences in the type and amount of SLAM expression were observed between SSPE and control cases. Lymphocytes of SSPE patients showed two types of SLAM bands in comparison to only one in control lymphocytes. Stimulation of cells with lipopolysaccharide (80 u/ml) and concanavalin A (1 microg/ml) in vitro led to the appearance of a second isoform in both groups. Brain homogenates of SSPE patients (n=2) displayed all four types of SLAM isoforms at significantly higher levels than those of control brains (n=2). Our results show native PAGE enables the detection of all SLAM isotypes. The expression of SLAM is increased in lymphocytes, monocytes, and brain tissues of SSPE patients.

  20. Telomerase contributes to fludarabine resistance in primary human leukemic lymphocytes.

    Science.gov (United States)

    Shawi, May; Chu, Tsz Wai; Martinez-Marignac, Veronica; Yu, Y; Gryaznov, Sergei M; Johnston, James B; Lees-Miller, Susan P; Assouline, Sarit E; Autexier, Chantal; Aloyz, Raquel

    2013-01-01

    We report that Imetelstat, a telomerase inhibitor that binds to the RNA component of telomerase (hTR), can sensitize primary CLL lymphocytes to fludarabine in vitro. This effect was observed in lymphocytes from clinically resistant cases and with cytogenetic abnormalities associated with bad prognosis. Imetelstat mediated-sensitization to fludarabine was not associated with telomerase activity, but with the basal expression of Ku80. Since both Imetelstat and Ku80 bind hTR, we assessed 1) if Ku80 and Imetelstat alter each other's binding to hTR in vitro and 2) the effect of an oligonucleotide complementary to the Ku binding site in hTR (Ku oligo) on the survival of primary CLL lymphocytes exposed to fludarabine. We show that Imetelstat interferes with the binding of Ku70/80 (Ku) to hTR and that the Ku oligo can sensitize CLL lymphocytes to FLU. Our results suggest that Ku binding to hTR may contribute to fludarabine resistance in CLL lmphocytes. This is the first report highlighting the potentially broad effectiveness of Imetelstat in CLL, and the potential biological and clinical implications of a functional interaction between Ku and hTR in primary human cancer cells.

  1. Telomerase contributes to fludarabine resistance in primary human leukemic lymphocytes.

    Directory of Open Access Journals (Sweden)

    May Shawi

    Full Text Available We report that Imetelstat, a telomerase inhibitor that binds to the RNA component of telomerase (hTR, can sensitize primary CLL lymphocytes to fludarabine in vitro. This effect was observed in lymphocytes from clinically resistant cases and with cytogenetic abnormalities associated with bad prognosis. Imetelstat mediated-sensitization to fludarabine was not associated with telomerase activity, but with the basal expression of Ku80. Since both Imetelstat and Ku80 bind hTR, we assessed 1 if Ku80 and Imetelstat alter each other's binding to hTR in vitro and 2 the effect of an oligonucleotide complementary to the Ku binding site in hTR (Ku oligo on the survival of primary CLL lymphocytes exposed to fludarabine. We show that Imetelstat interferes with the binding of Ku70/80 (Ku to hTR and that the Ku oligo can sensitize CLL lymphocytes to FLU. Our results suggest that Ku binding to hTR may contribute to fludarabine resistance in CLL lmphocytes. This is the first report highlighting the potentially broad effectiveness of Imetelstat in CLL, and the potential biological and clinical implications of a functional interaction between Ku and hTR in primary human cancer cells.

  2. Paraneoplastic pemphigus as the initial presentation of chronic lymphocytic leukemia

    NARCIS (Netherlands)

    van Mook, WNKA; Fickers, MMF; Theunissen, PHMH; vander Kley, JAMJ; Duijvestijn, JA; Pas, HH; Flikweert, DC

    2001-01-01

    The case history of a 61-year-old male patient is described, who presented with severe stomatitis, conjunctivitis and leukocytosis. The diagnosis chronic lymphocytic leukemia (CLL) stage A (0) was made, for which no treatment was necessary. Progression of stomatitis and conjunctivitis and erythosqua

  3. Effects of a Simulated Tennis Match on Lymphocyte Subset Measurements

    Science.gov (United States)

    Schafer, Mark; Kell, Holly; Navalta, James; Tibana, Ramires; Lyons, Scott; Arnett, Scott

    2014-01-01

    Tennis is an activity requiring both endurance and anaerobic components, which could have immunosuppressive effects postexercise. Purpose: The purpose of this investigation was to determine the effect of a simulated tennis match on apoptotic and migratory markers on lymphocyte subsets. Method: Male high school (n = 5) and college (n = 3) tennis…

  4. Invasive aspergillosis related to ibrutinib therapy for chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Benjamin Arthurs, MD

    2017-01-01

    Full Text Available We report a case of invasive pulmonary aspergillosis in a patient taking ibrutinib, a Bruton's tyrosine kinase inhibitor used to treat refractory chronic lymphocytic leukemia. We hypothesize that ibrutinib promoted this infection by suppressing innate immune responses against Aspergillus. Clinicians should be aware of potential Aspergillus infections in patients treated with this drug.

  5. Role of Circulating Lymphocytes in Patients with Sepsis

    Directory of Open Access Journals (Sweden)

    Raul de Pablo

    2014-01-01

    Full Text Available Sepsis is a systemic inflammatory response syndrome due to infection. The incidence rate is estimated to be up to 19 million cases worldwide per year and the number of cases is rising. Infection triggers a complex and prolonged host response, in which both the innate and adaptive immune response are involved. The disturbance of immune system cells plays a key role in the induction of abnormal levels of immunoregulatory molecules. Furthermore, the involvement of effector immune system cells also impairs the host response to the infective agents and tissue damage. Recently, postmortem studies of patients who died of sepsis have provided important insights into why septic patients die and showed an extensive depletion of CD4 and CD8 lymphocytes and they found that circulating blood cells showed similar findings. Thus, the knowledge of the characterization of circulating lymphocyte abnormalities is relevant for the understanding of the sepsis pathophysiology. In addition, monitoring the immune response in sepsis, including circulating lymphocyte subsets count, appears to be potential biomarker for predicting the clinical outcome of the patient. This paper analyzes the lymphocyte involvement and dysfunction found in patients with sepsis and new opportunities to prevent sepsis and guide therapeutic intervention have been revealed.

  6. Increased circulating apoptotic lymphocytes in children with Down syndrome

    NARCIS (Netherlands)

    Gemen, E.F.A.; Verstegen, R.H.J.; Leuvenink, J.; Vries, E. de

    2012-01-01

    Down syndrome (DS) resembles immunodeficiency with increased infections, auto-immune diseases, and hematological malignancies. Until now, immunological studies in DS mainly focused on T-lymphocytes. We recently described a profound B-lymphocytopenia in children with DS. This could be caused by

  7. The expanding role of bendamustine in chronic lymphocytic leukemia

    OpenAIRE

    Nair KS; Ujjani C

    2015-01-01

    Kruti Sheth Nair, Chaitra Ujjani Lombardi Comprehensive Cancer Center, Medstar Georgetown University Hospital, Washington, DC, USA Abstract: As the most prevalent form of adult leukemia, chronic lymphocytic leukemia (CLL) affects thousands of patients each year. Given the indolent nature of the disease, symptomatic patients frequently experience multiple relapses throughout their clinical course. Better therapeutic options are needed, particularly for the elderly population that characterize...

  8. Growing B Lymphocytes in a Three-Dimensional Culture System

    Science.gov (United States)

    Wu, J. H. David; Bottaro, Andrea

    2010-01-01

    A three-dimensional (3D) culture system for growing long-lived B lymphocytes has been invented. The capabilities afforded by the system can be expected to expand the range of options for immunological research and related activities, including testing of immunogenicity of vaccine candidates in vitro, generation of human monoclonal antibodies, and immunotherapy. Mature lymphocytes, which are the effectors of adaptive immune responses in vertebrates, are extremely susceptible to apoptotic death, and depend on continuous reception of survival-inducing stimulation (in the forms of cytokines, cell-to-cell contacts, and antigen receptor signaling) from the microenvironment. For this reason, efforts to develop systems for long-term culture of functional, non-transformed and non-activated mature lymphocytes have been unsuccessful until now. The bone-marrow microenvironment supports the growth and differentiation of many hematopoietic lineages, in addition to B-lymphocytes. Primary bone-marrow cell cultures designed to promote the development of specific cell types in vitro are highly desirable experimental systems, amenable to manipulation under controlled conditions. However, the dynamic and complex network of stromal cells and insoluble matrix proteins is disrupted in prior plate- and flask-based culture systems, wherein the microenvironments have a predominantly two-dimensional (2D) character. In 2D bone-marrow cultures, normal B-lymphoid cells become progressively skewed toward precursor B-cell populations that do not retain a normal immunophenotype, and such mature B-lymphocytes as those harvested from the spleen or lymph nodes do not survive beyond several days ex vivo in the absence of mitogenic stimulation. The present 3D culture system is a bioreactor that contains highly porous artificial scaffolding that supports the long-term culture of bone marrow, spleen, and lymph-node samples. In this system, unlike in 2D culture systems, B-cell subpopulations developing

  9. Automated Scoring and Analysis of Micronucleated Human Lymphocytes.

    Science.gov (United States)

    Callisen, Hannes Heinrich

    Physical and chemical mutagens and carcinogens in our environment produce chromosome abberations in the circulating peripheral blood lymphocytes. The abberations, in turn, give rise to micronuclei when the lymphocytes proliferate in culture. In order to improve the micronucleus assay as a method for screening human populations for chromosome damage, I have (1) developed a high-resolution optical low-light-level micrometry expert system (HOLMES) to digitize and process microscope images of micronuclei in human peripheral blood lymphocytes, (2) defined a protocol of image processing techniques to objectively and uniquely identify and score micronuclei, and (3) analysed digital images of lymphocytes in order to study methods for (a) verifying the identification of suspect micronuclei, (b) classifying proliferating and non-proliferating lymphocytes, and (c) understanding the mechanisms of micronuclei formation and micronuclei fate during cell division. For the purpose of scoring micronuclei, HOLMES promises to (a) improve counting statistics since a greater number of cells can be scored without operator/microscopist fatigue, (b) provide for a more objective and consistent criterion for the identification of micronuclei than the human observer, and (c) yield quantitative information on nuclear and micronuclear characteristics useful in better understanding the micronucleus life cycle. My results on computer aided identification of micronuclei on microscope slides are gratifying. They demonstrate that automation of the micronucleus assay is feasible. Manual verification of HOLMES' results show correct extraction of micronuclei from the scene for 70% of the digitized images and correct identification of the micronuclei for 90% of the extracted objects. Moreover, quantitative analysis on digitized images of lymphocytes using HOLMES has revealed several exciting results: (a) micronuclear DNA content may be estimated from simple area measurements, (b) micronuclei seem to

  10. File list: ALL.Bld.20.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  17. File list: Oth.Bld.10.AllAg.T-Lymphocytes,_Regulatory [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  18. File list: Pol.Bld.10.AllAg.T-Lymphocytes,_Regulatory [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  19. File list: Oth.Bld.50.AllAg.T-Lymphocytes,_Regulatory [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  20. File list: Oth.Bld.50.AllAg.T-Lymphocytes,_Regulatory [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  1. File list: DNS.Bld.10.AllAg.T-Lymphocytes,_Regulatory [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  2. File list: DNS.Bld.05.AllAg.T-Lymphocytes,_Regulatory [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  3. File list: Pol.Bld.05.AllAg.T-Lymphocytes,_Regulatory [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  4. File list: DNS.Bld.05.AllAg.T-Lymphocytes,_Regulatory [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  5. File list: Pol.Bld.50.AllAg.T-Lymphocytes,_Regulatory [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  6. File list: DNS.Bld.20.AllAg.T-Lymphocytes,_Regulatory [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  7. File list: ALL.Bld.50.AllAg.T-Lymphocytes,_Regulatory [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  8. File list: Pol.Bld.50.AllAg.T-Lymphocytes,_Regulatory [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  9. File list: Unc.Bld.10.AllAg.T-Lymphocytes,_Regulatory [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  10. File list: Pol.Bld.05.AllAg.T-Lymphocytes,_Regulatory [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  11. File list: Oth.Bld.05.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  12. File list: Oth.Bld.50.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  13. File list: Unc.Bld.20.AllAg.Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  14. File list: Oth.Bld.20.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  15. File list: DNS.Bld.10.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available DNS.Bld.10.AllAg.B-Lymphocytes hg19 DNase-seq Blood B-Lymphocytes ERX337094,SRX1894...09,SRX189387 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/DNS.Bld.10.AllAg.B-Lymphocytes.bed ...

  16. File list: InP.Bld.50.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Bld.50.AllAg.T-Lymphocytes hg19 Input control Blood T-Lymphocytes SRX1425818,SR...X1425819,SRX1425817 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Bld.50.AllAg.T-Lymphocytes.bed ...

  17. File list: ALL.Bld.05.AllAg.Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  18. File list: His.Bld.50.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Bld.50.AllAg.T-Lymphocytes mm9 Histone Blood T-Lymphocytes SRX467476,SRX648139,...8,SRX021892,SRX648141,SRX484261,SRX484258,SRX484263,SRX484259,SRX021891 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/His.Bld.50.AllAg.T-Lymphocytes.bed ...

  19. File list: Pol.Bld.05.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Bld.05.AllAg.B-Lymphocytes hg19 RNA polymerase Blood B-Lymphocytes SRX170357 ht...tp://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Pol.Bld.05.AllAg.B-Lymphocytes.bed ...

  20. File list: His.Bld.05.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  1. File list: InP.Bld.05.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Bld.05.AllAg.T-Lymphocytes mm9 Input control Blood T-Lymphocytes SRX484257,SRX4...X132017 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/InP.Bld.05.AllAg.T-Lymphocytes.bed ...

  2. File list: Unc.Bld.05.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Bld.05.AllAg.B-Lymphocytes mm9 Unclassified Blood B-Lymphocytes SRX398229,SRX20...5602,SRX186173 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Unc.Bld.05.AllAg.B-Lymphocytes.bed ...

  3. File list: Unc.Bld.05.AllAg.Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  4. File list: Oth.Bld.20.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.20.AllAg.T-Lymphocytes mm9 TFs and others Blood T-Lymphocytes SRX646168,SRX...SRX132012,SRX041283,SRX041282,SRX041284 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.20.AllAg.T-Lymphocytes.bed ...

  5. File list: Oth.Bld.10.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  6. File list: His.Bld.20.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  7. File list: ALL.Bld.10.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  8. File list: InP.Bld.05.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  9. File list: His.Bld.50.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  10. File list: ALL.Bld.50.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  11. File list: ALL.Bld.05.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  12. File list: ALL.Bld.05.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  13. File list: Pol.Bld.10.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  14. File list: InP.Bld.20.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  15. File list: ALL.Bld.50.AllAg.Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  16. File list: ALL.Bld.10.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  17. File list: Oth.Bld.10.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  18. File list: His.Bld.20.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Bld.20.AllAg.T-Lymphocytes mm9 Histone Blood T-Lymphocytes SRX467476,SRX648139,...8,SRX648141,SRX021891,SRX021892,SRX484261,SRX484263,SRX484258,SRX484259 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/His.Bld.20.AllAg.T-Lymphocytes.bed ...

  19. File list: His.Bld.05.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Bld.05.AllAg.B-Lymphocytes hg19 Histone Blood B-Lymphocytes SRX730824,SRX730843...6,SRX730832,SRX170352 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/His.Bld.05.AllAg.B-Lymphocytes.bed ...

  20. File list: ALL.Bld.50.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  1. File list: NoD.Bld.05.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  2. File list: NoD.Bld.10.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  3. File list: Oth.Bld.50.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  4. File list: His.Bld.10.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Bld.10.AllAg.T-Lymphocytes mm9 Histone Blood T-Lymphocytes SRX467476,SRX648139,...8,SRX648141,SRX021892,SRX484263,SRX484258,SRX484261,SRX484259,SRX021891 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/His.Bld.10.AllAg.T-Lymphocytes.bed ...

  5. File list: NoD.Bld.20.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available NoD.Bld.20.AllAg.B-Lymphocytes mm9 No description Blood B-Lymphocytes SRX338804,SRX...RX347812,SRX347811,SRX347813 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/NoD.Bld.20.AllAg.B-Lymphocytes.bed ...

  6. File list: ALL.Bld.10.AllAg.Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  7. File list: Unc.Bld.10.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Bld.10.AllAg.T-Lymphocytes mm9 Unclassified Blood T-Lymphocytes SRX398234,SRX14...1252,SRX141254 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Unc.Bld.10.AllAg.T-Lymphocytes.bed ...

  8. File list: InP.Bld.20.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  9. File list: ALL.Bld.20.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  10. File list: ALL.Bld.10.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Bld.10.AllAg.T-Lymphocytes hg19 All antigens Blood T-Lymphocytes SRX1425818,SRX...8 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Bld.10.AllAg.T-Lymphocytes.bed ...

  11. File list: InP.Bld.50.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Bld.50.AllAg.T-Lymphocytes mm9 Input control Blood T-Lymphocytes SRX484257,SRX1...X132020 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/InP.Bld.50.AllAg.T-Lymphocytes.bed ...

  12. File list: ALL.Bld.05.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Bld.05.AllAg.B-Lymphocytes hg19 All antigens Blood B-Lymphocytes ERX200498,SRX7...996,SRX722331,SRX189409,SRX189387,SRX730816,SRX730836,SRX730832,SRX170352,ERX297444 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Bld.05.AllAg.B-Lymphocytes.bed ...

  13. Abnormalities of lymphocyte function and phenotypic pattern in a case of toxic epidermal necrolysis

    DEFF Research Database (Denmark)

    Hagdrup, H; Tønnesen, E; Clemmensen, O

    1992-01-01

    We examined the blood lymphocyte function and phenotypic pattern in a patient with toxic epidermal necrolysis after taking salazopyrin. We studied cell surface markers, natural killer cell activity and mitogen-induced lymphocyte transformation. Our results point to temporary immunosuppression...... as evidenced by lymphopenia with a large "null cell" population, reduced natural killer cell activity, and impaired lymphocyte response to mitogens....

  14. File list: Oth.Bld.05.AllAg.T-Lymphocytes [Chip-atlas[Archive

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  15. File list: DNS.Bld.10.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  16. File list: DNS.Bld.50.AllAg.B-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  17. File list: Unc.Bld.50.AllAg.T-Lymphocytes [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  20. File list: DNS.Bld.50.AllAg.B-Lymphocytes [Chip-atlas[Archive

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  1. File list: Pol.Bld.20.AllAg.T-Lymphocytes,_Regulatory [Chip-atlas[Archive

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  5. File list: Unc.Bld.10.AllAg.T-Lymphocytes,_Regulatory [Chip-atlas[Archive

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  6. File list: Pol.Bld.10.AllAg.T-Lymphocytes,_Regulatory [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  7. Suppression of lymphocyte proliferation by parainfluenza virus type 3-infected bovine alveolar macrophages.

    Science.gov (United States)

    Basaraba, R J; Brown, P R; Laegreid, W W; Silflow, R M; Evermann, J F; Leid, R W

    1993-06-01

    Lymphocytes stimulated with concanavalin A (Con A) or antigen in the presence of bovine parainfluenza virus type 3 (PIV-3) infected bovine alveolar macrophages (BAM) or monocytes, had depressed [3H]thymidine incorporation. This failure of lymphocytes to incorporate radiolabel required live virus, was time dependent and was most pronounced when BAM were infected for 48 hr prior to the addition of lymphocytes. The rate of infection of alveolar macrophages and the release of infectious virus into culture supernatants paralleled suppression of lymphocyte mitogenesis by PIV-3. However, the peak titre of exogenous, live or inactivated virus was not suppressive when added to lymphocyte macrophage cultures just prior to Con A stimulation. Neither the loss of viable alveolar macrophages nor a shift in antigen or mitogen dose response in virally infected cultures could account for the deficit in [3H]thymidine incorporation by lymphocytes. Despite the presence of lymphocyte-associated virus antigen detected by direct immunofluorescence, no increase in PIV-3 titre above baseline was seen from infected lymphocytes, irrespective of mitogen stimulation. Likewise, lymphocytes did not contribute to the extracellular virus pool in lymphocyte-macrophage cultures as the increases in viral titre above basal levels in supernatants were equal to levels released by macrophages alone. The expression of viral antigen on lymphocytes stimulated in the presence of PIV-3-infected BAM suggests a non-productive or abortive infection of lymphocytes mediated through contact with infected macrophages.

  8. Long intergenic noncoding RNAs: novel drivers of human lymphocyte differentiation

    Directory of Open Access Journals (Sweden)

    Ilaria ePanzeri

    2015-04-01

    Full Text Available Upon recognition of a foreign antigen, CD4+ naïve T lymphocytes proliferate and differentiate into subsets with distinct functions. This process is fundamental for the proper immune system function, as CD4+ T cells orchestrate both the innate and adaptive immune response. Traditionally, this differentiation event has been regarded as the acquisition of an irreversible cell fate so that memory and effector CD4+ T subsets were considered terminally differentiated cells or lineages. Consequently, these lineages are conventionally defined thanks to their prototypical set of cytokines and transcription factors. However, recent findings suggest that CD4+ T lymphocytes possess a remarkable phenotypic plasticity, as they can often redirect their functional program depending on the milieu they encounter. Therefore new questions are now compelling such as which are the molecular determinants underlying plasticity and stability and how the balance between these two opposite forces drives the cell fate. As already mentioned, in some cases the mere expression of cytokines and master regulators could not fully explain lymphocytes plasticity. We should consider other layers of regulation, including epigenetic factors such as the modulation of chromatin state or the transcription of noncoding RNAs, whose high cell-specificity give a hint on their involvement in cell fate determination. In this review, we will focus on the recent advances in understanding CD4+ T lymphocytes subsets specification from an epigenetic point of view. In particular, we will emphasize the emerging importance of noncoding RNAs as key players in these differentiation events. We will also present here new data from our laboratory highlighting the contribution of long noncoding RNAs in driving human CD4+ T lymphocytes differentiation.

  9. Utility of DF-1 for Radioprotection in Lymphocytes

    Science.gov (United States)

    Reynolds, Julia; Casey, Rachael; Wu, Honglu; Huff, Janice; Emami, Kamal; Moore, Valerie; Jeevarajan, Antony

    2007-01-01

    The development of degenerative changes in the vasculature, such as atherosclerosis, is a known consequence of exposure to ionizing radiation, and is thus a concern for astronaut health following long duration space flight. Cellular damage caused by radiation is due to free radical generation and DNA damage. The goal of this project was to assess the ability of a C60-derivative, DF-1, to mitigate cellular damage resulting from radiation exposure in primary human lymphocytes. DF-1 is a water-soluble C60 fullerene encapsulated in dendrimeric functional groups that is proposed to exhibit antioxidant properties. Human lymphocytes are radiosensitive and travel throughout the body potentially causing bystander effects in any tissues they contact. These cells were subjected to varying doses of gamma radiation in the presence or absence of DF-1. Cells were collected at 48 hours post-irradiation for chromosomal aberration studies and at 72 hours post-irradiation for micronuclei studies. These studies showed that the irradiated cells contained more chromosomal aberrations and micronuclei than the control cells. Addition of the DF-1 reduced the amount of observed DNA damage in the irradiated cells. Growth curves were measured for the lymphocytes exposed to 0 and 4 Gray gamma irradiations, and we observed less growth in the cells irradiated at 4 Gy. 2,7-dichlorofluorescein diacetate was used to detect reactive oxygen species production, and increased production of ROS was observed in the irradiated lymphocytes. Human lymphocytes were subjected to varying doses of gamma or photon radiation in the presence and absence of DF-1 and a known radioprotectant, amifostine. After irradiation, the production of reactive oxygen species, growth curves and cell viability were measured. These cells were also collected to quantify chromosomal aberrations and micronuclei formation. We predict that irradiated cells will show the most damage and that DF-1 will provide protective effects similar

  10. Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios: are they useful for predicting gestational diabetes mellitus during pregnancy?

    Directory of Open Access Journals (Sweden)

    Sargın MA

    2016-04-01

    Full Text Available Mehmet Akif Sargın, Murat Yassa, Bilge Dogan Taymur, Ayhan Celik, Emrah Ergun, Niyazi Tug Department of Obstetrics and Gynecology, Fatih Sultan Mehmet Research and Training Hospital, Istanbul, Turkey Objective: We aimed to investigate whether the neutrophil-to-lymphocyte ratio (NLR and platelet-to-lymphocyte ratio (PLR could be utilized to screen for gestational diabetes mellitus (GDM.Subjects and methods: NLR and PLR were assessed by retrospective analysis of 762 healthy and pregnant women with GDM. The patients were stratified into four groups, as follows: GDM (n=144, impaired glucose tolerance (n=76, only screen positive (n=238, and control (n=304.Results: The leukocyte, neutrophil, and lymphocyte counts were significantly higher in the study groups compared with the control group (P=0.001; P<0.01. There were no statistically significant differences between the groups with respect to the NLR and PLR (P>0.05.Conclusion: We do not recommend that blood NLR and PLR can be used to screen for GDM. However, increase in the leukocyte count is an important marker for GDM as it provides evidence of subclinical inflammation. Keywords: inflammation, lymphocytes, neutrophils, platelets, pregnancy

  11. CLONAL CHRONIC LYMPHOCYTIC LEUKEMIA-LIKE B-LYMPHOCYTES IN THE BLOOD OF PATIENTS WITH CUTANEOUS T-CELL DISORDERS

    NARCIS (Netherlands)

    DAENEN, S; VADER, PCV; BLOM, N; PIETENS, J; HOLLEMA, H; SMIT, JW

    1993-01-01

    A population of B cells with characteristics of chronic lymphocytic leukaemia was found in the peripheral blood of four patients who presented with cutaneous infiltration of atypical CD4+ T cells with cerebriform nuclei. The B cells had a low density of immunoglobulin on their surface membrane, expr

  12. Predictive role of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios for diagnosis of acute appendicitis during pregnancy

    Directory of Open Access Journals (Sweden)

    Fatih Mehmet Yazar

    2015-11-01

    Full Text Available Acute appendicitis (AA is not uncommon during pregnancy but can be difficult to diagnose. This study evaluated the neutrophil-to-lymphocyte ratio (NLR and platelet-to-lymphocyte ratio (PLR in addition to conventional diagnostic indicators of the disease to diagnose AA during pregnancy. Age, gestational age, white blood cell (WBC count, Alvarado scores, C-reactive protein (CRP, lymphocyte count, NLR and PLR were compared among 28 pregnant women who underwent surgery for AA, 35 pregnant women wrongly suspected as having AA, 29 healthy pregnant women, and 30 nonpregnant healthy women. Mean WBC counts and CRP levels were higher in women with proven AA than in those of control groups (all p < 0.05. Among all the groups, the median NLR and PLR were significantly different in women with proven AA (all p < 0.05. Receiver operating characteristic analysis was used to determine cut-off values for WBC count, CRP, lymphocyte count, NLR and PLR, and multiple logistic regression analysis showed that NLR and PLR used with routine methods could diagnose AA with 90.5% accuracy. Used in addition to routine diagnostic methods, NLR and PLR increased the accuracy of the diagnosis of AA in pregnant women.

  13. Non-apical membrane antigen 1 (AMA1 IgGs from Malian children interfere with functional activity of AMA1 IgGs as judged by growth inhibition assay.

    Directory of Open Access Journals (Sweden)

    Kazutoyo Miura

    Full Text Available BACKGROUND: Apical membrane antigen 1 (AMA1 is one of the best-studied blood-stage malaria vaccine candidates. When an AMA1 vaccine was tested in a malaria naïve population, it induced functionally active antibodies judged by Growth Inhibition Assay (GIA. However, the same vaccine failed to induce higher growth-inhibitory activity in adults living in a malaria endemic area. Vaccination did induce functionally active antibodies in malaria-exposed children with less than 20% inhibition in GIA at baseline, but not in children with more than that level of baseline inhibition. METHODS: Total IgGs were purified from plasmas collected from the pediatric trial before and after immunization and pools of total IgGs were made. Another set of total IgGs was purified from U.S. adults immunized with AMA1 (US-total IgG. From these total IgGs, AMA1-specific and non-AMA1 IgGs were affinity purified and the functional activity of these IgGs was evaluated by GIA. Competition ELISA was performed with the U.S.-total IgG and non-AMA1 IgGs from malaria-exposed children. RESULTS: AMA1-specific IgGs from malaria-exposed children and U.S. vaccinees showed similar growth-inhibitory activity at the same concentrations. When mixed with U.S.-total IgG, non-AMA1 IgGs from children showed an interference effect in GIA. Interestingly, the interference effect was higher with non-AMA1 IgGs from higher titer pools. The non-AMA1 IgGs did not compete with anti-AMA1 antibody in U.S.-total IgG in the competition ELISA. CONCLUSION: Children living in a malaria endemic area have a fraction of IgGs that interferes with the biological activity of anti-AMA1 antibody as judged by GIA. While the mechanism of interference is not resolved in this study, these results suggest it is not caused by direct competition between non-AMA1 IgG and AMA1 protein. This study indicates that anti-malaria IgGs induced by natural exposure may interfere with the biological effect of antibody induced by an AMA1

  14. Cytotoxicity of lymphocytes from melanoma patients against autologous tumor cells and its potentiation in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Bykovskaya, S.N.; Iobadze, M.S.; Kupriyanova, T.A.; Demidov, L.V.

    1987-06-01

    The specific and natural cytotoxicity of peripheral blood lymphocytes from patients with melanomas was compared and stimulation with autologous tumor cells or a pool of allogeneic lymphocytes from five healthy blood donors also was used to potentiate the specific antitumor activity of the patients' lymphocytes. To assess cytolytic ability, cells of an autologous tumor, cells of the K-562 line, autologous peripheral blood lymphocytes, and blast cells obtained from these lymphocytes after stimulation by phytohemagglutinin were used as the target cells. The target cells were incubated in a medium containing sodium chromate and were labelled with the chromium 51 isotope.

  15. Coexistence of primary myelofibrosis and chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Burgstaller S

    2014-10-01

    Full Text Available Sonja Burgstaller, Josef Thaler Klinikum Wels-Grieskirchen, Abteilung für Innere Medizin IV, Wels, AustriaAbstract: Coexistence of two hematologic malignancies in one patient is generally a rare phenomenon. The topic of this article is the coincidence of primary myelofibrosis and chronic lymphocytic leukemia, which has been reported up to now in only 16 patients. In summary, simultaneous detection of both diseases was notable in half of the patients at presentation. In the case of a subsequent diagnosis of both disorders, primary myelofibrosis preceded the lymphoproliferative disease in the majority of patients. The clinical course seems to be more benign than for each disorder itself. A substantial proportion of patients did not require any treatment at all. Knowledge about the pathogenetic mechanisms, treatment approaches, and prognosis of these patients is limited.Keywords: primary myelofibrosis, chronic lymphocytic leukemia, coexistent

  16. Lymphocytic mural folliculitis and pancreatic carcinoma in a cat.

    Science.gov (United States)

    Lobetti, Remo

    2015-06-01

    A 9-year-old castrated domestic shorthair cat was presented with a 6 week history of progressive non-pruritic alopecia, polyphagia and weight loss. A diagnosis of lymphocytic mural folliculitis was made and the cat was treated with a combination of prednisolone and ciclosporin; this produced an improvement in the alopecia but no resolution. Sixteen months after the initial assessment and diagnosis, the cat was re-evaluated for intermittent vomiting and weight loss with normal appetite. On examination the dermatopathy was still evident and a mass involving the duodenum and pancreas was present, which was diagnosed as a pancreatic carcinoma. From this case it would appear that lymphocytic mural folliculitis might be an early dermatological manifestation of pancreatic neoplasia.

  17. Role of ofatumumab in treatment of chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Veliz M

    2011-05-01

    Full Text Available Marays Veliz, Javier Pinilla-IbarzH Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USAAbstract: The management of chronic lymphocytic leukemia (CLL has dramatically improved in the past decade with the addition of anti-CD20 monoclonal antibodies to the treatment armamentarium. Ofatumumab is a novel anti-CD20 monoclonal antibody recently approved in the US and Europe for the treatment of CLL refractory to alemtuzumab and fludarabine. Preclinical data showed improved complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity compared with rituximab. Clinical studies have shown single-agent activity for ofatumumab in CLL and in other low-grade non-Hodgkin's lymphomas. Combination studies are being conducted to enhance the therapeutic efficacy of ofatumumab. This paper reviews some of the key clinical studies that led to approval of ofatumumab, and future directions.Keywords: ofatumumab, chronic lymphocytic leukemia, efficacy, safety

  18. Imaging the choreography of lymphocyte trafficking and the immune response.

    Science.gov (United States)

    Cahalan, Michael D; Parker, Ian

    2006-08-01

    The functioning of the immune system depends upon exquisitely choreographed interactions between its cellular constituents. Two-photon microscopy now enables us to visualize cell motility and cell-cell interactions deep within intact tissues and organs, both in explanted preparations and in vivo. Real-time immunoimaging techniques have illuminated the roles of random and chemokine-driven motility for cellular search strategies, the complex dynamics of cellular interactions, and the micro-anatomical localization and control of lymphocyte trafficking. Recently, advances have been made in these areas of research, as exemplified by studies investigating T cell-dendritic cell interactions, T cell-B cell interactions, and the regulation of lymphocyte egress from the lymph node.

  19. Genotoxic effects of bistratene A on human lymphocytes.

    Science.gov (United States)

    Rojas, E; Valverde, M; Vega, L; Salvador, A; Ramirez, P; Herrera, L A; Watters, D; Lavin, M F; Ostrosky-Wegman, P

    1996-03-01

    Bistratene A, a toxin isolated from the colonial ascidian Lissoclinum bistratum causes a decrease in mitotic index and retardation of lymphocyte proliferation kinetics when it is added at 48 h to 72-h human lymphocyte cultures. In the same cultures, the incidence of sister chromatid exchanges was not altered by this compound. We also observed an increase in the number of polyploid cells in the cultures, and alterations of the beta-tubulin organization by immunocytochemistry with an antibody against beta-tubulin. Bistratene A induces DNA damage in a dose-dependent fashion in leukocytes, as measured by the alkaline single cell gel electrophoresis assay. These results show that bistratene A interferes with microtubule assembly, is cytotoxic and cytostatic, and that it causes DNA damage.

  20. Syk Inhibition with Fostamatinib Leads to Transitional B Lymphocyte Depletion

    Science.gov (United States)

    Barr, Paul M.; Wei, Chungwen; Roger, James; Schaefer-Cutillo, Julia; Kelly, Jennifer L.; Rosenberg, Alexander F.; Jung, John; Sanz, Iñaki; Friedberg, Jonathan W.

    2012-01-01

    Cell signaling initiated by the B cell receptor is critical to normal development of B lymphocytes, most notably at the transitional B cell stage. Inhibition of this signaling pathway with the syk inhibitor, fostamatinib, has produced significant efficacy in lymphoid malignancies and autoimmune conditions. Here, we demonstrate that short-term use of fostamatinib impairs B lymphocyte development at the transitional stage without affecting mature B cell populations. Additionally, IL-10 producing B cells remained relatively constant throughout the treatment period. These findings provide insight into the mechanism of action of B cell receptor inhibition in autoimmune disease. As the development of agents targeting B cell receptor signaling proceeds, monitoring for long-term consequences as well as functional evaluation of B cell subsets may further improve our understanding of this rapidly growing class of novel agents. PMID:22284392

  1. [239Pu and chromosomal aberrations in human peripheral blood lymphocytes].

    Science.gov (United States)

    Okladnikova, N D; Osovets, S V; Kudriavtseva, T I

    2009-01-01

    The genome status in somatic cells was assessed using the chromosomal aberration (CA) test in peripheral blood lymphocytes from 194 plutonium workers exposed to occupational radiation mainly from low-transportable compounds of airborne 230Pu. Pu body burden at the time of cytogenetic study varied from values close to the method sensitivity to values multiply exceeding the permissible level. Standard (routine) methods of peripheral blood lymphocytes cultivation were applied. Chromatid- and chromosomal-type structural changes were estimated. Aberrations were estimated per 100 examined metaphase cells. The quantitative relationship between the CA frequency and Pu body burden and the absorbed dose to the lung was found. Mathematical processing of results was carried out based on the phenomenological model. The results were shown as theoretical and experimental curves. The threshold of the CA yield was 0.43 +/- 0.03 kBq (Pu body burden) and 6.12 +/- 1.20 cGy (absorbed dose to the lung).

  2. Engineered lymphocytes to treat dinitrobenzene sulphonic acid colitis in mice.

    Science.gov (United States)

    Felley, Christian; Michetti, Pierre

    2003-12-01

    Current treatments of inflammatory bowel diseases are limited either by their lack of efficacy or their potential toxicity. In recent years, major advances have been obtained by the development of biological therapies. However, these types of treatment are systemic and can lead to serious adverse events. The new venue of local biological treatments would be most welcome. In this issue of the Journal, Castagliuolo et al. show that lymphocytes engineered to produce TGF-beta1 can reverse dinitrobenzene sulphonic acid-induced colitis in mice. These engineered lymphocytes selectively accumulate in the intestinal mucosa due to the homing properties of their alpha4beta7 integrins, a ligand for MAdCAM1. A local treatment restricted to the inflamed mucosa can thus be obtained. This opens a brand new area of research with the hope of restoring the immunoregulatory balance selectively in the inflamed tissues.

  3. Acute lymphocytic leukemia recurring in the spinal epidural space.

    Science.gov (United States)

    Higashida, Tetsuhiro; Kawasaki, Takashi; Sakata, Katsumi; Tanabe, Yutaka; Kanno, Hiroshi; Yamamoto, Isao

    2007-08-01

    A 27-year-old man presented with a very rare spinal epidural mass associated with recurrence of acute lymphocytic leukemia (ALL) manifesting as acute progressive neurological deficits. The patient presented with shoulder pain and ambulatory difficulties 3 years after remission of ALL treated by bone marrow transplantation. Magnetic resonance imaging revealed an epidural mass extending from C-7 to T-3, which compressed the cord and extended to the intervertebral foramen along the roots. After decompression surgery, the symptoms dramatically improved. Histological examination showed clusters of immature lymphocytes consistent with recurrence of leukemia, so chemotherapy and radiation therapy were carried out. At 1 year after the operation, no local mass expansion or systemic progression of leukemia had occurred. Leukemic mass must be considered in the differential diagnosis of spinal epidural mass, even in patients with ALL.

  4. The expanding role of bendamustine in chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Nair KS

    2015-07-01

    Full Text Available Kruti Sheth Nair, Chaitra Ujjani Lombardi Comprehensive Cancer Center, Medstar Georgetown University Hospital, Washington, DC, USA Abstract: As the most prevalent form of adult leukemia, chronic lymphocytic leukemia (CLL affects thousands of patients each year. Given the indolent nature of the disease, symptomatic patients frequently experience multiple relapses throughout their clinical course. Better therapeutic options are needed, particularly for the elderly population that characterizes the majority of affected patients. Bendamustine, a hybrid alkylating agent, has demonstrated remarkable activity in CLL in conjunction with a tolerable safety profile. Although historically used in relapsed and refractory disease, it has recently gained a role in the front-line setting, including younger, physically fit patients. Current investigatory efforts are focused on exploring the combination of bendamustine with novel therapies in CLL. Keywords: chronic lymphocytic leukemia, overall survival, aspartate aminotransferase, chlorambucil, bendamustine

  5. Glucose-dependent de Novo Lipogenesis in B Lymphocytes

    Science.gov (United States)

    Dufort, Fay J.; Gumina, Maria R.; Ta, Nathan L.; Tao, Yongzhen; Heyse, Shannon A.; Scott, David A.; Richardson, Adam D.; Seyfried, Thomas N.; Chiles, Thomas C.

    2014-01-01

    Bacterially derived lipopolysaccharide (LPS) stimulates naive B lymphocytes to differentiate into immunoglobulin (Ig)-secreting plasma cells. Differentiation of B lymphocytes is characterized by a proliferative phase followed by expansion of the intracellular membrane secretory network to support Ig production. A key question in lymphocyte biology is how naive B cells reprogram metabolism to support de novo lipogenesis necessary for proliferation and expansion of the endomembrane network in response to LPS. We report that extracellularly acquired glucose is metabolized, in part, to support de novo lipogenesis in response to LPS stimulation of splenic B lymphocytes. LPS stimulation leads to increased levels of endogenous ATP-citrate lyase (ACLY), and this is accompanied by increased ACLY enzymatic activity. ACLY produces cytosolic acetyl-CoA from mitochondrially derived citrate. Inhibition of ACLY activity in LPS-stimulated B cells with the selective inhibitor 2-hydroxy-N-arylbenzenesulfonamide (compound-9; C-9) blocks glucose incorporation into de novo lipid biosynthesis, including cholesterol, free fatty acids, and neutral and acidic phospholipids. Moreover, inhibition of ACLY activity in splenic B cells results in inhibition of proliferation and defective endomembrane expansion and reduced expression of CD138 and Blimp-1, markers for plasma-like B cell differentiation. ACLY activity is also required for LPS-induced IgM production in CH12 B lymphoma cells. These data demonstrate that ACLY mediates glucose-dependent de novo lipogenesis in response to LPS signaling and identify a role for ACLY in several phenotypic changes that define plasma cell differentiation. PMID:24469453

  6. Intramembrane particles and the organization of lymphocyte membrane proteins.

    Science.gov (United States)

    Kuby, J M; Wofsy, L

    1981-03-01

    An experimental system was developed in which the majority of all lymphocyte cell-surface proteins, regardless of antigenic specificity, could be cross-linked and redistributed in the membrane to determine whether this would induce a corresponding redistribution of intramembrane particles (IMP). Mouse spleen cells were treated with P-diazoniumphenyl- beta-D-lactoside (lac) to modify all exposed cell-surface proteins. Extensive azo- coupling was achieved without significantly reducing cell viability or compromising cellular function in mitogen- or antigen-stimulated cultures. When the lac-modified cell- surface proteins were capped with a sandwich of rabbit antilactoside antibody and fluorescein-goat anti-rabbit Ig, freeze-fracture preparations obtained from these cells revealed no obvious redistribution of IMP on the majority of fracture faces. However, detailed analysis showed a statistically significant 35 percent decrease (P less than 0.01) in average IMP density in the E face of the lac-capped spleen cells compared with control cells, whereas a few E-face micrographs showed intense IMP aggregation. In contrast, there was no significant alteration of P-face IMP densities or distribution. Apparently, the majority of E-face IMP and virtually all P-face IMP densities or distribution. Apparently, the majority of E-face IMP and virtually all P-face IMP do not present accessible antigenic sites on the lymphocyte surface and do not associate in a stable manner with surface protein antigens. This finding suggests that IMP, as observed in freeze-fracture analysis, may not comprise a representative reflection of lymphocyte transmembrane protein molecules and complexes because other evidence establishes: (a) that at least some common lymphocyte surface antigens are indeed exposed portions of transmembrane proteins and (b) that the aggregation of molecules of any surface antigen results in altered organization of contractile proteins at the cytoplasmic face of the membrane.

  7. A study of peripheral T-Lymphocytes in alopecia areata

    Directory of Open Access Journals (Sweden)

    Sharma R

    1995-01-01

    Full Text Available Estimation of peripheral T-lymphocytes (active and total was carried out in 100 cases of alopecia areata as per method described by Boyam (1977 and West et al (1978. Clinically patients were divided in two groups, alopecia areata circumscribed (group I and severe alopecia areata (group II. Thirty healthy subjects served as controls. Decrease in percentage of both active and total E-RFC was observed in 70% cases. The decrease was more significant in group II.

  8. T lymphocyte subset imbalances in patients contribute to ankylosing spondylitis

    Science.gov (United States)

    WANG, CHENGGONG; LIAO, QIANDE; HU, YIHE; ZHONG, DA

    2015-01-01

    Ankylosing spondylitis is a chronic inflammatory rheumatic disease, which is characterized by inflammation of the spine and the sacroiliac joints. To date, the disease etiology remains unclear. In the present study, the correlation of T lymphocyte subset changes with the progression of ankylosing spondylitis was investigated. A total of 55 patients with ankylosing spondylitis (22 severe and 23 mild cases) and 20 healthy individuals were selected. Firstly, the punctured cells in the lesions and the serum were collected, and the lymphocytes and the peripheral blood mononuclear cells were prepared. Secondly, quantitative PCR, ELISA and flow cytometry analyses were carried out to detect the levels of a series of immunoglobulins, complements, helper T cells, cytotoxic T cells, regulatory cells and cytokines. The expression levels of α-globulin, γ-globulin, immunoglobulin (Ig)G, IgA, IgM, serum complement C3, and complement C4 were found to be significantly increased in ankylosing spondylitis patients. In addition, the percentage of Th1 and Th17 cells was found to be significantly higher in the ankylosing spondylitis groups (mild and severe) compared with the healthy individuals. As a result, the Th1/Th2 and Th17/Treg ratios were significantly higher in patients with ankylosing spondylitis. In addition, T lymphocyte subset ratio imbalances contributed to an increased expression of immune mediators, including interferon (IFN)-γ and interleukin (IL)-17A. The mRNA and protein expression levels of IFN-γ and IL-17A were found to be higher in the ankylosing spondylitis groups compared with the control group. The present study provided further evidence on the function and underlying mechanism of T lymphocyte subsets, which may be useful in the diagnosis and treatment of ankylosing spondylitis. PMID:25452811

  9. T lymphocyte subset imbalances in patients contribute to ankylosing spondylitis.

    Science.gov (United States)

    Wang, Chenggong; Liao, Qiande; Hu, Yihe; Zhong, DA

    2015-01-01

    Ankylosing spondylitis is a chronic inflammatory rheumatic disease, which is characterized by inflammation of the spine and the sacroiliac joints. To date, the disease etiology remains unclear. In the present study, the correlation of T lymphocyte subset changes with the progression of ankylosing spondylitis was investigated. A total of 55 patients with ankylosing spondylitis (22 severe and 23 mild cases) and 20 healthy individuals were selected. Firstly, the punctured cells in the lesions and the serum were collected, and the lymphocytes and the peripheral blood mononuclear cells were prepared. Secondly, quantitative PCR, ELISA and flow cytometry analyses were carried out to detect the levels of a series of immunoglobulins, complements, helper T cells, cytotoxic T cells, regulatory cells and cytokines. The expression levels of α-globulin, γ-globulin, immunoglobulin (Ig)G, IgA, IgM, serum complement C3, and complement C4 were found to be significantly increased in ankylosing spondylitis patients. In addition, the percentage of Th1 and Th17 cells was found to be significantly higher in the ankylosing spondylitis groups (mild and severe) compared with the healthy individuals. As a result, the Th1/Th2 and Th17/Treg ratios were significantly higher in patients with ankylosing spondylitis. In addition, T lymphocyte subset ratio imbalances contributed to an increased expression of immune mediators, including interferon (IFN)-γ and interleukin (IL)-17A. The mRNA and protein expression levels of IFN-γ and IL-17A were found to be higher in the ankylosing spondylitis groups compared with the control group. The present study provided further evidence on the function and underlying mechanism of T lymphocyte subsets, which may be useful in the diagnosis and treatment of ankylosing spondylitis.

  10. Mechanisms and Consequences of Ebolavirus-Induced Lymphocyte Apoptosis

    Science.gov (United States)

    2011-01-31

    common finding in many other hemorrhagic fever viruses, in- cluding Lassa , Marburg, Crimean Congo hemorrhagic fever , and some Hantavirus infections... fever , resulting in death in up to 90% of infected humans. EBOVinfection induces massive bystander lymphocyte apoptosis; however, neither the cellular...Jonathan E. McDunn,‡ Richard S. Hotchkiss,‡ and Sina Bavari* Ebolavirus (EBOV) is a member of the filovirus family and causes severe hemorrhagic fever

  11. Bilateral lymphocytic alveolitis: a common reaction after unilateral thoracic irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Martin, C.; Romero, S.; Arriero, J.M.; Hernandez, L. [Hospital General Universitario, Servicios de Neumologia, Alicante (Spain); Sanchez-Paya, J. [Hospital General Universitario, Epidemiologia, Alicante (Spain); Massuti, B. [Hospital General Universitario, Oncologia, Alicante (Spain)

    1999-04-01

    The main aim of the present study was to assess the early diagnostic value of bronchoalveolar lavage (BAL) in radiation-induced lung injury in patients with breast carcinoma. Twenty-six females receiving postoperative radiotherapy for breast cancer were evaluated before and 0, 15, 30, 60 , and 180 days after radiotherapy. History, physical examination, chest radiographs, and pulmonary function tests were obtained. BAL, including lymphocyte subsets analysis, was limited to the second evaluation after radiotherapy. A group of 21 healthy females were used as control. Findings after radiotherapy in asymptomatic patients were compared with findings in a group of patients with radiation pneumonitis. Irradiated patients showed a significantly (p<0.01) greater percentage (29.5{+-}15.7%) of BAL lymphocytes than controls (6.2{+-}3.3%). No statistical differences existed in BAL findings between the irradiated and unirradiated sides of the chest. Percentages of BAL lymphocytes did not differ significantly between patients who developed subsequent pneumonitis (24.5{+-}13.5%) and those who did not develop pneumonitis (32.8{+-}16.5%). Patients with pneumonitis at the time of BAL had significantly higher (p<0.05) alveolar CD4 subset cells (24.8{+-}10.2%) than asymptomatic patients (15.2{+-}8.9%). Maximal reductions in total lung capacity (p<0.01), and residual volume (p<0.05) occurred 60 days after irradiation. The early lymphocytic alveolitis induced by unilateral thoracic radiotherapy in most patients with breast cancer is always bilateral and does not predict the subsequent development of radiological evidence of pneumonitis. (au) 38 refs.

  12. [Computer-assisted histocompatibility assessment in mixed lymphocyte culture (MLC)].

    Science.gov (United States)

    Schwartz, D; Hajek-Rosenmayr, A

    1987-02-20

    Analysis of the results of mixed lymphocyte culture (MLC) for compatibility testing preceding transplantation of bone marrow and other organs has so far required a vast input, both in terms of laboratory staff and work hours. We have developed a computer programme which performs this work rapidly. Graphics of the reaction patterns can be obtained, moreover, and these can prove a helpful tool in interpretation of the results.

  13. Gymnemic Acid Stimulates In Vitro Splenic Lymphocyte Proliferation.

    Science.gov (United States)

    Singh, Vineet Kumar; Dwivedi, Padmanabh; Chaudhary, B R; Singh, Ramesh

    2016-02-01

    Gymnemic acid is a mixture of triterpenoid saponins of oleanane class, isolated from Gymnema sylvestre Wild R.Br (family: Asclepidaceae), an herbal plant used in traditional medicine to treat diabetes. Effect of gymnemic acid (0.1-20 µg/mL) on in vitro mitogen (concanavalin A and lipopolysaccharide)-induced splenic lymphocyte proliferation was studied using rat as model. Significant (p sylvestre is scientifically supplemented with its immunomodulatory properties.

  14. The clinical implications of mixed lymphocyte reaction with leukemic cells.

    Science.gov (United States)

    Kim, Hee-Je; Kim, Tai-Gyu; Cho, Hyun Il; Han, Hoon; Min, Woo-Sung; Kim, Chun-Choo

    2002-11-01

    To evaluate the clinical implications of a mixed lymphocyte reaction between leukemic cells and lymphocytes from HLA-matched sibling donors, we attempted to generate donor-derived, graft-versus-leukemia-effective cells and to define their characteristics. We studied 8 patients with chronic myelogenous leukemia (CML), including 5 patients in the chronic phase (CP), 3 patients in the accelerated phase (AP), and 2 patients with acute myelogenous leukemia (AML) in their first complete remission. Cells from these patients were used as stimulators in a mixed lymphocyte reaction.The effects of natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs) were separated by observing tests for cytotoxicity to target cells, including K562 cells, the patient's leukemic cells, and phytohemagglutinin (PHA) blasts. Donor-derived antileukemic CTLs againstthe patient's own leukemic cells are productive in vitro. The efficacy of generating CTLs against leukemic target cells was (in decreasing order) AML, CML-CP, and CML-AP. Cytotoxic activity against leukemic targets was prominent in 4 cases--2 CML-CP and the 2 AML cases. On the contrary, the 3 cases of CML-AP showed low CTL activity. In cases showing 1 positive result among 3 targets (K562 cells, the patient's leukemic cells, and PHA blasts), the relapse rate was significantly lower (P = .022) on follow-up (median, 33 months; 7-40 months) after hematopoietic stem cell transplantation. By a combined analysis of the cytotoxicity effects for all 3 target cells, we were able to demonstrate a correlation between leukemic relapse and the variable degree of the cytotoxicity test results. Although the total sample numbers for this study were low, we speculate that these results may come from differences in the individual characteristics of the leukemic cells that are in line with their clinical disease status.

  15. Obinutuzumab treatment in the elderly patient with chronic lymphocytic leukemia

    OpenAIRE

    Seiter K; Mamorska-Dyga A

    2015-01-01

    Karen Seiter, Aleksandra Mamorska-DygaDepartment of Medicine, Division of Hematology/Oncology, New York Medical College, Valhalla, NY, USA Abstract: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in Western countries. Fludarabine-based regimens demonstrate higher response rates in younger patients but have a significant risk of infection and are thus poorly tolerated by older, frail patients. Anti-CD20 monoclonal antibodies have added to the efficacy of chemotherapy ...

  16. The cytotoxic T lymphocyte immune synapse at a glance.

    Science.gov (United States)

    Dieckmann, Nele M G; Frazer, Gordon L; Asano, Yukako; Stinchcombe, Jane C; Griffiths, Gillian M

    2016-08-01

    The immune synapse provides an important structure for communication with immune cells. Studies on immune synapses formed by cytotoxic T lymphocytes (CTLs) highlight the dynamic changes and specialised mechanisms required to facilitate focal signalling and polarised secretion in immune cells. In this Cell Science at a Glance article and the accompanying poster, we illustrate the different steps that reveal the specialised mechanisms used to focus secretion at the CTL immune synapse and allow CTLs to be such efficient and precise serial killers.

  17. In vitro genotoxicity of pyridine in human lymphocytes.

    Science.gov (United States)

    Emelnsia, Aida D; Rather, Irfan A

    2016-05-01

    This work was carried out to study the genotoxicity of pyridine in vitro on human leucocyte culture. Cyclophosphamide, a well-known carcinogen was used as positive control. The four different concentrations of pyridine and cyclophosphamide showed breaks and pulverization of chromosomes in dose dependent manner. Higher number of pulverization was observed with higher concentration of pyridine (3.25μg/mL). Based on this data, our results confirm that both pyridine and its precursor showed genotoxicity against human lymphocytes.

  18. Pet Rodents and Fatal Lymphocytic Choriomeningitis in Transplant Patients

    Centers for Disease Control (CDC) Podcasts

    2007-05-16

    Three organ transplant recipients died from infection with lymphocytic choriomeningitis virus (LCMV), which was traced back to a hamster owned by the daughter of the organ donor. Dr. Brian Amman, a mammalogist with the Special Pathogens Branch at CDC, discusses the dangers LCMV may pose to people with immune disorders, as well as to pregnant women.  Created: 5/16/2007 by CDC, Office of the Director.   Date Released: 5/16/2007.

  19. In vivo evidence of a functional association between immune cells in blood and brain in healthy human subjects.

    Science.gov (United States)

    Kanegawa, Naoki; Collste, Karin; Forsberg, Anton; Schain, Martin; Arakawa, Ryosuke; Jucaite, Aurelija; Lekander, Mats; Olgart Höglund, Caroline; Kosek, Eva; Lampa, Jon; Halldin, Christer; Farde, Lars; Varrone, Andrea; Cervenka, Simon

    2016-05-01

    Microglia, the resident macrophages in the central nervous system, are thought to be maintained by a local self-renewal mechanism. Although preclinical and in vitro studies have suggested that the brain may contain immune cells also from peripheral origin, the functional association between immune cells in the periphery and brain at physiological conditions is poorly understood. We examined 32 healthy individuals using positron emission tomography (PET) and [(11)C]PBR28, a radioligand for the 18-kDa translocator protein (TSPO) which is expressed both in brain microglia and blood immune cells. In 26 individuals, two measurements were performed with varying time intervals. In a subgroup of 19 individuals, of which 12 had repeat examinations, leukocyte numbers in blood was measured on each day of PET measurements. All individuals were genotyped for TSPO polymorphism and categorized as high, mixed, and low affinity binders. We assessed TSPO binding expressed as total distribution volume of [(11)C]PBR28 in brain and in blood cells. TSPO binding in brain was strongly and positively correlated to binding in blood cells both at baseline and when analyzing change between two PET examinations. Furthermore, there was a significant correlation between change of leukocyte numbers and change in TSPO binding in brain, and a trend-level correlation to change in TSPO binding in blood cells. These in vivo findings indicate an association between immunological cells in blood and brain via intact BBB, suggesting a functional interaction between these two compartments, such as interchange of peripherally derived cells or a common regulatory mechanism. Measurement of radioligand binding in blood cells may be a way to control for peripheral immune function in PET studies using TSPO as a marker of brain immune activation.

  20. A case of chronic lymphocytic leukemia with massive ascites

    Directory of Open Access Journals (Sweden)

    Meliha Nalcaci

    2012-10-01

    Full Text Available An 81-year old woman with a history of chronic lymphocytic leukemia (CLL was admitted with night sweats and abdominal distension. A complete blood count showed hemoglobin 5 g/dL, white blood cell (WBC count 28.5x109/L and platelets 38.4x109/L. Peripheral blood smear examination showed a large number of smudge cells and lymphocytosis composed of mature-looking lymphocytes with clumped nuclear chromatin. Computed tomography scan demonstrated enlarged cervical, axillary, paraaortic, retroperitoneal and mesenteric lymph nodes with concomitant omental thickening and ascites. Also, the liver and the spleen were enlarged in the presence of multiple ill-defined hypoechoic areas in the latter. Histopathological analysis of the cervical lymph node biopsy was consistent with CLL. Bone marrow examination showed diffuse infiltration of the marrow with small lymphocytes. Analysis of the ascitic fluid revealed an exudate with WBC 1220 cells/mL. Cytocentrifuge preparation of the ascitic fluid showed small mature lymphoid cells containing hyperchromatic nuclei with coarsely gran- ular chromatin. On flow cytometric analysis of the ascitic fluid, expression of CD5, CD19, CD20, CD22, CD23, CD45 and HLA-DR was compatible with a diagnosis of CLL, in accordance with the results of the peripheral blood analysis. The patient was treated with chemotherapy consisting of cyclophosphamide, vincristine and prednisolone but died within one month after development of non-chylous ascites.

  1. Apicobasal Polarity Controls Lymphocyte Adhesion to Hepatic Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Natalia Reglero-Real

    2014-09-01

    Full Text Available Loss of apicobasal polarity is a hallmark of epithelial pathologies. Leukocyte infiltration and crosstalk with dysfunctional epithelial barriers are crucial for the inflammatory response. Here, we show that apicobasal architecture regulates the adhesion between hepatic epithelial cells and lymphocytes. Polarized hepatocytes and epithelium from bile ducts segregate the intercellular adhesion molecule 1 (ICAM-1 adhesion receptor onto their apical, microvilli-rich membranes, which are less accessible by circulating immune cells. Upon cell depolarization, hepatic ICAM-1 becomes exposed and increases lymphocyte binding. Polarized hepatic cells prevent ICAM-1 exposure to lymphocytes by redirecting basolateral ICAM-1 to apical domains. Loss of ICAM-1 polarity occurs in human inflammatory liver diseases and can be induced by the inflammatory cytokine tumor necrosis factor alpha (TNF-α. We propose that adhesion receptor polarization is a parenchymal immune checkpoint that allows functional epithelium to hamper leukocyte binding. This contributes to the haptotactic guidance of leukocytes toward neighboring damaged or chronically inflamed epithelial cells that expose their adhesion machinery.

  2. Suiciding of lymphocytic precursor cells by tritiated nucleosides, in vitro.

    Science.gov (United States)

    Uyeki, E M; Nishimura, T; Bisel, T U

    1978-02-01

    Differences in suiciding by various tritiated nucleosides were observed between two functional assays for in vitro lymphocytic precursor cell development, the hemolysin plaque-forming cell (PFC) assay and the B lymphocytic colony-forming cell (CFC-L) assay, using BDF1 mouse spleen cells. PFC growth was markedly reduced by an early (days 0-1) pulse of tritiated deoxyadenosine ([3H]dAdo), but relatively unaffected by a pulse of tritiated thymidine ([3H]dThd) during the same interval. In contrast, CFC-L formation significantly dropped after an early (day 0) [3H]dThd pulse, as well as after pulses of [3H]dAdo and the corresponding tritiated ribosides, uridine and adenosine. This implied a cycling state in an early lymphocytic precursor cell, as opposed to the PFC insensitivity to an early [3H]dThd pulse. The response pattern of colonies and clusters to [3H]dThd supported our notion of a delayed suiciding of CFC contributing to the increase in cluster numbers.

  3. Chromosomal instability in the lymphocytes of breast cancer patients

    Directory of Open Access Journals (Sweden)

    Harsimran Kaur

    2009-01-01

    Full Text Available Genomic instability in the tumor tissue has been correlated with tumor progression. In the present study, chromosomal aberrations (CAs in peripheral blood lymphocytes (PBLs of breast tumor patients were studied to assess whether chromosomal instability (CIN in PBLs correlates with aggressiveness of breast tumor (i.e., disease stage and has any prognostic utility. Cultured blood lymphocyte metaphases were scored for aberrations in 31 breast cancer patients and 20 healthy age and sex-matched controls. A variety of CAs, including aneuploidy, polyploidy, terminal deletions, acentric fragments, double minutes, chromatid separations, ring chromosome, marker chromosome, chromatid gaps, and breaks were seen in PBLs of the patients. The CAs in patients were higher than in controls. A comparison of the frequency of metaphases with aberrations by grouping the patients according to the stage of advancement of disease did not reveal any consistent pattern of variation in lymphocytic CIN. Neither was any specific chromosomal abnormality found to be associated with the stage of cancer. This might be indicative of the fact that cancer patients have constitutional CIN, which predisposes them to the disease, and this inherent difference in the level of genomic instability might play a role in disease progression and response to treatment.

  4. The diagnostic importance of the bronchoalveolar lavage in lymphocytic alveolitis.

    Science.gov (United States)

    Mlika, Mona; Kria, Nourane; Braham, Emna; Chebbi, Chokri; El Mezni, Faouzi

    2017-01-01

    Multidisciplinary concertation is mandatory in order to assess interstitial pneumonias. The study of the bronchoalveolar lavage helps evoking a diagnosis according to the lavage profile. In lymphocytic alveolitis, immunocytochemistry, or in flux cytometry are necessary in order to identify the different clusters of lymphocytes implicated. Our objective was to evaluate the profile of 31 lymphocytic alveolitis using 2 different techniques which are the immunocytochemistry and the in flow cytometry in order to evaluate the efficacy of each technique and to compare the different results to the final diagnoses. We describe a retrospective study about 31 patients admitted to our hospital in order to explore an interstitial pneumonia between January and July 2014. Bronchial endoscopy and bronchoalveolar lavage were performed in all cases. The sensitivity of the in flow cytometry was estimated to 53% and its specificity reached 33%. On the other hand, the immunocytochemistry presented a specificity of 42.8% and a sensitivity of 42.8%. The final diagnoses retained consisted in sarcoidosis in 12 cases, infectious pneumonia in 10 cases, hypersensitivity pneumonia in 3 cases, cryptogenic pneumonia in 3 cases, idiopathic fibrosis in 2 cases, and adenocarcinoma in 1 case. The relevance of both techniques depends on many factors. They necessitate an available material, well-trained technicians, and experimented pathologists.

  5. Electrostimulation of rat callus cells and human lymphocytes in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Aro, H.; Eerola, E.; Aho, A.J.; Penttinen, R.

    1984-01-01

    Asymmetrical pulsing low voltage current was supplied via electrodes to cultured rat fracture callus cells and human peripheral blood lymphocytes. The (/sup 3/H)thymidine incorporation of the callus cells and 5-(/sup 125/I)iodo-2'-deoxyuridine incorporation of the lymphocytes were determined. The growth pattern of callus cells (estimated by cellular density) did not respond to electrical stimulation. However, the uptake of (/sup 3/H)thymidine was increased at the early phase of cell proliferation and inhibited at later phases of proliferation. The (/sup 3/H)thymidine uptake of confluent callus cell cultures did not respond to electrical stimulation. Lymphocytes reacted in a similar way; stimulated cells took up more DNA precursor than control cells at the early phase of stimulation. During cell division, induced by the mitogens phytohemagglutinin and Concanavalin-A, the uptake of DNA precursor by stimulated cells was constantly inhibited. The results suggest that electrical stimuli affect the uptake mechanisms of cell membranes. The duality of the effect seems to be dependent on the cell cycle.

  6. Interference of CD95 expression on human lymphocytes.

    Science.gov (United States)

    Petanova, Jitka; Fucikova, Terezie; Bencko, Vladimir

    2002-02-01

    The study presents the exogenous influence of cadmium in comparison with zinc on the apoptosis of human lymphocytes by CD95 expression and its kinetic changes. The salts of both metals were used in final concentrations of 20 microM in cell cultures with whole blood. The duration of cultivation was 18 and 90 hours. The expression of surface antigens was evaluated by flow cytometry with monoclonal antibodies. In cultures of not stimulated cells we found in average 51.54% CD95 positive lymphocytes. The kinetic study of untreated cells showed elevation after 18 hours of cultivation and a very low expression after 90 hours. The CD95 expression on lymphocytes in cell culture with cadmium and zinc was lower after 18 hours of cultivation than in untreated cells. After 90 hours cultivation we found low levels of CD95 expression on cells treated with cadmium and a great individual variability in the number of positive cells upon the influence of zinc.

  7. [Retarded excision of pyrimidine dimers in human unstimulated lymphocytes].

    Science.gov (United States)

    Snopov, S A; Roza, L; de Gruijl, F R

    2006-01-01

    Using immuno-labelling of cyclobutane pyrimidine dimers (CPDs) in nuclei of peripheral lymphocytes after their UVC-irradiation and cultivation, we have found that within the first four hours of cultivation the CPD-specific fluorescent signal from cell nuclei increased. Earlier, a similar increase in binding of antibody specific for pyrimidine (6-4) pyrimidone photoproducts to undenatured DNA isolated from UV-irradiated Chinese hamster ovary cells was reported (Mitchell et al., 1986). Our experiments showed that nucleotide excision repair enzyme might induce such of DNA modification in lymphocyte nuclei that increased specific antibody binding to DNA fragments with lesions. We suggest that enzymatic formation of open structures in DNA predominated qualitatively over dual-incision and excision of these fragments, and resulted in the enhanced exposure of the pyrimidine dimers in nuclei to specific antibodies. The results evidence that nucleotid excision repair in unstimualted human lymphocytes being deficient in dual incision and removal of UV-induced DNA lesions appear to be capable of performing chromatin relaxation and pre-incision uncoiling of DNA fragments with lesions.

  8. Cell-extrinsic defective lymphocyte development in Lmna(-/- mice.

    Directory of Open Access Journals (Sweden)

    J Scott Hale

    Full Text Available BACKGROUND: Mutations in the LMNA gene, which encodes all A-type lamins, result in a variety of human diseases termed laminopathies. Lmna(-/- mice appear normal at birth but become runted as early as 2 weeks of age and develop multiple tissue defects that mimic some aspects of human laminopathies. Lmna(-/- mice also display smaller spleens and thymuses. In this study, we investigated whether altered lymphoid organ sizes are correlated with specific defects in lymphocyte development. PRINCIPAL FINDINGS: Lmna(-/- mice displayed severe age-dependent defects in T and B cell development which coincided with runting. Lmna(-/- bone marrow reconstituted normal T and B cell development in irradiated wild-type recipients, driving generation of functional and self-MHC restricted CD4(+ and CD8(+ T cells. Transplantation of Lmna(-/- neonatal thymus lobes into syngeneic wild-type recipients resulted in good engraftment of thymic tissue and normal thymocyte development. CONCLUSIONS: Collectively, these data demonstrate that the severe defects in lymphocyte development that characterize Lmna(-/- mice do not result directly from the loss of A-type lamin function in lymphocytes or thymic stroma. Instead, the immune defects in Lmna(-/- mice likely reflect indirect damage, perhaps resulting from prolonged stress due to the striated muscle dystrophies that occur in these mice.

  9. Preparation of Internal Quality Control Material for Lymphocyte Subset Analysis.

    Science.gov (United States)

    Roh, Eun Youn; Shin, Sue; Yoon, Jong Hyun; Oh, Sohee; Park, Kyoung Un; Lee, Nuri; Song, Eun Young

    2016-07-01

    Lymphocyte subset analysis is widely used in clinical laboratories, and more than two levels of daily QC materials are required for reliable results. Commercially available, expensive QC materials have short shelf lives and may not be suitable in resource-poor settings. We compared different methods for preparing homemade QC material, including fixation with 1%, 2%, or 4% paraformaldehyde (PFA); freezing with 10% dimethylsulfoxide (DMSO), 0.1% bovine serum albumin-phosphate buffered saline, or after ethanolic dehydration; and using cryopreservation temperatures of -20°C, -80°C, or -196°C. We found an optimal experimental condition, which is 'fixation with 4% PFA, freezing with 10% DMSO, and storage at 80°C'. To evaluate long-term stability of QC materials prepared in this optimal condition, two levels of QC materials (QM1 and QM2) were thawed after 30, 33, 35, 37, 60, 62, 64, and 67 days of cryopreservation. Lymphocyte subset was analyzed with BD Multitest IMK kit (BD Biosciences, USA). QM1 and QM2 were stable after 1-2 months of cryopreservation (CV materials for lymphocyte subset analysis in resource-poor settings.

  10. Atopic dermatitis: serum immunoglobulins and T-lymphocyte subpopulations.

    Science.gov (United States)

    Valdés Sánchez, A F; Gómez Echevarría, A H; Lastra Alfonso, G

    1991-04-01

    A group of patients with atopic dermatitis who attended the Allergy Outpatient Service of the Hermanos Ameijeiras Clinical Surgical Hospital from May, 1987 to May, 1988 were studied. The patients were assigned to 2 groups; the first one composed of 38 patients and the second one composed of 12 non-allergic, supposedly healthy subjects. Different tests were carried out for the quantification of total serum immunoglobulins (A, G, M, E) by means of the radial immunodiffusion method and the ELISA ultramicromethod. They were also submitted to quantification of lymphocyte subpopulations by means of the indirect immunofluorescence test with monoclonal antibodies, using Cuban antiserum prepared at the National Institute of Oncology and Radiobiology. In our study IgG and IgA values were within normal limits in patients, contrary to the statistically significant increase in IgM and IgE values. The relative values of total T-lymphocytes (anti-T3) and of the suppressor lymphocyte subpopulations decreased.

  11. Micronucleated lymphocytes in parents of Down syndrome children

    Directory of Open Access Journals (Sweden)

    R.L. Silva-Grecco

    2012-07-01

    Full Text Available Down syndrome (DS is the most common disease due to an autosomal aneuploidy in live born children and also the major known genetic cause of mental retardation. The risk of a DS pregnancy increases substantially with increasing maternal age. However, several women aged less than 35 years at conception have a child with DS. The micronucleus (MN assay can identify chromosome breakage or chromosome malsegregation and is an ideal biomarker to investigate genomic instability. The aim of the present study was to determine the frequency of peripheral lymphocytes with MN in the parents of DS individuals. The subjects were 17 couples, 1 father and 9 mothers, and 24 couples who had at least one healthy child formed the control group. For each individual we evaluated the frequency of binucleated micronucleated lymphocytes (BNMN% as number of binucleated lymphocytes containing one or more MN per 1000 binucleated cells. The mean age of DS parents and controls was 32.6 and 29.8 years, respectively. The frequency of MN in DS parents was significantly higher compared to controls. The higher frequency of MN in DS parents suggests a higher predisposition of DS parents to aneuploidy events in this sample.

  12. The Use of Isolated Human Lymphocytes in Mycotoxin Cytotoxicity Testing

    Directory of Open Access Journals (Sweden)

    Mike F. Dutton

    2008-08-01

    Full Text Available The cytotoxicity of selected mycotoxins against isolated human lymphocytes was investigated, as a means of detecting mycotoxins in extracts derived from cereal samples. The methodology was based on the ability of viable cells to reduce methyl tetrazolium bromide to a purple formazan dye that could be quantitated by spectrophometric means and hence give a measure of the cytotoxicity of added substances. The results showed that there was good correlation with the occurrence of identified mycotoxins with only a minimum of false positives. For example, of the 13 samples of barley or barley derivatives that were positive for the mycotoxins, fumonisin B1 (FB1 deoxynivalenol (DON and ochratoxin A (OTA, all gave positive cytotoxicity responses. Two samples negative for mycotoxins gave no cytotoxicity responses. There was little variation between the results for lymphocytes drawn from the same healthy volunteer on three different occasions. Furthermore, for two of the mycotoxins tested (FB1 and DON it was possible to correlate general levels of mycotoxins present to the cytotoxic response of the lymphocytes but not for OTA, where it was concluded that interfering substances prevented direct correlation. It was concluded that this method was suited for general application as it could handle relatively high number of samples in a short period of time.

  13. Lymphocyte subpopulations during cytomegalovirus disease in renal transplant recipients

    Directory of Open Access Journals (Sweden)

    S.M. Castro

    2003-06-01

    Full Text Available We have determined the number of circulating T, B and natural killer cells in renal transplant recipients in order to detect changes during cytomegalovirus (CMV infections. Serial blood samples were taken from 61 patients on standard triple immunosuppression therapy (cyclosporin A, azathioprine and prednisone. Using two-color flow cytometry analysis, the absolute number of CD3+, CD4+, CD8+, CD19+, CD3+HLA-DR+ and CD16+56+ cells was determined. Forty-eight patients (78.7% developed active CMV infection, and all of them subsequently recovered. Twenty of the infected patients (32.8% presented symptoms compatible with CMV disease during the infectious process. The number of lymphocytes and their main subpopulations were normal before the onset of CMV disease. During the disease there was a decrease followed by a significant increase (P<0.005 in the number of CD3+, CD4+, CD8+ and CD3+HLA-DR+ cells. No significant changes were observed in natural killer cells or B lymphocytes during the disease. We conclude, as observed in all viremic patients recovering from infection, that recovery is associated with an increase in the number of T cell subsets. The monitoring of different lymphocyte subsets along with antigenemia can be extremely useful in the detection of patients at high risk of developing CMV symptoms, allowing the early introduction of antiviral therapy or the reduction of immunosuppression therapy.

  14. Control of T lymphocyte morphology by the GTPase Rho

    Directory of Open Access Journals (Sweden)

    Caudell Eva G

    2003-02-01

    Full Text Available Abstract Background Rho family GTPase regulation of the actin cytoskeleton governs a variety of cell responses. In this report, we have analyzed the role of the GTPase Rho in maintenance of the T lymphocyte actin cytoskeleton. Results Inactivation of the GTPase Rho in the human T lymphocytic cell line HPB-ALL does not inhibit constitutively high adhesion to the integrin β1 substrate fibronectin. It did however result in the aberrant extension of finger-like dendritic processes on the substrates VCAM-1, Fn, and mAb specific to β1 integrins. Time-lapse video microscopy demonstrated that C3 induced extensions were primarily the result of an altered pseudopod elongation rather than retraction. Once the stellate pseudopodia extended, none retracted, and cells became completely immobile. Filipodial structures were absent and the dendritic-like processes in C3 treated cells were rich in filamentous actin. Immunolocalization of RhoA in untreated HPB-ALL cells spreading on fibronectin demonstrated a diffuse staining pattern within the pseudopodia. In C3 treated cells, clusters of RhoA were pronounced and localized within the altered extensions. Conclusions GTPase Rho is actively involved in the regulation of T lymphocyte morphology and motility.

  15. Elevated Neutrophil Lymphocyte Ratio in Recurrent Optic Neuritis

    Directory of Open Access Journals (Sweden)

    Hande Guclu

    2015-01-01

    Full Text Available Purpose. To demonstrate the relation between optic neuritis (ON and systemic inflammation markers as neutrophil lymphocyte ratio (N/L ratio, platelet count, mean platelet volume (MPV, and red cell distribution width (RDW and furthermore to evaluate the utilization of these markers to predict the frequency of the ON episodes. Methods. Forty-two patients with acute ON and forty healthy subjects were enrolled into the study. The medical records were reviewed for age, sex, hemoglobin (Hb, Haematocrit (Htc, RDW, platelet count, MPV, white blood cell count (WBC, neutrophil and lymphocyte count, and neutrophil lymphocyte ratio (N/L ratio. Results. The mean N/L ratio, platelet counts, and RDW were significantly higher in ON group (p=0.000, p=0.048, and p=0.002. There was a significant relation between N/L ratio and number of episodes (r=0.492, p=0.001. There was a statistically significant difference for MPV between one episode group and recurrent ON group (p=0.035. Conclusions. Simple and inexpensive laboratory methods could help us show systemic inflammation and monitor ON patients. Higher N/L ratio can be a useful marker for predicting recurrent attacks.

  16. miRNA expression profiles in chronic lymphocytic and acute lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    D.L. Zanette

    2007-11-01

    Full Text Available MicroRNAs (miRNAs are a class of small endogenous RNAs that play important regulatory roles by targeting mRNAs for cleavage or translational repression. miRNAs act in diverse biological processes including development, cell growth, apoptosis, and hematopoiesis, suggesting their association with cancer. We determined the miRNA expression profile of chronic and acute lymphocytic leukemias (CLL and ALL using the TaqMan® MicroRNA Assays Human Panel (Applied Biosystems. Pooled leukemia samples were compared to pooled CD19+ samples from healthy individuals (calibrator by the 2-DDCt method. Total RNA input was normalized based on the Ct values obtained for hsa-miR-30b. The five most highly expressed miRNAs were miR-128b, miR-204, miR-218, miR-331, and miR-181b-1 in ALL, and miR-331, miR-29a, miR-195, miR-34a, and miR-29c in CLL. To our knowledge, this is the first report associating miR-128b, miR-204 and miR-331 to hematological malignancies. The miR-17-92 cluster was also found to be up-regulated in ALL, as previously reported for some types of lymphomas. The differences observed in gene expression levels were validated for miR-331 and miR-128b in ALL and CD19+ samples. These miRNAs were up-regulated in ALL, in agreement with our initial results. A brief target analysis was performed for miR-331. One of its putative targets, SOCS1, promotes STAT activation, which is a known mediator of cell proliferation and survival, suggesting the possibility of an association between miR-331 and these processes. This initial screening provided information on miRNA differentially expressed in normal and malignant B-cells that could suggest the potential roles of these miRNAs in hematopoiesis and leukemogenesis.

  17. Expression change of prostate cancer antigen-1 in prostate cancer and its prognostic significance%前列腺癌抗原-1在前列腺癌患者中的表达及其预后意义

    Institute of Scientific and Technical Information of China (English)

    刘秉乾; 张国兵; 刘新奎; 武玉东; 魏金星; 范志强; 冯超杰; 周玉石

    2014-01-01

    Objective To explore the change of expression of prostate cancer antigen-1 in prostate cancer and its prognostic significance.Methods Immunohistochemistry was used to detect the expression of PCA-1 protein in 178 cases of prostate cancer and 79 cases of benign prostatic hyperplasia (BPH).The relationship of PCA-1 protein expression with clinical pathological parameters and prognosis in prostate cancer was analyzed.Results The positive rates of PCA-1 expression were 82.0% (146/178)in prostate cancer cases,and 13.9% (11/79)in BPH cases respectively (P<0.05).And its expression was associated with Gleason score,clinical staging and bone metastasis (all P<0.05),and not related with age,LUTS,TUVP and Eastern Cooperative Oncology Group (ECOG) score (all P>0.05).There was a negative correlation between PCA-1 expression and overall survival rate in prostate cancer patients.PCA-1 was the independent prognostic factor for overall survival in prostate cancer patients (HR =2.023,95% CI =1.467-2.789).Conclusions PCA-1 may play an important role in the development of prostate cancer,which can be a novel marker for predicting prognosis in prostate cancer.%目的 探讨前列腺癌抗原-1 (PCA-1)在前列腺癌患者中的表达及其与预后的关系.方法 采用免疫组化法检测178例前列腺癌患者和79例良性前列腺增生患者(BPH)组织中PCA-1的表达,分析其表达水平与患者临床病理特点及预后的关系. 结果 免疫组织化学检查显示PCA-1在前列腺癌及BPH组织中的表达阳性率分别为82.0%(146/178)和13.9%(11/79)(P<0.05),其表达与肿瘤的Gleason评分、临床分期和远处转移相关(均P<0.05),与有无下尿路症状(LUTS)、经尿道前列腺气化电切术(TUVP)、年龄及美国东部肿瘤协作组(ECOG)评分无关(均P>0.05),其表达水平与肿瘤分化程度、临床分期以及是否远处转移呈正相关(P<0.05),与患者的总体生存率呈负相关.PCA-1是影

  18. A highly sensitive method for quantitation of mast cell surface antigen-1%肥大细胞表面抗原-1高灵敏度定量分析法的建立

    Institute of Scientific and Technical Information of China (English)

    陈洪淼; 宋振镇; 陈壮荔; 王振; 胡国鹏; 冯魏

    2012-01-01

    Mast cell plays a pivotal role in type I allergy, innate immunity, chronic inflammation and tissue remodeling. The recently cloned mast cell surface antigen-1 (MASA-1) protein is mainly expressed on the surface of activated mast cells, and is useful in the determination of the activation status of mast cells. The aim of this study is to develop a rapid and sensitive method for fhe quantitation of MASA-I. Based previously prepared a mouse monoclonal antibody against human MASA-1, we optimized the conditions including coating concentration, temperature and incubation time, and finally established a sandwich ELISA with a sensitivity of 0.5 ng/ml. By using this method, the MASA-1 levels in the bronchoalveolar lavage fluid of patients with respiratory system disorders are measured to be within the range of 0-130 ng/ml. The MASA-1 level correlates with the cell number of MASA-1 -positive cells, but not with that of cells stained by toluidine blue. Compared with the cell staining technique, the ELISA system is more rapid and accurate, and allows handling of large number of same samples in parallel, therefore is applicable in both research study and clinical test relating to mast cell.%目的 建立肥大细胞表面抗原-1 (MASA- 1)的高灵敏度定量分析方法.方法 首先制备抗人MASA-1的单克隆抗体,然后结合先前制备的多克隆抗体,通过优化包被浓度、温度和反应时间等条件.建立夹心酶联免疫定量方法 结果 成功制备了特异性高的小鼠抗人MASA-1的单克隆抗体;夹心ELISA法的检测灵敏度可达0.5 ng/ml.利用该法测出各种呼吸系统疾病病人的肺清洗液中的MASA-1含量为0~130 ng/ml.MASA-1的浓度与甲苯胺蓝染色阳性细胞数之间不存在相关关系,但与MASA-1染色阳性细胞数之间呈显著正相关关系.结论 相对于MASA-1细胞染色法,本研究开发的酶联免疫法具有快速、准确及能同时分析大量样品的优点,有助于肥大细胞的实验室研究和临床检测.

  19. Mechanisms of Idelalisib-Associated Diarrhea in Patients With Relapsed Chronic Lymphocytic Leukemia, Indolent Non-hodgkin Lymphoma, or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2016-10-06

    Absence of Signs or Symptoms; B-Cell Non-Hodgkin Lymphoma; Digestive System Signs and Symptoms; Indolent Adult Non-Hodgkin Lymphoma; Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Indolent Adult Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma

  20. The immunodeficiency of bone marrow-transplanted patients. The effect of patient lymphocytes on the response of donor lymphocytes to mitogens and allogeneic cells

    DEFF Research Database (Denmark)

    Ødum, Niels; Hofmann, B; Platz, P

    1985-01-01

    Lymphocytes from patients after bone marrow transplantation (BMT) are in most cases predominantly of the Leu-2+ (cytotoxic/suppressor) phenotypes and are almost unresponsive to mitogens. In contrast, normal Leu-3+-depleted, Leu-2+-enriched lymphocyte suspensions retain approximately 50...