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P38 MAP Kinase Signaling Is Required for the Conversion of CD4+CD25? T Cells into iTreg  [PDF]
Samuel Huber, J?rg Schrader, Gerhard Fritz, Katrin Presser, Steffen Schmitt, Ari Waisman, Stefan Lüth, Manfred Blessing, Johannes Herkel, Christoph Schramm
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003302
Abstract: CD4+CD25+ regulatory T cells (Treg) are important mediators of immune tolerance. A subset of Treg can be generated in the periphery by TGF-beta dependent conversion of conventional CD4+CD25? T cells into induced Treg (iTreg). In chronic viral infection or malignancy, such induced iTreg, which limit the depletion of aberrant or infected cells, may be of pathogenic relevance. To identify potential targets for therapeutic intervention, we investigated the TGF-beta signaling in Treg. In contrast to conventional CD4+ T cells, Treg exhibited marked activation of the p38 MAP kinase pathway. Inhibition of p38 MAP kinase activity prevented the TGF-beta-dependent conversion of CD4+CD25? T cells into Foxp3+ iTreg in vitro. Of note, the suppressive capacity of nTreg was not affected by inhibiting p38 MAP kinase. Our findings indicate that signaling via p38 MAP kinase seems to be important for the peripheral generation of iTreg; p38 MAP kinase could thus be a therapeutic target to enhance immunity to chronic viral infection or cancer.
Glutamic Acid Decarboxylase-Derived Epitopes with Specific Domains Expand CD4+CD25+ Regulatory T Cells  [PDF]
Guojiang Chen, Gencheng Han, Jiannan Feng, Jianan Wang, Renxi Wang, Ruonan Xu, Beifen Shen, Jiahua Qian, Yan Li
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0007034
Abstract: Background CD4+CD25+ regulatory T cell (Treg)-based immunotherapy is considered a promising regimen for controlling the progression of autoimmune diabetes. In this study, we tested the hypothesis that the therapeutic effects of Tregs in response to the antigenic epitope stimulation depend on the structural properties of the epitopes used. Methodology/Principal Findings Splenic lymphocytes from nonobese diabetic (NOD) mice were stimulated with different glutamic acid decarboxylase (GAD)-derived epitopes for 7–10 days and the frequency and function of Tregs was analyzed. We found that, although all expanded Tregs showed suppressive functions in vitro, only p524 (GAD524–538)-expanded CD4+CD25+ T cells inhibited diabetes development in the co-transfer models, while p509 (GAD509–528)- or p530 (GAD530–543)-expanded CD4+CD25+ T cells had no such effects. Using computer-guided molecular modeling and docking methods, the differences in structural characteristics of these epitopes and the interaction mode (including binding energy and identified domains in the epitopes) between the above-mentioned epitopes and MHC class II I-Ag7 were analyzed. The theoretical results showed that the epitope p524, which induced protective Tregs, possessed negative surface-electrostatic potential and bound two chains of MHC class II I-Ag7, while the epitopes p509 and p530 which had no such ability exhibited positive surface-electrostatic potential and bound one chain of I-Ag7. Furthermore, p524 bound to I-Ag7 more stably than p509 and p530. Of importance, we hypothesized and subsequently confirmed experimentally that the epitope (GAD570–585, p570), which displayed similar characteristics to p524, was a protective epitope by showing that p570-expanded CD4+CD25+ T cells suppressed the onset of diabetes in NOD mice. Conclusions/Significance These data suggest that molecular modeling-based structural analysis of epitopes may be an instrumental tool for prediction of protective epitopes to expand functional Tregs.
Prediction of antigenic epitopes on protein surfaces by consensus scoring
Shide Liang, Dandan Zheng, Chi Zhang, Martin Zacharias
BMC Bioinformatics , 2009, DOI: 10.1186/1471-2105-10-302
Abstract: We present a new antigen Epitope Prediction method, which uses ConsEnsus Scoring (EPCES) from six different scoring functions - residue epitope propensity, conservation score, side-chain energy score, contact number, surface planarity score, and secondary structure composition. Applied to unbounded antigen structures from an independent test set, EPCES was able to predict antigenic eptitopes with 47.8% sensitivity, 69.5% specificity and an AUC value of 0.632. The performance of the method is statistically similar to other published methods. The AUC value of EPCES is slightly higher compared to the best results of existing algorithms by about 0.034.Our work shows consensus scoring of multiple features has a better performance than any single term. The successful prediction is also due to the new score of residue epitope propensity based on atomic solvent accessibility.Realistic prediction of protein surface regions that are preferentially recognized by antibodies (antigenic epitopes) can help in the design of vaccine components and immuno-diagnostic reagents. Antigenic epitopes are classified as continuous or discontinues epitopes. If the residues involved in an epitope are contiguous in the polypeptide chain, this epitope is called a continuous epitope or a linear epitope. On the other hand, a discontinuous or non-linear epitope is composed of residues that are not necessarily continuous in the polypeptide sequence but have spatial proximity on the surface of a protein structure. A significant fraction of epitopes are discontinuous in the sense that antibody binding is not fully determined by a linear peptide segment but also influenced by adjacent surface regions [1].However, the majority of available epitope prediction methods focus on continuous epitopes due to the convenience of the investigation in which the amino acid sequence of a protein is taken as the input. Such prediction methods are based upon the amino acid properties including hydrophilicity [2,3], so
Spotentiality for Induced Inflammatory Exposure of Antigenic Epitopes in Ischemia and Neoplasia
Lawrence M Agius MD
International Journal of Molecular Medicine and Advance Sciences , 2011,
Abstract: Failed activation of the immune response to neoplastic cell proliferation and spread would implicate systems of exposure and of presentation of antigenic epitopes on cells. Such failure in antigenicity of tissue components would characterize primary inception of the lesion as a neoplasm that subsequently increases in size and progresses. It is with reference to inflammation as a mechanism of exposure and of presentation of antigen that one might envisage neoplastic and ischemic tissues as a dual coupling potentially related to both immune stimulation and activation of clones of lymphocytes, inflammatory cells and macrophages. Such cell components of tissue would participate in the realization of various compounding pathways of propagation involving cytokines and chemokines in inducing further progression of the neoplasm or in suppressing tumor growth and spread. Ischemia and post-ischemic perfusion injury of tissues appear applicable in inducing a coupled inflammatory and immune reactivity in various tissues including neoplasms.
Prediction of antigenic epitopes and MHC binders of neurotoxin alpha-KTx 3.8 from Mesobuthus tamulus sindicus
VS Gomase, K Shyamkumar
African Journal of Biotechnology , 2009,
Abstract: The potassium channel inhibitor alpha-KTx 3.8, a 38-residue peptide was isolated from the venom of Mesobuthus tamulus sindicus. In this assay we have predicted the binding affinity of alpha-KTx 3.8 having 38 amino acids, which shows 30 nonamers. Peptide fragments of the neurotoxin can be used to select nonamers for use in rational vaccine design and to increase the understanding of roles of the immune system in neurotoxin studies. Small segment ‘4-INVKCRGSPQCIQPCR-19’of neurotoxin protein called the antigenic epitopes is sufficient for eliciting the desired immune response. We also found the SVM based MHCII-IAb peptide regions, 26- GKCMNGKCH, 20- DAGMRFGKC, 1- GVPINVKCR, 19- RDAGMRFGK, (optimal score is 0.388); MHCII-IAd peptide regions, 20- DAGMRFGKC, 14- CIQPCRDAG, 10- GSPQCIQPC, 25- FGKCMNGKC, (optimal score is 0.386); MHCII-IAg7 peptide regions, 18- CRDAGMRFG, 17- PCRDAGMRF, 14- CIQPCRDAG, 3- PINVKCRGS, (optimal score is 1.341); and MHCIIRT1. B peptide regions, 16- QPCRDAGMR, 29- MNGKCHCTP, 8- CRGSPQCIQ, 7- KCRGSPQCI, (optimal score is -0.039) which represented predicted binders from neurotoxin protein. CTL epitope with their (ANN/SVM) scores were predicted to be 1- GVPINVKCR (0.81/0.87220559). This theme is implemented in designing subunit and synthetic peptide vaccines. We have predicted a successful immunization.
Large-scale analysis of antigenic diversity of T-cell epitopes in dengue virus  [cached]
Khan Asif M,Heiny AT,Lee Kenneth X,Srinivasan KN
BMC Bioinformatics , 2006, DOI: 10.1186/1471-2105-7-s5-s4
Abstract: Background Antigenic diversity in dengue virus strains has been studied, but large-scale and detailed systematic analyses have not been reported. In this study, we report a bioinformatics method for analyzing viral antigenic diversity in the context of T-cell mediated immune responses. We applied this method to study the relationship between short-peptide antigenic diversity and protein sequence diversity of dengue virus. We also studied the effects of sequence determinants on viral antigenic diversity. Short peptides, principally 9-mers were studied because they represent the predominant length of binding cores of T-cell epitopes, which are important for formulation of vaccines. Results Our analysis showed that the number of unique protein sequences required to represent complete antigenic diversity of short peptides in dengue virus is significantly smaller than that required to represent complete protein sequence diversity. Short-peptide antigenic diversity shows an asymptotic relationship to the number of unique protein sequences, indicating that for large sequence sets (~200) the addition of new protein sequences has marginal effect to increasing antigenic diversity. A near-linear relationship was observed between the extent of antigenic diversity and the length of protein sequences, suggesting that, for the practical purpose of vaccine development, antigenic diversity of short peptides from dengue virus can be represented by short regions of sequences (~<100 aa) within viral antigens that are specific targets of immune responses (such as T-cell epitopes specific to particular human leukocyte antigen alleles). Conclusion This study provides evidence that there are limited numbers of antigenic combinations in protein sequence variants of a viral species and that short regions of the viral protein are sufficient to capture antigenic diversity of T-cell epitopes. The approach described herein has direct application to the analysis of other viruses, in particular those that show high diversity and/or rapid evolution, such as influenza A virus and human immunodeficiency virus (HIV).
EPSVR and EPMeta: prediction of antigenic epitopes using support vector regression and multiple server results
Shide Liang, Dandan Zheng, Daron M Standley, Bo Yao, Martin Zacharias, Chi Zhang
BMC Bioinformatics , 2010, DOI: 10.1186/1471-2105-11-381
Abstract: In this work, we present two novel server applications for discontinuous epitope prediction: EPSVR and EPMeta, where EPMeta is a meta server. EPSVR, EPMeta, and datasets are available at http://sysbio.unl.edu/services webcite.The server application for discontinuous epitope prediction, EPSVR, uses a Support Vector Regression (SVR) method to integrate six scoring terms. Furthermore, we combined EPSVR with five existing epitope prediction servers to construct EPMeta. All methods were benchmarked by our curated independent test set, in which all antigens had no complex structures with the antibody, and their epitopes were identified by various biochemical experiments. The area under the receiver operating characteristic curve (AUC) of EPSVR was 0.597, higher than that of any other existing single server, and EPMeta had a better performance than any single server - with an AUC of 0.638, significantly higher than PEPITO and Disctope (p-value < 0.05).Antigenic epitopes are regions of protein surface that are preferentially recognized by antibodies. Prediction of antigenic epitopes can help during the design of vaccine components and immuno-diagnostic reagents, but predicting effective epitopes is still an open problem in bioinformatics. Usually, B-cell antigenic epitopes are classified as either continuous or discontinuous. The majority of available epitope prediction methods focus on continuous epitopes [1-12].Although discontinuous epitopes dominate most antigenic epitope families [13], due to their computational complexity, only a very limited number of prediction methods exist for discontinuous epitope prediction: CEP [14], DiscoTope [15], PEPITO [16], ElliPro [17], SEPPA [18], EPITOPIA[19,20] and our previous work, EPCES [21]. All discontinuous epitope prediction methods require the three-dimensional structure of the antigenic protein. The small number of available antigen-antibody complex structures limits the development of reliable discontinuous epitope prediction
In-vitro inhibition of IFNγ+ iTreg mediated by monoclonal antibodies against cell surface determinants essential for iTreg function  [cached]
Daniel Volker,Sadeghi Mahmoud,Wang Haihao,Opelz Gerhard
BMC Immunology , 2012, DOI: 10.1186/1471-2172-13-47
Abstract: Background IFNγ-producing CD4+CD25+Foxp3+ PBL represent a subtype of iTreg that are associated with good long-term graft outcome in renal transplant recipients and suppress alloresponses in-vitro. To study the mechanism of immunosuppression, we attempted to block cell surface receptors and thereby inhibited the function of this iTreg subset in-vitro using monoclonal antibodies and recombinant proteins. Methods PBL of healthy control individuals were stimulated polyclonally in-vitro in the presence of monoclonal antibodies or recombinant proteins against/of CD178, CD152, CD279, CD28, CD95, and HLA-DR. Induction of IFNγ+ iTreg and proliferation of effector cells was determined using four-color fluorescence flow cytometry. Blockade of iTreg function was analyzed using polyclonally stimulated co-cultures with separated CD4+CD25+CD127-IFNγ+ PBL. Results High monoclonal antibody concentrations inhibited the induction of CD4+CD25+Foxp3+IFNγ+ PBL (anti-CD152, anti-CD279, anti-CD95: p < 0.05) and CD4+CD25+CD127-IFNγ+ PBL (anti-CD178, anti-CD152, anti-CD279, anti-CD95: p < 0.05). Effector cell proliferation increased with increasing antibody concentrations in culture medium (anti-CD178 and anti-CD279: p < 0.05). Conversely, high concentrations of recombinant proteins induced formation of CD4+CD25+Foxp3+IFNγ+ PBL (rCD152 and rCD95: p < 0.05) and decreased cell proliferation dose-dependently (rCD178 and rCD95: p < 0.05). Our data suggest an inverse association of iTreg induction with effector cell proliferation in cell culture which is dependent on the concentration of monoclonal antibodies against iTreg surface determinants. 3-day co-cultures of polyclonally stimulated PBL with separated CD4+CD25+CD127-IFNγ+ PBL showed lower cell proliferation than co-cultures with CD4+CD25+CD127-IFNγ- PBL (p < 0.05). Cell proliferation increased strongly in CD4+CD25+CD127-IFNγ- PBL-containing co-cultures in the presence of monoclonal antibody (anti-CD28, anti-CD152, anti-CD279: p < 0.05) but remained low in co-cultures with CD4+CD25+CD127-IFNγ+ PBL (with the exception anti-CD28 monoclonal antibody: p < 0.05). Monoclonal antibodies prevent iTreg induction in co-cultures with CD4+CD25+CD127-IFNγ- PBL but do not efficiently block suppressive iTreg function in co-cultures with CD4+CD25+CD127-IFNγ+ PBL. Conclusions CD178, CD152, CD279, CD28, CD95, and HLA-DR determinants are important for induction and suppressive function of IFNγ+ iTreg.
SVMTriP: A Method to Predict Antigenic Epitopes Using Support Vector Machine to Integrate Tri-Peptide Similarity and Propensity  [PDF]
Bo Yao, Lin Zhang, Shide Liang, Chi Zhang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0045152
Abstract: Identifying protein surface regions preferentially recognizable by antibodies (antigenic epitopes) is at the heart of new immuno-diagnostic reagent discovery and vaccine design, and computational methods for antigenic epitope prediction provide crucial means to serve this purpose. Many linear B-cell epitope prediction methods were developed, such as BepiPred, ABCPred, AAP, BCPred, BayesB, BEOracle/BROracle, and BEST, towards this goal. However, effective immunological research demands more robust performance of the prediction method than what the current algorithms could provide. In this work, a new method to predict linear antigenic epitopes is developed; Support Vector Machine has been utilized by combining the Tri-peptide similarity and Propensity scores (SVMTriP). Applied to non-redundant B-cell linear epitopes extracted from IEDB, SVMTriP achieves a sensitivity of 80.1% and a precision of 55.2% with a five-fold cross-validation. The AUC value is 0.702. The combination of similarity and propensity of tri-peptide subsequences can improve the prediction performance for linear B-cell epitopes. Moreover, SVMTriP is capable of recognizing viral peptides from a human protein sequence background. A web server based on our method is constructed for public use. The server and all datasets used in the current study are available at http://sysbio.unl.edu/SVMTriP.
Antigenic epitopes prediction and MHC binder of a paralytic insecticidal toxin (ITX-1) of Tegenaria agrestis (hobo spider)
AG Ingale
Open Access Bioinformatics , 2010, DOI: http://dx.doi.org/10.2147/OAB.S11886
Abstract: ntigenic epitopes prediction and MHC binder of a paralytic insecticidal toxin (ITX-1) of Tegenaria agrestis (hobo spider) Original Research (3794) Total Article Views Authors: AG Ingale Published Date August 2010 Volume 2010:2 Pages 97 - 103 DOI: http://dx.doi.org/10.2147/OAB.S11886 AG Ingale Department of Biotechnology, School of Life Sciences, North Maharashtra University, Jalgaon, India Abstract: Spider peptide toxins with nanomolar affinities for their receptors are promising pharmacological tools for understanding the physiological role of ion channels and as leads for the development of novel therapeutic agents and strategies for ion channel-related diseases. Paralytic insecticidal toxin (Tegenaria agrestis) involved multiple antigenic components to direct and empower the immune system to protect the host from infection. MHC molecules are cell surface proteins, which take active part in host immune reactions and involvement of MHC class in response to almost all antigens, and it affects specific sites. Predicted MHC binding regions act like red flags for specific antigens and generate an immune response against the parent antigen. So a small fragment of antigen can induce an immune response against whole antigen. This theme is implemented in designing subunit and synthetic peptide vaccines. In this study, we analyzed secondary structure and antigenic determinants, which form antibodies against infection. The method integrates prediction of peptide MHC class binding and solvent accessible regions. Antigenic epitopes of paralytic insecticidal toxin are important antigenic determinants against the various toxic reactions and infections. There are 3 antigenic determinants in sequence. The results show highest pick at position 4–25 (QLMICLVLLPCFFCEPDEICRA) amino acid residue and 34–51 (YKSNVCNGCGDQVAACEA) amino acid residue.
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