The Immune Epitope Database 2.0

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 immune receptors and the experimental contexts in which these molecules were determined to be immune epitopes. Epitopes recognized in humans, nonhuman primates, rodents, pigs, cats and all other tested species are included. Both positive and negative experimental results are captured. Over the course of 4 years, the data from 180 978 experiments were curated manually from the literature, which covers ∼99% of all publicly available information on peptide epitopes mapped in infectious agents (excluding HIV) and 93% of those mapped in allergens. In addition, data that would otherwise be 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

Epitopes in ChEBI - A Collaboration with the IEDB

*ChEBI background:* Chemical Entities of Biological Interest (ChEBI) is a curated database of small chemical entities important in biosystems. As well as a description of entities, it provides a semantically rich knowledge base; and an internal hierarchy that organises the entities by their molecular structure types and potential rôles.

*The ChEBI-IEDB collaboration:* The Immune Epitope and Analysis Resource (IEDB) is a project supported by contract from the National Institute of Allergy and Infectious Diseases (NIAID). Its goal is to make epitope-related data on infectious diseases and immune disorders freely available to researchers worldwide. In June 2009, ChEBI began working with the IEDB on a project aimed at incorporating into ChEBI, by manual curation, a pilot subset of immunologically important chemicals identified as immune epitopes.

*The significance of the project:* Numerous reports attest to an increasing global prevalence of immune-related diseases, with a multiplicity of contributing factors. This situation underscores the need for cross-talk among the various scientific disciplines, and makes ChEBI involvement in this project particularly relevant. 

*Collaboration outcome:* That collaboration among curators working on different databases can be reciprocally beneficial has been amply demonstrated by the ChEBI-IEDB teamwork described: while the incorporated IEDB items have substantially enriched ChEBI, the latter’s multiplicity of synonyms, structure tree lay-out and expertise in describing non-peptidic epitopes have been equally useful to the IEDB in facilitating the search process.
*Status quo and plans:* We continue to refine our task of assisting the identification, understanding and utilisation of biologically meaningful chemical entities by engaging in further joint projects

A fast Peptide Match service for UniProt Knowledgebase

Summary: We have developed a new web application for peptide matching using Apache Lucene-based search engine. The Peptide Match service is designed to quickly retrieve all occurrences of a given query peptide from UniProt Knowledgebase (UniProtKB) with isoforms. The matched proteins are shown in summary tables with rich annotations, including matched sequence region(s) and links to corresponding proteins in a number of proteomic/peptide spectral databases. The results are grouped by taxonomy and can be browsed by organism, taxonomic group or taxonomy tree. The service supports queries where isobaric leucine and isoleucine are treated equivalent, and an option for searching UniRef100 representative sequences, as well as dynamic queries to major proteomic databases. In addition to the web interface, we also provide RESTful web services. The underlying data are updated every 4 weeks in accordance with the UniProt releases. Availability: http://proteininformationresource.org/peptide.shtml Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics onlin

The mucosal adjuvant cholera toxin B instructs non-mucosal dendritic cells to promote IgA production via retinoic acid and TGF-β

It is currently unknown how mucosal adjuvants cause induction of secretory immunoglobulin A (IgA), and how T cell-dependent (TD) or -independent (TI) pathways might be involved. Mucosal dendritic cells (DCs) are the primary antigen presenting cells driving TI IgA synthesis, by producing a proliferation-inducing ligand (APRIL), B cell activating factor (BAFF), Retinoic Acid (RA), TGF-beta or nitric oxide (NO). We hypothesized that the mucosal adjuvant Cholera Toxin subunit B (CTB) could imprint non-mucosal DCs to induce IgA synthesis, and studied the mechanism of its induction. In vitro, CTB-treated bone marrow derived DCs primed for IgA production by B cells without the help of T cells, yet required co-signaling by different Toll-like receptor (TLR) ligands acting via the MyD88 pathway. CTB-DC induced IgA production was blocked in vitro or in vivo when RA receptor antagonist, TGF-beta signaling inhibitor or neutralizing anti-TGF-beta was added, demonstrating the involvement of RA and TGF-beta in promoting IgA responses. There was no major involvement for BAFF, APRIL or NO. This study highlights that synergism between CTB and MyD88-dependent TLR signals selectively imprints a TI IgA-inducing capacity in non-mucosal DCs, explaining how CTB acts as an IgA promoting adjuvant

IEDB-3D: structural data within the immune epitope database

IEDB-3D is the 3D structural component of the Immune Epitope Database (IEDB) available via the ‘Browse by 3D Structure’ page at http://www.iedb.org. IEDB-3D catalogs B- and T-cell epitopes and Major Histocompatibility Complex (MHC) ligands for which 3D structures of complexes with antibodies, T-cell receptors or MHC molecules are available in the Protein Data Bank (PDB). Journal articles that are primary citations of PDB structures and that define immune epitopes are curated within IEDB as any other reference along with accompanying functional assays and immunologically relevant information. For each curated structure, IEDB-3D provides calculated data on intermolecular contacts and interface areas and includes an application, EpitopeViewer, to visualize the structures. IEDB-3D is fully embedded within IEDB, thus allowing structural data, both curated and calculated, and all accompanying information to be queried using multiple search interfaces. These include queries for epitopes recognized in different pathogens, eliciting different functional immune responses, and recognized by different components of the immune system. The query results can be downloaded in Microsoft Excel format, or the entire database, together with structural data both curated and calculated, can be downloaded in either XML or MySQL formats

The therapeutic promise of disrupting the PD-1/PD-L1 immune checkpoint in cancer: unleashing the CD8 T cell mediated anti-tumor activity results in significant, unprecedented clinical efficacy in various solid tumors.

The role of immune checkpoints in modulating the magnitude as well as the functional profile of T cell responses is increasingly understood in molecular detail. Antibody-mediated blockade of co-inhibitory receptors has been shown to restore T cell function in both chronic viral infections and cancer. The latter has been successfully translated to new therapeutic options in the treatment of cancer. Indeed, monoclonal antibodies blocking either CTLA-4 or PD-1 have recently been approved for the treatment of metastatic melanoma in the United States, Europe and Japan. In this commentary, we summarize and put into perspective five letters recently published back to back in the November 27 (2014) issue of Nature reporting on different immunological and clinical aspects of blockade of the PD-1/PD-L1 pathway in tumor bearing hosts. Notably, treatment with anti-PD-L1 blocking antibody was shown result in profound clinical responses in patients with several solid tumor including bladder, lung and head and neck carcinomas among others. These five simultaneous publications highlight the tremendous therapeutic potential of targeting the PD-1/PD-L1 immune checkpoint and emphasize the need to identify appropriate biomarkers to guide their optimal clinical application

Stability-mediated epistasis constrains the evolution of an influenza protein.

John Maynard Smith compared protein evolution to the game where one word is converted into another a single letter at a time, with the constraint that all intermediates are words: WORD→WORE→GORE→GONE→GENE. In this analogy, epistasis constrains evolution, with some mutations tolerated only after the occurrence of others. To test whether epistasis similarly constrains actual protein evolution, we created all intermediates along a 39-mutation evolutionary trajectory of influenza nucleoprotein, and also introduced each mutation individually into the parent. Several mutations were deleterious to the parent despite becoming fixed during evolution without negative impact. These mutations were destabilizing, and were preceded or accompanied by stabilizing mutations that alleviated their adverse effects. The constrained mutations occurred at sites enriched in T-cell epitopes, suggesting they promote viral immune escape. Our results paint a coherent portrait of epistasis during nucleoprotein evolution, with stabilizing mutations permitting otherwise inaccessible destabilizing mutations which are sometimes of adaptive value. DOI:http://dx.doi.org/10.7554/eLife.00631.001

Protegen: a web-based protective antigen database and analysis system

Protective antigens are specifically targeted by the acquired immune response of the host and are able to induce protection in the host against infectious and non-infectious diseases. Protective antigens play important roles in vaccine development, as biological markers for disease diagnosis, and for analysis of fundamental host immunity against diseases. Protegen is a web-based central database and analysis system that curates, stores and analyzes protective antigens. Basic antigen information and experimental evidence are curated from peer-reviewed articles. More detailed gene/protein information (e.g. DNA and protein sequences, and COG classification) are automatically extracted from existing databases using internally developed scripts. Bioinformatics programs are also applied to compute different antigen features, such as protein weight and pI, and subcellular localizations of bacterial proteins. Presently, 590 protective antigens have been curated against over 100 infectious diseases caused by pathogens and non-infectious diseases (including cancers and allergies). A user-friendly web query and visualization interface is developed for interactive protective antigen search. A customized BLAST sequence similarity search is also developed for analysis of new sequences provided by the users. To support data exchange, the information of protective antigens is stored in the Vaccine Ontology (VO) in OWL format and can also be exported to FASTA and Excel files. Protegen is publically available at http://www.violinet.org/protegen