Predicting TCR sequences for unseen antigen epitopes using structural and sequence features

Briefings in Bioinformatics, Journal Year: 2024, Volume and Issue: 25(3)

Published: March 27, 2024

Abstract T-cell receptor (TCR) recognition of antigens is fundamental to the adaptive immune response. With expansion experimental techniques, a substantial database matched TCR–antigen pairs has emerged, presenting opportunities for computational prediction models. However, accurately forecasting binding affinities unseen antigen–TCR remains major challenge. Here, we present convolutional-self-attention TCR (CATCR), novel framework tailored enhance epitope and interactions. Our approach utilizes convolutional neural networks extract peptide features from residue contact matrices, as generated by OpenFold, transformer encode segment-based coded sequences. We introduce CATCR-D, discriminator that can assess analyzing structural sequence epitopes CDR3-β regions. Additionally, comprises CATCR-G, generative module designed sequences, which applies pretrained encoder deduce characteristics decoder predicting matching CATCR-D achieved an AUROC 0.89 on previously epitope–TCR outperformed four benchmark models margin 17.4%. CATCR-G demonstrated high precision, recall F1 scores, surpassing 95% in bidirectional representations transformers score assessments. results indicate CATCR effective tool Incorporating insights enhances our understanding general rules governing TCR–epitope significantly. The ability predict TCRs using information promising, broadening repository data could further improve precision predictions.

Language: Английский

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In vivo Phage Display: A promising selection strategy for the improvement of antibody targeting and drug delivery properties

Frontiers in Microbiology, Journal Year: 2022, Volume and Issue: 13

Published: Sept. 26, 2022

The discovery of hybridoma technology, described by Kohler and Milstein in 1975, the resulting ability to generate monoclonal antibodies (mAbs) initiated a new era antibody research clinical development. However, limitations technology as routine generation method conjunction with high immunogenicity responses have led development alternative approaches for streamlined identification most effective antibodies. Within this context, display selection technologies such phage display, ribosome yeast bacterial mammalian cell surface been widely promoted over past three decades ideal alternatives traditional methods. on phages is probably widespread powerful these methods and, since its invention late 1980s, significant technological advancements design, construction, libraries made, several fully human generated are currently approved or various stages. With evolving novel disease targets emerging therapeutic antibodies, bispecific drug conjugates (ADCs), chimeric antigen receptor T (CAR

Language: Английский

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B cells: The many facets of B cells in allergic diseases

Journal of Allergy and Clinical Immunology, Journal Year: 2023, Volume and Issue: 152(3), P. 567 - 581

Published: May 27, 2023

Language: Английский

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Nanoparticle-based immunotherapeutics: From the properties of nanocores to the differential effects of administration routes

Advanced Drug Delivery Reviews, Journal Year: 2023, Volume and Issue: 197, P. 114829 - 114829

Published: April 28, 2023

The engagement with the immune system is one of main cornerstones in development nanotechnologies for therapy and diagnostics. Recent advances have made possible tuning features like size, shape biomolecular modifications that influence such interactions, however, capabilities modulation nanoparticles are still not well defined exploited. This review focuses on recent preclinical research application to modulate responses, making them relevant applications. We discuss newest evidence field, which include vivo experiments an extensive physicochemical characterization as detailed study induced response. emphasize need incorporating knowledge about response regulation design nanoparticles, including effect by parameters administration route differential interactions subsets.

Language: Английский

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A window into the human immune system: comprehensive characterization of the complexity of antibody complementary-determining regions in functional antibodies

mAbs, Journal Year: 2023, Volume and Issue: 15(1)

Published: Oct. 24, 2023

The human immune system uses antibodies to neutralize foreign antigens. They are composed of heavy and light chains, both with constant variable regions. region has six hypervariable loops, also known as complementary-determining regions (CDRs) that determine antibody diversity antigen specificity. Knowledge their significance, certain residues present in these areas, is vital for therapeutics development. This study includes an analysis more than 11,000 sequences from the International Immunogenetics information (IMGT). included parameters such length distribution, overall amino acid diversity, frequency per CDR residue position within chains. Overall, our findings confirm existing knowledge, CDRH3's high variability, increased aromatic usage, particularly tyrosine, charged polar like aspartic acid, serine, flexible glycine. Specific positions each influence occurrences, implying a unique type distribution pattern. We compared usage CDRs non-CDR regions, globular transmembrane proteins, which revealed distinguishing features, arginine. These should prove useful future optimization, improvement affinity, synthetic library design, or creation de-novo silico.

Language: Английский

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Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: July 13, 2023

The adaptive immune system of jawed vertebrates generates a highly diverse repertoire antibodies to meet the antigenic challenges constantly evolving biological ecosystem. Most diversity is generated by two mechanisms: V(D)J gene recombination and somatic hypermutation (SHM). SHM introduces changes in variable domain antibodies, mostly regions that form paratope, yielding with higher antigen binding affinity. However, recognition only possible if antibody folds into stable functional conformation. Therefore, key force determining survival B cell clones undergoing ability mutated heavy light chains efficiently fold assemble antibody. structural context where selection mutations occurs, both benefit from protective mechanisms counteract potentially deleterious impact changes. patients monoclonal gammopathies, proliferating plasma clone may overproduce chain, which then secreted bloodstream. This places chain out provided quaternary structure antibody, increasing risk misfolding aggregation due destabilizing mutations. Light chain-derived (AL) amyloidosis, deposition disease (LCDD), Fanconi syndrome, myeloma (cast) nephropathy are group diseases derived pathologic chains, recognized play role. In this review, we address promote pathological an emphasis on AL amyloidosis. We also analyze contribution (V L ) segments cytotoxicity, organ tropism, fibrils. Finally, most recent advances development computational algorithms predict role cardiotoxicity amyloidogenic discuss perspectives approach faces.

Language: Английский

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Genome-wide analysis of DNA replication and DNA double-strand breaks using TrAEL-seq

PLoS Biology, Journal Year: 2021, Volume and Issue: 19(3), P. e3000886 - e3000886

Published: March 24, 2021

Faithful replication of the entire genome requires forks to copy large contiguous tracts DNA, and sites persistent fork stalling present a major threat stability. Understanding distribution at which stall, ensuing processing events, genome-wide methods that profile position formation recombinogenic DNA ends. Here, we describe Tr ansferase- A ctivated E nd L igation seq uencing (TrAEL-seq), method captures single-stranded 3′ ends with base pair resolution. TrAEL-seq labels both breaks forks, providing maps progression in yeast mammalian cells. Replication are similar those obtained by Okazaki fragment sequencing; however, is performed on asynchronous populations wild-type cells without incorporation labels, cell sorting, or biochemical purification intermediates, rendering far simpler more widely applicable than existing direction profiling methods. The specificity for also allows accurate detection double-strand break after initiation end resection, demonstrate mapping meiotic hotspots dmc1 Δ mutant competent resection but not strand invasion. Overall, provides flexible robust methodology high sensitivity resolution studying repair, will be significant use determining mechanisms instability.

Language: Английский

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Individualized VDJ recombination predisposes the available Ig sequence space

Genome Research, Journal Year: 2021, Volume and Issue: 31(12), P. 2209 - 2224

Published: Nov. 23, 2021

The process of recombination between variable (V), diversity (D), and joining (J) immunoglobulin (Ig) gene segments determines an individual's naive Ig repertoire and, consequently, (auto)antigen recognition. VDJ follows probabilistic rules that can be modeled statistically. So far, it remains unknown whether differ individuals. If these differed, identical (auto)antigen-specific sequences would generated with individual-specific probabilities, signifying the available sequence space is individual specific. We devised a sensitivity-tested distance measure enables inter-individual comparison models. discovered, accounting for several sources noise as well allelic variation in sequencing data, not only unrelated individuals but also human monozygotic twins even inbred mice possess statistically distinguishable This suggests that, addition to genetic, there nongenetic modulation recombination. demonstrate population-wide individualized result orders magnitude difference probability generate sequences. Our findings have implications immune receptor-based medicine approaches relevant vaccination, infection, autoimmunity.

Language: Английский

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The Role of B Cells and B Cell Therapies in Immune-Mediated Liver Diseases

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: April 14, 2021

B cells form a branch of the adaptive immune system, essential for body’s defense against pathogens. cell dysfunction has been implicated in pathogenesis mediated liver diseases including autoimmune hepatitis, IgG4-related hepatobiliary disease, primary biliary cholangitis and sclerosing cholangitis. may initiate maintain related several ways production autoantibodies activation T via antigen presentation or cytokine production. Here we comprehensively review current knowledge on mechanisms diseases, exploring disease pathogenesis, therapies, novel treatment targets. We identify key areas where future research should focus to enable development targeted therapies.

Language: Английский

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Accelerated Evolution by Diversity-Generating Retroelements

Annual Review of Microbiology, Journal Year: 2022, Volume and Issue: 76(1), P. 389 - 411

Published: June 2, 2022

Diversity-generating retroelements (DGRs) create vast amounts of targeted, functional diversity by facilitating the rapid evolution ligand-binding protein domains. Thousands DGRs have been identified in bacteria, archaea, and their respective viruses. They are broadly distributed throughout microbial world, with enrichment observed certain taxa environments. The diversification machinery works through a novel mechanism termed mutagenic retrohoming, whereby nucleotide sequence information is copied from an invariant DNA template repeat (TR) into RNA intermediate, selectively mutagenized at TR adenines during cDNA synthesis DGR-encoded reverse transcriptase, transferred to variable (VR) region within variable-protein gene ( 54 ). This unidirectional flow leaves TR-DNA sequences unmodified, allowing for repeated rounds retrohoming optimize function. DGR target genes often modular can encode one or more wide variety discrete domains appended diversifiable motif. Bacterial proteins localize cellsurfaces, although subset appear be cytoplasmic, while phage-encoded commonly diversify tail fiber–associated receptor-binding proteins. Here, we provide comprehensive review consequences accelerated these unique beneficial genetic elements.

Language: Английский

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