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Seminars in Immunology Aug 2020Epitopes, in the context of T cell recognition, are short peptides typically derived by antigen processing, and presented on the cell surface bound to MHC molecules (HLA... (Review)
Review
Epitopes, in the context of T cell recognition, are short peptides typically derived by antigen processing, and presented on the cell surface bound to MHC molecules (HLA molecules in humans) for TCR scrutiny. The identification of epitopes is a context-dependent process, with consideration given to, for example, the source pathogen and protein, the host organism, and state of the immune reaction (e.g., following natural infection, vaccination, etc.). In the following review, we consider the various approaches used to define T cell epitopes, including both bioinformatic and experimental approaches, and discuss the concepts of immunodominance and immunoprevalence. We also discuss HLA polymorphism and epitope restriction, and the resulting impact on the identification of, and potential population coverage afforded by, epitopes or epitope-based vaccines. Finally, some examples of the practical application of T cell epitope identification are provided, showing how epitopes have been valuable for deriving novel immunological insights in the context of the immune response to various pathogens and allergens.
Topics: Animals; Computational Biology; Epitope Mapping; Epitopes, T-Lymphocyte; HLA Antigens; Humans; Immunoassay; Immunodominant Epitopes; Polymorphism, Genetic; Protein Binding; T-Lymphocytes; Vaccines
PubMed: 33131981
DOI: 10.1016/j.smim.2020.101418 -
Immunogenetics Feb 2020The Immune Epitope Database and Analysis Resource (IEDB) contains information related to antibodies and T cells across an expansive scope of research fields (infectious... (Review)
Review
The Immune Epitope Database and Analysis Resource (IEDB) contains information related to antibodies and T cells across an expansive scope of research fields (infectious diseases, allergy, autoimmunity, and transplantation). Capture and representation of the data to reflect growing scientific standards and techniques have required continual refinement of our rigorous curation and query and reporting processes beginning with the automated classification of over 28 million PubMed abstracts, and resulting in easily searchable data from over 20,000 published manuscripts. Data related to MHC binding and elution, nonpeptidics, natural processing, receptors, and 3D structure is first captured through manual curation and subsequently maintained through recuration to reflect evolving scientific standards. Upon promotion to the free, public database, users can query and export records of specific relevance via the online web portal which undergoes iterative development to best enable efficient data access. In parallel, the companion Analysis Resource site hosts a variety of tools that assist in the bioinformatic analyses of epitopes and related structures, which can be applied to IEDB-derived and independent datasets alike. Available tools are classified into two categories: analysis and prediction. Analysis tools include epitope clustering, sequence conservancy, and more, while prediction tools cover T and B cell epitope binding, immunogenicity, and TCR/BCR structures. In addition to these tools, benchmarking servers which allow for unbiased performance comparison are also offered. In order to expand and support the user-base of both the database and Analysis Resource, the research team actively engages in community outreach through publication of ongoing work, conference attendance and presentations, hosting of user workshops, and the provision of online help. This review provides a description of the IEDB database infrastructure, curation and recuration processes, query and reporting capabilities, the Analysis Resource, and our Community Outreach efforts, including assessment of the impact of the IEDB across the research community.
Topics: Animals; Data Management; Databases, Protein; Epitopes; Humans; Proteins; Time Factors
PubMed: 31761977
DOI: 10.1007/s00251-019-01137-6 -
PLoS Computational Biology Feb 2022In-silico methods for the prediction of epitopes can support and improve workflows for vaccine design, antibody production, and disease therapy. So far, the scope of B...
In-silico methods for the prediction of epitopes can support and improve workflows for vaccine design, antibody production, and disease therapy. So far, the scope of B cell and T cell epitope prediction has been directed exclusively towards peptidic antigens. Nevertheless, various non-peptidic molecular classes can be recognized by immune cells. These compounds have not been systematically studied yet, and prediction approaches are lacking. The ability to predict the epitope activity of non-peptidic compounds could have vast implications; for example, for immunogenic risk assessment of the vast number of drugs and other xenobiotics. Here we present the first general attempt to predict the epitope activity of non-peptidic compounds using the Immune Epitope Database (IEDB) as a source for positive samples. The molecules stored in the Chemical Entities of Biological Interest (ChEBI) database were chosen as background samples. The molecules were clustered into eight homogeneous molecular groups, and classifiers were built for each cluster with the aim of separating the epitopes from the background. Different molecular feature encoding schemes and machine learning models were compared against each other. For those models where a high performance could be achieved based on simple decision rules, the molecular features were then further investigated. Additionally, the findings were used to build a web server that allows for the immunogenic investigation of non-peptidic molecules (http://tools-staging.iedb.org/np_epitope_predictor). The prediction quality was tested with samples from independent evaluation datasets, and the implemented method received noteworthy Receiver Operating Characteristic-Area Under Curve (ROC-AUC) values, ranging from 0.69-0.96 depending on the molecule cluster.
Topics: Area Under Curve; Epitopes, B-Lymphocyte; Epitopes, T-Lymphocyte; Peptides; ROC Curve
PubMed: 35180214
DOI: 10.1371/journal.pcbi.1009151 -
The Journal of Biological Chemistry Dec 2020Defining discontinuous antigenic epitopes remains a substantial challenge, as exemplified by the case of lipid transfer polyproteins, which are common pollen allergens....
Defining discontinuous antigenic epitopes remains a substantial challenge, as exemplified by the case of lipid transfer polyproteins, which are common pollen allergens. Hydrogen/deuterium exchange monitored by NMR can be used to map epitopes onto folded protein surfaces, but only if the complex rapidly dissociates. Modifying the standard NMR-exchange measurement to detect substoichiometric complexes overcomes this time scale limitation and provides new insights into recognition of lipid transfer polyprotein by antibodies. In the future, this new and exciting development should see broad application to a range of tight macromolecular interactions.
Topics: Carrier Proteins; Deuterium Exchange Measurement; Epitope Mapping; Epitopes; Magnetic Resonance Spectroscopy; Protein Structure, Secondary
PubMed: 33453987
DOI: 10.1074/jbc.H120.016607 -
Nucleic Acids Research Jan 2023We established The Cancer Epitope Database and Analysis Resource (CEDAR) to catalog all epitope data in the context of cancer. The specific molecular targets of adaptive...
We established The Cancer Epitope Database and Analysis Resource (CEDAR) to catalog all epitope data in the context of cancer. The specific molecular targets of adaptive T cell and B cell immune responses are referred to as epitopes. Epitopes derived from cancer antigens are of high relevance as they are recognized by anti-cancer immune cells. Detailed knowledge of the molecular characteristic of cancer epitopes and associated metadata is relevant to understanding and planning prophylactic and therapeutic applications and accurately characterizing naturally occurring immune responses and cancer immunopathology. CEDAR provides a freely accessible, comprehensive collection of cancer epitope and receptor data curated from the literature and serves as a companion site to the Immune Epitope Database (IEDB), which is focused on infectious, autoimmune, and allergic diseases. CEDAR is freely accessible at https://cedar.iedb.org/.
Topics: Humans; Data Management; Databases, Protein; Epitopes; Antigens, Neoplasm; Databases, Chemical
PubMed: 36250634
DOI: 10.1093/nar/gkac902 -
Immunogenetics Apr 2010In the last decade, significant progress has been made in expanding the scope and depth of publicly available immunological databases and online analysis resources,... (Review)
Review
In the last decade, significant progress has been made in expanding the scope and depth of publicly available immunological databases and online analysis resources, which have become an integral part of the repertoire of tools available to the scientific community for basic and applied research. Herein, we present a general overview of different resources and databases currently available. Because of our association with the Immune Epitope Database and Analysis Resource, this resource is reviewed in more detail. Our review includes aspects such as the development of formal ontologies and the type and breadth of analytical tools available to predict epitopes and analyze immune epitope data. A common feature of immunological databases is the requirement to host large amounts of data extracted from disparate sources. Accordingly, we discuss and review processes to curate the immunological literature, as well as examples of how the curated data can be used to generate a meta-analysis of the epitope knowledge currently available for diseases of worldwide concern, such as influenza and malaria. Finally, we review the impact of immunological databases, by analyzing their usage and citations, and by categorizing the type of citations. Taken together, the results highlight the growing impact and utility of immunological databases for the scientific community.
Topics: Computational Biology; Database Management Systems; Databases, Factual; Epitopes; Humans; Internet
PubMed: 20213141
DOI: 10.1007/s00251-010-0435-2 -
Methods (San Diego, Calif.) Mar 2014The structure determination of major allergens is a prerequisite for analyzing surface exposed areas of the allergen and for mapping conformational epitopes. These may... (Review)
Review
The structure determination of major allergens is a prerequisite for analyzing surface exposed areas of the allergen and for mapping conformational epitopes. These may be determined by experimental methods including crystallographic and NMR-based approaches or predicted by computational methods. In this review we summarize the existing structural information on allergens and their classification in protein fold families. The currently available allergen-antibody complexes are described and the experimentally obtained epitopes compared. Furthermore we discuss established methods for linear and conformational epitope mapping, putting special emphasis on a recently developed approach, which uses the structural similarity of proteins in combination with the experimental cross-reactivity data for epitope prediction.
Topics: Allergens; Animals; Crystallography, X-Ray; Epitope Mapping; Epitopes; Humans; Hypersensitivity; Models, Molecular; Nuclear Magnetic Resonance, Biomolecular; Protein Structure, Secondary; Protein Structure, Tertiary; Recombinant Fusion Proteins; Software
PubMed: 23891546
DOI: 10.1016/j.ymeth.2013.07.024 -
Characterization of a Nanobody-Epitope Tag Interaction and Its Application for Receptor Engineering.ACS Chemical Biology Aug 2022Peptide epitope tags offer a valuable means for detection and manipulation of protein targets for which high quality detection reagents are not available. Most commonly...
Peptide epitope tags offer a valuable means for detection and manipulation of protein targets for which high quality detection reagents are not available. Most commonly used epitope tags are bound by conventional, full-size antibodies (Abs). The complex architecture of Abs complicates their application in protein engineering and intracellular applications. To address these shortcomings, single domain antibodies (nanobodies, Nbs) that recognize short peptide epitopes have become increasingly prized. Here, we characterize the interaction between a Nb (Nb) and a 14-mer peptide epitope. We identify residues in the peptide epitope essential for high affinity binding. Using this information in combination with computational modeling we propose a mode of interaction between Nb and this epitope. We apply this nanobody-epitope pair to augment the potency of a ligand at an engineered adenosine A2A receptor. This characterization of the nanobody-epitope pair opens the door to diverse applications including mechanistic studies of the G protein-coupled receptor function.
Topics: Antibodies; Epitopes; Peptides; Protein Engineering; Single-Domain Antibodies
PubMed: 35930411
DOI: 10.1021/acschembio.2c00407 -
Current Opinion in Virology Apr 2015Rational approaches will be required to develop universal vaccines for viral pathogens such as human immunodeficiency virus, hepatitis C virus, and influenza, for which... (Review)
Review
Rational approaches will be required to develop universal vaccines for viral pathogens such as human immunodeficiency virus, hepatitis C virus, and influenza, for which empirical approaches have failed. The main objective of a rational vaccine strategy is to design novel immunogens that are capable of inducing long-term protective immunity. In practice, this requires structure-based engineering of the target neutralizing epitopes and a quantitative readout of vaccine-induced immune responses. Therefore, computational tools that can facilitate these two areas have played increasingly important roles in rational vaccine design in recent years. Here we review the computational techniques developed for protein structure prediction and antibody repertoire analysis, and demonstrate how they can be applied to the design and evaluation of epitope vaccines.
Topics: Animals; Antigens; Computational Biology; Drug Discovery; Epitopes; Humans; Immunologic Techniques; Protein Engineering; Vaccines
PubMed: 25837467
DOI: 10.1016/j.coviro.2015.03.013 -
Current Opinion in Virology Jun 2013Despite the tremendous successes of current vaccines, infectious diseases still take a heavy toll on the global population, and that provides strong rationale for... (Review)
Review
Despite the tremendous successes of current vaccines, infectious diseases still take a heavy toll on the global population, and that provides strong rationale for broadening our vaccine development repertoire. Structural vaccinology, in which protein structure information is utilized to design immunogens, has promise to provide new vaccines against traditionally difficult targets. Crystal structures of antigens containing one or more protection epitopes, especially when in complex with a protective antibody, are the launching point for immunogen design. Integrating structure and sequence information for families of broadly neutralizing antibodies (bNAbs) has recently enabled the creation of germline-targeting immunogens that bind and activate germline B-cells in order to initiate the elicitation of such antibodies. The contacts between antigen and neutralizing antibody define a structural epitope, and methods have been developed to transplant epitopes to scaffold proteins for structural stabilization, and to design minimized antigens that retain one or more key epitopes while eliminating other potentially distracting or unnecessary features. To develop vaccines that protect against antigenically variable pathogens, pioneering structure-based work demonstrated that multiple strain-specific epitopes could be engineered onto a single immunogen. We review these recent structural vaccinology efforts to engineer germline-targeting, epitope-specific, and/or broad coverage immunogens.
Topics: Antibodies, Neutralizing; Antigens; Drug Discovery; Epitopes; Humans; Protein Engineering; Vaccines
PubMed: 23806515
DOI: 10.1016/j.coviro.2013.05.010