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While many genetic variants have been associated with risk for human diseases, how these variants affect gene expression in various cell types remains largely unknown. To address this gap, the DICE (database of immune cell expression, expression quantitative trait loci [eQTLs], and epigenomics) project was established. Considering all human immune cell types and conditions studied, we identified cis-eQTLs for a total of 12,254 unique genes, which represent 61% of all protein-coding genes expressed in these cell types. Strikingly, a large fraction (41%) of these genes showed a strong cis-association with genotype only in a single cell type. We also found that biological sex is associated with major differences in immune cell gene expression in a highly cell-specific manner. These datasets will help reveal the effects of disease risk-associated genetic polymorphisms on specific immune cell types, providing mechanistic insights into how they might influence pathogenesis (https://dice-database.org).
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Regulación de la Expresión Génica/inmunología , Genotipo , Polimorfismo de Nucleótido Simple/inmunología , Sitios de Carácter Cuantitativo/inmunología , Caracteres Sexuales , Adolescente , Adulto , Femenino , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The Next-Generation (NG) IEDB Tools website (https://nextgen-tools.iedb.org) provides users with a redesigned interface to many of the algorithms for epitope prediction and analysis that were originally released on the legacy IEDB Tools website. The initial release focuses on consolidation of all tools related to HLA class I epitopes (MHC binding, elution, immunogenicity, and processing), making all of these predictions accessible from a single application and allowing for their simultaneous execution with minimal user inputs. Additionally, the PEPMatch tool for identifying highly similar epitopes in a set of curated proteomes, as well as a tool for epitope clustering, are available on the site. The NG Tools site allows users to build data pipelines by sending the output of one tool as input for the next. Over the next several years, all pre-existing IEDB Tools, and any newly developed tools, will be integrated into this new site. Here we describe the philosophy behind the redesign and demonstrate the utility and productivity enhancements that are enabled by the new interface.
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Algoritmos , Epítopos , Programas Informáticos , Epítopos/inmunología , Epítopos/química , Humanos , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/química , Antígenos de Histocompatibilidad Clase I/metabolismo , Internet , Bases de Datos de ProteínasRESUMEN
Motivation: Datasets that are derived from different studies (e.g. MHC ligand elution, MHC binding, B/T cell epitope screening etc.) often vary in terms of experimental approaches, sizes of peptides tested, including partial and or nested overlapping peptides and in the number of donors tested. Results: We present a customized application of the Immune Epitope Database's ImmunomeBrowser tool, which can be used to effectively aggregate and visualize heterogeneous immunological data. User provided peptide sets and associated response data is mapped to a user-provided protein reference sequence. The output consists of tables and figures representing the aggregated data represented by a Response Frequency score and associated estimated confidence interval. This allows the user to visualizing regions associated with dominant responses and their boundaries. The results are presented both as a user interactive javascript based web interface and a tabular format in a selected reference sequence. Availability and implementation: The 'ImmunomeBrowser' has been a longstanding feature of the IEDB (http://www.iedb.org). The present application extends the use of this tool to work with user-provided datasets, rather than the output of IEDB queries. This new server version of the ImmunomeBrowser is freely accessible at http://tools.iedb.org/immunomebrowser/.
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Bases de Datos de Proteínas , Epítopos/química , Péptidos , Proteínas/química , Programas Informáticos , Secuencia de Aminoácidos , Biología Computacional , LigandosRESUMEN
BACKGROUND: Biological interpretation of gene/protein lists resulting from -omics experiments can be a complex task. A common approach consists of reviewing Gene Ontology (GO) annotations for entries in such lists and searching for enrichment patterns. Unfortunately, there is a gap between machine-readable output of GO software and its human-interpretable form. This gap can be bridged by allowing users to simultaneously visualize and interact with term-term and gene-term relationships. RESULTS: We created the open-source GOnet web-application (available at http://tools.dice-database.org/GOnet/ ), which takes a list of gene or protein entries from human or mouse data and performs GO term annotation analysis (mapping of provided entries to GO subsets) or GO term enrichment analysis (scanning for GO categories overrepresented in the input list). The application is capable of producing parsable data formats and importantly, interactive visualizations of the GO analysis results. The interactive results allow exploration of genes and GO terms as a graph that depicts the natural hierarchy of the terms and retains relationships between terms and genes/proteins. As a result, GOnet provides insight into the functional interconnection of the submitted entries. CONCLUSIONS: The application can be used for GO analysis of any biological data sources resulting in gene/protein lists. It can be helpful for experimentalists as well as computational biologists working on biological interpretation of -omics data resulting in such lists.
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Ontología de Genes , Programas Informáticos , Algoritmos , Animales , Humanos , RatonesRESUMEN
Systems vaccinology studies have identified factors affecting individual vaccine responses, but comparing these findings is challenging due to varying study designs. To address this lack of reproducibility, we established a community resource for comparing Bordetella pertussis booster responses and to host annual contests for predicting patients' vaccination outcomes. We report here on our experiences with the "dry-run" prediction contest. We found that, among 20+ models adopted from the literature, the most successful model predicting vaccination outcome was based on age alone. This confirms our concerns about the reproducibility of conclusions between different vaccinology studies. Further, we found that, for newly trained models, handling of baseline information on the target variables was crucial. Overall, multiple co-inertia analysis gave the best results of the tested modeling approaches. Our goal is to engage community in these prediction challenges by making data and models available and opening a public contest in August 2024.
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Multiómica , Vacunas , Humanos , Vacunología/métodos , Reproducibilidad de los Resultados , Simulación por ComputadorRESUMEN
The Immune Epitope Database (IEDB) catalogs T cell, B cell, and major histocompatibility complex ligand information in the context of infectious disease, allergy, autoimmunity, and transplantation. An important component of this information is three-dimensional structural data on T cell receptors, antibodies, and pairwise residue interactions between immune receptors and antigens, which we refer to as IEDB-3D. Such data is highly valuable for mechanically understanding receptor:ligand interactions. Here, we present IEDB-3D 2.0, which comprises a complete overhaul of how we obtain and present 3D structural data. A new 3D viewer experience that utilizes iCn3D has been implemented to replace outdated java-based technology. In addition, we have designed a new epitope mapping system that matches each epitope available in the IEDB with its antigen structural data. Finally, immunogenicity data retrieved from the IEDB's ImmunomeBrowser can now be used to highlight immunogenic regions of an antigen directly in iCn3D. Overall, the IEDB-3D 2.0 provides an updated tool platform to visualize epitope data cataloged in the IEDB.
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Anticuerpos , Antígenos , Epítopos/química , Ligandos , Bases de Datos de ProteínasRESUMEN
Computational models that predict an individual's response to a vaccine offer the potential for mechanistic insights and personalized vaccination strategies. These models are increasingly derived from systems vaccinology studies that generate immune profiles from human cohorts pre- and post-vaccination. Most of these studies involve relatively small cohorts and profile the response to a single vaccine. The ability to assess the performance of the resulting models would be improved by comparing their performance on independent datasets, as has been done with great success in other areas of biology such as protein structure predictions. To transfer this approach to system vaccinology studies, we established a prototype platform that focuses on the evaluation of Computational Models of Immunity to Pertussis Booster vaccinations (CMI-PB). A community resource, CMI-PB generates experimental data for the explicit purpose of model evaluation, which is performed through a series of annual data releases and associated contests. We here report on our experience with the first such 'dry run' for a contest where the goal was to predict individual immune responses based on pre-vaccination multi-omic profiles. Over 30 models adopted from the literature were tested, but only one was predictive, and was based on age alone. The performance of new models built using CMI-PB training data was much better, but varied significantly based on the choice of pre-vaccination features used and the model building strategy. This suggests that previously published models developed for other vaccines do not generalize well to Pertussis Booster vaccination. Overall, these results reinforced the need for comparative analysis across models and datasets that CMI-PB aims to achieve. We are seeking wider community engagement for our first public prediction contest, which will open in early 2024.
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The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has seen multiple anti-SARS-CoV-2 antibodies being generated globally. It is difficult, however, to assemble a useful compendium of these biological properties if they are derived from experimental measurements performed at different sites under different experimental conditions. The Coronavirus Immunotherapeutic Consortium (COVIC) circumvents these issues by experimentally testing blinded antibodies side by side for several functional activities. To collect these data in a consistent fashion and make it publicly available, we established the COVIC database (COVIC-DB, https://covicdb.lji.org/). This database enables systematic analysis and interpretation of this large-scale dataset by providing a comprehensive view of various features such as affinity, neutralization, in vivo protection and effector functions for each antibody. Interactive graphs enable direct comparisons of antibodies based on select functional properties. We demonstrate how the COVIC-DB can be utilized to examine relationships among antibody features, thereby guiding the design of therapeutic antibody cocktails. Database URL https://covicdb.lji.org/.