ABSTRACT
Dynamic changes in protein glycosylation impact human health and disease progression. However, current resources that capture disease and phenotype information focus primarily on the macromolecules within the central dogma of molecular biology (DNA, RNA, proteins). To gain a better understanding of organisms, there is a need to capture the functional impact of glycans and glycosylation on biological processes. A workshop titled "Functional impact of glycans and their curation" was held in conjunction with the 16th Annual International Biocuration Conference to discuss ongoing worldwide activities related to glycan function curation. This workshop brought together subject matter experts, tool developers, and biocurators from over 20 projects and bioinformatics resources. Participants discussed four key topics for each of their resources: (i) how they curate glycan function-related data from publications and other sources, (ii) what type of data they would like to acquire, (iii) what data they currently have, and (iv) what standards they use. Their answers contributed input that provided a comprehensive overview of state-of-the-art glycan function curation and annotations. This report summarizes the outcome of discussions, including potential solutions and areas where curators, data wranglers, and text mining experts can collaborate to address current gaps in glycan and glycosylation annotations, leveraging each other's work to improve their respective resources and encourage impactful data sharing among resources. Database URL: https://wiki.glygen.org/Glycan_Function_Workshop_2023.
Subject(s)
Data Curation , Polysaccharides , Polysaccharides/metabolism , Humans , Data Curation/methods , Glycosylation , Italy , BiocurationABSTRACT
Introduction: Therapeutic monoclonal antibodies (mAbs) have demonstrated promising outcomes in diverse clinical indications, including but not limited to graft rejection, cancer, and autoimmune diseases lately.Recognizing the crucial need for the scientific community to quickly and easily access dependable information on monoclonal antibodies (mAbs), IMGT®, the international ImMunoGeneTics information system®, provides a unique and invaluable resource: IMGT/mAb-DB, a comprehensive database of therapeutic mAbs, accessible via a user-friendly web interface. However, this approach restricts more sophisticated queries and segregates information from other databases. Methods: To connect IMGT/mAb-DB with the rest of the IMGT databases, we created IMGT/mAb-KG, a knowledge graph for therapeutic monoclonal antibodies connected to IMGT structures and genomics databases. IMGT/mAb-KG is developed using the most effective methodologies and standards of semantic web and acquires data from IMGT/mAb-DB. Concerning interoperability, IMGT/mAb-KG reuses terms from biomedical resources and is connected to related resources. Results and discussion: In February 2024, IMGT/mAb-KG, encompassing a total of 139,629 triplets, provides access to 1,489 mAbs, approximately 500 targets, and over 500 clinical indications. It offers detailed insights into the mechanisms of action of mAbs, their construction, and their various products and associated studies. Linked to other resources such as Thera-SAbDab (Therapeutic Structural Antibody Database), PharmGKB (a comprehensive resource curating knowledge on the impact of genetic variation on drug response), PubMed, and HGNC (HUGO Gene Nomenclature Committee), IMGT/mAb-KG is an essential resource for mAb development. A user-friendly web interface facilitates the exploration and analyse of the content of IMGT/mAb-KG.
Subject(s)
Antibodies, Monoclonal , Humans , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/immunology , Immunogenetics/methods , Databases, FactualABSTRACT
Breast milk, often referred to as "liquid gold," is a complex biofluid that provides essential nutrients, immune factors, and developmental cues for newborns. Recent advancements in the field of exosome research have shed light on the critical role of exosomes in breast milk. Exosomes are nanosized vesicles that carry bioactive molecules, including proteins, lipids, nucleic acids, and miRNAs. These tiny messengers play a vital role in intercellular communication and are now being recognized as key players in infant health and development. This paper explores the emerging field of milk exosomics, emphasizing the potential of exosome fingerprinting to uncover valuable insights into the composition and function of breast milk. By deciphering the exosomal cargo, we can gain a deeper understanding of how breast milk influences neonatal health and may even pave the way for personalized nutrition strategies.
ABSTRACT
The naked mole-rat (Heterocephalus glaber) is a long-lived rodent species showing resistance to the development of cancer. Although naked mole-rats have been reported to lack natural killer (NK) cells, γδ T cell-based immunity has been suggested in this species, which could represent an important arm of the immune system for antitumor responses. Here, we investigate the biology of these unconventional T cells in peripheral tissues (blood, spleen) and thymus of the naked mole-rat at different ages by TCR repertoire profiling and single-cell gene expression analysis. Using our own TCR annotation in the naked mole-rat genome, we report that the γδ TCR repertoire is dominated by a public invariant Vγ4-2/Vδ1-4 TCR, containing the complementary-determining-region-3 (CDR3)γ CTYWDSNYAKKLF / CDR3δ CALWELRTGGITAQLVF that are likely generated by short-homology-repeat-driven DNA rearrangements. This invariant TCR is specifically found in γδ T cells expressing genes associated with NK cytotoxicity and is generated in both the thoracic and cervical thymus of the naked mole-rat until adult life. Our results indicate that invariant Vγ4-2/Vδ1-4 NK-like effector T cells in the naked mole-rat can contribute to tumor immunosurveillance by γδ TCR-mediated recognition of a common molecular signal.
Subject(s)
Mole Rats , Receptors, Antigen, T-Cell, gamma-delta , Thymus Gland , Animals , Mole Rats/immunology , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Receptors, Antigen, T-Cell, gamma-delta/genetics , Receptors, Antigen, T-Cell, gamma-delta/immunology , Thymus Gland/immunology , Thymus Gland/cytology , Killer Cells, Natural/immunology , Spleen/immunology , Complementarity Determining Regions/genetics , Natural Killer T-Cells/immunologyABSTRACT
The evolutionary conserved Notch signaling pathway functions as a mediator of direct cell-cell communication between neighboring cells during development. Notch plays a crucial role in various fundamental biological processes in a wide range of tissues. Accordingly, the aberrant signaling of this pathway underlies multiple genetic pathologies such as developmental syndromes, congenital disorders, neurodegenerative diseases, and cancer. Over the last two decades, significant data have shown that the Notch signaling pathway displays a significant function in the mature brains of vertebrates and invertebrates beyond neuronal development and specification during embryonic development. Neuronal connection, synaptic plasticity, learning, and memory appear to be regulated by this pathway. Specific mutations in human Notch family proteins have been linked to several neurodegenerative diseases including Alzheimer's disease, CADASIL, and ischemic injury. Neurodegenerative diseases are incurable disorders of the central nervous system that cause the progressive degeneration and/or death of brain nerve cells, affecting both mental function and movement (ataxia). There is currently a lot of study being conducted to better understand the molecular mechanisms by which Notch plays an essential role in the mature brain. In this study, an in silico analysis of polymorphisms and mutations in human Notch family members that lead to neurodegenerative diseases was performed in order to investigate the correlations among Notch family proteins and neurodegenerative diseases. Particular emphasis was placed on the study of mutations in the Notch3 protein and the structure analysis of the mutant Notch3 protein that leads to the manifestation of the CADASIL syndrome in order to spot possible conserved mutations and interpret the effect of these mutations in the Notch3 protein structure. Conserved mutations of cysteine residues may be candidate pharmacological targets for the potential therapy of CADASIL syndrome.
Subject(s)
CADASIL , Neurodegenerative Diseases , Polymorphism, Single Nucleotide , Receptors, Notch , Humans , CADASIL/genetics , CADASIL/metabolism , CADASIL/pathology , Receptors, Notch/metabolism , Receptors, Notch/genetics , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Mutation , Signal Transduction , Receptor, Notch3/genetics , Receptor, Notch3/metabolismABSTRACT
BACKGROUND: Myasthenia Gravis (MG) is a rare autoimmune disease presenting with auto-antibodies that affect the neuromuscular junction. In addition to symptomatic treatment options, novel therapeutics include monoclonal antibodies (mAbs). IMGT®, the international ImMunoGeneTics information system®, extends the characterization of therapeutic antibodies with a systematic description of their mechanisms of action (MOA) and makes them available through its database for mAbs and fusion proteins, IMGT/mAb-DB. METHODS: Using available literature data combined with amino acid sequence analyses from mAbs managed in IMGT/2Dstructure-DB, the IMGT® protein database, biocuration allowed us to define in a standardized way descriptions of MOAs of mAbs that target molecules towards MG treatment. RESULTS: New therapeutic targets include FcRn and molecules such as CD38, CD40, CD19, MS4A1, and interleukin-6 receptor. A standardized graphical representation of the MOAs of selected mAbs was created and integrated within IMGT/mAb-DB. The main mechanisms involved in these mAbs are either blocking or neutralizing. Therapies directed to B cell depletion and plasma cells have a blocking MOA with an immunosuppressant effect along with Fc-effector function (MS4A1, CD38) or FcγRIIb engager effect (CD19). Monoclonal antibodies targeting the complement also have a blocking MOA with a complement inhibitor effect, and treatments targeting T cells have a blocking MOA with an immunosuppressant effect (CD40) and Fc-effector function (IL6R). On the other hand, FcRn antagonists present a neutralizing MOA with an FcRn inhibitor effect. CONCLUSION: The MOA of each new mAb needs to be considered in association with the immunopathogenesis of each of the subtypes of MG in order to integrate the new mAbs as a viable and safe option in the therapy decision process. In IMGT/mAb-DB, mAbs for MG are characterized by their sequence, domains, and chains, and their MOA is described.
ABSTRACT
Background: Cancer cells activate different immune checkpoint (IC) pathways in order to evade immunosurveillance. Immunotherapies involving ICs either block or stimulate these pathways and enhance the efficiency of the immune system to recognize and attack cancer cells. In this way, the development of monoclonal antibodies (mAbs) targeting ICs has significant success in cancer treatment. Recently, a systematic description of the mechanisms of action (MOA) of the mAbs has been introduced in IMGT/mAb-DB, the IMGT® database dedicated to mAbs for therapeutic applications. The characterization of these antibodies provides a comprehensive understanding of how mAbs work in cancer. Methods: In depth biocuration taking advantage of the abundant literature data as well as amino acid sequence analyses from mAbs managed in IMGT/2Dstructure-DB, the IMGT® protein database, allowed to define a standardized and consistent description of the MOA of mAbs targeting immune checkpoints in cancer therapy. Results: A fine description and a standardized graphical representation of the MOA of selected mAbs are integrated within IMGT/mAb-DB highlighting two main mechanisms in cancer immunotherapy, either Blocking or Agonist. In both cases, the mAbs enhance cytotoxic T lymphocyte (CTL)-mediated anti-tumor immune response (Immunostimulant effect) against tumor cells. On the one hand, mAbs targeting co-inhibitory receptors may have a functional Fc region to increase anti-tumor activity by effector properties that deplete Treg cells (Fc-effector function effect) or may have limited FcγR binding to prevent Teff cells depletion and reduce adverse events. On the other hand, agonist mAbs targeting co-stimulatory receptors may bind to FcγRs, resulting in antibody crosslinking (FcγR crosslinking effect) and substantial agonism. Conclusion: In IMGT/mAb-DB, mAbs for cancer therapy are characterized by their chains, domains and sequence and by several therapeutic metadata, including their MOA. MOAs were recently included as a search criterion to query the database. IMGT® is continuing standardized work to describe the MOA of mAbs targeting additional immune checkpoints and novel molecules in cancer therapy, as well as expanding this study to other clinical domains.
Subject(s)
Antibodies, Monoclonal , Neoplasms , Humans , Antibodies, Monoclonal/therapeutic use , Receptors, IgG , Databases, Protein , ImmunotherapyABSTRACT
The variable domains (V-DOMAIN) of the antigen receptors, immunoglobulins (IG) or antibodies and T cell receptors (TR), which specifically recognize the antigens show a huge diversity in their sequences. This diversity results from the complex mechanisms involved in the synthesis of these domains at the DNA level (rearrangements of the variable (V), diversity (D), and joining (J) genes; N-diversity; and, for the IG, somatic hypermutations). The recognition of V, D, and J as "genes" and their entry in databases mark the creation of IMGT by Marie-Paule Lefranc, and the origin of immunoinformatics in 1989. For 30 years, IMGT®, the international ImMunoGeneTics information system® http://www.imgt.org , has implemented databases and developed tools for IG and TR immunoinformatics, based on the IMGT Scientific chart rules and IMGT-ONTOLOGY concepts and axioms, and more particularly, the princeps ones: IMGT genes and alleles (CLASSIFICATION axiom) and the IMGT unique numbering and IMGT Collier de Perles (NUMEROTATION axiom). This chapter describes the online tools for the characterization and annotation of the expressed V-DOMAIN sequences: (a) IMGT/V-QUEST analyzes in detail IG and TR rearranged nucleotide sequences, (b) IMGT/HighV-QUEST is its high throughput version, which includes a module for the identification of IMGT clonotypes and generates immunoprofiles of expressed V, D, and J genes and alleles, (c) IMGT/StatClonotype performs the pairwise comparison of IMGT/HighV-QUEST immunoprofiles, (d) IMGT/DomainGapAlign analyzes amino acid sequences and is frequently used in antibody engineering and humanization, and (e) IMGT/Collier-de-Perles provides two-dimensional (2D) graphical representations of V-DOMAIN, bridging the gap between sequences and 3D structures. These IMGT® tools are widely used in repertoire analyses of the adaptive immune responses in normal and pathological situations and in the design of engineered IG and TR for therapeutic applications.
Subject(s)
Computational Biology , Immunogenetics , Amino Acid Sequence , Antibodies/genetics , Computational Biology/methods , Immunogenetics/methods , Receptors, Antigen, T-Cell/chemistry , Receptors, Antigen, T-Cell/geneticsABSTRACT
The somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene is a critical biomarker for assessing the prognosis of patients with chronic lymphocytic leukemia (CLL). Importantly, independent studies have documented that IGHV SHM status is also a predictor of responses to therapy, including both chemoimmunotherapy (CIT) and novel, targeted agents. Moreover, immunogenetic analysis in CLL has revealed that different patients may express (quasi)identical, stereotyped B cell receptor immunoglobulin (BcR IG) and are classified into subsets based on this common feature. Patients in certain stereotyped subsets display consistent biology, clinical presentation, and outcome that are distinct from other patients, even with concordant IGHV gene SHM status. All of the above highlights the relevance of immunogenetic analysis in CLL, which is considered a cornerstone for accurate risk stratification and clinical decision making. Recommendations for robust immunogenetic analysis exist thanks to dedicated efforts by ERIC, the European Research Initiative on CLL, covering all test phases, from the pre-analytical and analytical to the post-analytical, pertaining to the analysis, interpretation, and reporting of the findings. That said, these recommendations apply to Sanger sequencing, which is increasingly being superseded by next generation sequencing (NGS), further underscoring the need for an update. Here, we present an overview of the clinical utility of immunogenetics in CLL and update our analytical recommendations with the aim to assist in the refined management of patients with CLL.
Subject(s)
Genes, Immunoglobulin , Leukemia, Lymphocytic, Chronic, B-Cell , High-Throughput Nucleotide Sequencing , Humans , Immunoglobulins/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Receptors, Antigen, B-Cell/geneticsABSTRACT
The adaptive immune system, along with the innate immune system, are the two main biological processes that protect an organism from pathogens. The adaptive immune system is characterized by the specificity and extreme diversity of its antigen receptors. These antigen receptors are the immunoglobulins (IG) or antibodies of the B cells and the T cell receptors (TR) of the T cells. The IG are proteins that have a dual role in immunity: they recognize antigens and trigger elimination mechanisms, to rid the body of foreign cells. The synthesis of the immunoglobulin heavy and light chains requires gene rearrangements at the DNA level in the IGH, IGK, and IGL loci. The rhesus monkey (Macaca mulatta) is one of the most widely used nonhuman primate species in biomedical research. In this manuscript, we provide a thorough analysis of the three IG loci of the Mmul_10 assembly of rhesus monkey, integrating IMGT previously existing data. Detailed characterization of IG genes includes their localization and position in the loci, the determination of the allele functionality, and the description of the regulatory elements of their promoters as well as the sequences of the conventional recombination signals (RS). This complete annotation of the genomic IG loci of Mmul_10 assembly and the highly detailed IG gene characterization could be used as a model, in additional rhesus monkey assemblies, for the analysis of the IG allelic polymorphism and structural variation, which have been described in rhesus monkeys.
ABSTRACT
IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org/, is at the forefront of the immunogenetics and immunoinformatics fields with more than 30 years of experience. IMGT® makes available databases and tools to the scientific community pertaining to the adaptive immune response, based on the IMGT-ONTOLOGY. We focus on the recent features of the IMGT® databases, tools, reference directories and web resources, within the three main axes of IMGT® research and development. Axis I consists in understanding the adaptive immune response, by deciphering the identification and characterization of the immunoglobulin (IG) and T cell receptor (TR) genes in jawed vertebrates. It is the starting point of the two other axes, namely the analysis and exploration of the expressed IG and TR repertoires based on comparison with IMGT reference directories in normal and pathological situations (Axis II) and the analysis of amino acid changes and functions of 2D and 3D structures of antibody and TR engineering (Axis III).
Subject(s)
Adaptive Immunity/immunology , Databases, Genetic , Immunogenetics , Vertebrates/genetics , Adaptive Immunity/genetics , Animals , Antibodies/classification , Antibodies/immunology , Humans , Immunoglobulins/genetics , Immunoglobulins/immunology , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Vertebrates/immunologyABSTRACT
The bottlenose dolphin (Tursiops truncatus) belongs to the Cetartiodactyla and, similarly to other cetaceans, represents the most successful mammalian colonization of the aquatic environment. Here we report a genomic, evolutionary, and expression study of T. truncatus T cell receptor beta (TRB) genes. Although the organization of the dolphin TRB locus is similar to that of the other artiodactyl species, with three in tandem D-J-C clusters located at its 3' end, its uniqueness is given by the reduction of the total length due essentially to the absence of duplications and to the deletions that have drastically reduced the number of the germline TRBV genes. We have analyzed the relevant mature transcripts from two subjects. The simultaneous availability of rearranged T cell receptor α (TRA) and TRB cDNA from the peripheral blood of one of the two specimens, and the human/dolphin amino acids multi-sequence alignments, allowed us to calculate the most likely interactions at the protein interface between the alpha/beta heterodimer in complex with major histocompatibility class I (MH1) protein. Interacting amino acids located in the complementarity-determining region according to IMGT numbering (CDR-IMGT) of the dolphin variable V-alpha and beta domains were identified. According to comparative modelization, the atom pair contact sites analysis between the human MH1 grove (G) domains and the T cell receptor (TR) V domains confirms conservation of the structure of the dolphin TR/pMH.
Subject(s)
Bottle-Nosed Dolphin/genetics , Receptors, Antigen, T-Cell, alpha-beta/genetics , Sequence Analysis, DNA/methods , Sequence Analysis, Protein/methods , Animals , Chromosome Mapping , Female , Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor , Gene Rearrangement, beta-Chain T-Cell Antigen Receptor , Histocompatibility Antigens Class I/metabolism , Humans , Male , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Sequence Alignment , beta 2-Microglobulin/metabolismABSTRACT
Lipid Droplets (LD) are dynamic organelles that originate in the Endoplasmic Reticulum and mostly bud off toward the cytoplasm, where they store neutral lipids for energy and protection purposes. LD also have diverse proteins on their surface, many of which are necessary for the their correct homeostasis. However, these organelles also act as reservoirs of proteins that can be made available elsewhere in the cell. In this sense, they act as sinks that titrate key regulators of many cellular processes. Among the specialized factors that reside on cytoplasmic LD are proteins destined for functions in the nucleus, but little is known about them and their impact on nuclear processes. By screening for nuclear proteins in publicly available LD proteomes, we found that they contain a subset of nucleoporins from the Nuclear Pore Complex (NPC). Exploring this, we demonstrate that LD act as a physiological reservoir, for nucleoporins, that impacts the conformation of NPCs and hence their function in nucleo-cytoplasmic transport, chromatin configuration, and genome stability. Furthermore, our in silico modeling predicts a role for LD-released fatty acids in regulating the transit of nucleoporins from LD through the cytoplasm and to nuclear pores.
Subject(s)
Fatty Acids/metabolism , Lipid Droplets/metabolism , Nuclear Pore/metabolism , HumansABSTRACT
The adaptive immune response provides the vertebrate immune system with the ability to recognize and remember specific pathogens to generate immunity, and mount stronger attacks each time the pathogen is encountered. T cell receptors are the antigen receptors of the adaptive immune response expressed by T cells, which specifically recognize processed antigens, presented as peptides by the highly polymorphic major histocompatibility (MH) proteins. T cell receptors (TR) are divided into two groups, αß and γδ, which express distinct TR containing either α and ß, or γ and δ chains, respectively. The TRα locus (TRA) and TRδ locus (TRD) of bovine (Bos taurus) and the sheep (Ovis aries) have recently been described and annotated by IMGT® biocurators. The aim of the present study is to present the results of the biocuration and to compare the genes of the TRA/TRD loci among these ruminant species based on the Homo sapiens repertoire. The comparative analysis shows similarities but also differences, including the fact that these two species have a TRA/TRD locus about three times larger than that of humans and therefore have many more genes which may demonstrate duplications and/or deletions during evolution.
Subject(s)
Cattle/genetics , Genes, T-Cell Receptor alpha/genetics , Genes, T-Cell Receptor delta/genetics , Genetic Loci/immunology , Sheep, Domestic/genetics , Adaptive Immunity/genetics , Animals , Cattle/immunology , Evolution, Molecular , Molecular Sequence Annotation , Sheep, Domestic/immunology , Species SpecificityABSTRACT
Notch family proteins play a key role in a variety of developmental processes by controlling cell fate decisions and operating in a great number of biological processes in several organ systems, such as hematopoiesis, somatogenesis, vasculogenesis, neurogenesis and homeostasis. The Notch signaling pathway is crucial for the majority of developmental programs and regulates multiple pathogenic processes. Notch family receptors' activation has been largely related to its multiple effects in sustaining oncogenesis. The Notch signaling pathway constitutes an ancient and conserved mechanism for cell to cell communication. Much of what is known about Notch family proteins function comes from studies done in Caenorhabditis Elegans and Drosophila Melanogaster. Although, human Notch homologs had also been identified, the molecular mechanisms which modulate the Notch signaling pathway remained substantially unknown. In this study, an updated evolutionary analysis of the Notch family members among 603 different organisms of all kingdoms, from bacteria to humans, was performed in order to discover key regions that have been conserved throughout evolution and play a major role in the Notch signaling pathway. The major goal of this study is the presentation of a novel updated phylogenetic tree for the Notch family as a reliable phylogeny "map", in order to correlate information of the closely related members and identify new possible pharmacological targets that can be used in pathogenic cases, including cancer.
ABSTRACT
IMGT®, the international ImMunoGeneTics information system® is the global reference in immunogenetics and immunoinformatics. By its creation in 1989 by Marie-Paule Lefranc (Université de Montpellier and CNRS), IMGT® marked the advent of immunoinformatics, which emerged at the interface between immunogenetics and bioinformatics. IMGT® is specialized in the immunoglobulins (IG) or antibodies, T cell receptors (TR), major histocompatibility (MH), and proteins of the IgSF and MhSF superfamilies. T cell receptors are divided into two groups, αß and γδ TR, which express distinct TR containing either α and ß, or γ and δ chains, respectively. The TRß locus (TRB) was recently described and annotated by IMGT® biocurators for several veterinary species, i.e., cat (Felis catus), dog (Canis lupus familiaris), ferret (Mustela putorius furo), pig (Sus scrofa), rabbit (Oryctolagus cuniculus), rhesus monkey (Macaca mulatta), and sheep (Ovis aries). The aim of the present study is to compare the genes of the TRB locus among these different veterinary species based on Homo sapiens. The results reveal that there are similarities but also differences including the number of genes by subgroup which may demonstrate duplications and/or deletions during evolution.
Subject(s)
Computational Biology/methods , Genes, T-Cell Receptor beta , Genetic Loci , Immunogenetics/methods , Receptors, Antigen, T-Cell, alpha-beta/genetics , Animals , Cats , Databases, Genetic , Dogs , Ferrets/genetics , Ferrets/immunology , Humans , Macaca mulatta/genetics , Macaca mulatta/immunology , Multigene Family , Phylogeny , Rabbits , Sheep/genetics , Sheep/immunology , Swine/genetics , Swine/immunologyABSTRACT
Immunoglobulins or antibodies are the main effector molecules of the B-cell lineage and are encoded by hundreds of variable (V), diversity (D), and joining (J) germline genes, which recombine to generate enormous IG diversity. Recently, high-throughput adaptive immune receptor repertoire sequencing (AIRR-seq) of recombined V-(D)-J genes has offered unprecedented insights into the dynamics of IG repertoires in health and disease. Faithful biological interpretation of AIRR-seq studies depends upon the annotation of raw AIRR-seq data, using reference germline gene databases to identify the germline genes within each rearrangement. Existing reference databases are incomplete, as shown by recent AIRR-seq studies that have inferred the existence of many previously unreported polymorphisms. Completing the documentation of genetic variation in germline gene databases is therefore of crucial importance. Lymphocyte receptor genes and alleles are currently assigned by the Immunoglobulins, T cell Receptors and Major Histocompatibility Nomenclature Subcommittee of the International Union of Immunological Societies (IUIS) and managed in IMGT®, the international ImMunoGeneTics information system® (IMGT). In 2017, the IMGT Group reached agreement with a group of AIRR-seq researchers on the principles of a streamlined process for identifying and naming inferred allelic sequences, for their incorporation into IMGT®. These researchers represented the AIRR Community, a network of over 300 researchers whose objective is to promote all aspects of immunoglobulin and T-cell receptor repertoire studies, including the standardization of experimental and computational aspects of AIRR-seq data generation and analysis. The Inferred Allele Review Committee (IARC) was established by the AIRR Community to devise policies, criteria, and procedures to perform this function. Formalized evaluations of novel inferred sequences have now begun and submissions are invited via a new dedicated portal (https://ogrdb.airr-community.org). Here, we summarize recommendations developed by the IARC-focusing, to begin with, on human IGHV genes-with the goal of facilitating the acceptance of inferred allelic variants of germline IGHV genes. We believe that this initiative will improve the quality of AIRR-seq studies by facilitating the description of human IG germline gene variation, and that in time, it will expand to the documentation of TR and IG genes in many vertebrate species.
Subject(s)
Alleles , Genes, Immunoglobulin , Genetic Variation/genetics , Terminology as Topic , V(D)J Recombination , Base Sequence , Databases, Genetic , Datasets as Topic , Gene Library , Germ-Line Mutation , High-Throughput Nucleotide Sequencing , Humans , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Polymerase Chain Reaction/methods , Sequence Alignment , Sequence Homology, Nucleic Acid , VDJ Exons/geneticsABSTRACT
The DNA damage response (DDR) ensures cellular adaptation to genotoxic insults. In the crowded environment of the nucleus, the assembly of productive DDR complexes requires multiple protein modifications. How the apical E1 ubiquitin activation enzyme UBA1 integrates spatially and temporally in the DDR remains elusive. Using a human cell-free system, we show that poly(ADP-ribose) polymerase 1 promotes the recruitment of UBA1 to DNA. We find that the association of UBA1 with poly(ADP-ribosyl)ated protein-DNA complexes is necessary for the phosphorylation replication protein A and checkpoint kinase 1 by the serine/threonine protein kinase ataxia-telangiectasia and RAD3-related, a prototypal response to DNA damage. UBA1 interacts directly with poly(ADP-ribose) via a solvent-accessible and positively charged patch conserved in the Animalia kingdom but not in Fungi. Thus, ubiquitin activation can anchor to poly(ADP-ribose)-seeded protein assemblies, ensuring the formation of functional ataxia-telangiectasia mutated and RAD3-related-signalling complexes.
ABSTRACT
IMGT®, the international ImMunoGeneTics information system® ( http://www.imgt.org ), was created in 1989 by Marie-Paule Lefranc (Université de Montpellier and CNRS) to manage the huge diversity of the antigen receptors, immunoglobulins (IG) or antibodies, and T cell receptors (TR). The founding of IMGT® marked the advent of immunoinformatics, which emerged at the interface between immunogenetics and bioinformatics. Standardized sequence and structure analysis of antibody using IMGT® databases and tools allow one to bridge, for the first time, the gap between antibody sequences and three-dimensional (3D) structures. This is achieved through the IMGT Scientific chart rules, based on the IMGT-ONTOLOGY concepts of classification (IMGT gene and allele nomenclature), description (IMGT standardized labels), and numerotation (IMGT unique numbering and IMGT Collier de Perles). IMGT® is acknowledged as the global reference for immunogenetics and immunoinformatics, and its standards are particularly useful for antibody engineering and humanization. IMGT® databases for antibody nucleotide sequences and genes include IMGT/LIGM-DB and IMGT/GENE-DB, respectively, and nucleotide sequence analysis is performed by the IMGT/V-QUEST and IMGT/JunctionAnalysis tools and for NGS by IMGT/HighV-QUEST. In this chapter, we focus on IMGT® databases and tools for amino acid sequences, two-dimensional (2D) and three-dimensional (3D) structures: the IMGT/DomainGapAlign and IMGT Collier de Perles tools and the IMGT/2Dstructure-DB and IMGT/3Dstructure-DB database. IMGT/mAb-DB provides the query interface for monoclonal antibodies (mAb), fusion proteins for immune applications (FPIA), and composite proteins for clinical applications (CPCA) and related proteins of interest (RPI) and links to the proposed and recommended lists of the World Health Organization International Nonproprietary Name (WHO INN) programme, to IMGT/2Dstructure-DB for amino acid sequences, and to IMGT/3Dstructure-DB and its associated tools (IMGT/StructuralQuery, IMGT/DomainSuperimpose) for crystallized antibodies.