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Sample records for benchmarking b-cell epitope

  1. Reliable B cell epitope predictions: impacts of method development and improved benchmarking.

    Directory of Open Access Journals (Sweden)

    Jens Vindahl Kringelum

    Full Text Available The interaction between antibodies and antigens is one of the most important immune system mechanisms for clearing infectious organisms from the host. Antibodies bind to antigens at sites referred to as B-cell epitopes. Identification of the exact location of B-cell epitopes is essential in several biomedical applications such as; rational vaccine design, development of disease diagnostics and immunotherapeutics. However, experimental mapping of epitopes is resource intensive making in silico methods an appealing complementary approach. To date, the reported performance of methods for in silico mapping of B-cell epitopes has been moderate. Several issues regarding the evaluation data sets may however have led to the performance values being underestimated: Rarely, all potential epitopes have been mapped on an antigen, and antibodies are generally raised against the antigen in a given biological context not against the antigen monomer. Improper dealing with these aspects leads to many artificial false positive predictions and hence to incorrect low performance values. To demonstrate the impact of proper benchmark definitions, we here present an updated version of the DiscoTope method incorporating a novel spatial neighborhood definition and half-sphere exposure as surface measure. Compared to other state-of-the-art prediction methods, Discotope-2.0 displayed improved performance both in cross-validation and in independent evaluations. Using DiscoTope-2.0, we assessed the impact on performance when using proper benchmark definitions. For 13 proteins in the training data set where sufficient biological information was available to make a proper benchmark redefinition, the average AUC performance was improved from 0.791 to 0.824. Similarly, the average AUC performance on an independent evaluation data set improved from 0.712 to 0.727. Our results thus demonstrate that given proper benchmark definitions, B-cell epitope prediction methods achieve

  2. Benchmarking B-Cell Epitope Prediction for the Design of Peptide-Based Vaccines: Problems and Prospects

    Directory of Open Access Journals (Sweden)

    Salvador Eugenio C. Caoili

    2010-01-01

    Full Text Available To better support the design of peptide-based vaccines, refinement of methods to predict B-cell epitopes necessitates meaningful benchmarking against empirical data on the cross-reactivity of polyclonal antipeptide antibodies with proteins, such that the positive data reflect functionally relevant cross-reactivity (which is consistent with antibody-mediated change in protein function and the negative data reflect genuine absence of cross-reactivity (rather than apparent absence of cross-reactivity due to artifactual masking of B-cell epitopes in immunoassays. These data are heterogeneous in view of multiple factors that complicate B-cell epitope prediction, notably physicochemical factors that define key structural differences between immunizing peptides and their cognate proteins (e.g., unmatched electrical charges along the peptide-protein sequence alignments. If the data are partitioned with respect to these factors, iterative parallel benchmarking against the resulting subsets of data provides a basis for systematically identifying and addressing the limitations of methods for B-cell epitope prediction as applied to vaccine design.

  3. Benchmarking B-Cell Epitope Prediction for the Design of Peptide-Based Vaccines: Problems and Prospects

    OpenAIRE

    Caoili, Salvador Eugenio C.

    2010-01-01

    To better support the design of peptide-based vaccines, refinement of methods to predict B-cell epitopes necessitates meaningful benchmarking against empirical data on the cross-reactivity of polyclonal antipeptide antibodies with proteins, such that the positive data reflect functionally relevant cross-reactivity (which is consistent with antibody-mediated change in protein function) and the negative data reflect genuine absence of cross-reactivity (rather than apparent absence of cross-reac...

  4. Reliable B cell epitope predictions: impacts of method development and improved benchmarking

    DEFF Research Database (Denmark)

    Kringelum, Jens Vindahl; Lundegaard, Claus; Lund, Ole;

    2012-01-01

    biomedical applications such as; rational vaccine design, development of disease diagnostics and immunotherapeutics. However, experimental mapping of epitopes is resource intensive making in silico methods an appealing complementary approach. To date, the reported performance of methods for in silico mapping...

  5. The Relationship between B-cell Epitope and Mimotope Sequences.

    Science.gov (United States)

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

    2016-01-01

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

  6. In silico quantitative prediction of B-cell epitope

    Directory of Open Access Journals (Sweden)

    Raúl Isea

    2015-11-01

    Full Text Available This paper shows a computational approach for quantitative prediction of B cell epitopes. The function was defined, which reflects the average value of B epitopes, according to eight predictors of different B epitopes, as well as structural and energetic considerations of the origin protein. The proposed methodology could be useful to develop both dengue and chikungunya vaccines

  7. In silico quantitative prediction of B-cell epitope

    OpenAIRE

    Raúl Isea

    2015-01-01

    This paper shows a computational approach for quantitative prediction of B cell epitopes. The function was defined, which reflects the average value of B epitopes, according to eight predictors of different B epitopes, as well as structural and energetic considerations of the origin protein. The proposed methodology could be useful to develop both dengue and chikungunya vaccines

  8. Conformational B-Cell Epitopes Prediction from Sequences Using Cost-Sensitive Ensemble Classifiers and Spatial Clustering

    Directory of Open Access Journals (Sweden)

    Jian Zhang

    2014-01-01

    Full Text Available B-cell epitopes are regions of the antigen surface which can be recognized by certain antibodies and elicit the immune response. Identification of epitopes for a given antigen chain finds vital applications in vaccine and drug research. Experimental prediction of B-cell epitopes is time-consuming and resource intensive, which may benefit from the computational approaches to identify B-cell epitopes. In this paper, a novel cost-sensitive ensemble algorithm is proposed for predicting the antigenic determinant residues and then a spatial clustering algorithm is adopted to identify the potential epitopes. Firstly, we explore various discriminative features from primary sequences. Secondly, cost-sensitive ensemble scheme is introduced to deal with imbalanced learning problem. Thirdly, we adopt spatial algorithm to tell which residues may potentially form the epitopes. Based on the strategies mentioned above, a new predictor, called CBEP (conformational B-cell epitopes prediction, is proposed in this study. CBEP achieves good prediction performance with the mean AUC scores (AUCs of 0.721 and 0.703 on two benchmark datasets (bound and unbound using the leave-one-out cross-validation (LOOCV. When compared with previous prediction tools, CBEP produces higher sensitivity and comparable specificity values. A web server named CBEP which implements the proposed method is available for academic use.

  9. Conformational B-cell epitopes prediction from sequences using cost-sensitive ensemble classifiers and spatial clustering.

    Science.gov (United States)

    Zhang, Jian; Zhao, Xiaowei; Sun, Pingping; Gao, Bo; Ma, Zhiqiang

    2014-01-01

    B-cell epitopes are regions of the antigen surface which can be recognized by certain antibodies and elicit the immune response. Identification of epitopes for a given antigen chain finds vital applications in vaccine and drug research. Experimental prediction of B-cell epitopes is time-consuming and resource intensive, which may benefit from the computational approaches to identify B-cell epitopes. In this paper, a novel cost-sensitive ensemble algorithm is proposed for predicting the antigenic determinant residues and then a spatial clustering algorithm is adopted to identify the potential epitopes. Firstly, we explore various discriminative features from primary sequences. Secondly, cost-sensitive ensemble scheme is introduced to deal with imbalanced learning problem. Thirdly, we adopt spatial algorithm to tell which residues may potentially form the epitopes. Based on the strategies mentioned above, a new predictor, called CBEP (conformational B-cell epitopes prediction), is proposed in this study. CBEP achieves good prediction performance with the mean AUC scores (AUCs) of 0.721 and 0.703 on two benchmark datasets (bound and unbound) using the leave-one-out cross-validation (LOOCV). When compared with previous prediction tools, CBEP produces higher sensitivity and comparable specificity values. A web server named CBEP which implements the proposed method is available for academic use. PMID:25045691

  10. Improved method for linear B-cell epitope prediction using antigen's primary sequence.

    Directory of Open Access Journals (Sweden)

    Harinder Singh

    Full Text Available One of the major challenges in designing a peptide-based vaccine is the identification of antigenic regions in an antigen that can stimulate B-cell's response, also called B-cell epitopes. In the past, several methods have been developed for the prediction of conformational and linear (or continuous B-cell epitopes. However, the existing methods for predicting linear B-cell epitopes are far from perfection. In this study, an attempt has been made to develop an improved method for predicting linear B-cell epitopes. We have retrieved experimentally validated B-cell epitopes as well as non B-cell epitopes from Immune Epitope Database and derived two types of datasets called Lbtope_Variable and Lbtope_Fixed length datasets. The Lbtope_Variable dataset contains 14876 B-cell epitope and 23321 non-epitopes of variable length where as Lbtope_Fixed length dataset contains 12063 B-cell epitopes and 20589 non-epitopes of fixed length. We also evaluated the performance of models on above datasets after removing highly identical peptides from the datasets. In addition, we have derived third dataset Lbtope_Confirm having 1042 epitopes and 1795 non-epitopes where each epitope or non-epitope has been experimentally validated in at least two studies. A number of models have been developed to discriminate epitopes and non-epitopes using different machine-learning techniques like Support Vector Machine, and K-Nearest Neighbor. We achieved accuracy from ∼54% to 86% using diverse s features like binary profile, dipeptide composition, AAP (amino acid pair profile. In this study, for the first time experimentally validated non B-cell epitopes have been used for developing method for predicting linear B-cell epitopes. In previous studies, random peptides have been used as non B-cell epitopes. In order to provide service to scientific community, a web server LBtope has been developed for predicting and designing B-cell epitopes (http://crdd.osdd.net/raghava/lbtope/.

  11. Improved Method for Linear B-Cell Epitope Prediction Using Antigen’s Primary Sequence

    OpenAIRE

    Singh, Harinder; Ansari, Hifzur Rahman; Gajendra P. S. Raghava

    2013-01-01

    One of the major challenges in designing a peptide-based vaccine is the identification of antigenic regions in an antigen that can stimulate B-cell’s response, also called B-cell epitopes. In the past, several methods have been developed for the prediction of conformational and linear (or continuous) B-cell epitopes. However, the existing methods for predicting linear B-cell epitopes are far from perfection. In this study, an attempt has been made to develop an improved method for predicting ...

  12. Structural analysis of B-cell epitopes in antibody:protein complexes

    DEFF Research Database (Denmark)

    Kringelum, Jens Vindahl; Nielsen, Morten; Padkjær, Søren Berg; Lund, Ole

    developed a novel framework for comparing and superimposing B-cell epitopes and applied it on a dataset of 107 non-similar antigen:antibody structures extracted from the PDB database. With the presented framework, we were able to describe the general B-cell epitope as a flat, oblong, oval shaped volume......The binding of antigens to antibodies is one of the key events in an immune response against foreign molecules and is a critical element of several biomedical applications including vaccines and immunotherapeutics. For development of such applications, the identification of antibody binding sites...... (B-cell epitopes) is essential. However experimental epitope mapping is highly cost-intensive and computer-aided methods do in general have moderate performance. One major reason for this moderate performance is an incomplete understanding of what characterizes an epitope. To fill this gap, we here...

  13. Positive-unlabeled learning for the prediction of conformational B-cell epitopes

    OpenAIRE

    Ren, Jing; Liu, Qian; Ellis, John; Li, Jinyan

    2015-01-01

    Background The incomplete ground truth of training data of B-cell epitopes is a demanding issue in computational epitope prediction. The challenge is that only a small fraction of the surface residues of an antigen are confirmed as antigenic residues (positive training data); the remaining residues are unlabeled. As some of these uncertain residues can possibly be grouped to form novel but currently unknown epitopes, it is misguided to unanimously classify all the unlabeled residues as negati...

  14. Synthetic B-Cell Epitopes Eliciting Cross-Neutralizing Antibodies: Strategies for Future Dengue Vaccine.

    Science.gov (United States)

    Ramanathan, Babu; Poh, Chit Laa; Kirk, Kristin; McBride, William John Hannan; Aaskov, John; Grollo, Lara

    2016-01-01

    Dengue virus (DENV) is a major public health threat worldwide. A key element in protection from dengue fever is the neutralising antibody response. Anti-dengue IgG purified from DENV-2 infected human sera showed reactivity against several peptides when evaluated by ELISA and epitope extraction techniques. A multi-step computational approach predicted six antigenic regions within the E protein of DENV-2 that concur with the 6 epitopes identified by the combined ELISA and epitope extraction approach. The selected peptides representing B-cell epitopes were attached to a known dengue T-helper epitope and evaluated for their vaccine potency. Immunization of mice revealed two novel synthetic vaccine constructs that elicited good humoral immune responses and produced cross-reactive neutralising antibodies against DENV-1, 2 and 3. The findings indicate new directions for epitope mapping and contribute towards the future development of multi-epitope based synthetic peptide vaccine. PMID:27223692

  15. Synthetic B-Cell Epitopes Eliciting Cross-Neutralizing Antibodies: Strategies for Future Dengue Vaccine.

    Directory of Open Access Journals (Sweden)

    Babu Ramanathan

    Full Text Available Dengue virus (DENV is a major public health threat worldwide. A key element in protection from dengue fever is the neutralising antibody response. Anti-dengue IgG purified from DENV-2 infected human sera showed reactivity against several peptides when evaluated by ELISA and epitope extraction techniques. A multi-step computational approach predicted six antigenic regions within the E protein of DENV-2 that concur with the 6 epitopes identified by the combined ELISA and epitope extraction approach. The selected peptides representing B-cell epitopes were attached to a known dengue T-helper epitope and evaluated for their vaccine potency. Immunization of mice revealed two novel synthetic vaccine constructs that elicited good humoral immune responses and produced cross-reactive neutralising antibodies against DENV-1, 2 and 3. The findings indicate new directions for epitope mapping and contribute towards the future development of multi-epitope based synthetic peptide vaccine.

  16. Determination of B-Cell Epitopes in Patients with Celiac Disease: Peptide Microarrays.

    Directory of Open Access Journals (Sweden)

    Rok Seon Choung

    Full Text Available Most antibodies recognize conformational or discontinuous epitopes that have a specific 3-dimensional shape; however, determination of discontinuous B-cell epitopes is a major challenge in bioscience. Moreover, the current methods for identifying peptide epitopes often involve laborious, high-cost peptide screening programs. Here, we present a novel microarray method for identifying discontinuous B-cell epitopes in celiac disease (CD by using a silicon-based peptide array and computational methods.Using a novel silicon-based microarray platform with a multi-pillar chip, overlapping 12-mer peptide sequences of all native and deamidated gliadins, which are known to trigger CD, were synthesized in situ and used to identify peptide epitopes.Using a computational algorithm that considered disease specificity of peptide sequences, 2 distinct epitope sets were identified. Further, by combining the most discriminative 3-mer gliadin sequences with randomly interpolated3- or 6-mer peptide sequences, novel discontinuous epitopes were identified and further optimized to maximize disease discrimination. The final discontinuous epitope sets were tested in a confirmatory cohort of CD patients and controls, yielding 99% sensitivity and 100% specificity.These novel sets of epitopes derived from gliadin have a high degree of accuracy in differentiating CD from controls, compared with standard serologic tests. The method of ultra-high-density peptide microarray described here would be broadly useful to develop high-fidelity diagnostic tests and explore pathogenesis.

  17. Towards a consensus on datasets and evaluation metrics for developing B-cell epitope prediction tools

    DEFF Research Database (Denmark)

    Greenbaum, Jason A.; Andersen, Pernille; Blythe, Martin;

    2007-01-01

    and immunology communities. Improving the accuracy of B-cell epitope prediction methods depends on a community consensus on the data and metrics utilized to develop and evaluate such tools. A workshop, sponsored by the National Institute of Allergy and Infectious Disease (NIAID), was recently held in Washington......, DC to discuss the current state of the B-cell epitope prediction field. Many of the currently available tools were surveyed and a set of recommendations was devised to facilitate improvements in the currently existing tools and to expedite future tool development. An underlying theme...... of the recommendations put forth by the panel is increased collaboration among research groups. By developing common datasets, standardized data formats, and the means with which to consolidate information, we hope to greatly enhance the development of B-cell epitope prediction tools. (c) 2007 John Wiley & Sons, Ltd....

  18. B-cell epitope mapping for the design of vaccines and effective diagnostics

    Directory of Open Access Journals (Sweden)

    Tarek A. Ahmad

    2016-01-01

    Full Text Available The increasing resistance of many microbial strains to antibiotics, delayed laboratory results, and side effects of many chemotherapeutics has raised the need to search for sensitive diagnostics and new prophylactic strategies especially prevention by vaccination. Understanding the epitope/antibody interaction is the key to constructing potent vaccines and effective diagnostics. B-cell epitope mapping is a promising approach to identifying the main antigenic determinants of microorganisms, in special concern the discontinuous conformational ones. Epitope-based vaccines have remarkable privilege over the conventional ones since they are specific, able to avoid undesirable immune responses, generate long lasting immunity, and are reasonably cheaper. This up-to-date review discusses and compares the different physical, computational, and molecular methods that have been used in epitope mapping. The role of each method in the identification of potent epitopes in viruses, bacteria, fungi, parasites, as well as human diseases are tagged and documented. Simultaneously, frequent combinatorial methods are highlighted. The article aims to assist researchers to design the most suitable protocol for mapping their B-cell epitopes.

  19. The relationship between colonization and haemagglutination inhibiting and B cell epitopes of Porphyromonas gingivalis

    Science.gov (United States)

    KELLY, C G; BOOTH, V; KENDAL, H; SLANEY, J M; CURTIS, M A; LEHNER, T

    1997-01-01

    Passive immunization with the monoclonal antibody 61BG1.3 selectively prevents colonization by Porphyromonas gingivalis in humans (Booth V, Ashley FP, Lehner T. Infect Immun 1996; 64:422-7). The protective MoAb recognizes the j3 component of the RI protease of P. gingivalis which is formed by proteolytic processing of a polyprotein precursor termed PrpRl. This subunit is both a haemagglutinin and an antigen which is recognized by sera from patients with periodontitis. In this study the relationship was investigated between a colonization epitope which is recognized by the MoAb 61BG1.3, a haemagglutinating and B cell epitope which are recognized by sera from patients with periodontitis. B cell epitopes were mapped by Western blotting with a series of truncated recombinant polypeptides spanning the adhesion domain within residues 784–1130 of PrpRl and by ELISA using a panel of synthetic peptides spanning the same sequence. The epitope which is recognized by the protective MoAb was mapped within residues 907–931 of PrpRl, while serum responses of patients were directed predominantly to the adjacent carboxy-terminal sequence within residues 934–1042. The haemagglutinating epitope was mapped to residues 1073–1112. In view of our previous findings that the MoAb 61BG1.3 prevents colonization of P. gingivalis in vivo and inhibits haemagglutination, these two epitopes may be in proximity in the native protein. Active or passive immunization strategies which target the protective or haemagglutinating epitopes of the adhesion domain of PrpRl may provide a means of preventing infection with P. gingivalis. PMID:9367414

  20. Docking of B-cell epitope antigen to specific hepatitis B antibody

    Indian Academy of Sciences (India)

    R Rajkannan; E J Padma Malar

    2007-09-01

    The interaction of pres1 region of hepatitis B virus B-cell epitope antigen with specific hepatitis B neutralizing monoclonal antibody was examined by docking study. We modelled the 3D complex structure of B-cell epitope antigen residues CTTPAQGNSMFPSCCCTKPTDGNCY by homology modelling and docked it with the crystal structure of monoclonal antibody specific for the pres1 region of the hepatitis B virus. At the optimized docked conformation, the interactions between the amino acids of antigen and antibody were examined. It is found that the docked complex is stabilized by 59.3 kcal/mol. The stability of the docked antigen-antibody complex is due to hydrogen bonding and van der Waals interactions. The amino acids of the antigen and antibody responsible for the interaction were identified.

  1. Epitope mapping porcine reproductive and respiratory syndrome virus by phage display: the nsp2 fragment of the replicase polyprotein contains a cluster of B-cell epitopes

    DEFF Research Database (Denmark)

    Oleksiewicz, M.B.; Bøtner, Anette; Toft, P.; Normann, Preben; Storgaard, Torben

    2001-01-01

    We screened phage display libraries of porcine reproductive and respiratory syndrome virus (PRRSV) protein fragments with sera from experimentally infected pigs to identify linear B-cell epitopes that are commonly recognized during infection in vivo. We identified 10 linear epitope sites (ES) 11 to...

  2. Full protection of swine against foot-and-mouth disease by a bivalent B-cell epitope dendrimer peptide

    NARCIS (Netherlands)

    Blanco, Esther; Guerra, Beatriz; Torre, de la Beatriz; Defaus, Sira; Dekker, A.; Andreu, D.; Sobrino, Francisco

    2016-01-01

    Foot-and-mouth disease virus (FMDV) causes a highly contagious disease of cloven-hoofed animals. We have reported (Cubillos et al., 2008) that a synthetic dendrimeric peptide consisting of four copies of a B-cell epitope [VP1(136–154)] linked through thioether bonds to a T-cell epitope [3A(21–35)] o

  3. Identification of a Coccidioides immitis antigen 2 domain that expresses B-cell-reactive epitopes.

    OpenAIRE

    Zhu, Y; Tryon, V; Magee, D M; Cox, R. A.

    1997-01-01

    Antigen 2 (Ag2), a major immunoreactive component of Coccidioides immitis mycelium- and spherule-phase cell walls, was recently cloned in our laboratory and was shown to elicit T-cell responses in Coccidioides-immune mice. In this investigation, we evaluated recombinant Ag2 (rAg2) and PCR-generated Ag2 truncations for expression of B-cell-reactive epitopes in enzyme-linked immunosorbent and immunoblot assays with sera from patients with active coccidioidomycosis, a hyperimmune goat anti-Ag2 s...

  4. B-Pred, a structure based B-cell epitopes prediction server

    Directory of Open Access Journals (Sweden)

    Giacò L

    2012-07-01

    Full Text Available Luciano Giacò,1 Massimo Amicosante,2 Maurizio Fraziano,1 Pier Federico Gherardini,1 Gabriele Ausiello,1 Manuela Helmer-Citterich,1 Vittorio Colizzi,1 Andrea Cabibbo11Department of Biology, 2Department of Internal Medicine, University of Rome "Tor Vergata", Rome, ItalyAbstract: The ability to predict immunogenic regions in selected proteins by in-silico methods has broad implications, such as allowing a quick selection of potential reagents to be used as diagnostics, vaccines, immunotherapeutics, or research tools in several branches of biological and biotechnological research. However, the prediction of antibody target sites in proteins using computational methodologies has proven to be a highly challenging task, which is likely due to the somewhat elusive nature of B-cell epitopes. This paper proposes a web-based platform for scoring potential immunological reagents based on the structures or 3D models of the proteins of interest. The method scores a protein's peptides set, which is derived from a sliding window, based on the average solvent exposure, with a filter on the average local model quality for each peptide. The platform was validated on a custom-assembled database of 1336 experimentally determined epitopes from 106 proteins for which a reliable 3D model could be obtained through standard modeling techniques. Despite showing poor sensitivity, this method can achieve a specificity of 0.70 and a positive predictive value of 0.29 by combining these two simple parameters. These values are slightly higher than those obtained with other established sequence-based or structure-based methods that have been evaluated using the same epitopes dataset. This method is implemented in a web server called B-Pred, which is accessible at http://immuno.bio.uniroma2.it/bpred. The server contains a number of original features that allow users to perform personalized reagent searches by manipulating the sliding window's width and sliding step, changing the

  5. The Analysis of B-Cell Epitopes of Influenza Virus Hemagglutinin.

    Science.gov (United States)

    Shcherbinin, D N; Alekseeva, S V; Shmarov, M M; Smirnov, Yu A; Naroditskiy, B S; Gintsburg, A L

    2016-01-01

    Vaccination has been successfully used to prevent influenza for a long time. Influenza virus hemagglutinin (HA), which induces a humoral immune response in humans and protection against the flu, is the main antigenic component of modern influenza vaccines. However, new seasonal and pandemic influenza virus variants with altered structures of HA occasionally occur. This allows the pathogen to avoid neutralization with antibodies produced in response to previous vaccination. Development of a vaccine with the new variants of HA acting as antigens takes a long time. Therefore, during an epidemic, it is important to have passive immunization agents to prevent and treat influenza, which can be monoclonal or single-domain antibodies with universal specificity (broad-spectrum agents). We considered antibodies to conserved epitopes of influenza virus antigens as universal ones. In this paper, we tried to characterize the main B-cell epitopes of hemagglutinin and analyze our own and literature data on broadly neutralizing antibodies. We conducted a computer analysis of the best known conformational epitopes of influenza virus HAs using materials of different databases. The analysis showed that the core of the HA molecule, whose antibodies demonstrate pronounced heterosubtypic activity, can be used as a target for the search for and development of broad-spectrum antibodies to the influenza virus. PMID:27099781

  6. Epitopia: a web-server for predicting B-cell epitopes

    Directory of Open Access Journals (Sweden)

    Martz Eric

    2009-09-01

    Full Text Available Abstract Background Detecting candidate B-cell epitopes in a protein is a basic and fundamental step in many immunological applications. Due to the impracticality of experimental approaches to systematically scan the entire protein, a computational tool that predicts the most probable epitope regions is desirable. Results The Epitopia server is a web-based tool that aims to predict immunogenic regions in either a protein three-dimensional structure or a linear sequence. Epitopia implements a machine-learning algorithm that was trained to discern antigenic features within a given protein. The Epitopia algorithm has been compared to other available epitope prediction tools and was found to have higher predictive power. A special emphasis was put on the development of a user-friendly graphical interface for displaying the results. Conclusion Epitopia is a user-friendly web-server that predicts immunogenic regions for both a protein structure and a protein sequence. Its accuracy and functionality make it a highly useful tool. Epitopia is available at http://epitopia.tau.ac.il and includes extensive explanations and example predictions.

  7. B-Pred, a structure based B-cell epitopes prediction server.

    Science.gov (United States)

    Giacò, Luciano; Amicosante, Massimo; Fraziano, Maurizio; Gherardini, Pier Federico; Ausiello, Gabriele; Helmer-Citterich, Manuela; Colizzi, Vittorio; Cabibbo, Andrea

    2012-01-01

    The ability to predict immunogenic regions in selected proteins by in-silico methods has broad implications, such as allowing a quick selection of potential reagents to be used as diagnostics, vaccines, immunotherapeutics, or research tools in several branches of biological and biotechnological research. However, the prediction of antibody target sites in proteins using computational methodologies has proven to be a highly challenging task, which is likely due to the somewhat elusive nature of B-cell epitopes. This paper proposes a web-based platform for scoring potential immunological reagents based on the structures or 3D models of the proteins of interest. The method scores a protein's peptides set, which is derived from a sliding window, based on the average solvent exposure, with a filter on the average local model quality for each peptide. The platform was validated on a custom-assembled database of 1336 experimentally determined epitopes from 106 proteins for which a reliable 3D model could be obtained through standard modeling techniques. Despite showing poor sensitivity, this method can achieve a specificity of 0.70 and a positive predictive value of 0.29 by combining these two simple parameters. These values are slightly higher than those obtained with other established sequence-based or structure-based methods that have been evaluated using the same epitopes dataset. This method is implemented in a web server called B-Pred, which is accessible at http://immuno.bio.uniroma2.it/bpred. The server contains a number of original features that allow users to perform personalized reagent searches by manipulating the sliding window's width and sliding step, changing the exposure and model quality thresholds, and running sequential queries with different parameters. The B-Pred server should assist experimentalists in the rational selection of epitope antigens for a wide range of applications. PMID:22888263

  8. Conserved B-cell epitopes among human bocavirus species indicate potential diagnostic targets.

    Directory of Open Access Journals (Sweden)

    Zhuo Zhou

    Full Text Available BACKGROUND: Human bocavirus species 1-4 (HBoV1-4 have been associated with respiratory and enteric infections in children. However, the immunological mechanisms in response to HBoV infections are not fully understood. Though previous studies have shown cross-reactivities between HBoV species, the epitopes responsible for this phenomenon remain unknown. In this study, we used genomic and immunologic approaches to identify the reactive epitopes conserved across multiple HBoV species and explored their potential as the basis of a novel diagnostic test for HBoVs. METHODOLOGY/PRINCIPAL FINDINGS: We generated HBoV1-3 VP2 gene fragment phage display libraries (GFPDLs and used these libraries to analyze mouse antisera against VP2 protein of HBoV1, 2, and 3, and human sera positive for HBoVs. Using this approach, we mapped four epitope clusters of HBoVs and identified two immunodominant peptides--P1 (¹MSDTDIQDQQPDTVDAPQNT²⁰, and P2 (¹⁶²EHAYPNASHPWDEDVMPDL¹⁸⁰--that are conserved among HBoV1-4. To confirm epitope immunogenicity, we immunized mice with the immunodominant P1 and P2 peptides identified in our screen and found that they elicited high titer antibodies in mice. These two antibodies could only recognize the VP2 of HBoV 1-4 in Western blot assays, rather than those of the two other parvoviruses human parvovirus B19 and human parvovirus 4 (PARV4. Based on our findings, we evaluated epitope-based peptide-IgM ELISAs as potential diagnostic tools for HBoVs IgM antibodies. We found that the P1+P2-IgM ELISA showed a higher sensitivity and specificity in HBoVs IgM detection than the assays using a single peptide. CONCLUSIONS/SIGNIFICANCE: The identification of the conserved B-cell epitopes among human bocavirus species contributes to our understanding of immunological cross-reactivities of HBoVs, and provides important insights for the development of HBoV diagnostic tools.

  9. Construction and characterization of an HCV-derived multi-epitope peptide antigen containing B-cell HVR1 mimotopes and T-cell conserved epitopes

    Institute of Scientific and Technical Information of China (English)

    GAO; Jun; GONG; Yuping; ZHAO; Ping; ZHU; Qing; YANG; Xiaoping; QI; Zhongtian

    2006-01-01

    Hepatitis C (HCV) genome is highly variable, particularly in the hypervariable region 1(HVR1) of its E2 envelope gene. The variability of HCV genome has been a major obstacle for developing HCV vaccines. Due to B-cell HVR1 mimotopes mimicking the antigenicity of natural HVR1 epitopes and some T-cell epitopes from the consensus sequence of HCV genes conserving among the different HCV genotypes, we synthesized an minigene of HCV-derived multi-epitope peptide antigen (CMEP), which contains 9 B-cell HVR1 mimotopes in E2, 2 conserved CTL epitopes in C, 1conserved CTL epitope in NS3 and 1 conserved Th epitope in NS3. This minigene was cloned into a GST expression vector to generate a fusion protein GST-CMER The immunogenic properties of CEMP were characterized by HCV infected patients' sera, and found that the reactivity frequency reached 75%. The cross reactivity of anti-CEMP antibody with different natural HVR1 variants was up to 90%. Meanwhile, we constructed an HCV DNA vaccine candidate, plasmid pVAX1.0-st-CMEP carrying the recombinant gene (st) of a secretion signal peptide and PADRE universal Th cell epitope sequence in front of the CMEP minigene. Immunization of rabbits with pVAX1.0-st-CMEP resulted in the production of antibody, which was of the same cross reactivity as the fusion protein GST-CMEP.Our findings indicate that the HCV-derived multi-epitope peptide antigen in some degree possessed the characteristics of neutralizing HCV epitopes, and would be of the value as a candidate for the development of HCV vaccines.

  10. Multiple linear B-cell epitopes of classical swine fever virus glycoprotein E2 expressed in E.coli as multiple epitope vaccine induces a protective immune response

    Directory of Open Access Journals (Sweden)

    Wei Jian-Chao

    2011-07-01

    Full Text Available Abstract Classical swine fever is a highly contagious disease of swine caused by classical swine fever virus, an OIE list A pathogen. Epitope-based vaccines is one of the current focuses in the development of new vaccines against classical swine fever virus (CSFV. Two B-cell linear epitopes rE2-ba from the E2 glycoprotein of CSFV, rE2-a (CFRREKPFPHRMDCVTTTVENED, aa844-865 and rE2-b (CKEDYRYAISSTNEIGLLGAGGLT, aa693-716, were constructed and heterologously expressed in Escherichia coli as multiple epitope vaccine. Fifteen 6-week-old specified-pathogen-free (SPF piglets were intramuscularly immunized with epitopes twice at 2-week intervals. All epitope-vaccinated pigs could mount an anamnestic response after booster vaccination with neutralizing antibody titers ranging from 1:16 to 1:256. At this time, the pigs were subjected to challenge infection with a dose of 1 × 106 TCID50 virulent CSFV strain. After challenge infection, all of the rE2-ba-immunized pigs were alive and without symptoms or signs of CSF. In contrast, the control pigs continuously exhibited signs of CSF and had to be euthanized because of severe clinical symptoms at 5 days post challenge infection. The data from in vivo experiments shown that the multiple epitope rE2-ba shown a greater protection (similar to that of HCLV vaccine than that of mono-epitope peptide(rE2-a or rE2-b. Therefore, The results demonstrated that this multiple epitope peptide expressed in a prokaryotic system can be used as a potential DIVA (differentiating infected from vaccinated animals vaccine. The E.coli-expressed E2 multiple B-cell linear epitopes retains correct immunogenicity and is able to induce a protective immune response against CSFV infection.

  11. Identification of critical residues of linear B cell epitope on Goodpasture autoantigen.

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    Xiao-yu Jia

    Full Text Available The autoantigen of anti-glomerular basement membrane (GBM disease has been identified as the non-collagenous domain 1 of α3 chain of type IV collagen, α3(IVNC1. Our previous study revealed a peptide on α3(IVNC1 as a major linear epitope for B cells and potentially nephrogenic, designated as P14 (α3129-150. This peptide has also been proven to be the epitope of auto-reactive T cells in anti-GBM patients. This study was aimed to further characterize the critical motif of P14.16 patients with anti-GBM disease and positive anti-P14 antibodies were enrolled. A set of truncated and alanine substituted peptides derived from P14 were synthesized. Circulating antibodies against the peptides were detected by enzyme linked immunosorbent assay (ELISA.We found that all sera with anti-P14 antibodies reacted with the 13-mer sequence in the C-terminus of P14 (P14c exclusively. The level of antibodies against P14 was highly correlated with the level of antibodies against P14c (r=0.970, P<0.001. P14c was the core immunogenic region and the amino acid sequence (ISLWKGFSFIMFT was highly hydrophobic. Each amino acid residue in P14c was sequentially replaced by alanine. Three residues of glycine142, phenylalanine143, and phenylalanine145 were identified crucial for antibody binding based on the remarkable decline (P<0.001 of antibody reaction after each residue replacement.We defined GFxF (α3142, 143,145 as the critical motif of P14. It may provide some clues for understanding the etiology of anti-GBM disease.

  12. An Improved Method for Predicting Linear B-cell Epitope Using Deep Maxout Networks.

    Science.gov (United States)

    Lian, Yao; Huang, Ze Chi; Ge, Meng; Pan, Xian Ming

    2015-06-01

    To establish a relation between an protein amino acid sequence and its tendencies to generate antibody response, and to investigate an improved in silico method for linear B-cell epitope (LBE) prediction. We present a sequence-based LBE predictor developed using deep maxout network (DMN) with dropout training techniques. A graphics processing unit (GPU) was used to reduce the training time of the model. A 10-fold cross-validation test on a large, non-redundant and experimentally verified dataset (Lbtope_Fixed_ non_redundant) was performed to evaluate the performance. DMN-LBE achieved an accuracy of 68.33% and an area under the receiver operating characteristic curve (AUC) of 0.743, outperforming other prediction methods in the field. A web server, DMN-LBE, of the improved prediction model has been provided for public free use. We anticipate that DMN-LBE will be beneficial to vaccine development, antibody production, disease diagnosis, and therapy. PMID:26177908

  13. CD20 mutations involving the rituximab epitope are rare in diffuse large B-cell lymphomas and are not a significant cause of R-CHOP failure

    OpenAIRE

    Johnson, Nathalie A.; Leach, Stephen; Woolcock, Bruce; deLeeuw, Ronald J; Bashashati, Ali; Sehn, Laurie H.; Connors, Joseph M; Chhanabhai, Mukesh; Brooks-Wilson, Angela; Gascoyne, Randy D.

    2009-01-01

    The findings of this study indicate that CD20 mutations nvolving the rituximab epitope are rare in both de novo and relapsed diffuse large B-cell lymphoma, and do not represent a significant cause of R-CHOP resistance.

  14. Porcine B-cells recognize epitopes that are conserved between the structural proteins of American- and European-type porcine reproductive and respiratory syndrome virus

    DEFF Research Database (Denmark)

    Oleksiewicz, Martin B.; Bøtner, Anette; Normann, Preben

    2002-01-01

    By selecting phage display libraries with immune sera from experimentally infected pigs, porcine B-cell epitopes in the open reading frame (ORF) 2, 3, 5 and 6 proteins of European-type porcine reproductive and respiratory syndrome virus (PRRSV) were identified. The sequences of all the epitopes...

  15. Full protection of swine against foot-and-mouth disease by a bivalent B-cell epitope dendrimer peptide.

    Science.gov (United States)

    Blanco, Esther; Guerra, Beatriz; de la Torre, Beatriz G; Defaus, Sira; Dekker, Aldo; Andreu, David; Sobrino, Francisco

    2016-05-01

    Foot-and-mouth disease virus (FMDV) causes a highly contagious disease of cloven-hoofed animals. We have reported (Cubillos et al., 2008) that a synthetic dendrimeric peptide consisting of four copies of a B-cell epitope [VP1(136-154)] linked through thioether bonds to a T-cell epitope [3A(21-35)] of FMDV [B4T(thi)] elicits potent B- and T-cell specific responses and confers solid protection in pigs to type C FMDV challenge. Herein we show that downsized versions of this peptide bearing two copies of a B-cell epitope from a type O isolate and using thioether [B2T(thi)] or maleimide [B2T(mal)] conjugation chemistries for their synthesis elicited in swine similar or higher B and T-cell specific responses than tetravalent B4T(thi). Moreover, while partial protection was observed in animals immunized with B4T(thi) (60%) and B2T(thi) (80%), B2T(mal) conferred full (100%) protection against FMDV challenge, associated to high levels of circulating IgG2 and mucosal IgGA, and entirely prevented virus shedding. Interestingly, B2T(mal) is also the most advantageous option in terms of synthetic practicality. Taken together, the results reported here point out to B2T(mal) as a highly valuable, cost-effective FMDV candidate vaccine. PMID:26956030

  16. Molecular characterization and T and B cell epitopes prediction of Mycoplasma synoviae 53 strain VlhA hemagglutinin

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    Ilana Lopes Camargo

    2007-01-01

    Full Text Available Mycoplasma sinoviae is a major pathogen of poultry causing synovitis and respiratory infection. M. synoviae hemagglutinin (VlhA is a lipoprotein encoded by related multigene families that appear to have arisen by horizontal gene transfer. It is an abundant immunodominant surface protein involved in host-parasite interaction mediating binding to host erythrocytes. Herein, we have performed in silico analysis of the vlhA gene product from the Mycoplasma synoviae 53 strain and compared it to the VlhA protein of M. synoviae WUV1853 strain. The VlhA of the M. synoviae 53 strain possesses 569 amino acids and showed 85% identity with the VlhA protein of the M. synoviae WUV1853 strain. Further, a signal peptide was identified from amino acid M1 to D28 and a cleavage site between D28 and Q29, both located in the N-terminal domain of the molecule. Additionally, an insertion of PAPT amino acids was observed between T30-P35 and a deletion of the amino acids GTPGNP within the PRR region of the VlhA from the M. synoviae 53 strain, which may be related to its reduced virulence. Finally, we have identified 17 B cell epitopes and 22 T cells epitopes within the VlhA from the M. synoviae 53 strain. The B cell epitope S263-D277 and the T cell epitopes N45-N54 and G58-N67 showed 100% and 87-100% identity, respectively, with regions of VlhA protein of tested Mycoplasma synoviae and Mycoplasma galisepticum strains. Thus, these peptides represent new candidate molecules for the development of efficient diagnostic assays and new subunit vaccines.

  17. Human pregnancy-associated malaria-specific B cells target polymorphic, conformational epitopes in VAR2CSA

    DEFF Research Database (Denmark)

    Barfod, L.; Bernasconi, N. L.; Dahlback, M.; Jarrossay, D.; Andersen, Pernille; Salanti, A.; Ofori, M. F.; Turner, L.; Resende, M.; Nielsen, M.A.; Theander, T. G.; Sallusto, F.; Lanzavecchia, A.; Hviid, L.

    -molecular-weight (> 200 kDa) proteins, while seven reacted with either the DBL3-X or the DBL5-epsilon domains of VAR2CSA expressed either as Baculovirus constructs or on the surface of transfected Jurkat cells. We used a panel of recombinant antigens representing DBL3-X domains from P. falciparum field isolates to...... evaluate B-cell epitope diversity among parasite isolates, and identified the binding site of one monoclonal antibody using a chimeric DBL3-X construct. Our findings show that there is a high-frequency memory response to VSA(PAM), indicating that VAR2CSA is a primary target of naturally acquired PAM...

  18. Screening and identification of novel B cell epitopes of Toxoplasma gondii SAG1

    OpenAIRE

    Wang, Yanhua; Wang, Guangxiang; Zhang, Delin; Yin, Hong; Wang, Meng

    2013-01-01

    Background The identification of protein epitopes is useful for diagnostic purposes and for the development of peptide vaccines. In this study, the epitopes of Toxoplasma gondii SAG1 were identified using synthetic peptide techniques with the aid of bioinformatics. Findings Eleven peptides derived from T. gondii SAG1 were assessed by ELISA using pig sera from different time points after infection. Four (PS4, PS6, PS10 and PS11), out of the eleven peptides tested were recognized by all sera. T...

  19. Conserved B-Cell Epitopes among Human Bocavirus Species Indicate Potential Diagnostic Targets

    OpenAIRE

    Zhou, Zhuo; Xin GAO; Wang, Yaying; Zhou, Hongli; Wu, Chao; Paranhos-Baccalà, Gláucia; Vernet, Guy; Guo, Li; Wang, Jianwei

    2014-01-01

    Background Human bocavirus species 1–4 (HBoV1–4) have been associated with respiratory and enteric infections in children. However, the immunological mechanisms in response to HBoV infections are not fully understood. Though previous studies have shown cross-reactivities between HBoV species, the epitopes responsible for this phenomenon remain unknown. In this study, we used genomic and immunologic approaches to identify the reactive epitopes conserved across multiple HBoV species and explore...

  20. Fine level epitope mapping and conservation analysis of two novel linear B-cell epitopes of the avian infectious bronchitis coronavirus nucleocapsid protein.

    Science.gov (United States)

    Han, Zongxi; Zhao, Fei; Shao, Yuhao; Liu, Xiaoli; Kong, Xiangang; Song, Yang; Liu, Shengwang

    2013-01-01

    The nucleocapsid (N) protein of the infectious bronchitis virus (IBV) may play an essential role in the replication and translation of viral RNA. The N protein can also induce high titers of cross-reactive antibodies and cell-mediated immunity, which protects chickens from acute infection. In this study, we generated two monoclonal antibodies (mAbs), designated as 6D10 and 4F10, which were directed against the N protein of IBV using the whole viral particles as immunogens. Both of the mAbs do not cross react with Newcastle disease virus (NDV), infectious laryngotracheitis virus (ILTV) and subtype H9 avian influenza virus (AIV). After screening a phage display peptide library and peptide scanning, we identified two linear B-cell epitopes that were recognized by the mAbs 6D10 and 4F10, which corresponded to the amino acid sequences (242)FGPRTK(247) and (195)DLIARAAKI(203), respectively, in the IBV N protein. Alignments of amino acid sequences from a large number of IBV isolates indicated that the two epitopes, especially (242)FGPRTK(247), were well conserved among IBV strains. This conclusion was further confirmed by the relationships of 18 heterologous sequences to the 2 mAbs. The novel mAbs and the epitopes identified will be useful for developing diagnostic assays for IBV infections. PMID:23123213

  1. Identification of strain-specific B-cell epitopes in Trypanosoma cruzi using genome-scale epitope prediction and high-throughput immunoscreening with peptide arrays.

    Directory of Open Access Journals (Sweden)

    Tiago Antônio de Oliveira Mendes

    Full Text Available BACKGROUND: The factors influencing variation in the clinical forms of Chagas disease have not been elucidated; however, it is likely that the genetics of both the host and the parasite are involved. Several studies have attempted to correlate the T. cruzi strains involved in infection with the clinical forms of the disease by using hemoculture and/or PCR-based genotyping of parasites from infected human tissues. However, both techniques have limitations that hamper the analysis of large numbers of samples. The goal of this work was to identify conserved and polymorphic linear B-cell epitopes of T. cruzi that could be used for serodiagnosis and serotyping of Chagas disease using ELISA. METHODOLOGY: By performing B-cell epitope prediction on proteins derived from pair of alleles of the hybrid CL Brener genome, we have identified conserved and polymorphic epitopes in the two CL Brener haplotypes. The rationale underlying this strategy is that, because CL Brener is a recent hybrid between the TcII and TcIII DTUs (discrete typing units, it is likely that polymorphic epitopes in pairs of alleles could also be polymorphic in the parental genotypes. We excluded sequences that are also present in the Leishmania major, L. infantum, L. braziliensis and T. brucei genomes to minimize the chance of cross-reactivity. A peptide array containing 150 peptides was covalently linked to a cellulose membrane, and the reactivity of the peptides was tested using sera from C57BL/6 mice chronically infected with the Colombiana (TcI and CL Brener (TcVI clones and Y (TcII strain. FINDINGS AND CONCLUSIONS: A total of 36 peptides were considered reactive, and the cross-reactivity among the strains is in agreement with the evolutionary origin of the different T. cruzi DTUs. Four peptides were tested against a panel of chagasic patients using ELISA. A conserved peptide showed 95.8% sensitivity, 88.5% specificity, and 92.7% accuracy for the identification of T. cruzi in

  2. Epitope Prediction Based on Random Peptide Library Screening: Benchmark Dataset and Prediction Tools Evaluation

    OpenAIRE

    Yanxin Huang; Hongyan Wang; Zhiqiang Ma; Yinghua Lv; Pingping Sun; Wenhan Chen

    2011-01-01

    Epitope prediction based on random peptide library screening has become a focus as a promising method in immunoinformatics research. Some novel software and web-based servers have been proposed in recent years and have succeeded in given test cases. However, since the number of available mimotopes with the relevant structure of template-target complex is limited, a systematic evaluation of these methods is still absent. In this study, a new benchmark dataset was defined. Using this benchmark ...

  3. A Nanoparticle Based Sp17 Peptide Vaccine Exposes New Immuno-Dominant and Species Cross-reactive B Cell Epitopes

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    Sue D. Xiang

    2015-10-01

    Full Text Available Sperm protein antigen 17 (Sp17, expressed in primary as well as in metastatic lesions in >83% of patients with ovarian cancer, is a promising ovarian cancer vaccine candidate. Herein we describe the formulation of nanoparticle based vaccines based on human Sp17 (hSp17 sequence derived peptides, and map the immuno-dominant T cell and antibody epitopes induced using such formulations. The primary T and B cell immuno-dominant region within Sp17 was found to be the same when using biocompatible nanoparticle carriers or the conventional “mix-in” pro-inflammatory adjuvant CpG, both mapping to amino acids (aa 111–142. However, delivery of hSp17111–142 as a nanoparticle conjugate promoted a number of new properties, changing the dominant antibody isotype induced from IgG2a to IgG1 and the fine specificity of the B cell epitopes within hSp17111–142, from an immuno-dominant region 134–142 aa for CpG, to region 121–138 aa for nanoparticles. Associated with this change in specificity was a substantial increase in antibody cross-reactivity between mouse and human Sp17. These results indicate conjugation of antigen to nanoparticles can have major effects on fine antigen specificity, which surprisingly could be beneficially used to increase the cross-reactivity of antibody responses.

  4. A Nanoparticle Based Sp17 Peptide Vaccine Exposes New Immuno-Dominant and Species Cross-reactive B Cell Epitopes.

    Science.gov (United States)

    Xiang, Sue D; Gao, Qian; Wilson, Kirsty L; Heyerick, Arne; Plebanski, Magdalena

    2015-01-01

    Sperm protein antigen 17 (Sp17), expressed in primary as well as in metastatic lesions in >83% of patients with ovarian cancer, is a promising ovarian cancer vaccine candidate. Herein we describe the formulation of nanoparticle based vaccines based on human Sp17 (hSp17) sequence derived peptides, and map the immuno-dominant T cell and antibody epitopes induced using such formulations. The primary T and B cell immuno-dominant region within Sp17 was found to be the same when using biocompatible nanoparticle carriers or the conventional "mix-in" pro-inflammatory adjuvant CpG, both mapping to amino acids (aa) 111-142. However, delivery of hSp17111-142 as a nanoparticle conjugate promoted a number of new properties, changing the dominant antibody isotype induced from IgG2a to IgG1 and the fine specificity of the B cell epitopes within hSp17111-142, from an immuno-dominant region 134-142 aa for CpG, to region 121-138 aa for nanoparticles. Associated with this change in specificity was a substantial increase in antibody cross-reactivity between mouse and human Sp17. These results indicate conjugation of antigen to nanoparticles can have major effects on fine antigen specificity, which surprisingly could be beneficially used to increase the cross-reactivity of antibody responses. PMID:26529027

  5. Identification of human linear B-cell epitope sites on the envelope glycoproteins of Crimean-Congo haemorrhagic fever virus.

    Science.gov (United States)

    Goedhals, D; Paweska, J T; Burt, F J

    2015-05-01

    A peptide library was used to screen for regions containing potential linear B-cell epitope sites in the glycoproteins and nucleoprotein of Crimean-Congo haemorrhagic fever virus (CCHFV) in an enzyme-linked immunosorbent assay (ELISA). The library consisted of 156 peptides, spanning the nucleoprotein and mature GN and GC proteins in a 19-mer with 9-mer overlap format. Using pooled serum samples from convalescent patients to screen the library, six peptides were identified as potential epitope sites. Further testing of these six peptides with individual patient sera identified two of these peptides as probable epitope sites, with peptide G1451-1469 reacting to 13/15 and peptide G1613-1631 to 14/15 human sera. These peptides are situated on the GC protein at amino acid positions 1451-1469 (relative to CCHFV isolate SPU103/97) (TCTGCYACSSGISCKVRIH) and 1613-1631 (FMFGWRILFCFKCCRRTRG). Identified peptides may have application in ELISA for diagnostic or serosurveillance purposes. PMID:25185583

  6. Identification of continuous human B-cell epitopes in the VP35, VP40, nucleoprotein and glycoprotein of Ebola virus.

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    Pierre Becquart

    Full Text Available Ebola virus (EBOV is a highly virulent human pathogen. Recovery of infected patients is associated with efficient EBOV-specific immunoglobulin G (IgG responses, whereas fatal outcome is associated with defective humoral immunity. As B-cell epitopes on EBOV are poorly defined, we sought to identify specific epitopes in four EBOV proteins (Glycoprotein (GP, Nucleoprotein (NP, and matrix Viral Protein (VP40 and VP35. For the first time, we tested EBOV IgG+ sera from asymptomatic individuals and symptomatic Gabonese survivors, collected during the early humoral response (seven days after the end of symptoms and the late memory phase (7-12 years post-infection. We also tested sera from EBOV-seropositive patients who had never had clinical signs of hemorrhagic fever or who lived in non-epidemic areas (asymptomatic subjects. We found that serum from asymptomatic individuals was more strongly reactive to VP40 peptides than to GP, NP or VP35. Interestingly, anti-EBOV IgG from asymptomatic patients targeted three immunodominant regions of VP40 reported to play a crucial role in virus assembly and budding. In contrast, serum from most survivors of the three outbreaks, collected a few days after the end of symptoms, reacted mainly with GP peptides. However, in asymptomatic subjects the longest immunodominant domains were identified in GP, and analysis of the GP crystal structure revealed that these domains covered a larger surface area of the chalice bowl formed by three GP1 subunits. The B-cell epitopes we identified in the EBOV VP35, VP40, NP and GP proteins may represent important tools for understanding the humoral response to this virus and for developing new antibody-based therapeutics or detection methods.

  7. Identification and fine mapping of a linear B cell epitope of human vimentin

    DEFF Research Database (Denmark)

    Dam, Catharina Essendrup; Houen, Gunnar; Hansen, Paul R.;

    2014-01-01

    sequence LDSLPLVDTH was identified as the complete epitope, corresponding to amino acids 428-437 in the C-terminal end of the human vimentin protein. Alanine scanning and functionality scanning applying substituted peptides were used to identify amino acids essential for antibody reactivity. In particular...

  8. Immunogenicity of a chimeric peptide corresponding to T helper and B cell epitopes of the Chlamydia trachomatis major outer membrane protein

    OpenAIRE

    1992-01-01

    The immunogenicity of a chimeric T/B cell peptide corresponding to antigenically characterized epitopes of the Chlamydia trachomatis major outer membrane protein (MOMP) was studied in mice to further define its potential use in the development of a subunit vaccine in preventing blinding trachoma in humans. The chimeric peptide, designated A8-VDI, corresponds to a conserved MOMP T helper (Th) cell epitope(s) (A8, residues 106-130) and serovar A VDI (residues 66-80), which contains the serovar-...

  9. Identification of a human immunodominant B-cell epitope within the immunoglobulin A1 protease of Streptococcus pneumoniae

    Science.gov (United States)

    De Paolis, Francesca; Beghetto, Elisa; Spadoni, Andrea; Montagnani, Francesca; Felici, Franco; Oggioni, Marco R; Gargano, Nicola

    2007-01-01

    Background The IgA1 protease of Streptococcus pneumoniae is a proteolytic enzyme that specifically cleaves the hinge regions of human IgA1, which dominates most mucosal surfaces and is the major IgA isotype in serum. This protease is expressed in all of the known pneumococcal strains and plays a major role in pathogen's resistance to the host immune response. The present work was focused at identifying the immunodominant regions of pneumococcal IgA1 protease recognized by the human antibody response. Results An antigenic sequence corresponding to amino acids 420–457 (epiA) of the iga gene product was identified by screening a pneumococcal phage display library with patients' sera. The epiA peptide is conserved in all pneumococci and in two out of three S. mitis strains, while it is not present in other oral streptococci so far sequenced. This epitope was specifically recognized by antibodies present in sera from 90% of healthy adults, thus representing an important target of the humoral response to S. pneumoniae and S. mitis infection. Moreover, sera from 68% of children less than 4 years old reacted with the epiA peptide, indicating that the human immune response against streptococcal antigens occurs during childhood. Conclusion The broad and specific recognition of the epiA polypeptide by human sera demonstrate that the pneumococcal IgA1 protease contains an immunodominant B-cell epitope. The use of phage display libraries to identify microbe or disease-specific antigens recognized by human sera is a valuable approach to epitope discovery. PMID:18088426

  10. Identification of a human immunodominant B-cell epitope within the immunoglobulin A1 protease of Streptococcus pneumoniae

    Directory of Open Access Journals (Sweden)

    Felici Franco

    2007-12-01

    Full Text Available Abstract Background The IgA1 protease of Streptococcus pneumoniae is a proteolytic enzyme that specifically cleaves the hinge regions of human IgA1, which dominates most mucosal surfaces and is the major IgA isotype in serum. This protease is expressed in all of the known pneumococcal strains and plays a major role in pathogen's resistance to the host immune response. The present work was focused at identifying the immunodominant regions of pneumococcal IgA1 protease recognized by the human antibody response. Results An antigenic sequence corresponding to amino acids 420–457 (epiA of the iga gene product was identified by screening a pneumococcal phage display library with patients' sera. The epiA peptide is conserved in all pneumococci and in two out of three S. mitis strains, while it is not present in other oral streptococci so far sequenced. This epitope was specifically recognized by antibodies present in sera from 90% of healthy adults, thus representing an important target of the humoral response to S. pneumoniae and S. mitis infection. Moreover, sera from 68% of children less than 4 years old reacted with the epiA peptide, indicating that the human immune response against streptococcal antigens occurs during childhood. Conclusion The broad and specific recognition of the epiA polypeptide by human sera demonstrate that the pneumococcal IgA1 protease contains an immunodominant B-cell epitope. The use of phage display libraries to identify microbe or disease-specific antigens recognized by human sera is a valuable approach to epitope discovery.

  11. In silico Identification and Validation of a Linear and Naturally Immunogenic B-Cell Epitope of the Plasmodium vivax Malaria Vaccine Candidate Merozoite Surface Protein-9.

    Science.gov (United States)

    Rodrigues-da-Silva, Rodrigo Nunes; Martins da Silva, João Hermínio; Singh, Balwan; Jiang, Jianlin; Meyer, Esmeralda V S; Santos, Fátima; Banic, Dalma Maria; Moreno, Alberto; Galinski, Mary R; Oliveira-Ferreira, Joseli; Lima-Junior, Josué da Costa

    2016-01-01

    Synthetic peptide vaccines provide the advantages of safety, stability and low cost. The success of this approach is highly dependent on efficient epitope identification and synthetic strategies for efficacious delivery. In malaria, the Merozoite Surface Protein-9 of Plasmodium vivax (PvMSP9) has been considered a vaccine candidate based on the evidence that specific antibodies were able to inhibit merozoite invasion and recombinant proteins were highly immunogenic in mice and humans. However the identities of linear B-cell epitopes within PvMSP9 as targets of functional antibodies remain undefined. We used several publicly-available algorithms for in silico analyses and prediction of relevant B cell epitopes within PMSP9. We show that the tandem repeat sequence EAAPENAEPVHENA (PvMSP9E795-A808) present at the C-terminal region is a promising target for antibodies, given its high combined score to be a linear epitope and located in a putative intrinsically unstructured region of the native protein. To confirm the predictive value of the computational approach, plasma samples from 545 naturally exposed individuals were screened for IgG reactivity against the recombinant PvMSP9-RIRII729-972 and a synthetic peptide representing the predicted B cell epitope PvMSP9E795-A808. 316 individuals (58%) were responders to the full repetitive region PvMSP9-RIRII, of which 177 (56%) also presented total IgG reactivity against the synthetic peptide, confirming it validity as a B cell epitope. The reactivity indexes of anti-PvMSP9-RIRII and anti-PvMSP9E795-A808 antibodies were correlated. Interestingly, a potential role in the acquisition of protective immunity was associated with the linear epitope, since the IgG1 subclass against PvMSP9E795-A808 was the prevalent subclass and this directly correlated with time elapsed since the last malaria episode; however this was not observed in the antibody responses against the full PvMSP9-RIRII. In conclusion, our findings identified and

  12. Identification of two linear B-cell epitopes from West Nile virus NS1 by screening a phage-displayed random peptide library

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    Qin Yong-Li

    2011-07-01

    Full Text Available Abstract Background The West Nile virus (WNV nonstructural protein 1 (NS1 is an important antigenic protein that elicits protective antibody responses in animals and can be used for the serological diagnosis of WNV infection. Although previous work has demonstrated the vital role of WNV NS1-specific antibody responses, the specific epitopes in the NS1 have not been identified. Results The present study describes the identification of two linear B-cell epitopes in WNV NS1 through screening a phage-displayed random 12-mer peptide library with two monoclonal antibodies (mAbs 3C7 and 4D1 that directed against the NS1. The mAbs 3C7 and 4D1 recognized phages displaying peptides with the consensus motifs LTATTEK and VVDGPETKEC, respectively. Exact sequences of both motifs were found in the NS1 (895LTATTEK901 and 925VVDGPETKEC934. Further identification of the displayed B cell epitopes were conducted using a set of truncated peptides expressed as MBP fusion proteins. The data indicated that 896TATTEK901 and925VVDGPETKEC934 are minimal determinants of the linear B cell epitopes recognized by the mAbs 3C7 and 4D1, respectively. Antibodies present in the serum of WNV-positive horses recognized the minimal linear epitopes in Western blot analysis, indicating that the two peptides are antigenic in horses during infection. Furthermore, we found that the epitope recognized by 3C7 is conserved only among WNV strains, whereas the epitope recognized by 4D1 is a common motif shared among WNV and other members of Japanese encephalitis virus (JEV serocomplex. Conclusions We identified TATTEK and VVDGPETKEC as NS1-specific linear B-cell epitopes recognized by the mAbs 3C7 and 4D1, respectively. The knowledge and reagents generated in this study may have potential applications in differential diagnosis and the development of epitope-based marker vaccines against WNV and other viruses of JEV serocomplex.

  13. Large-scale analysis of B-cell epitopes on influenza virus hemagglutinin - implications for cross-reactivity of neutralizing antibodies

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    Jing eSun

    2014-02-01

    Full Text Available Influenza viruses continue to cause substantial morbidity and mortality worldwide. Fast gene mutation on surface proteins of influenza virus result in increasing resistance to current vaccines and available antiviral drugs. Broadly neutralizing antibodies represent targets for prophylactic and therapeutic treatments of influenza. We performed a systematic bioinformatics study of cross-reactivity of neutralizing antibodies against influenza virus surface glycoprotein hemagglutinin (HA. This study utilized the available crystal structures of HA complexed with the antibodies for the analysis of tens of thousands of HA sequences. The detailed description of B-cell epitopes, measurement of epitope area similarity among different strains, and estimation of antibody neutralizing coverage provide insights into cross-reactivity status of existing neutralizing antibodies against influenza virus. We have developed a method to assess the likely cross-reactivity potential of broadly neutralizing antibodies for influenza strains, either newly emerged or existing. Our method catalogs influenza strains by a new concept named discontinuous peptide, and then provide assessment of cross-reactivity. Potentially cross-reactive strains are those that share 100% identity with experimentally verified neutralized strains. By cataloging influenza strains and their B-cell epitopes for known broadly neutralizing antibodies, our method provides guidance for selection of representative strains for further experimental design. The knowledge of sequences, their B-cell epitopes, and differences between historical influenza strains, we enhance our preparedness and the ability to respond to the emerging pandemic threats.

  14. Amyloid-β-Anti-Amyloid-β Complex Structure Reveals an Extended Conformation in the Immunodominant B-Cell Epitope

    Energy Technology Data Exchange (ETDEWEB)

    Miles, Luke A; Wun, Kwok S; Crespi, Gabriela A.N.; Fodero-Tavoletti, Michelle T; Galatis, Denise; Bagley, Christopher J; Beyreuther, Konrad; Masters, Colin L; Cappai, Roberto; McKinstry, William J; Barnham, Kevin J; Parker, Michael W [SVIMR-A; (Hanson); (Heidelberg); (Melbourne)

    2012-04-17

    Alzheimer's disease (AD) is the most common form of dementia. Amyloid-β (Aβ) peptide, generated by proteolytic cleavage of the amyloid precursor protein, is central to AD pathogenesis. Most pharmaceutical activity in AD research has focused on Aβ, its generation and clearance from the brain. In particular, there is much interest in immunotherapy approaches with a number of anti-Aβ antibodies in clinical trials. We have developed a monoclonal antibody, called WO2, which recognises the Aβ peptide. To this end, we have determined the three-dimensional structure, to near atomic resolution, of both the antibody and the complex with its antigen, the Aβ peptide. The structures reveal the molecular basis for WO2 recognition and binding of Aβ. The Aβ peptide adopts an extended, coil-like conformation across its major immunodominant B-cell epitope between residues 2 and 8. We have also studied the antibody-bound Aβ peptide in the presence of metals known to affect its aggregation state and show that WO2 inhibits these interactions. Thus, antibodies that target the N-terminal region of Aβ, such as WO2, hold promise for therapeutic development.

  15. Human pregnancy-associated malaria-specific B cells target polymorphic, conformational epitopes in VAR2CSA

    DEFF Research Database (Denmark)

    Barfod, L.; Bernasconi, N. L.; Dahlback, M.;

    2007-01-01

    Pregnancy-associated malaria (PAM) is caused by Plasmodium falciparum-infected erythrocytes (IEs) that bind to chondroitin sulphate A (CSA) in the placenta by PAM-associated clonally variant surface antigens (VSA). Pregnancy-specific VSA (VSA(PAM)), which include the PfEMP1 variant VAR2CSA, are t......-specific protective immunity, and demonstrate the value of human monoclonal antibodies and conformationally intact recombinant antigens in VSA characterization......., are targets of IgG-mediated protective immunity to PAM. Here, we report an investigation of the specificity of naturally acquired immunity to PAM, using eight human monoclonal IgG1 antibodies that react exclusively with intact CSA-adhering IEs expressing VSA(PAM). Four reacted in Western blotting with high...... to evaluate B-cell epitope diversity among parasite isolates, and identified the binding site of one monoclonal antibody using a chimeric DBL3-X construct. Our findings show that there is a high-frequency memory response to VSA(PAM), indicating that VAR2CSA is a primary target of naturally acquired PAM...

  16. Molecular evolution of a central region containing B cell epitopes in the gene encoding the p67 sporozoite antigen within a field population of Theileria parva

    OpenAIRE

    Obara, Isaiah; Ulrike, Seitzer; Musoke, Tony; Paul R Spooner; Jabbar, Ahmed; Odongo, David; Kemp, Stephen; Silva, Joana C.; Bishop, Richard P.

    2015-01-01

    Protective immunity induced by the infective sporozoite stage of Theileria parva indicates a potential role for antibodies directed against conserved serologically reactive regions of the major sporozoite surface antigen p67 in vaccination to control the parasite. We have examined the allelic variation and determined the extent of B cell epitope polymorphism of the gene encoding p67 among field isolates originating from cattle exposed to infected ticks in the Marula area of the rift valley in...

  17. Epitope-Specific Evolution of Human B Cell Responses to Borrelia burgdorferi VlsE Protein from Early to Late Stages of Lyme Disease.

    Science.gov (United States)

    Jacek, Elzbieta; Tang, Kevin S; Komorowski, Lars; Ajamian, Mary; Probst, Christian; Stevenson, Brian; Wormser, Gary P; Marques, Adriana R; Alaedini, Armin

    2016-02-01

    Most immunogenic proteins of Borrelia burgdorferi, the causative agent of Lyme disease, are known or expected to contain multiple B cell epitopes. However, the kinetics of the development of human B cell responses toward the various epitopes of individual proteins during the course of Lyme disease has not been examined. Using the highly immunogenic VlsE as a model Ag, we investigated the evolution of humoral immune responses toward its immunodominant sequences in 90 patients with a range of early to late manifestations of Lyme disease. The results demonstrate the existence of asynchronous, independently developing, Ab responses against the two major immunogenic regions of the VlsE molecule in the human host. Despite their strong immunogenicity, the target epitopes were inaccessible to Abs on intact spirochetes, suggesting a lack of direct immunoprotective effect. These observations document the association of immune reactivity toward specific VlsE sequences with different phases of Lyme disease, demonstrating the potential use of detailed epitope mapping of Ags for staging of the infection, and offer insights regarding the pathogen's possible immune evasion mechanisms. PMID:26718339

  18. A role for collagen IV cross-links in conferring immune privilege to the Goodpasture autoantigen: structural basis for the crypticity of B cell epitopes.

    Science.gov (United States)

    Vanacore, Roberto M; Ham, Amy-Joan L; Cartailler, Jean-Philippe; Sundaramoorthy, Munirathinam; Todd, Parvin; Pedchenko, Vadim; Sado, Yoshikazu; Borza, Dorin-Bogdan; Hudson, Billy G

    2008-08-15

    The detailed structural basis for the cryptic nature (crypticity) of a B cell epitope harbored by an autoantigen is unknown. Because the immune system may be ignorant of the existence of such "cryptic" epitopes, their exposure could be an important feature in autoimmunity. Here we investigated the structural basis for the crypticity of the epitopes of the Goodpasture autoantigen, the alpha3alpha4alpha5 noncollagenous-1 (NC1) hexamer, a globular domain that connects two triple-helical molecules of the alpha3alpha4alpha5 collagen IV network. The NC1 hexamer occurs in two isoforms as follows: the M-isoform composed of monomer subunits in which the epitopes are accessible to autoantibodies, and the D-isoform composed of both monomer and dimer subunits in which the epitopes are cryptic. The D-isoform was characterized with respect to quaternary structure, as revealed by mass spectrometry of dimer subunits, homology modeling, and molecular dynamics simulation. The results revealed that the D-isoform contains two kinds of cross-links as follows: S-hydroxylysyl-methionine and S-lysyl-methionine cross-links, which stabilize the alpha3alpha5-heterodimers and alpha4alpha4-homodimers, respectively. Construction and analysis of a three-dimensional model of the D-isoform of the alpha3alpha4alpha5 NC1 hexamer revealed that crypticity is a consequence of the following: (a) sequestration of key residues between neighboring subunits that are stabilized by domain-swapping interactions, and (b) by cross-linking of subunits at the trimer-trimer interface, which stabilizes the structural integrity of the NC1 hexamer and protects against binding of autoantibodies. The sequestrated epitopes and cross-linked subunits represent a novel structural mechanism for conferring immune privilege at the level of quaternary structure. Perturbation of the quaternary structure may be a key factor in the etiology of Goodpasture disease. PMID:18499662

  19. Large-scale analysis of B-cell epitopes on influenza virus hemagglutinin - implications for cross-reactivity of neutralizing antibodies

    DEFF Research Database (Denmark)

    Sun, Jing; Kudahl, Ulrich J.; Simon, Christian;

    2014-01-01

    Influenza viruses continue to cause substantial morbidity and mortality worldwide. Fast gene mutation on surface proteins of influenza virus result in increasing resistance to current vaccines and available antiviral drugs. Broadly neutralizing antibodies (bnAbs) represent targets for prophylactic...... and therapeutic treatments of influenza. We performed a systematic bioinformatics study of cross-reactivity of neutralizing antibodies (nAbs) against influenza virus surface glycoprotein hemagglutinin (HA). This study utilized the available crystal structures of HA complexed with the antibodies for...... the analysis of tens of thousands of HA sequences. The detailed description of B-cell epitopes, measurement of epitope area similarity among different strains, and estimation of antibody neutralizing coverage provide insights into cross-reactivity status of existing nAbs against influenza virus. We...

  20. Identification of a novel B-cell epitope specific for avian leukosis virus subgroup J gp85 protein.

    Science.gov (United States)

    Li, Xiaofei; Zhu, Haibo; Wang, Qi; Sun, Jiashan; Gao, Yanni; Qi, Xiaole; Wang, Yongqiang; Gao, Honglei; Gao, Yulong; Wang, Xiaomei

    2015-04-01

    Avian leukosis virus subgroup J (ALV-J) is an avian oncogenic retrovirus that has caused severe economic losses in China. Gp85 protein is the main envelope protein and the most variable structural protein of ALV-J. It is also involved in virus neutralization. In this study, a specific monoclonal antibody, 4A3, was produced against the ALV-J gp85 protein. Immunofluorescence assays showed that 4A3 could react with different strains of ALV-J, including the British prototype isolate HPRS103, the American strains, an early Chinese broiler isolate, and layer isolates. A linear epitope on the gp85 protein was identified using a series of partially overlapping fragments spanning the gp85-encoding gene and subjecting them to western blot analysis. The results indicated that (134)AEAELRDFI(142) was the minimal linear epitope that could be recognized by mAb 4A3. Enzyme-linked immunosorbent assay (ELISA) revealed that chicken anti-ALV-J sera and mouse anti-ALV-J gp85 sera could also recognize the minimal linear epitope. Alignment analysis of amino acid sequences indicated that the epitope was highly conserved among 34 ALV-J strains. Furthermore, the epitope was not conserved among subgroup A and B of avian leukosis virus (ALV). Taken together, the mAb and the identified epitope may provide valuable tools for the development of new diagnostic methods for ALV-J. PMID:25655260

  1. Identification of three PPV1 VP2 protein-specific B cell linear epitopes using monoclonal antibodies against baculovirus-expressed recombinant VP2 protein.

    Science.gov (United States)

    Sun, Jianhui; Huang, Liping; Wei, Yanwu; Wang, Yiping; Chen, Dongjie; Du, Wenjuan; Wu, Hongli; Feng, Li; Liu, Changming

    2015-11-01

    Porcine parvovirus type 1 (PPV1) is a major causative agent of embryonic and fetal death in swine. The PPV1 VP2 protein is closely associated with viral immunogenicity for eliciting neutralizing antibodies, but its antigenic structures have been largely unknown. We generated three monoclonal antibodies (MAbs) against baculovirus-expressed recombinant PPV1 VP2 protein. A PEPSCAN analysis identified the minimal B cell linear epitopes of PPV1 VP2 based on these MAbs. Three core epitopes, (228)QQITDA(233), (284)RSLGLPPK(291), and (344)FEYSNGGPFLTPI(356), were defined and mapped onto three-dimensional models of the PPV1 virion and VP2 monomer. The epitope (228)QQITDA(233) is exposed on the virion surface, and the other two are located inside the protein. An alignment of the PPV1 VP2 amino acid sequences showed that (284)RSLGLPPK(291) and (344)FEYSNGGPFLTPI(356) are absolutely conserved, whereas (228)QQITDA(233) has a single substitution at residue 233 in some (S → A or T). We developed a VP2 epitope-based indirect enzyme-linked immunosorbent assay (iELISA) to test for anti-PPV1 antibodies. In a comparative analysis with an immunoperoxidase monolayer assay using 135 guinea pig sera, the VP2-epitope-based iELISA had a concordance rate of 85.19 %, sensitivity of 83.33 %, and specificity of 85.47 %. MAb 8H6 was used to monitor VP2 during the PPV1 replication cycle in vitro with an indirect immunofluorescence assay, which indicated that newly encapsulated virions are released from the nucleus at 24 h postinfection and the PPV1 replication cycle takes less than 24 h. This study provides valuable information clarifying the antigenic structure of PPV1 VP2 and lays the foundations for PPV1 serodiagnosis and antigen detection. PMID:26153140

  2. Identification of a highly conserved and surface exposed B-cell epitope on the nucleoprotein of influenza A virus.

    Science.gov (United States)

    Gui, Xun; Ge, Pinghui; Wang, Xuliang; Yang, Kunyu; Yu, Hai; Zhao, Qinjian; Chen, Yixin; Xia, Ningshao

    2014-06-01

    Influenza virus still poses a major threat to human health worldwide. The nucleoprotein (NP) of influenza A virus plays an essential role in the viral replication and transcription and hence becomes a promising therapeutic target. NP forms a complicated conformation under native conditions and might denature when performing immunoassays such as western blot in the study of NP function. Therefore, it is useful to make an NP specific monoclonal antibody (mAb) that recognizes linear epitope instead of conformational epitope. In this study, a recombinant NP (rNP) of influenza A virus was over-expressed and used to generate a panel of anti-NP mAbs. These anti-NP mAbs were grouped into three classes based on their reactivity in Western blots. Only Class I mAb can react with linear rNP fragments. One of Class I mAb, 4D2, was characterized further by epitope mapping with a series of overlapping synthetic peptides, indicating that the 4D2 epitope is a surface exposed, linear epitope between amino acid residues 243 and 251. This epitope is highly conserved among different influenza A viruses with an identity of 98.4% (17,922/18,210). Western blot, co-immunoprecipitation, immunofluorescence, and immunohistochemistry experiments all indicated 4D2 is highly specific to NP of influenza A virus. The results demonstrated that 4D2 can be used as a research tool for functional study of NP in the replication cycle of influenza A virus. Further work is needed to understand the function and importance of this epitope. PMID:24136709

  3. Identification of a novel canine distemper virus B-cell epitope using a monoclonal antibody against nucleocapsid protein.

    Science.gov (United States)

    Yi, Li; Cheng, Yuening; Zhang, Miao; Cao, Zhigang; Tong, Mingwei; Wang, Jianke; Zhao, Hang; Lin, Peng; Cheng, Shipeng

    2016-02-01

    Canine distemper virus (CDV) is a member of the genus Morbillivirus within the family Paramyxoviridae and has caused severe economic losses in China. Nucleocapsid protein (N) is the major structural viral protein and can be used to diagnose CDV and other morbilliviruses. In this study, a specific monoclonal antibody, 1N8, was produced against the CDV N protein (amino acids 277-471). A linear N protein epitope was identified by subjecting a series of partially overlapping synthesized peptides to enzyme-linked immunosorbent assay (ELISA) analysis. The results indicated that (350)LNFGRSYFDPA(360) was the minimal linear epitope that could be recognized by mAb 1N8. ELISA assays revealed that mouse anti-CDV sera could also recognize the minimal linear epitope. Alignment analysis of the amino acid sequences indicated that the epitope was highly conserved among CDV strains. Furthermore, the epitope was conserved among other morbilliviruses, which was confirmed with PRRV using western blotting. Taken together, the results of this study may have potential applications in the development of suitable diagnostic techniques for CDV or other morbilliviruses. PMID:26514066

  4. Mapping of B-cell epitopes in E. coli asparaginase II, an enzyme used in leukemia treatment.

    Science.gov (United States)

    Werner, Anne; Röhm, Klaus-Heinrich; Müller, Hans-Joachim

    2005-06-01

    The enzyme L-asparaginase is a crucial component in the treatment of acute lymphoblastic leukemia (ALL). As all asparaginases in clinical use are derived from microorganisms, immunological reactions are the most important adverse events associated with asparaginase treatment. Two different methods, phage display and the SPOTs method, were used for the determination of clinically relevant epitopes. Comparison of the results showed that essentially the same domains were identified by the two methods, and thus ascertainment of relevant epitopes can be assumed. Determination of the specificity of the epitopes will be performed with serum from patients with different modes of immunological reactions and from individuals without evidence of an immune response after asparaginase administration. PMID:16006240

  5. Mapping B-cell epitopes for the peroxidoxin of Leishmania (Viannia braziliensis and its potential for the clinical diagnosis of tegumentary and visceral leishmaniasis.

    Directory of Open Access Journals (Sweden)

    Daniel Menezes-Souza

    Full Text Available The search toward the establishment of novel serological tests for the diagnosis of leishmaniasis and proper differential diagnosis may represent one alternative to the invasive parasitological methods currently used to identify infected individuals. In the present work, we investigated the potential use of recombinant peroxidoxin (rPeroxidoxin of Leishmania (Viannia braziliensis as a potential antigen for the immunodiagnosis of human tegumentary (TL and visceral leishmaniasis (VL and canine visceral leishmaniasis (CVL. Linear B-cell epitope mapping was performed to identify polymorphic epitopes when comparing orthologous sequences present in Trypanosoma cruzi, the agent for Chagas disease (CD, and the Homo sapiens and Canis familiaris hosts. The serological assay (ELISA demonstrated that TL, VL and CVL individuals showed high levels of antibodies against rPeroxidoxin, allowing identification of infected ones with considerable sensitivity and great ability to discriminate (specificity between non-infected and CD individuals (98.46% and 100%; 98.18% and 95.71%; 95.79% and 100%, respectively. An rPeroxidoxin ELISA also showed a greater ability to discriminate between vaccinated and infected animals, which is an important requirement for the public campaign control of CVL. A depletion ELISA assay using soluble peptides of this B-cell epitope confirmed the recognition of these sites only by Leishmania-infected individuals. Moreover, this work identifies two antigenic polymorphic linear B-cell epitopes of L. braziliensis. Specific recognition of TL and VL patients was confirmed by significantly decreased IgG reactivity against rPeroxidoxin after depletion of peptide-1- and peptide-2-specific antibodies (peptide 1: reduced by 32%, 42% and 5% for CL, ML and VL, respectively; peptide-2: reduced by 24%, 22% and 13% for CL, ML and VL, respectively and only peptide-2 for CVL (reduced 9%. Overall, rPeroxidoxin may be a potential antigen for the

  6. Antigen presentation by non-immune B-cell hybridoma clones: presentation of synthetic antigenic sites reveals clones that exhibit no specificity and clones that present only one epitope

    Science.gov (United States)

    Cohly, H. H.; Morrison, D. R.; Atassi, M. Z.

    1989-01-01

    Recently, we reported the preparation and antigen-presenting properties of hybridoma B-cell clones obtained after fusing non-secreting, non-antigen presenting Balb/c 653-myeloma cells with non-immune SJL spleen cells. It was found that antigen presentation at the clonal level can be specific or non-specific, depending on the particular B-cell clone. In the present work, one specific and one general presenter B-cell clones were tested for their epitope presentation ability to SJL T-cells that were specific to lysozyme or myoglobin. B-cell clone A1G12, a general presenter which presented both lysozyme and myoglobin to their respective T-cell lines, was found to present all five myoglobin epitopes while clone A1L16, a lysozyme specific presenter presented only one of the three epitopes of lysozyme. The latter reveals a hitherto unknown submolecular specificity (to a given epitope within a protein) for antigen presenting cells at the clonal level. Therefore, the specificity of T-cell recognition does not only derive from the T-cell but may also be dependent on the epitope specificity of the antigen-presenting B-cell.

  7. T cell-independent type I antibody response against B cell epitopes expressed repetitively on recombinant virus particles

    OpenAIRE

    Fehr, Thomas; Skrastina, Dace; Pumpens, Paul; Zinkernagel, Rolf M.

    1998-01-01

    Recombinant viral or virus-like particles offer new tools for vaccine development. This study investigated hepatitis B core antigen (HBcAg) capsids and RNA phage Qβ coats as carriers of a foreign epitope to induce antibody responses in mice. HBcAg capsids were shown to induce T cell-independent (TI) antibodies. We found that these particles behave as antigen-specific TI type 1 (TI-1) Ag comparable to other rigidly structured viruses. When a 5-aa long epitope of the pre-S1 domain of hepatitis ...

  8. Identification and characterization of B-cell epitopes in the DBL4e domain of VAR2CSA

    DEFF Research Database (Denmark)

    Ditlev, Sisse B; Nielsen, Morten A; Resende, Mafalda; Agerbæk, Mette Ø; Pinto, Vera V; Andersen, Pernille H; Magistrado, Pamela; Lusingu, John; Dahlbäck, Madeleine; Theander, Thor G; Salanti, Ali

    2012-01-01

    capacity to inhibit parasite adhesion to CSA. This region was further characterized and together these results suggest that even though antibodies against the synthetic peptides which cover this region did not recognize native protein, the results using the mutant domain suggest that this linear epitope...

  9. A new Leishmania-specific hypothetical protein and its non-described specific B cell conformational epitope applied in the serodiagnosis of canine visceral leishmaniasis.

    Science.gov (United States)

    Lage, Daniela P; Martins, Vívian T; Duarte, Mariana C; Costa, Lourena E; Garde, Esther; Dimer, Laura M; Kursancew, Amanda C S; Chávez-Fumagalli, Miguel A; de Magalhães-Soares, Danielle F; Menezes-Souza, Daniel; Roatt, Bruno M; Machado-de-Ávila, Ricardo A; Soto, Manuel; Tavares, Carlos A P; Coelho, Eduardo A F

    2016-04-01

    The serodiagnosis of canine visceral leishmaniasis (CVL) presents problems related to its sensitivity and/or specificity. In the present study, a new Leishmania-specific hypothetical protein, LiHyD, was produced as a recombinant protein (rLiHyD) and evaluated in ELISA experiments for the CVL serodiagnosis. LiHyD was characterized as antigenic in a recent immunoproteomic search performed with Leishmania infantum proteins and the sera of dogs developing visceral leishmaniasis (VL). Aiming to compare the efficacy between whole proteins and synthetic peptides, two linear and one conformational B cell epitopes of LiHyD were synthesized and also evaluated as diagnostic markers. The four antigens were recognized by the sera of dogs suffering VL. On the contrary, low reactivity was observed when they were assayed with sera from non-infected healthy dogs living in endemic or non-endemic areas of leishmaniasis. In addition, no reactivity was found against them using sera from dogs experimentally infected by Trypanosoma cruzi, Babesia canis, or Ehrlichia canis, or sera from animals vaccinated with the Leish-Tec® vaccine, a prophylactic preparation commercially available for CVL prevention in Brazil. As comparative diagnostic tools, a recombinant version of the amastigote-specific A2 protein and a soluble crude Leishmania extract were studied. Both antigens presented lower sensitivity and/or specificity values than the LiHyD-based products. The rLiHyD presented better results for the CVL serodiagnosis than its linear epitopes, although the peptide recreating the conformational epitope resulted also appropriate as a diagnostic marker of CVL. To the best of our knowledge, this is the first study showing the use of a conformational epitope derived from a Leishmania protein for serodiagnosis of CVL. PMID:26782811

  10. Mapping of B-Cell Epitopes on a Novel 11.5-Kilodalton Fasciola hepatica-Schistosoma mansoni Cross-Reactive Antigen Belonging to a Member of the F. hepatica Saposin-Like Protein Family

    OpenAIRE

    Torres, Daricel; Espino, Ana M.

    2006-01-01

    FhSAP-2 is a novel member of the Fasciola hepatica saposin-like protein family that induces protection in rabbits against a challenge infection. We investigated the presence of lineal B-cell epitopes within this protein using a set of overlapping synthetic peptides. Peptides were tested in enzyme-linked immunosorbent assays against sera from rabbits infected with F. hepatica. Two dominant epitopes were identified, which were also highly reactive with sera from mice infected with Schistosoma m...

  11. General characterization of Tityus fasciolatus scorpion venom. Molecular identification of toxins and localization of linear B-cell epitopes.

    Science.gov (United States)

    Mendes, T M; Guimarães-Okamoto, P T C; Machado-de-Avila, R A; Oliveira, D; Melo, M M; Lobato, Z I; Kalapothakis, E; Chávez-Olórtegui, C

    2015-06-01

    This communication describes the general characteristics of the venom from the Brazilian scorpion Tityus fasciolatus, which is an endemic species found in the central Brazil (States of Goiás and Minas Gerais), being responsible for sting accidents in this area. The soluble venom obtained from this scorpion is toxic to mice being the LD50 is 2.984 mg/kg (subcutaneally). SDS-PAGE of the soluble venom resulted in 10 fractions ranged in size from 6 to 10-80 kDa. Sheep were employed for anti-T. fasciolatus venom serum production. Western blotting analysis showed that most of these venom proteins are immunogenic. T. fasciolatus anti-venom revealed consistent cross-reactivity with venom antigens from Tityus serrulatus. Using known primers for T. serrulatus toxins, we have identified three toxins sequences from T. fasciolatus venom. Linear epitopes of these toxins were localized and fifty-five overlapping pentadecapeptides covering complete amino acid sequence of the three toxins were synthesized in cellulose membrane (spot-synthesis technique). The epitopes were located on the 3D structures and some important residues for structure/function were identified. PMID:25817000

  12. Induction of neutralizing antibodies by a tobacco chloroplast-derived vaccine based on a B cell epitope from canine parvovirus

    International Nuclear Information System (INIS)

    The 2L21 epitope of the VP2 protein from the canine parvovirus (CPV), fused to the cholera toxin B subunit (CTB-2L21), was expressed in transgenic tobacco chloroplasts. Mice and rabbits that received protein-enriched leaf extracts by parenteral route produced high titers of anti-2L21 antibodies able to recognize the VP2 protein. Rabbit sera were able to neutralize CPV in an in vitro infection assay with an efficacy similar to the anti-2L21 neutralizing monoclonal antibody 3C9. Anti-2L21 IgG and seric IgA antibodies were elicited when mice were gavaged with a suspension of pulverized tissues from CTB-2L21 transformed plants. Combined immunization (a single parenteral injection followed by oral boosters) shows that oral boosters help to maintain the anti-2L21 IgG response induced after a single injection, whereas parenteral administration of the antigen primes the subsequent oral boosters by promoting the induction of anti-2L21 seric IgA antibodies. Despite the induced humoral response, antibodies elicited by oral delivery did not show neutralizing capacity in the in vitro assay. The high yield of the fusion protein permits the preparation of a high number of vaccine doses from a single plant and makes feasible the oral vaccination using a small amount of crude plant material. However, a big effort has still to be done to enhance the protective efficacy of subunit vaccines by the oral route

  13. Serum Concentrations of Antibodies against Outer Membrane Protein P6, Protein D, and T- and B-Cell Combined Antigenic Epitopes of Nontypeable Haemophilus influenzae in Children and Adults of Different Ages.

    Science.gov (United States)

    Hua, Chun-Zhen; Hu, Wei-Lin; Shang, Shi-Qiang; Li, Jian-Ping; Hong, Li-Quan; Yan, Jie

    2016-02-01

    Nontypeable Haemophilus influenzae (NTHi) is one of the most common etiologies of acute otitis media, rhinosinusitis, and pneumonia. Outer membrane proteins (OMPs) are the main focus in new vaccine development against NTHi, as the H. influenzae type b (Hib) vaccine does not cover noncapsulated NTHi. The OMPs P6 and protein D are the most promising candidate antigens for an NTHi vaccine, and low antibody levels against them in serum may be correlated with infection caused by NTHi. In the current study, we measured the antibody titers against P6, protein D, and their T- and B-cell combined peptide epitopes in healthy individuals of different ages. We found that children B-cell combined antigenic epitopes. Antibody titers increased at ages 1 to 6 months, peaked at 7 months to 3 years, and remained high at 4 to 6 years. The antibody titers started to decrease after 6 years and were the lowest in the 21- to 30-year group. The geometric mean titers (GMTs) of T- and B-cell combined antigenic epitopes in P6 and protein D were positively correlated with those of the protein antigens. Among 12 peptides tested, P6-61, P6-123, and protein D-167 epitopes were better recognized than others in human serum. These findings might contribute to the development of an effective serotype-independent vaccine for H. influenzae. PMID:26677200

  14. Prediction of Secondary Structure and B Cell Epitope of GH Protein from Acipenser sinensis%中华鲟GH蛋白二级结构和B细胞抗原表位的预测

    Institute of Scientific and Technical Information of China (English)

    刘红艳; 杨东; 张繁荣; 余来宁

    2009-01-01

    [Objective] The aim was to predict the secondary structure and B cell epitope of growth hormone (GH) protein from Acipenser sinensis. [Method] With the amino acid sequence of GH protein from A.sinensis as the base, the secondary structure of GH protein from A.sinensis was predicted by the method of Garnier-Robson, Chou-Fasman and Karplus-Schulz, and its cell epitope was predicted by the method of Kyte-Doolittle, Emini and Jameson-Wolf. [Result] The sections of 18-23, 55-56, 67-73, 83-86, 112-114, 151-157 and 209-211 in the N terminal of GH protein molecule had softer structure and these sections could sway or fold to produce more complex tertiary structure. The sections of 19-23, 51-71, 84-95, 128-139, 164-176 and 189-196 in the N terminal of GH protein could be the epitope of B cell and there were flexible regions in these sections or near these sections of GH protein molecule. So the dominant regions could be in these sections or near these sections. [Conclusion] The research provided the basis for the preparation of monoclonal antibody of GH protein from A.sinensis and provided the reference for the discussion for the molecular regulation mechanism of A.sinensis.

  15. Identification and characterization of a virus-specific continuous B-cell epitope on the PrM/M protein of Japanese Encephalitis Virus: potential application in the detection of antibodies to distinguish Japanese Encephalitis Virus infection from West Nile Virus and Dengue Virus infections

    Directory of Open Access Journals (Sweden)

    Liu Wen-Xin

    2010-09-01

    Full Text Available Abstract Background Differential diagnose of Japanese encephalitis virus (JEV infection from other flavivirus especially West Nile virus (WNV and Dengue virus (DV infection was greatly hindered for the serological cross-reactive. Virus specific epitopes could benefit for developing JEV specific antibodies detection methods. To identify the JEV specific epitopes, we fully mapped and characterized the continuous B-cell epitope of the PrM/M protein of JEV. Results To map the epitopes on the PrM/M protein, we designed a set of 20 partially overlapping fragments spanning the whole PrM, fused them with GST, and expressed them in an expression vector. Linear epitope M14 (105VNKKEAWLDSTKATRY120 was detected by enzyme-linked immunosorbent assay (ELISA. By removing amino acid residues individually from the carboxy and amino terminal of peptide M14, we confirmed that the minimal unit of the linear epitope of PrM/M was M14-13 (108KEAWLDSTKAT118. This epitope was highly conserved across different JEV strains. Moreover, this epitope did not cross-react with WNV-positive and DENV-positive sera. Conclusion Epitope M14-13 was a JEV specific lineal B-cell epitpe. The results may provide a useful basis for the development of epitope-based virus specific diagnostic clinical techniques.

  16. A Synthetic Virus-Like Particle Streptococcal Vaccine Candidate Using B-Cell Epitopes from the Proline-Rich Region of Pneumococcal Surface Protein A

    Directory of Open Access Journals (Sweden)

    Marco Tamborrini

    2015-10-01

    Full Text Available Alternatives to the well-established capsular polysaccharide-based vaccines against Streptococcus pneumoniae that circumvent limitations arising from limited serotype coverage and the emergence of resistance due to capsule switching (serotype replacement are being widely pursued. Much attention is now focused on the development of recombinant subunit vaccines based on highly conserved pneumococcal surface proteins and virulence factors. A further step might involve focusing the host humoral immune response onto protective protein epitopes using as immunogens structurally optimized epitope mimetics. One approach to deliver such epitope mimetics to the immune system is through the use of synthetic virus-like particles (SVLPs. SVLPs are made from synthetic coiled-coil lipopeptides that are designed to spontaneously self-assemble into 20–30 nm diameter nanoparticles in aqueous buffer. Multivalent display of epitope mimetics on the surface of SVLPs generates highly immunogenic nanoparticles that elicit strong epitope-specific humoral immune responses without the need for external adjuvants. Here, we set out to demonstrate that this approach can yield vaccine candidates able to elicit a protective immune response, using epitopes derived from the proline-rich region of pneumococcal surface protein A (PspA. These streptococcal SVLP-based vaccine candidates are shown to elicit strong humoral immune responses in mice. Following active immunization and challenge with lethal doses of streptococcus, SVLP-based immunogens are able to elicit significant protection in mice. Furthermore, a mimetic-specific monoclonal antibody is shown to mediate partial protection upon passive immunization. The results show that SVLPs combined with synthetic epitope mimetics may have potential for the development of an effective vaccine against Streptococcus pneumoniae.

  17. Identification of immunodominant regions and linear B cell epitopes of the gE envelope protein of varicella-zoster virus.

    Science.gov (United States)

    Fowler, W J; Garcia-Valcarcel, M; Hill-Perkins, M S; Murphy, G; Harper, D R; Jeffries, D J; Burns, N R; Adams, S E; Kingsman, A J; Layton, G T

    1995-12-20

    The envelope proteins of varicella-zoster virus (VZV) are highly immunogenic and one of the most abundant is glycoprotein E (gE). However, its immunodominant regions and epitopes have not been identified. In this study, using human sera from individuals with recent varicella or zoster infections, we have localized antigenic sequences of gE using recombinant hybrid Ty-virus-like particles (VLPs) carrying overlapping fragments of the gE protein. gE(1-134)-VLPs (particles carrying amino acids 1-134 of gE) and, to a lesser extent, gE(101-161)-VLPs were found to be the most antigenic when tested by Western blotting and ELISA. Other fragments of gE (spanning residues 161-623) showed weak or no antigenicity. Pepscan analysis of human sera on overlapping synthetic peptides representing residues 1-135 of gE revealed that the most antigenic region was between residues 50 and 135. Three immunodominant sequences (residues 86-105, 116-135, and, to a lesser extent, 56-75) were detected using sera from both varicella and zoster patients. All sera from varicella, but not zoster, patients reacted strongly with an epitope in peptide 66-85. Other epitopes were recognized weakly by some varicella or zoster sera. More sera need to be tested to assess the potential disease specificity of these epitopes. The neutralizing monoclonal antibody (MAb) IF-B9 reacted with residues 71-90; however, another neutralizing MAb, SG1A, which bound to both gE(1-134)-VLPs and gE(101-161)-VLPs did not bind to any peptide. The identification of immunodominant sequences of gE will help toward the development of a subunit VZV vaccine. PMID:8553555

  18. Antibody-protein interactions: benchmark datasets and prediction tools evaluation

    Directory of Open Access Journals (Sweden)

    Ponomarenko Julia V

    2007-10-01

    Full Text Available Abstract Background The ability to predict antibody binding sites (aka antigenic determinants or B-cell epitopes for a given protein is a precursor to new vaccine design and diagnostics. Among the various methods of B-cell epitope identification X-ray crystallography is one of the most reliable methods. Using these experimental data computational methods exist for B-cell epitope prediction. As the number of structures of antibody-protein complexes grows, further interest in prediction methods using 3D structure is anticipated. This work aims to establish a benchmark for 3D structure-based epitope prediction methods. Results Two B-cell epitope benchmark datasets inferred from the 3D structures of antibody-protein complexes were defined. The first is a dataset of 62 representative 3D structures of protein antigens with inferred structural epitopes. The second is a dataset of 82 structures of antibody-protein complexes containing different structural epitopes. Using these datasets, eight web-servers developed for antibody and protein binding sites prediction have been evaluated. In no method did performance exceed a 40% precision and 46% recall. The values of the area under the receiver operating characteristic curve for the evaluated methods were about 0.6 for ConSurf, DiscoTope, and PPI-PRED methods and above 0.65 but not exceeding 0.70 for protein-protein docking methods when the best of the top ten models for the bound docking were considered; the remaining methods performed close to random. The benchmark datasets are included as a supplement to this paper. Conclusion It may be possible to improve epitope prediction methods through training on datasets which include only immune epitopes and through utilizing more features characterizing epitopes, for example, the evolutionary conservation score. Notwithstanding, overall poor performance may reflect the generality of antigenicity and hence the inability to decipher B-cell epitopes as an

  19. Immune Epitope Database and Analysis Resource (IEDB)

    Data.gov (United States)

    U.S. Department of Health & Human Services — This repository contains antibody/B cell and T cell epitope information and epitope prediction and analysis tools for use by the research community worldwide....

  20. Conjugation of alginate to a synthetic peptide containing T- and B-cell epitopes as an induction for protective immunity against Pseudomonas aeruginosa.

    Science.gov (United States)

    Farjaha, Ali; Owlia, Parviz; Siadat, Seyed Davar; Mousavi, Seyed Fazlollah; Shafieeardestani, Mehdi

    2014-12-20

    Pseudomonas aeruginosa is a major cause of respiratory tract infections worldwide, particularly in hospitalized patients with immunosuppressed conditions and cystic fibrosis (CF). Excessive use of antibiotics means that there is currently resistance among bacterial infections to many drugs. Vaccination is a strategy that can reduce mortality and morbidity rates in infections such as those caused by P. aeruginosa. Alginate has a critical role in such infections and affects pathogenicity of the bacterium. In this work, the bioinformatics approach was used to design and synthesis a carrier peptide (ERRANAVRDVLVNEY), derived from OMP F P. aeruginosa. This peptide contained both B- and T-cell epitopes based on prediction models. Conjugation of alginate to carrier peptide was performed and then analyzed by Fourier transform infrared spectroscopy (FTIR). Results of this study on mice showed that the conjugate elicited anti-alginate-IgG that were not detected after immunization with naive alginate. The effect of the antibodies to alginate conjugate was evaluated as highly opsonic and showed moderate to high-level killing activity against two mucoid strains. IgG1 was also dominant among IgG subclasses. Mice vaccinated with the conjugate vaccine survived lethal challenges (2 ×LD 50). Furthermore, using an acute pneumonia model of infection in mice, determined that levels of P. aeruginosa in mice were significantly reduced in the vaccinated group. Thus, tests confirmed ability of this conjugate to elicit protective and opsonophagocytic antibodies that candidate our vaccine for further studies. PMID:25449544

  1. Optimization screening for the B cell epitope of the extracellular domain of the follicle stimulating hormone receptor%卵泡刺激素受体(FSHR)胞外区B细胞表位的优化筛选

    Institute of Scientific and Technical Information of China (English)

    杨利华; 李鸥; 王树峰; 梁志清; 吴玉章; 何畏

    2012-01-01

    目的:采用生物信息学技术,对前期研究获得的卵泡刺激素受体(FSHR)的B细胞表位肽段进一步筛选、优化,以获得理想的FSHR靶标抗原.方法:①利用InsightⅡ分子模拟软件寻找FSHR与FSH相互作用的区域.②应用DNA STAR 软件中的Protein模块对优化后抗原进行综合分析.③肽结合实验对优化后抗原进行免疫原性检测.结果:≥5个氨基酸片段的柔性区域位于FSHR第30 - 44、52 - 65、112 - 121、174 - 182、190 - 210、223 - 245区段.当FSHR胞外区第37位缬氨酸被赖氨酸或谷氨酸替代时,具有较好的亲水性及抗原性.而肽结合实验证实肽32 - 44具有更好的免疫原性.结论:FSHR胞外区肽段32-44有可能成为避孕疫苗的理想抗原.%Objective; To obtain the desired antigen targeting - FSHR, we screened and optimized the B cell epitope for the extracellular domain of the follicle stimulating hormone receptor (FSHR) . Methods; ①Insight II molecular simulation software was used to i-dentity amino acid sites of interaction interface between FSH and FSHR. ②The secondary structure and surface properties of the extracellular domain of FSHR, such as physical and chemical properties, hydrophilicity, antigenicity and plasticity, were analyzed by a variety of methods. ③The peptide of the epitopes was synthesized and used for coating streptavidin plate. The immunogenicity of the peptides was determined. Results; Many distinct antigenic epitopes in the extracellular domain of FSHR were identified by computation, the possible location of which was in the regions of 30 ~ 44, 52 ~ 65 , 112 ~ 121, 174 ~ 182, 190 ~ 210 and 223 ~ 245. When the FSHR ectodomain 37th valine was replaced by lysine and glutamic acid, the antigen had better hydrophilicity and antigenic. However, the peptide 32-44 was confirmed the best immunogenicity in ELISA assay. Conclusion; FSHR ectodomain peptide 32 ~44 can be the ideal contraceptive vaccine antigens.

  2. 猪带绦虫六钩蚴TSO45-4B抗原FnⅢ结构域相应的线性B细胞表位肽免疫原性研究%Research on immunity response about Taenia solium oncosphere TSO45-4B antigens FnⅢ structure domain linear B cells epitope peptides

    Institute of Scientific and Technical Information of China (English)

    王媛媛; 陶志勇; 杨小迪; 王小莉; 常雪莲; 陈勇; 孙新; 夏惠; 方强

    2013-01-01

    Objective: To observe the humoral immune response induced by Taenia solium oncosphere TSO45-4B antigens Fn Ⅲ structure domain linear B cells epitope peptides in mice. Methods: The two predicted B cell epitope peptides of TSO45-4B Fn Ⅲ structure domain conjugated with carrier protein of keyhole limpet hemocyanin were synthesized and used to immunize mice. The mice specific serum antibody titer to the epitope peptides synthesized was tested by ELISA. Results: The specific antibody to one of the predicted epitope peptides synthesized was found in mice serum,and the titer was 1: 1 280. Conclusions: One of the two predicted linear B cell epitope peptides of TSO45-4B FnⅢ structure domain can induce the humoral immune response in mice.%目的:观察载体蛋白偶联的TSO45-4B抗原FnⅢ结构域相应的线性B细胞表位肽诱导的体液免疫反应.方法:人工合成TSO45-4B抗原FnⅢ结构域2条预测表位肽,偶联钥孔血蓝蛋白免疫小鼠,采用ELISA法检测小鼠血清中预测表位肽特异性抗体滴度.结果:免疫小鼠血清中检测到1条预测表位肽特异性抗体,其效价达到1:1 280.结论:设计的1条TSO45-4B抗原FnⅢ结构域线性B细胞表位肽可诱导小鼠产生体液免疫反应.

  3. Benchmarking Benchmarks

    NARCIS (Netherlands)

    D.C. Blitz (David)

    2011-01-01

    textabstractBenchmarking benchmarks is a bundle of six studies that are inspired by the prevalence of benchmarking in academic finance research as well as in investment practice. Three studies examine if current benchmark asset pricing models adequately describe the cross-section of stock returns. W

  4. Prediction and identification of Taenia solium oncosphere TSO45-4B antigen FnⅢ structure domain linear B cell epitopes%猪带绦虫六钩蚴TSO45-4B抗原FnⅢ结构域线性B细胞表位预测及鉴定

    Institute of Scientific and Technical Information of China (English)

    王媛媛; 王小莉; 常雪莲; 陶志勇; 夏惠; 方强

    2012-01-01

    Objective To predict and identify Taenia solium oncosphere TSO45-4B antigen FnⅢ structure domain linear B cell epitopes. Methods The B cell epitopes of TSO45-4B FnⅢ structure domain were predicted through the sequence analysis by using bioinformatics online tools and the protein space conformation was predicted by SWISS-MODEL. The peptides were synthesized according to the predicted linear epitopes. The immunoreactivity of sera of cysticercosis patients to the peptides synthesized was tested by using ELISA. Results Two linear B cell epitopes of TSO45-4B FnⅢ structure domain were predicted, and one of the predicted epitope peptides synthesized could be recognized by the sera of cysticercosis patients. Conclusion Two linear B cell epitopes of TSO45-4B Fn Ⅲ structure domain are predicted and one of them has been confirmed successfully.%目的 预测并鉴定猪带绦虫六钩蚴TSO45-4B抗原FnⅢ结构域线性B细胞表位.方法 利用生物信息学在线工具分析TSO45-4B抗原FnⅢ结构域序列并预测其线性B细胞表位;采用SWISS-MODEL软件预测TSO45-4B的蛋白空间结构,并合成两条预测表位肽.采用酶联免疫吸附试验(ELISA)检测猪囊尾蚴病人血清与两条预测表位肽的免疫反应性.结果 获得2个TSO45-4B抗原FnⅢ结构域线性B细胞预测表位,其中1条预测表位合成肽可为猪囊尾蚴病患者血清识别.结论 成功预测并鉴定了猪带绦虫六钩蚴TSO45-4B抗原FnⅢ结构域线性B细胞表位.

  5. Immune epitope database analysis resource

    DEFF Research Database (Denmark)

    Kim, Yohan; Ponomarenko, Julia; Zhu, Zhanyang;

    2012-01-01

    homology mapping tool was updated to enable mapping of discontinuous epitopes onto 3D structures. Furthermore, to serve a wider range of users, the number of ways in which IEDB-AR can be accessed has been expanded. Specifically, the predictive tools can be programmatically accessed using a web interface......The immune epitope database analysis resource (IEDB-AR: http://tools.iedb.org) is a collection of tools for prediction and analysis of molecular targets of T- and B-cell immune responses (i.e. epitopes). Since its last publication in the NAR webserver issue in 2008, a new generation of peptide......:MHC binding and T-cell epitope predictive tools have been added. As validated by different labs and in the first international competition for predicting peptide:MHC-I binding, their predictive performances have improved considerably. In addition, a new B-cell epitope prediction tool was added, and the...

  6. Cloning,expression and purification of B cell epitope antigen peptide of EGFR dimerization%EGFR二聚化B细胞表位抗原肤基因克隆、表达与纯化

    Institute of Scientific and Technical Information of China (English)

    朱磊; 吴梅芝; 赵林; 黄绮玲; 梁梅; 李黄金

    2011-01-01

    目的 利用基因工程手段建立表皮生长因子受体(EGFR)二聚化B细胞表位抗原肽MVF-ER的高效制备方法.方法 采用重叠延伸PCR扩增MVF-ER后克隆于表达载体pET32a,于大肠杆菌BL21(DE3)进行表达,产物采用肠激酶酶切和镍离子鳌合亲和层析法纯化.结果 通过10对引物5步重叠延伸得到273bp的扩增产物,目的基因与硫氧环蛋白(Trx)融合后可高效表达,经酶切和层析后得到纯度为95%的抗原肤.结论 成功建立抗原肽"MVF-ER"的高效制备方法,为进一步研究EGFR过表达恶性肿瘤的治疗性疫苗打下了坚实基础.%We aim to establish a high performance preparation system for B cell epitope antigen peptide of EGFR dimerization for further research on therapeutic vaccine of EGFR over-expression tumors. The MVF-ER gene of 273 bp was amplified by splicing overlap extension PCR (SOE-PCR), then cloned into the vector of pET32a, and expressed in E.coli BL21 (DE3) in the form of fusion with Trx. The expression product was purified by Ni+ affinity chromatography. The antigen peptide was recovered from the fusion protein by enterokinase and purified to a purity of 95% confirmed by SDS-PAGE. The results above showed that the preparation method of MVF-ER antigen peptide was successfully established, which will facilitate further study of the therapeutic cancer vaccine.

  7. ElliPro: a new structure-based tool for the prediction of antibody epitopes

    Directory of Open Access Journals (Sweden)

    Fusseder Nicholas

    2008-12-01

    Full Text Available Abstract Background Reliable prediction of antibody, or B-cell, epitopes remains challenging yet highly desirable for the design of vaccines and immunodiagnostics. A correlation between antigenicity, solvent accessibility, and flexibility in proteins was demonstrated. Subsequently, Thornton and colleagues proposed a method for identifying continuous epitopes in the protein regions protruding from the protein's globular surface. The aim of this work was to implement that method as a web-tool and evaluate its performance on discontinuous epitopes known from the structures of antibody-protein complexes. Results Here we present ElliPro, a web-tool that implements Thornton's method and, together with a residue clustering algorithm, the MODELLER program and the Jmol viewer, allows the prediction and visualization of antibody epitopes in a given protein sequence or structure. ElliPro has been tested on a benchmark dataset of discontinuous epitopes inferred from 3D structures of antibody-protein complexes. In comparison with six other structure-based methods that can be used for epitope prediction, ElliPro performed the best and gave an AUC value of 0.732, when the most significant prediction was considered for each protein. Since the rank of the best prediction was at most in the top three for more than 70% of proteins and never exceeded five, ElliPro is considered a useful research tool for identifying antibody epitopes in protein antigens. ElliPro is available at http://tools.immuneepitope.org/tools/ElliPro. Conclusion The results from ElliPro suggest that further research on antibody epitopes considering more features that discriminate epitopes from non-epitopes may further improve predictions. As ElliPro is based on the geometrical properties of protein structure and does not require training, it might be more generally applied for predicting different types of protein-protein interactions.

  8. Linear B-cell epitopes in BthTX-1, BthTX-II and BthA-1, phospholipase A₂'s from Bothrops jararacussu snake venom, recognized by therapeutically neutralizing commercial horse antivenom.

    Science.gov (United States)

    De-Simone, Salvatore G; Napoleão-Pego, Paloma; Teixeira-Pinto, Luiz A L; Santos, Jonathas D L; De-Simone, Thatiane S; Melgarejo, Anibal R; Aguiar, Aniesse S; Marchi-Salvador, Daniela P

    2013-09-01

    The benefits from treatment with antivenom sera are indubitable. However, the mechanism for toxin neutralization has not been completely elucidated. A mixture of anti-bothropic and anti-crotalic horse antivenom has been reported to be more effective in neutralizing the effects of Bothrops jararacussu snake venom than anti-bothropic antivenom alone. This study determined which regions in the three PLA₂s from B. jararacussu snake venom are bound by antibodies in tetravalent anti-bothropic and monovalent anti-crotalic commercial horse antivenom. Mapping experiments of BthTX-I, BthTX-II and BthA-I using two small libraries of 69 peptides each revealed six major IgG-binding epitopes that were recognized by both anti-bothropic and anti-crotalic horse antivenom. Two epitopes in BthTX-I were only recognized by the anti-bothropic horse antivenom, while anti-crotalic horse antivenom recognized four unique epitopes across the three PLA₂s. Our studies suggest that the harmful activities of the PLA₂s present in the venom of B. jararacussu are neutralized by the combinatorial treatment with both antivenom sera through their complementary binding sites, which provides a wide coverage on the PLA₂s. This is the first peptide microarray of PLA₂s from B. jararacussu snake venom to survey the performance of commercial horse antiophidic antivenom. Regions recognized by the protective antivenom sera are prime candidates for improved venom cocktails or a chimeric protein encoding the multiple epitopes to immunize animals as well as for designing future synthetic vaccines. PMID:23792452

  9. 空肠弯曲菌主要外膜蛋白 OMP18的B 细胞抗原表位分析及功能鉴定%Analysis and identification of B cell epitopes of the OMP18 from Campy lobacter jejuni

    Institute of Scientific and Technical Information of China (English)

    楼宏强; 胡野; 王岚; 单小云; 盛秀胜; 高素华

    2014-01-01

    目的:从生物信息学角度了解空肠弯曲菌主要外膜蛋白OM P18的跨膜结构、B细胞抗原表位及其抗原性、基因序列保守性等特征,并鉴定空肠弯曲菌主要外膜蛋白优势B细胞抗原表位,为后续抗体检测和疫苗研究提供实验依据。方法使用NCBI/Blast ,TMHMM Server V2.0,DNA Star等生物信息学分析软件对空肠弯曲菌主要外膜蛋白OMP18进行蛋白跨膜结构预测、线性B细胞抗原表位及其抗原性分析、并对不同空肠弯曲菌OM P18蛋白的氨基酸序列同源性进行比较。采用空肠弯曲菌全菌抗体IgG为一抗,基于ELISA技术对优势线性B细胞抗原表位进行筛选鉴定。结果生物信息学预测结果表明外膜蛋白OM P18定位于空肠弯曲菌外膜且不存在跨膜结构。蛋白序列保守存在于各空肠弯曲菌株中,序列同源性达95%以上。同时,我们发现该外膜蛋白中存在3个明显的B细胞线性表位,且具有很强的抗原性。ELISA检测鉴定结果表明3个B细胞抗原表位都能有效识别空肠弯曲菌全菌抗体。结论空肠弯曲菌主要外膜蛋白O M P18保守存在于细菌表面,存在3个重要的B细胞线性抗原表位,可用于后续的抗体检测和疫苗开发研究。%In this study ,we aimed to understand the sequence characteristics ,transmembrane structures ,line B cell epitopes present in the OMP18 from Campylobacter jejuni ,and provide candidate antigens for the antibody detection and vac-cine development .NCBI/Blast ,TMHMM Server V2 and DNA Star softwares were used for the OMP18 sequence analysis . Based on the ELISA ,the whole bacterial antibody IgG of Campylobacter jejuni was used for the identification of the predicted line B cell epitopes .The OMP18 gene was found conserved in different Campylobacter jejuni strains .The OMP18 was predic-ted to be located on the outer surface of the bacteria .And three line B cell epitopes were determined to be present in

  10. Design of targeted B cell killing agents.

    Directory of Open Access Journals (Sweden)

    Alexey V Stepanov

    Full Text Available B cells play an important role in the pathogenesis of both systemic and organ-specific autoimmune diseases. Autoreactive B cells not only produce autoantibodies, but also are capable to efficiently present specific autoantigens to T cells. Furthermore, B cells can secrete proinflammatory cytokines and amplify the vicious process of self-destruction. B cell-directed therapy is a potentially important approach for treatment of various autoimmune diseases. The depletion of B cells by anti-CD20/19 monoclonal antibody Retuximab® used in autoimmune diseases therapy leads to systemic side effects and should be significantly improved. In this study we designed a repertoire of genetically engineered B cell killers that specifically affected one kind of cells carrying a respective B cell receptor. We constructed immunotoxins (ITs, fused with c-myc epitope as a model targeting sequence, based on barnase, Pseudomonas toxin, Shiga-like toxin E.coli and Fc domain of human antibody IgGγ1. C-MYC hybridoma cell line producing anti-c-myc IgG was chosen as a model for targeted cell depletion. C-myc sequence fused with toxins provided addressed delivery of the toxic agent to the target cells. We demonstrated functional activity of designed ITs in vitro and showed recognition of the fusion molecules by antibodies produced by targeted hybridoma. To study specificity of the proposed B cells killing molecules, we tested a set of created ITs ex vivo, using C-MYC and irrelevant hybridoma cell lines. Pseudomonas-containing IT showed one of the highest cytotoxic effects on the model cells, however, possessed promiscuous specificity. Shiga-like toxin construct demonstrated mild both cytotoxicity and specificity. Barnase and Fc-containing ITs revealed excellent balance between their legibility and toxic properties. Moreover, barnase and Fc molecules fused with c-myc epitope were able to selectively deplete c-myc-specific B cells and decrease production of anti

  11. The Chikungunya Virus Capsid Protein Contains Linear B Cell Epitopes in the N- and C-Terminal Regions that are Dependent on an Intact C-Terminus for Antibody Recognition

    Directory of Open Access Journals (Sweden)

    Lucas Y. H. Goh

    2015-06-01

    Full Text Available Chikungunya virus (CHIKV is an arthropod-borne agent that causes severe arthritic disease in humans and is considered a serious health threat in areas where competent mosquito vectors are prevalent. CHIKV has recently been responsible for several millions of cases of disease, involving over 40 countries. The recent re-emergence of CHIKV and its potential threat to human health has stimulated interest in better understanding of the biology and pathogenesis of the virus, and requirement for improved treatment, prevention and control measures. In this study, we mapped the binding sites of a panel of eleven monoclonal antibodies (mAbs previously generated towards the capsid protein (CP of CHIKV. Using N- and C-terminally truncated recombinant forms of the CHIKV CP, two putative binding regions, between residues 1–35 and 140–210, were identified. Competitive binding also revealed that five of the CP-specific mAbs recognized a series of overlapping epitopes in the latter domain. We also identified a smaller, N-terminally truncated product of native CP that may represent an alternative translation product of the CHIKV 26S RNA and have potential functional significance during CHIKV replication. Our data also provides evidence that the C-terminus of CP is required for authentic antigenic structure of CP. This study shows that these anti-CP mAbs will be valuable research tools for further investigating the structure and function of the CHIKV CP.

  12. Expression of T and B cells combined epitopes protein of Leptospira interrogans and the immunity analysis%问号钩端螺旋体T和B细胞表位联合基因的原核表达及其产物免疫性分析

    Institute of Scientific and Technical Information of China (English)

    丁士标; 李召东; 严杰; 林旭瑷

    2011-01-01

    目的 构建问号钩端螺旋体(简称钩体)LipL32、OmpL1和LipL21蛋白的优势T-和B-细胞联合表位融合基因及其原核表达系统,并对表达产物的免疫原性进行鉴定.方法 人工合成多表位联合基因并构建其原核表达系统.采用SDS-PAGE检测重组蛋白;采用MAT检测重组蛋白兔抗血清与我国钩体标准参考株的凝集效价;Western blot和ELISA检测重组蛋白的免疫原性.结果 获得了多表位融合基因并构建了原核表达系统.表达产物的相对分子质量约为23×103,且主要以可溶性形式存在;重组蛋白兔抗血清免疫双扩散效价为1∶8,该抗血清能与我国15群的钩体标准参考株发生凝集反应,ELISA证明该重组蛋白能检测不同群型钩体感染患者血清中的抗钩体抗体.结论 成功构建了包含钩体LipL32、OmpL1和LipL21蛋白的优势T和B细胞联合表位基因及其原核表达系统,表达产物具有良好的抗原性和交叉免疫反应性,可作为研制通用型问号钩体基因工程疫苗及血清学检测的抗原.%Objective To construct the T-cells and B-cells combined epitope peptide gene based on the LipL32,OmpL1 and LipL21 protein from Leptospira interrogans and E.coli expression system,and better understanding of the immunological activity of the recombinant protein. Methods The immunodomaint T- and B-cells combined epitopes of LipL32,OmpL1 and LipL21 were identified and used to synthetic a new gene and then construct its prokaryotic expression system.The expression of recombinant protein was determined by SDS-PAGE; MAT was used to determine the titer of the antiserum to L. interrogans standard strains of China ; Western blot and ELISA were used to identify the immunity activity of the recombinant protein.Results The synthetic gene was effectively expressed in E.coli BL21 ( DE3 ) strain and mainly presented in dissoluble protein.Western blot result showed that the expression protein react well with the

  13. Advances of Bioinformatics Tools Applied in Virus Epitopes Prediction

    Institute of Scientific and Technical Information of China (English)

    Ping Chen; Simon Rayner; Kang-hong Hu

    2011-01-01

    In recent years, the in silico epitopes prediction tools have facilitated the progress of vaccines development significantly and many have been applied to predict epitopes in viruses successfully. Herein, a general overview of different tools currently available, including T cell and B cell epitopes prediction tools, is presented. And the principles of different prediction algorithms are reviewed briefly. Finally, several examples are present to illustrate the application of the prediction tools.

  14. 4种血清型登革病毒NS1蛋白序列及B细胞抗原表位特异性分析%Analysis on genome and amino acids sequence and B cell epitopes for 4 serotypes of dengue virus NS1 protein

    Institute of Scientific and Technical Information of China (English)

    陈艳佳; 熊建英; 朱利; 曹虹; 赵卫

    2013-01-01

    目的 比较4种血清型登革病毒NS1蛋白型特异性抗原表位基因序列及氨基酸序列之间的差异,为利用基因差异进行血清学分型及疫苗研究提供新的线索.方法 利用DNAstar数据包中的Editseq程序,从20株登革病毒分离株的全基因组序列中将NS1基因型特异性抗原表位序列截取出来,再用Clustal X软件进行多序列比对,进行同源性分析,找出型内最为保守的抗原表位序列.并将比对结果在120株登革病毒序列中进一步验证.结果 NS1蛋白36~45和71~85位氨基酸为型特异性抗原表位,高度保守,型内完全相同,型间不同.结论 NS1蛋白36~45位氨基酸可以作为登革病毒血清分型和研制亚单位疫苗的靶标.%OBJECTIVE To compare genome and amino acids sequences and possible B cell epitopes of 4 serotypes of dengue virus NS1 protein, to explore a new method of gene typing and provide new clues to vaccine research. METHODS Cut off the corresponding gene sequences of NS1 protein from the complete genome of 20 dengue virus isolates, then multisequencing was carried out to find the gene which was conservative within the same serotype and variant in the other serotypes. RESULTS Specific antigens of NS1 protein (36-45 and 71-85 amino acids) were conservative within the same serotype and variant in other serotypes. CONCLUSION Specific antigens of NS1 protein (36-45 amino acids) are the bases of dengue virus typing and targets of subunit vaccine development.

  15. B cells and immunological tolerance.

    Science.gov (United States)

    Manjarrez-Orduño, Nataly; Quách, Tâm D; Sanz, Iñaki

    2009-02-01

    Work from multiple groups continues to provide additional evidence for the powerful and highly diverse roles, both protective and pathogenic, that B cells play in autoimmune diseases. Similarly, it has become abundantly clear that antibody-independent functions may account for the opposing influences that B cells exercise over other arms of the immune response and ultimately over autoimmunity itself. Finally, it is becoming apparent that the clinical impact of B-cell depletion therapy may be, to a large extent, determined by the functional balance between different B-cell subsets that may be generated by this therapeutic intervention. In this review, we postulate that our perspective of B-cell tolerance and our experimental approach to its understanding are fundamentally changed by this view of B cells. Accordingly, we first discuss current knowledge of B-cell tolerance conventionally defined as the censoring of autoantibody-producing B cells (with an emphasis on human B cells). Therefore, we discuss a different model that contemplates B cells not only as targets of tolerance but also as mediators of tolerance. This model is based on the notion that the onset of clinical autoimmune disease may require a B-cell gain-of-pathogenic function (or a B-cell loss-of-regulatory-function) and that accordingly, disease remission may depend on the restoration of the physiological balance between B-cell pathogenic and protective functions. PMID:19148217

  16. Immunogenic peptides comprising a T-helper epitope and a B-cell neutralizing antibody epitope

    Science.gov (United States)

    Haynes, Barton F.; Korber, Bette T.; De Lorimier, Robert M.

    2006-12-26

    The present invention relates, generally, to a polyvalent immunogen and, more particularly, to a method of inducing neutralizing antibodies against HIV and to a polyvalent immunogen suitable for use in such a method.

  17. Ibrutinib for B cell malignancies

    OpenAIRE

    Novero, Aileen; Ravella, Pavan M; Chen, Yamei; Dous, George; Liu, Delong

    2014-01-01

    Research over the role of Bruton’s agammaglobulinemia tyrosine kinase (BTK) in B-lymphocyte development, differentiation, signaling and survival has led to better understanding of the pathogenesis of B-cell malignancies. Down-regulation of BTK activity is an attractive novel strategy for treating patients with B-cell malignancies. Ibrutinib (PCI-32765), a potent inhibitor of BTK induces impressive responses in B-cell malignancies through irreversible bond with cysteine-481 in the active site ...

  18. Molecular modeling and conformational IgG epitope mapping on bovine β-casein

    NARCIS (Netherlands)

    Liu, Fahui; Gao, Jinyan; Li, Xin; Chen, Hongbing

    2016-01-01

    Characterizing conformational B-cell epitopes is a key step for understanding the immunological basis of allergy contributed by β-casein. There is no resolved conformational structure of β-casein in protein data bank, and most of the previous research on epitope identification of β-casein focused

  19. Virus-Like Particles of Chimeric Recombinant Porcine Circovirus Type 2 as Antigen Vehicle Carrying Foreign Epitopes

    OpenAIRE

    2014-01-01

    Virus-like particles (VLPs) of chimeric porcine circovirus type 2 (PCV2) were generated by replacing the nuclear localization signal (NLS; at 1–39 aa) of PCV2 capsid protein (Cap) with classical swine fever virus (CSFV) T-cell epitope (1446–1460 aa), CSFV B-cell epitope (693–716 aa) and CSFV T-cell epitope conjugated with B-cell epitope. The recombinant proteins were expressed using the baculovirus expression system and detected by immunoblotting and indirect immunofluorescence assay. The ab...

  20. Vaccine Design for H5N1 Based on B- and T-cell Epitope Predictions

    Science.gov (United States)

    Tambunan, Usman Sumo Friend; Sipahutar, Feimmy Ruth Pratiwi; Parikesit, Arli Aditya; Kerami, Djati

    2016-01-01

    From 2003 to 2013, Indonesia had the highest number of avian influenza A cases in humans, with 192 cases and 160 fatalities. Avian influenza is caused by influenza virus type A, such as subtype H5N1. This virus has two glycoproteins: hemagglutinin and neuraminidase, which will become the primary target to be neutralized by vaccine. Vaccine is the most effective immunologic intervention. In this study, we use the epitope-based vaccine design from hemagglutinin and neuraminidase of H5N1 Indonesian strain virus by using immunoinformatics approach in order to predict the binding of B-cell and T-cell epitopes (class I and class II human leukocyte antigen [HLA]). BCPREDS was used to predict the B-cell epitope. Propred, Propred I, netMHCpan, and netMHCIIpan were used to predict the T-cell epitope. Two B-cell epitopes of hemagglutinin candidates and one B-cell epitope of neuraminidase candidates were obtained to bind T-cell CD4+ (class II HLA), and also five T-cell epitope hemagglutinin and four T-cell epitope neuraminidase were obtained to bind T-cell CD8+ (class I HLA). The visualization of epitopes was done using MOE 2008.10. It shows that the binding affinity of epitope–HLA was based on minimum binding free energy (ΔGbinding). Based on this result, visualization, and dynamic simulation, four hemagglutinin epitopes (MEKIVLLLA, CPYLGSPSF, KCQTPMGAI, and IGTSTLNQR) and two neuraminidase epitopes (NPNQKIITI and CYPDAGEIT) were computed as having the best binding affinity from HLA ligand. The results mentioned above are from in silico experiments and need to be validated using wet experiment. PMID:27147821

  1. An assessment on epitope prediction methods for protozoa genomes

    Directory of Open Access Journals (Sweden)

    Resende Daniela M

    2012-11-01

    Full Text Available Abstract Background Epitope prediction using computational methods represents one of the most promising approaches to vaccine development. Reduction of time, cost, and the availability of completely sequenced genomes are key points and highly motivating regarding the use of reverse vaccinology. Parasites of genus Leishmania are widely spread and they are the etiologic agents of leishmaniasis. Currently, there is no efficient vaccine against this pathogen and the drug treatment is highly toxic. The lack of sufficiently large datasets of experimentally validated parasites epitopes represents a serious limitation, especially for trypanomatids genomes. In this work we highlight the predictive performances of several algorithms that were evaluated through the development of a MySQL database built with the purpose of: a evaluating individual algorithms prediction performances and their combination for CD8+ T cell epitopes, B-cell epitopes and subcellular localization by means of AUC (Area Under Curve performance and a threshold dependent method that employs a confusion matrix; b integrating data from experimentally validated and in silico predicted epitopes; and c integrating the subcellular localization predictions and experimental data. NetCTL, NetMHC, BepiPred, BCPred12, and AAP12 algorithms were used for in silico epitope prediction and WoLF PSORT, Sigcleave and TargetP for in silico subcellular localization prediction against trypanosomatid genomes. Results A database-driven epitope prediction method was developed with built-in functions that were capable of: a removing experimental data redundancy; b parsing algorithms predictions and storage experimental validated and predict data; and c evaluating algorithm performances. Results show that a better performance is achieved when the combined prediction is considered. This is particularly true for B cell epitope predictors, where the combined prediction of AAP12 and BCPred12 reached an AUC value

  2. Immunogenicity of multiple antigen peptides containing Plasmodium vivax CS epitopes in BALB/c mice

    Directory of Open Access Journals (Sweden)

    Myriam A. Herrera

    1994-01-01

    Full Text Available Multiple antigen peptide systems (MAPs allow the incorporation of various epitopes in to a single synthetic peptide immunogen. We have characterized the immune response of BALB/c mice to a series of MAPs assembled with different B and T cell epitopes derived from the Plasmodium vivax circumsporozoite (CS protein. A B-cell epitope from the central repeat domain and two T-cell epitopes from the amino and carboxyl flanking regions were used to assembled eight different MAPs. An additional universal T cell epitope (ptt-30 from tetanus toxin protein was included. Immunogenicity in terms of antibody responses and in vitro T lymphocyte proliferation was evaluated. MAPs containing B and T cell epitopes induced high titers of anti-peptides antibodies, which recognized the native protein on sporozoites as determined by IFAT. The antibody specificity was also determined by a competitive inhibition assay with different MAPs. A MAP containing the B cell epitope (p11 and the universal epitope ptt-30 together with another composed of p11 and the promiscuous T cell epitope (p25 proved to be the most immunogenic. The strong antibody response and specificity for the cognate protein indicates that further studies designed to assess the potential of these proteins as human malaria vaccine candidates are warranted.

  3. Evolution of B Cell Immunity

    OpenAIRE

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

    2013-01-01

    Two types of adaptive immune strategies are known to have evolved in vertebrates: the VLR-based system, which is present in jawless organisms and is mediated by VLRA and VLRB lymphocytes, and the BCR/TCR-based system, which is present in jawed species and is provided by B and T cell receptors expressed on B and T cells, respectively. Here we summarize features of B cells and their predecessors in the different animal phyla, focusing the review on B cells from jawed vertebrates. We point out t...

  4. Benchmarking HRD.

    Science.gov (United States)

    Ford, Donald J.

    1993-01-01

    Discusses benchmarking, the continuous process of measuring one's products, services, and practices against those recognized as leaders in that field to identify areas for improvement. Examines ways in which benchmarking can benefit human resources functions. (JOW)

  5. Multidimensional benchmarking

    OpenAIRE

    Campbell, Akiko

    2016-01-01

    Benchmarking is a process of comparison between performance characteristics of separate, often competing organizations intended to enable each participant to improve its own performance in the marketplace (Kay, 2007). Benchmarking sets organizations’ performance standards based on what “others” are achieving. Most widely adopted approaches are quantitative and reveal numerical performance gaps where organizations lag behind benchmarks; however, quantitative benchmarking on its own rarely yi...

  6. Computational Analysis of Cysteine Proteases(Clan CA, Family C1)of Leishmania major to Find Potential Epitopic Regions

    Institute of Scientific and Technical Information of China (English)

    Babak Saffari; Hassan Mohabatkar

    2009-01-01

    Leishmania is associated with a broad spectrum of diseases, ranging from simple cutaneous to invasive visceral leishmaniasis. Here, the sequences of ten cysteine proteases of types A, B and C of Leishmania major were obtained from GeneDB database. Prediction of MHC class I epitopes of these cysteine proteases was per-formed by NetCTL program version 1.2. In addition, by using BcePred server, different structural properties of the proteins were predicted to find out their po-tential B cell epitopes. According to this computational analysis, nine regions were predicted as B cell epitopes. The results provide useful information for designing peptide-based vaccines.

  7. Thyrotropin Receptor Epitope and Human Leukocyte Antigen in Graves' Disease.

    Science.gov (United States)

    Inaba, Hidefumi; De Groot, Leslie J; Akamizu, Takashi

    2016-01-01

    Graves' disease (GD) is an organ-specific autoimmune disease, and thyrotropin (TSH) receptor (TSHR) is a major autoantigen in this condition. Since the extracellular domain of human TSHR (TSHR-ECD) is shed into the circulation, TSHR-ECD is a preferentially immunogenic portion of TSHR. Both genetic factors and environmental factors contribute to development of GD. Inheritance of human leukocyte antigen (HLA) genes, especially HLA-DR3, is associated with GD. TSHR-ECD protein is endocytosed into antigen-presenting cells (APCs), and processed to TSHR-ECD peptides. These peptide epitopes bind to HLA-class II molecules, and subsequently the complex of HLA-class II and TSHR-ECD epitope is presented to CD4+ T cells. The activated CD4+ T cells secrete cytokines/chemokines that stimulate B-cells to produce TSAb, and in turn hyperthyroidism occurs. Numerous studies have been done to identify T- and B-cell epitopes in TSHR-ECD, including (1) in silico, (2) in vitro, (3) in vivo, and (4) clinical experiments. Murine models of GD and HLA-transgenic mice have played a pivotal role in elucidating the immunological mechanisms. To date, linear or conformational epitopes of TSHR-ECD, as well as the molecular structure of the epitope-binding groove in HLA-DR, were reported to be related to the pathogenesis in GD. Dysfunction of central tolerance in the thymus, or in peripheral tolerance, such as regulatory T cells, could allow development of GD. Novel treatments using TSHR antagonists or mutated TSHR peptides have been reported to be effective. We review and update the role of immunogenic TSHR epitopes and HLA in GD, and offer perspectives on TSHR epitope specific treatments. PMID:27602020

  8. ElliPro: a new structure-based tool for the prediction of antibody epitopes

    OpenAIRE

    Fusseder Nicholas; Bourne Philip E; Li Wei; Bui Huynh-Hoa; Ponomarenko Julia; Sette Alessandro; Peters Bjoern

    2008-01-01

    Abstract Background Reliable prediction of antibody, or B-cell, epitopes remains challenging yet highly desirable for the design of vaccines and immunodiagnostics. A correlation between antigenicity, solvent accessibility, and flexibility in proteins was demonstrated. Subsequently, Thornton and colleagues proposed a method for identifying continuous epitopes in the protein regions protruding from the protein's globular surface. The aim of this work was to implement that method as a web-tool a...

  9. Human Antibodies that Recognize Novel Immunodominant Quaternary Epitopes on the HIV-1 Env Protein.

    Directory of Open Access Journals (Sweden)

    Mark D Hicar

    Full Text Available Numerous broadly neutralizing antibodies (Abs target epitopes that are formed or enhanced during mature HIV envelope formation (i.e. quaternary epitopes. Generally, it is thought that Env epitopes that induce broadly neutralizing Abs are difficult to access and poorly immunogenic because of the characteristic oligomerization, conformational flexibility, sequence diversity and extensive glycosylation of Env protein. To enhance for isolation of quaternary epitope-targeting Abs (QtAbs, we previously used HIV virus-like particles (VLPs to bind B cells from long-term non-progressor subjects to identify a panel of monoclonal Abs. When expressed as recombinant full-length Abs, a subset of these novel Abs exhibited the binding profiles of QtAbs, as they either failed to bind to monomeric Env protein or showed much higher affinity for Env trimers and VLPs. These QtAbs represented a significant proportion of the B-cell response identified with VLPs. The Ab genes of these clones were highly mutated, but they did not neutralize common HIV strains. We sought to further define the epitopes targeted by these QtAbs. Competition-binding and mapping studies revealed these Abs targeted four separate epitopes; they also failed to compete for binding by Abs to known major neutralizing epitopes. Detailed epitope mapping studies revealed that two of the four epitopes were located in the gp41 subunit of Env. These QtAbs bound pre-fusion forms of antigen and showed differential binding kinetics depending on whether oligomers were produced as recombinant gp140 trimers or as full-length Env incorporated into VLPs. Antigenic regions within gp41 present unexpectedly diverse structural epitopes, including these QtAb epitopes, which may be targeted by the naturally occurring Ab response to HIV infection.

  10. Human Antibodies that Recognize Novel Immunodominant Quaternary Epitopes on the HIV-1 Env Protein.

    Science.gov (United States)

    Hicar, Mark D; Chen, Xuemin; Sulli, Chidananda; Barnes, Trevor; Goodman, Jason; Sojar, Hakimuddin; Briney, Bryan; Willis, Jordan; Chukwuma, Valentine U; Kalams, Spyros A; Doranz, Benjamin J; Spearman, Paul; Crowe, James E

    2016-01-01

    Numerous broadly neutralizing antibodies (Abs) target epitopes that are formed or enhanced during mature HIV envelope formation (i.e. quaternary epitopes). Generally, it is thought that Env epitopes that induce broadly neutralizing Abs are difficult to access and poorly immunogenic because of the characteristic oligomerization, conformational flexibility, sequence diversity and extensive glycosylation of Env protein. To enhance for isolation of quaternary epitope-targeting Abs (QtAbs), we previously used HIV virus-like particles (VLPs) to bind B cells from long-term non-progressor subjects to identify a panel of monoclonal Abs. When expressed as recombinant full-length Abs, a subset of these novel Abs exhibited the binding profiles of QtAbs, as they either failed to bind to monomeric Env protein or showed much higher affinity for Env trimers and VLPs. These QtAbs represented a significant proportion of the B-cell response identified with VLPs. The Ab genes of these clones were highly mutated, but they did not neutralize common HIV strains. We sought to further define the epitopes targeted by these QtAbs. Competition-binding and mapping studies revealed these Abs targeted four separate epitopes; they also failed to compete for binding by Abs to known major neutralizing epitopes. Detailed epitope mapping studies revealed that two of the four epitopes were located in the gp41 subunit of Env. These QtAbs bound pre-fusion forms of antigen and showed differential binding kinetics depending on whether oligomers were produced as recombinant gp140 trimers or as full-length Env incorporated into VLPs. Antigenic regions within gp41 present unexpectedly diverse structural epitopes, including these QtAb epitopes, which may be targeted by the naturally occurring Ab response to HIV infection. PMID:27411063

  11. Financial benchmarking

    OpenAIRE

    Boldyreva, Anna

    2014-01-01

    This bachelor's thesis is focused on financial benchmarking of TULIPA PRAHA s.r.o. The aim of this work is to evaluate financial situation of the company, identify its strengths and weaknesses and to find out how efficient is the performance of this company in comparison with top companies within the same field by using INFA benchmarking diagnostic system of financial indicators. The theoretical part includes the characteristic of financial analysis, which financial benchmarking is based on a...

  12. Benchmark selection

    DEFF Research Database (Denmark)

    Hougaard, Jens Leth; Tvede, Mich

    2002-01-01

    Within a production theoretic framework, this paper considers an axiomatic approach to benchmark selection. It is shown that two simple and weak axioms; efficiency and comprehensive monotonicity characterize a natural family of benchmarks which typically becomes unique. Further axioms are added in...... order to obtain a unique selection...

  13. Interactive benchmarking

    DEFF Research Database (Denmark)

    Lawson, Lartey; Nielsen, Kurt

    2005-01-01

    We discuss individual learning by interactive benchmarking using stochastic frontier models. The interactions allow the user to tailor the performance evaluation to preferences and explore alternative improvement strategies by selecting and searching the different frontiers using directional...... suggested benchmarking tool. The study investigates how different characteristics on dairy farms influences the technical efficiency....

  14. Precious benchmarking

    International Nuclear Information System (INIS)

    Recently, there has been a new word added to our vocabulary - benchmarking. Because of benchmarking, our colleagues travel to power plants all around the world and guests from the European power plants visit us. We asked Marek Niznansky from the Nuclear Safety Department in Jaslovske Bohunice NPP to explain us this term. (author)

  15. New helping friends for B cells.

    OpenAIRE

    Cerutti, Andrea; Puga, Irene; Cols, Montserrat

    2012-01-01

    Over the past decade, a growing recognition of the importance of neutralizing antibodies in host defense combined with the success of B-cell depletion therapies in treating autoimmune disorders has led to an increased focus on better understanding the pathways underpinning B-cell antibody production. In general, B cells require cognate interaction with T helper cells in the germinal center of lymphoid follicles to generate protective antibodies. However, recent evidence shows that B cells rec...

  16. Refinement of a DNA based Alzheimer disease epitope vaccine in rabbits

    OpenAIRE

    Ghochikyan, Anahit; Davtyan, Hayk; Petrushina, Irina; Hovakimyan, Armine; Movsesyan, Nina; Davtyan, Arpine; Kiyatkin, Anatoly; Cribbs, David H.; Agadjanyan, Michael G.

    2013-01-01

    We previously demonstrated that our second-generation DNA-based Alzheimer disease (AD) epitope vaccine comprising three copies of a short amyloid-β (Aβ) B cell epitope, Aβ11 fused with the foreign promiscuous Th epitope, PADRE (p3Aβ11-PADRE) was immunogenic in mice. However, since DNA vaccines exhibit poor immunogenicity in large animals and humans, in this study, we sought to improve the immunogenicity of p3Aβ11-PADRE by modifying this vaccine to express protein 3Aβ11-PADRE with a free N-ter...

  17. Dominating IgE-binding epitope of Bet v 1, the major allergen of birch pollen, characterized by X-ray crystallography and site-directed mutagenesis

    DEFF Research Database (Denmark)

    Spangfort, Michael D; Mirza, Osman; Ipsen, Henrik;

    2003-01-01

    surface area of Bet v 1 and is clearly conformational. A synthetic peptide representing a sequential motif in the epitope (11 of 16 residues) did not inhibit the binding of mAb BV16 to Bet v 1, illustrating limitations in the use of peptides for B cell epitope characterization. The single amino acid...

  18. Vaccination of mice with plasmids expressing processed capsid protein of foot-and-mouth disease virus - Importance of dominant and subdominant epitopes for antigenicity and protection

    DEFF Research Database (Denmark)

    Frimann, Tine; Barfoed, Annette Malene; Aasted, Bent;

    2007-01-01

    The capsid of foot-and-mouth disease virus (FMDV) displays several independent B cell epitopes, which stimulate the production of neutralising antibodies. Some of these epitopes are highly variable between virus strains, but dominate the immune response. The site A on VP1 is the most prominent...

  19. Crystallization and X-ray study of the artificial TBI protein, an experimental multiple-epitope vaccine against type 1 human immunodeficiency virus

    International Nuclear Information System (INIS)

    The artificial protein TBI constructed from four T-cell epitopes and five neutralizing B-cell epitopes is an experimental new-generation multiple-epitope vaccine against human immunodeficiency virus (HIV-1). The TBI protein was expressed in Escherichia coli cells, isolated, and purified to the homogeneous state. The growth conditions for protein crystal were found, and the crystals thus grown were studied by the method of X-ray diffraction analysis

  20. P. falciparum and P. vivax Epitope-Focused VLPs Elicit Sterile Immunity to Blood Stage Infections.

    Directory of Open Access Journals (Sweden)

    David C Whitacre

    Full Text Available In order to design P. falciparum preerythrocytic vaccine candidates, a library of circumsporozoite (CS T and B cell epitopes displayed on the woodchuck hepatitis virus core antigen (WHcAg VLP platform was produced. To test the protective efficacy of the WHcAg-CS VLPs, hybrid CS P. berghei/P. falciparum (Pb/Pf sporozoites were used to challenge immunized mice. VLPs carrying 1 or 2 different CS repeat B cell epitopes and 3 VLPs carrying different CS non-repeat B cell epitopes elicited high levels of anti-insert antibodies (Abs. Whereas, VLPs carrying CS repeat B cell epitopes conferred 98% protection of the liver against a 10,000 Pb/Pf sporozoite challenge, VLPs carrying the CS non-repeat B cell eptiopes were minimally-to-non-protective. One-to-three CS-specific CD4/CD8 T cell sites were also fused to VLPs, which primed CS-specific as well as WHcAg-specific T cells. However, a VLP carrying only the 3 T cell domains failed to protect against a sporozoite challenge, indicating a requirement for anti-CS repeat Abs. A VLP carrying 2 CS repeat B cell epitopes and 3 CS T cell sites in alum adjuvant elicited high titer anti-CS Abs (endpoint dilution titer >1x10(6 and provided 80-100% protection against blood stage malaria. Using a similar strategy, VLPs were constructed carrying P. vivax CS repeat B cell epitopes (WHc-Pv-78, which elicited high levels of anti-CS Abs and conferred 99% protection of the liver against a 10,000 Pb/Pv sporozoite challenge and elicited sterile immunity to blood stage infection. These results indicate that immunization with epitope-focused VLPs carrying selected B and T cell epitopes from the P. falciparum and P. vivax CS proteins can elicit sterile immunity against blood stage malaria. Hybrid WHcAg-CS VLPs could provide the basis for a bivalent P. falciparum/P. vivax malaria vaccine.

  1. WLUP benchmarks

    International Nuclear Information System (INIS)

    The IAEA-WIMS Library Update Project (WLUP) is on the end stage. The final library will be released on 2002. It is a result of research and development made by more than ten investigators during 10 years. The organization of benchmarks for testing and choosing the best set of data has been coordinated by the author of this paper. It is presented the organization, name conventions, contents and documentation of WLUP benchmarks, and an updated list of the main parameters for all cases. First, the benchmarks objectives and types are given. Then, comparisons of results from different WIMSD libraries are included. Finally it is described the program QVALUE for analysis and plot of results. Some examples are given. The set of benchmarks implemented on this work is a fundamental tool for testing new multigroup libraries. (author)

  2. Virus-Like Display of a Neo-Self Antigen Reverses B Cell Anergy in a B Cell Receptor Transgenic Mouse Model1

    Science.gov (United States)

    Chackerian, Bryce; Durfee, Marisa R.; Schiller, John T.

    2012-01-01

    The ability to distinguish between self and foreign Ags is a central feature of immune recognition. For B cells, however, immune tolerance is not absolute, and factors that include Ag valency, the availability of T help, and polyclonal B cell stimuli can influence the induction of autoantibody responses. Here, we evaluated whether multivalent virus-like particle (VLP)-based immunogens could induce autoantibody responses in well-characterized transgenic (Tg) mice that express a soluble form of hen egg lysozyme (HEL) and in which B cell tolerance to HEL is maintained by anergy. Immunization with multivalent VLP-arrayed HEL, but not a trivalent form of HEL, induced high-titer Ab responses against HEL in both soluble HEL Tg mice and double Tg mice that also express a monoclonal HEL-specific BCR. Induction of autoantibodies against HEL was not dependent on coadministration of strong adjuvants, such as CFA. In contrast to previous data showing the T-independent induction of Abs to foreign epitopes on VLPs, the ability of HEL-conjugated VLPs to induce anti-HEL Abs in tolerant mice was dependent on the presence of CD4+ Th cells, and could be enhanced by the presence of pre-existing cognate T cells. In in vitro studies, VLP-conjugated HEL was more potent than trivalent HEL in up-regulating surface activation markers on purified anergic B cells. Moreover, immunization with VLP-HEL reversed B cell anergy in vivo in an adoptive transfer model. Thus, Ag multivalency and T help cooperate to reverse B cell anergy, a major mechanism of B cell tolerance. PMID:18424700

  3. Innate B cells: oxymoron or validated concept?

    OpenAIRE

    Ware, Carl F.; Chris Benedict

    2012-01-01

    B lymphocytes promote the initial innate interferon response to viral pathogens without the need for antigen receptor activation. B cell dependent IFN production requires the cytokine, lymphotoxin-β. The LTβ pathway is well known to regulate lymphoid organogenesis and homeostasis by differentiating stromal cells and macrophages. However, in response to viral pathogens these same B cell-regulated populations rapidly produce type 1 interferons. Thus, B cells act as innate effector cells via LTβ...

  4. Comprehensive Mapping Antigenic Epitopes of NS1 Protein of Japanese Encephalitis Virus with Monoclonal Antibodies.

    Science.gov (United States)

    Hua, Rong-Hong; Liu, Li-Ke; Chen, Zhen-Shi; Li, Ye-Nan; Bu, Zhi-Gao

    2013-01-01

    Japanese encephalitis virus (JEV) non-structural protein 1 (NS1) contributes to virus replication and elicits protective immune responses during infection. JEV NS1-specific antibody responses could be a target in the differential diagnosis of different flavivirus infections. However, the epitopes on JEV NS1 are poorly characterized. The present study describes the full mapping of linear B-cell epitopes in JEV NS1. We generated eleven NS1-specific monoclonal antibodies from mice immunized with recombinant NS1. For epitope mapping of monoclonal antibodies, a set of 51 partially-overlapping peptides covering the entire NS1 protein were expressed with a GST-tag and then screened using monoclonal antibodies. Through enzyme-linked immunosorbent assay (ELISA), five linear epitope-containing peptides were identified. By sequentially removing amino acid residues from the carboxy and amino terminal of peptides, the minimal units of the five linear epitopes were identified and confirmed using monoclonal antibodies. Five linear epitopes are located in amino acids residues (5)AIDITRK(11), (72)RDELNVL(78), (251)KSKHNRREGY(260), (269)DENGIVLD(276), and (341)DETTLVRS(348). Furthermore, it was found that the epitopes are highly conserved among JEV strains through sequence alignment. Notably, none of the homologous regions on NS1 proteins from other flaviviruses reacted with the MAbs when they were tested for cross-reactivity, and all five epitope peptides were not recognized by sera against West Nile virus or Dengue virus. These novel virus-specific linear B-cell epitopes of JEV NS1 would benefit the development of new vaccines and diagnostic assays. PMID:23825668

  5. Comprehensive Mapping Antigenic Epitopes of NS1 Protein of Japanese Encephalitis Virus with Monoclonal Antibodies.

    Directory of Open Access Journals (Sweden)

    Rong-Hong Hua

    Full Text Available Japanese encephalitis virus (JEV non-structural protein 1 (NS1 contributes to virus replication and elicits protective immune responses during infection. JEV NS1-specific antibody responses could be a target in the differential diagnosis of different flavivirus infections. However, the epitopes on JEV NS1 are poorly characterized. The present study describes the full mapping of linear B-cell epitopes in JEV NS1. We generated eleven NS1-specific monoclonal antibodies from mice immunized with recombinant NS1. For epitope mapping of monoclonal antibodies, a set of 51 partially-overlapping peptides covering the entire NS1 protein were expressed with a GST-tag and then screened using monoclonal antibodies. Through enzyme-linked immunosorbent assay (ELISA, five linear epitope-containing peptides were identified. By sequentially removing amino acid residues from the carboxy and amino terminal of peptides, the minimal units of the five linear epitopes were identified and confirmed using monoclonal antibodies. Five linear epitopes are located in amino acids residues (5AIDITRK(11, (72RDELNVL(78, (251KSKHNRREGY(260, (269DENGIVLD(276, and (341DETTLVRS(348. Furthermore, it was found that the epitopes are highly conserved among JEV strains through sequence alignment. Notably, none of the homologous regions on NS1 proteins from other flaviviruses reacted with the MAbs when they were tested for cross-reactivity, and all five epitope peptides were not recognized by sera against West Nile virus or Dengue virus. These novel virus-specific linear B-cell epitopes of JEV NS1 would benefit the development of new vaccines and diagnostic assays.

  6. Identification of a variant antigenic neutralizing epitope in hypervariable region 1 of avian leukosis virus subgroup J.

    Science.gov (United States)

    Hou, Minbo; Zhou, Defang; Li, Gen; Guo, Huijun; Liu, Jianzhu; Wang, Guihua; Zheng, Qiankun; Cheng, Ziqiang

    2016-03-01

    Avian leukosis virus subgroup J (ALV-J) is a hypervariable oncogenic retrovirus that causes great economic loss in poultry. Antigenic variations in the variable regions make the development of an effective vaccine a challenging task. In the present study, we identified a variant antigenic neutralizing epitope using reverse vaccinology methods. First, we predicted the B-cell epitopes in gp85 gene of ALV-J strains by DNAman and bioinformatics. Fourteen candidate epitopes were selected and linked in tandem with glycines or serines as a multi-epitope gene. The expressed protein of multi-epitope gene can induce high-titer antibody that can recognize nature ALV-J and neutralize the infectivity of ALV-J strains. Next, we identified a high effective epitope using eight overlapping fragments of gp85 gene reacting with mAb 2D5 and anti-multi-epitope sera. The identified epitope contained one of the predicted epitopes and localized in hyervariable region 1 (hr1), indicating a variant epitope. To better understand if the variants of the epitope have a good antigenicity, we synthesized four variants to react with mAb 2D5 and anti-ALV-J sera. The result showed that all variants could react with the two kinds of antibodies though they showed different antigenicity, while could not react with ALV-J negative sera. Thus, the variant antigenic neutralizing epitope was determined as 137-LRDFIA/E/TKWKS/GDDL/HLIRPYVNQS-158. The result shows a potential use of this variant epitopes as a novel multi-epitope vaccine against ALV-J in poultry. PMID:26850757

  7. B-Cell Hematologic Malignancy Vaccination Registry

    Science.gov (United States)

    2015-09-15

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

  8. Tolerogenicity of resting and activated B cells

    OpenAIRE

    1994-01-01

    Antigen presentation by resting splenic B cells has been shown previously to induce T helper 1 cell (Th1) anergy. In contrast to expectations, it was found here that B cells treated with F(ab')2 goat anti-mouse immunoglobulin (IgM) for 24 or 48 h also presented antigen (Ag) to Th1 cells in a manner that induced dramatic Ag-specific proliferative inactivation. The tolerogenicity of the anti-Ig-treated B cells was consistent with the observation that these B cells were only slightly more effici...

  9. Benchmark exercise

    International Nuclear Information System (INIS)

    The motivation to conduct this benchmark exercise, a summary of the results, and a discussion of and conclusions from the intercomparison are given in Section 5.2. This section contains further details of the results of the calculations and intercomparisons, illustrated by tables and figures, but avoiding repetition of Section 5.2 as far as possible. (author)

  10. Epigenetic Control of B Cell Development and B-Cell-Related Immune Disorders.

    Science.gov (United States)

    Bao, Yan; Cao, Xuetao

    2016-06-01

    B lymphocytes are generally recognized as the essential component of humoral immunity and also a regulator of innate immunity. The development of B cells is precisely regulated by a variety of factors via different mechanisms, including cytokine/cytokine receptors, signal transduction molecules, and transcription factors. Recent findings suggest that epigenetic factors, such as DNA methylation, histone modification, and non-coding RNA, play critical roles in establishing B cell lineage-specific gene expression profiles to define and sustain B cell identity and function. Epigenetic modifications are also sensitive to external stimuli and might bridge genetic and environmental factors in the pathogenesis or control of B-cell-related immune disorders, such as autoimmune diseases, lymphoma, and leukemia. Better understanding of the epigenetic mechanisms for regulating B cell development and involving B cell abnormal differentiation and function will shed light on the design of new therapeutic approaches to B-cell-related diseases, and potential candidates of epigenetic modulators may be identified to target epigenetic pathways to prevent or treat B cell disorders. We summarize the relevance of epigenetic marks and landscapes in the stages of B cell development, discuss the interaction of the transcriptional networks and epigenetic changes, and review the involvement of epigenetic risk in the pathogenesis of B-cell-related diseases. Understanding how specific epigenetic alterations contribute to the development of B-cell-related autoimmunity and malignancies is instrumental to control B cell disorders. PMID:26066671

  11. KLF2--a negative regulator of pre-B cell clonal expansion and B cell activation.

    Directory of Open Access Journals (Sweden)

    Rebecca Winkelmann

    Full Text Available Maturation as well as antigen-dependent activation of B cells is accompanied by alternating phases of proliferation and quiescence. We and others have previously shown that Krüppel-like factor 2 (KLF2, a regulator of T cell quiescence and migration, is upregulated in small resting precursor (pre-B cells after assembly of the immature pre-B cell receptor (pre-BCR and is downregulated upon antigen-induced proliferation of mature B cells. These findings suggest that KLF2, besides its function in maintaining follicular B cell identity, peripheral B cell homeostasis and homing of antigen-specific plasma cells to the bone marrow, also controls clonal expansion phases in the B cell lineage. Here, we demonstrate that enforced expression of KLF2 in primary pre-B cells results in a severe block of pre-BCR-induced proliferation, upregulation of the cell cycle inhibitors p21 and p27 and downregulation of c-myc. Furthermore, retroviral KLF2 transduction of primary B cells impairs LPS-induced activation, favors apoptosis and results in reduced abundance of factors, such as AID, IRF4 and BLIMP1, that control the antigen-dependent phase of B cell activation and plasma cell differentiation. Hence, we conclude that KLF2 is not only a key player in terminating pre-B cell clonal expansion but also a potent suppressor of B cell activation.

  12. B Cells and Autoantibodies in Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Anne-Katrin Pröbstel

    2015-07-01

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

  13. Identification and validation of T-cell epitopes in outer membrane protein (OMP) of Salmonella typhi.

    Science.gov (United States)

    Tanu, Arifur Rahman; Ashraf, Mohammad Arif; Hossain, Md Faruk; Ismail, Md; Shekhar, Hossain Uddin

    2014-01-01

    This study aims to design epitope-based peptides for the utility of vaccine development by targeting outer membrane protein F (Omp F), because two available licensed vaccines, live oral Ty21a and injectable polysaccharide, are 50% to 80% protective with a higher rate of side effects. Conventional vaccines take longer time for development and have less differentiation power between vaccinated and infected cells. On the other hand, Peptide-based vaccines present few advantages over other vaccines, such as stability of peptide, ease to manufacture, better storage, avoidance of infectious agents during manufacture, and different molecules can be linked with peptides to enhance their immunogenicity. Omp F is highly conserved and facilitates attachment and fusion of Salmonella typhi with host cells. Using various databases and tools, immune parameters of conserved sequences from Omp F of different isolates of Salmonella typhi were tested to predict probable epitopes. Binding analysis of the peptides with MHC molecules, epitopes conservancy, population coverage, and linear B cell epitope prediction were analyzed. Among all those predicted peptides, ESYTDMAPY epitope interacted with six MHC alleles and it shows highest amount of interaction compared to others. The cumulative population coverage for these epitopes as vaccine candidates was approximately 70%. Structural analysis suggested that epitope ESYTDMAPY fitted well into the epitope-binding groove of HLA-C*12:03, as this HLA molecule was common which interact with each and every predicted epitopes. So, this potential epitope may be linked with other molecules to enhance its immunogenicity and used for vaccine development. PMID:25258481

  14. Effects of type II collagen epitope carbamylation and citrullination in human leucocyte antigen (HLA)-DR4(+) monozygotic twins discordant for rheumatoid arthritis.

    Science.gov (United States)

    De Santis, M; Ceribelli, A; Cavaciocchi, F; Generali, E; Massarotti, M; Isailovic, N; Crotti, C; Scherer, H U; Montecucco, C; Selmi, C

    2016-09-01

    The aim of this study is to investigate the effect of the native, citrullinated or carbamylated type II human collagen T cell- and B cell-epitopes on the adaptive immune response in rheumatoid arthritis (RA). Peripheral blood T and B cells obtained from a human leucocyte D4-related (antigen DR4(-) HLA-DR4)(+) woman with early RA, her healthy monozygotic twin and an unrelated HLA-DR3(+) woman with early RA were analysed for activation (CD154/CD69), apoptosis (annexin/7-aminoactinomycin), cytokine production [interferon (IFN)γ/interleukin (IL)-17/IL-4/IL-10/IL-6] and functional phenotype (CD45Ra/CCR7) after stimulation with the collagen native T cell epitope (T261-273), the K264 carbamylated T cell epitope (carT261-273), the native B cell epitope (B359-369) or the R360 citrullinated B cell epitope (citB359-369), and the combinations of these. The T cell memory compartment was activated by T cell epitopes in both discordant DR4(+) twins, but not in the DR3(+) RA. The collagen-specific activation of CD4(+) T cells was induced with both the native and carbamylated T cell epitopes only in the RA twin. Both T cell epitopes also induced IL-17 production in the RA twin, but a greater IL-4 and IL-10 response in the healthy twin. The citrullinated B cell epitope, particularly when combined with the carbamylated T cell epitope, induced B cell activation and an increased IL-6/IL-10 ratio in the RA twin compared to a greater IL-10 production in the healthy twin. Our data suggest that circulating collagen-specific T and B cells are found in HLA-DR4(+) subjects, but only RA activated cells express co-stimulatory molecules and produce proinflammatory cytokines. Carbamylation and citrullination further modulate the activation and cytokine polarization of T and B cells. PMID:27314557

  15. Gluten-specific antibodies of celiac disease gut plasma cells recognize long proteolytic fragments that typically harbor T-cell epitopes.

    Science.gov (United States)

    Dørum, Siri; Steinsbø, Øyvind; Bergseng, Elin; Arntzen, Magnus Ø; de Souza, Gustavo A; Sollid, Ludvig M

    2016-01-01

    This study aimed to identify proteolytic fragments of gluten proteins recognized by recombinant IgG1 monoclonal antibodies generated from single IgA plasma cells of celiac disease lesions. Peptides bound by monoclonal antibodies in complex gut-enzyme digests of gluten treated with the deamidating enzyme transglutaminase 2, were identified by mass spectrometry after antibody pull-down with protein G beads. The antibody bound peptides were long deamidated peptide fragments that contained the substrate recognition sequence of transglutaminase 2. Characteristically, the fragments contained epitopes with the sequence QPEQPFP and variants thereof in multiple copies, and they typically also harbored many different gluten T-cell epitopes. In the pull-down setting where antibodies were immobilized on a solid phase, peptide fragments with multivalent display of epitopes were targeted. This scenario resembles the situation of the B-cell receptor on the surface of B cells. Conceivably, B cells of celiac disease patients select gluten epitopes that are repeated multiple times in long peptide fragments generated by gut digestive enzymes. As the fragments also contain many different T-cell epitopes, this will lead to generation of strong antibody responses by effective presentation of several distinct T-cell epitopes and establishment of T-cell help to B cells. PMID:27146306

  16. Gluten-specific antibodies of celiac disease gut plasma cells recognize long proteolytic fragments that typically harbor T-cell epitopes

    Science.gov (United States)

    Dørum, Siri; Steinsbø, Øyvind; Bergseng, Elin; Arntzen, Magnus Ø.; de Souza, Gustavo A.; Sollid, Ludvig M.

    2016-01-01

    This study aimed to identify proteolytic fragments of gluten proteins recognized by recombinant IgG1 monoclonal antibodies generated from single IgA plasma cells of celiac disease lesions. Peptides bound by monoclonal antibodies in complex gut-enzyme digests of gluten treated with the deamidating enzyme transglutaminase 2, were identified by mass spectrometry after antibody pull-down with protein G beads. The antibody bound peptides were long deamidated peptide fragments that contained the substrate recognition sequence of transglutaminase 2. Characteristically, the fragments contained epitopes with the sequence QPEQPFP and variants thereof in multiple copies, and they typically also harbored many different gluten T-cell epitopes. In the pull-down setting where antibodies were immobilized on a solid phase, peptide fragments with multivalent display of epitopes were targeted. This scenario resembles the situation of the B-cell receptor on the surface of B cells. Conceivably, B cells of celiac disease patients select gluten epitopes that are repeated multiple times in long peptide fragments generated by gut digestive enzymes. As the fragments also contain many different T-cell epitopes, this will lead to generation of strong antibody responses by effective presentation of several distinct T-cell epitopes and establishment of T-cell help to B cells. PMID:27146306

  17. B-cell waste classification sampling plan

    Energy Technology Data Exchange (ETDEWEB)

    HOBART, R.L.

    1999-11-20

    This report documents the methods used to collect samples and analyze data necessary to verify and/or determine the radionuclide content of the 324 Facility B-Cell decontamination and decommissioning waste stream.

  18. B-cell waste classification sampling plan

    International Nuclear Information System (INIS)

    This report documents the methods used to collect samples and analyze data necessary to verify and/or determine the radionuclide content of the 324 Facility B-Cell decontamination and decommissioning waste stream

  19. MicroRNAs in B-cells

    DEFF Research Database (Denmark)

    Marques, Sara Correia; Laursen, Maria Bach; Bødker, Julie Støve; Kjeldsen, Malene Krag; Larsen, Steffen Falgreen; Schmitz, Alexander; Bøgsted, Martin; Johnsen, Hans Erik; Dybkær, Karen

    2015-01-01

    transformation due to their function as oncogenes or tumor suppressors. We know that miRNAs are involved in the development of normal B-cells and that different B-cell subsets express specific miRNA profiles according to their degree of differentiation. B-cell-derived malignancies contain transcription......MicroRNAs (miRNAs) are small non-coding RNAs that play important post-transcriptional regulatory roles in a wide range of biological processes. They are fundamental to the normal development of cells, and evidence suggests that the deregulation of specific miRNAs is involved in malignant...... signatures reminiscent of their cell of origin. Therefore, we believe that normal and malignant B-cells share features of regulatory networks controlling differentiation and the ability to respond to treatment. The involvement of miRNAs in these processes makes them good biomarker candidates. B...

  20. Analysis of structures and epitopes of a novel secreted protein MYR1 in Toxoplasma gondii.

    Science.gov (United States)

    Zhou, Jian; Lu, Gang; He, Shenyi

    2016-01-01

    Toxoplasma gondii (Nicolle et Manceaux, 1908) is an obligate intracellular apicomplexan parasite and can infect warmblooded animals and humans all over the world. Development of effective vaccines is considered the only ideal way to control infection with T. gondii. However, only one live vaccine is commercially available for use in sheep and goats. Thus more effective antigenic proteins are searched for. In the present study we report a novel protein by secreted T. gondii termed Myc regulation 1 (MYR1). The physical and chemical characteristics, epitopes, hydrophilicity and functional sites of MYR1 were analysed by multiple bioinformatic approaches. The 3D models of MYR1 proteins were constructed and analysed. Furthermore, liner B-cell epitopes and T-cell epitopes of MYR1 protein and SAG1 were predicted. Compared to SAG1, MYR1 with good B-cell epitopes and T-cell epitopes had a potentiality to become a more successful vaccine against T. gondii. The bioinformatics analysis of MYR1 proteins could laid the foundation for further studies of its biological function experimentally and provide valuable information necessary for a better prevention and treatment of toxoplasmosis. PMID:27580381

  1. T and B cell cooperation: a dance of life and death.

    Science.gov (United States)

    Bernard, Alain; Coitot, Sylvie; Brémont, Aurore; Bernard, Ghislaine

    2005-02-15

    In order for the body to develop a good antibody response, B cells need to react intimately with antigen specific T cells. Experimental evidence using hapten-carriers revealed that T and B cells do not recognize the same epitope and this led to the view that the physical contact is mediated by the antigen. Although the modern concept of antigen presentation has changed our perception on how the antigen can bridge both cells, the basic virtues of earlier bridging models remain. Over the past few years, a number of surface ligand-receptor pathways have been described, most of them belonging either to the CD28/B7 Ig or to the TNF/TNFR-like families. These act in concert, whether they are agonist or antagonist, in a timely and spatially organized manner. They form cascades of successive induction and recruitment to ensure that T-B cooperation is closely controlled at all stages of antibody induction. PMID:15699753

  2. The Analysis of B-Cell Epitopes of Influenza Virus Hemagglutinin

    OpenAIRE

    Shcherbinin, D.N.; S. V Alekseeva; Shmarov, M.M.; Smirnov, Yu.A.; Naroditskiy, B.S.; Gintsburg, A.L.

    2016-01-01

    Vaccination has been successfully used to prevent influenza for a long time. Influenza virus hemagglutinin (HA), which induces a humoral immune response in humans and protection against the flu, is the main antigenic component of modern influenza vaccines. However, new seasonal and pandemic influenza virus variants with altered structures of HA occasionally occur. This allows the pathogen to avoid neutralization with antibodies produced in response to previous vaccination. Development of a va...

  3. THE ANALYSIS OF B-CELL EPITOPES OF INFLUENZA VIRUS HEMAGGLUTININ

    OpenAIRE

    Shcherbinin, D.N.; S. V Alekseeva; Shmarov, M.M.; SMIRNOV YU.A.; Naroditskiy, B.S.; Gintsburg, A.L.

    2016-01-01

    Vaccination has been successfully used to prevent influenza for a long time. Influenza virus hemagglutinin (HA), which induces a humoral immune response in humans and protection against the flu, is the main antigenic component of modern influenza vaccines. However, new seasonal and pandemic influenza virus variants with altered structures of HA occasionally occur. This allows the pathogen to avoid neutralization with antibodies produced in response to previous vaccination. Development of a va...

  4. B-Pred, a structure based B-cell epitopes prediction server

    OpenAIRE

    Cabibbo, Andrea

    2012-01-01

    Luciano Giacò,1 Massimo Amicosante,2 Maurizio Fraziano,1 Pier Federico Gherardini,1 Gabriele Ausiello,1 Manuela Helmer-Citterich,1 Vittorio Colizzi,1 Andrea Cabibbo11Department of Biology, 2Department of Internal Medicine, University of Rome "Tor Vergata", Rome, ItalyAbstract: The ability to predict immunogenic regions in selected proteins by in-silico methods has broad implications, such as allowing a quick selection of potential reagents to be used as diagnostic...

  5. Large-scale validation of methods for cytotoxic T-lymphocyte epitope prediction

    DEFF Research Database (Denmark)

    Larsen, Mette V; Lundegaard, Claus; Lamberth, Kasper; Buus, Søren; Lund, Ole; Nielsen, Morten

    2007-01-01

    . It does so by integrating predictions of proteasomal cleavage, TAP transport efficiency, and MHC class I affinity. At least four other methods have been developed recently that likewise attempt to predict CTL epitopes: EpiJen, MAPPP, MHC-pathway, and WAPP. In order to compare the performance of...... prediction methods, objective benchmarks and standardized performance measures are needed. Here, we develop such large-scale benchmark and corresponding performance measures and report the performance of an updated version 1.2 of NetCTL in comparison with the four other methods. RESULTS: We define a number...... of performance measures that can handle the different types of output data from the five methods. We use two evaluation datasets consisting of known HIV CTL epitopes and their source proteins. The source proteins are split into all possible 9 mers and except for annotated epitopes; all other 9 mers...

  6. Epitope prediction methods

    DEFF Research Database (Denmark)

    Karosiene, Edita

    introduces the NetMHCIIpan-3.0 predictor based on artificial neural networks, which is capable of giving binding affinities to any human MHC class II molecule. Chapter 4 of this thesis gives an overview of bioinformatics tools developed by the Immunological Bioinformatics group at Center for Biological...... machine learning techniques. Several MHC class I binding prediction algorithms have been developed and due to their high accuracy they are used by many immunologists to facilitate the conventional experimental process of epitope discovery. However, the accuracy of these methods depends on data defining...... the MHC molecule in question, making it difficult for the non-expert end-user to choose the most suitable predictor. The first paper in this thesis presents a new, publicly available, consensus method for MHC class I predictions. The NetMHCcons predictor combines three state-of-the-art prediction...

  7. Virus-Like Particles of Chimeric Recombinant Porcine Circovirus Type 2 as Antigen Vehicle Carrying Foreign Epitopes

    Directory of Open Access Journals (Sweden)

    Huawei Zhang

    2014-12-01

    Full Text Available Virus-like particles (VLPs of chimeric porcine circovirus type 2 (PCV2 were generated by replacing the nuclear localization signal (NLS; at 1–39 aa of PCV2 capsid protein (Cap with classical swine fever virus (CSFV T-cell epitope (1446–1460 aa, CSFV B-cell epitope (693–716 aa and CSFV T-cell epitope conjugated with B-cell epitope. The recombinant proteins were expressed using the baculovirus expression system and detected by immunoblotting and indirect immunofluorescence assay. The abilities to form PCV2 VLPs were confirmed by transmission electron microscopy. Immunogenicities of the three recombinant proteins were evaluated in mice. Our Results indicated that Cap protein NLS deletion or substitution with CSFV epitopes did not affect the VLPs assembly. Three chimeric Cap proteins could form VLPs and induce efficient humoral and cellular immunity against PCV2 and CSFV in mice. Results show that PCV2 VLPs can be used as an efficient antigen carrier for delivery of foreign epitopes, and a potential novel vaccine.

  8. Virus-like particles of chimeric recombinant porcine circovirus type 2 as antigen vehicle carrying foreign epitopes.

    Science.gov (United States)

    Zhang, Huawei; Qian, Ping; Liu, Lifeng; Qian, Suhong; Chen, Huanchun; Li, Xiangmin

    2014-12-01

    Virus-like particles (VLPs) of chimeric porcine circovirus type 2 (PCV2) were generated by replacing the nuclear localization signal (NLS; at 1-39 aa) of PCV2 capsid protein (Cap) with classical swine fever virus (CSFV) T-cell epitope (1446-1460 aa), CSFV B-cell epitope (693-716 aa) and CSFV T-cell epitope conjugated with B-cell epitope. The recombinant proteins were expressed using the baculovirus expression system and detected by immunoblotting and indirect immunofluorescence assay. The abilities to form PCV2 VLPs were confirmed by transmission electron microscopy. Immunogenicities of the three recombinant proteins were evaluated in mice. Our Results indicated that Cap protein NLS deletion or substitution with CSFV epitopes did not affect the VLPs assembly. Three chimeric Cap proteins could form VLPs and induce efficient humoral and cellular immunity against PCV2 and CSFV in mice. Results show that PCV2 VLPs can be used as an efficient antigen carrier for delivery of foreign epitopes, and a potential novel vaccine. PMID:25490764

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

    Directory of Open Access Journals (Sweden)

    Emmanuelle Dugas-Bourdages

    2014-01-01

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

  10. Recombinant expression of in silico identified Bcell epitope of epsilon toxin of Clostridium perfringens in translational fusion with a carrier protein

    OpenAIRE

    Kaushik, Himani; Deshmukh, Sachin; Mathur, Deepika Dayal; Tiwari, Archana; Garg, Lalit C

    2013-01-01

    Epsilon toxin secreted by Clostridium perfringens types B and D has been directly implicated as the causative agent of fatal enterotoxemia in domestic animals. The aim of the present study is to use in silico approach for identification of B-cell epitope(s) of epsilon toxin, and its expression in fusion with a carrier protein to analyze its potential as vaccine candidate(s). Using different computational analyses and bioinformatics tools, a number of antigenic determinant regions of epsilon t...

  11. Novel CD8(+) cytotoxic T cell epitopes in bovine leukemia virus with cattle.

    Science.gov (United States)

    Bai, Lanlan; Takeshima, Shin-Nosuke; Isogai, Emiko; Kohara, Junko; Aida, Yoko

    2015-12-16

    Bovine leukemia virus (BLV) is associated with enzootic bovine leukosis and is closely related to human T cell leukemia virus (HTLV). The cytotoxic T lymphocyte (CTL) plays a key role in suppressing the progression of disease caused by BLV. T and B cell epitopes in BLV have been studied, but CD8(+) CTL epitopes remain poorly understood. We used a library of 115 synthetic peptides covering the entirety of the Env proteins (gp51 and gp30), the Gag proteins (p15, p24, and p12), and the Tax protein of BLV to identify 11 novel CD8(+) T cell epitopes (gp51N5, gp51N11, gp51N12, gp30N5, gp30N6, gp30N8, gp30N16, tax16, tax18, tax19, and tax20) in four calves experimentally infected with BLV. The number of CD8(+) T cell epitopes that could be identified in each calf correlated with the BLV proviral load. Interestingly, among the 11 epitopes identified, only gp51N11 was capable of inducing CD8(+) T cell-mediated cytotoxicity in all four calves, but it is not a suitable vaccine target because it shows a high degree of polymorphism according to the Wu-Kabat variability index. By contrast, no CTL epitopes were identified from the Gag structural protein. In addition, several epitopes were obtained from gp30 and Tax, indicating that cellular immunity against BLV is strongly targeted to these proteins. CD8(+) CTL epitopes from gp30 and Tax were less polymorphic than epitopes from. Indeed, peptides tax16, tax18, tax19, and tax20 include a leucine-rich activation domain that encompasses a transcriptional activation domain, and the gp30N16 peptide contains a proline-rich region that interacts with a protein tyrosine phosphatase SHP1 to regulate B cell activation. Moreover, at least one CD8(+) CTL epitope derived from gp30 was identified in each of the four calves. These results indicate that BLV gp30 may be the best candidate for the development of a BLV vaccine. PMID:26552001

  12. Molecular dissection of the human B cell response against cytomegalovirus infection by lambda display.

    Science.gov (United States)

    Beghetto, Elisa; Paolis, Francesca De; Spadoni, Andrea; Del Porto, Paola; Buffolano, Wilma; Gargano, Nicola

    2008-07-01

    Human cytomegalovirus (HCMV), a ubiquitous herpesvirus, is the main cause of congenital abnormalities and mental retardation in newborns and is also responsible for severe life-threatening complications in immunocompromised individuals, including AIDS patients and transplant recipients. The disorders generated by cytomegalovirus are closely associated with the competence of the host immune system and both humoral and cell-mediated mechanisms are involved in the response to viral infection. To identify viral proteins recognized by host antibody responses, a cytomegalovirus genome library was created and displayed on lambda bacteriophage. The challenge of such a library with sera from individuals with congenital or acquired infection allowed the identification of a wide panel of recombinant bacteriophages carrying cytomegalovirus B cell epitopes. Epitope-containing fragments within the families of tegument proteins (pUL25, pUL32), structural proteins (pUL48, pUL56) and glycoproteins (pUL55) were identified. Moreover, library screening permitted isolation of phage clones carrying an antigenic region of an uncharacterized HCMV protein encoded by the UL71 open reading frame (ORF), highlighting the potential of lambda display technology in antigen and epitope discovery. PMID:18499273

  13. Early T Cell Recognition of B Cells following Epstein-Barr Virus Infection: Identifying Potential Targets for Prophylactic Vaccination.

    Science.gov (United States)

    Brooks, Jill M; Long, Heather M; Tierney, Rose J; Shannon-Lowe, Claire; Leese, Alison M; Fitzpatrick, Martin; Taylor, Graham S; Rickinson, Alan B

    2016-04-01

    Epstein-Barr virus, a B-lymphotropic herpesvirus, is the cause of infectious mononucleosis, has strong aetiologic links with several malignancies and has been implicated in certain autoimmune diseases. Efforts to develop a prophylactic vaccine to prevent or reduce EBV-associated disease have, to date, focused on the induction of neutralising antibody responses. However, such vaccines might be further improved by inducing T cell responses capable of recognising and killing recently-infected B cells. In that context, EBNA2, EBNA-LP and BHRF1 are the first viral antigens expressed during the initial stage of B cell growth transformation, yet have been poorly characterised as CD8+ T cell targets. Here we describe CD8+ T cell responses against each of these three "first wave" proteins, identifying target epitopes and HLA restricting alleles. While EBNA-LP and BHRF1 each contained one strong CD8 epitope, epitopes within EBNA2 induced immunodominant responses through several less common HLA class I alleles (e.g. B*3801 and B*5501), as well as subdominant responses through common class I alleles (e.g. B7 and C*0304). Importantly, such EBNA2-specific CD8+ T cells recognised B cells within the first day post-infection, prior to CD8+ T cells against well-characterised latent target antigens such as EBNA3B or LMP2, and effectively inhibited outgrowth of EBV-transformed B cell lines. We infer that "first wave" antigens of the growth-transforming infection, especially EBNA2, constitute potential CD8+ T cell immunogens for inclusion in prophylactic EBV vaccine design. PMID:27096949

  14. Early T Cell Recognition of B Cells following Epstein-Barr Virus Infection: Identifying Potential Targets for Prophylactic Vaccination.

    Directory of Open Access Journals (Sweden)

    Jill M Brooks

    2016-04-01

    Full Text Available Epstein-Barr virus, a B-lymphotropic herpesvirus, is the cause of infectious mononucleosis, has strong aetiologic links with several malignancies and has been implicated in certain autoimmune diseases. Efforts to develop a prophylactic vaccine to prevent or reduce EBV-associated disease have, to date, focused on the induction of neutralising antibody responses. However, such vaccines might be further improved by inducing T cell responses capable of recognising and killing recently-infected B cells. In that context, EBNA2, EBNA-LP and BHRF1 are the first viral antigens expressed during the initial stage of B cell growth transformation, yet have been poorly characterised as CD8+ T cell targets. Here we describe CD8+ T cell responses against each of these three "first wave" proteins, identifying target epitopes and HLA restricting alleles. While EBNA-LP and BHRF1 each contained one strong CD8 epitope, epitopes within EBNA2 induced immunodominant responses through several less common HLA class I alleles (e.g. B*3801 and B*5501, as well as subdominant responses through common class I alleles (e.g. B7 and C*0304. Importantly, such EBNA2-specific CD8+ T cells recognised B cells within the first day post-infection, prior to CD8+ T cells against well-characterised latent target antigens such as EBNA3B or LMP2, and effectively inhibited outgrowth of EBV-transformed B cell lines. We infer that "first wave" antigens of the growth-transforming infection, especially EBNA2, constitute potential CD8+ T cell immunogens for inclusion in prophylactic EBV vaccine design.

  15. The PRISM Benchmark Suite

    OpenAIRE

    Kwiatkowsa, Marta; Norman, Gethin; Parker, David

    2012-01-01

    We present the PRISM benchmark suite: a collection of probabilistic models and property specifications, designed to facilitate testing, benchmarking and comparisons of probabilistic verification tools and implementations.

  16. Kvantitativ benchmark - Produktionsvirksomheder

    DEFF Research Database (Denmark)

    Sørensen, Ole H.; Andersen, Vibeke

    Rapport med resultatet af kvantitativ benchmark over produktionsvirksomhederne i VIPS projektet.......Rapport med resultatet af kvantitativ benchmark over produktionsvirksomhederne i VIPS projektet....

  17. Benchmarking in Student Affairs.

    Science.gov (United States)

    Mosier, Robert E.; Schwarzmueller, Gary J.

    2002-01-01

    Discusses the use of benchmarking in student affairs, focusing on issues related to student housing. Provides examples of how benchmarking has influenced administrative practice at many institutions. (EV)

  18. The Pre-B Cell Receptor and Its Function during B Cell Development

    Institute of Scientific and Technical Information of China (English)

    Min Zhang; Gopesh Srivastava1; Liwei Lu

    2004-01-01

    The process of B cell development in the bone marrow occurs by the stepwise rearrangements of the V, D, and Jsegments of the Ig H and L chain gene loci. During early B cell genesis, productive IgH chain generearrangement leads to assembly of the pre-B cell receptor (pre-BCR), which acts as an important checkpointat the pro-B/preB transitional stage. The pre-BCR, transiently expressed by developing precursor B cells,comprises the Ig μH chain, surrogate light (SL) chains VpreB and λ5, as well as the signal-transducing heterodimer Igα/Igβ. Signaling through the pre-BCR regulates allelic exclusion at the Ig H locus, stimulates cell proliferation, and induces differentiation to small post-mitotic pre-B cells that further undergo the rearrangement of the IgL chain genes. Recent advances in elucidating the key roles of pre-BCR in B cell development have provided a better understanding of normal B lymphopoiesis and its dysregulated state leading to B cell neoplasia.

  19. The Pre-B Cell Receptor and Its Function during B Cell Development

    Institute of Scientific and Technical Information of China (English)

    MinZhang; GopeshSrivastava; LiweiLu

    2004-01-01

    The process of B cell development in the bone marrow occurs by the stepwise rearrangements of the V, D, and J segments of the Ig H and L chain gene loci. During early B cell genesis, productive IgH chain gene rearrangement leads to assembly of the pre-B cell receptor (pre-BCR), which acts as an important checkpoint at the pro-B/preB transitional stage. The pre-BCR, transiently expressed by developing precursor B cells, comprises the Ig μH chain, surrogate light (SL) chains VpreB and λ5, as well as the signal-transducing hetero-dimer Igα/Igβ. Signaling through the pre-BCR regulates allelic exclusion at the Ig H locus, stimulates cell proliferation, and induces differentiation to small post-mitotic pre-B cells that further undergo the rearrangement of the IgL chain genes. Recent advances in elucidating the key roles of pre-BCR in B cell development have provided a better understanding of normal B lymphopoiesis and its dysregulated state leading to B cell neoplasia. Cellular & Molecular Immunology. 2004;1(2):89-94.

  20. Prediction on Antigenic Epitope Characteristics of Bt Cry2Ab Protein in Transgenic Crops

    Institute of Scientific and Technical Information of China (English)

    Jierong GAO; Ying HE; Zehong ZOU; Ailin TAO; Yuncan AI

    2012-01-01

    Abstract [Objective] This study aimed to predict the structural characteristics of Bt Cry2Ab protein in transgenic crops with bioinformatic analysis to provide the theoreti- cal clues for design of antibody Cry2Ab. [Method] The amino acid sequence of Cry2Ab protein was searched from NCBI database. The B cell epitopes were pre- dicted with DNAStar. The binding affinity between Cry2Ab protein and MHC-II molecules was analyzed with NetMHCII 2.2 Server to predict the T cell epitopes. [Result] Prediction result suggested the potential B cell epitope of Cry2Ab locating in the region of 208-215. Analysis of the binding affinity between Cry2Ab and MHC-II molecules suggested the regions of 177-185, 299-307 and 255-263 were the po- tential T cell epitopes. Human with HLA-DRB10101 alleles and HLA-DRB10701 al- leles were more sensitive to Cry2Ab protein. [Conclusion] This study facilitates to un- derstand the structural characteristics of Cry2Ab protein and provides a new clue to improve the assessment method for potential allergenicity of genetically modified food.

  1. Benchmarking and Performance Measurement.

    Science.gov (United States)

    Town, J. Stephen

    This paper defines benchmarking and its relationship to quality management, describes a project which applied the technique in a library context, and explores the relationship between performance measurement and benchmarking. Numerous benchmarking methods contain similar elements: deciding what to benchmark; identifying partners; gathering…

  2. Impaired regulatory B cells in myasthenia gravis.

    Science.gov (United States)

    Sheng, Jian Rong; Rezania, Kourosh; Soliven, Betty

    2016-08-15

    Regulatory B cells (Bregs) attenuate the severity of experimental autoimmune myasthenia gravis (EAMG) in an interleukin-10 (IL-10)-dependent manner. The goal of this study was to investigate the role of human Bregs in MG focusing on CD19(+)CD1d(hi) CD5(+) and CD19(+)CD24(hi)CD38(hi) subsets. We found that MG patients exhibited a decrease in the frequency of both Breg subsets and IL-10 producing B cells within each subset, which correlated with disease severity. In addition, there was impaired suppression of Th1 polarization in MG. These findings, taken together with EAMG data, indicate that Bregs play an important role in regulating the severity of MG. PMID:27397074

  3. Designing an efficient multi-epitope peptide vaccine against Vibrio cholerae via combined immunoinformatics and protein interaction based approaches.

    Science.gov (United States)

    Nezafat, Navid; Karimi, Zeinab; Eslami, Mahboobeh; Mohkam, Milad; Zandian, Sanam; Ghasemi, Younes

    2016-06-01

    Cholera continues to be a major global health concern. Among different Vibrio cholerae strains, only O1 and O139 cause acute diarrheal diseases that are related to epidemic and pandemic outbreaks. The currently available cholera vaccines are mainly lived and attenuated vaccines consisting of V. cholerae virulence factors such as toxin-coregulated pili (TCP), outer membrane proteins (Omps), and nontoxic cholera toxin B subunit (CTB). Nowadays, there is a great interest in designing an efficient epitope vaccine against cholera. Epitope vaccines consisting of immunodominant epitopes and adjuvant molecules enhance the possibility of inciting potent protective immunity. In this study, V. cholerae protective antigens (OmpW, OmpU, TcpA and TcpF) and the CTB, which is broadly used as an immunostimulatory adjuvant, were analyzed using different bioinformatics and immunoinformatics tools. The common regions between promiscuous epitopes, binding to various HLA-II supertype alleles, and B-cell epitopes were defined based upon the aforementioned protective antigens. The ultimately selected epitopes and CTB adjuvant were fused together using proper GPGPG linkers to enhance vaccine immunogenicity. A three-dimensional model of the thus constructed vaccine was generated using I-TASSER. The model was structurally validated using the ProSA-web error-detection software and the Ramachandran plot. The validation results indicated that the initial 3D model needed refinement. Subsequently, a high-quality model obtained after various refinement cycles was used for defining conformational B-cell epitopes. Several linear and conformational B-cell epitopes were determined within the epitope vaccine, suggesting likely antibody triggering features of our designed vaccine. Next, molecular docking was performed between the 3D vaccine model and the tertiary structure of the toll like receptor 2 (TLR2). To gain further insight into the interaction between vaccine and TLR2, molecular dynamics

  4. Primary Hepatosplenic Large B-Cell Lymphoma

    Directory of Open Access Journals (Sweden)

    M.R. Morales-Polanco

    2008-03-01

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

  5. A novel antibody discovery platform identifies anti-influenza A broadly neutralizing antibodies from human memory B cells.

    Science.gov (United States)

    Xiao, Xiaodong; Chen, Yan; Varkey, Reena; Kallewaard, Nicole; Koksal, Adem C; Zhu, Qing; Wu, Herren; Chowdhury, Partha S; Dall'Acqua, William F

    2016-07-01

    Monoclonal antibody isolation directly from circulating human B cells is a powerful tool to delineate humoral responses to pathological conditions and discover antibody therapeutics. We have developed a platform aimed at improving the efficiencies of B cell selection and V gene recovery. Here, memory B cells are activated and amplified using Epstein-Barr virus infection, co-cultured with CHO-muCD40L cells, and then assessed by functional screenings. An in vitro transcription and translation (IVTT) approach was used to analyze variable (V) genes recovered from each B cell sample and identify the relevant heavy/light chain pair(s). We achieved efficient amplification and activation of memory B cells, and eliminated the need to: 1) seed B cells at clonal level (≤1 cell/well) or perform limited dilution cloning; 2) immortalize B cells; or 3) assemble V genes into an IgG expression vector to confirm the relevant heavy/light chain pairing. Cross-reactive antibodies targeting a conserved epitope on influenza A hemagglutinin were successfully isolated from a healthy donor. In-depth analysis of the isolated antibodies suggested their potential uses as anti-influenza A antibody therapeutics and uncovered a distinct affinity maturation pathway. Importantly, our results showed that cognate heavy/light chain pairings contributed to both the expression level and binding abilities of our newly isolated VH1-69 family, influenza A neutralizing antibodies, contrasting with previous observations that light chains do not significantly contribute to the function of this group of antibodies. Our results further suggest the potential use of the IVTT as a powerful antibody developability assessment tool. PMID:27049174

  6. Multi-epitope Models Explain How Pre-existing Antibodies Affect the Generation of Broadly Protective Responses to Influenza

    Science.gov (United States)

    Zarnitsyna, Veronika I.; Lavine, Jennie; Ellebedy, Ali; Ahmed, Rafi; Antia, Rustom

    2016-01-01

    The development of next-generation influenza vaccines that elicit strain-transcendent immunity against both seasonal and pandemic viruses is a key public health goal. Targeting the evolutionarily conserved epitopes on the stem of influenza’s major surface molecule, hemagglutinin, is an appealing prospect, and novel vaccine formulations show promising results in animal model systems. However, studies in humans indicate that natural infection and vaccination result in limited boosting of antibodies to the stem of HA, and the level of stem-specific antibody elicited is insufficient to provide broad strain-transcendent immunity. Here, we use mathematical models of the humoral immune response to explore how pre-existing immunity affects the ability of vaccines to boost antibodies to the head and stem of HA in humans, and, in particular, how it leads to the apparent lack of boosting of broadly cross-reactive antibodies to the stem epitopes. We consider hypotheses where binding of antibody to an epitope: (i) results in more rapid clearance of the antigen; (ii) leads to the formation of antigen-antibody complexes which inhibit B cell activation through Fcγ receptor-mediated mechanism; and (iii) masks the epitope and prevents the stimulation and proliferation of specific B cells. We find that only epitope masking but not the former two mechanisms to be key in recapitulating patterns in data. We discuss the ramifications of our findings for the development of vaccines against both seasonal and pandemic influenza. PMID:27336297

  7. Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals.

    Directory of Open Access Journals (Sweden)

    Davide Corti

    Full Text Available BACKGROUND: The isolation of human monoclonal antibodies (mAbs that neutralize a broad spectrum of primary HIV-1 isolates and the characterization of the human neutralizing antibody B cell response to HIV-1 infection are important goals that are central to the design of an effective antibody-based vaccine. METHODS AND FINDINGS: We immortalized IgG(+ memory B cells from individuals infected with diverse clades of HIV-1 and selected on the basis of plasma neutralization profiles that were cross-clade and relatively potent. Culture supernatants were screened using various recombinant forms of the envelope glycoproteins (Env in multiple parallel assays. We isolated 58 mAbs that were mapped to different Env surfaces, most of which showed neutralizing activity. One mAb in particular (HJ16 specific for a novel epitope proximal to the CD4 binding site on gp120 selectively neutralized a multi-clade panel of Tier-2 HIV-1 pseudoviruses, and demonstrated reactivity that was comparable in breadth, but distinct in neutralization specificity, to that of the other CD4 binding site-specific neutralizing mAb b12. A second mAb (HGN194 bound a conserved epitope in the V3 crown and neutralized all Tier-1 and a proportion of Tier-2 pseudoviruses tested, irrespective of clade. A third mAb (HK20 with broad neutralizing activity, particularly as a Fab fragment, recognized a highly conserved epitope in the HR-1 region of gp41, but showed striking assay-dependent selectivity in its activity. CONCLUSIONS: This study reveals that by using appropriate screening methods, a large proportion of memory B cells can be isolated that produce mAbs with HIV-1 neutralizing activity. Three of these mAbs show unusual breadth of neutralization and therefore add to the current panel of HIV-1 neutralizing antibodies with potential for passive protection and template-based vaccine design.

  8. Gastrointestinal B-cell lymphomas: From understanding B-cell physiology to classification and molecular pathology.

    Science.gov (United States)

    Sagaert, Xavier; Tousseyn, Thomas; Yantiss, Rhonda K

    2012-12-15

    The gut is the most common extranodal site where lymphomas arise. Although all histological lymphoma types may develop in the gut, small and large B-cell lymphomas predominate. The sometimes unexpected finding of a lymphoid lesion in an endoscopic biopsy of the gut may challenge both the clinician (who is not always familiar with lymphoma pathogenesis) and the pathologist (who will often be hampered in his/her diagnostic skill by the limited amount of available tissue). Moreover, the past 2 decades have spawned an avalanche of new data that encompasses both the function of the reactive B-cell as well as the pathogenic pathways that lead to its neoplastic counterpart, the B-cell lymphoma. Therefore, this review aims to offer clinicians an overview of B-cell lymphomas in the gut, and their pertinent molecular features that have led to new insights regarding lymphomagenesis. It addresses the question as how to incorporate all presently available information on normal and neoplastic B-cell differentiation, and how this knowledge can be applied in daily clinical practice (e.g., diagnostic tools, prognostic biomarkers or therapeutic targets) to optimalise the managment of this heterogeneous group of neoplasms. PMID:23443141

  9. B-Cell Response during Protozoan Parasite Infections

    OpenAIRE

    Amezcua Vesely, María C; Bermejo, Daniela A.; Montes, Carolina L.; Acosta-Rodríguez, Eva V.; Adriana Gruppi

    2012-01-01

    In this review, we discuss how protozoan parasites alter immature and mature B cell compartment. B1 and marginal zone (MZ) B cells, considered innate like B cells, are activated during protozoan parasite infections, and they generate short lived plasma cells providing a prompt antibody source. In addition, protozoan infections induce massive B cell response with polyclonal activation that leads to hypergammaglobulnemia with serum antibodies specific for the parasites and self and/or non relat...

  10. Resource Competition Determines Selection of B Cell Repertoires

    OpenAIRE

    de Boer, R J; Freitas, A. A.; Perelson, A. S.

    2001-01-01

    Previous experiments with mouse chimeras demonstrated that cellular competition for antigen- specific survival signals plays a crucial role in the maintenance of the naive B cell repertoire. Transgenic (Tg) B cell populations in these chimeras have a shortened lifespan and poor competitive abilities as compared to more diverse non-Tg populations in the same mice. We develop a mathematical model to investigate the mechanism of B cell competition. The model allows for various B cell clones, gen...

  11. Aquatic Life Benchmarks

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Aquatic Life Benchmarks is an EPA-developed set of criteria for freshwater species. These benchmarks are based on toxicity values reviewed by EPA and used in...

  12. A new EV71 VP3 epitope in norovirus P particle vector displays neutralizing activity and protection in vivo in mice.

    Science.gov (United States)

    Jiang, Liping; Fan, Rongjun; Sun, Shiyang; Fan, Peihu; Su, Weiheng; Zhou, Yan; Gao, Feng; Xu, Fei; Kong, Wei; Jiang, Chunlai

    2015-11-27

    Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16), as the main agents causing hand, foot and mouth disease (HFMD), have become a serious public health concern in the Asia-Pacific region. Recently, various neutralizing B cell epitopes of EV71 were identified as targets for promising vaccine candidates. Structural studies of Picornaviridae indicated that potent immunodominant epitopes typically lie in the hypervariable loop of capsid surfaces. However, cross-neutralizing antibodies and cross-protection between EV71 and CVA16 have not been observed. Therefore, we speculated that divergent sequences of the two viruses are key epitopes for inducing protective neutralizing responses. In this study, we selected 10 divergent epitope candidates based on alignment of the EV71 and CVA16 P1 amino acid sequences using the Multalin interface page, and these epitopes are conserved among all subgenotypes of EV71. Simultaneously, by utilizing the norovirus P particle as a novel vaccine delivery carrier, we identified the 71-6 epitope (amino acid 176-190 of VP3) as a conformational neutralizing epitope against EV71 in an in vitro micro-neutralization assay as well as an in vivo protection assay in mice. Altogether, these results indicated that the incorporation of the 71-6 epitope into the norovirus P domain can provide a promising candidate for an effective synthetic peptide-based vaccine against EV71. PMID:26529072

  13. Phenytoin Induced Cutaneous B Cell Pseudolymphoma.

    Science.gov (United States)

    Riyaz, Najeeba; Sasidharanpillai, Sarita; Aravindan, Karumathil P; Nobin, Babu K; Raghavan, Nisha T; Nikhila, Pappinissery K

    2015-01-01

    Cutaneous pseudolymphomas are benign lymphoproliferative processes mimicking lymphomas clinically and histologically. One of the precipitating factors for pseudolymphoma is drugs like anticonvulsants, antidepressants and angiotensin-converting enzyme inhibitors. According to existing literature phenytoin-induced cutaneous pseudolymphomas are usually T-cell predominant. Most often withdrawal of the drug with or without short-course systemic steroids can attain a cure. Rarely malignant transformation has been reported years later despite withdrawal of the offending drug, which necessitates a long-term follow up of the affected. We report an 80-year-old male patient who was receiving phenytoin sodium and who presented with diffuse erythema and infiltrated skin lesions which histologically resembled cutaneous B-cell lymphoma. Substituting phenytoin with levetiracetam achieved resolution of symptoms. Further evaluation was suggestive of a reactive process. A detailed drug history is of paramount importance in differentiating drug-induced pseudolymphoma from lymphoma. Searching literature we could not find any previous reports of phenytoin-induced cutaneous B-cell pseudolymphoma. PMID:26538730

  14. Molecular modeling and in-silico engineering of Cardamom mosaic virus coat protein for the presentation of immunogenic epitopes of Leptospira LipL32.

    Science.gov (United States)

    Kumar, Vikram; Damodharan, S; Pandaranayaka, Eswari P J; Madathiparambil, Madanan G; Tennyson, Jebasingh

    2016-01-01

    Expression of Cardamom mosaic virus (CdMV) coat protein (CP) in E. coli forms virus-like particles. In this study, the structure of CdMV CP was predicted and used as a platform to display epitopes of the most abundant surface-associated protein, LipL32 of Leptospira at C, N, and both the termini of CdMV CP. In silico, we have mapped sequential and conformational B-cell epitopes from the crystal structure of LipL32 of Leptospira interrogans serovar Copenhageni str. Fiocruz L1-130 using IEDB Elipro, ABCpred, BCPRED, and VaxiJen servers. Our results show that the epitopes displayed at the N-terminus of CdMV CP are promising vaccine candidates as compared to those displayed at the C-terminus or at both the termini. LipL32 epitopes, EP2, EP3, EP4, and EP6 are found to be promising B-cell epitopes for vaccine development. Based on the type of amino acids, length, surface accessibility, and docking energy with CdMV CP model, the order of antigenicity of the LipL32 epitopes was found to be EP4 > EP3 > EP2 > EP6. PMID:25692534

  15. Benchmarking semantic web technology

    CERN Document Server

    García-Castro, R

    2009-01-01

    This book addresses the problem of benchmarking Semantic Web Technologies; first, from a methodological point of view, proposing a general methodology to follow in benchmarking activities over Semantic Web Technologies and, second, from a practical point of view, presenting two international benchmarking activities that involved benchmarking the interoperability of Semantic Web technologies using RDF(S) as the interchange language in one activity and OWL in the other.The book presents in detail how the different resources needed for these interoperability benchmarking activities were defined:

  16. The Transcription Factor Bach2 Is Phosphorylated at Multiple Sites in Murine B Cells but a Single Site Prevents Its Nuclear Localization.

    Science.gov (United States)

    Ando, Ryo; Shima, Hiroki; Tamahara, Toru; Sato, Yoshihiro; Watanabe-Matsui, Miki; Kato, Hiroki; Sax, Nicolas; Motohashi, Hozumi; Taguchi, Keiko; Yamamoto, Masayuki; Nio, Masaki; Maeda, Tatsuya; Ochiai, Kyoko; Muto, Akihiko; Igarashi, Kazuhiko

    2016-01-22

    The transcription factor Bach2 regulates the immune system at multiple points, including class switch recombination (CSR) in activated B cells and the function of T cells in part by restricting their terminal differentiation. However, the regulation of Bach2 expression and its activity in the immune cells are still unclear. Here, we demonstrated that Bach2 mRNA expression decreased in Pten-deficient primary B cells. Bach2 was phosphorylated in primary B cells, which was increased upon the activation of the B cell receptor by an anti-immunoglobulin M (IgM) antibody or CD40 ligand. Using specific inhibitors of kinases, the phosphorylation of Bach2 in activated B cells was shown to depend on the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway. The complex of mTOR and Raptor phosphorylated Bach2 in vitro. We identified multiple new phosphorylation sites of Bach2 by mass spectrometry analysis of epitope-tagged Bach2 expressed in the mature B cell line BAL17. Among the sites identified, serine 535 (Ser-535) was critical for the regulation of Bach2 because a single mutation of Ser-535 abolished cytoplasmic accumulation of Bach2, promoting its nuclear accumulation in pre-B cells, whereas Ser-509 played an auxiliary role. Bach2 repressor activity was enhanced by the Ser-535 mutation in B cells. These results suggest that the PI3K-Akt-mTOR pathway inhibits Bach2 by both repressing its expression and inducing its phosphorylation in B cells. PMID:26620562

  17. CNS accumulation of regulatory B cells is VLA-4-dependent

    Science.gov (United States)

    Lehmann-Horn, Klaus; Sagan, Sharon A.; Winger, Ryan C.; Spencer, Collin M.; Bernard, Claude C.A.; Sobel, Raymond A.

    2016-01-01

    Objective: To investigate the role of very late antigen-4 (VLA-4) on regulatory B cells (Breg) in CNS autoimmune disease. Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in mice selectively deficient for VLA-4 on B cells (CD19cre/α4f/f) by immunization with myelin oligodendrocyte glycoprotein (MOG) peptide (p)35–55 or recombinant human (rh) MOG protein. B-cell and T-cell populations were examined by flow cytometry and immunohistochemistry. Breg were evaluated by intracellular IL-10 staining of B cells and, secondly, by coexpression of CD1d and CD5. Results: As previously reported, EAE was less severe in B-cell VLA-4-deficient vs control CD19cre mice when induced by rhMOG, a model that is B-cell-dependent and leads to efficient B-cell activation and antibody production. Paradoxically, B-cell VLA-4-deficient mice developed more severe clinical disease than control mice when EAE was induced with MOG p35-55, a B-cell-independent encephalitogen that does not efficiently activate B cells. Peripheral T-cell and humoral immune responses were not altered in B-cell VLA-4-deficient mice. In MOG p35-55-induced EAE, B-cell VLA-4 deficiency reduced CNS accumulation of B but not T cells. Breg were detected in the CNS of control mice with MOG p35-55-induced EAE. However, more severe EAE in B-cell VLA-4-deficient mice was associated with virtual absence of CNS Breg. Conclusions: Our results demonstrate that CNS accumulation of Breg is VLA-4-dependent and suggest that Breg may contribute to regulation of CNS autoimmunity in situ. These observations underscore the need to choose the appropriate encephalitogen when studying how B cells contribute to pathogenesis or regulation of CNS autoimmunity. PMID:27027096

  18. Regulation of normal B-cell differentiation and malignant B-cell survival by OCT2.

    Science.gov (United States)

    Hodson, Daniel J; Shaffer, Arthur L; Xiao, Wenming; Wright, George W; Schmitz, Roland; Phelan, James D; Yang, Yandan; Webster, Daniel E; Rui, Lixin; Kohlhammer, Holger; Nakagawa, Masao; Waldmann, Thomas A; Staudt, Louis M

    2016-04-01

    The requirement for the B-cell transcription factor OCT2 (octamer-binding protein 2, encoded by Pou2f2) in germinal center B cells has proved controversial. Here, we report that germinal center B cells are formed normally after depletion of OCT2 in a conditional knockout mouse, but their proliferation is reduced and in vivo differentiation to antibody-secreting plasma cells is blocked. This finding led us to examine the role of OCT2 in germinal center-derived lymphomas. shRNA knockdown showed that almost all diffuse large B-cell lymphoma (DLBCL) cell lines are addicted to the expression of OCT2 and its coactivator OCA-B. Genome-wide chromatin immunoprecipitation (ChIP) analysis and gene-expression profiling revealed the broad transcriptional program regulated by OCT2 that includes the expression of STAT3, IL-10, ELL2, XBP1, MYC, TERT, and ADA. Importantly, genetic alteration of OCT2 is not a requirement for cellular addiction in DLBCL. However, we detected amplifications of the POU2F2 locus in DLBCL tumor biopsies and a recurrent mutation of threonine 223 in the DNA-binding domain of OCT2. This neomorphic mutation subtly alters the DNA-binding preference of OCT2, leading to the transactivation of noncanonical target genes including HIF1a and FCRL3 Finally, by introducing mutations designed to disrupt the OCT2-OCA-B interface, we reveal a requirement for this protein-protein interface that ultimately might be exploited therapeutically. Our findings, combined with the predominantly B-cell-restricted expression of OCT2 and the absence of a systemic phenotype in our knockout mice, suggest that an OCT2-targeted therapeutic strategy would be efficacious in both major subtypes of DLBCL while avoiding systemic toxicity. PMID:26993806

  19. Research Reactor Benchmarks

    International Nuclear Information System (INIS)

    A criticality benchmark experiment performed at the Jozef Stefan Institute TRIGA Mark II research reactor is described. This experiment and its evaluation are given as examples of benchmark experiments at research reactors. For this reason the differences and possible problems compared to other benchmark experiments are particularly emphasized. General guidelines for performing criticality benchmarks in research reactors are given. The criticality benchmark experiment was performed in a normal operating reactor core using commercially available fresh 20% enriched fuel elements containing 12 wt% uranium in uranium-zirconium hydride fuel material. Experimental conditions to minimize experimental errors and to enhance computer modeling accuracy are described. Uncertainties in multiplication factor due to fuel composition and geometry data are analyzed by sensitivity analysis. The simplifications in the benchmark model compared to the actual geometry are evaluated. Sample benchmark calculations with the MCNP and KENO Monte Carlo codes are given

  20. Interleukin 2 receptors on human B cells. Implications for the role of interleukin 2 in human B cell function

    OpenAIRE

    1985-01-01

    In the present study, we examined the expression of interleukin 2 (IL- 2) receptors on normal human B cells as well as established B cell lines. Anti-Tac monoclonal antibody did not bind to freshly separated normal human B cells. Unexpectedly, with the appropriate activation of the normal B cells by anti-mu antibody, phorbol myristate acetate, or Staphylococcus aureus Cowan I (SAC), Tac antigen was induced on the activated B cells. Anti-Tac antibody showed consistent reactivity with two B cel...

  1. B and T Cell Epitope-Based Peptides Predicted from Evolutionarily Conserved and Whole Protein Sequences of Ebola Virus as Vaccine Targets.

    Science.gov (United States)

    Yasmin, T; Nabi, A H M Nurun

    2016-05-01

    Ebola virus (EBV) has become a serious threat to public health. Different approaches were applied to predict continuous and discontinuous B cell epitopes as well as T cell epitopes from the sequence-based and available three-dimensional structural analyses of each protein of EBV. Peptides '(79) VPSATKRWGFRSGVPP(94) ' from GP1 and '(515) LHYWTTQDEGAAIGLA(530) ' from GP2 of Ebola were found to be the consensus peptidic sequences predicted as linear B cell epitope of which the latter contains a region (519) TTQDEG(524) that fulfilled all the criteria of accessibility, hydrophilicity, flexibility and beta turn region for becoming an ideal B cell epitope. Different nonamers as T cell epitopes were obtained that interacted with different numbers of MHC class I and class II alleles with a binding affinity of <100 nm. Interestingly, these alleles also bound to the MHC class I alleles mostly prevalent in African and South Asian regions. Of these, 'LANETTQAL' and 'FLYDRLAST' nonamers were predicted to be the most potent T cell epitopes and they, respectively, interacted with eight and twelve class I alleles that covered 63.79% and 54.16% of world population, respectively. These nonamers were found to be the core sequences of 15mer peptides that interacted with the most common class II allele, HLA-DRB1*01:01. They were further validated for their binding to specific class I alleles using docking technique. Thus, these predicted epitopes may be used as vaccine targets against EBV and can be validated in model hosts to verify their efficacy as vaccine. PMID:26939891

  2. Dynamic changes of B-cell compartments in kidney transplantation: lack of transitional B cells is associated with allograft rejection.

    Science.gov (United States)

    Svachova, Veronika; Sekerkova, Alena; Hruba, Petra; Tycova, Irena; Rodova, Marketa; Cecrdlova, Eva; Slatinska, Janka; Honsova, Eva; Striz, Ilja; Viklicky, Ondrej

    2016-05-01

    B cells play an important role in the immune responses which affect the outcomes of kidney allografts. Dynamic changes of B-cell compartments in clinical kidney transplantation are still poorly understood. B-cell subsets were prospectively monitored using flow cytometry for 1 year in 98 kidney transplant recipients. Data were correlated with immunosuppression and clinical outcomes. An increase in the total population of B lymphocytes was observed during the first week after transplantation. The level of IgM(high) CD38(high) CD24(high) transitional B cells reduced significantly up until the third month, with partial repopulation in the first year. Lower numbers of transitional B cells in the third month were associated with higher risk of graft rejection. IgM(+) IgD(+) CD27(-) naive B cells did not change within follow-up. IgM(+) CD27(+) nonswitched memory B cells and IgM(-) CD27(+) switched memory B cells increased on post-operative day 7. IgM(-) CD38(high) CD27(high) plasmablasts showed similar kinetics during the first post-transplant year, similar to transitional B cells. In conclusion, sensitized kidney transplant recipients as well as those with either acute or chronic rejection within the first post-transplant year exhibited lower levels of transitional B cells. Therefore, these data further support the hypothesis that transitional B cells have a protective role in kidney transplantation. PMID:26839984

  3. Comparison of in vitro immunogenicity, tolerogenicity and mitogenicity of dinitrophenyl-levan conjugates with varying epitope density.

    Science.gov (United States)

    Desaymard, C; Ivanyi, L

    1976-01-01

    The mitogenicity, immunogenicity and tolerogenicity of various DNP-levan (DNP-LE) conjugates were compared using in vitro methods. Anti-DNP antibody synthesis induced by DNP-LE conjugates was related to the epitope density of DNP, BUT WAS NOT AFFECTED BY Macrophage dependent and was not influenced by the degree of hapten conjugation. These results imply that mitogenicity of an antigen is not necessarily related to the specific triggering of B cells. PMID:58831

  4. Initiation of immune tolerance-controlled HIV gp41 neutralizing B cell lineages.

    Science.gov (United States)

    Zhang, Ruijun; Verkoczy, Laurent; Wiehe, Kevin; Munir Alam, S; Nicely, Nathan I; Santra, Sampa; Bradley, Todd; Pemble, Charles W; Zhang, Jinsong; Gao, Feng; Montefiori, David C; Bouton-Verville, Hilary; Kelsoe, Garnett; Larimore, Kevin; Greenberg, Phillip D; Parks, Robert; Foulger, Andrew; Peel, Jessica N; Luo, Kan; Lu, Xiaozhi; Trama, Ashley M; Vandergrift, Nathan; Tomaras, Georgia D; Kepler, Thomas B; Moody, M Anthony; Liao, Hua-Xin; Haynes, Barton F

    2016-04-27

    Development of an HIV vaccine is a global priority. A major roadblock to a vaccine is an inability to induce protective broadly neutralizing antibodies (bnAbs). HIV gp41 bnAbs have characteristics that predispose them to be controlled by tolerance. We used gp41 2F5 bnAb germline knock-in mice and macaques vaccinated with immunogens reactive with germline precursors to activate neutralizing antibodies. In germline knock-in mice, bnAb precursors were deleted, with remaining anergic B cells capable of being activated by germline-binding immunogens to make gp41-reactive immunoglobulin M (IgM). Immunized macaques made B cell clonal lineages targeted to the 2F5 bnAb epitope, but 2F5-like antibodies were either deleted or did not attain sufficient affinity for gp41-lipid complexes to achieve the neutralization potency of 2F5. Structural analysis of members of a vaccine-induced antibody lineage revealed that heavy chain complementarity-determining region 3 (HCDR3) hydrophobicity was important for neutralization. Thus, gp41 bnAbs are controlled by immune tolerance, requiring vaccination strategies to transiently circumvent tolerance controls. PMID:27122615

  5. Initiation of immune tolerance–controlled HIV gp41 neutralizing B cell lineages

    Science.gov (United States)

    Zhang, Ruijun; Verkoczy, Laurent; Wiehe, Kevin; Alam, S. Munir; Nicely, Nathan I.; Santra, Sampa; Bradley, Todd; Pemble, Charles W.; Zhang, Jinsong; Gao, Feng; Montefiori, David C.; Bouton-Verville, Hilary; Kelsoe, Garnett; Larimore, Kevin; Greenberg, Phillip D.; Parks, Robert; Foulger, Andrew; Peel, Jessica N.; Luo, Kan; Lu, Xiaozhi; Trama, Ashley M.; Vandergrift, Nathan; Tomaras, Georgia D.; Kepler, Thomas B.; Moody, M. Anthony; Liao, Hua-Xin; Haynes, Barton F.

    2016-01-01

    Development of an HIV vaccine is a global priority. A major roadblock to a vaccine is an inability to induce protective broadly neutralizing antibodies (bnAbs). HIV gp41 bnAbs have characteristics that predispose them to be controlled by tolerance. We used gp41 2F5 bnAb germline knock-in mice and macaques vaccinated with immunogens reactive with germline precursors to activate neutralizing antibodies. In germline knock-in mice, bnAb precursors were deleted, with remaining anergic B cells capable of being activated by germline-binding immunogens to make gp41-reactive immunoglobulin M (IgM). Immunized macaques made B cell clonal lineages targeted to the 2F5 bnAb epitope, but 2F5-like antibodies were either deleted or did not attain sufficient affinity for gp41-lipid complexes to achieve the neutralization potency of 2F5. Structural analysis of members of a vaccine-induced antibody lineage revealed that heavy chain complementarity-determining region 3 (HCDR3) hydrophobicity was important for neutralization. Thus, gp41 bnAbs are controlled by immune tolerance, requiring vaccination strategies to transiently circumvent tolerance controls. PMID:27122615

  6. Primary cardiac diffuse large B-cell lymphoma with activated B-cell-like phenotype

    Directory of Open Access Journals (Sweden)

    Vijaya Gadage

    2011-01-01

    Full Text Available Primary cardiac lymphoma (PCL is a rare and fatal disorder. It may often mimic other common cardiac tumors like cardiac myxoma because of similarities in the clinical presentation. We report a case of PCL of diffuse large B-cell type, in a 38-year-old, immunocompetent male who presented with superior vena cava syndrome that was excised as a myxoma. Histology revealed a large cell population diffusely and strongly expressing CD45, CD20, MUM1/IRF4 and FOXP1 hinting at an activated B-cell (ABC-like phenotype. After four cycles of Rituximab with CHOP (cyclophosphamide, hydroxydaunorubicin, Oncovin, and prednisolone the tumor regressed completely but the patient had a relapse and subsequently succumbed to the disease confirming the aggressive nature. The aggressive behavior of PCL may be possibly linked to its ABC-like origin.

  7. Differential programming of B cells in AID deficient mice.

    Directory of Open Access Journals (Sweden)

    Marc A Hogenbirk

    Full Text Available The Aicda locus encodes the activation induced cytidine deaminase (AID and is highly expressed in germinal center (GC B cells to initiate somatic hypermutation (SHM and class switch recombination (CSR of immunoglobulin (Ig genes. Besides these Ig specific activities in B cells, AID has been implicated in active DNA demethylation in non-B cell systems. We here determined a potential role of AID as an epigenetic eraser and transcriptional regulator in B cells. RNA-Seq on different B cell subsets revealed that Aicda(-/- B cells are developmentally affected. However as shown by RNA-Seq, MethylCap-Seq, and SNP analysis these transcriptome alterations may not relate to AID, but alternatively to a CBA mouse strain derived region around the targeted Aicda locus. These unexpected confounding parameters provide alternative, AID-independent interpretations on genotype-phenotype correlations previously reported in numerous studies on AID using the Aicda(-/- mouse strain.

  8. Innate response activator B cells: origins and functions.

    Science.gov (United States)

    Chousterman, Benjamin G; Swirski, Filip K

    2015-10-01

    Innate response activator (IRA) B cells are a subset of B-1a derived B cells that produce the growth factors granulocyte macrophage colony stimulating factor and IL-3. In mouse models of sepsis and pneumonia, B-1a B cells residing in serosal sites recognize bacteria, migrate to the spleen or lung, and differentiate to IRA B cells that then contribute to the host response by amplifying inflammation and producing polyreactive IgM. In atherosclerosis, IRA B cells accumulate in the spleen, where they promote extramedullary hematopoiesis and activate classical dendritic cells. In this review, we focus on the ontogeny and function of IRA B cells in acute and chronic inflammation. PMID:25957266

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

    DEFF Research Database (Denmark)

    Faurschou, Mikkel; Jayne, David R W

    2014-01-01

    Several monoclonal antibodies targeting B cells have been tested as therapeutics for inflammatory rheumatic diseases. We review important observations from randomized clinical trials regarding the efficacy and safety of anti-B cell antibody-based therapies for rheumatoid arthritis, systemic lupus...... erythematosus, antineutrophil cytoplasmic antibody-associated vasculitis, polymyositis/dermatomyositis, and primary Sjögren's syndrome. For some anti-B cell agents, clinical benefits have been convincingly demonstrated, while other B cell-targeted therapies failed to improve outcomes when added to standard......-of-care treatment or were associated with increased rates of adverse events. Although the risk-benefit balance seems to be acceptable for currently licensed anti-B cell agents, additional studies are required to fully assess the safety of treatment regimens involving prolonged interference with B cell counts and...

  10. Gastrointestinal B-cell lymphomas: From understanding B-cell physiology to classification and molecular pathology

    OpenAIRE

    2012-01-01

    The gut is the most common extranodal site where lymphomas arise. Although all histological lymphoma types may develop in the gut, small and large B-cell lymphomas predominate. The sometimes unexpected finding of a lymphoid lesion in an endoscopic biopsy of the gut may challenge both the clinician (who is not always familiar with lymphoma pathogenesis) and the pathologist (who will often be hampered in his/her diagnostic skill by the limited amount of available tissue). Moreover, the past 2 d...

  11. Design and Antigenic Epitopes Prediction of a New Trial Recombinant Multiepitopic Rotaviral Vaccine: In Silico Analyses.

    Science.gov (United States)

    Jafarpour, Sima; Ayat, Hoda; Ahadi, Ali Mohammad

    2015-01-01

    Rotavirus is the major etiologic factor of severe diarrheal disease. Natural infection provides protection against subsequent rotavirus infection and diarrhea. This research presents a new vaccine designed based on computational models. In this study, three types of epitopes are considered-linear, conformational, and combinational-in a proposed model protein. Several studies on rotavirus vaccines have shown that VP6 and VP4 proteins are good candidates for vaccine production. In the present study, a fusion protein was designed as a new generation of rotavirus vaccines by bioinformatics analyses. This model-based study using ABCpred, BCPREDS, Bcepred, and Ellipro web servers showed that the peptide presented in this article has the necessary properties to act as a vaccine. Prediction of linear B-cell epitopes of peptides is helpful to investigate whether these peptides are able to activate humoral immunity. PMID:25965449

  12. The Conic Benchmark Format

    DEFF Research Database (Denmark)

    Friberg, Henrik A.

    This document constitutes the technical reference manual of the Conic Benchmark Format with le extension: .cbf or .CBF. It unies linear, second-order cone (also known as conic quadratic) and semidenite optimization with mixed-integer variables. The format has been designed with benchmark libraries...... in mind, and therefore focuses on compact and easily parsable representations. The problem structure is separated from the problem data, and the format moreover facilitate benchmarking of hotstart capability through sequences of changes....

  13. Bayesian Benchmark Dose Analysis

    OpenAIRE

    Fang, Qijun; Piegorsch, Walter W.; Barnes, Katherine Y.

    2014-01-01

    An important objective in environmental risk assessment is estimation of minimum exposure levels, called Benchmark Doses (BMDs) that induce a pre-specified Benchmark Response (BMR) in a target population. Established inferential approaches for BMD analysis typically involve one-sided, frequentist confidence limits, leading in practice to what are called Benchmark Dose Lower Limits (BMDLs). Appeal to Bayesian modeling and credible limits for building BMDLs is far less developed, however. Indee...

  14. Risk Management with Benchmarking

    OpenAIRE

    Suleyman Basak; Alex Shapiro; Lucie Teplá

    2005-01-01

    Portfolio theory must address the fact that, in reality, portfolio managers are evaluated relative to a benchmark, and therefore adopt risk management practices to account for the benchmark performance. We capture this risk management consideration by allowing a prespecified shortfall from a target benchmark-linked return, consistent with growing interest in such practice. In a dynamic setting, we demonstrate how a risk-averse portfolio manager optimally under- or overperforms a target benchm...

  15. Quantifying evolutionary constraints on B cell affinity maturation

    OpenAIRE

    McCoy, Connor O.; Bedford, Trevor; Minin, Vladimir N.; Bradley, Philip; Robins, Harlan; Frederick A. Matsen IV

    2014-01-01

    The antibody repertoire of each individual is continuously updated by the evolutionary process of B cell receptor mutation and selection. It has recently become possible to gain detailed information concerning this process through high-throughput sequencing. Here, we develop modern statistical molecular evolution methods for the analysis of B cell sequence data, and then apply them to a very deep short-read data set of B cell receptors. We find that the substitution process is conserved acros...

  16. Monitoring B cell subsets and alloreactivity in kidney transplantation

    OpenAIRE

    Crespo Barrio, Marta; Heidtc, Sebastiaan; Redondo Pach??n, Mar??a Dolores; Pascual Santos, Julio

    2015-01-01

    B cells are the precursors of antibody producing plasma cells that can give rise to the formation of donor-specific antibodies. However, recent data suggest that besides their role in antibody production, B cells participate in antibody-independent responses, potentially leading to allograft rejection or allograft tolerance. The presence of CD20+ B cells in kidney graft biopsies has been shown during severe acute rejection episodes and during chronic rejection. Furthermore, operationally tole...

  17. Aeroelastic Benchmark Experiments Project

    Data.gov (United States)

    National Aeronautics and Space Administration — M4 Engineering proposes to conduct canonical aeroelastic benchmark experiments. These experiments will augment existing sources for aeroelastic data in the...

  18. MCNP neutron benchmarks

    International Nuclear Information System (INIS)

    Over 50 neutron benchmark calculations have recently been completed as part of an ongoing program to validate the MCNP Monte Carlo radiation transport code. The new and significant aspects of this work are as follows: These calculations are the first attempt at a validation program for MCNP and the first official benchmarking of version 4 of the code. We believe the chosen set of benchmarks is a comprehensive set that may be useful for benchmarking other radiation transport codes and data libraries. These calculations provide insight into how well neutron transport calculations can be expected to model a wide variety of problems

  19. How Activists Use Benchmarks

    DEFF Research Database (Denmark)

    Seabrooke, Leonard; Wigan, Duncan

    2015-01-01

    Non-governmental organisations use benchmarks as a form of symbolic violence to place political pressure on firms, states, and international organisations. The development of benchmarks requires three elements: (1) salience, that the community of concern is aware of the issue and views it as...... important; (2) will, that activists and issue entrepreneurs will carry the message forward; and (3) expertise, that benchmarks created can be defended as accurate representations of what is happening on the issue of concern. We contrast two types of benchmarking cycles where salience, will, and expertise...

  20. Regulatory T cells and B cells: implication on autoimmune diseases

    OpenAIRE

    Wang, Ping; Zheng, Song Guo

    2013-01-01

    The regulatory T (Treg) cells play an important role in the maintenance of homeostasis and the prevention of autoimmune diseases. Although most studies are focusing on the role of Treg cells in T cells and T cells-mediated diseases, these cells also directly affect B cells and other non-T cells. This manuscript updates the role of Treg cells on the B cells and B cell-mediated diseases. In addition, the mechanisms whereby Treg cells suppress B cell responses have been discussed.

  1. B cells as a target of immune modulation

    Directory of Open Access Journals (Sweden)

    Hawker Kathleen

    2009-01-01

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

  2. A transplant "immunome" screening platform defines a targetable epitope fingerprint of multiple myeloma.

    Science.gov (United States)

    Schieferdecker, Aneta; Oberle, Anna; Thiele, Benjamin; Hofmann, Fabian; Göthel, Markus; Miethe, Sebastian; Hust, Michael; Braig, Friederike; Voigt, Mareike; von Pein, Ute-Marie; Koch-Nolte, Friedrich; Haag, Friedrich; Alawi, Malik; Indenbirken, Daniela; Grundhoff, Adam; Bokemeyer, Carsten; Bacher, Ulrike; Kröger, Nicolaus; Binder, Mascha

    2016-06-23

    Multiple myeloma (MM) is a hematological cancer for which immune-based treatments are currently in development. Many of these rely on the identification of highly disease-specific, strongly and stably expressed antigens. Here, we profiled the myeloma B-cell immunome both to explore its predictive role in the context of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) and to identify novel immunotherapeutic targets. We used random peptide phage display, reverse immunization, and next-generation sequencing-assisted antibody phage display to establish a highly myeloma-specific epitope fingerprint targeted by B-cell responses of 18 patients in clinical remission. We found that allogeneic HSCT more efficiently allowed production of myeloma-specific antibodies compared with autologous HSCT and that a highly reactive epitope recognition signature correlated with superior response to treatment. Next, we performed myeloma cell surface screenings of phage-displayed patient transplant immunomes. Although some of the screenings yielded clear-cut surface binders, the majority of screenings did not, suggesting that many of the targeted antigens may in fact not be accessible to the B-cell immune system in untreated myeloma cells. This fit well with the identification of heat-shock proteins as a class of antigens that showed overall the broadest reactivity with myeloma patient sera after allogeneic HSCT and that may be significantly translocated to the cell surface upon treatment as a result of immunogenic cell death. Our data reveal a disease-specific epitope signature of MM that is predictive for response to treatment. Mining of transplant immunomes for strong myeloma surface binders may open up avenues for myeloma immunotherapy. PMID:27034429

  3. Immune-inflammatory responses in atherosclerosis: Role of an adaptive immunity mainly driven by T and B cells.

    Science.gov (United States)

    Chistiakov, Dimitry A; Orekhov, Alexander N; Bobryshev, Yuri V

    2016-09-01

    Adaptive immune response plays an important role in atherogenesis. In atherosclerosis, the proinflammatory immune response driven by Th1 is predominant but the anti-inflammatory response mediated mainly by regulatory T cells is also present. The role of Th2 and Th17 cells in atherogenesis is still debated. In the plaque, other T helper cells can be observed such as Th9 and Th22 but is little is known about their impact in atherosclerosis. Heterogeneity of CD4(+) T cell subsets presented in the plaque may suggest for plasticity of T cell that can switch the phenotype dependening on the local microenvironment and activating/blocking stimuli. Effector T cells are able to recognize self-antigens released by necrotic and apoptotic vascular cells and induce a humoral immune reaction. Tth cells resided in the germinal centers help B cells to switch the antibody class to the production of high-affinity antibodies. Humoral immunity is mediated by B cells that release antigen-specific antibodies. A variety of B cell subsets were found in human and murine atherosclerotic plaques. In mice, B1 cells could spontaneously produce atheroprotective natural IgM antibodies. Conventional B2 lymphocytes secrete either proatherogenic IgG, IgA, and IgE or atheroprotective IgG and IgM antibodies reactive with oxidation-specific epitopes on atherosclerosis-associated antigens. A small population of innate response activator (IRA) B cells, which is phenotypically intermediate between B1 and B2 cells, produces IgM but possesses proatherosclerotic properties. Finally, there is a minor subset of splenic regulatory B cells (Bregs) that protect against atherosclerotic inflammation through support of generation of Tregs and production of anti-inflammatory cytokines IL-10 and TGF-β and proapoptotic molecules. PMID:27262513

  4. Induction of multi-epitope specific antibodies against HIV-1 by multi-epitope vaccines

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Some neutralizing antibodies against HIV-1 envelope proteins were highly effective to inhibit the infection of different strains in vitro, and existed in the infected individuals with very low levels. We suggested multi-epitope-vaccine as a new strategy to increase levels of neutralizing antibodies and the abilities against HIV mutation in vivo. Two candidate multi-epitope-vaccines induced antibodies with predefined multi-epitope-specificity in rhesus macaque. These antibodies recognized corresponding neutralizing epitopes on epitope-peptides, gp41 peptides, V3 loop peptide, rsgp41 and rgp120. Besides, three candidate epitope-vaccines in combination (another kind of multi-epitopevaccines) showed similar potency to induce predefined multiple immune responses in rabbits. These results suggest that multi-epitope-vaccines may be a new strategy to induce multi-antiviral activities against HIV-1 infection and mutafions.

  5. The B-cell receptor orchestrates environment-mediated lymphoma survival and drug resistance in B-cell malignancies

    OpenAIRE

    Shain, KH; Tao, J.

    2013-01-01

    Specific niches within the lymphoma tumor microenvironment (TME) provide sanctuary for subpopulations of tumor cells through stromal cell–tumor cell interactions. These interactions notably dictate growth, response to therapy and resistance of residual malignant B cells to therapeutic agents. This minimal residual disease (MRD) remains a major challenge in the treatment of B-cell malignancies and contributes to subsequent disease relapse. B-cell receptor (BCR) signaling has emerged as essenti...

  6. Marginal zone B-cells, a gatekeeper of innate immunity.

    Science.gov (United States)

    Zouali, Moncef; Richard, Yolande

    2011-01-01

    To maintain the integrity of an organism constantly challenged by pathogens, the immune system is endowed with a variety of cell types. B lymphocytes were initially thought to only play a role in the adaptive branch of immunity. However, a number of converging observations revealed that two B-cell subsets, marginal zone (MZ) and B1 cells, exhibit unique developmental and functional characteristics, and can contribute to innate immune responses. In addition to their capacity to mount a local antibody response against type-2 T-cell-independent (TI-2) antigens, MZ B-cells can participate to T-cell-dependent (TD) immune responses through the capture and import of blood-borne antigens to follicular areas of the spleen. Here, we discuss the multiple roles of MZ B-cells in humans, non-human primates, and rodents. We also summarize studies - performed in transgenic mice expressing fully human antibodies on their B-cells and in macaques whose infection with Simian immunodeficiency virus (SIV) represents a suitable model for HIV-1 infection in humans - showing that infectious agents have developed strategies to subvert MZ B-cell functions. In these two experimental models, we observed that two microbial superantigens for B-cells (protein A from Staphylococcus aureus and protein L from Peptostreptococcus magnus) as well as inactivated AT-2 virions of HIV-1 and infectious SIV preferentially deplete innate-like B-cells - MZ B-cells and/or B1 B-cells - with different consequences on TI and TD antibody responses. These data revealed that viruses and bacteria have developed strategies to deplete innate-like B-cells during the acute phase of infection and to impair the antibody response. Unraveling the intimate mechanisms responsible for targeting MZ B-cells in humans will be important for understanding disease pathogenesis and for designing novel vaccine strategies. PMID:22566852

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

    Directory of Open Access Journals (Sweden)

    Sandrine Peruchon

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

  8. Shaping T Cell – B Cell Collaboration in the Response to Human Immunodeficiency Virus Type 1 Envelope Glycoprotein gp120 by Peptide Priming

    Science.gov (United States)

    Steede, N. Kalaya; Rust, Blake J.; Hossain, Mohammad M.; Freytag, Lucy C.; Robinson, James E.; Landry, Samuel J.

    2013-01-01

    Prime-boost vaccination regimes have shown promise for obtaining protective immunity to HIV. Poorly understood mechanisms of cellular immunity could be responsible for improved humoral responses. Although CD4+ T-cell help promotes B-cell development, the relationship of CD4+ T-cell specificity to antibody specificity has not been systematically investigated. Here, protein and peptide-specific immune responses to HIV-1 gp120 were characterized in groups of ten mucosally immunized BALB/c mice. Protein and peptide reactivity of serum antibody was tested for correlation with cytokine secretion by splenocytes restimulated with individual gp120 peptides. Antibody titer for gp120 correlated poorly with the peptide-stimulated T-cell response. In contrast, titers for conformational epitopes, measured as crossreactivity or CD4-blocking, correlated with average interleukin-2 and interleukin-5 production in response to gp120 peptides. Antibodies specific for conformational epitopes and individual gp120 peptides typically correlated with T-cell responses to several peptides. In order to modify the specificity of immune responses, animals were primed with a gp120 peptide prior to immunization with protein. Priming induced distinct peptide-specific correlations of antibodies and T-cells. The majority of correlated antibodies were specific for the primed peptides or other peptides nearby in the gp120 sequence. These studies suggest that the dominant B-cell subsets recruit the dominant T-cell subsets and that T-B collaborations can be shaped by epitope-specific priming. PMID:23776539

  9. Shaping T cell - B cell collaboration in the response to human immunodeficiency virus type 1 envelope glycoprotein gp120 by peptide priming.

    Directory of Open Access Journals (Sweden)

    N Kalaya Steede

    Full Text Available Prime-boost vaccination regimes have shown promise for obtaining protective immunity to HIV. Poorly understood mechanisms of cellular immunity could be responsible for improved humoral responses. Although CD4+ T-cell help promotes B-cell development, the relationship of CD4+ T-cell specificity to antibody specificity has not been systematically investigated. Here, protein and peptide-specific immune responses to HIV-1 gp120 were characterized in groups of ten mucosally immunized BALB/c mice. Protein and peptide reactivity of serum antibody was tested for correlation with cytokine secretion by splenocytes restimulated with individual gp120 peptides. Antibody titer for gp120 correlated poorly with the peptide-stimulated T-cell response. In contrast, titers for conformational epitopes, measured as crossreactivity or CD4-blocking, correlated with average interleukin-2 and interleukin-5 production in response to gp120 peptides. Antibodies specific for conformational epitopes and individual gp120 peptides typically correlated with T-cell responses to several peptides. In order to modify the specificity of immune responses, animals were primed with a gp120 peptide prior to immunization with protein. Priming induced distinct peptide-specific correlations of antibodies and T-cells. The majority of correlated antibodies were specific for the primed peptides or other peptides nearby in the gp120 sequence. These studies suggest that the dominant B-cell subsets recruit the dominant T-cell subsets and that T-B collaborations can be shaped by epitope-specific priming.

  10. Benchmark af erhvervsuddannelserne

    DEFF Research Database (Denmark)

    Bogetoft, Peter; Wittrup, Jesper

    I dette arbejdspapir diskuterer vi, hvorledes de danske erhvervsskoler kan benchmarkes, og vi præsenterer resultaterne af en række beregningsmodeller. Det er begrebsmæssigt kompliceret at benchmarke erhvervsskolerne. Skolerne udbyder en lang række forskellige uddannelser. Det gør det vanskeligt at...

  11. Thermal Performance Benchmarking (Presentation)

    Energy Technology Data Exchange (ETDEWEB)

    Moreno, G.

    2014-11-01

    This project will benchmark the thermal characteristics of automotive power electronics and electric motor thermal management systems. Recent vehicle systems will be benchmarked to establish baseline metrics, evaluate advantages and disadvantages of different thermal management systems, and identify areas of improvement to advance the state-of-the-art.

  12. Internet based benchmarking

    DEFF Research Database (Denmark)

    Bogetoft, Peter; Nielsen, Kurt

    2005-01-01

    We discuss the design of interactive, internet based benchmarking using parametric (statistical) as well as nonparametric (DEA) models. The user receives benchmarks and improvement potentials. The user is also given the possibility to search different efficiency frontiers and hereby to explore...

  13. DNA breaks early in replication in B cell cancers

    Science.gov (United States)

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

  14. Therapeutic strategies targeting B-cells in multiple sclerosis.

    Science.gov (United States)

    Milo, Ron

    2016-07-01

    Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) that traditionally has been considered to be mediated primarily by T-cells. Increasing evidence, however, suggests the fundamental role of B-cells in the pathogenesis of the disease. Recent strategies targeting B-cells in MS have demonstrated impressive and sometimes surprising results: B-cell depletion by monoclonal antibodies targeting the B-cell surface antigen CD20 (e.g. rituximab, ocrelizumab, ofatumumab) was shown to exert profound anti-inflammatory effect in MS with favorable risk-benefit ratio, with ocrelizumab demonstrating efficacy in both relapsing-remitting (RR) and primary-progressive (PP) MS in phase III clinical trials. Depletion of CD52 expressing T- and B-cells and monocytes by alemtuzumab resulted in impressive and durable suppression of disease activity in RRMS patients. On the other hand, strategies targeting B-cell cytokines such as atacicept resulted in increased disease activity. As our understanding of the biology of B-cells in MS is increasing, new compounds that target B-cells continue to be developed which promise to further expand the armamentarium of MS therapies and allow for more individualized therapy for patients with this complex disease. PMID:26970489

  15. Verification and validation benchmarks.

    Energy Technology Data Exchange (ETDEWEB)

    Oberkampf, William Louis; Trucano, Timothy Guy

    2007-02-01

    Verification and validation (V&V) are the primary means to assess the accuracy and reliability of computational simulations. V&V methods and procedures have fundamentally improved the credibility of simulations in several high-consequence fields, such as nuclear reactor safety, underground nuclear waste storage, and nuclear weapon safety. Although the terminology is not uniform across engineering disciplines, code verification deals with assessing the reliability of the software coding, and solution verification deals with assessing the numerical accuracy of the solution to a computational model. Validation addresses the physics modeling accuracy of a computational simulation by comparing the computational results with experimental data. Code verification benchmarks and validation benchmarks have been constructed for a number of years in every field of computational simulation. However, no comprehensive guidelines have been proposed for the construction and use of V&V benchmarks. For example, the field of nuclear reactor safety has not focused on code verification benchmarks, but it has placed great emphasis on developing validation benchmarks. Many of these validation benchmarks are closely related to the operations of actual reactors at near-safety-critical conditions, as opposed to being more fundamental-physics benchmarks. This paper presents recommendations for the effective design and use of code verification benchmarks based on manufactured solutions, classical analytical solutions, and highly accurate numerical solutions. In addition, this paper presents recommendations for the design and use of validation benchmarks, highlighting the careful design of building-block experiments, the estimation of experimental measurement uncertainty for both inputs and outputs to the code, validation metrics, and the role of model calibration in validation. It is argued that the understanding of predictive capability of a computational model is built on the level of

  16. Epitope mapping porcine reproductive and respiratory syndrome virus by phage display: the nsp2 fragment of the replicase polyprotein contains a cluster of B-cell epitopes

    DEFF Research Database (Denmark)

    Oleksiewicz, M.B.; Bøtner, Anette; Toft, P.; Normann, Preben; Storgaard, Torben

    2001-01-01

    was previously identified by monoclonal antibody mapping (J. J, M. Meulenberg, A. P. van Nieuwstadt, A, van Essen-Zandenbergen, and J, P, M, Langeveld, J. Virol, 71:6061-6067, 1997), but its immunogenicity had not been examined in pigs, We found that six experimentally PRRSV-infected pigs consistently...

  17. Memory B cell antibodies to HIV-1 gp140 cloned from individuals infected with clade A and B viruses.

    Directory of Open Access Journals (Sweden)

    Hugo Mouquet

    Full Text Available Understanding the antibody response to HIV-1 in humans that show broad neutralizing serologic activity is a crucial step in trying to reproduce such responses by vaccination. Investigating antibodies with cross clade reactivity is particularly important as these antibodies may target conserved epitopes on the HIV envelope gp160 protein. To this end we have used a clade B YU-2 gp140 trimeric antigen and single-cell antibody cloning methods to obtain 189 new anti-gp140 antibodies representing 51 independent B cell clones from the IgG memory B cells of 3 patients infected with HIV-1 clade A or B viruses and exhibiting broad neutralizing serologic activity. Our results support previous findings showing a diverse antibody response to HIV gp140 envelope protein, characterized by differentially expanded B-cell clones producing highly hypermutated antibodies with heterogenous gp140-specificity and neutralizing activity. In addition to their high-affinity binding to the HIV spike, the vast majority of the new anti-gp140 antibodies are also polyreactive. Although none of the new antibodies are as broad or potent as VRC01 or PG9, two clonally-related antibodies isolated from a clade A HIV-1 infected donor, directed against the gp120 variable loop 3, rank in the top 5% of the neutralizers identified in our large collection of 185 unique gp140-specific antibodies in terms of breadth and potency.

  18. Interaction between Mesenchymal Stem Cells and B-Cells

    Science.gov (United States)

    Fan, Linxiao; Hu, Chenxia; Chen, Jiajia; Cen, Panpan; Wang, Jie; Li, Lanjuan

    2016-01-01

    Mesenchymal stem cells (MSCs) are multipotent; non-hematopoietic stem cells. Because of their immunoregulatory abilities; MSCs are widely used for different clinical applications. Compared with that of other immune cells; the investigation of how MSCs specifically regulate B-cells has been superficial and insufficient. In addition; the few experimental studies on this regulation are often contradictory. In this review; we summarize the various interactions between different types or states of MSCs and B-cells; address how different types of MSCs and B-cells affect this interaction and examine how other immune cells influence the regulation of B-cells by MSCs. Finally; we hypothesize why there are conflicting results on the interaction between MSCs and B-cells in the literature. PMID:27164080

  19. Evaluation and use of in-silico structure-based epitope prediction with foot-and-mouth disease virus.

    Directory of Open Access Journals (Sweden)

    Daryl W Borley

    Full Text Available Understanding virus antigenicity is of fundamental importance for the development of better, more cross-reactive vaccines. However, as far as we are aware, no systematic work has yet been conducted using the 3D structure of a virus to identify novel epitopes. Therefore we have extended several existing structural prediction algorithms to build a method for identifying epitopes on the appropriate outer surface of intact virus capsids (which are structurally different from globular proteins in both shape and arrangement of multiple repeated elements and applied it here as a proof of principle concept to the capsid of foot-and-mouth disease virus (FMDV. We have analysed how reliably several freely available structure-based B cell epitope prediction programs can identify already known viral epitopes of FMDV in the context of the viral capsid. To do this we constructed a simple objective metric to measure the sensitivity and discrimination of such algorithms. After optimising the parameters for five methods using an independent training set we used this measure to evaluate the methods. Individually any one algorithm performed rather poorly (three performing better than the other two suggesting that there may be value in developing virus-specific software. Taking a very conservative approach requiring a consensus between all three top methods predicts a number of previously described antigenic residues as potential epitopes on more than one serotype of FMDV, consistent with experimental results. The consensus results identified novel residues as potential epitopes on more than one serotype. These include residues 190-192 of VP2 (not previously determined to be antigenic, residues 69-71 and 193-197 of VP3 spanning the pentamer-pentamer interface, and another region incorporating residues 83, 84 and 169-174 of VP1 (all only previously experimentally defined on serotype A. The computer programs needed to create a semi-automated procedure for carrying out

  20. Epitope Prediction Assays Combined with Validation Assays Strongly Narrows down Putative Cytotoxic T Lymphocyte Epitopes

    Directory of Open Access Journals (Sweden)

    Peng Peng Ip

    2015-03-01

    Full Text Available Tumor vaccine design requires prediction and validation of immunogenic MHC class I epitopes expressed by target cells as well as MHC class II epitopes expressed by antigen-presenting cells essential for the induction of optimal immune responses. Epitope prediction methods are based on different algorithms and are instrumental for a first screening of possible epitopes. However, their results do not reflect a one-to-one correlation with experimental data. We combined several in silico prediction methods to unravel the most promising C57BL/6 mouse-restricted Hepatitis C virus (HCV MHC class I epitopes and validated these epitopes in vitro and in vivo. Cytotoxic T lymphocyte (CTL epitopes within the HCV non-structural proteins were identified, and proteasomal cleavage sites and helper T cell (Th epitopes at close proximity to these CTL epitopes were analyzed using multiple prediction algorithms. This combined in silico analysis enhances the precision of identification of functional HCV-specific CTL epitopes. This approach will be applicable to the design of human vaccines not only for HCV, but also for other antigens in which T-cell responses play a crucial role.

  1. CD83 Modulates B Cell Activation and Germinal Center Responses.

    Science.gov (United States)

    Krzyzak, Lena; Seitz, Christine; Urbat, Anne; Hutzler, Stefan; Ostalecki, Christian; Gläsner, Joachim; Hiergeist, Andreas; Gessner, André; Winkler, Thomas H; Steinkasserer, Alexander; Nitschke, Lars

    2016-05-01

    CD83 is a maturation marker for dendritic cells. In the B cell lineage, CD83 is expressed especially on activated B cells and on light zone B cells during the germinal center (GC) reaction. The function of CD83 during GC responses is unclear. CD83(-/-) mice have a strong reduction of CD4(+) T cells, which makes it difficult to analyze a functional role of CD83 on B cells during GC responses. Therefore, in the present study we generated a B cell-specific CD83 conditional knockout (CD83 B-cKO) model. CD83 B-cKO B cells show defective upregulation of MHC class II and CD86 expression and impaired proliferation after different stimuli. Analyses of GC responses after immunization with various Ags revealed a characteristic shift in dark zone and light zone B cell numbers, with an increase of B cells in the dark zone of CD83 B-cKO mice. This effect was not accompanied by alterations in the level of IgG immune responses or by major differences in affinity maturation. However, an enhanced IgE response was observed in CD83 B-cKO mice. Additionally, we observed a strong competitive disadvantage of CD83-cKO B cells in GC responses in mixed bone marrow chimeras. Furthermore, infection of mice with Borrelia burgdorferi revealed a defect in bacterial clearance of CD83 B-cKO mice with a shift toward a Th2 response, indicated by a strong increase in IgE titers. Taken together, our results show that CD83 is important for B cell activation and modulates GC composition and IgE Ab responses in vivo. PMID:26983787

  2. Protection against enterovirus 71 with neutralizing epitope incorporation within adenovirus type 3 hexon.

    Directory of Open Access Journals (Sweden)

    Xingui Tian

    Full Text Available Enterovirus 71 (EV71 is responsible for hand, foot and mouth disease with high mortality among children. Various neutralizing B cell epitopes of EV71 have been identified as potential vaccine candidates. Capsid-incorporation of antigens into adenovirus (Ad has been developed for a novel vaccine approach. We constructed Ad3-based EV71 vaccine vectors by incorporating a neutralizing epitope SP70 containing 15 amino acids derived from capsid protein VP1 of EV71 within the different surface-exposed domains of the capsid protein hexon of Ad3EGFP, a recombinant adenovirus type 3 (Ad3 expressing enhanced green fluorescence protein. Thermostability and growth kinetic assays suggested that the SP70 epitope incorporation into hypervariable region (HVR1, HVR2, or HVR7 of the hexon did not affect Ad fitness. The SP70 epitopes were thought to be exposed on all hexon-modified intact virion surfaces. Repeated administration of BALB/c mice with the modified Ads resulted in boosting of the anti-SP70 humoral immune response. Importantly, the modified Ads immunization of mother mice conferred protection in vivo to neonatal mice against the lethal EV71 challenge, and the modified Ads-immunized mice serum also conferred passive protection against the lethal challenge in newborn mice. Compared with the recombinant GST-fused SP70 protein immunization, immunization with the Ads containing SP70 in HVR1 or HVR2 elicited higher SP70-specific IgG titers, higher neutralization titers, and conferred more effective protection to neonatal mice. Thus, this study provides valuable information for hexon-modified Ad3 vector development as a promising EV71 vaccine candidate and as an epitope-delivering vehicle for other pathogens.

  3. Prolactin Rescues Immature B-Cells from Apoptosis Induced by B-Cell Receptor Cross-Linking

    Science.gov (United States)

    Flores-Fernández, Rocio; Blanco-Favela, Francisco; Fuentes-Pananá, Ezequiel M.; Chávez-Sánchez, Luis; Gorocica-Rosete, Patricia; Pizaña-Venegas, Alberto; Chávez-Rueda, Adriana Karina

    2016-01-01

    Prolactin has an immunomodulatory effect and has been associated with B-cell-triggered autoimmune diseases, such as systemic lupus erythematosus (SLE). In mice that develop SLE, the PRL receptor is expressed in early bone marrow B-cells, and increased levels of PRL hasten disease manifestations, which are correlated with a reduction in the absolute number of immature B-cells. The aim of this work was to determine the effect of PRL in an in vitro system of B-cell tolerance using WEHI-231 cells and immature B-cells from lupus prone MRL/lpr mice. WEHI-231 cells express the long isoform of the PRL receptor, and PRL rescued the cells from cell death by decreasing the apoptosis induced by the cross-linking of the B-cell antigen receptor (BCR) as measured by Annexin V and active caspase-3. This decrease in apoptosis may have been due to the PRL and receptor interaction, which increased the relative expression of antiapoptotic Bcl-xL and decreased the relative expression of proapoptotic Bad. In immature B-cells from MRL/lpr mice, PRL increased the viability and decreased the apoptosis induced by the cross-linking of BCR, which may favor the maturation of self-reactive B-cells and contribute to the onset of disease. PMID:27314053

  4. Epitope discovery with phylogenetic hidden Markov models.

    LENUS (Irish Health Repository)

    Lacerda, Miguel

    2010-05-01

    Existing methods for the prediction of immunologically active T-cell epitopes are based on the amino acid sequence or structure of pathogen proteins. Additional information regarding the locations of epitopes may be acquired by considering the evolution of viruses in hosts with different immune backgrounds. In particular, immune-dependent evolutionary patterns at sites within or near T-cell epitopes can be used to enhance epitope identification. We have developed a mutation-selection model of T-cell epitope evolution that allows the human leukocyte antigen (HLA) genotype of the host to influence the evolutionary process. This is one of the first examples of the incorporation of environmental parameters into a phylogenetic model and has many other potential applications where the selection pressures exerted on an organism can be related directly to environmental factors. We combine this novel evolutionary model with a hidden Markov model to identify contiguous amino acid positions that appear to evolve under immune pressure in the presence of specific host immune alleles and that therefore represent potential epitopes. This phylogenetic hidden Markov model provides a rigorous probabilistic framework that can be combined with sequence or structural information to improve epitope prediction. As a demonstration, we apply the model to a data set of HIV-1 protein-coding sequences and host HLA genotypes.

  5. A performance geodynamo benchmark

    Science.gov (United States)

    Matsui, H.; Heien, E. M.

    2014-12-01

    In the last ten years, a number of numerical dynamo models have successfully represented basic characteristics of the geomagnetic field. However, to approach the parameters regime of the Earth's outer core, we need massively parallel computational environment for extremely large spatial resolutions. Local methods are expected to be more suitable for massively parallel computation because the local methods needs less data communication than the spherical harmonics expansion, but only a few groups have reported results of the dynamo benchmark using local methods (Harder and Hansen, 2005; Matsui and Okuda, 2005; Chan et al., 2007) because of the difficulty treating magnetic boundary conditions based on the local methods. On the other hand, some numerical dynamo models using spherical harmonics expansion has performed successfully with thousands of processes. We perform benchmark tests to asses various numerical methods to asses the next generation of geodynamo simulations. The purpose of the present benchmark test is to assess numerical geodynamo models on a massively parallel computational platform. To compare among many numerical methods as possible, we consider the model with the insulated magnetic boundary by Christensen et al. (2001) and with the pseudo vacuum magnetic boundary, because the pseudo vacuum boundaries are implemented easier by using the local method than the magnetic insulated boundaries. In the present study, we consider two kinds of benchmarks, so-called accuracy benchmark and performance benchmark. In the present study, we will report the results of the performance benchmark. We perform the participated dynamo models under the same computational environment (XSEDE TACC Stampede), and investigate computational performance. To simplify the problem, we choose the same model and parameter regime as the accuracy benchmark test, but perform the simulations with much finer spatial resolutions as possible to investigate computational capability (e

  6. Benchmarking expert system tools

    Science.gov (United States)

    Riley, Gary

    1988-01-01

    As part of its evaluation of new technologies, the Artificial Intelligence Section of the Mission Planning and Analysis Div. at NASA-Johnson has made timing tests of several expert system building tools. Among the production systems tested were Automated Reasoning Tool, several versions of OPS5, and CLIPS (C Language Integrated Production System), an expert system builder developed by the AI section. Also included in the test were a Zetalisp version of the benchmark along with four versions of the benchmark written in Knowledge Engineering Environment, an object oriented, frame based expert system tool. The benchmarks used for testing are studied.

  7. Toxicological Benchmarks for Wildlife

    Energy Technology Data Exchange (ETDEWEB)

    Sample, B.E. Opresko, D.M. Suter, G.W.

    1993-01-01

    Ecological risks of environmental contaminants are evaluated by using a two-tiered process. In the first tier, a screening assessment is performed where concentrations of contaminants in the environment are compared to no observed adverse effects level (NOAEL)-based toxicological benchmarks. These benchmarks represent concentrations of chemicals (i.e., concentrations presumed to be nonhazardous to the biota) in environmental media (water, sediment, soil, food, etc.). While exceedance of these benchmarks does not indicate any particular level or type of risk, concentrations below the benchmarks should not result in significant effects. In practice, when contaminant concentrations in food or water resources are less than these toxicological benchmarks, the contaminants may be excluded from further consideration. However, if the concentration of a contaminant exceeds a benchmark, that contaminant should be retained as a contaminant of potential concern (COPC) and investigated further. The second tier in ecological risk assessment, the baseline ecological risk assessment, may use toxicological benchmarks as part of a weight-of-evidence approach (Suter 1993). Under this approach, based toxicological benchmarks are one of several lines of evidence used to support or refute the presence of ecological effects. Other sources of evidence include media toxicity tests, surveys of biota (abundance and diversity), measures of contaminant body burdens, and biomarkers. This report presents NOAEL- and lowest observed adverse effects level (LOAEL)-based toxicological benchmarks for assessment of effects of 85 chemicals on 9 representative mammalian wildlife species (short-tailed shrew, little brown bat, meadow vole, white-footed mouse, cottontail rabbit, mink, red fox, and whitetail deer) or 11 avian wildlife species (American robin, rough-winged swallow, American woodcock, wild turkey, belted kingfisher, great blue heron, barred owl, barn owl, Cooper's hawk, and red

  8. Shielding benchmark problems, (2)

    International Nuclear Information System (INIS)

    Shielding benchmark problems prepared by Working Group of Assessment of Shielding Experiments in the Research Committee on Shielding Design in the Atomic Energy Society of Japan were compiled by Shielding Laboratory in Japan Atomic Energy Research Institute. Fourteen shielding benchmark problems are presented newly in addition to twenty-one problems proposed already, for evaluating the calculational algorithm and accuracy of computer codes based on discrete ordinates method and Monte Carlo method and for evaluating the nuclear data used in codes. The present benchmark problems are principally for investigating the backscattering and the streaming of neutrons and gamma rays in two- and three-dimensional configurations. (author)

  9. MimoPro: a more efficient Web-based tool for epitope prediction using phage display libraries

    Directory of Open Access Journals (Sweden)

    Guo William W

    2011-05-01

    Full Text Available Abstract Background A B-cell epitope is a group of residues on the surface of an antigen which stimulates humoral responses. Locating these epitopes on antigens is important for the purpose of effective vaccine design. In recent years, mapping affinity-selected peptides screened from a random phage display library to the native epitope has become popular in epitope prediction. These peptides, also known as mimotopes, share the similar structure and function with the corresponding native epitopes. Great effort has been made in using this similarity between such mimotopes and native epitopes in prediction, which has resulted in better outcomes than statistics-based methods can. However, it cannot maintain a high degree of satisfaction in various circumstances. Results In this study, we propose a new method that maps a group of mimotopes back to a source antigen so as to locate the interacting epitope on the antigen. The core of this method is a searching algorithm that is incorporated with both dynamic programming (DP and branch and bound (BB optimization and operated on a series of overlapping patches on the surface of a protein. These patches are then transformed to a number of graphs using an adaptable distance threshold (ADT regulated by an appropriate compactness factor (CF, a novel parameter proposed in this study. Compared with both Pep-3D-Search and PepSurf, two leading graph-based search tools, on average from the results of 18 test cases, MimoPro, the Web-based implementation of our proposed method, performed better in sensitivity, precision, and Matthews correlation coefficient (MCC than both did in epitope prediction. In addition, MimoPro is significantly faster than both Pep-3D-Search and PepSurf in processing. Conclusions Our search algorithm designed for processing well constructed graphs using an ADT regulated by CF is more sensitive and significantly faster than other graph-based approaches in epitope prediction. MimoPro is a

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

    Directory of Open Access Journals (Sweden)

    Noel Thomas Pauli

    2011-12-01

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

  11. YY1 Is Required for Germinal Center B Cell Development

    Science.gov (United States)

    Vuyyuru, Raja; Jha, Vibha; Hodewadekar, Suchita; Manser, Tim; Atchison, Michael L.

    2016-01-01

    YY1 has been implicated as a master regulator of germinal center B cell development as YY1 binding sites are frequently present in promoters of germinal center-expressed genes. YY1 is known to be important for other stages of B cell development including the pro-B and pre-B cells stages. To determine if YY1 plays a critical role in germinal center development, we evaluated YY1 expression during B cell development, and used a YY1 conditional knock-out approach for deletion of YY1 in germinal center B cells (CRE driven by the immunoglobulin heavy chain γ1 switch region promoter; γ1-CRE). We found that YY1 is most highly expressed in germinal center B cells and is increased 3 fold in splenic B cells activated by treatment with anti-IgM and anti-CD40. In addition, deletion of the yy1 gene by action of γ1-CRE recombinase resulted in significant loss of GC cells in both un-immunized and immunized contexts with corresponding loss of serum IgG1. Our results show a crucial role for YY1 in the germinal center reaction. PMID:27167731

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

    Science.gov (United States)

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

    2016-08-01

    The presence of inflammatory infiltrates with B cells, specifically plasma cells, is the hallmark of periodontitis lesions. The composition of these infiltrates in various stages of homeostasis and disease development is not well documented. Human tissue biopsies from sites with gingival health (n = 29), gingivitis (n = 8), and periodontitis (n = 21) as well as gingival tissue after treated periodontitis (n = 6) were obtained and analyzed for their composition of B cell subsets. Ag specificity, Ig secretion, and expression of receptor activator of NF-κB ligand and granzyme B were performed. Although most of the B cell subsets in healthy gingiva and gingivitis tissues were CD19(+)CD27(+)CD38(-) memory B cells, the major B cell component in periodontitis was CD19(+)CD27(+)CD38(+)CD138(+)HLA-DR(low) plasma cells, not plasmablasts. Plasma cell aggregates were observed at the base of the periodontal pocket and scattered throughout the gingiva, especially apically toward the advancing front of the lesion. High expression of CXCL12, a proliferation-inducing ligand, B cell-activating factor, IL-10, IL-6, and IL-21 molecules involved in local B cell responses was detected in both gingivitis and periodontitis tissues. Periodontitis tissue plasma cells mainly secreted IgG specific to periodontal pathogens and also expressed receptor activator of NF-κB ligand, a bone resorption cytokine. Memory B cells resided in the connective tissue subjacent to the junctional epithelium in healthy gingiva. This suggested a role of memory B cells in maintaining periodontal homeostasis. PMID:27335500

  13. Hepatitis B synthetic immunogen comprised of nucleocapsid T-cell sites and an envelope B-cell epitope.

    OpenAIRE

    Milich, D R; Hughes, J L; A. McLachlan; Thornton, G B; Moriarty, A.

    1988-01-01

    Previous studies located T-cell recognition of the nucleocapsid of the hepatitis B virus (HBcAg) to residues 120-140 in mice bearing the H-2s or H-2b haplotypes. Herein, we demonstrate that B10.S (H-2s) and B10 (H-2b) H-2 congenic strains recognize distinct T-cell sites within the p120-140 (a synthetic peptide corresponding to residues 120-140 of HBcAg) sequence defined by p120-131 and p129-140, respectively. Peptide p120-131 stimulates B10.S HBcAg-primed T cells, and reciprocally p120-131-pr...

  14. Dominant B-cell epitopes from cancer/stem cell antigen SOX2 recognized by serum samples from cancer patients

    OpenAIRE

    Shih, Julia; Rahman, Munira; Luong, Quang T; Lomeli, Shirley H.; Riss, Joseph; Prins, Robert M.; Gure, Ali O.; Zeng, Gang

    2014-01-01

    Human sex determining region Y-box 2 (SOX2) is an important transcriptional factor involved in the pluripotency and stemness of human embryonic stem cells. SOX2 plays important roles in maintaining cancer stem cell activities of melanoma and cancers of the brain, prostate, breast, and lung. SOX2 is also a lineage survival oncogene for squamous cell carcinoma of the lung and esophagus. Spontaneous cellular and humoral immune responses against SOX2 present in cancer patients classify it as a tu...

  15. Diagnostic Algorithm Benchmarking

    Science.gov (United States)

    Poll, Scott

    2011-01-01

    A poster for the NASA Aviation Safety Program Annual Technical Meeting. It describes empirical benchmarking on diagnostic algorithms using data from the ADAPT Electrical Power System testbed and a diagnostic software framework.

  16. GeodeticBenchmark_GEOMON

    Data.gov (United States)

    Vermont Center for Geographic Information — The GeodeticBenchmark_GEOMON data layer consists of geodetic control monuments (points) that have a known position or spatial reference. The locations of these...

  17. Benchmarking in University Toolbox

    OpenAIRE

    Katarzyna Kuźmicz

    2015-01-01

    In the face of global competition and rising challenges that higher education institutions (HEIs) meet, it is imperative to increase innovativeness and efficiency of their management. Benchmarking can be the appropriate tool to search for a point of reference necessary to assess institution’s competitive position and learn from the best in order to improve. The primary purpose of the paper is to present in-depth analysis of benchmarking application in HEIs worldwide. The study involves indica...

  18. Accelerator shielding benchmark problems

    International Nuclear Information System (INIS)

    Accelerator shielding benchmark problems prepared by Working Group of Accelerator Shielding in the Research Committee on Radiation Behavior in the Atomic Energy Society of Japan were compiled by Radiation Safety Control Center of National Laboratory for High Energy Physics. Twenty-five accelerator shielding benchmark problems are presented for evaluating the calculational algorithm, the accuracy of computer codes and the nuclear data used in codes. (author)

  19. Benchmarking conflict resolution algorithms

    OpenAIRE

    Vanaret, Charlie; Gianazza, David; Durand, Nicolas; Gotteland, Jean-Baptiste

    2012-01-01

    Applying a benchmarking approach to conflict resolution problems is a hard task, as the analytical form of the constraints is not simple. This is especially the case when using realistic dynamics and models, considering accelerating aircraft that may follow flight paths that are not direct. Currently, there is a lack of common problems and data that would allow researchers to compare the performances of several conflict resolution algorithms. The present paper introduces a benchmarking approa...

  20. Benchmarking and regulation

    OpenAIRE

    Agrell, Per Joakim; Bogetoft, Peter

    2013-01-01

    Benchmarking methods, and in particular Data Envelopment Analysis (DEA), have become well-established and informative tools for economic regulation. DEA is now routinely used by European regulators to set reasonable revenue caps for energy transmission and distribution system operators. The application of benchmarking in regulation, however, requires specific steps in terms of data validation, model specification and outlier detection that are not systematically documented in open publication...

  1. Accelerator shielding benchmark problems

    Energy Technology Data Exchange (ETDEWEB)

    Hirayama, H.; Ban, S.; Nakamura, T. [and others

    1993-01-01

    Accelerator shielding benchmark problems prepared by Working Group of Accelerator Shielding in the Research Committee on Radiation Behavior in the Atomic Energy Society of Japan were compiled by Radiation Safety Control Center of National Laboratory for High Energy Physics. Twenty-five accelerator shielding benchmark problems are presented for evaluating the calculational algorithm, the accuracy of computer codes and the nuclear data used in codes. (author).

  2. The Immune Epitope Database 2.0

    DEFF Research Database (Denmark)

    Hoof, Ilka; Vita, R; Zarebski, L;

    2010-01-01

    The Immune Epitope Database (IEDB, www.iedb.org) provides a catalog of experimentally characterized B and T cell epitopes, as well as data on Major Histocompatibility Complex (MHC) binding and MHC ligand elution experiments. The database represents the molecular structures recognized by adaptive...... unavailable to the public from 129,186 experiments were submitted directly by investigators. The curation of epitopes related to autoimmunity is expected to be completed by the end of 2010. The database can be queried by epitope structure, source organism, MHC restriction, assay type or host organism, among...... other criteria. The database structure, as well as its querying, browsing and reporting interfaces, was completely redesigned for the IEDB 2.0 release, which became publicly available in early 2009....

  3. Transgelin-2 in B-Cells Controls T-Cell Activation by Stabilizing T Cell - B Cell Conjugates

    Science.gov (United States)

    Chae, Myoung-Won; Kim, Hye-Ran; Kim, Chang-Hyun; Jun, Chang-Duk; Park, Zee-Yong

    2016-01-01

    The immunological synapse (IS), a dynamic and organized junction between T-cells and antigen presenting cells (APCs), is critical for initiating adaptive immunity. The actin cytoskeleton plays a major role in T-cell reorganization during IS formation, and we previously reported that transgelin-2, an actin-binding protein expressed in T-cells, stabilizes cortical F-actin, promoting T-cell activation in response to antigen stimulation. Transgelin-2 is also highly expressed in B-cells, although no specific function has been reported. In this study, we found that deficiency in transgelin-2 (TAGLN2-/-) in B-cells had little effect on B-cell development and activation, as measured by the expression of CD69, MHC class II molecules, and CD80/86. Nevertheless, in B-cells, transgelin-2 accumulated in the IS during the interaction with T-cells. These results led us to hypothesize that transgelin-2 may also be involved in IS stability in B-cells, thereby influencing T-cell function. Notably, we found that transgelin-2 deficiency in B-cells reduced T-cell activation, as determined by the release of IL-2 and interferon-γ and the expression of CD69. Furthermore, the reduced T-cell activation was correlated with reduced B-cell–T-cell conjugate formation. Collectively, these results suggest that actin stability in B-cells during IS formation is critical for the initiation of adaptive T-cell immunity. PMID:27232882

  4. HIV-dependent depletion of influenza-specific memory B cells impacts B cell responsiveness to seasonal influenza immunisation.

    Science.gov (United States)

    Wheatley, Adam K; Kristensen, Anne B; Lay, William N; Kent, Stephen J

    2016-01-01

    Infection with HIV drives significant alterations in B cell phenotype and function that can markedly influence antibody responses to immunisation. Anti-retroviral therapy (ART) can partially reverse many aspects of B cell dysregulation, however complete normalisation of vaccine responsiveness is not always observed. Here we examine the effects of underlying HIV infection upon humoral immunity to seasonal influenza vaccines. Serological and memory B cell responses were assessed in 26 HIV+ subjects receiving ART and 30 healthy controls immunised with the 2015 Southern Hemisphere trivalent inactivated influenza vaccine (IIV3). Frequencies and phenotypes of influenza hemagglutinin (HA)-specific B cells were assessed by flow cytometry using recombinant HA probes. Serum antibody was measured using hemagglutination inhibition assays. Serological responses to IIV3 were comparable between HIV+ and HIV- subjects. Likewise, the activation and expansion of memory B cell populations specific for vaccine-component influenza strains was observed in both cohorts, however peak frequencies were diminished in HIV+ subjects compared to uninfected controls. Lower circulating frequencies of memory B cells recognising vaccine-component and historical influenza strains were observed in HIV+ subjects at baseline, that were generally restored to levels comparable with HIV- controls post-vaccination. HIV infection is therefore associated with depletion of selected HA-specific memory B cell pools. PMID:27220898

  5. HIV-dependent depletion of influenza-specific memory B cells impacts B cell responsiveness to seasonal influenza immunisation

    Science.gov (United States)

    Wheatley, Adam K.; Kristensen, Anne B.; Lay, William N.; Kent, Stephen J.

    2016-01-01

    Infection with HIV drives significant alterations in B cell phenotype and function that can markedly influence antibody responses to immunisation. Anti-retroviral therapy (ART) can partially reverse many aspects of B cell dysregulation, however complete normalisation of vaccine responsiveness is not always observed. Here we examine the effects of underlying HIV infection upon humoral immunity to seasonal influenza vaccines. Serological and memory B cell responses were assessed in 26 HIV+ subjects receiving ART and 30 healthy controls immunised with the 2015 Southern Hemisphere trivalent inactivated influenza vaccine (IIV3). Frequencies and phenotypes of influenza hemagglutinin (HA)-specific B cells were assessed by flow cytometry using recombinant HA probes. Serum antibody was measured using hemagglutination inhibition assays. Serological responses to IIV3 were comparable between HIV+ and HIV− subjects. Likewise, the activation and expansion of memory B cell populations specific for vaccine-component influenza strains was observed in both cohorts, however peak frequencies were diminished in HIV+ subjects compared to uninfected controls. Lower circulating frequencies of memory B cells recognising vaccine-component and historical influenza strains were observed in HIV+ subjects at baseline, that were generally restored to levels comparable with HIV− controls post-vaccination. HIV infection is therefore associated with depletion of selected HA-specific memory B cell pools. PMID:27220898

  6. Computational prediction and analysis of envelop glycoprotein epitopes of DENV-2 and DENV-3 Pakistani isolates: a first step towards Dengue vaccine development.

    Directory of Open Access Journals (Sweden)

    Hafsa Amat-ur-Rasool

    Full Text Available Dengue fever of tropics is a mosquito transmitted devastating disease caused by dengue virus (DENV. There is no effective vaccine available, so far, against any of its four serotypes (DENV-1, DENV-2, DENV-3, and DENV-4. There is a need for the development of preventive and therapeutic vaccines against DENV to decrease the prevalence of dengue fever, especially in Pakistan. In this research, linear and conformational B-cell epitopes of envelope glycoprotein of DENV-2 and DENV-3 (the most prevalent serotypes in Pakistan were predicted. We used Kolaskar and Tongaonkar method for linear epitope prediction, Emini's method for surface accessibility prediction and Karplus and Schulz's algorithm for flexibility determination. To propose three dimensional epitopes, the E proteins for both serotypes were homology modeled by using Phyre2 V 2.0 server, and ElliPro was used for the prediction of surface epitopes on their globular structure. Total 21 and 19 linear epitopes were predicted for DENV-2 and DENV-3 Pakistani isolates respectively. Whereas, 5 and 4 discontinuous epitopes were proposed for DENV-2 and DENV-3 Pakistani isolates respectively. Moreover, the values of surface accessibility, flexibility and solvent-accessibility can be helpful in analyzing vaccines against DENV-2 and DENV-3. In conclusion, the proposed continuous and discontinuous antigenic peptides can be valuable candidates for diagnostic and therapeutics of DENV.

  7. Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies.

    Science.gov (United States)

    Rodgers, David T; Mazagova, Magdalena; Hampton, Eric N; Cao, Yu; Ramadoss, Nitya S; Hardy, Ian R; Schulman, Andrew; Du, Juanjuan; Wang, Feng; Singer, Oded; Ma, Jennifer; Nunez, Vanessa; Shen, Jiayin; Woods, Ashley K; Wright, Timothy M; Schultz, Peter G; Kim, Chan Hyuk; Young, Travis S

    2016-01-26

    Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive results in clinical trials for B-cell malignancies. However, safety concerns related to the inability to control CAR-T cells once infused into the patient remain a significant challenge. Here we report the engineering of recombinant antibody-based bifunctional switches that consist of a tumor antigen-specific Fab molecule engrafted with a peptide neo-epitope, which is bound exclusively by a peptide-specific switchable CAR-T cell (sCAR-T). The switch redirects the activity of the bio-orthogonal sCAR-T cells through the selective formation of immunological synapses, in which the sCAR-T cell, switch, and target cell interact in a structurally defined and temporally controlled manner. Optimized switches specific for CD19 controlled the activity, tissue-homing, cytokine release, and phenotype of sCAR-T cells in a dose-titratable manner in a Nalm-6 xenograft rodent model of B-cell leukemia. The sCAR-T-cell dosing regimen could be tuned to provide efficacy comparable to the corresponding conventional CART-19, but with lower cytokine levels, thereby offering a method of mitigating cytokine release syndrome in clinical translation. Furthermore, we demonstrate that this methodology is readily adaptable to targeting CD20 on cancer cells using the same sCAR-T cell, suggesting that this approach may be broadly applicable to heterogeneous and resistant tumor populations, as well as other liquid and solid tumor antigens. PMID:26759369

  8. The KMAT: Benchmarking Knowledge Management.

    Science.gov (United States)

    de Jager, Martha

    Provides an overview of knowledge management and benchmarking, including the benefits and methods of benchmarking (e.g., competitive, cooperative, collaborative, and internal benchmarking). Arthur Andersen's KMAT (Knowledge Management Assessment Tool) is described. The KMAT is a collaborative benchmarking tool, designed to help organizations make…

  9. B-Cell waste classification sampling and analysis plan

    International Nuclear Information System (INIS)

    This report documents the methods used to collect and analyze samples to obtain data necessary to verify and/or determine the radionuclide content of the 324 Facility B-Cell decontamination and decommissioning waste stream

  10. B-Cell waste classification sampling and analysis plan

    Energy Technology Data Exchange (ETDEWEB)

    HOBART, R.L.

    1999-09-22

    This report documents the methods used to collect and analyze samples to obtain data necessary to verify and/or determine the radionuclide content of the 324 Facility B-Cell decontamination and decommissioning waste stream.

  11. B-cell survival factors in autoimmune rheumatic disorders

    Science.gov (United States)

    Morais, Sandra A.; Vilas-Boas, Andreia

    2015-01-01

    Autoimmune rheumatic disorders have complex etiopathogenetic mechanisms in which B cells play a central role. The importance of factors stimulating B cells, notably the B-cell activating factor (BAFF) and A proliferation inducing ligand (APRIL) axis is now recognized. BAFF and APRIL are cytokines essential for B-cell proliferation and survival from the immature stages to the development of plasma cells. Their levels are increased in some subsets of patients with autoimmune disorders. Several recent biologic drugs have been developed to block this axis, namely belimumab [already licensed for systemic lupus erythematosus (SLE) treatment], tabalumab, atacicept and blisibimod. Many clinical trials to evaluate the safety and efficacy of these drugs in several autoimmune disorders are ongoing, or have been completed recently. This review updates the information on the use of biologic agents blocking BAFF/APRIL for patients with SLE, rheumatoid arthritis, Sjögren’s syndrome and myositis. PMID:26288664

  12. Quantifying evolutionary constraints on B-cell affinity maturation

    OpenAIRE

    McCoy, Connor O.; Bedford, Trevor; Minin, Vladimir N.; Bradley, Philip; Robins, Harlan; Frederick A Matsen

    2015-01-01

    The antibody repertoire of each individual is continuously updated by the evolutionary process of B-cell receptor (BCR) mutation and selection. It has recently become possible to gain detailed information concerning this process through high-throughput sequencing. Here, we develop modern statistical molecular evolution methods for the analysis of B-cell sequence data, and then apply them to a very deep short-read dataset of BCRs. We find that the substitution process is conserved across indiv...

  13. Interleukin 2-induced proliferation of leukemic human B cells

    OpenAIRE

    1985-01-01

    The proliferative responses of purified leukemic human B cells from nine B cell chronic lymphocytic leukemias to recombinant interleukin 2 (IL-2), spontaneously, and after preactivation by Staphylococcus aureus Cowan I (SAC) or anti-mu antibodies were studied. Three patterns of response were observed: (a) no response (three cases); (b) a moderate spontaneous response enhanced by anti-mu (one case); (c) a high proliferative response after preactivation by anti-mu and/or SAC (five cases). IL-2 ...

  14. Trafficking of B cell antigen in lymph nodes

    DEFF Research Database (Denmark)

    Gonzalez, Santiago F.; Degn, Søren Egedal; Pitcher, Lisa A.; Woodruff, Matthew; Heesters, Balthasar A.; Carroll, Michael C.

    2011-01-01

    The clonal selection theory first proposed by Macfarlane Burnet is a cornerstone of immunology ( 1 ). At the time, it revolutionized the thinking of immunologists because it provided a simple explanation for lymphocyte specificity, immunological memory, and elimination of self-reactive clones ( 2...... microscopy ( 4, 5 ) have provided new insights into the trafficking of B cells and their antigen. In this review, we summarize these advances in the context of our current view of B cell circulation and activation....

  15. Epitope peptides of influenza H3N2 virus neuraminidase gene designed by immunoinformatics

    Institute of Scientific and Technical Information of China (English)

    Lijun Liang; Ping Huang; Miaoheng Wen; Hanzhong Ni; Songnuan Tan; Yonghui Zhang; Qiuxia Chen

    2012-01-01

    The virus surface protein neuraminidase (NA) is a main subtype-specific antigen in influenza type A viruses.Neuraminidase functions as an enzyme to break the bonds between hemagglutinin (HA) and sialic acid to release newly formed viruses from infected cells.In this study,NA genes from the H3N2 subtype virus were sequenced and NA proteins were screened for B-cell epitopes and assessed based on immunoinformatics.Based on this information,three peptides ES8,RR9,and WK7 (covering amino acid residues 221-228,292-300,and 383-389,respectively) of the NA protein were selected and synthesized artificially.These peptides were used to immunize New Zealand rabbits subcutaneously to raise antisera.Results showed that these three peptides were capable of eliciting antibodies against H3N2 viruses in a specific and sensitive manner,detected in vitro by enzyme-linked immunosorbent assay. Furthermore,hemadsorption anti-releasing effects occurred in three antisera mixtures at a dilution of 1∶40.Alignment using database software showed that amino acid residues in these three epitope peptides were substituted at specific sites in all the NAs sequenced in this study.We suggest that these NA epitope peptides might be used in conjunction with HA proteins as vaccine antigens.

  16. De Novo Transcriptome Analysis of Allium cepa L. (Onion Bulb to Identify Allergens and Epitopes.

    Directory of Open Access Journals (Sweden)

    Hemalatha Rajkumar

    Full Text Available Allium cepa (onion is a diploid plant with one of the largest nuclear genomes among all diploids. Onion is an example of an under-researched crop which has a complex heterozygous genome. There are no allergenic proteins and genomic data available for onions. This study was conducted to establish a transcriptome catalogue of onion bulb that will enable us to study onion related genes involved in medicinal use and allergies. Transcriptome dataset generated from onion bulb using the Illumina HiSeq 2000 technology showed a total of 99,074,309 high quality raw reads (~20 Gb. Based on sequence homology onion genes were categorized into 49 different functional groups. Most of the genes however, were classified under 'unknown' in all three gene ontology categories. Of the categorized genes, 61.2% showed metabolic functions followed by cellular components such as binding, cellular processes; catalytic activity and cell part. With BLASTx top hit analysis, a total of 2,511 homologous allergenic sequences were found, which had 37-100% similarity with 46 different types of allergens existing in the database. From the 46 contigs or allergens, 521 B-cell linear epitopes were identified using BepiPred linear epitope prediction tool. This is the first comprehensive insight into the transcriptome of onion bulb tissue using the NGS technology, which can be used to map IgE epitopes and prediction of structures and functions of various proteins.

  17. Transcriptome analysis of Solanum melongena L. (eggplant) fruit to identify putative allergens and their epitopes.

    Science.gov (United States)

    Ramesh, Kumar Ramagoni; Hemalatha, R; Vijayendra, Chary Anchoju; Arshi, Uz Zaman Syed; Dushyant, Singh Baghel; Dinesh, Kumar Bharadwaj

    2016-01-15

    Eggplant is the third most important Solanaceae crop after tomato and potato, particularly in India and China. A transcriptome analysis of eggplant's fruit was performed to study genes involved in medicinal importance and allergies. Illumina HiSeq 2000 system generated 89,763,638 raw reads (~18 Gb) from eggplant. High quality reads (59,039,694) obtained after trimming process, were assembled into a total of 149,224 non redundant set of transcripts. Out of 80,482 annotated sequences of eggplant fruit (BLASTx results against nr-green plant database), 40,752 transcripts showed significant similarity with predicted proteins of Solanum tuberosum (51%) followed by Solanum lycopersicum (34%) and other sequenced plant genomes. With BLASTx top hit analysis against existing allergens, a total of 1986 homologous allergen sequences were found, which had >37% similarity with 48 different allergens existing in the database. From the 48 putative allergens, 526 B-cell linear epitopes were identified using BepiPred linear epitope prediction tool. Transcript sequences generated from this study can be used to map epitopes of monoclonal antibodies and polyclonal sera from patients. With the support of this whole transcriptome catalogue of eggplant fruit, complete list of genes can be predicted based on which secondary structures of proteins may be modeled. PMID:26424595

  18. Scope for using plant viruses to present epitopes from animal pathogens.

    Science.gov (United States)

    Porta; Lomonossoff

    1998-01-01

    Epitope presentation to the immune system for vaccination purposes can be achieved either via an inactivated or attenuated form of a pathogen or via its isolated antigenic sequences. When free, these peptides can adopt a variety of conformations, most of which will not exist in their native environment. Conjugation to carrier proteins restricts mobility of the peptides and increases their immunogenicity. A high local concentration of epitopes boosts the immune response further and can be generated by the use of self-aggregating carriers, such as the capsid proteins of viruses. In this regard plant viruses have in recent years started to make an impact as safer alternatives to the use of bacterial and attenuated animal viruses: the latter both require propagation in costly cell-culture systems where they can undergo reversion towards a virulent form and/or become contaminated by other pathogens. Plant virus-based vectors can be multiplied cheaply and to high yields (exceeding 1 mg/g plant tissue) in host plants. Both helical (tobacco mosaic virus, potato virus X, alfalfa mosaic virus) and icosahedral (cowpea mosaic virus, tomato bushy stunt virus) particles have been used to express a number of animal B-cell epitopes, whose immunogenic properties have been explored to varying degrees. Copyright 1998 John Wiley & Sons, Ltd. PMID:10398492

  19. Benchmarking in Mobarakeh Steel Company

    OpenAIRE

    Sasan Ghasemi; Mohammad Nazemi; Mehran Nejati

    2008-01-01

    Benchmarking is considered as one of the most effective ways of improving performance in companies. Although benchmarking in business organizations is a relatively new concept and practice, it has rapidly gained acceptance worldwide. This paper introduces the benchmarking project conducted in Esfahan's Mobarakeh Steel Company, as the first systematic benchmarking project conducted in Iran. It aims to share the process deployed for the benchmarking project in this company and illustrate how th...

  20. Benchmarking the Netherlands. Benchmarking for growth

    International Nuclear Information System (INIS)

    This is the fourth edition of the Ministry of Economic Affairs' publication 'Benchmarking the Netherlands', which aims to assess the competitiveness of the Dutch economy. The methodology and objective of the benchmarking remain the same. The basic conditions for economic activity (institutions, regulation, etc.) in a number of benchmark countries are compared in order to learn from the solutions found by other countries for common economic problems. This publication is devoted entirely to the potential output of the Dutch economy. In other words, its ability to achieve sustainable growth and create work over a longer period without capacity becoming an obstacle. This is important because economic growth is needed to increase prosperity in the broad sense and meeting social needs. Prosperity in both a material (per capita GDP) and immaterial (living environment, environment, health, etc) sense, in other words. The economy's potential output is determined by two structural factors: the growth of potential employment and the structural increase in labour productivity. Analysis by the Netherlands Bureau for Economic Policy Analysis (CPB) shows that in recent years the increase in the capacity for economic growth has been realised mainly by increasing the supply of labour and reducing the equilibrium unemployment rate. In view of the ageing of the population in the coming years and decades the supply of labour is unlikely to continue growing at the pace we have become accustomed to in recent years. According to a number of recent studies, to achieve a respectable rate of sustainable economic growth the aim will therefore have to be to increase labour productivity. To realise this we have to focus on for six pillars of economic policy: (1) human capital, (2) functioning of markets, (3) entrepreneurship, (4) spatial planning, (5) innovation, and (6) sustainability. These six pillars determine the course for economic policy aiming at higher productivity growth. Throughout

  1. MCNP neutron benchmarks

    International Nuclear Information System (INIS)

    More than 50 neutron benchmark calculations have recently been completed as part of an ongoing program to validate the MCNP Monte Carlo radiation transport code. The benchmark calculations reported here are part of an ongoing multiyear, multiperson effort to benchmark version 4 of the MCNP code. The MCNP is a Monte Carlo three-dimensional general-purpose, continuous-energy neutron, photon, and electron transport code. It is used around the world for many applications including aerospace, oil-well logging, physics experiments, criticality safety, reactor analysis, medical imaging, defense applications, accelerator design, radiation hardening, radiation shielding, health physics, fusion research, and education. The first phase of the benchmark project consisted of analytic and photon problems. The second phase consists of the ENDF/B-V neutron problems reported in this paper and in more detail in the comprehensive report. A cooperative program being carried out a General Electric, San Jose, consists of light water reactor benchmark problems. A subsequent phase focusing on electron problems is planned

  2. Shielding Benchmark Computational Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Hunter, H.T.; Slater, C.O.; Holland, L.B.; Tracz, G.; Marshall, W.J.; Parsons, J.L.

    2000-09-17

    Over the past several decades, nuclear science has relied on experimental research to verify and validate information about shielding nuclear radiation for a variety of applications. These benchmarks are compared with results from computer code models and are useful for the development of more accurate cross-section libraries, computer code development of radiation transport modeling, and building accurate tests for miniature shielding mockups of new nuclear facilities. When documenting measurements, one must describe many parts of the experimental results to allow a complete computational analysis. Both old and new benchmark experiments, by any definition, must provide a sound basis for modeling more complex geometries required for quality assurance and cost savings in nuclear project development. Benchmarks may involve one or many materials and thicknesses, types of sources, and measurement techniques. In this paper the benchmark experiments of varying complexity are chosen to study the transport properties of some popular materials and thicknesses. These were analyzed using three-dimensional (3-D) models and continuous energy libraries of MCNP4B2, a Monte Carlo code developed at Los Alamos National Laboratory, New Mexico. A shielding benchmark library provided the experimental data and allowed a wide range of choices for source, geometry, and measurement data. The experimental data had often been used in previous analyses by reputable groups such as the Cross Section Evaluation Working Group (CSEWG) and the Organization for Economic Cooperation and Development/Nuclear Energy Agency Nuclear Science Committee (OECD/NEANSC).

  3. Different sensitivity of germinal center B cell-like diffuse large B cell lymphoma cells towards ibrutinib treatment

    OpenAIRE

    Zheng, Xiaohui; Ding, Ning; Song, Yuqin; Feng, Lixia; Zhu, Jun

    2014-01-01

    Background Although rituximab in the combination of CHOP chemotherapy has been widely used as the standard treatment for several kinds of B-cell non-Hodgkin lymphoma (B-NHL), a great number of B-NHL patients treated with this immunotherapy still develop primary and secondary resistance. Recently Bruton’s tyrosine kinase (Btk) inhibitor ibrutinib showed promising therapeutic effect in relapsed/refractory CLL and B-cell NHL, which provided essential alternatives for these patients. Methods The ...

  4. Comprehensive mapping of common immunodominant epitopes in the West Nile virus nonstructural protein 1 recognized by avian antibody responses.

    Science.gov (United States)

    Sun, Encheng; Zhao, Jing; Liu, Nihong; Yang, Tao; Xu, Qingyuan; Qin, Yongli; Bu, Zhigao; Yang, Yinhui; Lunt, Ross A; Wang, Linfa; Wu, Donglai

    2012-01-01

    West Nile virus (WNV) is a mosquito-borne flavivirus that primarily infects birds but occasionally infects humans and horses. Certain species of birds, including crows, house sparrows, geese, blue jays and ravens, are considered highly susceptible hosts to WNV. The nonstructural protein 1 (NS1) of WNV can elicit protective immune responses, including NS1-reactive antibodies, during infection of animals. The antigenicity of NS1 suggests that NS1-reactive antibodies could provide a basis for serological diagnostic reagents. To further define serological reagents for diagnostic use, the antigenic sites in NS1 that are targeted by host immune responses need to be identified and the potential diagnostic value of individual antigenic sites also needs to be defined. The present study describes comprehensive mapping of common immunodominant linear B-cell epitopes in the WNV NS1 using avian WNV NS1 antisera. We screened antisera from chickens, ducks and geese immunized with purified NS1 for reactivity against 35 partially overlapping peptides covering the entire WNV NS1. This study identified twelve, nine and six peptide epitopes recognized by chicken, duck and goose antibody responses, respectively. Three epitopes (NS1-3, 14 and 24) were recognized by antibodies elicited by immunization in all three avian species tested. We also found that NS1-3 and 24 were WNV-specific epitopes, whereas the NS1-14 epitope was conserved among the Japanese encephalitis virus (JEV) serocomplex viruses based on the reactivity of avian WNV NS1 antisera against polypeptides derived from the NS1 sequences of viruses of the JEV serocomplex. Further analysis showed that the three common polypeptide epitopes were not recognized by antibodies in Avian Influenza Virus (AIV), Newcastle Disease Virus (NDV), Duck Plague Virus (DPV) and Goose Parvovirus (GPV) antisera. The knowledge and reagents generated in this study have potential applications in differential diagnostic approaches and subunit vaccines

  5. Comprehensive mapping of common immunodominant epitopes in the West Nile virus nonstructural protein 1 recognized by avian antibody responses.

    Directory of Open Access Journals (Sweden)

    Encheng Sun

    Full Text Available West Nile virus (WNV is a mosquito-borne flavivirus that primarily infects birds but occasionally infects humans and horses. Certain species of birds, including crows, house sparrows, geese, blue jays and ravens, are considered highly susceptible hosts to WNV. The nonstructural protein 1 (NS1 of WNV can elicit protective immune responses, including NS1-reactive antibodies, during infection of animals. The antigenicity of NS1 suggests that NS1-reactive antibodies could provide a basis for serological diagnostic reagents. To further define serological reagents for diagnostic use, the antigenic sites in NS1 that are targeted by host immune responses need to be identified and the potential diagnostic value of individual antigenic sites also needs to be defined. The present study describes comprehensive mapping of common immunodominant linear B-cell epitopes in the WNV NS1 using avian WNV NS1 antisera. We screened antisera from chickens, ducks and geese immunized with purified NS1 for reactivity against 35 partially overlapping peptides covering the entire WNV NS1. This study identified twelve, nine and six peptide epitopes recognized by chicken, duck and goose antibody responses, respectively. Three epitopes (NS1-3, 14 and 24 were recognized by antibodies elicited by immunization in all three avian species tested. We also found that NS1-3 and 24 were WNV-specific epitopes, whereas the NS1-14 epitope was conserved among the Japanese encephalitis virus (JEV serocomplex viruses based on the reactivity of avian WNV NS1 antisera against polypeptides derived from the NS1 sequences of viruses of the JEV serocomplex. Further analysis showed that the three common polypeptide epitopes were not recognized by antibodies in Avian Influenza Virus (AIV, Newcastle Disease Virus (NDV, Duck Plague Virus (DPV and Goose Parvovirus (GPV antisera. The knowledge and reagents generated in this study have potential applications in differential diagnostic approaches and

  6. Characteristics of T-cell and B-cell immune respoonses to pollen allergens in Bulgarian patients with pollinosis

    Directory of Open Access Journals (Sweden)

    ZHIVKA KOSTOVA

    2015-12-01

    Full Text Available Characterization of the pollen allergens and identification of the main T-cell and B-cell epitopes is of crucial importance, since the clarification of the cellular and molecular mechanisms will allow long-term control of this type allergic diseases and development of safe immunotherapeutic medication. The objective of this study was to identify which pollen allergens are responsible for the T-cell activation in atopic patients with pollinosis and to determine whether the same allergens are responsible for the IgE-mediated reactions. Thirty-seven patients with pollinosis and thirteen non-allergic subjects were recruited. Peripheral blood samples were collected out of the pollen season. T-cell responses (IFN-γ production towards different pollen allergens and levels of pollen specific IgE and IgG in the sera were measured by ELISA. The T-cell reactivity in most patients was directed towards the grass pollen B1, tree pollen I and autumn pollen B5. 70% of the allergic individuals responded to allergens from Lolium perenne, 84% to Dactylis glomerata, 11% to Phleum pratense, 65% to Betula pendula and 70% to Taxus baccata. Elevated serum levels of specific IgE in the allergic patients (p<0.01 were measured against the tree pollen I and autumn pollen, which include widespread deciduous trees (birch, willow, poplar and yew and Artemisia absinthium, respectively. Our results show that the T-cell reactivity and antibody responses may be directed towards different or the same allergens. In addition, we propose that short synthetic peptides, which contain overlapping T- and B-cell epitopes can be used for specific immunotherapy treatment if they lack antibody recognition domains.

  7. Presentation of antigen by B cells subsets. Pt. 1. Lyb-5+ and Lyb-5- B cells differ in ability to stimulate specific T cells

    International Nuclear Information System (INIS)

    We have examined the antigen presenting cell (APC) function of different B cells. Resident, peritoneal B cells from normal mice were more efficient than splenic B cells in presenting antigen to CD4+ T cell lines. Peritoneal B cells from X-linked immunodeficient (Xid) mice, by contrast, stimulated no detectable responses. Xid splenic B cells were much less efficient APC than normal splenic B cells. B cells from neonatal mice also were very poor APC until the mice were 3 to 4 weeks old. Xid B cells presented antigen to T cell hybridomas as well as normal B cells showing that they process antigen normally. Thus, the defect is most likely in providing secondary signals. The ability of B cells to present antigen efficiency correlates with the percentage of B cells reported to express the Lyb-5 antigen. Anti-Lyb-5 serum and complement abrogated the APC activity of B cells suggesting that Lyb-5+, but not Lyb-5- cells are efficient APC. We also found that activated and resting normal splenic B cells, separated by buoyant density, presented antigen equally. Both populations also contained Lyb-5+ B cells although they were a larger fraction of the activated cells. Lyb-5 is now thought to be an activation antigen rather than a differentiation antigen. If this idea is correct, then our data indicate that anti-Lyb-5 more cleanly separates activated and resting B cells than buoyant density techniques. (author). 38 refs, 7 figs, 1 tab

  8. The B-cell receptor orchestrates environment-mediated lymphoma survival and drug resistance in B-cell malignancies.

    Science.gov (United States)

    Shain, K H; Tao, J

    2014-08-01

    Specific niches within the lymphoma tumor microenvironment (TME) provide sanctuary for subpopulations of tumor cells through stromal cell-tumor cell interactions. These interactions notably dictate growth, response to therapy and resistance of residual malignant B cells to therapeutic agents. This minimal residual disease (MRD) remains a major challenge in the treatment of B-cell malignancies and contributes to subsequent disease relapse. B-cell receptor (BCR) signaling has emerged as essential mediator of B-cell homing, survival and environment-mediated drug resistance (EMDR). Central to EMDR are chemokine- and integrin-mediated interactions between lymphoma and the TME. Further, stromal cell-B cell adhesion confers a sustained BCR signaling leading to chemokine and integrin activation. Recently, the inhibitors of BCR signaling have garnered a substantial clinical interest because of their effectiveness in B-cell disorders. The efficacy of these agents is, at least in part, attributed to attenuation of BCR-dependent lymphoma-TME interactions. In this review, we discuss the pivotal role of BCR signaling in the integration of intrinsic and extrinsic determinants of TME-mediated lymphoma survival and drug resistance. PMID:24037527

  9. Stereotyped patterns of B-cell receptor in splenic marginal zone lymphoma

    KAUST Repository

    Zibellini, S.

    2010-05-29

    Antigen stimulation may be important for splenic marginal zone lymphoma pathogenesis. To address this hypothesis, the occurrence of stereotyped B-cell receptors was investigated in 133 SMZL (26 HCV+) compared with 4,414 HCDR3 sequences from public databases. Sixteen SMZL (12%) showed stereotyped BCR; 7 of 86 (8%) SMZL sequences retrieved from public databases also belonged to stereotyped HCDR3 subsets. Three categories of subsets were identified: i) SMZL-specific subsets (n=5), composed only of 12 SMZL (9 HCV- from our series); ii) Non-Hodgkin\\'s lymphoma-like subsets (n=5), comprising 5 SMZL (4 from our series) clustering with other indolent lymphomas; iii) "CLL-like subsets" (n=6), comprising 6 SMZL (3 from our series) that belonged to known CLL subsets (n=4) or clustered with public CLL sequences. Immunoglobulin 3D modeling of 3 subsets revealed similarities in antigen binding regions not limited to HCDR3. Overall, data suggest that the pathogenesis of splenic marginal zone lymphoma may involve also HCV unrelated epitopes or an antigenic trigger common to other indolent lymphomas. ©2010 Ferrata Storti Foundation.

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

    Science.gov (United States)

    2016-04-26

    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

  11. Deviating From the Benchmarks

    DEFF Research Database (Denmark)

    Rocha, Vera; Van Praag, Mirjam; Carneiro, Anabela

    This paper studies three related questions: To what extent otherwise similar startups employ different quantities and qualities of human capital at the moment of entry? How persistent are initial human capital choices over time? And how does deviating from human capital benchmarks influence firm...... survival? The analysis is based on a matched employer-employee dataset and covers about 17,500 startups in manufacturing and services. We adopt a new procedure to estimate individual benchmarks for the quantity and quality of initial human resources, acknowledging correlations between hiring decisions......, founders human capital, and the ownership structure of startups (solo entrepreneurs versus entrepreneurial teams). We then study the survival implications of exogenous deviations from these benchmarks, based on spline models for survival data. Our results indicate that (especially negative) deviations from...

  12. CD4 T cell epitope specificity determines follicular versus non-follicular helper differentiation in the polyclonal response to influenza infection or vaccination.

    Science.gov (United States)

    Knowlden, Zackery A G; Sant, Andrea J

    2016-01-01

    Follicular helper T cells (Tfh) are essential for B cell production of high-affinity, class-switched antibodies. Much interest in Tfh development focuses on the priming environment of CD4 T cells. Here we explored the role that peptide specificity plays in the partitioning of the polyclonal CD4 T cell repertoire between Tfh and NonTfh lineages during the response to influenza. Surprisingly, we found that CD4 T cells specific for different epitopes exhibited distinct tendencies to segregate into Tfh or NonTfh. To alter the microenvironment and abundance, viral antigens were introduced as purified recombinant proteins in adjuvant as native proteins. Also, the most prototypical epitopes were expressed in a completely foreign protein. In many cases, the epitope-specific response patterns of Tfh vs. NonTfh persisted. The functional TcR avidity of only a subset of epitope-specific cells correlated with the tendency to drive a Tfh response. Thus, we conclude that in a polyclonal CD4 T cell repertoire, features of TcR-peptide:MHC class II complex have a strong deterministic influence on the ability of CD4 T cells to become a Tfh or a NonTfh. Our data is most consistent with at least 2 checkpoints of Tfh selection that include both TcR affinity and B cell presentation. PMID:27329272

  13. Chimeric peptide containing both B and T cells epitope of tumor-associated antigen L6 enhances anti-tumor effects in HLA-A2 transgenic mice.

    Science.gov (United States)

    Lin, Su-I; Huang, Ming-Hsi; Chang, Yu-Wen; Chen, I-Hua; Roffler, Steve; Chen, Bing-Mae; Sher, Yuh-Pyng; Liu, Shih-Jen

    2016-07-28

    Synthetic peptides are attractive for cancer immunotherapy because of their safety and flexibility. In this report, we identified a new B cell epitope of tumor-associated antigen L6 (TAL6) that could induce antibody-dependent cellular cytotoxicity (ADCC) in vivo. We incorporated the B cell epitope with a cytotoxic T lymphocyte (CTL) and a helper T (Th) epitope to form a chimeric long peptide. We formulated the chimeric peptide with different adjuvants to immunize HLA-A2 transgenic mice and evaluate their immunogenicity. The chimeric peptide formulated with an emulsion type nanoparticle (PELC) adjuvant and a toll-like receptor 9 agonist (CpG ODN) (PELC/CpG) induced the greatest ADCC and CTL responses. The induced anti-tumor immunity inhibited the growth of TAL6-positive cancer cells. Moreover, we observed that immunization with the chimeric peptide inhibited cancer cell migration in vitro and metastasis in vivo. These data suggest that a chimeric peptide containing both B and T cell epitopes of TAL6 formulated with PELC/CpG adjuvant is feasible for cancer immunotherapy. PMID:27130449

  14. CD4 T cell epitope specificity determines follicular versus non-follicular helper differentiation in the polyclonal response to influenza infection or vaccination

    Science.gov (United States)

    Knowlden, Zackery A. G.; Sant, Andrea J.

    2016-01-01

    Follicular helper T cells (Tfh) are essential for B cell production of high-affinity, class-switched antibodies. Much interest in Tfh development focuses on the priming environment of CD4 T cells. Here we explored the role that peptide specificity plays in the partitioning of the polyclonal CD4 T cell repertoire between Tfh and NonTfh lineages during the response to influenza. Surprisingly, we found that CD4 T cells specific for different epitopes exhibited distinct tendencies to segregate into Tfh or NonTfh. To alter the microenvironment and abundance, viral antigens were introduced as purified recombinant proteins in adjuvant as native proteins. Also, the most prototypical epitopes were expressed in a completely foreign protein. In many cases, the epitope-specific response patterns of Tfh vs. NonTfh persisted. The functional TcR avidity of only a subset of epitope-specific cells correlated with the tendency to drive a Tfh response. Thus, we conclude that in a polyclonal CD4 T cell repertoire, features of TcR-peptide:MHC class II complex have a strong deterministic influence on the ability of CD4 T cells to become a Tfh or a NonTfh. Our data is most consistent with at least 2 checkpoints of Tfh selection that include both TcR affinity and B cell presentation. PMID:27329272

  15. PD-L1 expression in B-cell lymphomas and virus-associated malignancies--letter

    DEFF Research Database (Denmark)

    Andersen, Mads Hald

    2013-01-01

    actually trigger their own inhibition by secreting cytokines that drive tumor PD-L1 expression (3). However, the immune system itself seems also to have established a respective counteractive mechanism, that is, PD-L1–specific, CD8+, cytotoxic T cells. Thus, PD-L1–reactive T cells can readily be isolated...... processed and thus derived PD-L1 epitopes. PD-L1 antibodies target surface protein, whereas PD-L1–specific T cells recognize and kill cells, which are expressing PD-L1 epitopes on the surface derived from intracellular PD-L1. It is important to note that PD-L1 additionally is expressed on normal immune......In a very important recent study, Chen and colleagues describe that PD-L1 (B7-H1, CD274) is expressed on both malignant cells and infiltrating macrophages in a subset of aggressive B-cell lymphomas (1). The article highlights the possibilities of targeting the PD-1/PD-L1 pathway in these...

  16. Benchmarking for Best Practice

    CERN Document Server

    Zairi, Mohamed

    1998-01-01

    Benchmarking for Best Practice uses up-to-the-minute case-studies of individual companies and industry-wide quality schemes to show how and why implementation has succeeded. For any practitioner wanting to establish best practice in a wide variety of business areas, this book makes essential reading. .It is also an ideal textbook on the applications of TQM since it describes concepts, covers definitions and illustrates the applications with first-hand examples. Professor Mohamed Zairi is an international expert and leading figure in the field of benchmarking. His pioneering work in this area l

  17. Remote Sensing Segmentation Benchmark

    Czech Academy of Sciences Publication Activity Database

    Mikeš, Stanislav; Haindl, Michal; Scarpa, G.

    Piscataway, NJ : IEEE Press, 2012, s. 1-4. ISBN 978-1-4673-4960-4. [IAPR Workshop on Pattern Recognition in Remote Sensing (PRRS). Tsukuba Science City (JP), 11.11.2012] R&D Projects: GA ČR GAP103/11/0335; GA ČR GA102/08/0593 Grant ostatní: CESNET(CZ) 409/2011 Keywords : remote sensing * segmentation * benchmark Subject RIV: BD - Theory of Information http://library.utia.cas.cz/separaty/2013/RO/mikes-remote sensing segmentation benchmark.pdf

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

    International Nuclear Information System (INIS)

    Highlights: → TIM-1 is highly expressed on anti-IgM + anti-CD40-stimulated B cells. → Anti-TIM-1 mAb enhanced proliferation and Ig production on activated B cell in vitro. → TIM-1 signaling regulates Ab production by response to TI-2 and TD antigens in vivo. -- Abstract: Members of the T cell Ig and mucin (TIM) family have recently been implicated in the control of T cell-mediated immune responses. In this study, we found TIM-1 expression on anti-IgM- or anti-CD40-stimulated splenic B cells, which was further up-regulated by the combination of anti-IgM and anti-CD40 Abs. On the other hand, TIM-1 ligand was constitutively expressed on B cells and inducible on anti-CD3+ anti-CD28-stimulated CD4+ T cells. In vitro stimulation of activated B cells by anti-TIM-1 mAb enhanced proliferation and expression of a plasma cell marker syndecan-1 (CD138). We further examined the effect of TIM-1 signaling on antibody production in vitro and in vivo. Higher levels of IgG2b and IgG3 secretion were detected in the culture supernatants of the anti-TIM-1-stimulated B cells as compared with the control IgG-stimulated B cells. When immunized with T-independent antigen TNP-Ficoll, TNP-specific IgG1, IgG2b, and IgG3 Abs were slightly increased in the anti-TIM-1-treated mice. When immunized with T-dependent antigen OVA, serum levels of OVA-specific IgG2b, IgG3, and IgE Abs were significantly increased in the anti-TIM-1-treated mice as compared with the control IgG-treated mice. These results suggest that TIM-1 signaling in B cells augments antibody production by enhancing B cell proliferation and differentiation.

  19. Identification of three new type-specific antigen epitopes in the capsid protein of porcine circovirus type 1.

    Science.gov (United States)

    Huang, Liping; Lu, Yuehua; Wei, Yanwu; Guo, Longjun; Liu, Changming

    2012-07-01

    Porcine circovirus type 1 (PCV1) has been identified as a contaminant of porcine kidney cell line (PK-15). Serological evidence and genetic studies have suggested that PCV1 is widespread in domestic pigs. In this study, monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs) were generated against a recombinant PCV1 Cap protein (PCV1-Cap), which was expressed using the baculovirus system. PEPSCAN analysis was used to identify epitopes on the PCV1-Cap with mAbs and pAbs. Three linear B-cell epitopes, including residues (85)GGTNPLP(91), (162)FTPKPELDKTIDWFHPNNK(180) and (219)YVQFREFILKDPLNK(233), specific for PCV1-Cap, were finely defined. These results will facilitate future investigations into antigenic differences and differential diagnosis between PCV1 and PCV2. PMID:22437253

  20. Regulation of germinal center B-cell differentiation.

    Science.gov (United States)

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

    2016-03-01

    Germinal centers (GC) are the main sites where antigen-activated B-cell clones expand and undergo immunoglobulin gene hypermutation and selection. Iterations of this process will lead to affinity maturation, replicating Darwinian evolution on the cellular level. GC B-cell selection can lead to four different outcomes: further expansion and evolution, apoptosis (non-selection), or output from the GC with differentiation into memory B cells or plasma cells. T-helper cells in GC have been shown to have a central role in regulating B-cell selection by sensing the density of major histocompatibility complex (MHC):peptide antigen complexes. Antigen is provided on follicular dendritic cells in the form of immune complex. Antibody on these immune complexes regulates antigen accessibility by shielding antigen from B-cell receptor access. Replacement of antibody on immune complexes by antibody generated from GC-derived plasma cell output will gradually reduce the availability of antigen. This antibody feedback can lead to a situation where a slow rise in selection stringency caused by a changing environment leads to directional evolution toward higher affinity antibody. PMID:26864101

  1. B-cell depletion in the treatment of lupus nephritis.

    Science.gov (United States)

    Gregersen, Jon W; Jayne, David R W

    2012-09-01

    Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is clinically heterogeneous and affects multiple organs. Lupus nephritis is the most frequent severe manifestation of SLE. Conventional immunosuppressive therapy has increased the life expectancy of patients diagnosed with lupus nephritis, but only 70-80% of patients respond to this treatment and its adverse effects are considerable. B cells are central to the pathogenesis of SLE and are, therefore, an attractive therapeutic target. B-cell depletion has been used successfully to treat other autoimmune diseases, such as rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis, and many case reports and small nonrandomized trials of B-cell-depleting agents in patients with lupus nephritis have reported positive results. By contrast, two large placebo-controlled trials designed to investigate the efficacy of the B-cell-depleting agents rituximab and ocrelizumab as a treatment for lupus nephritis, failed to meet their primary efficacy end points (LUNAR and BELONG, respectively). This Review discusses the current evidence on the use of B-cell depletion in the treatment of lupus nephritis, which is derived from case studies and clinical trials including a total of over 800 patients. PMID:22801948

  2. Benchmarking the World's Best

    Science.gov (United States)

    Tucker, Marc S.

    2012-01-01

    A century ago, the United States was a world leader in industrial benchmarking. However, after World War II, once no one could compete with the U.S., it became complacent. Many industrialized countries now have higher student achievement and more equitable and efficient education systems. A higher proportion of young people in their workforces…

  3. Benchmarks: WICHE Region 2012

    Science.gov (United States)

    Western Interstate Commission for Higher Education, 2013

    2013-01-01

    Benchmarks: WICHE Region 2012 presents information on the West's progress in improving access to, success in, and financing of higher education. The information is updated annually to monitor change over time and encourage its use as a tool for informed discussion in policy and education communities. To establish a general context for the…

  4. Benchmark problem proposal

    International Nuclear Information System (INIS)

    The meeting of the Radiation Energy Spectra Unfolding Workshop organized by the Radiation Shielding Information Center is discussed. The plans of the unfolding code benchmarking effort to establish methods of standardization for both the few channel neutron and many channel gamma-ray and neutron spectroscopy problems are presented

  5. Benchmarking and Performance Management

    Directory of Open Access Journals (Sweden)

    Adrian TANTAU

    2010-12-01

    Full Text Available The relevance of the chosen topic is explained by the meaning of the firm efficiency concept - the firm efficiency means the revealed performance (how well the firm performs in the actual market environment given the basic characteristics of the firms and their markets that are expected to drive their profitability (firm size, market power etc.. This complex and relative performance could be due to such things as product innovation, management quality, work organization, some other factors can be a cause even if they are not directly observed by the researcher. The critical need for the management individuals/group to continuously improve their firm/company’s efficiency and effectiveness, the need for the managers to know which are the success factors and the competitiveness determinants determine consequently, what performance measures are most critical in determining their firm’s overall success. Benchmarking, when done properly, can accurately identify both successful companies and the underlying reasons for their success. Innovation and benchmarking firm level performance are critical interdependent activities. Firm level variables, used to infer performance, are often interdependent due to operational reasons. Hence, the managers need to take the dependencies among these variables into account when forecasting and benchmarking performance. This paper studies firm level performance using financial ratio and other type of profitability measures. It uses econometric models to describe and then propose a method to forecast and benchmark performance.

  6. CCF benchmark test

    International Nuclear Information System (INIS)

    A benchmark test on common cause failures (CCF) was performed giving interested institutions in Germany the opportunity of demonstrating and justifying their interpretations of events, their methods and models for analyzed CCF. The participants of this benchmark test belonged to expert and consultant organisations and to industrial institutions. The task for the benchmark test was to analyze two typical groups of motor-operated valves in German nuclear power plants. The benchmark test was carried out in two steps. In the first step the participants were to assess in a qualitative way some 200 event-reports on isolation valves. They then were to establish, quantitatively, the reliability parameters for the CCF in the two groups of motor-operated valves using their own methods and their own calculation models. In a second step the reliability parameters were to be recalculated on the basis of a common reference of well defined events, chosen from all given events, in order to analyze the influence of the calculation models on the reliability parameters. (orig.)

  7. Benchmarking Public Procurement 2016

    OpenAIRE

    World Bank Group

    2015-01-01

    Benchmarking Public Procurement 2016 Report aims to develop actionable indicators which will help countries identify and monitor policies and regulations that impact how private sector companies do business with the government. The project builds on the Doing Business methodology and was initiated at the request of the G20 Anti-Corruption Working Group.

  8. NAS Parallel Benchmarks Results

    Science.gov (United States)

    Subhash, Saini; Bailey, David H.; Lasinski, T. A. (Technical Monitor)

    1995-01-01

    The NAS Parallel Benchmarks (NPB) were developed in 1991 at NASA Ames Research Center to study the performance of parallel supercomputers. The eight benchmark problems are specified in a pencil and paper fashion i.e. the complete details of the problem to be solved are given in a technical document, and except for a few restrictions, benchmarkers are free to select the language constructs and implementation techniques best suited for a particular system. In this paper, we present new NPB performance results for the following systems: (a) Parallel-Vector Processors: Cray C90, Cray T'90 and Fujitsu VPP500; (b) Highly Parallel Processors: Cray T3D, IBM SP2 and IBM SP-TN2 (Thin Nodes 2); (c) Symmetric Multiprocessing Processors: Convex Exemplar SPP1000, Cray J90, DEC Alpha Server 8400 5/300, and SGI Power Challenge XL. We also present sustained performance per dollar for Class B LU, SP and BT benchmarks. We also mention NAS future plans of NPB.

  9. Novel Therapies for Aggressive B-Cell Lymphoma

    Directory of Open Access Journals (Sweden)

    Kenneth A. Foon

    2012-01-01

    Full Text Available Aggressive B-cell lymphoma (BCL comprises a heterogeneous group of malignancies, including diffuse large B-cell lymphoma (DLBCL, Burkitt lymphoma, and mantle cell lymphoma (MCL. DLBCL, with its 3 subtypes, is the most common type of lymphoma. Advances in chemoimmunotherapy have substantially improved disease control. However, depending on the subtype, patients with DLBCL still exhibit substantially different survival rates. In MCL, a mature B-cell lymphoma, the addition of rituximab to conventional chemotherapy regimens has increased response rates, but not survival. Burkitt lymphoma, the most aggressive BCL, is characterized by a high proliferative index and requires more intensive chemotherapy regimens than DLBCL. Hence, there is a need for more effective therapies for all three diseases. Increased understanding of the molecular features of aggressive BCL has led to the development of a range of novel therapies, many of which target the tumor in a tailored manner and are summarized in this paper.

  10. Inferring processes underlying B-cell repertoire diversity.

    Science.gov (United States)

    Elhanati, Yuval; Sethna, Zachary; Marcou, Quentin; Callan, Curtis G; Mora, Thierry; Walczak, Aleksandra M

    2015-09-01

    We quantify the VDJ recombination and somatic hypermutation processes in human B cells using probabilistic inference methods on high-throughput DNA sequence repertoires of human B-cell receptor heavy chains. Our analysis captures the statistical properties of the naive repertoire, first after its initial generation via VDJ recombination and then after selection for functionality. We also infer statistical properties of the somatic hypermutation machinery (exclusive of subsequent effects of selection). Our main results are the following: the B-cell repertoire is substantially more diverse than T-cell repertoires, owing to longer junctional insertions; sequences that pass initial selection are distinguished by having a higher probability of being generated in a VDJ recombination event; somatic hypermutations have a non-uniform distribution along the V gene that is well explained by an independent site model for the sequence context around the hypermutation site. PMID:26194757

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

    Directory of Open Access Journals (Sweden)

    Matilde Cacciatore

    2012-01-01

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

  12. Evolution of B-cell malignancy; Pre-B-cell leukemia resulting from MYC activation in a B-cell neoplasm with a rearranged BCL2 gene

    International Nuclear Information System (INIS)

    The authors have analyzed the molecular genetics of the breakpoints involved in the t(8;14) and t(14;18) translocations of an acute pre-B-cell leukemia from a patient with a history of follicular lymphoma. In this patient's leukemic cells, the breakpoint of the t(14;18) translocation occurred in the major breakpoint-cluster region of the BCL2 gene and became linked to the JH4 joining-region gene segment of the immunoglobulin heavy-chain locus on the 14q+ chromosome as previously observed in follicular lymphoma. An N region and heptamer and nonamer signal sequences indicated that this translocation occurred as a mistake in VH-DH-JH joining (where VH and DH are the variable and diversity segments). In the t(8;14) translocation, the breakpoint was located immediately 5' of the first exon of the MYC protooncogene, which was juxtaposed with the Cγ2 constant gene segment of the second 14q+ chromosome. The finding of repeated sequences typical of switch regions suggested that this translocation occurred during heavy-chain isotype switching, resulting in progression to pre-B-cell leukemia with both the 5(8;14) and the t(14;18) translocations. The terminal deoxynucleotidyltransferase-positive phenotype of the patient's leukemic cells further suggests that the pre-B-cell leukemia was derived from a pre-B cell carrying a t(14;18) translocation in the original follicular lymphoma. The polymerase chain reaction method was then used to identify cancer cells in the bone marrow of the patient

  13. Editing Anti-DNA B Cells by Vλx

    OpenAIRE

    Li, Yijin; Louzoun, Yoram; Weigert, Martin

    2004-01-01

    Receptor editing is performed by replacement of Vκ genes that contribute to autoreactivity. In addition, the Cκ locus can be deleted by Vκ rearrangement to intronic or 3′ of Cκ RS sequences (also referred to as κ deletion elements). B cells that delete the Cκ can then express λ light chains. However, the λ locus, either of man or mouse, does not allow V gene replacement. Nor does it appear to be deleted. Therefore, editing of autoreactive λ B cells may require alternative pathways. We have fo...

  14. Primary B-cell deficiencies reveal a link between human IL-17-producing CD4 T-cell homeostasis and B-cell differentiation.

    Directory of Open Access Journals (Sweden)

    Rita R Barbosa

    Full Text Available IL-17 is a pro-inflammatory cytokine implicated in autoimmune and inflammatory conditions. The development/survival of IL-17-producing CD4 T cells (Th17 share critical cues with B-cell differentiation and the circulating follicular T helper subset was recently shown to be enriched in Th17 cells able to help B-cell differentiation. We investigated a putative link between Th17-cell homeostasis and B cells by studying the Th17-cell compartment in primary B-cell immunodeficiencies. Common Variable Immunodeficiency Disorders (CVID, defined by defects in B-cell differentiation into plasma and memory B cells, are frequently associated with autoimmune and inflammatory manifestations but we found no relationship between these and Th17-cell frequency. In fact, CVID patients showed a decrease in Th17-cell frequency in parallel with the expansion of activated non-differentiated B cells (CD21(lowCD38(low. Moreover, Congenital Agammaglobulinemia patients, lacking B cells due to impaired early B-cell development, had a severe reduction of circulating Th17 cells. Finally, we found a direct correlation in healthy individuals between circulating Th17-cell frequency and both switched-memory B cells and serum BAFF levels, a crucial cytokine for B-cell survival. Overall, our data support a relationship between Th17-cell homeostasis and B-cell maturation, with implications for the understanding of the pathogenesis of inflammatory/autoimmune diseases and the physiology of B-cell depleting therapies.

  15. Benchmarking i den offentlige sektor

    DEFF Research Database (Denmark)

    Bukh, Per Nikolaj; Dietrichson, Lars; Sandalgaard, Niels

    2008-01-01

    I artiklen vil vi kort diskutere behovet for benchmarking i fraværet af traditionelle markedsmekanismer. Herefter vil vi nærmere redegøre for, hvad benchmarking er med udgangspunkt i fire forskellige anvendelser af benchmarking. Regulering af forsyningsvirksomheder vil blive behandlet, hvorefter...

  16. Large scale genome analysis shows that the epitopes for broadly cross-reactive antibodies are predominant in the pandemic 2009 influenza virus A H1N1 strain.

    Science.gov (United States)

    Lara-Ramírez, Edgar E; Segura-Cabrera, Aldo; Salazar, Ma Isabel; Rodríguez-Pérez, Mario A; Guo, Xianwu

    2013-11-01

    The past pandemic strain H1N1 (A (H1N1)pdm09) has now become a common component of current seasonal influenza viruses. It has changed the pre-existing immunity of the human population to succeeding infections. In the present study, a total of 14,210 distinct sequences downloaded from National Center for Biotechnology Information (NCBI) database were used for the analysis. The epitope compositions in A (H1N1)pdm09, classic seasonal strains, swine strains as well as highly virulent avian strain H5N1, identified with the aid of the Immune Epitope DataBase (IEDB), were compared at genomic level. The result showed that A (H1N1) pdm09 contains the 90% of B-cell epitopes for broadly cross-reactive antibodies (EBCA), which is in consonance with the recent reports on the experimental identification of new epitopes or antibodies for this virus and the binding tests with influenza virus protein HA of different subtypes. Our analysis supports that high proportional EBCA depends on the epitope pattern of A (H1N1)pdm09 virus. This study may be helpful for better understanding of A (H1N1)pdm09 and the production of new influenza vaccines. PMID:24257096

  17. Large Scale Genome Analysis Shows that the Epitopes for Broadly Cross-Reactive Antibodies Are Predominant in the Pandemic 2009 Influenza Virus A H1N1 Strain

    Directory of Open Access Journals (Sweden)

    Edgar E. Lara-Ramírez

    2013-11-01

    Full Text Available The past pandemic strain H1N1 (A (H1N1pdm09 has now become a common component of current seasonal influenza viruses. It has changed the pre-existing immunity of the human population to succeeding infections. In the present study, a total of 14,210 distinct sequences downloaded from National Center for Biotechnology Information (NCBI database were used for the analysis. The epitope compositions in A (H1N1pdm09, classic seasonal strains, swine strains as well as highly virulent avian strain H5N1, identified with the aid of the Immune Epitope DataBase (IEDB, were compared at genomic level. The result showed that A (H1N1 pdm09 contains the 90% of B-cell epitopes for broadly cross-reactive antibodies (EBCA, which is in consonance with the recent reports on the experimental identification of new epitopes or antibodies for this virus and the binding tests with influenza virus protein HA of different subtypes. Our analysis supports that high proportional EBCA depends on the epitope pattern of A (H1N1pdm09 virus. This study may be helpful for better understanding of A (H1N1pdm09 and the production of new influenza vaccines.

  18. Th1 and Th2 help for B cells

    DEFF Research Database (Denmark)

    Poudrier, J; Owens, T

    1995-01-01

    IL-5 (125 U/ml) synergizes with Th1 cells to induce B cell responses to IL-2, that are maintained following T-cell removal, e.g. autonomous. Th1 help in the absence of IL-5 resulted in weak or undetectable responses following T cell removal. The mechanism of IL-5 synergy involved persistence of IL-2R...

  19. Isolation of human monoclonal antibodies from peripheral blood B cells.

    Science.gov (United States)

    Huang, Jinghe; Doria-Rose, Nicole A; Longo, Nancy S; Laub, Leo; Lin, Chien-Li; Turk, Ellen; Kang, Byong H; Migueles, Stephen A; Bailer, Robert T; Mascola, John R; Connors, Mark

    2013-10-01

    Isolation of monoclonal antibodies is an important technique for understanding the specificities and characteristics of antibodies that underlie the humoral immune response to a given antigen. Here we describe a technique for isolating monoclonal antibodies from human peripheral blood mononuclear cells. The protocol includes strategies for the isolation of switch-memory B cells from peripheral blood, the culture of B cells, the removal of the supernatant for screening and the lysis of B cells in preparation for immunoglobulin heavy-chain and light-chain amplification and cloning. We have observed that the addition of cytokines IL-2, IL-21 and irradiated 3T3-msCD40L feeder cells can successfully stimulate switch-memory B cells to produce high concentrations of IgG in the supernatant. The supernatant may then be screened by appropriate assays for binding or for other functions. This protocol can be completed in 2 weeks. It is adaptable to use in other species and enables the efficient isolation of antibodies with a desired functional characteristic without prior knowledge of specificity. PMID:24030440

  20. Innate B Cells Tell ILC How It's Done.

    Science.gov (United States)

    Nguyen, Trang T T; Baumgarth, Nicole

    2016-07-19

    Innate lymphoid cells (ILCs) are known as first responders to infections and as instructors of subsequent CD4(+) T cell cytokine profiles. In this issue of Immunity, Fan and colleagues now demonstrate that even earlier responding innate-like B cells (NKB) induce these protective ILC responses. PMID:27438761

  1. Immunomodulatory effect of Mesenchymal Stem Cells on B cells

    Directory of Open Access Journals (Sweden)

    Marcella eFranquesa

    2012-07-01

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

  2. Role of Calcium Signaling in B Cell Activation and Biology.

    Science.gov (United States)

    Baba, Yoshihiro; Kurosaki, Tomohiro

    2016-01-01

    Increase in intracellular levels of calcium ions (Ca2+) is one of the key triggering signals for the development of B cell response to the antigen. The diverse Ca2+ signals finely controlled by multiple factors participate in the regulation of gene expression, B cell development, and effector functions. B cell receptor (BCR)-initiated Ca2+ mobilization is sourced from two pathways: one is the release of Ca2+ from the intracellular stores, endoplasmic reticulum (ER), and other is the prolonged influx of extracellular Ca2+ induced by depleting the stores via store-operated calcium entry (SOCE) and calcium release-activated calcium (CRAC) channels. The identification of stromal interaction molecule 1(STIM1), the ER Ca2+ sensor, and Orai1, a key subunit of the CRAC channel pore, has now provided the tools to understand the mode of Ca2+ influx regulation and physiological relevance. Herein, we discuss our current understanding of the molecular mechanisms underlying BCR-triggered Ca2+ signaling as well as its contribution to the B cell biological processes and diseases. PMID:26369772

  3. Impact of Gastrointestinal Bacillus anthracis Infection on Hepatic B Cells

    Directory of Open Access Journals (Sweden)

    Natacha Colliou

    2015-09-01

    Full Text Available Ingestion of Bacillus anthracis results in rapid gastrointestinal (GI infection, known as GI anthrax. We previously showed that during GI anthrax, there is swift deterioration of intestinal barrier function leading to translocation of gut-associated bacteria into systemic circulation. Additionally, we described dysfunction in colonic B cells. In concordance with our previous studies, here, we report early migration of the Sterne strain of B. anthracis along with other gut-resident bacteria into the infected murine liver. Additionally, despite a global decrease in the B cell population, we observed an increase in both B-1a and marginal zone (MZ-like B cells. Both of these cell types are capable of producing immunoglobulins against common pathogens and commensals, which act as a general antibody barrier before an antigen-specific antibody response. Accumulation of these cells in the liver was associated with an increase in chemokine expression. These data suggest that the presence of Sterne and other commensals in the liver trigger migration of MZ-like B cells from the spleen to the liver to neutralize systemic spread. Further research is required to evaluate the possible cause of their failure to clear the infection within the liver, including the potential role of dysfunctional mitogen-activated protein kinase (MAPK signaling.

  4. Texture Segmentation Benchmark

    Czech Academy of Sciences Publication Activity Database

    Haindl, Michal; Mikeš, Stanislav

    Los Alamitos : IEEE Press, 2008, s. 2933-2936. ISBN 978-1-4244-2174-9. [19th International Conference on Pattern Recognition. Tampa (US), 07.12.2008-11.12.2008] R&D Projects: GA AV ČR 1ET400750407; GA MŠk 1M0572; GA ČR GA102/07/1594; GA ČR GA102/08/0593 Grant ostatní: GA MŠk(CZ) 2C06019 Institutional research plan: CEZ:AV0Z10750506 Keywords : texture segmentation * image segmentation * benchmark Subject RIV: BD - Theory of Information http://library.utia.cas.cz/separaty/2008/RO/haindl-texture segmentation benchmark.pdf

  5. Radiography benchmark 2014

    International Nuclear Information System (INIS)

    The purpose of the 2014 WFNDEC RT benchmark study was to compare predictions of various models of radiographic techniques, in particular those that predict the contribution of scattered radiation. All calculations were carried out for homogenous materials and a mono-energetic X-ray point source in the energy range between 100 keV and 10 MeV. The calculations were to include the best physics approach available considering electron binding effects. Secondary effects like X-ray fluorescence and bremsstrahlung production were to be taken into account if possible. The problem to be considered had two parts. Part I examined the spectrum and the spatial distribution of radiation behind a single iron plate. Part II considered two equally sized plates, made of iron and aluminum respectively, only evaluating the spatial distribution. Here we present the results of above benchmark study, comparing them to MCNP as the assumed reference model. The possible origins of the observed deviations are discussed

  6. Benchmarking of LSTM Networks

    OpenAIRE

    Breuel, Thomas M.

    2015-01-01

    LSTM (Long Short-Term Memory) recurrent neural networks have been highly successful in a number of application areas. This technical report describes the use of the MNIST and UW3 databases for benchmarking LSTM networks and explores the effect of di?erent architectural and hyperparameter choices on performance. Significant ?ndings include: (1) LSTM performance depends smoothly on learning rates, (2) batching and momentum has no significant effect on performance, (3) softmax training outperfor...

  7. Texture Fidelity Benchmark

    Czech Academy of Sciences Publication Activity Database

    Haindl, Michal; Kudělka, Miloš

    Los Alamitos, USA: IEEE Computer Society CPS, 2014. ISBN 978-1-4799-7971-4. [International Workshop on Computational Intelligence for Multimedia Understanding 2014 (IWCIM). Paris (FR), 01.11.2014-02.11.2014] R&D Projects: GA ČR(CZ) GA14-10911S Institutional support: RVO:67985556 Keywords : Benchmark testing * fidelity criteria * texture Subject RIV: BD - Theory of Information http://library.utia.cas.cz/separaty/2014/RO/haindl-0439654.pdf

  8. Cloud benchmarking for performance

    OpenAIRE

    Varghese, Blesson; Akgun, Ozgur; Miguel, Ian; Thai, Long; Barker, Adam

    2014-01-01

    How can applications be deployed on the cloud to achieve maximum performance? This question has become significant and challenging with the availability of a wide variety of Virtual Machines (VMs) with different performance capabilities in the cloud. The above question is addressed by proposing a six step benchmarking methodology in which a user provides a set of four weights that indicate how important each of the following groups: memory, processor, computation and storage are to the applic...

  9. Bacteria modulate the CD8+ T cell epitope repertoire of host cytosol-exposed proteins to manipulate the host immune response.

    Directory of Open Access Journals (Sweden)

    Yaakov Maman

    2011-10-01

    Full Text Available The main adaptive immune response to bacteria is mediated by B cells and CD4+ T-cells. However, some bacterial proteins reach the cytosol of host cells and are exposed to the host CD8+ T-cells response. Both gram-negative and gram-positive bacteria can translocate proteins to the cytosol through type III and IV secretion and ESX-1 systems, respectively. The translocated proteins are often essential for the bacterium survival. Once injected, these proteins can be degraded and presented on MHC-I molecules to CD8+ T-cells. The CD8+ T-cells, in turn, can induce cell death and destroy the bacteria's habitat. In viruses, escape mutations arise to avoid this detection. The accumulation of escape mutations in bacteria has never been systematically studied. We show for the first time that such mutations are systematically present in most bacteria tested. We combine multiple bioinformatic algorithms to compute CD8+ T-cell epitope libraries of bacteria with secretion systems that translocate proteins to the host cytosol. In all bacteria tested, proteins not translocated to the cytosol show no escape mutations in their CD8+ T-cell epitopes. However, proteins translocated to the cytosol show clear escape mutations and have low epitope densities for most tested HLA alleles. The low epitope densities suggest that bacteria, like viruses, are evolutionarily selected to ensure their survival in the presence of CD8+ T-cells. In contrast with most other translocated proteins examined, Pseudomonas aeruginosa's ExoU, which ultimately induces host cell death, was found to have high epitope density. This finding suggests a novel mechanism for the manipulation of CD8+ T-cells by pathogens. The ExoU effector may have evolved to maintain high epitope density enabling it to efficiently induce CD8+ T-cell mediated cell death. These results were tested using multiple epitope prediction algorithms, and were found to be consistent for most proteins tested.

  10. IgE-binding epitopes: a reappraisal

    NARCIS (Netherlands)

    R.C. Aalberse; R. Crameri

    2011-01-01

    Here, we discuss various questions related to IgE epitopes: What are the technical possibilities and pitfalls, what is currently known, how can we put this information into hypothetical frameworks and the unavoidable question: how useful is this information for patient care or allergenicity predicti

  11. Detection of influenza A virus homo- and heterosubtype-specific memory B-cells using a novel protein microarray-based analysis tool.

    Science.gov (United States)

    Baas, Dominique C; Koopmans, Marion P; de Bruin, Erwin; ten Hulscher, Hinke I; Buisman, Anne M; Hendrikx, Lotte H; van Beek, Janko; Godeke, Gert-Jan; Reimerink, Johan; van Binnendijk, Robert S

    2013-05-01

    The emergence of the A(H1N1) 2009 pandemic influenza virus was initially seen as a major world-wide health concern since a low degree of immunity to this virus strain was anticipated. However, age-specific infection attack rates and age-specific differences in seroresponse indicate that pre-existing immunity may have played a significant role in protection especially in older age groups. This study describes the use of a protein microarray as a multiplex analysis tool for detection of influenza virus H1 strain-specific memory B-cells before and after infection with A(H1N1)pdm09. The discrimination was based on detection of specific antibodies in culture supernatants from polyclonally stimulated B-cells against recombinant influenza virus HA1 proteins representing influenza virus subtypes H1 through H9. The protein microarray proved sensitive and specific for antibody detection in culture supernatants of B-cells, and with the potential to deduce a person's history of infection with particular influenza virus variants, including A(H1N1)pdm09. Blood samples obtained from different age groups prior to the pandemic in 2009 partly showed the presence of B-cells producing antibodies binding to the closely related A(H1N1) 1918 pandemic influenza virus, and of which the magnitude increased with age. These cross-reactive antibodies were produced by single memory B-cells present in these donors, and either bind to epitopes on HA1 which are shared within different H1 strains (homosubtypic response) or shared between different subtypes (heterosubtypic response). PMID:23508915

  12. Germinal center B cells recognize antigen through a specialized immune synapse architecture.

    Science.gov (United States)

    Nowosad, Carla R; Spillane, Katelyn M; Tolar, Pavel

    2016-07-01

    B cell activation is regulated by B cell antigen receptor (BCR) signaling and antigen internalization in immune synapses. Using large-scale imaging across B cell subsets, we found that, in contrast with naive and memory B cells, which gathered antigen toward the synapse center before internalization, germinal center (GC) B cells extracted antigen by a distinct pathway using small peripheral clusters. Both naive and GC B cell synapses required proximal BCR signaling, but GC cells signaled less through the protein kinase C-β-NF-κB pathway and produced stronger tugging forces on the BCR, thereby more stringently regulating antigen binding. Consequently, GC B cells extracted antigen with better affinity discrimination than naive B cells, suggesting that specialized biomechanical patterns in B cell synapses regulate T cell-dependent selection of high-affinity B cells in GCs. PMID:27183103

  13. The NAS Parallel Benchmarks

    Energy Technology Data Exchange (ETDEWEB)

    Bailey, David H.

    2009-11-15

    The NAS Parallel Benchmarks (NPB) are a suite of parallel computer performance benchmarks. They were originally developed at the NASA Ames Research Center in 1991 to assess high-end parallel supercomputers. Although they are no longer used as widely as they once were for comparing high-end system performance, they continue to be studied and analyzed a great deal in the high-performance computing community. The acronym 'NAS' originally stood for the Numerical Aeronautical Simulation Program at NASA Ames. The name of this organization was subsequently changed to the Numerical Aerospace Simulation Program, and more recently to the NASA Advanced Supercomputing Center, although the acronym remains 'NAS.' The developers of the original NPB suite were David H. Bailey, Eric Barszcz, John Barton, David Browning, Russell Carter, LeoDagum, Rod Fatoohi, Samuel Fineberg, Paul Frederickson, Thomas Lasinski, Rob Schreiber, Horst Simon, V. Venkatakrishnan and Sisira Weeratunga. The original NAS Parallel Benchmarks consisted of eight individual benchmark problems, each of which focused on some aspect of scientific computing. The principal focus was in computational aerophysics, although most of these benchmarks have much broader relevance, since in a much larger sense they are typical of many real-world scientific computing applications. The NPB suite grew out of the need for a more rational procedure to select new supercomputers for acquisition by NASA. The emergence of commercially available highly parallel computer systems in the late 1980s offered an attractive alternative to parallel vector supercomputers that had been the mainstay of high-end scientific computing. However, the introduction of highly parallel systems was accompanied by a regrettable level of hype, not only on the part of the commercial vendors but even, in some cases, by scientists using the systems. As a result, it was difficult to discern whether the new systems offered any fundamental

  14. Ibrutinib Before and After Stem Cell Transplant in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma

    Science.gov (United States)

    2016-09-01

    Activated B-Cell-Like Diffuse Large B-Cell Lymphoma; B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma

  15. Expression and immunoreactivity of HCV/HBV epitopes

    Institute of Scientific and Technical Information of China (English)

    Xin-Yu Xiong; Xiao Liu; Yuan-Ding Chen

    2005-01-01

    AIM: To develop the epitope-based vaccines to prevent Hepatitis C virus (HCV)/Hepatitis B virus (HBV) infections.METHODS: The HCV core epitopes C1 STNPKPQRKTKRNTNRRPQD (residuals aa2-21) and C2 VKFPGGGQIVGGVYLLPRR (residuals aa22-40), envelope epitope E GHRMAWDMMMNWSP (residuals aa315-328) and HBsAg epitope S CTTPAQGNSMFPSCCCTKPTDGNC (residuals aa124-147) were displayed in five different sites of the flock house virus capsid protein as a vector, and expressed in E. coli cells (pET-3 system).Immunoreactivity of the epitopes with anti-HCV and anti-HBV antibodies in the serum from hepatitis C and hepatitis B patients were determined.RESULTS: The expressed chimeric protein carrying the HCV epitopes C1, C2, E (two times), L3C1-I2E-L1C2-L2E could react with anti-HCV antibodies. The expressed chimeric protein carrying the HBV epitopes S, I3S could react with anti-HBs antibodies. The expressed chimeric proteins carrying the HCV epitopes C1, C2, E plus HBV epitope S, L3C1-I2E-L1C2-L2E-I3S could react with antiHCV and anti-HBs antibodies.CONCLUSION: These epitopes have highly specific and sensitive immunoreaction and are useful in the development of epitope-based vaccines.

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

    Directory of Open Access Journals (Sweden)

    Yosef Refaeli

    2008-06-01

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

  17. Self-benchmarking Guide for Data Centers: Metrics, Benchmarks, Actions

    Energy Technology Data Exchange (ETDEWEB)

    Mathew, Paul; Ganguly, Srirupa; Greenberg, Steve; Sartor, Dale

    2009-07-13

    This guide describes energy efficiency metrics and benchmarks that can be used to track the performance of and identify potential opportunities to reduce energy use in data centers. This guide is primarily intended for personnel who have responsibility for managing energy use in existing data centers - including facilities managers, energy managers, and their engineering consultants. Additionally, data center designers may also use the metrics and benchmarks described in this guide for goal-setting in new construction or major renovation. This guide provides the following information: (1) A step-by-step outline of the benchmarking process. (2) A set of performance metrics for the whole building as well as individual systems. For each metric, the guide provides a definition, performance benchmarks, and potential actions that can be inferred from evaluating this metric. (3) A list and descriptions of the data required for computing the metrics. This guide is complemented by spreadsheet templates for data collection and for computing the benchmarking metrics. This guide builds on prior data center benchmarking studies supported by the California Energy Commission. Much of the benchmarking data are drawn from the LBNL data center benchmarking database that was developed from these studies. Additional benchmark data were obtained from engineering experts including facility designers and energy managers. This guide also builds on recent research supported by the U.S. Department of Energy's Save Energy Now program.

  18. 324 Facility B-cell quality process plan

    International Nuclear Information System (INIS)

    B-Cell is currently being cleaned out (i.e., removal of equipment, fixtures and residual radioactive materials) and deactivated. TPA Milestone M-89-02 dictates that all mixed waste and equipment be removed from B-Cell by 5/31/99. The following sections describe the major activities that remain for completion of the TPA milestone. These include: Size Reduce Tank 119 and Miscellaneous Equipment; Load and Ship Low-Level Waste; Remove and Size Reduce the 1B Rack; Collect Dispersible Material from Cell Floor; Remove and Size Reduce the 2A Rack; Size Reduce the 1A Rack; Load and Ship Mixed Waste to PUREX Tunnels; and Move Spent Fuel to A-Cell;

  19. 324 Facility B-cell quality process plan

    Energy Technology Data Exchange (ETDEWEB)

    Carlson, J.L.

    1998-07-29

    B-Cell is currently being cleaned out (i.e., removal of equipment, fixtures and residual radioactive materials) and deactivated. TPA Milestone M-89-02 dictates that all mixed waste and equipment be removed from B-Cell by 5/31/99. The following sections describe the major activities that remain for completion of the TPA milestone. These include: Size Reduce Tank 119 and Miscellaneous Equipment; Load and Ship Low-Level Waste; Remove and Size Reduce the 1B Rack; Collect Dispersible Material from Cell Floor; Remove and Size Reduce the 2A Rack; Size Reduce the 1A Rack; Load and Ship Mixed Waste to PUREX Tunnels; and Move Spent Fuel to A-Cell;

  20. Assembly and Function of the Precursor B-Cell Receptor.

    Science.gov (United States)

    Übelhart, Rudolf; Werner, Markus; Jumaa, Hassan

    2016-01-01

    During early stages of development, precursor B lymphocytes express a characteristic type of antigen receptor known as the pre-B-cell receptor (pre-BCR). This receptor differs from conventional BCRs in that it possesses a germ line-encoded surrogate light chain (SLC), which is associated with the signal transduction machinery via heavy chain (HC) proteins that have been generated by productive rearrangement of the immunoglobulin HC genes. The pre-BCR marks a key step of B-cell commitment, as it activates the B-cell-specific signaling cascade and mediates the selection, expansion, and differentiation of cells expressing a productively rearranged HC protein. Another difference between the pre-BCR and conventional BCR might be the initial event that triggers receptor activation, as the pre-BCR is activated in the absence of external ligands, while conventional BCRs require antigen for activation. Nonetheless, the pre-BCR downstream signaling cascade is largely similar to that of the BCR suggesting that the characteristic LC of the pre-BCR mediates important receptor interactions thereby providing distinctive, germ line-encoded features to the pre-BCR. In fact, the SLC enables the pre-BCR to act as a surrogate autoreactive receptor. Here, we outline the structure and function of the pre-BCR and how the autonomous signaling capacity might be a direct consequence of pre-BCR assembly. In addition to its role in early B-cell development, we discuss how the ordered activation of downstream signaling cascades enables the pre-BCR to activate seemingly opposing cellular programs such as proliferation and differentiation. PMID:26415650

  1. Diffuse Large B Cell Lymphoma of the Breast

    OpenAIRE

    Feryal Karaca; Vehbi Ercolak; Cigdem Usul Afsar; Meral Gunaldi

    2015-01-01

    Primary breast lymphoma is rarely encountered in Non-Hodgkin Lymphomas. However, if early diagnosis is made, and treatment is started immediately in patients with low grade and stage, patient survival is increased. 39-year old female patient applied us due to a palpable mass. She was diagnosed with the Non-Hodgkin Lymphoma Diffuse Large B Cell Lymphoma after the investigations. Curative external radiotherapy was applied after 6 courses of CHOP-R chemotherapy to the patient with Stage-IIE favo...

  2. Regulation of B cell function by plasmacytoid dendritic cells

    OpenAIRE

    Gujer, Cornelia

    2011-01-01

    Dendritic cells (DCs) are early sentinels of pathogen exposure and central in the initiation and orchestration of adaptive immune responses. Apart from the prominent role of DCs in the activation of T cells, DCs have been shown to influence humoral B cell mediated responses. DCs are therefore important cells for regulating immune responses to vaccines. Many of the vaccines under development today are against pathogens such as Mycobacterium tuberculosis and HIV-1 that likely r...

  3. Sources of DNA for detecting B cell monoclonality using PCR.

    OpenAIRE

    Diss, T. C.; Pan, L.; Peng, H; Wotherspoon, A C; Isaacson, P G

    1994-01-01

    AIMS--To evaluate the polymerase chain reaction (PCR) demonstration of clonal immunoglobulin heavy chain gene rearrangements using routinely prepared, unstained, and stained formalin fixed, paraffin wax embedded tissue samples. METHODS--Extracts from (a) fresh frozen tissue samples, (b) unstained, and (c) haematoxylin and eosin stained formalin fixed, paraffin wax embedded 5 microns tissue sections from 42 cases of low grade B cell lymphoma, all shown to be monoclonal by Southern blot analysi...

  4. Refining the Neuberger Model: uracil processing by activated B cells

    OpenAIRE

    Maul, Robert W.; Gearhart, Patricia J.

    2014-01-01

    During the immune response, B cells undergo a programmed mutagenic cascade to promote increased affinity and expanded antibody function. The two processes, somatic hypermutation (SHM) and class switch recombination (CSR), are initiated by the protein activation-induced deaminase (AID), which converts cytosine to uracil in the immunoglobulin loci. The presence of uracil in DNA promotes DNA mutagenesis though a subset of DNA repair proteins. Two distinct mechanisms have been proposed to control...

  5. Anatomy of a new B-cell-specific enhancer.

    OpenAIRE

    Koch, W; Benoist, C.; Mathis, D

    1989-01-01

    The major histocompatibility complex class II molecules, like the immunoglobulins, are prominent B-lymphocyte markers. Herein, we describe a B-cell-specific enhancer associated with the murine class II gene, Ek alpha. This enhancer has a complex anatomy that suggests interactions between remotely spaced elements. Of particular interest is the finding that two CCAAT boxes spaced one kilobase apart are important for enhancer activity. Somewhat surprisingly, the E alpha and immunoglobulin enhanc...

  6. Adaptive Response of T and B Cells in Atherosclerosis.

    Science.gov (United States)

    Ketelhuth, Daniel F J; Hansson, Göran K

    2016-02-19

    Atherosclerosis is a chronic inflammatory disease that is initiated by the retention and accumulation of cholesterol-containing lipoproteins, particularly low-density lipoprotein, in the artery wall. In the arterial intima, lipoprotein components that are generated through oxidative, lipolytic, and proteolytic activities lead to the formation of several danger-associated molecular patterns, which can activate innate immune cells as well as vascular cells. Moreover, self- and non-self-antigens, such as apolipoprotein B-100 and heat shock proteins, can contribute to vascular inflammation by triggering the response of T and B cells locally. This process can influence the initiation, progression, and stability of plaques. Substantial clinical and experimental data support that the modulation of adaptive immune system may be used for treating and preventing atherosclerosis. This may lead to the development of more selective and less harmful interventions, while keeping host defense mechanisms against infections and tumors intact. Approaches such as vaccination might become a realistic option for cardiovascular disease, especially if they can elicit regulatory T and B cells and the secretion of atheroprotective antibodies. Nevertheless, difficulties in translating certain experimental data into new clinical therapies remain a challenge. In this review, we discuss important studies on the function of T- and B-cell immunity in atherosclerosis and their manipulation to develop novel therapeutic strategies against cardiovascular disease. PMID:26892965

  7. Antigen Processing by Autoreactive B Cells Promotes Determinant Spreading

    Institute of Scientific and Technical Information of China (English)

    Yang D.Dai; George Carayanniotis; Eli Sercarz

    2005-01-01

    Acute primary immune responses tend to focus on few immunodominant determinants using a very limited number of T cell clones for expansion, whereas chronic inflammatory responses generally recruit a large number of different T cell clones to attack a broader range of determinants of the invading pathogens or the inflamed tissues.In T cell-mediated organ-specific autoimmune disease, a transition from the acute to the chronic phase contributes to pathogenesis, and the broadening process is called determinant spreading. The cellular components catalyzing the spreading reaction are not identified. It has been suggested that autoreactive B cells may play a central role in diversifying autoreactive T cell responses, possibly through affecting antigen processing and presentation. The clonal identity and diversity of the B cells and antibodies seem critical in regulating T cell activity and subsequent tissue damage or repair. Here, we use two autoimmune animal models, experimental autoimmune thyroiditis (EAT)and type 1 diabetes (T1D), to discuss how autoreactive B cells or antibodies alter the processing and presentation of autoantigens to regulate specific T cell response.

  8. Small B cell lymphocytic lymphoma presenting as obstructive sleep apnea

    Directory of Open Access Journals (Sweden)

    Chang Weng-Cheng

    2004-07-01

    Full Text Available Abstract Background Most lymphomas that involve the tonsil are large B cell lymphomas. Large B-cell lymphoma is a high grade malignancy which progresses rapidly. Tonsillar lymphoma usually presents as either a unilaterally enlarged palatine tonsil or as an ulcerative and fungating lesion over the tonsillar area. Small lymphocytic lymphomas (SLL of the Waldeyer's ring are uncommon. Case presentation We report a 41-year-old male who presented with a ten-year history of snoring. Physical examination revealed smooth bilateral symmetrically enlarged tonsils without abnormal surface change or cervical lymphadenopathy. Palatal redundancy and a narrowed oropharyngeal airway were also noted. The respiratory disturbance index (RDI was 66 per hour, and severe obstruction sleep apnea (OSA was suspected. No B symptoms, sore throat, odynophagia or dysphagia was found. We performed uvulopalatopharyngoplasty (UPPP and pathological examination revealed incidental small B-cell lymphocytic lymphoma (SLL. Conclusion It is uncommon for lymphoma to initially present as OSA. SLL is an indolent malignancy and is not easy to detect in the early stage. We conclude that SLL may be a contributing factor of OSA in the present case.

  9. B cell remote-handled waste shipment cask alternatives study

    International Nuclear Information System (INIS)

    The decommissioning of the 324 Facility B Cell includes the onsite transport of grouted remote-handled radioactive waste from the 324 Facility to the 200 Areas for disposal. The grouted waste has been transported in the leased ATG Nuclear Services 3-82B Radioactive Waste Shipping Cask (3-82B cask). Because the 3-82B cask is a U.S. Nuclear Regulatory Commission (NRC)-certified Type B shipping cask, the lease cost is high, and the cask operations in the onsite environment may not be optimal. An alternatives study has been performed to develop cost and schedule information on alternative waste transportation systems to assist in determining which system should be used in the future. Five alternatives were identified for evaluation. These included continued lease of the 3-82B cask, fabrication of a new 3-82B cask, development and fabrication of an onsite cask, modification of the existing U.S. Department of Energy-owned cask (OH-142), and the lease of a different commercially available cask. Each alternative was compared to acceptance criteria for use in the B Cell as an initial screening. Only continued leasing of the 3-82B cask, fabrication of a new 3-82B cask, and the development and fabrication of an onsite cask were found to meet all of the B Cell acceptance criteria

  10. The acquisition of cytokine responsiveness by murine B cells

    DEFF Research Database (Denmark)

    Poudrier, J; Owens, T

    1994-01-01

    The mechanism whereby small resting (high buoyant density) murine B cells are induced to express interleukin-2 receptors (IL-2R) and to respond to IL-2 was addressed by staining with anti-IL-2R alpha and -IL-2R beta monoclonal antibodies (mAb), and using receptor-specific cDNA probes. Resting B...... staining and mRNA were induced by the combination of LPS plus IL-5. LPS+IL-5-treated B cells responded to IL-2 by Ig secretion. This indicates that B cells regulate their responsiveness to IL-2 similarly to T cells, via the combined level of expression of IL-2R beta and IL-2R alpha. The synergy between IL...... cells expressed undetectable levels of both IL-2R alpha and beta chains on their surface and did not respond to IL-2, even at supra-physiological concentrations. Sepharose-coupled, but not streptavidin-cross-linked, plastic-adsorbed or soluble, anti-mu up-regulated the expression of IL-2R alpha and beta...

  11. Immunoinformatics and modeling perspective of T cell epitope-based cancer immunotherapy: a holistic picture.

    Science.gov (United States)

    Mishra, Seema; Sinha, Subhata

    2009-12-01

    Cancer immunotherapy is fast gaining global attention with its unique position as a potential therapy showing promise in cancer prevention and cure. It utilizes the natural system of immunity as opposed to chemotherapy and radiotherapy that utilize chemical drugs and radiation, respectively. Cancer immunotherapy essentially involves treatment and/or prevention with vaccines in the form of peptide vaccines (T and B cell epitopes), DNA vaccines and vaccination using whole tumor cells, dendritic cells, viral vectors, antibodies and adoptive transfer of T cells to harness the body's own immune system towards the targeting of cancer cells for destruction. Given the time, cost and labor involved in the vaccine discovery and development, researchers have evinced interest in the novel field of immunoinformatics to cut down the escalation of these critical resources. Immunoinformatics is a relatively new buzzword in the scientific circuit that is showing its potential and delivering on its promise in expediting the development of effective cancer immunotherapeutic agents. This review attempts to present a holistic picture of our race against cancer and time using the science and technology of immunoinformatics and molecular modeling in T cell epitope-based cancer immunotherapy. It also attempts to showcase some problem areas as well as novel ones waiting to be explored where development of novel immunoinformatics tools and simulations in the context of cancer immunotherapy would be highly welcome. PMID:19795913

  12. Entropy-based benchmarking methods

    OpenAIRE

    Temurshoev, Umed

    2012-01-01

    We argue that benchmarking sign-volatile series should be based on the principle of movement and sign preservation, which states that a bench-marked series should reproduce the movement and signs in the original series. We show that the widely used variants of Denton (1971) method and the growth preservation method of Causey and Trager (1981) may violate this principle, while its requirements are explicitly taken into account in the pro-posed entropy-based benchmarking methods. Our illustrati...

  13. Benchmarking in the Semantic Web

    OpenAIRE

    García-Castro, Raúl; Gómez-Pérez, A.

    2009-01-01

    The Semantic Web technology needs to be thoroughly evaluated for providing objective results and obtaining massive improvement in its quality; thus, the transfer of this technology from research to industry will speed up. This chapter presents software benchmarking, a process that aims to improve the Semantic Web technology and to find the best practices. The chapter also describes a specific software benchmarking methodology and shows how this methodology has been used to benchmark the inter...

  14. Selecting benchmarks for reactor calculations

    OpenAIRE

    Alhassan, Erwin; Sjöstrand, Henrik; Duan, Junfeng; Helgesson, Petter; Pomp, Stephan; Österlund, Michael; Rochman, Dimitri; Koning, Arjan J.

    2014-01-01

    Criticality, reactor physics, fusion and shielding benchmarks are expected to play important roles in GENIV design, safety analysis and in the validation of analytical tools used to design these reactors. For existing reactor technology, benchmarks are used to validate computer codes and test nuclear data libraries. However the selection of these benchmarks are usually done by visual inspection which is dependent on the expertise and the experience of the user and there by resulting in a user...

  15. HPC Benchmark Suite NMx Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Intelligent Automation Inc., (IAI) and University of Central Florida (UCF) propose to develop a comprehensive numerical test suite for benchmarking current and...

  16. Epitopes expressed in different adenovirus capsid proteins induce different levels of epitope-specific immunity.

    Science.gov (United States)

    Krause, Anja; Joh, Ju H; Hackett, Neil R; Roelvink, Peter W; Bruder, Joseph T; Wickham, Thomas J; Kovesdi, Imre; Crystal, Ronald G; Worgall, Stefan

    2006-06-01

    On the basis of the concept that the capsid proteins of adenovirus (Ad) gene transfer vectors can be genetically manipulated to enhance the immunogenicity of Ad-based vaccines, the present study compared the antiantigen immunogenicity of Ad vectors with a common epitope of the hemagglutinin (HA) protein of the influenza A virus incorporated into the outer Ad capsid protein hexon, penton base, fiber knob, or protein IX. Incorporation of the same epitope into the different capsid proteins provided insights into the correlation between epitope position and antiepitope immunity. Following immunization of three different strains of mice (C57BL/6, BALB/c, and CBA) with either an equal number of Ad particles (resulting in a different total HA copy number) or different Ad particle numbers (to achieve the same HA copy number), the highest primary (immunoglobulin M [IgM]) and secondary (IgG) anti-HA humoral and cellular CD4 gamma interferon and interleukin-4 responses against HA were always achieved with the Ad vector carrying the HA epitope in fiber knob. These observations suggest that the immune response against an epitope inserted into Ad capsid proteins is not necessarily dependent on the capsid protein number and imply that the choice of incorporation site in Ad capsid proteins in their use as vaccines needs to be compared in vivo. PMID:16699033

  17. Composite diffuse large B-cell lymphoma and follicular B-cell lymphoma - case report and review of literature.

    Science.gov (United States)

    Turbatu, Andrei; Stoian, Marilena; Brezean, Iulian; Stoica, Victor Constantin Ion; Colita, Andrei; Dobrea, Camelia; State, Nicoleta; Ionescu, Cosmin; Ivanescu, Ana-Maria; Oprea, Madalina; Ghimici, Cecilia; Lupu, Anca Roxana

    2014-06-01

    Composite lymphoma refers to the co-occurrence of two or more morphologically and immunophenotypically separate lymphomas in the same topographic site at the time of clinical presentation. It is an infrequent type of lymphoid neoplasm, present in lymphoid tissue and may be due to the existence of two genetically related neoplasms such as transformation of a single lymphoma into another more aggressive lymphoma or be due to the presence of two clonally unrelated lymphomas. This paper is presenting a case of diffuse non-Hodgkin large B-cell lymphoma with areas of low grade and high grade follicular non-Hodgkin B-cell lymphoma in a retroperitoneal lymph node and spleen of an 62 year old woman. Histopathological examination and immunohistochemistry features proved the diagnosis of composite lymphoma. PMID:25705280

  18. Composite Diffuse Large B-Cell Lymphoma and Follicular B-Cell Lymphoma – Case Report and Review of Literature

    Science.gov (United States)

    TURBATU, Andrei; STOIAN, Marilena; BREZEAN, Iulian; STOICA, Victor Constantin Ion; COLITA, Andrei; DOBREA, Camelia; STATE, Nicoleta; IONESCU, Cosmin; IVANESCU, Ana-Maria; OPREA, Madalina; GHIMICI, Cecilia; LUPU, Anca Roxana

    2014-01-01

    Composite lymphoma refers to the co-occurrence of two or more morphologically and immunophenotypically separate lymphomas in the same topographic site at the time of clinical presentation. It is an infrequent type of lymphoid neoplasm, present in lymphoid tissue and may be due to the existence of two genetically related neoplasms such as transformation of a single lymphoma into another more aggressive lymphoma or be due to the presence of two clonally unrelated lymphomas. This paper is presenting a case of diffuse non-Hodgkin large B-cell lymphoma with areas of low grade and high grade follicular non-Hodgkin B-cell lymphoma in a retroperitoneal lymph node and spleen of an 62 year old woman. Histopathological examination and immunohistochemistry features proved the diagnosis of composite lymphoma. PMID:25705280

  19. Deletion modification enhances anthrax specific immunity and protective efficacy of a hepatitis B core particle-based anthrax epitope vaccine.

    Science.gov (United States)

    Yin, Ying; Zhang, Sheng; Cai, Chenguang; Zhang, Jun; Dong, Dayong; Guo, Qiang; Fu, Ling; Xu, Junjie; Chen, Wei

    2014-02-01

    Protective antigen (PA) is one of the major virulence factors of anthrax and is also the major constituent of the current anthrax vaccine. Previously, we found that the 2β2-2β3 loop of PA contains a dominant neutralizing epitope, the SFFD. We successfully inserted the 2β2-2β3 loop of PA into the major immunodominant region (MIR) of hepatitis B virus core (HBc) protein. The resulting fusion protein, termed HBc-N144-PA-loop2 (HBcL2), can effectively produce anthrax specific protective antibodies in an animal model. However, the protective immunity caused by HBcL2 could still be improved. In this research, we removed amino acids 79-81 from the HBc MIR of the HBcL2. This region was previously reported to be the major B cell epitope of HBc, and in keeping with this finding, we observed that the short deletion in the MIR not only diminished the intrinsic immunogenicity of HBc but also stimulated a higher titer of anthrax specific immunity. Most importantly, this deletion led to the full protection of the immunized mice against a lethal dose anthrax toxin challenge. We supposed that the conformational changes which occurred after the short deletion and foreign insertion in the MIR of HBc were the most likely reasons for the improvement in the immunogenicity of the HBc-based anthrax epitope vaccine. PMID:24054942

  20. Proof of principle for epitope-focused vaccine design

    Science.gov (United States)

    Correia, Bruno E.; Bates, John T.; Loomis, Rebecca J.; Baneyx, Gretchen; Carrico, Chris; Jardine, Joseph G.; Rupert, Peter; Correnti, Colin; Kalyuzhniy, Oleksandr; Vittal, Vinayak; Connell, Mary J.; Stevens, Eric; Schroeter, Alexandria; Chen, Man; MacPherson, Skye; Serra, Andreia M.; Adachi, Yumiko; Holmes, Margaret A.; Li, Yuxing; Klevit, Rachel E.; Graham, Barney S.; Wyatt, Richard T.; Baker, David; Strong, Roland K.; Crowe, James E.; Johnson, Philip R.; Schief, William R.

    2014-03-01

    Vaccines prevent infectious disease largely by inducing protective neutralizing antibodies against vulnerable epitopes. Several major pathogens have resisted traditional vaccine development, although vulnerable epitopes targeted by neutralizing antibodies have been identified for several such cases. Hence, new vaccine design methods to induce epitope-specific neutralizing antibodies are needed. Here we show, with a neutralization epitope from respiratory syncytial virus, that computational protein design can generate small, thermally and conformationally stable protein scaffolds that accurately mimic the viral epitope structure and induce potent neutralizing antibodies. These scaffolds represent promising leads for the research and development of a human respiratory syncytial virus vaccine needed to protect infants, young children and the elderly. More generally, the results provide proof of principle for epitope-focused and scaffold-based vaccine design, and encourage the evaluation and further development of these strategies for a variety of other vaccine targets, including antigenically highly variable pathogens such as human immunodeficiency virus and influenza.

  1. Regional Competitive Intelligence: Benchmarking and Policymaking

    OpenAIRE

    Huggins, Robert

    2010-01-01

    Im Bereich der Regionalpolitik erfreuen sich Benchmarking-Untersuchungen wachsender Beliebtheit. In diesem Beitrag werden das Konzept des regionalen Benchmarking sowie seine Verbindungen mit den regionalpolitischen Gestaltungsprozessen analysiert. Ich entwickle eine Typologie der regionalen Benchmarking-Untersuchungen und Benchmarker und unterziehe die Literatur einer kritischen Uumlberpruumlfung. Ich argumentiere, dass die Kritiker des regionalen Benchmarking nicht die Vielfalt und Entwicklu...

  2. Shielding benchmark test

    International Nuclear Information System (INIS)

    Iron data in JENDL-2 have been tested by analyzing shielding benchmark experiments for neutron transmission through iron block performed at KFK using CF-252 neutron source and at ORNL using collimated neutron beam from reactor. The analyses are made by a shielding analysis code system RADHEAT-V4 developed at JAERI. The calculated results are compared with the measured data. As for the KFK experiments, the C/E values are about 1.1. For the ORNL experiments, the calculated values agree with the measured data within an accuracy of 33% for the off-center geometry. The d-t neutron transmission measurements through carbon sphere made at LLNL are also analyzed preliminarily by using the revised JENDL data for fusion neutronics calculation. (author)

  3. Multiple HLA Epitopes Contribute to Type 1 Diabetes Susceptibility

    OpenAIRE

    Roark, Christina L.; Anderson, Kirsten M.; Simon, Lucas J.; Schuyler, Ronald P.; Aubrey, Michael T; Freed, Brian M.

    2013-01-01

    Disease susceptibility for type 1 diabetes is strongly associated with the inheritance of specific HLA alleles. However, conventional allele frequency analysis can miss HLA associations because many alleles are rare. In addition, disparate alleles that have similar peptide-binding sites, or shared epitopes, can be missed. To identify the HLA shared epitopes associated with diabetes, we analyzed high-resolution genotyping for class I and class II loci. The HLA epitopes most strongly associated...

  4. Benchmarking monthly homogenization algorithms

    Directory of Open Access Journals (Sweden)

    V. K. C. Venema

    2011-08-01

    Full Text Available The COST (European Cooperation in Science and Technology Action ES0601: Advances in homogenization methods of climate series: an integrated approach (HOME has executed a blind intercomparison and validation study for monthly homogenization algorithms. Time series of monthly temperature and precipitation were evaluated because of their importance for climate studies and because they represent two important types of statistics (additive and multiplicative. The algorithms were validated against a realistic benchmark dataset. The benchmark contains real inhomogeneous data as well as simulated data with inserted inhomogeneities. Random break-type inhomogeneities were added to the simulated datasets modeled as a Poisson process with normally distributed breakpoint sizes. To approximate real world conditions, breaks were introduced that occur simultaneously in multiple station series within a simulated network of station data. The simulated time series also contained outliers, missing data periods and local station trends. Further, a stochastic nonlinear global (network-wide trend was added.

    Participants provided 25 separate homogenized contributions as part of the blind study as well as 22 additional solutions submitted after the details of the imposed inhomogeneities were revealed. These homogenized datasets were assessed by a number of performance metrics including (i the centered root mean square error relative to the true homogeneous value at various averaging scales, (ii the error in linear trend estimates and (iii traditional contingency skill scores. The metrics were computed both using the individual station series as well as the network average regional series. The performance of the contributions depends significantly on the error metric considered. Contingency scores by themselves are not very informative. Although relative homogenization algorithms typically improve the homogeneity of temperature data, only the best ones improve

  5. SSI and structural benchmarks

    International Nuclear Information System (INIS)

    This paper presents the latest results of the ongoing program entitled, Standard Problems for Structural Computer Codes, currently being worked on at BNL for the USNRC, Office of Nuclear Regulatory Research. During FY 1986, efforts were focussed on three tasks, namely, (1) an investigation of ground water effects on the response of Category I structures, (2) the Soil-Structure Interaction Workshop and (3) studies on structural benchmarks associated with Category I structures. The objective of the studies on ground water effects is to verify the applicability and the limitations of the SSI methods currently used by the industry in performing seismic evaluations of nuclear plants which are located at sites with high water tables. In a previous study by BNL (NUREG/CR-4588), it has been concluded that the pore water can influence significantly the soil-structure interaction process. This result, however, is based on the assumption of fully saturated soil profiles. Consequently, the work was further extended to include cases associated with variable water table depths. In this paper, results related to cut-off depths beyond which the pore water effects can be ignored in seismic calculations, are addressed. Comprehensive numerical data are given for soil configurations typical to those encountered in nuclear plant sites. These data were generated by using a modified version of the SLAM code which is capable of handling problems related to the dynamic response of saturated soils. Further, the paper presents some key aspects of the Soil-Structure Interaction Workshop (NUREG/CP-0054) which was held in Bethesda, MD on June 1, 1986. Finally, recent efforts related to the task on the structural benchmarks are described

  6. Benchmarking foreign electronics technologies

    Energy Technology Data Exchange (ETDEWEB)

    Bostian, C.W.; Hodges, D.A.; Leachman, R.C.; Sheridan, T.B.; Tsang, W.T.; White, R.M.

    1994-12-01

    This report has been drafted in response to a request from the Japanese Technology Evaluation Center`s (JTEC) Panel on Benchmarking Select Technologies. Since April 1991, the Competitive Semiconductor Manufacturing (CSM) Program at the University of California at Berkeley has been engaged in a detailed study of quality, productivity, and competitiveness in semiconductor manufacturing worldwide. The program is a joint activity of the College of Engineering, the Haas School of Business, and the Berkeley Roundtable on the International Economy, under sponsorship of the Alfred P. Sloan Foundation, and with the cooperation of semiconductor producers from Asia, Europe and the United States. Professors David A. Hodges and Robert C. Leachman are the project`s Co-Directors. The present report for JTEC is primarily based on data and analysis drawn from that continuing program. The CSM program is being conducted by faculty, graduate students and research staff from UC Berkeley`s Schools of Engineering and Business, and Department of Economics. Many of the participating firms are represented on the program`s Industry Advisory Board. The Board played an important role in defining the research agenda. A pilot study was conducted in 1991 with the cooperation of three semiconductor plants. The research plan and survey documents were thereby refined. The main phase of the CSM benchmarking study began in mid-1992 and will continue at least through 1997. reports are presented on the manufacture of integrated circuits; data storage; wireless technology; human-machine interfaces; and optoelectronics. Selected papers are indexed separately for inclusion in the Energy Science and Technology Database.

  7. Benchmark experiments for nuclear data

    International Nuclear Information System (INIS)

    Benchmark experiments offer the most direct method for validation of nuclear data. Benchmark experiments for several areas of application of nuclear data were specified by CSEWG. These experiments are surveyed and tests of recent versions of ENDF/B are presented. (U.S.)

  8. Internal Benchmarking for Institutional Effectiveness

    Science.gov (United States)

    Ronco, Sharron L.

    2012-01-01

    Internal benchmarking is an established practice in business and industry for identifying best in-house practices and disseminating the knowledge about those practices to other groups in the organization. Internal benchmarking can be done with structures, processes, outcomes, or even individuals. In colleges or universities with multicampuses or a…

  9. Characterization of xenoantiserum produced against B cell acute lymphoblastic leukemia cell line

    Directory of Open Access Journals (Sweden)

    Akagi,Tadaatsu

    1982-10-01

    Full Text Available Antiserum was produced in white rabbit by intravenously injecting living cells of a B cell acute lymphoblastic leukemia (ALL line (BALL-1. The reactivity of the antiserum against various lymphoid cell lines was examined by membrane immunofluorescence after appropriate absorption. Serum absorbed with non-T, non-B (NALL-1 and T-ALL (TALL-1 cells recognized B cell antigens distinct from Ia-like antigens on both normal and neoplastic B cells. After further absorption with tonsillar cells or normal B cell line (KO-HL-3, it reacted only with BALL-1 cells and did not react with other leukemia/lymphoma and normal B cell lines. The serum absorbed with tonsillar cells reacted only with BALL-1 and some B cell lines. Thus we were able to obtain antisera with specificity to B cell antigen, B-ALL antigen, and B cell line antigen.

  10. Quantum benchmarks for Gaussian states

    CERN Document Server

    Chiribella, Giulio

    2014-01-01

    Teleportation and storage of continuous variable states of light and atoms are essential building blocks for the realization of large scale quantum networks. Rigorous validation of these implementations require identifying, and surpassing, benchmarks set by the most effective strategies attainable without the use of quantum resources. Such benchmarks have been established for special families of input states, like coherent states and particular subclasses of squeezed states. Here we solve the longstanding problem of defining quantum benchmarks for general pure Gaussian states with arbitrary phase, displacement, and squeezing, randomly sampled according to a realistic prior distribution. As a special case, we show that the fidelity benchmark for teleporting squeezed states with totally random phase and squeezing degree is 1/2, equal to the corresponding one for coherent states. We discuss the use of entangled resources to beat the benchmarks in experiments.

  11. B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma: Report of a case in the oral cavity

    Directory of Open Access Journals (Sweden)

    Jumana M Jaradat

    2013-01-01

    Full Text Available B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (DLBCL/BL is a new category of B-cell lymphoma according to the 4 th edition of the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (2008. The following report presents a case of this rare, newly described entity on the palate of a 59 year-old male.

  12. Cyclin Dl expression in B-cell non Hodgkin lymphoma.

    Science.gov (United States)

    Aref, Salah; Mossad, Y; El-Khodary, T; Awad, M; El-Shahat, E

    2006-10-01

    Disorders of the cell cycle regulatory machinery play a key role in the pathogenesis of cancer. Over-expression of cyclin D1 protein has been reported in several solid tumors and certain lymphoid malignancies, but little is known about the effect of its expression on clinical behavior and outcome in B-cell Non-Hodgkin lymphoma (NHL). In this study, we investigated the expression of cyclin Dl in group of patients with NHL and correlated the results with the clinical and laboratory data. The degree of expression of cyclin Dl protein was evaluated by flow cytometry in a group of NHL patients (n = 46) and in normal control group (n = 10). Cyclin Dl over expression was detected in 10 out of 46 (21.7%) patients; they were 5/5-mantle cell lymphoma (MCL) (100%) and 5/28 large B-cell lymphoma (17.8%). All other NHL subtypes showed normal cyclin D1 expression. The clinical signs (hepatomegaly, splenomegaly and B-symptoms, clinical staging) and laboratory data (hemoglobin, white cell count (WBCs), platelet count, and bone marrow infiltration) were not significantly different between NHL subgroup with cyclin Dl over expression and that with normal cyclin Dl expression. Serum lactic dehydrogenase (LDH) levels and lymphadenopathy were significantly higher in NHL group with cyclin D1 over expression as compared to those without. Also, cyclin D1 over expression is associated with poor outcome of NHL patients. Cyclin Dl over expression was evident among all cases of MCL and few cases of large B-cell lymphoma. Cyclin Dl over expression might be used as adjuvant tool for diagnosis of MCL; has role in NHL biology and is bad prognostic index in NHL. PMID:17607588

  13. Identification of Functional Human Splenic Memory B Cells by Expression of CD148 and CD27

    OpenAIRE

    Tangye, Stuart G.; Liu, Yong-Jun; Aversa, Gregorio; Phillips, Joseph H.; Vries, Jan E. de

    1998-01-01

    Memory B cells isolated from human tonsils are characterized by an activated cell surface phenotype, localization to mucosal epithelium, expression of somatically mutated immunoglobulin (Ig) variable (V) region genes, and a preferential differentiation into plasma cells in vitro. In spleens of both humans and rodents, a subset of memory B cells is believed to reside in the marginal zone of the white pulp. Similar to tonsil-derived memory B cells, splenic marginal zone B cells can be distingui...

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

    OpenAIRE

    Traitanon, Opas; Mathew, James M.; La Monica, Giovanna; Xu, Luting; Mas, Valeria; Gallon, Lorenzo

    2015-01-01

    The direct effect of immunosuppressive drugs calcineurin inhibitor (Tacrolimus, TAC) and mTOR inhibitor (Sirolimus, SRL) on B cell activation, differentiation and proliferation is not well documented. Purified human B cells from healthy volunteers were stimulated through the B Cell Receptor with Anti-IgM + anti-CD40 + IL21 in the absence / presence of TAC or SRL. A variety of parameters of B cell activity including activation, differentiation, cytokine productions and proliferation were monit...

  15. Aggressive B-cell lymphomas: how many categories do we need?

    OpenAIRE

    Said, Jonathan W.

    2012-01-01

    Aggressive B-cell lymphomas are diverse group of neoplasms that arise at different stages of B-cell development and by various mechanisms of neoplastic transformation. The aggressive B-cell lymphomas include many types, subtypes and variants of diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), mantle cell lymphoma and its blastoid variant, and B lymphoblastic lymphoma. Differences in histology, cytogenetic and molecular abnormalities, as well as the relationship with the tumor mic...

  16. Targeting Bruton's tyrosine kinase signaling as an emerging therapeutic agent of B-cell malignancies

    OpenAIRE

    Xia, Bing; QU, FULIAN; Yuan, Tian; Zhang, Yizhuo

    2015-01-01

    It is becoming increasingly evident that B-cell receptor (BCR) signaling is central to the development and function of B cells. BCR signaling has emerged as a pivotal pathway and a key driver of numerous B-cell lymphomas. Disruption of BCR signaling can be lethal to malignant B cells. Recently, kinase inhibitors that target BCR signaling have induced notable clinical responses. These inhibitors include spleen tyrosine kinase, mammalian target of rapamycin, phosphoinositide 3′-kinase and Bruto...

  17. Diffuse large B-cell lymphoma of the oral cavity

    International Nuclear Information System (INIS)

    The authors report a case of diffuse large B-cell lymphoma (DLBL) of the oral cavity. The patient was a 73-year-old white man who first presented at the Division of Stomatology with a large nodular mass in the hard palate and a nodular lesion in the upper lip, which were diagnosed as DLBL. The patient was treated with eight cycles of CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone), but the disease recurred 22 months after the end of the therapy. Both primary sites hard palate and upper lip were involved again and the patient was resubmitted to chemotherapy. (author)

  18. Hepatitis C virus - associated B cell non-Hodgkin's lymphoma

    Science.gov (United States)

    Mihăilă, Romeo-Gabriel

    2016-01-01

    The hepatitis C virus (HCV) infected patients are prone to develop bone marrow or various tissue infiltrates with monoclonal B cells, monoclonal B lymphocytosis or different types of B cell non-Hodgkin’s lymphoma (BCNHL), of which the most common are splenic marginal zone BCNHL, diffuse large BCNHL and follicular lymphoma. The association between chronic HCV infection and non Hodgkin’s lymphoma has been observed especially in areas with high prevalence of this viral infection. Outside the limitations of some studies that have been conducted, there are also geographic, environmental, and genetic factors that contribute to the epidemiological differences. Various microenvironmental signals, such as cytokines, viral antigenic external stimulation of lymphocyte receptors by HCV antigens, and intercellular interactions contribute to B cell proliferation. HCV lymphotropism and chronic antigenic stimulation are involved in B-lymphocyte expansion, as mixted cryoglobulinemia or monoclonal gammopathy of undetermined significance, which can progress to BCNHL. HCV replication in B lymphocytes has oncogenic effect mediated by intracellular HCV proteins. It is also involved in an important induction of reactive oxygen species that can lead to permanent B lymphocyte damage, as DNA mutations, after binding to surface B-cell receptors. Post-transplant lymphoproliferative disorder could appear and it has a multiclonal potentiality that may develop into different types of lymphomas. The hematopoietic stem cell transplant made for lymphoma in HCV-infected patients can increase the risk of earlier progression to liver fibrosis and cirrhosis. HCV infected patients with indolent BCNHL who receive antiviral therapy can be potentially cured. Viral clearance was related to lymphoma response, fact that highlights the probable involvement of HCV in lymphomagenesis. Direct acting antiviral drugs could be a solution for the patients who did not tolerate or respond to interferon, as they

  19. Intravenous immunoglobulin replacement therapy in common variable immunodeficiency induces B cell depletion through differentiation into apoptosis-prone CD21(low) B cells.

    Science.gov (United States)

    Mitrevski, Milica; Marrapodi, Ramona; Camponeschi, Alessandro; Lazzeri, Cristina; Todi, Laura; Quinti, Isabella; Fiorilli, Massimo; Visentini, Marcella

    2014-12-01

    Intravenous immunoglobulin (IVIG), besides its use as replacement therapy in patients with antibody deficiencies, is broadly used as an immunomodulatory agent for the treatment of autoimmune and inflammatory disorders. The mechanisms of action of IVIG include Fc receptor blockade, inhibition of cytokines and growth factors, modulation of macrophages and dendritic cells, enhancement of regulatory T cells, and modulation of B cells through the FcγRIIB receptor and CD22. Recent studies suggest that in vitro exposure of human B cells to IVIG determines functional changes reminiscent of anergy and that IVIG treatment of patients with common variable immunodeficiency (CVID) induces in B cells ERK activation, a feature of anergy. Here, we show that IVIG therapy drives the B cells of patients with CVID to down-regulate CD21 expression and to assume the peculiar phenotype of the anergic-like, apoptosis-prone CD21(low) B cells that are spontaneously expanded in a subset of CVID and in some other immunological disorders. The CD21(low) B cells newly generated after IVIG infusion undergo spontaneous apoptosis upon in vitro culture. Furthermore, IVIG infusion is rapidly followed by a significant, although discrete, decrease in the number of circulating B cells, but not of T cells or of natural killer cells. These findings suggest that IVIG therapy may constrain antibody responses by inducing B cell depletion through differentiation into CD21(low) B cells that undergo accelerated apoptosis. PMID:25407649

  20. B cell stimulatory factor 1 (BSF-1) prepares resting B cells to enter S phase in response to anti-IgM and lipopolysaccharide

    OpenAIRE

    1986-01-01

    BSF-1 prepares resting BALB/c, DBA/2, and BDF1 B cells to enter S phase more promptly in response to subsequent culture with anti-IgM-based stimulants. It prepares DBA/2 and BDF1 B cells to respond to LPS, but its preparative effect for LPS responses of BALB/c B cells is both inconstant and meager. Preparation mediated by BSF-1 requires extended contact of B cells with the stimulant for full effect. Half-maximal preparation requires approximately 12 h of contact, as judged by delayed addition...

  1. PAX5 promotes pre-B cell proliferation by regulating the expression of pre-B cell receptor and its downstream signaling.

    Science.gov (United States)

    Xue, Kai; Song, Jiazhe; Yang, Yan; Li, Zhi; Wu, Chunhua; Jin, Jinhua; Li, Wenzhe

    2016-05-01

    PAX5 is indispensable for the commitment of early lymphoid progenitors to the B cell lineage as well as for the development of B cells. Although previous studies have indicated that the Pax5-conditional-knockout mouse exhibited dedifferentiation of mature B cell and the development of aggressive lymphomas, the changes of Pax5 gene expressions in pre-B cells have not been analyzed. To understand the functional importance of Pax5 gene in the proliferation and survival of pre-B cells, we established a Pax5-knockdown model using 70Z/3 pre-B cell line. Pax5 knockdown 70Z/3 cells (70Z/3-KD cells) showed down-regulations of pre-BCR compounds such as CD19, BLNK, Id2 and λ5. The signaling via pre-BCRs was significantly diminished in the 70Z/3-KD cells, and this alteration was normalized by restored Pax5 gene expression. Loss of PAX5 reduced the growth rates in the 70Z/3-KD cells, compared to the mock cells. Meanwhile, the proliferation of pre-B cells was reduced by the knockdown of Pax5 gene. Moreover, further examinations showed that PAX5 was also activated in B cell acute lymphoblastic leukemia (B-ALL) as a cell proliferation enhancer. These findings suggested that pax5 is critically important for the proliferation and survival of pre-B cells. PMID:27016671

  2. A human antibody recognizing a conserved epitope of H5 hemagglutinin broadly neutralizes highly pathogenic avian influenza H5N1 viruses.

    Science.gov (United States)

    Hu, Hongxing; Voss, Jarrod; Zhang, Guoliang; Buchy, Philippi; Zuo, Teng; Wang, Lulan; Wang, Feng; Zhou, Fan; Wang, Guiqing; Tsai, Cheguo; Calder, Lesley; Gamblin, Steve J; Zhang, Linqi; Deubel, Vincent; Zhou, Boping; Skehel, John J; Zhou, Paul

    2012-03-01

    Influenza A virus infection is a persistent threat to public health worldwide due to its ability to evade immune surveillance through rapid genetic drift and shift. Current vaccines against influenza A virus provide immunity to viral isolates that are similar to vaccine strains. High-affinity neutralizing antibodies against conserved epitopes could provide immunity to diverse influenza virus strains and protection against future pandemic viruses. In this study, by using a highly sensitive H5N1 pseudotype-based neutralization assay to screen human monoclonal antibodies produced by memory B cells from an H5N1-infected individual and molecular cloning techniques, we developed three fully human monoclonal antibodies. Among them, antibody 65C6 exhibited potent neutralization activity against all H5 clades and subclades except for subclade 7.2 and prophylactic and therapeutic efficacy against highly pathogenic avian influenza H5N1 viruses in mice. Studies on hemagglutinin (HA)-antibody complexes by electron microscopy and epitope mapping indicate that antibody 65C6 binds to a conformational epitope comprising amino acid residues at positions 118, 121, 161, 164, and 167 (according to mature H5 numbering) on the tip of the membrane-distal globular domain of HA. Thus, we conclude that antibody 65C6 recognizes a neutralization epitope in the globular head of HA that is conserved among almost all divergent H5N1 influenza stains. PMID:22238297

  3. R-ICE and Lenalidomide in Treating Patients With First-Relapse/Primary Refractory Diffuse Large B-Cell Lymphoma

    Science.gov (United States)

    2015-12-30

    Diffuse Large B-Cell Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Transformed Recurrent Non-Hodgkin Lymphoma

  4. Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases

    DEFF Research Database (Denmark)

    Miletic, Ana V; Anzelon-Mills, Amy N; Mills, David M; Omori, Sidne A; Pedersen, Irene M; Shin, Dong-Mi; Ravetch, Jeffrey V; Bolland, Silvia; Morse, Herbert C; Rickert, Robert C

    2010-01-01

    , follicular or centroblastic lymphoma. bPTEN/SHIP(-/-) B cells exhibit enhanced survival and express more MCL1 and less Bim. These cells also express low amounts of p27(kip1) and high amounts of cyclin D3 and thus appear poised to undergo proliferative expansion. Unlike normal B cells, bPTEN/SHIP(-/-) B cells...

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    cells from patients with HT. In GD, B cells primed with TG induced IL-10-producing CD4+ T cells. To assess the maximal frequency of inducible IL-10+ B cells in the three donor groups PBMCs were stimulated with PMA/ionomycin. The resulting IL-10+ B-cell frequency was similar in the three groups and...

  6. B cells exposed to enterobacterial components suppress development of experimental colitis

    DEFF Research Database (Denmark)

    Schmidt, Esben Gjerløff Wedebye; Larsen, Hjalte List; Kristensen, Nanna Ny; Poulsen, Steen Seier; Claesson, Mogens Helweg; Pedersen, Anders Elm

    2012-01-01

    development of colitis. Suppression was dependent on B cell-derived IL-10, as co-transfer of IL-10 knockout ebx-B cells failed to suppress colitis. Ebx-B cell-mediated suppression of colitis was associated with a decrease in interferon gamma (IFN-¿)-producing T(H) 1 cells and increased frequencies of Foxp3...

  7. File list: ALL.Bld.10.AllAg.Pro-B_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Bld.10.AllAg.Pro-B_cells mm9 All antigens Blood Pro-B cells SRX1553109,SRX15531...9,SRX1143902 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/ALL.Bld.10.AllAg.Pro-B_cells.bed ...

  8. Epitope DNA vaccines against tuberculosis: spacers and ubiquitin modulates cellular immune responses elicited by epitope DNA vaccine

    Institute of Scientific and Technical Information of China (English)

    Wang QM; Sun SH; Hu ZL; Zhou FJ; Yin M; Xiao CJ; Zhang JC

    2005-01-01

    Cell-mediated immune responses are crucial in the protection against tuberculosis. In this study, we constructed epitope DNA vaccines (p3-M-38) encoding cytotoxic T lymphocyte (CTL) epitopes of MPT64 and 38 kDa proteins of Mycobacterium tuberculosis. In order to observe the influence of spacer sequence (Ala-Ala-Tyr) or ubiquitin (UbGR) on the efficacy of the two CTL epitopes, we also constructed DNA vaccines, p3-M-S(spacer)-38, p3-Ub (UbGR)-M-S-38 and p3-Ub-M-38. The immune responses elicited by the four DNA vaccines were tested in C57BL/6 (H-2b) mice. The cytotoxicity of T cells was detected by LDH-release method and by enzyme-linked immunospot assay for epitope-specific cells secreting interferon-gamma. The results showed that DNA immunization with p3-M-38 vaccine could induce epitope-specific CD8+ CTL response and that the spacer sequence (AAY) only enhanced M epitope presentation. The protein-targeting sequence (UbGR) enhanced the immunogenicity of the two epitopes. The finding that defined spacer sequences at C-terminus and protein-targeting degradation modulated the immune response of epitope string DNA vaccines will be of importance for the further development of multi-epitope DNA vaccines against tuberculosis.

  9. Modulation of B-cell receptor and microenvironment signaling by a guanine exchange factor in B-cell malignancies

    Institute of Scientific and Technical Information of China (English)

    Wei Liao; Sanjai Sharma

    2016-01-01

    Objective: Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cells over-express a guanine exchange factor (GEF), Rasgrf-1. This GEF increases active Ras as it catalyzes the removal of GDP from Ras so that GTP can bind and activate Ras. This study aims to study the mechanism of action of Rasgrf-1 in B-cell malignancies. Methods: N-terminus truncated Rasgrf-1 variants have a higher GEF activity as compared to the full-length transcript therefore a MCL cell line with stable over-expression of truncated Rasgrf-1 was established. The B-cell receptor (BCR) and chemokine signaling pathways were compared in the Rasgrf-1 over-expressing and a control transfected cell line. Results: Cells over-expressing truncated form of Rasgrf-1 have a higher proliferative rate as compared to control transfected cells. BCR was activated by lower concentrations of anti-IgM antibody in Rasgrf-1 over-expressing cells as compared to control cells indicating that these cells are more sensitive to BCR signaling. BCR signaling also phosphorylates Rasgrf-1 that further increases its GEF function and amplifies BCR signaling. This activation of Rasgrf-1 in over-expressing cells resulted in a higher expression of phospho-ERK, AKT, BTK and PKC-alpha as compared to control cells. Besides BCR, Rasgrf-1 over-expressing cells were also more sensitive to microenvironment stimuli as determined by resistance to apoptosis, chemotaxis and ERK pathway activation. Conclusions: This GEF protein sensitizes B-cells to BCR and chemokine mediated signaling and also upregulates a number of other signaling pathways which promotes growth and survival of these cells.

  10. MicroRNA signatures in B-cell lymphomas

    International Nuclear Information System (INIS)

    Accurate lymphoma diagnosis, prognosis and therapy still require additional markers. We explore the potential relevance of microRNA (miRNA) expression in a large series that included all major B-cell non-Hodgkin lymphoma (NHL) types. The data generated were also used to identify miRNAs differentially expressed in Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) samples. A series of 147 NHL samples and 15 controls were hybridized on a human miRNA one-color platform containing probes for 470 human miRNAs. Each lymphoma type was compared against the entire set of NHLs. BL was also directly compared with DLBCL, and 43 preselected miRNAs were analyzed in a new series of routinely processed samples of 28 BLs and 43 DLBCLs using quantitative reverse transcription-polymerase chain reaction. A signature of 128 miRNAs enabled the characterization of lymphoma neoplasms, reflecting the lymphoma type, cell of origin and/or discrete oncogene alterations. Comparative analysis of BL and DLBCL yielded 19 differentially expressed miRNAs, which were confirmed in a second confirmation series of 71 paraffin-embedded samples. The set of differentially expressed miRNAs found here expands the range of potential diagnostic markers for lymphoma diagnosis, especially when differential diagnosis of BL and DLBCL is required

  11. Anticancer Effect of Curcumin on B Cell non- Hodgkin's Lymphoma

    Institute of Scientific and Technical Information of China (English)

    SUN Chunyan; LIU Xinyue; CHEN Yan; LIU Fang

    2005-01-01

    To explore the anticancer effect of curcumin on human B cell non-Hodgkin's lymphoma and compare its effects on human B cell non-Hodgkin's lymphoma cells and normal peripheral blood mononuclear cells (NPBMNCs). MTT assay was used to study the effect of curcumin on the growth of Raji cells and NPBMNCs. The effect of curcumin on the apoptosis of Raji cells and NPBMNC were studied by flow cytometry and TDT-mediated dUTP nick and labeling (TUNEL). The effect of curcumin on the cell cycle of Raji cells were examined by propidium iodide staining flow cytometry. The results showed that curcumin strongly inhibited ±1.82 μmol/L and curcumin induced Raji cell apoptosis in a time- and dose-dependent manner. Raji cells treated with curcumin showed curcumin did not demonstrate apparent proliferation inhibition and apoptosis induction in NPBMNCs. It was concluded that curcumin is able to inhibit the proliferation of Raji cells by regulating the cell cycle and inducing the cell apoptosis. Morever, curcumin has low toxicity on NPBMNCs but can selectively induce apoptosis in Raji cells.

  12. Dominant neurologic symptomatology in intravascular large B-cell lymphoma.

    Science.gov (United States)

    Kubisova, K; Martanovic, P; Sisovsky, V; Tomleinova, Z; Steno, A; Janega, P; Rychly, B; Babal, P

    2016-01-01

    Intravascular large B-cell lymphoma (IVLBCL) is a rare variant of extranodal large B-cell lymphoma and it is characterized by selective intravascular proliferation of malignant cells. Typical features of the disease include aggressive behavior, rapid and frequently fatal course. Clinical picture is non-specific and heterogeneous, depending on the affected organ. It is not uncommon that this unique type of lymphoma is diagnosed post mortem. Herein, we report two cases of IVLBCL with neurologic symptomatology. In our clinical study patient 1 was an 80-year-old male with mixed paraparesis of lower extremities and difficulties with sphincter control. Patient 2 (56-year-old male) had vision malfunction, mental status changes and defect in phatic and motor functions. In both cases definite diagnosis was established by histological examination of necroptic material. We propose to include IVLBCL in differential diagnostic considerations in patients presenting with gradually impairing neurological status and spinal cord damage of unknown etiology (Fig. 2, Ref. 9). PMID:27546361

  13. Quantifying evolutionary constraints on B-cell affinity maturation.

    Science.gov (United States)

    McCoy, Connor O; Bedford, Trevor; Minin, Vladimir N; Bradley, Philip; Robins, Harlan; Matsen, Frederick A

    2015-09-01

    The antibody repertoire of each individual is continuously updated by the evolutionary process of B-cell receptor (BCR) mutation and selection. It has recently become possible to gain detailed information concerning this process through high-throughput sequencing. Here, we develop modern statistical molecular evolution methods for the analysis of B-cell sequence data, and then apply them to a very deep short-read dataset of BCRs. We find that the substitution process is conserved across individuals but varies significantly across gene segments. We investigate selection on BCRs using a novel method that side-steps the difficulties encountered by previous work in differentiating between selection and motif-driven mutation; this is done through stochastic mapping and empirical Bayes estimators that compare the evolution of in-frame and out-of-frame rearrangements. We use this new method to derive a per-residue map of selection, which provides a more nuanced view of the constraints on framework and variable regions. PMID:26194758

  14. Mast cells, basophils and B cell connection network.

    Science.gov (United States)

    Merluzzi, Sonia; Betto, Elena; Ceccaroni, Alice Amaranta; Magris, Raffaella; Giunta, Marina; Mion, Francesca

    2015-01-01

    It has been proven that both resting and activated mast cells (MCs) and basophils are able to induce a significant increase in proliferation and survival of naïve and activated B cells, and their differentiation into antibody-producing cells. The immunological context in which this regulation occurs is of particular interest and the idea that these innate cells induce antibody class switching and production is increasingly gaining ground. This direct role of MCs and basophils in acquired immunity requires cell to cell contact as well as soluble factors and exosomes. Here, we review our current understanding of the interaction between B cells and MCs or basophils as well as the evidence supporting B lymphocyte-MC/basophil crosstalk in pathological settings. Furthermore, we underline the obscure aspects of this interaction that could serve as important starting points for future research in the field of MC and basophil biology in the peculiar context of the connection between innate and adaptive immunity. PMID:24671125

  15. [Chronic B-cell lymphoproliferative disorders with hairy cells].

    Science.gov (United States)

    Troussard, Xavier; Cornet, Édouard

    2015-01-01

    The standardized blood smear examination is the first step in the diagnosis of a B-cell chronic lymphoproliferative disorder and can guide further investigations. In the laboratory, the identification of hairy cells on blood smear is a matter of daily practice. Hairy cell proliferations represent heterogeneous entities and their respective diagnoses can be difficult. If hairy cell leukemia (HCL) and splenic marginal zone lymphoma (SMZL) represent separate entities, the variant form of HCL (HCLv) and splenic diffuse red pulp small B-cell lymphoma (SDRPL) remain provisional entities in the 2008 WHO classification. We discuss the main clinical and biological characteristics of these four entities and appropriate means to characterize, identify and distinguish from each other; standardized blood smear examination, multiparameter flow cytometry analysis, analysis of the repertoire of immunoglobulins heavy chains genes and their mutational status (mutated or unmutated profile), molecular analyses: BRAF gene V600E mutation in HCL and MAP2K1 gene mutations in HCLv. We also discuss the main therapeutic aspects with emphasis on the new targeted drugs that enter into force in the therapeutic arsenal. PMID:25858127

  16. Selecting benchmarks for reactor calculations

    International Nuclear Information System (INIS)

    Criticality, reactor physics, fusion and shielding benchmarks are expected to play important roles in GENIV design, safety analysis and in the validation of analytical tools used to design these reactors. For existing reactor technology, benchmarks are used to validate computer codes and test nuclear data libraries. However the selection of these benchmarks are usually done by visual inspection which is dependent on the expertise and the experience of the user and thereby resulting in a user bias in the process. In this paper we present a method for the selection of these benchmarks for reactor applications and uncertainty reduction based on Total Monte Carlo (TMC) method. Similarities between an application case and one or several benchmarks are quantified using the correlation coefficient. Based on the method, we also propose two approaches for reducing nuclear data uncertainty using integral benchmark experiments as an additional constrain in the TMC method: a binary accept/reject method and a method of uncertainty reduction using weights. Finally, the methods were applied to a full Lead Fast Reactor core and a set of criticality benchmarks. (author)

  17. Polyclonal B-cell lymphocytosis with binucleated lymphocytes (PPBL

    Directory of Open Access Journals (Sweden)

    Xavier Troussard

    2008-10-01

    Full Text Available Xavier Troussard1, Edouard Cornet1, Jean-François Lesesve2, Carine Kourel3, Hossein Mossafa31Laboratoire d’Hématologie Côte de Nacre, Université Caen Basse Normandie Caen, Registre Régional des Hémopathies Malignes de Basse Normandie, France; 2Laboratoire d’Hématologie, Vandoeuvre-Les-Nancy Cedex, France; 3Département de Génétique Humaine, Laboratoire pasteur-Cerba, Cergy-Pontoise, FranceFor the Groupe Français d’Hématologie cellulaire (GFHCAbstract: Persistent polyclonal B-cell lymphocytosis (PPBL is a rare and recently described entity. The review of the literature show PPBL is diagnosed predominantly but not exclusively in women, usually smokers. PPBL is recognized by a moderate, chronic and absolute lymphocytosis (>4 × 109/l in the peripheral blood. In 10% of cases without lymphocytosis, the PPBL diagnosis has to be suggested by peripheral blood examination showing in all cases atypical binucleated lymphocytes. A polyclonal serum IgM is also associated and HLA-DR7 expression is present in most cases. Contrary to B-cell chronic lymphoproliferative disorders (B-CLPD, peripheral B cells are polyclonal with kappa and lambda light-chain expression and no clonal rearrangement of immunoglobulin heavy chain genes is usually demonstrated. The detection of an extra isochromosome for the long arm of chromosome 3 +i(3(q10 has to be considered as a specific marker of PPBL. We performed conventional cytogenetic analysis (CCA in 111 patients with typical PPBL we followed-up more than 4 years. +i(3q was detected in 34% (33/98, PCC in 8% (8/98 and both abnormalities in 31% (30/98. CCA showed neither +i(3q nor PCC in 28% (27/98. Fluorescence in situ hybridization (FISH was also performed in 84 cases and +i(3q was detected in 71% (60/84. When combining both procedures in 84 patients, +i(3q was detected in 17 patients with negative CCA and was confirmed in 43 patients with positive CCA. CCA and FISH were both negative in 24 cases. Whether

  18. Dominant epitopes and allergic cross-reactivity

    DEFF Research Database (Denmark)

    Mirza, Osman Asghar; Henriksen, A; Ipsen, H; Larsen, J N; Wissenbach, M; Spangfort, M D; Gajhede, M

    2000-01-01

    , that has been solved to 2.9 A resolution by x-ray diffraction. The mAb is shown to inhibit the binding of allergic patients' IgE to Bet v 1, and the allergen-IgG complex may therefore serve as a model for the study of allergen-IgE interactions relevant in allergy. The size of the BV16 epitope is 931 A2...... development of new and safer vaccines for allergen immunotherapy in the form of mutated allergens....

  19. Benchmarking biofuels; Biobrandstoffen benchmarken

    Energy Technology Data Exchange (ETDEWEB)

    Croezen, H.; Kampman, B.; Bergsma, G.

    2012-03-15

    A sustainability benchmark for transport biofuels has been developed and used to evaluate the various biofuels currently on the market. For comparison, electric vehicles, hydrogen vehicles and petrol/diesel vehicles were also included. A range of studies as well as growing insight are making it ever clearer that biomass-based transport fuels may have just as big a carbon footprint as fossil fuels like petrol or diesel, or even bigger. At the request of Greenpeace Netherlands, CE Delft has brought together current understanding on the sustainability of fossil fuels, biofuels and electric vehicles, with particular focus on the performance of the respective energy carriers on three sustainability criteria, with the first weighing the heaviest: (1) Greenhouse gas emissions; (2) Land use; and (3) Nutrient consumption [Dutch] Greenpeace Nederland heeft CE Delft gevraagd een duurzaamheidsmeetlat voor biobrandstoffen voor transport te ontwerpen en hierop de verschillende biobrandstoffen te scoren. Voor een vergelijk zijn ook elektrisch rijden, rijden op waterstof en rijden op benzine of diesel opgenomen. Door onderzoek en voortschrijdend inzicht blijkt steeds vaker dat transportbrandstoffen op basis van biomassa soms net zoveel of zelfs meer broeikasgassen veroorzaken dan fossiele brandstoffen als benzine en diesel. CE Delft heeft voor Greenpeace Nederland op een rijtje gezet wat de huidige inzichten zijn over de duurzaamheid van fossiele brandstoffen, biobrandstoffen en elektrisch rijden. Daarbij is gekeken naar de effecten van de brandstoffen op drie duurzaamheidscriteria, waarbij broeikasgasemissies het zwaarst wegen: (1) Broeikasgasemissies; (2) Landgebruik; en (3) Nutriëntengebruik.

  20. Cleanroom energy benchmarking results

    Energy Technology Data Exchange (ETDEWEB)

    Tschudi, William; Xu, Tengfang

    2001-09-01

    A utility market transformation project studied energy use and identified energy efficiency opportunities in cleanroom HVAC design and operation for fourteen cleanrooms. This paper presents the results of this work and relevant observations. Cleanroom owners and operators know that cleanrooms are energy intensive but have little information to compare their cleanroom's performance over time, or to others. Direct comparison of energy performance by traditional means, such as watts/ft{sup 2}, is not a good indicator with the wide range of industrial processes and cleanliness levels occurring in cleanrooms. In this project, metrics allow direct comparison of the efficiency of HVAC systems and components. Energy and flow measurements were taken to determine actual HVAC system energy efficiency. The results confirm a wide variation in operating efficiency and they identify other non-energy operating problems. Improvement opportunities were identified at each of the benchmarked facilities. Analysis of the best performing systems and components is summarized, as are areas for additional investigation.

  1. Issues in Benchmark Metric Selection

    Science.gov (United States)

    Crolotte, Alain

    It is true that a metric can influence a benchmark but will esoteric metrics create more problems than they will solve? We answer this question affirmatively by examining the case of the TPC-D metric which used the much debated geometric mean for the single-stream test. We will show how a simple choice influenced the benchmark and its conduct and, to some extent, DBMS development. After examining other alternatives our conclusion is that the “real” measure for a decision-support benchmark is the arithmetic mean.

  2. Benchmarking & European Sustainable Transport Policies

    DEFF Research Database (Denmark)

    Gudmundsson, H.

    2003-01-01

    support Sustainable European Transport Policies. The key message is that transport benchmarking has not yet been developed to cope with the challenges of this task. Rather than backing down completely, the paper suggests some critical conditions for applying and adopting benchmarking for this purpose. One...... way forward is to ensure a higher level of environmental integration in transport policy benchmarking. To this effect the paper will discuss the possible role of the socalled Transport and Environment Reporting Mechanism developed by the European Environment Agency. The paper provides an independent...

  3. Benchmark simulation models, quo vadis?

    DEFF Research Database (Denmark)

    Jeppsson, U.; Alex, J; Batstone, D. J.;

    2013-01-01

    As the work of the IWA Task Group on Benchmarking of Control Strategies for wastewater treatment plants (WWTPs) is coming to an end, it is essential to disseminate the knowledge gained. For this reason, all authors of the IWA Scientific and Technical Report on benchmarking have come together to...... and spatial extension, process modifications within the WWTP, the realism of models, control strategy extensions and the potential for new evaluation tools within the existing benchmark system. We find that there are major opportunities for application within all of these areas, either from existing...

  4. California commercial building energy benchmarking

    Energy Technology Data Exchange (ETDEWEB)

    Kinney, Satkartar; Piette, Mary Ann

    2003-07-01

    Building energy benchmarking is the comparison of whole-building energy use relative to a set of similar buildings. It provides a useful starting point for individual energy audits and for targeting buildings for energy-saving measures in multiple-site audits. Benchmarking is of interest and practical use to a number of groups. Energy service companies and performance contractors communicate energy savings potential with ''typical'' and ''best-practice'' benchmarks while control companies and utilities can provide direct tracking of energy use and combine data from multiple buildings. Benchmarking is also useful in the design stage of a new building or retrofit to determine if a design is relatively efficient. Energy managers and building owners have an ongoing interest in comparing energy performance to others. Large corporations, schools, and government agencies with numerous facilities also use benchmarking methods to compare their buildings to each other. The primary goal of Task 2.1.1 Web-based Benchmarking was the development of a web-based benchmarking tool, dubbed Cal-Arch, for benchmarking energy use in California commercial buildings. While there were several other benchmarking tools available to California consumers prior to the development of Cal-Arch, there were none that were based solely on California data. Most available benchmarking information, including the Energy Star performance rating, were developed using DOE's Commercial Building Energy Consumption Survey (CBECS), which does not provide state-level data. Each database and tool has advantages as well as limitations, such as the number of buildings and the coverage by type, climate regions and end uses. There is considerable commercial interest in benchmarking because it provides an inexpensive method of screening buildings for tune-ups and retrofits. However, private companies who collect and manage consumption data are concerned that the

  5. A Global Vision over Benchmarking Process: Benchmarking Based Enterprises

    OpenAIRE

    Catalina SITNIKOV; Giurca Vasilescu, Laura

    2008-01-01

    Benchmarking uses the knowledge and the experience of others to improve the enterprise. Starting from the analysis of the performance and underlying the strengths and weaknesses of the enterprise it should be assessed what must be done in order to improve its activity. Using benchmarking techniques, an enterprise looks at how processes in the value chain are performed. The approach based on the vision “from the whole towards the parts” (a fragmented image of the enterprise’s value chain) redu...

  6. High epitope expression levels increase competition between T cells.

    Directory of Open Access Journals (Sweden)

    Almut Scherer

    2006-08-01

    Full Text Available Both theoretical predictions and experimental findings suggest that T cell populations can compete with each other. There is some debate on whether T cells compete for aspecific stimuli, such as access to the surface on antigen-presenting cells (APCs or for specific stimuli, such as their cognate epitope ligand. We have developed an individual-based computer simulation model to study T cell competition. Our model shows that the expression level of foreign epitopes per APC determines whether T cell competition is mainly for specific or aspecific stimuli. Under low epitope expression, competition is mainly for the specific epitope stimuli, and, hence, different epitope-specific T cell populations coexist readily. However, if epitope expression levels are high, aspecific competition becomes more important. Such between-specificity competition can lead to competitive exclusion between different epitope-specific T cell populations. Our model allows us to delineate the circumstances that facilitate coexistence of T cells of different epitope specificity. Understanding mechanisms of T cell coexistence has important practical implications for immune therapies that require a broad immune response.

  7. Immune epitope database analysis resource (IEDB-AR)

    DEFF Research Database (Denmark)

    Zhang, Qing; Wang, Peng; Kim, Yohan;

    2008-01-01

    We present a new release of the immune epitope database analysis resource (IEDB-AR, http://tools.immuneepitope.org), a repository of web-based tools for the prediction and analysis of immune epitopes. New functionalities have been added to most of the previously implemented tools, and a total of...

  8. Invariant chain induces B cell maturation in a process that is independent of its chaperonic activity

    Science.gov (United States)

    Matza, Didi; Lantner, Frida; Bogoch, Yoel; Flaishon, Liat; Hershkoviz, Rami; Shachar, Idit

    2002-01-01

    Early stages of B cell development take place in the bone marrow, resulting in formation of immature B cells, which migrate to the spleen for their final differentiation into mature cells. This final maturation step is essential for B cells to become responsive to antigens and to participate in the immune response. Previously, we showed that the MHC class II chaperone, invariant chain (Ii), controls the differentiation of B cells from the immature to the mature stage. In this study, by generating transgenic mice expressing truncated Ii lacking its luminal domain, we could dissect the chaperonin activity of Ii from its role in B cell maturation. We demonstrate in vivo that Ii N-terminal domain is directly involved in the maturation of B cells and is sufficient to promote B cell differentiation. PMID:11867743

  9. CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production

    Science.gov (United States)

    Khairnar, Vishal; Duhan, Vikas; Maney, Sathish Kumar; Honke, Nadine; Shaabani, Namir; Pandyra, Aleksandra A.; Seifert, Marc; Pozdeev, Vitaly; Xu, Haifeng C.; Sharma, Piyush; Baldin, Fabian; Marquardsen, Florian; Merches, Katja; Lang, Elisabeth; Kirschning, Carsten; Westendorf, Astrid M.; Häussinger, Dieter; Lang, Florian; Dittmer, Ulf; Küppers, Ralf; Recher, Mike; Hardt, Cornelia; Scheffrahn, Inka; Beauchemin, Nicole; Göthert, Joachim R.; Singer, Bernhard B.; Lang, Philipp A.; Lang, Karl S.

    2015-01-01

    B cells are essential for antiviral immune defence because they produce neutralizing antibodies, present antigen and maintain the lymphoid architecture. Here we show that intrinsic signalling of CEACAM1 is essential for generating efficient B-cell responses. Although CEACAM1 exerts limited influence on the proliferation of B cells, expression of CEACAM1 induces survival of proliferating B cells via the BTK/Syk/NF-κB-axis. The absence of this signalling cascade in naive Ceacam1−/− mice limits the survival of B cells. During systemic infection with cytopathic vesicular stomatitis virus, Ceacam1−/− mice can barely induce neutralizing antibody responses and die early after infection. We find, therefore, that CEACAM1 is a crucial regulator of B-cell survival, influencing B-cell numbers and protective antiviral antibody responses. PMID:25692415

  10. CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production.

    Science.gov (United States)

    Khairnar, Vishal; Duhan, Vikas; Maney, Sathish Kumar; Honke, Nadine; Shaabani, Namir; Pandyra, Aleksandra A; Seifert, Marc; Pozdeev, Vitaly; Xu, Haifeng C; Sharma, Piyush; Baldin, Fabian; Marquardsen, Florian; Merches, Katja; Lang, Elisabeth; Kirschning, Carsten; Westendorf, Astrid M; Häussinger, Dieter; Lang, Florian; Dittmer, Ulf; Küppers, Ralf; Recher, Mike; Hardt, Cornelia; Scheffrahn, Inka; Beauchemin, Nicole; Göthert, Joachim R; Singer, Bernhard B; Lang, Philipp A; Lang, Karl S

    2015-01-01

    B cells are essential for antiviral immune defence because they produce neutralizing antibodies, present antigen and maintain the lymphoid architecture. Here we show that intrinsic signalling of CEACAM1 is essential for generating efficient B-cell responses. Although CEACAM1 exerts limited influence on the proliferation of B cells, expression of CEACAM1 induces survival of proliferating B cells via the BTK/Syk/NF-κB-axis. The absence of this signalling cascade in naive Ceacam1(-/-) mice limits the survival of B cells. During systemic infection with cytopathic vesicular stomatitis virus, Ceacam1(-/-) mice can barely induce neutralizing antibody responses and die early after infection. We find, therefore, that CEACAM1 is a crucial regulator of B-cell survival, influencing B-cell numbers and protective antiviral antibody responses. PMID:25692415

  11. Cutting Edge: Redox Signaling Hypersensitivity Distinguishes Human Germinal Center B Cells.

    Science.gov (United States)

    Polikowsky, Hannah G; Wogsland, Cara E; Diggins, Kirsten E; Huse, Kanutte; Irish, Jonathan M

    2015-08-15

    Differences in the quality of BCR signaling control key steps of B cell maturation and differentiation. Endogenously produced H2O2 is thought to fine tune the level of BCR signaling by reversibly inhibiting phosphatases. However, relatively little is known about how B cells at different stages sense and respond to such redox cues. In this study, we used phospho-specific flow cytometry and high-dimensional mass cytometry (CyTOF) to compare BCR signaling responses in mature human tonsillar B cells undergoing germinal center (GC) reactions. GC B cells, in contrast to mature naive B cells, memory B cells, and plasmablasts, were hypersensitive to a range of H2O2 concentrations and responded by phosphorylating SYK and other membrane-proximal BCR effectors in the absence of BCR engagement. These findings reveal that stage-specific redox responses distinguish human GC B cells. PMID:26157177

  12. B-cell exposure to self-antigen induces IL-10 producing B cells as well as IL-6- and TNF-α-producing B-cell subsets in healthy humans

    DEFF Research Database (Denmark)

    Langkjær, Anina; Kristensen, Birte; Hansen, Bjarke E;

    2012-01-01

    Human B cells are able to secrete IL-10 after stimulation with mitogens, but their ability to produce IL-10 and regulate T-cell responses after stimulation with self-antigens is unclear. We co-cultured thyroglobulin-pulsed B cells from healthy donors with autologous T cells and observed production...... of IL-10 and TGF-β, in addition to TNF-α and IL-6. Pulsing with foreign antigen, tetanus toxoid (TT), induced a Th1-response with minimal IL-10 production. After thyroglobulin-pulsing, 1.10±0.50% of B cells and 1.00±0.20% of CD4(+) T cells produced IL-10, compared to 0.29±0.19% of B cells (P=0.......01) and 0.13±0.15% of CD4(+) T cells (P=0.006) following TT-pulsing. Thyroglobulin-stimulated, IL-10-secreting B cells were enriched within CD5(+) and CD24(high) cells. While thyroglobulin-pulsed B cells induced only modest proliferation of CD4(+) T cells, B cells pulsed with TT induced vigorous...

  13. Fully human broadly neutralizing monoclonal antibodies against influenza A viruses generated from the memory B cells of a 2009 pandemic H1N1 influenza vaccine recipient

    International Nuclear Information System (INIS)

    Whether the 2009 pandemic H1N1 influenza vaccine can induce heterosubtypic cross-protective anti-hemagglutinin (HA) neutralizing antibodies is an important issue. We obtained a panel of fully human monoclonal antibodies from the memory B cells of a 2009 pandemic H1N1 influenza vaccine recipient. Most of the monoclonal antibodies targeted the HA protein but not the HA1 fragment. Among the analyzed antibodies, seven mAbs exhibited neutralizing activity against several influenza A viruses of different subtypes. The conserved linear epitope targeted by the neutralizing mAbs (FIEGGWTGMVDGWYGYHH) is part of the fusion peptide on HA2. Our work suggests that a heterosubtypic neutralizing antibody response primarily targeting the HA stem region exists in recipients of the 2009 pandemic H1N1 influenza vaccine. The HA stem region contains various conserved neutralizing epitopes with the fusion peptide as an important one. This work may aid in the design of a universal influenza A virus vaccine.

  14. Matrix metalloproteinase-10 is a target of T and B cell responses that correlate with synovial pathology in patients with antibiotic-refractory Lyme arthritis.

    Science.gov (United States)

    Crowley, Jameson T; Strle, Klemen; Drouin, Elise E; Pianta, Annalisa; Arvikar, Sheila L; Wang, Qi; Costello, Catherine E; Steere, Allen C

    2016-05-01

    Infection-induced autoimmunity is thought to be a contributing factor in antibiotic-refractory Lyme arthritis, but studies of autoimmunity have been hindered by difficulty in identifying relevant autoantigens. We developed a novel approach that begins with the identification of T cell epitopes in synovial tissue using tandem mass spectrometry. Herein, we identified an immunogenic HLA-DR-presented peptide (T cell epitope) derived from the source protein matrix metalloproteinase-10 (MMP-10) from the synovium of a patient with antibiotic-refractory arthritis. This finding provided a bridge for the identification of autoantibody responses to MMP-10, the "first autoimmune hit" in a subgroup of patients with erythema migrans, the initial skin lesion of the infection. Months later, after priming of the immune response to MMP-10 in early infection, a subset of patients with antibiotic-responsive or antibiotic-refractory arthritis had MMP-10 autoantibodies, but only patients with antibiotic-refractory arthritis had both T and B cell responses to the protein, providing evidence for a "second autoimmune hit". Further support for a biologically relevant autoimmune event was observed by the positive correlation of anti-MMP-10 autoantibodies with distinct synovial pathology. This experience demonstrates the power of new, discovery-based methods to identify relevant autoimmune responses in chronic inflammatory forms of arthritis. PMID:26922382

  15. Fully human broadly neutralizing monoclonal antibodies against influenza A viruses generated from the memory B cells of a 2009 pandemic H1N1 influenza vaccine recipient

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Weibin [Molecular Virus Unit, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025 (China); Chen, Aizhong [Key Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031 (China); Miao, Yi [Shanghai Xuhui Central Hospital, Shanghai 200031 (China); Xia, Shengli [Center for Disease Control and Prevention of Henan Province, Zhengzhou 450016 (China); Ling, Zhiyang; Xu, Ke; Wang, Tongyan [Molecular Virus Unit, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025 (China); Xu, Ying; Cui, Jun; Wu, Hongqiang; Hu, Guiyu; Tian, Lin; Wang, Lingling [Key Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031 (China); Shu, Yuelong [Chinese Center for Disease Control and Prevention, Beijing 102206 (China); Ma, Xiaowei [Hualan Biological Bacterin Company, Xinxiang 453003 (China); Xu, Bianli; Zhang, Jin [Center for Disease Control and Prevention of Henan Province, Zhengzhou 450016 (China); Lin, Xiaojun, E-mail: linxiaojun@hualan.com [Hualan Biological Bacterin Company, Xinxiang 453003 (China); Bian, Chao, E-mail: cbian@sibs.ac.cn [Key Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031 (China); Sun, Bing, E-mail: bsun@sibs.ac.cn [Molecular Virus Unit, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025 (China); Key Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031 (China)

    2013-01-20

    Whether the 2009 pandemic H1N1 influenza vaccine can induce heterosubtypic cross-protective anti-hemagglutinin (HA) neutralizing antibodies is an important issue. We obtained a panel of fully human monoclonal antibodies from the memory B cells of a 2009 pandemic H1N1 influenza vaccine recipient. Most of the monoclonal antibodies targeted the HA protein but not the HA1 fragment. Among the analyzed antibodies, seven mAbs exhibited neutralizing activity against several influenza A viruses of different subtypes. The conserved linear epitope targeted by the neutralizing mAbs (FIEGGWTGMVDGWYGYHH) is part of the fusion peptide on HA2. Our work suggests that a heterosubtypic neutralizing antibody response primarily targeting the HA stem region exists in recipients of the 2009 pandemic H1N1 influenza vaccine. The HA stem region contains various conserved neutralizing epitopes with the fusion peptide as an important one. This work may aid in the design of a universal influenza A virus vaccine.

  16. Intravascular Large B-Cell Lymphoma: A Difficult Diagnostic Challenge.

    Science.gov (United States)

    Khan, Maria S; McCubbin, Mark; Nand, Sucha

    2014-01-01

    Case Presentation. A 69-year-old Hispanic male, with a past history of diabetes and coronary disease, was admitted for fever, diarrhea, and confusion of 4 weeks duration. Physical examination showed a disoriented patient with multiple ecchymoses, possible ascites, and bilateral scrotal swelling. Hemoglobin was 6.7, prothrombin time (PT) 21.4 seconds with international normalized ratio 2.1, partial thromboplastin time (PTT) 55.6 seconds, fibrin split 10 µg/L, and lactate dehydrogenase (LDH) 1231 IU/L. Except for a positive DNA test for Epstein-Barr virus (EBV) infection, extensive diagnostic workup for infections, malignancy, or a neurological cause was negative. Mixing studies revealed a nonspecific inhibitor of PT and PTT but Factor VIII levels were normal. The patient was empirically treated with antibiotics but developed hypotension and died on day 27 of admission. At autopsy, patient was found to have intravascular diffuse large B-cell lymphoma involving skin, testes, lung, and muscles. The malignant cells were positive for CD20, CD791, Mum-1, and Pax-5 and negative for CD3, CD5, CD10, CD30, and Bcl-6. The malignant cells were 100% positive for Ki-67. Discussion. Intravascular large cell B-cell lymphoma (IVLBCL) is rare form of diffuse large B-cell lymphoma and tends to proliferate within small blood vessels, particularly capillaries and postcapillary venules. The cause of its affinity for vascular bed remains unknown. In many reports, IVLBCL was associated with HIV, HHV8, and EBV infections. The fact that our case showed evidence of EBV infection lends support to the association of this diagnosis to viral illness. The available literature on this subject is scant, and in many cases, the diagnosis was made only at autopsy. The typical presentation of this disorder is with B symptoms, progressive neurologic deficits, and skin findings. Bone marrow, spleen, and liver are involved in a minority of patients. Nearly all patients have elevated LDH, and about 65% are

  17. Analysis of cytotoxic T cell epitopes in relation to cancer

    DEFF Research Database (Denmark)

    Stranzl, Thomas

    kill the infected cells. The focus of my PhD project has been on improving a method for CTL epitope pathway prediction, on analyzing the epitope density in the alternative cancer exome, and on a study investigating minor histocompatibility antigens (mHags) associated with leukemia. Part I......CTL methods, the experimental effort to identify 90% of new epitopes can be reduced by 15% and 40%, respectively. Part III reports the results of an analysis investigating how the alternatively spliced cancer exome differs from the exome of normal tissue in terms of containing predicted MHC class I binding...... epitopes. We show that peptides unique to cancer splice variants comprise significantly fewer predicted HLA class I epitopes than peptides unique to spliced transcripts in normal tissue. We furthermore find that hydrophilic amino acids are significantly enriched in the unique carcinoma sequences, which...

  18. Identification of a B cell-dependent subpopulation of multiple sclerosis by measurements of brain-reactive B cells in the blood.

    Science.gov (United States)

    Kuerten, Stefanie; Pommerschein, Giovanna; Barth, Stefanie K; Hohmann, Christopher; Milles, Bianca; Sammer, Fabian W; Duffy, Cathrina E; Wunsch, Marie; Rovituso, Damiano M; Schroeter, Michael; Addicks, Klaus; Kaiser, Claudia C; Lehmann, Paul V

    2014-01-01

    B cells are increasingly coming into play in the pathogenesis of multiple sclerosis (MS). Here, we screened peripheral blood mononuclear cells (PBMC) from patients with clinically isolated syndrome (CIS), MS, other non-inflammatory neurological, inflammatory neurological or autoimmune diseases, and healthy donors for their B cell reactivity to CNS antigen using the enzyme-linked immunospot technique (ELISPOT) after 96 h of polyclonal stimulation. Our data show that nine of 15 patients with CIS (60.0%) and 53 of 67 patients with definite MS (79.1%) displayed CNS-reactive B cells, compared to none of the control donors. The presence of CNS-reactive B cells in the blood of the majority of patients with MS or at risk to develop MS along with their absence in control subjects suggests that they might be indicative of a B cell-dependent subpopulation of the disease. PMID:24607792

  19. Autoantibody recognition mechanisms of p53 epitopes

    Science.gov (United States)

    Phillips, J. C.

    2016-06-01

    There is an urgent need for economical blood based, noninvasive molecular biomarkers to assist in the detection and diagnosis of cancers in a cost-effective manner at an early stage, when curative interventions are still possible. Serum autoantibodies are attractive biomarkers for early cancer detection, but their development has been hindered by the punctuated genetic nature of the ten million known cancer mutations. A landmark study of 50,000 patients (Pedersen et al., 2013) showed that a few p53 15-mer epitopes are much more sensitive colon cancer biomarkers than p53, which in turn is a more sensitive cancer biomarker than any other protein. The function of p53 as a nearly universal "tumor suppressor" is well established, because of its strong immunogenicity in terms of not only antibody recruitment, but also stimulation of autoantibodies. Here we examine dimensionally compressed bioinformatic fractal scaling analysis for identifying the few sensitive epitopes from the p53 amino acid sequence, and show how it could be used for early cancer detection (ECD). We trim 15-mers to 7-mers, and identify specific 7-mers from other species that could be more sensitive to aggressive human cancers, such as liver cancer. Our results could provide a roadmap for ECD.

  20. Performance Targets and External Benchmarking

    DEFF Research Database (Denmark)

    Friis, Ivar; Hansen, Allan; Vámosi, Tamás S.

    Research on relative performance measures, transfer pricing, beyond budgeting initiatives, target costing, piece rates systems and value based management has for decades underlined the importance of external benchmarking in performance management. Research conceptualises external benchmarking as a...... market mechanism that can be brought inside the firm to provide incentives for continuous improvement and the development of competitive advances. However, whereas extant research primarily has focused on the importance and effects of using external benchmarks, less attention has been directed towards...... the conditions upon which the market mechanism is performing within organizations. This paper aims to contribute to research by providing more insight to the conditions for the use of external benchmarking as an element in performance management in organizations. Our study explores a particular type...

  1. Benchmarking and Sustainable Transport Policy

    DEFF Research Database (Denmark)

    Gudmundsson, Henrik; Wyatt, Andrew; Gordon, Lucy

    2004-01-01

    Order to learn from the best. In 2000 the European Commission initiated research to explore benchmarking as a tool to promote policies for ‘sustainable transport’. This paper reports findings and recommendations on how to address this challenge. The findings suggest that benchmarking is a valuable...... tool that may indeed help to move forward the transport policy agenda. However, there are major conditions and limitations. First of all it is not always so straightforward to delimit, measure and compare transport services in order to establish a clear benchmark. Secondly ‘sustainable transport......’ evokes a broad range of concerns that are hard to address fully at the level of specific practices. Thirdly policies are not directly comparable across space and context. For these reasons attempting to benchmark ‘sustainable transport policies’ against one another would be a highly complex task, which...

  2. Benchmarking Developing Asia's Manufacturing Sector

    OpenAIRE

    Felipe, Jesus; Gemma ESTRADA

    2007-01-01

    This paper documents the transformation of developing Asia's manufacturing sector during the last three decades and benchmarks its share in GDP with respect to the international regression line by estimating a logistic regression.

  3. Water Level Superseded Benchmark Sheets

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Images of National Coast & Geodetic Survey (now NOAA's National Geodetic Survey/NGS) tidal benchmarks which have been superseded by new markers or locations....

  4. Benchmarking hypercube hardware and software

    Science.gov (United States)

    Grunwald, Dirk C.; Reed, Daniel A.

    1986-01-01

    It was long a truism in computer systems design that balanced systems achieve the best performance. Message passing parallel processors are no different. To quantify the balance of a hypercube design, an experimental methodology was developed and the associated suite of benchmarks was applied to several existing hypercubes. The benchmark suite includes tests of both processor speed in the absence of internode communication and message transmission speed as a function of communication patterns.

  5. Strategic Behaviour under Regulation Benchmarking

    OpenAIRE

    Jamasb, Tooraj; Nillesen, Paul; Michael G. Pollitt

    2003-01-01

    Liberalisation of generation and supply activities in the electricity sectors is often followed by regulatory reform of distribution networks. In order to improve the efficiency of distribution utilities, some regulators have adopted incentive regulation schemes that rely on performance benchmarking. Although regulation benchmarking can influence the ?regulation game?, the subject has received limited attention. This paper discusses how strategic behaviour can result in inefficient behav...

  6. Diffuse Large B Cell Lymphoma of the Breast

    Directory of Open Access Journals (Sweden)

    Feryal Karaca

    2015-03-01

    Full Text Available Primary breast lymphoma is rarely encountered in Non-Hodgkin Lymphomas. However, if early diagnosis is made, and treatment is started immediately in patients with low grade and stage, patient survival is increased. 39-year old female patient applied us due to a palpable mass. She was diagnosed with the Non-Hodgkin Lymphoma Diffuse Large B Cell Lymphoma after the investigations. Curative external radiotherapy was applied after 6 courses of CHOP-R chemotherapy to the patient with Stage-IIE favorable, and B symptoms. After 48-month follow up, patient follow up is being continued without any progression, or recurrence or metastasis. [Cukurova Med J 2015; 40(1.000: 151-157

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

    Directory of Open Access Journals (Sweden)

    S. Marinaki

    2013-12-01

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

  8. Research on computer systems benchmarking

    Science.gov (United States)

    Smith, Alan Jay (Principal Investigator)

    1996-01-01

    This grant addresses the topic of research on computer systems benchmarking and is more generally concerned with performance issues in computer systems. This report reviews work in those areas during the period of NASA support under this grant. The bulk of the work performed concerned benchmarking and analysis of CPUs, compilers, caches, and benchmark programs. The first part of this work concerned the issue of benchmark performance prediction. A new approach to benchmarking and machine characterization was reported, using a machine characterizer that measures the performance of a given system in terms of a Fortran abstract machine. Another report focused on analyzing compiler performance. The performance impact of optimization in the context of our methodology for CPU performance characterization was based on the abstract machine model. Benchmark programs are analyzed in another paper. A machine-independent model of program execution was developed to characterize both machine performance and program execution. By merging these machine and program characterizations, execution time can be estimated for arbitrary machine/program combinations. The work was continued into the domain of parallel and vector machines, including the issue of caches in vector processors and multiprocessors. All of the afore-mentioned accomplishments are more specifically summarized in this report, as well as those smaller in magnitude supported by this grant.

  9. EpitopeViewer: a Java application for the visualization and analysis of immune epitopes in the Immune Epitope Database and Analysis Resource (IEDB)

    OpenAIRE

    Beaver, John E.; Bourne, Philip E.; Ponomarenko, Julia V.

    2007-01-01

    Background Structural information about epitopes, particularly the three-dimensional (3D) structures of antigens in complex with immune receptors, presents a valuable source of data for immunology. This information is available in the Protein Data Bank (PDB) and provided in curated form by the Immune Epitope Database and Analysis Resource (IEDB). With continued growth in these data and the importance in understanding molecular level interactions of immunological interest there is a need for n...

  10. Implementation of Benchmarking Transportation Logistics Practices and Future Benchmarking Organizations

    International Nuclear Information System (INIS)

    The purpose of the Office of Civilian Radioactive Waste Management's (OCRWM) Logistics Benchmarking Project is to identify established government and industry practices for the safe transportation of hazardous materials which can serve as a yardstick for design and operation of OCRWM's national transportation system for shipping spent nuclear fuel and high-level radioactive waste to the proposed repository at Yucca Mountain, Nevada. The project will present logistics and transportation practices and develop implementation recommendations for adaptation by the national transportation system. This paper will describe the process used to perform the initial benchmarking study, highlight interim findings, and explain how these findings are being implemented. It will also provide an overview of the next phase of benchmarking studies. The benchmarking effort will remain a high-priority activity throughout the planning and operational phases of the transportation system. The initial phase of the project focused on government transportation programs to identify those practices which are most clearly applicable to OCRWM. These Federal programs have decades of safe transportation experience, strive for excellence in operations, and implement effective stakeholder involvement, all of which parallel OCRWM's transportation mission and vision. The initial benchmarking project focused on four business processes that are critical to OCRWM's mission success, and can be incorporated into OCRWM planning and preparation in the near term. The processes examined were: transportation business model, contract management/out-sourcing, stakeholder relations, and contingency planning. More recently, OCRWM examined logistics operations of AREVA NC's Business Unit Logistics in France. The next phase of benchmarking will focus on integrated domestic and international commercial radioactive logistic operations. The prospective companies represent large scale shippers and have vast experience in

  11. The Functional Response of B Cells to Antigenic Stimulation: A Preliminary Report of Latent Tuberculosis

    Science.gov (United States)

    du Plessis, Willem J.; Kleynhans, Léanie; du Plessis, Nelita; Stanley, Kim; Malherbe, Stephanus T.; Maasdorp, Elizna; Ronacher, Katharina; Chegou, Novel N.; Walzl, Gerhard; Loxton, Andre G.

    2016-01-01

    Mycobacterium tuberculosis (M.tb) remains a successful pathogen, causing tuberculosis disease numbers to constantly increase. Although great progress has been made in delineating the disease, the host-pathogen interaction is incompletely described. B cells have shown to function as both effectors and regulators of immunity via non-humoral methods in both innate and adaptive immune settings. Here we assessed specific B cell functional interaction following stimulation with a broad range of antigens within the LTBI milieu. Our results indicate that B cells readily produce pro- and anti-inflammatory cytokines (including IL-1β, IL-10, IL-17, IL-21 and TNF-α) in response to stimulation. TLR4 and TLR9 based stimulations achieved the greatest secreted cytokine-production response and BCG stimulation displayed a clear preference for inducing IL-1β production. We also show that the cytokines produced by B cells are implicated strongly in cell-mediated communication and that plasma (memory) B cells (CD19+CD27+CD138+) is the subset with the greatest contribution to cytokine production. Collectively our data provides insight into B cell responses, where they are implicated in and quantifies responses from specific B cell phenotypes. These findings warrant further functional B cell research with a focus on specific B cell phenotypes under conditions of active TB disease to further our knowledge about the contribution of various cell subsets which could have implications for future vaccine development or refined B cell orientated treatment in the health setting. PMID:27050308

  12. Induction of polyclonal B cell activation and differentiation by the AIDS retrovirus (HTLV-III/LAV)

    International Nuclear Information System (INIS)

    The immune systems of individuals infected with HTLV-III/LAV are characterized by a profound defect in cellular immunity together with paradoxical polyclonal B cell activation. The present study examined the direct effects of HTLV-III/LAV on B lymphocytes. Peripheral blood B cells from healthy donors were incubated with a variety of HTLV-III/LAV isolates for 1 h and 3H-thymidine incorporation was measured at multiple time points. Responses ranged from 9000-28,000 cpm and peaked on day 4. This B cell activation was not enhanced by the addition of interleukin-2 to culture, was not synergistic with Staphylococcus aureus Cowan I, was not modulated by the addition of T lymphocytes to culture, and was not associated with B cell transformation. Supernatant Ig could first be detected in virus-activated cultures at day 4, plateaued by day 8, and yielded a mean of 12,500 ng IgG+IgM/ml/50,000 B cells. Thus, HTLV-III/LAV is a potent T cell independent B cell mitogen capable of inducing B cell activation, proliferation, and differentiation comparable in magnitude to that of the most potent B cell activators. This biological property of HTLV-III/LAV may help explain the profound polyclonal B cell activation observed in patients with AIDS and may provide investigators with another probe for investigating the mechanisms of B cell activation

  13. Conserved regions ofPlasmodium vivax potential vaccine candidate antigens in Sri Lanka:Consciousin silico analysis of prospective conformational epitope regions

    Institute of Scientific and Technical Information of China (English)

    Shanika Amarasinghe; Hashendra Kathriarachchi; Preethi Udagama

    2014-01-01

    Objective:To do mapping and modeling of conformationalB cell epitope regions of highly conserved and protective regions of three merozoitecandidate vaccine proteins ofPlasmodium vivax(P. vivax) ,ie. merozoite purface protein-1(PvMSP-1), apical membrane antigen -1 domainⅡ(PvAMA1-DⅡ) and regionⅡ of theDuffy binding protein(PvDBPⅡ), and to analyze the immunogenic properties of these predicted epitopes.Methods:3-D structures of amino acid haplotypes fromSriLanka(available inGeneBank) ofPvMSP-119(n=27),PvAMA1-DⅡ(n=21) andPvDBPⅡ(n=33) were modeled.SEPPA, selected as the best online server was used for conformational epitope predictions, while prediction and modeling of protein structure and properties related to immunogenicity was carried out withGeno3D server,SCRATCHProtein Server,NetSurfPServer and standalonesoftware,Genious5.4.4.Results:SEPPA revealed that regions of predicted conformational epitopes formed4 clusters inPvMSP-I19, and3 clusters each inPvAMA1-DⅡ andPvDBPⅡ, all of which displayed a high degree of hydrophilicity, contained solvent exposed residues, displayed high probability of antigenicity and showed positive antigenic propensity values, that indicated high degree of immunogenicity.Conclusions:Findings of this study revealed and confirmed that different parts of the sequences of each of the conserved regions of the three selected potential vaccine candidate antigens ofP. vivax are important with regard to conformational epitope prediction that warrants further laboratory experimental investigations in in vivo animal models.

  14. CD19 CAR-targeted T cells induce long-term remission and B Cell Aplasia in an immunocompetent mouse model of B cell acute lymphoblastic leukemia.

    Directory of Open Access Journals (Sweden)

    Marco L Davila

    Full Text Available Although many adults with B cell acute lymphoblastic leukemia (B-ALL are induced into remission, most will relapse, underscoring the dire need for novel therapies for this disease. We developed murine CD19-specific chimeric antigen receptors (CARs and an immunocompetent mouse model of B-ALL that recapitulates the disease at genetic, cellular, and pathologic levels. Mouse T cells transduced with an all-murine CD3ζ/CD28-based CAR that is equivalent to the one being used in our clinical trials, eradicate B-ALL in mice and mediate long-term B cell aplasias. In this model, we find that increasing conditioning chemotherapy increases tumor eradication, B cell aplasia, and CAR-modified T cell persistence. Quantification of recipient B lineage cells allowed us to estimate an in vivo effector to endogenous target ratio for B cell aplasia maintenance. In mice exhibiting a dramatic B cell reduction we identified a small population of progenitor B cells in the bone marrow that may serve as a reservoir for long-term CAR-modified T cell stimulation. Lastly, we determine that infusion of CD8+ CAR-modified T cells alone is sufficient to maintain long-term B cell eradication. The mouse model we report here should prove valuable for investigating CAR-based and other therapies for adult B-ALL.

  15. Physiology of B cells in mice with X-linked immunodeficiency. II. Influence of the thymus and mature T cells on B cell differentiation

    International Nuclear Information System (INIS)

    Evidence is presented that the in vivo differentiation of B cells expressing X-linked immunodeficiency (xid) is controlled by mature T cells. Normal (C57BL/6 X CBA/J)F1 mice were thymectomized (ATx), heavily irradiated, and reconstituted with CBA/N (xid) or CBA/Ca (nondefective) marrow. In contrast to sham-operated mice, ATx recipients of xid marrow showed an almost total absence of Ig+ B cells in lymph nodes (LN) and thoracic duct lymph at 2 mo post-reconstitution; B cells were markedly reduced in the spleen in some mice but only moderately in others. Addition of mature T cells soon after marrow reconstitution substantially abrogated the B cell depletion. In control experiments with nondefective B cells, the number of B cells developing in ATx irradiated recipients of normal (xid-) marrow cells was not detectably lower than in sham-operated recipients. These data imply that a subset of T-dependent B cells is either missing in normal mice or present in only very small numbers

  16. A xylogalacturonan epitope is specifically associated with plant cell detachment

    DEFF Research Database (Denmark)

    Willats, William George Tycho; McCartney, L.; Steele-King, C.G.;

    2004-01-01

    A monoclonal antibody (LM8) was generated with specificity for xyloglacturonan (XGA) isolated from pea (Pisum sativum L.) testae. Characterization of the LM8 epitope indicates that it is a region of XGA that is highly substituted with xylose. Immunocytochemical analysis indicates that this epitop...... that is specifically associated with a plant cell separation process that results in complete cell detachment....... is restricted to loosely attached inner parenchyma cells at the inner face of the pea testa and does not occur in other cells of the testa. Elsewhere in the pea seedling, the LM8 epitope was found only in association with root cap cell development at the root apex. Furthermore, the LM8 epitope is...... specifically associated with root cap cells in a range of angiosperm species. In embryogenic carrot suspension cell cultures the epitope is abundant at the surface of cell walls of loosely attached cells in both induced and non-induced cultures. The LM8 epitope is the first cell wall epitope to be identified...

  17. Chimeric Epitope Vaccine from Multistage Antigens for Lymphatic Filariasis.

    Science.gov (United States)

    Anugraha, G; Madhumathi, J; Prince, P R; Prita, P J Jeya; Khatri, V K; Amdare, N P; Reddy, M V R; Kaliraj, P

    2015-10-01

    Lymphatic filariasis, a mosquito-borne parasitic disease, affects more than 120 million people worldwide. Vaccination for filariasis by targeting different stages of the parasite will be a boon to the existing MDA efforts of WHO which required repeated administration of the drug to reduce the infection level and sustained transmission. Onset of a filaria-specific immune response achieved through antigen vaccines can act synergistically with these drugs to enhance the parasite killing. Multi-epitope vaccine approach has been proved to be successful against several parasitic diseases as it overcomes the limitations associated with the whole antigen vaccines. Earlier results from our group suggested the protective efficacy of multi-epitope vaccine comprising two immunodominant epitopes from Brugia malayi antioxidant thioredoxin (TRX), several epitopes from transglutaminase (TGA) and abundant larval transcript-2 (ALT-2). In this study, the prophylactic efficacy of the filarial epitope protein (FEP), a chimera of selective epitopes identified from our earlier study, was tested in a murine model (jird) of filariasis with L3 larvae. FEP conferred a significantly (P < 0.0001) high protection (69.5%) over the control in jirds. We also observed that the multi-epitope recombinant construct (FEP) induces multiple types of protective immune responses, thus ensuring the successful elimination of the parasite; this poses FEP as a potential vaccine candidate. PMID:26179420

  18. Dissecting antibodies with regards to linear and conformational epitopes.

    Science.gov (United States)

    Forsström, Björn; Axnäs, Barbara Bisławska; Rockberg, Johan; Danielsson, Hanna; Bohlin, Anna; Uhlen, Mathias

    2015-01-01

    An important issue for the performance and specificity of an antibody is the nature of the binding to its protein target, including if the recognition involves linear or conformational epitopes. Here, we dissect polyclonal sera by creating epitope-specific antibody fractions using a combination of epitope mapping and an affinity capture approach involving both synthesized peptides and recombinant protein fragments. This allowed us to study the relative amounts of antibodies to linear and conformational epitopes in the polyclonal sera as well as the ability of each antibody-fraction to detect its target protein in Western blot assays. The majority of the analyzed polyclonal sera were found to have most of the target-specific antibodies directed towards linear epitopes and these were in many cases giving Western blot bands of correct molecular weight. In contrast, many of the antibodies towards conformational epitopes did not bind their target proteins in the Western blot assays. The results from this work have given us insights regarding the nature of the antibody response generated by immunization with recombinant protein fragments and has demonstrated the advantage of using antibodies recognizing linear epitopes for immunoassay involving wholly or partially denatured protein targets. PMID:25816293

  19. Dissecting antibodies with regards to linear and conformational epitopes.

    Directory of Open Access Journals (Sweden)

    Björn Forsström

    Full Text Available An important issue for the performance and specificity of an antibody is the nature of the binding to its protein target, including if the recognition involves linear or conformational epitopes. Here, we dissect polyclonal sera by creating epitope-specific antibody fractions using a combination of epitope mapping and an affinity capture approach involving both synthesized peptides and recombinant protein fragments. This allowed us to study the relative amounts of antibodies to linear and conformational epitopes in the polyclonal sera as well as the ability of each antibody-fraction to detect its target protein in Western blot assays. The majority of the analyzed polyclonal sera were found to have most of the target-specific antibodies directed towards linear epitopes and these were in many cases giving Western blot bands of correct molecular weight. In contrast, many of the antibodies towards conformational epitopes did not bind their target proteins in the Western blot assays. The results from this work have given us insights regarding the nature of the antibody response generated by immunization with recombinant protein fragments and has demonstrated the advantage of using antibodies recognizing linear epitopes for immunoassay involving wholly or partially denatured protein targets.

  20. Identification of Autoantigen Epitopes in Alopecia Areata.

    Science.gov (United States)

    Wang, Eddy H C; Yu, Mei; Breitkopf, Trisia; Akhoundsadegh, Noushin; Wang, Xiaojie; Shi, Feng-Tao; Leung, Gigi; Dutz, Jan P; Shapiro, Jerry; McElwee, Kevin J

    2016-08-01

    Alopecia areata (AA) is believed to be a cell-mediated autoimmune hair loss disease. Both CD4 and cytotoxic CD8 T cells (CTLs) are important for the onset and progression of AA. Hair follicle (HF) keratinocyte and/or melanocyte antigen epitopes are suspected potential targets of autoreactive CTLs, but the specific epitopes have not yet been identified. We investigated the potential for a panel of known epitopes, expressed by HF keratinocytes and melanocytes, to induce activation of CTL populations in peripheral blood mononuclear cells. Specific synthetic epitopes derived from HF antigens trichohyalin and tyrosinase-related protein-2 induced significantly higher frequencies of response in AA CTLs compared with healthy controls (IFN-gamma secretion). Apoptosis assays revealed conditioned media from AA peripheral blood mononuclear cells stimulated with trichohyalin peptides elevated the expression of apoptosis markers in primary HF keratinocytes. A cytokine array revealed higher expression of IL-13 and chemokine ligand 5 (CCL5, RANTES) from AA peripheral blood mononuclear cells stimulated with trichohyalin peptides compared with controls. The data indicate that AA affected subjects present with an increased frequency of CTLs responsive to epitopes originating from keratinocytes and melanocytes; the activated CTLs secreted soluble factors that induced apoptosis in HF keratinocytes. Potentially, CTL response to self-antigen epitopes, particularly trichohyalin epitopes, could be a prognostic marker for human AA. PMID:27094591

  1. Cbl Suppresses B Cell Receptor–Mediated Phospholipase C (Plc)-γ2 Activation by Regulating B Cell Linker Protein–Plc-γ2 Binding

    OpenAIRE

    Yasuda, Tomoharu; Maeda, Akito; Kurosaki, Mari; Tezuka, Tohru; Hironaka, Katsunori; Yamamoto, Tadashi; Kurosaki, Tomohiro

    2000-01-01

    Accumulating evidence indicates that the Cbl protein plays a negative role in immune receptor signaling; however, the mode of Cbl action in B cell receptor (BCR) signaling still remains unclear. DT40 B cells deficient in Cbl showed enhanced BCR-mediated phospholipase C (PLC)-γ2 activation, thereby leading to increased apoptosis. A possible explanation for the involvement of Cbl in PLC-γ2 activation was provided by findings that Cbl interacts via its Src homology 2 (SH2) domain with B cell lin...

  2. MYC Negative Rectal B-Cell Lymphoma, Unclassifiable, with Features Intermediate between Diffuse Large B-Cell Lymphoma and Burkitt’s Lymphoma in an Immunocompetent Patient

    OpenAIRE

    Parikh, Jignesh G.; Ted Strom; Ilya Stone

    2013-01-01

    B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt’s lymphoma (BLUI) is a recently added entity to the World Health Organization (WHO) classification to address a grey zone between large B-cell lymphoma (DLBCL) and Burkitt’s lymphoma (BL). These are rare aggressive lymphomas, which were previously also known as Burkitt’s-like lymphoma (BLL). BL and BLUI/BLL of the colon mostly involve the ileocecal region. In the rectum, BL and BLUI/B...

  3. Activation of B cells by 1 microm particulate lysozyme or peptides: a Th-dependent pathway requiring CD40-CD40 ligand interaction.

    Science.gov (United States)

    Sedlik, C; Rojas, M; Leclerc, C

    1998-08-01

    Many antigens encountered by the immune system are included in complex structures such as bacteria or parasites. We previously developed an in vivo model to study the immunogenicity of particulate antigens, based on covalent linkage of proteins or peptides to 1 microm latex particles and showed that these antigens cannot be presented to MHC class II-restricted specific T cells by B cells. However, they induce strong CD4+ T cell responses when injected to mice without adjuvant. The present study demonstrates that four out of the five proteins tested did not stimulate antibody synthesis when linked to 1 microm microparticles, although a strong IgG production was induced by the same proteins administered in soluble form with adjuvant. In contrast, lysozyme and two synthetic peptides containing B and T cell viral epitopes induced strong and long-lasting specific antibody responses when linked to 1 micrometer synthetic beads. The isotypic pattern of antibodies induced by particulate lysozyme was similar to that induced by the soluble protein in alum. Studies using CD4+ T cell-depleted mice revealed that the induction of antibodies by particulate lysozyme strictly required Th cell activity. Moreover, the T-B cell cooperation involved in B cell activation by antigens linked to beads required CD40-CD40 ligand interaction. Thus, these particulate antigens provide a useful tool to study the mechanisms of induction of antibody response against complex bacterial or parasitic antigens. Moreover, they may represent attractive candidates to elaborate efficient new vaccines using short synthetic peptides. PMID:9723697

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

    DEFF Research Database (Denmark)

    Hoff, Soren T; Salman, Ahmed M; Ruhwald, Morten;

    2015-01-01

    BACKGROUND: The role of B cells in human host response to Mycobacterium tuberculosis (Mtb) infection is still controversial, but recent evidence suggest that B cell follicle like structures within the lung may influence host responses through regulation of the local cytokine environment. A...... candidate for such regulation could be the chemokine CXCL10. CXCL10 is mainly produced by human monocytes, but a few reports have also found CXCL10 production by human B cells. The objective of this study was to investigate CXCL10 production by human B cells in response to in vitro stimulation with Mtb...... antigens. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed human blood samples from 30 volunteer donors using multiparameter flow cytometry, and identified a subgroup of B cells producing CXCL10 in response to in vitro stimulation with antigens. T cells did not produce CXCL10, but CXCL10 production by B cells...

  5. Microbial Translocation and B Cell Dysfunction in Human Immunodeficiency Virus Disease

    Directory of Open Access Journals (Sweden)

    Wei Jiang

    2012-01-01

    Full Text Available The gut mucosal barrier disrupted in HIV disease, resulting in increased systemic exposure to microbial products such as Lipo Polys Accharide (LPS. The association of enhanced microbial translocation and B cell dysfunction in HIV disease is not fully understood. High dose and short term exposure of microbial Toll-Like Receptor (TLR agonists were used as vaccine adjuvants, however, low dose and long term exposure of TLR agonists could be harmful. The characteristics of B cell dysfunction in HIV disease included B cell, especially memory B cell depletion, enhanced levels of autoimmune antibodies and impaired vaccine or antigen responsiveness. This review discusses and explores the possibility of the effect of microbial translocation on memory B cell depletion and impaired vaccine responses in HIV infection. By determining the mechanisms of B cell depletion and perturbations in HIV disease, it may be possible to design interventions that can improve immune responses to vaccines, reduce selected opportunistic infections and perhaps slow disease progression.

  6. Rehabilitation or the death penalty: autoimmune B cells in the dock.

    Science.gov (United States)

    Dahal, Lekh N; Cragg, Mark S

    2015-03-01

    CD20-based monoclonal antibodies have become established as treatments for lymphoma, rheumatoid arthritis, systemic lupus erythematosus, vasculitis and dermatomyositis, with the principle therapeutic mechanism relating to B-cell depletion through effector cell engagement. An article by Brühl et al. in this issue of the European Journal of Immunology [Eur. J. Immunol. 2015. 45: 705-715] reveals a fundamentally distinct mechanism of silencing autoimmune B-cell responses. Rather than B-cell depletion, the authors use anti-CD79b antibodies to induce B-cell tolerance and suppress humoral immune responses against collagen to prevent the development of arthritis in mice. Here we highlight the differences in the mechanisms used by anti-CD20 and anti-CD79b Ab therapy and discuss why depletion of B cells may not be required to treat autoimmune arthritis and other B-cell-associated pathologies. PMID:25639261

  7. Closed-Loop Neuromorphic Benchmarks

    Science.gov (United States)

    Stewart, Terrence C.; DeWolf, Travis; Kleinhans, Ashley; Eliasmith, Chris

    2015-01-01

    Evaluating the effectiveness and performance of neuromorphic hardware is difficult. It is even more difficult when the task of interest is a closed-loop task; that is, a task where the output from the neuromorphic hardware affects some environment, which then in turn affects the hardware's future input. However, closed-loop situations are one of the primary potential uses of neuromorphic hardware. To address this, we present a methodology for generating closed-loop benchmarks that makes use of a hybrid of real physical embodiment and a type of “minimal” simulation. Minimal simulation has been shown to lead to robust real-world performance, while still maintaining the practical advantages of simulation, such as making it easy for the same benchmark to be used by many researchers. This method is flexible enough to allow researchers to explicitly modify the benchmarks to identify specific task domains where particular hardware excels. To demonstrate the method, we present a set of novel benchmarks that focus on motor control for an arbitrary system with unknown external forces. Using these benchmarks, we show that an error-driven learning rule can consistently improve motor control performance across a randomly generated family of closed-loop simulations, even when there are up to 15 interacting joints to be controlled. PMID:26696820

  8. Benchmarking of human resources management

    Directory of Open Access Journals (Sweden)

    David M. Akinnusi

    2008-12-01

    Full Text Available This paper reviews the role of human resource management (HRM which, today, plays a strategic partnership role in management. The focus of the paper is on HRM in the public sector, where much hope rests on HRM as a means of transforming the public service and achieving much needed service delivery. However, a critical evaluation of HRM practices in the public sector reveals that these services leave much to be desired. The paper suggests the adoption of benchmarking as a process to revamp HRM in the public sector so that it is able to deliver on its promises. It describes the nature and process of benchmarking and highlights the inherent difficulties in applying benchmarking in HRM. It concludes with some suggestions for a plan of action. The process of identifying “best” practices in HRM requires the best collaborative efforts of HRM practitioners and academicians. If used creatively, benchmarking has the potential to bring about radical and positive changes in HRM in the public sector. The adoption of the benchmarking process is, in itself, a litmus test of the extent to which HRM in the public sector has grown professionally.

  9. ZZ IHEAS-BENCHMARKS, High-Energy Accelerator Shielding Benchmarks

    International Nuclear Information System (INIS)

    Description of program or function: Six kinds of Benchmark problems were selected for evaluating the model codes and the nuclear data for the intermediate and high energy accelerator shielding by the Shielding Subcommittee in the Research Committee on Reactor Physics. The benchmark problems contain three kinds of neutron production data from thick targets due to proton, alpha and electron, and three kinds of shielding data for secondary neutron and photon generated by proton. Neutron and photo-neutron reaction cross section data are also provided for neutrons up to 500 MeV and photons up to 300 MeV, respectively

  10. Characterization of xenoantiserum produced against B cell acute lymphoblastic leukemia cell line

    OpenAIRE

    Akagi,Tadaatsu; Sonobe, Hiroshi; Miyoshi, Isao; Yoshimoto,Shizuo

    1982-01-01

    Antiserum was produced in white rabbit by intravenously injecting living cells of a B cell acute lymphoblastic leukemia (ALL) line (BALL-1). The reactivity of the antiserum against various lymphoid cell lines was examined by membrane immunofluorescence after appropriate absorption. Serum absorbed with non-T, non-B (NALL-1) and T-ALL (TALL-1) cells recognized B cell antigens distinct from Ia-like antigens on both normal and neoplastic B cells. After further absorption with tonsillar cells or n...

  11. T Cells That Promote B-Cell Maturation in Systemic Autoimmunity

    OpenAIRE

    Weinstein, Jason S.; Hernandez, Sairy G.; Craft, Joe

    2012-01-01

    Follicular helper T (Tfh) cells play an essential role in helping B cells generate antibodies upon pathogen encounters. Such T-cell help classically occurs in germinal centers (GCs) located in B-cell follicles of secondary lymphoid organs, a site of immunoglobulin affinity maturation and isotype switching. B-cell maturation also occurs extrafollicularly, in the red pulp of the spleen and medullary cords in lymph nodes, with plasma cell formation and antibody production. Development of extrafo...

  12. Whole-genome fingerprint of the DNA methylome during human B cell differentiation

    OpenAIRE

    Kulis, Marta; Merkel, Angelika; Heath, Simon; Queirós, Ana C; Schuyler, Ronald P.; Castellano, Giancarlo; Beekman, Renée; Raineri, Emanuele; Esteve, Anna; Clot, Guillem; Verdaguer-Dot, Néria; Duran-Ferrer, Martí; Russiñol, Nuria; Vilarrasa-Blasi, Roser; Ecker, Simone

    2015-01-01

    International audience We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, whic...

  13. B cell infection and activation by rabies virus-based vaccines.

    Science.gov (United States)

    Lytle, Andrew G; Norton, James E; Dorfmeier, Corin L; Shen, Shixue; McGettigan, James P

    2013-08-01

    Replication-deficient rabies viruses (RABV) are promising rabies postexposure vaccines due to their prompt and potent stimulation of protective virus neutralizing antibody titers, which are produced in mice by both T-dependent and T-independent mechanisms. To promote such early and robust B cell stimulation, we hypothesized that live RABV-based vaccines directly infect B cells, thereby activating a large pool of antigen-presenting cells (APCs) capable of providing early priming and costimulation to CD4(+) T cells. In this report, we show that live RABV-based vaccine vectors efficiently infect naive primary murine and human B cells ex vivo. Infection of B cells resulted in the significant upregulation of early markers of B cell activation and antigen presentation, including CD69, major histocompatibility complex class II (MHC-II), and CD40 in murine B cells or HLA-DR and CD40 in human B cells compared to mock-infected cells or cells treated with an inactivated RABV-based vaccine. Furthermore, primary B cells infected with a live RABV expressing ovalbumin were able to prime and stimulate naive CD4(+) OT-II T cells to proliferate and to secrete interleukin-2 (IL-2), demonstrating a functional consequence of B cell infection and activation by live RABV-based vaccine vectors. We propose that this direct B cell stimulation by live RABV-based vaccines is a potential mechanism underlying their induction of early protective T cell-dependent B cell responses, and that designing live RABV-based vaccines to infect and activate B cells represents a promising strategy to develop a single-dose postexposure rabies vaccine where the generation of early protective antibody titers is critical. PMID:23760241

  14. Recombinant human interleukin 2 acts as a B cell growth and differentiation promoting factor

    OpenAIRE

    Emmrich, F.; Moll, Heidrun; Markus M Simon

    2009-01-01

    Human B cells appropriately activated by a B cell mitogen are rendered susceptible to human Interleukin 2 (IL-2) as demonstrated with recombinant human IL-2 (rec. h IL-2). They show increased proliferation and drastically enhanced immunoglobulin secretion. Susceptibility to IL-2 is accompanied with the expression of the IL-2 receptor (Tac antigen) on B cells. The data suggest that IL-2 is one of the lymphokines directly involved in the activation of B lymphocytes.

  15. Uptake and presentation of myelin basic protein by normal human B cells.

    Directory of Open Access Journals (Sweden)

    Marie Klinge Brimnes

    Full Text Available B cells may play both pathogenic and protective roles in T-cell mediated autoimmune diseases such as multiple sclerosis (MS. These functions relate to the ability of B cells to bind and present antigens. Under serum-free conditions we observed that 3-4% of circulating B cells from healthy donors were capable of binding the MS-associated self-antigen myelin basic protein (MBP and of presenting the immunodominant peptide MBP85-99, as determined by staining with the mAb MK16 recognising the peptide presented by HLA-DR15-positive cells. In the presence of serum, however, the majority of B cells bound MBP in a complement-dependent manner, and almost half of the B cells became engaged in presentation of MBP85-99. Even though complement receptor 1 (CR1, CD35 and CR2 (CD21 both contributed to binding of MBP to B cells, only CR2 was important for the subsequent presentation of MBP85-99. A high proportion of MBP85-99 presenting B cells expressed CD27, and showed increased expression of CD86 compared to non-presenting B cells. MBP-pulsed B cells induced a low frequency of IL-10-producing CD4+ T cells in 3 out of 6 donors, indicating an immunoregulatory role of B cells presenting MBP-derived peptides. The mechanisms described here refute the general assumption that B-cell presentation of self-antigens requires uptake via specific B-cell receptors, and may be important for maintenance of tolerance as well as for driving T-cell responses in autoimmune diseases.

  16. B-cell subsets, signaling and their roles in secretion of autoantibodies.

    Science.gov (United States)

    Iwata, S; Tanaka, Y

    2016-07-01

    B cells play a pivotal role in the pathogenesis of autoimmune diseases. In patients with systemic lupus erythematosus (SLE), the percentages of plasmablasts and IgD(-)CD27(-) double-negative memory B cells in peripheral blood are significantly increased, while IgD(+)CD27(+) IgM memory B cells are significantly decreased compared to healthy donors. The phenotypic change is significantly associated with disease activity and concentration of autoantibodies. Treatment of B-cell depletion using rituximab results in the reconstitution of peripheral B cells in SLE patients with subsequent improvement in disease activity. Numerous studies have described abnormalities in B-cell receptor (BCR)-mediated signaling in B cells of SLE patients. Since differences in BCR signaling are considered to dictate the survival or death of naïve and memory B cells, aberrant BCR signal can lead to abnormality of B-cell subsets in SLE patients. Although Syk and Btk function as key molecules in BCR signaling, their pathological role in SLE remains unclear. We found that Syk and Btk do not only transduce activation signal through BCR, but also mediate crosstalk between BCR and Toll-like receptor (TLR) as well as BCR and JAK-STAT pathways in human B cells in vitro. In addition, pronounced Syk and Btk phosphorylation was observed in B cells of patients with active SLE compared to those of healthy individuals. The results suggest the involvement of Syk and Btk activation in abnormalities of BCR-mediated signaling and B-cell phenotypes during the pathological process of SLE and that Syk, Btk and JAK are potential therapeutic targets in SLE. PMID:27252261

  17. Bruton tyrosine kinase inhibitors: a promising novel targeted treatment for B cell lymphomas

    OpenAIRE

    Aalipour, Amin; Advani, Ranjana H.

    2013-01-01

    Constitutive or aberrant signalling of the B cell receptor signalling cascade has been implicated in the propagation and maintenance of a variety of B cell malignancies. Small molecule inhibitors of Bruton tyrosine kinase (BTK), a protein early in this cascade and specifically expressed in B cells, have emerged as a new class of targeted agents. There are several BTK inhibitors, including ONO-WG-307, LFM-A13, dasatinib, CC-292, and PCI-32765 (ibrutinib), in preclinical and/or clinical develop...

  18. Systemic Sclerosis Patients Present Alterations in the Expression of Molecules Involved in B-Cell Regulation

    Science.gov (United States)

    Soto, Lilian; Ferrier, Ashley; Aravena, Octavio; Fonseca, Elianet; Berendsen, Jorge; Biere, Andrea; Bueno, Daniel; Ramos, Verónica; Aguillón, Juan Carlos; Catalán, Diego

    2015-01-01

    The activation threshold of B cells is tightly regulated by an array of inhibitory and activator receptors in such a way that disturbances in their expression can lead to the appearance of autoimmunity. The aim of this study was to evaluate the expression of activating and inhibitory molecules involved in the modulation of B cell functions in transitional, naive, and memory B-cell subpopulations from systemic sclerosis patients. To achieve this, blood samples were drawn from 31 systemic sclerosis patients and 53 healthy individuals. Surface expression of CD86, MHC II, CD19, CD21, CD40, CD22, Siglec 10, CD35, and FcγRIIB was determined by flow cytometry. IL-10 production was evaluated by intracellular flow cytometry from isolated B cells. Soluble IL-6 and IL-10 levels were measured by ELISA from supernatants of stimulated B cells. Systemic sclerosis patients exhibit an increased frequency of transitional and naive B cells related to memory B cells compared with healthy controls. Transitional and naive B cells from patients express higher levels of CD86 and FcγRIIB than healthy donors. Also, B cells from patients show high expression of CD19 and CD40, whereas memory cells from systemic sclerosis patients show reduced expression of CD35. CD19 and CD35 expression levels associate with different autoantibody profiles. IL-10+ B cells and secreted levels of IL-10 were markedly reduced in patients. In conclusion, systemic sclerosis patients show alterations in the expression of molecules involved in B-cell regulation. These abnormalities may be determinant in the B-cell hyperactivation observed in systemic sclerosis. PMID:26483788

  19. Identification of cytotoxic T lymphocyte epitopes on swine viruses: multi-epitope design for universal T cell vaccine.

    Directory of Open Access Journals (Sweden)

    Yu-Chieh Liao

    Full Text Available Classical swine fever (CSF, foot-and-mouth disease (FMD and porcine reproductive and respiratory syndrome (PRRS are the primary diseases affecting the pig industry globally. Vaccine induced CD8(+ T cell-mediated immune response might be long-lived and cross-serotype and thus deserve further attention. Although large panels of synthetic overlapping peptides spanning the entire length of the polyproteins of a virus facilitate the detection of cytotoxic T lymphocyte (CTL epitopes, it is an exceedingly costly and cumbersome approach. Alternatively, computational predictions have been proven to be of satisfactory accuracy and are easily performed. Such a method enables the systematic identification of genome-wide CTL epitopes by incorporating epitope prediction tools in analyzing large numbers of viral sequences. In this study, we have implemented an integrated bioinformatics pipeline for the identification of CTL epitopes of swine viruses including the CSF virus (CSFV, FMD virus (FMDV and PRRS virus (PRRSV and assembled these epitopes on a web resource to facilitate vaccine design. Identification of epitopes for cross protections to different subtypes of virus are also reported in this study and may be useful for the development of a universal vaccine against such viral infections among the swine population. The CTL epitopes identified in this study have been evaluated in silico and possibly provide more and wider protection in compared to traditional single-reference vaccine design. The web resource is free and open to all users through http://sb.nhri.org.tw/ICES.

  20. B Cells Promote Th1- Skewed NKT Cell Response by CD1d-TCR Interaction

    OpenAIRE

    Shin, Jung Hoon; Park, Se-Ho

    2013-01-01

    CD1d expressing dendritic cells (DCs) are good glyco-lipid antigen presenting cells for NKT cells. However, resting B cells are very weak stimulators for NKT cells. Although α-galactosylceramide (α-GalCer) loaded B cells can activate NKT cells, it is not well defined whether B cells interfere NKT cell stimulating activity of DCs. Unexpectedly, we found in this study that B cells can promote Th1-skewed NKT cell response, which means a increased level of IFN-γ by NKT cells, concomitant with a d...

  1. B cells help alloreactive T cells differentiate into memory T cells1

    OpenAIRE

    Ng, Yue-Harn; Oberbarnscheidt, Martin H.; Chandramoorthy, Harish Chinna Konda; Hoffman, Rosemary; Chalasani, Geetha

    2010-01-01

    B cells are recognized as effector cells in allograft rejection that are dependent upon T cell help to produce alloantibodies causing graft injury. It is not known if B cells can also help T cells differentiate into memory cells in the alloimmune response. We found that in B cell-deficient hosts, differentiation of alloreactive T cells into effectors was intact whereas their development into memory T cells was impaired. To test if B cell help for T cells was required for their continued diffe...

  2. Affinity-purified interleukin 2 induces proliferation of large but not small B cells.

    OpenAIRE

    Mond, J J; C. Thompson; Finkelman, F.D.; Farrar, J.; Schaefer, M.; Robb, R J

    1985-01-01

    Immunoaffinity-purified interleukin 2 (IL2) stimulated proliferation of large but not small B cells. Stimulation was observed even when B cells were cultured at very low cell densities (3 X 10(4) per microwell containing 0.2 ml of medium). Addition of small numbers of purified splenic T cells did not enhance the IL2-induced B-cell proliferative response. These results suggest that IL2 was not operating through contaminating T cells. B cells cultured with anti-Ig antibody in vitro showed enhan...

  3. Clonal expansion of immunoglobulin M+CD27+ B cells in HCV-associated mixed cryoglobulinemia

    OpenAIRE

    Charles, Edgar D.; Green, Rashidah M.; Marukian, Svetlana; Talal, Andrew H.; Lake-Bakaar, Gerond V.; Jacobson, Ira M.; Rice, Charles M.; Dustin, Lynn B.

    2008-01-01

    Hepatitis C virus (HCV) is associated with B-cell lymphoproliferative disorders such as mixed cryoglobulinemia (MC) and B-cell non-Hodgkin lymphoma (B-NHL). The pathogenesis of these disorders remains unclear, and it has been proposed that HCV drives the pro-liferation of B cells. Here we demonstrate that certain HCV+MC+ subjects have clonal expansions of immunoglobulin M (IgM)+κ+IgDlow/−CD21lowCD27+ B cells. Using RT-PCR to amplify Ig from these singly sorted cells, we show that these predom...

  4. Adhesion of Human B Cells to Germinal Centers in Vitro Involves VLA-4 and INCAM-110

    Science.gov (United States)

    Freedman, Arnold S.; Munro, J. Michael; Rice, G. Edgar; Bevilacqua, Michael P.; Morimoto, Chikao; McIntyre, Bradley W.; Rhynhart, Kurt; Pober, Jordan S.; Nadler, Lee M.

    1990-08-01

    Human B lymphocytes localize and differentiate within the microenvironment of lymphoid germinal centers. A frozen section binding assay was developed for the identification of those molecules involved in the adhesive interactions between B cells and lymphoid follicles. Activated human B cells and B cell lines were found to selectively adhere to germinal centers. The VLA-4 molecule on the lymphocyte and the adhesion molecule INCAM-110, expressed on follicular dendritic cells, supported this interaction. This cellular interaction model can be used for the study of how B cells differentiate.

  5. The regulatory role of B cells in autoimmunity, infections and cancer: Perspectives beyond IL10 production.

    Science.gov (United States)

    Gorosito Serrán, Melisa; Fiocca Vernengo, Facundo; Beccaria, Cristian G; Acosta Rodriguez, Eva V; Montes, Carolina L; Gruppi, Adriana

    2015-11-14

    The term regulatory B cells (B regs) is ascribed to a heterogeneous population of B cells with the function of suppressing inflammatory responses. They have been described mainly during the last decade in the context of different immune-mediated diseases. Most of the work on B regs has been focused on IL-10-producing B cells. However, B cells can exert regulatory functions independently of IL-10 production. Here we discuss the phenotypes, development and effector mechanisms of B regs and advances in their role in autoimmunity, infections and cancer. PMID:26424657

  6. Infection and Persistence of Rhesus Monkey Rhadinovirus in Immortalized B-Cell Lines

    OpenAIRE

    Bilello, John P.; Lang, Sabine M.; Wang, Fred; Aster, Jon C.; Desrosiers, Ronald C.

    2006-01-01

    Similar to its close relative human herpesvirus 8, rhesus monkey rhadinovirus (RRV) persists predominantly in B cells of its natural host. Rhesus monkey B-cell lines immortalized by the Epstein-Barr-related virus from rhesus monkeys (rhEBV) were used as targets for infection by RRV. These cultured B cells were susceptible to infection by RRV and continued to produce low titers of RRV for months of continuous culture. Infection by RRV did not detectably alter the growth rates of these B-cell l...

  7. CEACAM1 mediates B cell aggregation in central nervous system autoimmunity.

    Science.gov (United States)

    Rovituso, Damiano M; Scheffler, Laura; Wunsch, Marie; Kleinschnitz, Christoph; Dörck, Sebastian; Ulzheimer, Jochen; Bayas, Antonios; Steinman, Lawrence; Ergün, Süleyman; Kuerten, Stefanie

    2016-01-01

    B cell aggregates in the central nervous system (CNS) have been associated with rapid disease progression in patients with multiple sclerosis (MS). Here we demonstrate a key role of carcinoembryogenic antigen-related cell adhesion molecule1 (CEACAM1) in B cell aggregate formation in MS patients and a B cell-dependent mouse model of MS. CEACAM1 expression was increased on peripheral blood B cells and CEACAM1(+) B cells were present in brain infiltrates of MS patients. Administration of the anti-CEACAM1 antibody T84.1 was efficient in blocking aggregation of B cells derived from MS patients. Along these lines, application of the monoclonal anti-CEACAM1 antibody mCC1 was able to inhibit CNS B cell aggregate formation and significantly attenuated established MS-like disease in mice in the absence of any adverse effects. CEACAM1 was co-expressed with the regulator molecule T cell immunoglobulin and mucin domain -3 (TIM-3) on B cells, a novel molecule that has recently been described to induce anergy in T cells. Interestingly, elevated coexpression on B cells coincided with an autoreactive T helper cell phenotype in MS patients. Overall, these data identify CEACAM1 as a clinically highly interesting target in MS pathogenesis and open new therapeutic avenues for the treatment of the disease. PMID:27435215

  8. CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production

    OpenAIRE

    Khairnar, Vishal; Duhan, Vikas; Maney, Sathish Kumar; Honke, Nadine; Shaabani, Namir; Pandyra, Aleksandra A; Seifert, Marc; Pozdeev, Vitaly; Xu, Haifeng C.; Sharma, Piyush; Baldin, Fabian; Marquardsen, Florian; Merches, Katja; Lang, Elisabeth; Kirschning, Carsten

    2015-01-01

    B cells are essential for antiviral immune defence because they produce neutralizing antibodies, present antigen and maintain the lymphoid architecture. Here we show that intrinsic signalling of CEACAM1 is essential for generating efficient B-cell responses. Although CEACAM1 exerts limited influence on the proliferation of B cells, expression of CEACAM1 induces survival of proliferating B cells via the BTK/Syk/NF-κB-axis. The absence of this signalling cascade in naive Ceacam1 −/− mice limits...

  9. Multifocal Extranodal Involvement of Diffuse Large B-Cell Lymphoma

    Directory of Open Access Journals (Sweden)

    Devrim Cabuk

    2013-01-01

    Full Text Available Endobronchial involvement of extrapulmonary malignant tumors is uncommon and mostly associated with breast, kidney, colon, and rectum carcinomas. A 68-year-old male with a prior diagnosis of colon non-Hodgkin lymphoma (NHL was admitted to the hospital with a complaint of cough, sputum, and dyspnea. The chest radiograph showed right hilar enlargement and opacity at the right middle zone suggestive of a mass lesion. Computed tomography of thorax revealed a right-sided mass lesion extending to thoracic wall with the destruction of the third and the fourth ribs and a right hilar mass lesion. Fiberoptic bronchoscopy was performed in order to evaluate endobronchial involvement and showed stenosis with mucosal tumor infiltration in right upper lobe bronchus. The pathological examination of bronchoscopic biopsy specimen reported diffuse large B-cell lymphoma and the patient was accepted as the endobronchial recurrence of sigmoid colon NHL. The patient is still under treatment of R-ICE (rituximab-ifosfamide-carboplatin-etoposide chemotherapy and partial regression of pulmonary lesions was noted after 3 courses of treatment.

  10. Primary Mediastinal Large B-Cell Lymphoma during Pregnancy

    Directory of Open Access Journals (Sweden)

    Cesar A. Perez

    2012-01-01

    Full Text Available Non-Hodgkin’s Lymphoma (NHL rarely presents during pregnancy and primary mediastinal large B-cell lymphoma (PMLBCL accounts for approximately 2.5% of patients with NHL. The case of a 22-year-old woman who was diagnosed with Stage IIA PMLBCL during week 13 of her intrauterine pregnancy is described. The staging consisted in computed tomography (CT of the chest and magnetic resonance imaging (MRI of the abdomen and pelvis. She was managed with R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for a total of six cycles and, because of the early presentation during the second trimester, she received the entire chemotherapy course during the pregnancy. She delivered a healthy baby at 34 weeks of pregnancy and a 18FDG-PET/CT scan demonstrated complete remission after delivery. After 20 months of follow up she remains with no evidence of disease and her 1-year-old son has shown no developmental delays or physical abnormalities. PMLBCL, although an uncommon subgroup of DLBCL, may present during pregnancy and R-CHOP should be considered as one suitable option in this complex scenario.

  11. Induction of apoptosis in chicken bursal B cells

    International Nuclear Information System (INIS)

    Cell death in general can be a physiological process of cell number regulation in tissue, or it can be the result of exo or endogenous injuries, such a low-dose of radiation. Chicken B cell population in the bursa of Fabricius are very susceptible to PCD. Our present studies concern the development of radiation damage of chicken defence mechanisms. In 6 experiments pathogen free chicken were irradiated by gamma rays with the total doses of 0.25, 0.5, 1.0, 2.0 and 4.0 Gy. The induction of apoptosis was checked by Flow-cyto-meter 12 h after irradiation in bursa cell suspension. There is some increase in the number of induced apoptotic cells 12 h after irradiation at the dose 0.5-.4.0 Gy. There were no significant changes in the proportion of proliferating lymphocytes (G2 M), but cellularity decreased significantly at dose 2.0 and 4.0 Gy/12 h after irradiation. (author)

  12. EVALUATION OF CYTOKINE GENE POLYMORPHISM IN B CELL LYMPHOID MALIGNANCIES

    Directory of Open Access Journals (Sweden)

    E. L. Nazarova

    2014-01-01

    Full Text Available Previous studies with some solid tumors has shown that polymorphisms of certain cytokine genes may be used as predictors of clinical outcome in the patients. It seemed important to evaluate potential correlations between production of certain pro- and anti-inflammatory cytokines and co-receptor molecules, and promoter polymorphism of the cytokine genes involved into regulation of cell proliferation, differentiation, apoptosis, lipid metabolism and blood clotting in the patients with hematological malignancies. The article contains our results concerning associations between of IL-1β, -2, -4, -10, -17, TNFα, and allelic polymorphisms of their genes in 62 patients with B cell lymphoid malignancies in an ethnically homogenous group (self-identified as Russians. We have shown that the GА and AA genotypes of the G-308A polymorphism in TNFα gene are significantly associated with increased production of this cytokine, being more common in aggressive non-Hodgkin lymphomas, more rare in multiple myeloma and in indolent non-Hodgkin lymphomas.

  13. Antibody and B cell responses to Plasmodium sporozoites

    Directory of Open Access Journals (Sweden)

    Johanna N Dups

    2014-11-01

    Full Text Available Antibodies are capable of blocking infection of the liver by Plasmodium sporozoites. Accordingly the induction of anti-sporozoite antibodies is a major aim of various vaccine approaches to malaria. In recent years our knowledge of the specificity and quantities of antibodies required for protection has been greatly expanded by clinical trials of various whole sporozoite and subunit vaccines. Moreover, the development of humanized mouse models and transgenic parasites have also aided our ability to assess the specificity of antibodies and their ability to block infection. Nonetheless, considerable gaps remain in our knowledge - in particular in understanding what antigens are recognized by infection blocking antibodies and in knowing how we can induce robust, long-lived antibody responses. Maintaining high levels of circulating antibodies is likely to be of primary importance, as antibodies must block infection in the short time it takes for sporozoites to reach the liver from the skin. It is clear that a better understanding of the development of protective B cell-mediated immunity will aid the development and refinement of malaria vaccines.

  14. Radiation Detection Computational Benchmark Scenarios

    Energy Technology Data Exchange (ETDEWEB)

    Shaver, Mark W.; Casella, Andrew M.; Wittman, Richard S.; McDonald, Ben S.

    2013-09-24

    Modeling forms an important component of radiation detection development, allowing for testing of new detector designs, evaluation of existing equipment against a wide variety of potential threat sources, and assessing operation performance of radiation detection systems. This can, however, result in large and complex scenarios which are time consuming to model. A variety of approaches to radiation transport modeling exist with complementary strengths and weaknesses for different problems. This variety of approaches, and the development of promising new tools (such as ORNL’s ADVANTG) which combine benefits of multiple approaches, illustrates the need for a means of evaluating or comparing different techniques for radiation detection problems. This report presents a set of 9 benchmark problems for comparing different types of radiation transport calculations, identifying appropriate tools for classes of problems, and testing and guiding the development of new methods. The benchmarks were drawn primarily from existing or previous calculations with a preference for scenarios which include experimental data, or otherwise have results with a high level of confidence, are non-sensitive, and represent problem sets of interest to NA-22. From a technical perspective, the benchmarks were chosen to span a range of difficulty and to include gamma transport, neutron transport, or both and represent different important physical processes and a range of sensitivity to angular or energy fidelity. Following benchmark identification, existing information about geometry, measurements, and previous calculations were assembled. Monte Carlo results (MCNP decks) were reviewed or created and re-run in order to attain accurate computational times and to verify agreement with experimental data, when present. Benchmark information was then conveyed to ORNL in order to guide testing and development of hybrid calculations. The results of those ADVANTG calculations were then sent to PNNL for

  15. PageRank Pipeline Benchmark: Proposal for a Holistic System Benchmark for Big-Data Platforms

    OpenAIRE

    Dreher, Patrick; Byun, Chansup; Hill, Chris; Gadepally, Vijay; Kuszmaul, Bradley; Kepner, Jeremy

    2016-01-01

    The rise of big data systems has created a need for benchmarks to measure and compare the capabilities of these systems. Big data benchmarks present unique scalability challenges. The supercomputing community has wrestled with these challenges for decades and developed methodologies for creating rigorous scalable benchmarks (e.g., HPC Challenge). The proposed PageRank pipeline benchmark employs supercomputing benchmarking methodologies to create a scalable benchmark that is reflective of many...

  16. Atomic Energy Research benchmark activity

    International Nuclear Information System (INIS)

    The test problems utilized in the validation and verification process of computer programs in Atomic Energie Research are collected into one bunch. This is the first step towards issuing a volume in which tests for VVER are collected, along with reference solutions and a number of solutions. The benchmarks do not include the ZR-6 experiments because they have been published along with a number of comparisons in the Final reports of TIC. The present collection focuses on operational and mathematical benchmarks which cover almost the entire range of reaktor calculation. (Author)

  17. 3-D neutron transport benchmarks

    International Nuclear Information System (INIS)

    A set of 3-D neutron transport benchmark problems proposed by the Osaka University to NEACRP in 1988 has been calculated by many participants and the corresponding results are summarized in this report. The results of Keff, control rod worth and region-averaged fluxes for the four proposed core models, calculated by using various 3-D transport codes are compared and discussed. The calculational methods used were: Monte Carlo, Discrete Ordinates (Sn), Spherical Harmonics (Pn), Nodal Transport and others. The solutions of the four core models are quite useful as benchmarks for checking the validity of 3-D neutron transport codes

  18. OCA-B integrates B cell antigen receptor-, CD40L- and IL 4-mediated signals for the germinal center pathway of B cell development.

    OpenAIRE

    Qin, X F; Reichlin, A; Luo, Y.; Roeder, R. G.; Nussenzweig, M.C.

    1998-01-01

    Many of the key decisions in lymphocyte differentiation and activation are dependent on integration of antigen receptor and co-receptor signals. Although there is significant understanding of these receptors and their signaling pathways, little is known about the molecular requirements for signal integration at the level of activation of gene expression. Here we show that in primary B cells, expression of the B-cell specific transcription coactivator OCA-B (also known as OBF-1 or Bob-1) is re...

  19. Engagement of CD22 on B cells with the monoclonal antibody epratuzumab stimulates the phosphorylation of upstream inhibitory signals of the B cell receptor.

    Science.gov (United States)

    Lumb, Simon; Fleischer, Sarah J; Wiedemann, Annika; Daridon, Capucine; Maloney, Alison; Shock, Anthony; Dörner, Thomas

    2016-06-01

    The binding of antigen to the B cell receptor (BCR) results in a cascade of signalling events that ultimately drive B cell activation. Uncontrolled B cell activation is regulated by negative feedback loops that involve inhibitory co-receptors such as CD22 and CD32B that exert their functions following phosphorylation of immunoreceptor tyrosine-based inhibition motifs (ITIMs). The CD22-targeted antibody epratuzumab has previously been shown to inhibit BCR-driven signalling events, but its effects on ITIM phosphorylation of CD22 and CD32B have not been properly evaluated. The present study therefore employed both immunoprecipitation and flow cytometry approaches to elucidate the effects of epratuzumab on direct phosphorylation of key tyrosine (Tyr) residues on both these proteins, using both transformed B cell lines and primary human B cells. Epratuzumab induced the phosphorylation of Tyr(822) on CD22 and enhanced its co-localisation with SHP-1. Additionally, in spite of high basal phosphorylation of other key ITIMs on CD22, in primary human B cells epratuzumab also enhanced phosphorylation of Tyr(807), a residue involved in the recruitment of Grb2. Such initiation events could explain the effects of epratuzumab on downstream signalling in B cells. Finally, we were able to demonstrate that epratuzumab stimulated the phosphorylation of Tyr(292) on the low affinity inhibitory Fc receptor CD32B which would further attenuate BCR-induced signalling. Together, these data demonstrate that engagement of CD22 with epratuzumab leads to the direct phosphorylation of key upstream inhibitory receptors of BCR signalling and may help to explain how this antibody modulates B cell function. PMID:27125377

  20. Early B-cell factor 1 (EBF1) is critical for transcriptional control of SLAMF1 gene in human B cells.

    Science.gov (United States)

    Schwartz, Anton M; Putlyaeva, Lidia V; Covich, Milica; Klepikova, Anna V; Akulich, Kseniya A; Vorontsov, Ilya E; Korneev, Kirill V; Dmitriev, Sergey E; Polanovsky, Oleg L; Sidorenko, Svetlana P; Kulakovskiy, Ivan V; Kuprash, Dmitry V

    2016-10-01

    Signaling lymphocytic activation molecule family member 1 (SLAMF1)/CD150 is a co-stimulatory receptor expressed on a variety of hematopoietic cells, in particular on mature lymphocytes activated by specific antigen, costimulation and cytokines. Changes in CD150 expression level have been reported in association with autoimmunity and with B-cell chronic lymphocytic leukemia. We characterized the core promoter for SLAMF1 gene in human B-cell lines and explored binding sites for a number of transcription factors involved in B cell differentiation and activation. Mutations of SP1, STAT6, IRF4, NF-kB, ELF1, TCF3, and SPI1/PU.1 sites resulted in significantly decreased promoter activity of varying magnitude, depending on the cell line tested. The most profound effect on the promoter strength was observed upon mutation of the binding site for Early B-cell factor 1 (EBF1). This mutation produced a 10-20 fold drop in promoter activity and pinpointed EBF1 as the master regulator of human SLAMF1 gene in B cells. We also identified three potent transcriptional enhancers in human SLAMF1 locus, each containing functional EBF1 binding sites. Thus, EBF1 interacts with specific binding sites located both in the promoter and in the enhancer regions of the SLAMF1 gene and is critical for its expression in human B cells. PMID:27424222

  1. CYTOMEGALOVIRUS VECTORS VIOLATE CD8+ T CELL EPITOPE RECOGNITION PARADIGMS

    OpenAIRE

    Hansen, Scott G.; Sacha, Jonah B.; Hughes, Colette M.; Ford, Julia C.; Burwitz, Benjamin J.; Scholz, Isabel; Gilbride, Roxanne M.; Lewis, Matthew S.; Gilliam, Awbrey N.; Ventura, Abigail B.; Malouli, Daniel; Xu, Guangwu; Richards, Rebecca; Whizin, Nathan; Reed, Jason S.

    2013-01-01

    CD8+ T cell responses focus on a small fraction of pathogen- or vaccine-encoded peptides, and for some pathogens, these restricted recognition hierarchies limit the effectiveness of anti-pathogen immunity. We found that simian immunodeficiency virus (SIV) protein-expressing Rhesus Cytomegalovirus (RhCMV) vectors elicit SIV-specific CD8+ T cells that recognize unusual, diverse and highly promiscuous epitopes, including dominant responses to epitopes restricted by class II major histocompatibil...

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

    Directory of Open Access Journals (Sweden)

    Marta Benito-Miguel

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

  3. Induction of heat shock proteins in B-cell exosomes.

    Science.gov (United States)

    Clayton, Aled; Turkes, Attilla; Navabi, Hossein; Mason, Malcolm D; Tabi, Zsuzsanna

    2005-08-15

    Exosomes are nanometer-sized vesicles secreted by a diverse range of live cells that probably have physiological roles in modulating cellular immunity. The extracellular factors that regulate the quantity and phenotype of exosomes produced are poorly understood, and the properties of exosomes that dictate their immune functions are not yet clear. We investigated the effect of cellular stress on the exosomes produced by B-lymphoblastoid cell lines. Under steady-state conditions, the exosomes were positive for hsp27, hsc70, hsp70 and hsp90, and other recognised exosome markers such as MHC class I, CD81, and LAMP-2. Exposing cells to heat stress (42 degrees C for up to 3 hours), resulted in a marked increase in these heat shock proteins (hsps), while the expression of other stress proteins such as hsp60 and gp96 remained negative, and other exosome markers remained unchanged. Stress also triggered a small increase in the quantity of exosomes produced [with a ratio of 1.245+/-0.07 to 1 (mean+/-s.e.m., n=20) of 3-hour-stress-exosomes to control-exosomes]. Flow-cytometric analysis of exosome-coated beads and immuno-precipitation of intact exosomes demonstrated that hsps were located within the exosome lumen, and not present at the exosome-surface, suggesting that such exosomes may not interact with target cells through cell-surface hsp-receptors. Functional studies further supported this finding, in that exosomes from control or heat-stressed B cells did not trigger dendritic cell maturation, assessed by analysis of dendritic-cell-surface phenotype, and cytokine secretion profile. Our findings demonstrate that specific alterations in exosome phenotype are a hitherto unknown component of the cellular response to environmental stress and their extracellular function does not involve the direct activation of dendritic cells. PMID:16046478

  4. Benchmarking biodiversity performances of farmers

    NARCIS (Netherlands)

    Snoo, de G.R.; Lokhorst, A.M.; Dijk, van J.; Staats, H.; Musters, C.J.M.

    2010-01-01

    Farmers are the key players when it comes to the enhancement of farmland biodiversity. In this study, a benchmark system that focuses on improving farmers’ nature conservation was developed and tested among Dutch arable farmers in different social settings. The results show that especially tailored

  5. Benchmark calculations for EGS5

    International Nuclear Information System (INIS)

    In the past few years, EGS4 has undergone an extensive upgrade to EGS5, in particularly in the areas of low-energy electron physics, low-energy photon physics, PEGS cross section generation, and the coding from Mortran to Fortran programming. Benchmark calculations have been made to assure the accuracy, reliability and high quality of the EGS5 code system. This study reports three benchmark examples that show the successful upgrade from EGS4 to EGS5 based on the excellent agreements among EGS4, EGS5 and measurements. The first benchmark example is the 1969 Crannell Experiment to measure the three-dimensional distribution of energy deposition for 1-GeV electrons shower in water and aluminum tanks. The second example is the 1995 Compton-scattered spectra measurements for 20-40 keV, linearly polarized photon by Namito et. al., in KEK, which was a main part of the low-energy photon expansion work for both EGS4 and EGS5. The third example is the 1986 heterogeneity benchmark experiment by Shortt et. al., who used a monoenergetic 20-MeV electron beam to hit the front face of a water tank containing both air and aluminum cylinders and measured spatial depth dose distribution using a small solid-state detector. (author)

  6. Nominal GDP: Target or Benchmark?

    OpenAIRE

    Hetzel, Robert L.

    2015-01-01

    Some observers have argued that the Federal Reserve would best fulfill its mandate by adopting a target for nominal gross domestic product (GDP). Insights from the monetarist tradition suggest that nominal GDP targeting could be destabilizing. However, adopting benchmarks for both nominal and real GDP could offer useful information about when monetary policy is too tight or too loose.

  7. Monte Carlo photon benchmark problems

    International Nuclear Information System (INIS)

    Photon benchmark calculations have been performed to validate the MCNP Monte Carlo computer code. These are compared to both the COG Monte Carlo computer code and either experimental or analytic results. The calculated solutions indicate that the Monte Carlo method, and MCNP and COG in particular, can accurately model a wide range of physical problems. 8 refs., 5 figs

  8. Benchmarked Library Websites Comparative Study

    KAUST Repository

    Ramli, Rindra M.

    2015-01-01

    This presentation provides an analysis of services provided by the benchmarked library websites. The exploratory study includes comparison of these websites against a list of criterion and presents a list of services that are most commonly deployed by the selected websites. In addition to that, the investigators proposed a list of services that could be provided via the KAUST library website.

  9. PRISMATIC CORE COUPLED TRANSIENT BENCHMARK

    Energy Technology Data Exchange (ETDEWEB)

    J. Ortensi; M.A. Pope; G. Strydom; R.S. Sen; M.D. DeHart; H.D. Gougar; C. Ellis; A. Baxter; V. Seker; T.J. Downar; K. Vierow; K. Ivanov

    2011-06-01

    The Prismatic Modular Reactor (PMR) is one of the High Temperature Reactor (HTR) design concepts that have existed for some time. Several prismatic units have operated in the world (DRAGON, Fort St. Vrain, Peach Bottom) and one unit is still in operation (HTTR). The deterministic neutronics and thermal-fluids transient analysis tools and methods currently available for the design and analysis of PMRs have lagged behind the state of the art compared to LWR reactor technologies. This has motivated the development of more accurate and efficient tools for the design and safety evaluations of the PMR. In addition to the work invested in new methods, it is essential to develop appropriate benchmarks to verify and validate the new methods in computer codes. The purpose of this benchmark is to establish a well-defined problem, based on a common given set of data, to compare methods and tools in core simulation and thermal hydraulics analysis with a specific focus on transient events. The benchmark-working group is currently seeking OECD/NEA sponsorship. This benchmark is being pursued and is heavily based on the success of the PBMR-400 exercise.

  10. Low frequency of broadly neutralizing HIV antibodies during chronic infection even in quaternary epitope targeting antibodies containing large numbers of somatic mutations.

    Science.gov (United States)

    Hicar, Mark D; Chen, Xuemin; Kalams, Spyros A; Sojar, Hakimuddin; Landucci, Gary; Forthal, Donald N; Spearman, Paul; Crowe, James E

    2016-02-01

    Neutralizing antibodies (Abs) are thought to be a critical component of an appropriate HIV vaccine response. It has been proposed that Abs recognizing conformationally dependent quaternary epitopes on the HIV envelope (Env) trimer may be necessary to neutralize diverse HIV strains. A number of recently described broadly neutralizing monoclonal Abs (mAbs) recognize complex and quaternary epitopes. Generally, many such Abs exhibit extensive numbers of somatic mutations and unique structural characteristics. We sought to characterize the native antibody (Ab) response against circulating HIV focusing on such conformational responses, without a prior selection based on neutralization. Using a capture system based on VLPs incorporating cleaved envelope protein, we identified a selection of B cells that produce quaternary epitope targeting Abs (QtAbs). Similar to a number of broadly neutralizing Abs, the Ab genes encoding these QtAbs showed extensive numbers of somatic mutations. However, when expressed as recombinant molecules, these Abs failed to neutralize virus or mediate ADCVI activity. Molecular analysis showed unusually high numbers of mutations in the Ab heavy chain framework 3 region of the variable genes. The analysis suggests that large numbers of somatic mutations occur in Ab genes encoding HIV Abs in chronically infected individuals in a non-directed, stochastic, manner. PMID:26748387

  11. Epitope Mapping of Avian Influenza M2e Protein: Different Species Recognise Various Epitopes

    Science.gov (United States)

    Hasan, Noor Haliza; Ignjatovic, Jagoda; Tarigan, Simson; Peaston, Anne; Hemmatzadeh, Farhid

    2016-01-01

    A common approach for developing diagnostic tests for influenza virus detection is the use of mouse or rabbit monoclonal and/or polyclonal antibodies against a target antigen of the virus. However, comparative mapping of the target antigen using antibodies from different animal sources has not been evaluated before. This is important because identification of antigenic determinants of the target antigen in different species plays a central role to ensure the efficiency of a diagnostic test, such as competitive ELISA or immunohistochemistry-based tests. Interest in the matrix 2 ectodomain (M2e) protein of avian influenza virus (AIV) as a candidate for a universal vaccine and also as a marker for detection of virus infection in vaccinated animals (DIVA) is the rationale for the selection of this protein for comparative mapping evaluation. This study aimed to map the epitopes of the M2e protein of avian influenza virus H5N1 using chicken, mouse and rabbit monoclonal or monospecific antibodies. Our findings revealed that rabbit antibodies (rAbs) recognized epitope 6EVETPTRN13 of the M2e, located at the N-terminal of the protein, while mouse (mAb) and chicken antibodies (cAbs) recognized epitope 10PTRNEWECK18, located at the centre region of the protein. The findings highlighted the difference between the M2e antigenic determinants recognized by different species that emphasized the importance of comparative mapping of antibody reactivity from different animals to the same antigen, especially in the case of multi-host infectious agents such as influenza. The findings are of importance for antigenic mapping, as well as diagnostic test and vaccine development. PMID:27362795

  12. Identification of uniquely expressed transcription factors in highly purified B-cell lymphoma samples

    DEFF Research Database (Denmark)

    Andréasson, Ulrika; Edén, Patrik; Peterson, Carsten; Högerkorp, Carl-Magnus; Jerkeman, Mats; Andersen, Niels Smedegaard; Berglund, Mattias; Sundström, Christer; Rosenquist, Richard; Borrebaeck, Carl A K; Ek, Sara

    2010-01-01

    Transcription factors (TFs) are critical for B-cell differentiation, affecting gene expression both by repression and transcriptional activation. Still, this information is not used for classification of B-cell lymphomas (BCLs). Traditionally, BCLs are diagnosed based on a phenotypic resemblance ...

  13. T-dependent B-cell activation is signalled by an early increase in potassium influx

    DEFF Research Database (Denmark)

    Owens, T; Kaplan, J G

    1982-01-01

    (previously demonstrated when B and T lymphocytes were separately stimulated) also occurs when B cells are stimulated through cooperation with mitogen-activated T cells, and is also detectable early in culture. T-dependent activation of B cells is therefore detectable considerably earlier than by conventional...

  14. Study of BKM120 & Rituximab in Patients With Relapsed or Refractory Indolent B-Cell Lymphoma

    Science.gov (United States)

    2016-06-14

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

  15. Identification of a negative regulatory role for spi-C in the murine B cell lineage.

    Science.gov (United States)

    Li, Stephen K H; Solomon, Lauren A; Fulkerson, Patricia C; DeKoter, Rodney P

    2015-04-15

    Spi-C is an E26 transformation-specific family transcription factor that is highly related to PU.1 and Spi-B. Spi-C is expressed in developing B cells, but its function in B cell development and function is not well characterized. To determine whether Spi-C functions as a negative regulator of Spi-B (encoded by Spib), mice were generated that were germline knockout for Spib and heterozygous for Spic (Spib(-/-)Spic(+/-)). Interestingly, loss of one Spic allele substantially rescued B cell frequencies and absolute numbers in Spib(-/-) mouse spleens. Spib(-/-)Spic(+/-) B cells had restored proliferation compared with Spib(-/-) B cells in response to anti-IgM or LPS stimulation. Investigation of a potential mechanism for the Spib(-/-)Spic(+/-) phenotype revealed that steady-state levels of Nfkb1, encoding p50, were elevated in Spib(-/-)Spic(+/-) B cells compared with Spib(-/-) B cells. Spi-B was shown to directly activate the Nfkb1 gene, whereas Spi-C was shown to repress this gene. These results indicate a novel role for Spi-C as a negative regulator of B cell development and function. PMID:25769919

  16. DEFECTS IN INSULIN-SECRETION IN NIDDM - B-CELL GLUCOSE INSENSITIVITY OR GLUCOSE TOXICITY

    NARCIS (Netherlands)

    VANHAEFTEN, TW

    1993-01-01

    In NIDDM, first-phase insulin release to glucose is (almost) absent. However, in contrast to older studies which suggested that in NIDDM the B-cell is ''blind'' for glucose, recent evidence indicates that the B-cell is not insensitive for glucose as far as second phase release is concerned. This sug

  17. Atypical and classical memory B cells produce Plasmodium falciparum neutralizing antibodies

    DEFF Research Database (Denmark)

    Muellenbeck, Matthias F; Ueberheide, Beatrix; Amulic, Borko;

    2013-01-01

    . We show at the single cell level that natural Pf infection induces the development of classical memory B cells (CM) and atypical memory B cells (AtM) that produce broadly neutralizing antibodies against blood stage Pf parasites. CM and AtM contribute to anti-Pf serum IgG production, but only AtM show...

  18. Selective loss of B-cell phenotype in lymphocyte predominant Hodgkin lymphoma.

    NARCIS (Netherlands)

    Tedoldi, S.; Mottok, A.; Ying, J.; Paterson, J.C.; Cui, Y.; Facchetti, F.; Krieken, J.H.J.M. van; Ponzoni, M.; Ozkal, S.; Masir, N.; Natkunam, Y.; Pileri, S.; Hansmann, M.L.; Mason, D.; Tao, Q.; Marafioti, T.

    2007-01-01

    The neoplastic Reed-Sternberg cells characteristic of classical Hodgkin's lymphoma (cHL) are of B-cell origin but they almost always show striking loss of a range of B-cell-associated molecules. In contrast, the neoplastic cells found in lymphocyte predominant Hodgkin's lymphoma (LPHL) (L&H cells) a

  19. Expression pattern of FCRL (FREB, FcRX) in normal and neoplastic human B cells.

    Science.gov (United States)

    Masir, Noraidah; Jones, Margaret; Pozzobon, Michela; Marafioti, Teresa; Volkova, Olga Y; Mechetina, Ludmila V; Hansmann, Martin-Leo; Natkunam, Yasodha; Taranin, Alexander V; Mason, David Y

    2004-11-01

    FCRL (also known as FREB and FcRX) is a recently described member of the family of Fc receptors for immunoglobulin G (IgG). In the present study we analysed its expression in normal and neoplastic lymphoid tissue using immunohistochemical techniques. FCRL was preferentially expressed in a proportion of germinal centre cells and, more weakly, in mantle zone B cells. In addition, strong labelling was observed in marginal zone B cells in the spleen, representing one of the few markers for this cell type. The majority of cases of small B-cell lymphoma, diffuse large B-cell lymphoma and lymphocyte predominance Hodgkin's disease were positive for FCRL. However, the number of positive cells varied widely, and in consequence we could not define a cut-off that distinguished subsets of diffuse large B-cell lymphoma. Our results also showed that FCRL tended to be negative in T-cell-rich B-cell lymphoma and in classical Hodgkin's disease. FCRL may therefore represent a novel marker for normal B cells (e.g. splenic marginal zone cells) and may also be useful as a potential marker of B-cell neoplasms. PMID:15491296

  20. A multi-scale model for correlation in B cell VDJ usage of zebrafish

    International Nuclear Information System (INIS)

    The zebrafish (Danio rerio) is one of the model animals used for the study of immunology because the dynamics in the adaptive immune system of zebrafish are similar to that in higher animals. In this work, we built a multi-scale model to simulate the dynamics of B cells in the primary and secondary immune responses of zebrafish. We use this model to explain the reported correlation between VDJ usage of B cell repertoires in individual zebrafish. We use a delay ordinary differential equation (ODE) system to model the immune responses in the 6-month lifespan of a zebrafish. This mean field theory gives the number of high-affinity B cells as a function of time during an infection. The sequences of those B cells are then taken from a distribution calculated by a 'microscopic' random energy model. This generalized NK model shows that mature B cells specific to one antigen largely possess a single VDJ recombination. The model allows first-principle calculation of the probability, p, that two zebrafish responding to the same antigen will select the same VDJ recombination. This probability p increases with the B cell population size and the B cell selection intensity. The probability p decreases with the B cell hypermutation rate. The multi-scale model predicts correlations in the immune system of the zebrafish that are highly similar to that from experiment

  1. A multi-scale model for correlation in B cell VDJ usage of zebrafish

    Science.gov (United States)

    Pan, Keyao; Deem, Michael W.

    2011-10-01

    The zebrafish (Danio rerio) is one of the model animals used for the study of immunology because the dynamics in the adaptive immune system of zebrafish are similar to that in higher animals. In this work, we built a multi-scale model to simulate the dynamics of B cells in the primary and secondary immune responses of zebrafish. We use this model to explain the reported correlation between VDJ usage of B cell repertoires in individual zebrafish. We use a delay ordinary differential equation (ODE) system to model the immune responses in the 6-month lifespan of a zebrafish. This mean field theory gives the number of high-affinity B cells as a function of time during an infection. The sequences of those B cells are then taken from a distribution calculated by a 'microscopic' random energy model. This generalized NK model shows that mature B cells specific to one antigen largely possess a single VDJ recombination. The model allows first-principle calculation of the probability, p, that two zebrafish responding to the same antigen will select the same VDJ recombination. This probability p increases with the B cell population size and the B cell selection intensity. The probability p decreases with the B cell hypermutation rate. The multi-scale model predicts correlations in the immune system of the zebrafish that are highly similar to that from experiment.

  2. A NOVel ELISPOT assay to quantify HLA-specific B cells in HLA-immunized individuals

    NARCIS (Netherlands)

    Heidt, S.; Roelen, D.L.; Vaal, Y.J. de; Kester, M.G.; Eijsink, C.; Thomas, S.; Besouw, N.M. van; Volk, H.D.; Weimar, W.; Claas, F.H.; Mulder, A.

    2012-01-01

    Quantification of the humoral alloimmune response is generally achieved by measuring serum HLA antibodies, which provides no information about the cells involved in the humoral immune response. Therefore, we have developed an HLA-specific B-cell ELISPOT assay allowing for quantification of B cells p

  3. Large-scale analysis of B-cell epitopes on influenza virus hemagglutinin - implications for cross-reactivity of neutralizing antibodies

    OpenAIRE

    Jing eSun; Ulrich eKudahl; Zhiwei eCao; Christian eSimon; Reinherz, Ellis L; Vladimir eBrusic

    2014-01-01

    Influenza viruses continue to cause substantial morbidity and mortality worldwide. Fast gene mutation on surface proteins of influenza virus result in increasing resistance to current vaccines and available antiviral drugs. Broadly neutralizing antibodies represent targets for prophylactic and therapeutic treatments of influenza. We performed a systematic bioinformatics study of cross-reactivity of neutralizing antibodies against influenza virus surface glycoprotein hemagglutinin (HA). This s...

  4. Large-scale analysis of B-cell epitopes on influenza virus hemagglutinin - implications for cross-reactivity of neutralizing antibodies.

    OpenAIRE

    Sun, Jing; Kudahl, Ulrich J.; Simon, Christian; Cao, Zhiwei; Reinherz, Ellis L; Brusic, Vladimir

    2014-01-01

    Influenza viruses continue to cause substantial morbidity and mortality worldwide. Fast gene mutation on surface proteins of influenza virus result in increasing resistance to current vaccines and available antiviral drugs. Broadly neutralizing antibodies (bnAbs) represent targets for prophylactic and therapeutic treatments of influenza. We performed a systematic bioinformatics study of cross-reactivity of neutralizing antibodies (nAbs) against influenza virus surface glycoprotein hemagglutin...

  5. Influenza B-cells Protective Epitope Characterization: A Passkey for the Rational Design of New Broad-Range Anti-Influenza Vaccines

    OpenAIRE

    Roberto Burioni; Massimo Clementi; Matteo Castelli; Nicasio Mancini; Elena Criscuolo; Nicola Clementi

    2012-01-01

    The emergence of new influenza strains causing pandemics represents a serious threat to human health. From 1918, four influenza pandemics occurred, caused by H1N1, H2N2 and H3N2 subtypes. Moreover, in 1997 a novel influenza avian strain belonging to the H5N1 subtype infected humans. Nowadays, even if its transmission is still circumscribed to avian species, the capability of the virus to infect humans directly from avian reservoirs can result in fatalities. Moreover, the risk that this or nov...

  6. Influenza B-Cells Protective Epitope Characterization: A Passkey for the Rational Design of New Broad-Range Anti-Influenza Vaccines

    Directory of Open Access Journals (Sweden)

    Roberto Burioni

    2012-11-01

    Full Text Available The emergence of new influenza strains causing pandemics represents a serious threat to human health. From 1918, four influenza pandemics occurred, caused by H1N1, H2N2 and H3N2 subtypes. Moreover, in 1997 a novel influenza avian strain belonging to the H5N1 subtype infected humans. Nowadays, even if its transmission is still circumscribed to avian species, the capability of the virus to infect humans directly from avian reservoirs can result in fatalities. Moreover, the risk that this or novel avian strains could adapt to inter-human transmission, the development of resistance to anti-viral drugs and the lack of an effective prevention are all incumbent problems for the world population. In this scenario, the identification of broadly neutralizing monoclonal antibodies (mAbs directed against conserved regions shared among influenza isolates has raised hopes for the development of monoclonal antibody-based immunotherapy and “universal” anti-influenza vaccines.

  7. Identification of Hitherto Undefined B-Cell Epitopes by Antibodies in the Sera of Vitiligo Patients Using Phage-Display Peptide Library

    Directory of Open Access Journals (Sweden)

    Zohreh Jadali

    2003-12-01

    Full Text Available A random 12 mers phage library was used to screen a pool of immunoglo¬bulin fractions obtained from vitiligo patients. Subsequent to panning experiments, a panel of affinity selected phage from vitiligo patients were obtained. This panel was tested using an ELIS A for their reactivity with pooled sera from patients and normal controls. Among the 16 randomly selected clones, two of clones showed distinct positive reactivity with the patient's sera compared with controls. The peptides displayed by these phages expressed the following amino acid sequences: SHMPLANQYQWA and NHVQAWEQFWDS. Thus, screening with phage-displayed random peptide library of vitiligo sera can reveal peptide sequences that mimic vitiligo-related self-antigen.

  8. B-cell clonality in the liver of hepatitis C virus-infected patients

    Institute of Scientific and Technical Information of China (English)

    He-Bin Fan; You-Fu Zhu; An-Shen Chen; Mu-Xiu Zhou; Fu-Ming Yan; Xiao-Ju Ma; Hao Zhou

    2009-01-01

    AIM: The association of hepatitis C virus (HCV) infection with type Ⅱ mixed cryoglobulinemia is well established, but the role of HCV in B-cell lymphoma remains controversial. In patients with HCV infection, B-cell clonal expansions have been detected in peripheral blood and bone marrow, and a high been documented. Liver biopsies in chronic HCV infection frequently show portal lymphoid infiltrates with features of B follicles, whose clonality has not yet been investigated. The object of this study was to determine the frequency of liver-infiltrating monoclonal B-cells in 40 patients with HCV infection. METHODS: Eight hundred and forty-eight patients were studied prospectively, including 40 HCV-positive patients and 808 patients with chronic hepatitis B virus (HBV) infection. Immunohistochemical study for B- and T-cell markers was performed on the paraffin-embedded liver tissue sections. The clonality of lymphoid B-cells was tested using a polymerase chain reaction (PCR) approach designed to identify immunoglobulin heavy chain gene ( IgH) rearrangements. RESULTS: Liver-infiltrating monoclonal B-cells were detected in the liver for 4 (10%) of 40 HCV-positive patients but were present in only 3 (0.37%) of 808 liver biopsy specimens with chronic HBV infection. Chi-square testing showed that the monoclonal B-cells infiltration in the liver was more frequent in the HCV-infected patients ( P = 0.000). A clonal IgH rearrangement was detected in 5 (71.4%) of 7 liver biopsy specimens with monoclonal B-cells infiltration. In 2 of 5 patients with both a clonal B-cell expansion and monoclonal B-cells infiltration in the liver, a definite B-cell malignancy was finally diagnosed. CONCLUSION: Liver-infiltrating monoclonal B-cells are detected in the liver of patients with chronic HCV and HBV infection. A high percentage of patients with monoclonal B-cells infiltration and B-cell clonality in the liver were finally diagnosed as having a definite B-cell malignancy.

  9. Preparation of antisera specific for human B cells by immunization of rabbits with immune complexes

    International Nuclear Information System (INIS)

    Three rabbit antisera are described which are specific without absorption (titer 1:100) for separated human B cells, as measured by complement and non-complement fixing assays. The method of production of these sera involved injections of rabbits with precipitin lines formed between 10μ1 of three separate detergent solubilized membrane preparations and 4μ1 aliquots of rabbit antisera to human B cells. In addition to being B cell specific, the three sera block the MLC reaction, inhibit aggregated IgG binding to B cells, and show differential degrees of B cell lysis when tested on a panel of separated B and T cells. These and other properties suggest that the target specificities of the antibodies are the human equivalent of the murine Ia antigens. (author)

  10. Uptake and presentation of myelin basic protein by normal human B cells

    DEFF Research Database (Denmark)

    Brimnes, Marie Klinge; Hansen, Bjarke Endel; Nielsen, Leif Kofoed;

    2014-01-01

    were capable of binding the MS-associated self-antigen myelin basic protein (MBP) and of presenting the immunodominant peptide MBP85-99, as determined by staining with the mAb MK16 recognising the peptide presented by HLA-DR15-positive cells. In the presence of serum, however, the majority of B cells...... proportion of MBP85-99 presenting B cells expressed CD27, and showed increased expression of CD86 compared to non-presenting B cells. MBP-pulsed B cells induced a low frequency of IL-10-producing CD4+ T cells in 3 out of 6 donors, indicating an immunoregulatory role of B cells presenting MBP-derived peptides...

  11. Antigen-specific monoclonal antibodies isolated from B cells expressing constitutively active STAT5.

    Directory of Open Access Journals (Sweden)

    Ferenc A Scheeren

    Full Text Available BACKGROUND: Fully human monoclonal antibodies directed against specific pathogens have a high therapeutic potential, but are difficult to generate. METHODOLOGY/PRINCIPAL FINDINGS: Memory B cells were immortalized by expressing an inducible active mutant of the transcription factor Signal Transducer and Activator of Transcription 5 (STAT5. Active STAT5 inhibits the differentiation of B cells while increasing their replicative life span. We obtained cloned B cell lines, which produced antibodies in the presence of interleukin 21 after turning off STAT5. We used this method to obtain monoclonal antibodies against the model antigen tetanus toxin. CONCLUSIONS/SIGNIFICANCE: Here we describe a novel and relatively simple method of immortalizing antigen-specific human B cells for isolation of human monoclonal antibodies. These results show that STAT5 overexpression can be employed to isolate antigen specific antibodies from human memory B cells.

  12. Sulfhydryl-based tumor antigen-carrier protein conjugates stimulate superior antitumor immunity against B cell lymphomas.

    Science.gov (United States)

    Betting, David J; Kafi, Kamran; Abdollahi-Fard, Alireza; Hurvitz, Sara A; Timmerman, John M

    2008-09-15

    Therapeutic vaccination of B cell lymphoma patients with tumor-specific Ig (idiotype, or Id) chemically coupled to the immunogenic foreign carrier protein keyhole limpet hemocyanin (KLH) using glutaraldehyde has shown promising results in early clinical trials, and phase III trials are underway. However, glutaraldehyde Id-KLH vaccines fail to elicit anti-Id immune and clinical responses in many patients, possibly because glutaraldehyde reacts with lysine, cysteine, tyrosine, and histidine residues, damaging critical immunogenic epitopes. A sulfhydryl-based tumor Ag-carrier protein conjugation system using maleimide chemistry was used to enhance the efficacy of Id-KLH vaccines. Maleimide Id-KLH conjugates eradicated A20 lymphoma from most tumor-bearing mice, whereas glutaraldehyde Id-KLH had little efficacy. Maleimide Id-KLH elicited tumor-specific IgG Abs and T cells, with CD8(+) T cells being the major effectors of antilymphoma immunity. Maleimide Id-KLH vaccines also demonstrated superior efficacy in 38C13 and BCL-1 lymphoma models, where Abs were shown to be critical for protection. Importantly, standard glutaraldehyde Id-KLH conjugation procedures could result in "overconjugation" of the tumor Ag, leading to decreased efficacy, whereas the heterobifunctional maleimide-based conjugation yielded potent vaccine product regardless of conjugation duration. Under lysosomal processing conditions, the Id-carrier protein linkage was cleavable only after maleimide conjugation. Maleimide KLH conjugation was easily performed with human Igs analogous to those used in Id-KLH clinical trials. These data support the evaluation of sulfhydryl-based Id-KLH vaccines in lymphoma clinical trials and possibly the use of tumor Ag-carrier protein vaccines for other cancers. PMID:18768870

  13. BONFIRE: benchmarking computers and computer networks

    OpenAIRE

    Bouckaert, Stefan; Vanhie-Van Gerwen, Jono; Moerman, Ingrid; Phillips, Stephen; Wilander, Jerker

    2011-01-01

    The benchmarking concept is not new in the field of computing or computer networking. With “benchmarking tools”, one usually refers to a program or set of programs, used to evaluate the performance of a solution under certain reference conditions, relative to the performance of another solution. Since the 1970s, benchmarking techniques have been used to measure the performance of computers and computer networks. Benchmarking of applications and virtual machines in an Infrastructure-as-a-Servi...

  14. B cell depletion with rituximab in patients with rheumatoid arthritis: Multiplex bead array reveals the kinetics of IgG and IgA antibodies to citrullinated antigens.

    Science.gov (United States)

    Cambridge, Geraldine; Leandro, Maria J; Lahey, Lauren J; Fairhead, Thomas; Robinson, William H; Sokolove, Jeremy

    2016-06-01

    -Relapse. Individual responses to particular Cit-epitopes were not linked to particular patterns of fluctuation, but IgG- and IgA-ACPA to individual Cit-antigens often followed similar courses. Some new IgG- and IgA-ACPA, generally to different Cit-antigens however, arose at Relapse in 4 patients. The complexities of the ACPA response after rituximab may therefore reflect its ability to deplete or modify the function of parent B cell clones, which varies between patients. Although relapse following rituximab invariably follows naïve B cell exit from the bone marrow, these studies show that interactions between both 'new' and residual autoreactive memory B cells may be key to resumption of symptoms. The lack of identification of any immunodominant specificity suggests that the process of citrullination, rather than any particular Cit-antigen drives the autoimmune response in RA patients. PMID:27055777

  15. Human Lyb-2 homolog CD72 is a marker for progenitor B-cell leukemias.

    Science.gov (United States)

    Schwarting, R; Castello, R; Moldenhauer, G; Pezzutto, A; von Hoegen, I; Ludwig, W D; Parnes, J R; Dörken, B

    1992-11-01

    S-HCL 2 is the prototype antibody of the recently defined CD72 cluster (human Lyb-2). Under nonreducing conditions, S-HCL 2 monoclonal antibody (mAb) precipitates a glycoprotein of 80-86 kDa. Under reducing conditions, a dimer of 43 and 39 kDa, with core proteins of 40 and 36 kDa, is precipitated. CD72 expression in normal and malignant tissues is different from expression of all other previously described human B-cell antigens. In peripheral blood and bone marrow, the antigen appears to be present on all B lymphocytes, with the exception of plasma cells. In tissue, immunohistochemical staining revealed positivity for all known B-cell compartments; however, pulpa macrophages of the spleen and von Kupffer cells exhibited distinct positivity for CD72 also. Among 83 malignant non-Hodgkin's lymphomas examined by immunohistochemistry (alkaline phosphatase anti-alkaline phosphatase technique), all 54 B-cell lymphomas, including precursor B-cell lymphomas, Burkitt's lymphomas, germinal center lymphomas, chronic lymphocytic leukemias, and hairy cell leukemias, were CD72 positive, but no T-cell lymphomas were. Flow cytometry study of more than 80 mainly acute leukemias (52 B-cell leukemias) showed reactivity with S-HCL 2 mAb over the full range of B-cell differentiation. In particular, very early B cells in cytoplasmic Ig (cIg)-negative, CD19-positive pre-pre-B-cell leukemias and hybrid leukemias (mixed myeloid and B-cell type) were consistently positive for CD72 on the cell surface. Therefore, CD72 may become an important marker for progenitor B-cell leukemias. PMID:1384316

  16. Patients with Tuberculosis Have a Dysfunctional Circulating B-Cell Compartment, Which Normalizes following Successful Treatment

    Science.gov (United States)

    del Nonno, Franca; Baiocchini, Andrea; Petrone, Linda; Vanini, Valentina; Smits, Hermelijn H.; Palmieri, Fabrizio; Goletti, Delia; Ottenhoff, Tom H. M.

    2016-01-01

    B-cells not only produce immunoglobulins and present antigens to T-cells, but also additional key roles in the immune system. Current knowledge on the role of B-cells in infections caused by intracellular bacteria is fragmentary and contradictory. We therefore analysed the phenotypical and functional properties of B-cells during infection and disease caused by Mycobacterium tuberculosis (Mtb), the bacillus causing tuberculosis (TB), and included individuals with latent TB infection (LTBI), active TB, individuals treated successfully for TB, and healthy controls. Patients with active or treated TB disease had an increased proportion of antibodies reactive with mycobacteria. Patients with active TB had reduced circulating B-cell frequencies, whereas only minor increases in B-cells were detected in the lungs of individuals deceased from TB. Both active TB patients and individuals with LTBI had increased relative fractions of B-cells with an atypical phenotype. Importantly, these B-cells displayed impaired proliferation, immunoglobulin- and cytokine- production. These defects disappeared upon successful treatment. Moreover, T-cell activity was strongest in individuals successfully treated for TB, compared to active TB patients and LTBI subjects, and was dependent on the presence of functionally competent B-cells as shown by cellular depletion experiments. Thus, our results reveal that general B-cell function is impaired during active TB and LTBI, and that this B-cell dysfunction compromises cellular host immunity during Mtb infection. These new insights may provide novel strategies for correcting Mtb infection-induced immune dysfunction towards restored protective immunity. PMID:27304615

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

    Directory of Open Access Journals (Sweden)

    Opas Traitanon

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

  18. Dimethyl fumarate treatment of relapsing-remitting multiple sclerosis influences B-cell subsets

    Science.gov (United States)

    Lundy, Steven K.; Wu, Qi; Wang, Qin; Dowling, Catherine A.; Taitano, Sophina H.; Mao, Guangmei

    2016-01-01

    Objective: To test the hypothesis that dimethyl fumarate (Tecfidera, BG-12) affects B-cell subsets in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: Peripheral blood B cells were compared for surface marker expression in patients with RRMS prior to initiation of treatment, after 4–6 months, and at more than 1 year of treatment with BG-12. Production of interleukin (IL)–10 by RRMS patient B cells was also analyzed. Results: Total numbers of peripheral blood B lymphocytes declined after 4–6 months of BG-12 treatment, due to losses in both the CD27+ memory B cells and CD27neg B-cell subsets. Some interpatient variability was observed. In contrast, circulating CD24highCD38high (T2-MZP) B cells increased in percentage in the majority of patients with RRMS after 4–6 months and were present in higher numbers in all of the patients after 12 months of treatment. The CD43+CD27+ B-1 B cells also increased at the later time point in most patients but were unchanged at 4–6 months compared to pretreatment levels. Purified B cells from 7 of the 9 patients with RRMS tested after 4–6 months of treatment were able to produce IL-10 following CD40 ligand stimulation, and the amount corresponded with the combined levels of T2-MZP and B-1 B cells in the sample. None of the patients with RRMS in this study have had a relapse while taking BG-12. Conclusions: These data suggest that BG-12 differentially affects B-cell subsets in patients with RRMS, resulting in increased numbers of circulating B lymphocytes with regulatory capacity. PMID:27006972

  19. TGF-β-Induced Regulatory T Cells Directly Suppress B Cell Responses through a Noncytotoxic Mechanism.

    Science.gov (United States)

    Xu, Anping; Liu, Ya; Chen, Weiqian; Wang, Julie; Xue, Youqiu; Huang, Feng; Rong, Liming; Lin, Jin; Liu, Dahai; Yan, Mei; Li, Quan-Zhen; Li, Bin; Song, Jianxun; Olsen, Nancy; Zheng, Song Guo

    2016-05-01

    Foxp3(+) regulatory T cells (Treg) playing a crucial role in the maintenance of immune tolerance and prevention of autoimmune diseases consist of thymus-derived naturally occurring CD4(+)Foxp3(+) Treg cells (nTreg) and those that can be induced ex vivo with TGF-β (iTreg). Although both Treg subsets share similar phenotypes and functional characteristics, they also have potential biologic differences on their biology. The role of iTreg in regulating B cells remains unclear so far. The suppression assays of Treg subsets on activation, proliferation, and Abs production of B cells were measured using a Treg and B cell coculture system in vitro. Transwell and Ab blockade experiments were performed to assess the roles of cell contact and soluble cytokines. Treg were adoptively transferred to lupus mice to assess in vivo effects on B cells. Like nTreg, iTreg subset also directly suppressed activation and proliferation of B cells. nTreg subset suppressed B cell responses through cytotoxic manner related to expression of granzyme A, granzyme B, and perforin, whereas the role of iTreg subset on B cells did not involve in cytotoxic action but depending on TGF-β signaling. Furthermore, iTreg subset can significantly suppress Ab produced by lupus B cells in vitro. Comparison experiments using autoantibodies microarrays demonstrated that adoptive transfer of iTreg had a superior effect than nTreg subset on suppressing lupus B cell responses in vivo. Our data implicate a role and advantage of iTreg subset in treating B cell-mediated autoimmune diseases, boosting the translational potential of these findings. PMID:27001954

  20. YY1 plays an essential role at all stages of B-cell differentiation.

    Science.gov (United States)

    Kleiman, Eden; Jia, Haiqun; Loguercio, Salvatore; Su, Andrew I; Feeney, Ann J

    2016-07-01

    Ying Yang 1 (YY1) is a ubiquitously expressed transcription factor shown to be essential for pro-B-cell development. However, the role of YY1 in other B-cell populations has never been investigated. Recent bioinformatics analysis data have implicated YY1 in the germinal center (GC) B-cell transcriptional program. In accord with this prediction, we demonstrated that deletion of YY1 by Cγ1-Cre completely prevented differentiation of GC B cells and plasma cells. To determine if YY1 was also required for the differentiation of other B-cell populations, we deleted YY1 with CD19-Cre and found that all peripheral B-cell subsets, including B1 B cells, require YY1 for their differentiation. Transitional 1 (T1) B cells were the most dependent upon YY1, being sensitive to even a half-dosage of YY1 and also to short-term YY1 deletion by tamoxifen-induced Cre. We show that YY1 exerts its effects, in part, by promoting B-cell survival and proliferation. ChIP-sequencing shows that YY1 predominantly binds to promoters, and pathway analysis of the genes that bind YY1 show enrichment in ribosomal functions, mitochondrial functions such as bioenergetics, and functions related to transcription such as mRNA splicing. By RNA-sequencing analysis of differentially expressed genes, we demonstrated that YY1 normally activates genes involved in mitochondrial bioenergetics, whereas it normally down-regulates genes involved in transcription, mRNA splicing, NF-κB signaling pathways, the AP-1 transcription factor network, chromatin remodeling, cytokine signaling pathways, cell adhesion, and cell proliferation. Our results show the crucial role that YY1 plays in regulating broad general processes throughout all stages of B-cell differentiation. PMID:27335461