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1.  The IMGT/HLA database 
Nucleic Acids Research  2012;41(Database issue):D1222-D1227.
It is 14 years since the IMGT/HLA database was first released, providing the HLA community with a searchable repository of highly curated HLA sequences. The HLA complex is located within the 6p21.3 region of human chromosome 6 and contains more than 220 genes of diverse function. Of these, 21 genes encode proteins of the immune system that are highly polymorphic. The naming of these HLA genes and alleles and their quality control is the responsibility of the World Health Organization Nomenclature Committee for Factors of the HLA System. Through the work of the HLA Informatics Group and in collaboration with the European Bioinformatics Institute, we are able to provide public access to these data through the website http://www.ebi.ac.uk/imgt/hla/. Regular updates to the website ensure that new and confirmatory sequences are dispersed to the HLA community and the wider research and clinical communities. This article describes the latest updates and additional tools added to the IMGT/HLA project.
doi:10.1093/nar/gks949
PMCID: PMC3531221  PMID: 23080122
2.  The IMGT/HLA database 
Nucleic Acids Research  2010;39(Database issue):D1171-D1176.
It is 12 years since the IMGT/HLA database was first released, providing the HLA community with a searchable repository of highly curated HLA sequences. The HLA complex is located within the 6p21.3 region of human chromosome 6 and contains more than 220 genes of diverse function. Many of the genes encode proteins of the immune system and are highly polymorphic. The naming of these HLA genes and alleles and their quality control is the responsibility of the WHO Nomenclature Committee for Factors of the HLA System. Through the work of the HLA Informatics Group and in collaboration with the European Bioinformatics Institute, we are able to provide public access to this data through the web site http://www.ebi.ac.uk/imgt/hla/. Regular updates to the web site ensure that new and confirmatory sequences are dispersed to the HLA community, and the wider research and clinical communities.
doi:10.1093/nar/gkq998
PMCID: PMC3013815  PMID: 21071412
3.  IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex 
Nucleic Acids Research  2003;31(1):311-314.
The IMGT/HLA database (http://www.ebi.ac.uk/imgt/hla) has provided a centralized repository for the sequences of the alleles named by the WHO Nomenclature Committee for Factors of the HLA System for the past four years. Since its initial release the database has grown and is the primary source of information for the study of sequences of the human major histocompatibilty complex. The initial release of the database contained a limited number of tools. As a result of feedback from our users and developments in HLA we have been able to provide new tools and facilities. The HLA sequences have also been extended to include intron sequences and the 3′ and 5′ untranslated regions in the alignments and also the inclusion of new genes such as MICA. The IMGT/MHC database (http://www.ebi.ac.uk/imgt/mhc) was released in March 2002 to provide a similar resource for other species. The first release of IMGT/MHC contains the sequences of non-human primates (apes, new and old world monkeys), canines and feline sequences. Further species will be added shortly and the database aims to become the primary source of MHC data for non-human sequences.
PMCID: PMC165517  PMID: 12520010
4.  IMGT/HLA Database—a sequence database for the human major histocompatibility complex 
Nucleic Acids Research  2001;29(1):210-213.
The IMGT/HLA Database (www.ebi.ac.uk/imgt/hla/) specialises in sequences of polymorphic genes of the HLA system, the human major histocompatibility complex (MHC). The HLA complex is located within the 6p21.3 region on the short arm of human chromosome 6 and contains more than 220 genes of diverse function. Many of the genes encode proteins of the immune system and these include the 21 highly polymorphic HLA genes, which influence the outcome of clinical transplantation and confer susceptibility to a wide range of non-infectious diseases. The database contains sequences for all HLA alleles officially recognised by the WHO Nomenclature Committee for Factors of the HLA System and provides users with online tools and facilities for their retrieval and analysis. These include allele reports, alignment tools and detailed descriptions of the source cells. The online IMGT/HLA submission tool allows both new and confirmatory sequences to be submitted directly to the WHO Nomenclature Committee. The latest version (release 1.7.0 July 2000) contains 1220 HLA alleles derived from over 2700 component sequences from the EMBL/GenBank/DDBJ databases. The HLA database provides a model which will be extended to provide specialist databases for polymorphic MHC genes of other species.
PMCID: PMC29780  PMID: 11125094
5.  IMGT, the international ImMunoGeneTics database. 
Nucleic Acids Research  1997;25(1):206-211.
IMGT, the international ImMunoGeneTics database, is an integrated database specializing in immunoglobulins, T-cell receptors (TcR) and major histocompatibility complex (MHC) of all vertebrate species, initiated and co-ordinated by Marie-Paule Lefranc, CNRS, Montpellier II University, Montpellier, France (lefranc@ligm.crbm.cnrs-mop.fr). IMGT includes two databases: LIGM-DB (for immunoglobulins and TcR) and MHC/HLA-DB. IMGT comprises expertly annotated sequences and alignment tables. LIGM-DB contains more than 19 000 immunoglobulin and TcR sequences from 78 species. MHC/HLA-DB contains class I and class II human leukocyte antigen alignment tables. An IMGT tool, DNAPLOT, developed for immunoglobulins, TcR and MHC sequence alignments, is also available. IMGT works in close collaboration with the EMBL database. IMGT goals are to establish a common data access to all immunogenetics data, including sequences, oligonucleotide primers, gene maps and other genetic data of immunoglobulins, TcR and MHC molecules, and to provide a graphical user-friendly data access. IMGT will have important implications in medical research (repertoire in autoimmune diseases, AIDS, leukemias, lymphomas), therapeutical approaches (antibody engineering), genome diversity and genome evolution studies. IMGT can be accessed at http://imgt.cnusc.fr:8104 and http://www.ebi.ac.uk/IMGT
PMCID: PMC146384  PMID: 9016537
6.  IMGT, the international ImMunoGeneTics database® 
Nucleic Acids Research  2003;31(1):307-310.
The international ImMunoGeneTics database® (IMGT) (http://imgt.cines.fr), is a high quality integrated information system specializing in Immunoglobulins (IG), T cell Receptors (TR) and Major Histocompatibility Complex (MHC) of human and other vertebrates, created in 1989, by the Laboratoire d'ImmunoGénétique Moléculaire (LIGM), at the Université Montpellier II, CNRS, Montpellier, France. IMGT provides a common access to standardized data which include nucleotide and protein sequences, oligonucleotide primers, gene maps, genetic polymorphisms, specificities, 2D and 3D structures. IMGT includes three sequence databases (IMGT/LIGM-DB, IMGT/MHC-DB, IMGT/PRIMER-DB), one genome database (IMGT/GENE-DB) with different interfaces (IMGT/GeneSearch, IMGT/GeneView, IMGT/LocusView), one 3D structure database (IMGT/3Dstructure-DB), Web resources comprising 8000 HTML pages (‘IMGT Marie-Paule page’) and interactive tools for sequence analysis (IMGT/V-QUEST, IMGT/JunctionAnalysis, IMGT/Allele-Align, IMGT/PhyloGene). IMGT data are expertly annotated according to the rules of the IMGT Scientific chart, based on IMGT-ONTOLOGY. IMGT tools are particularly useful for the analysis of the IG and TR repertoires in physiological normal and pathological situations. IMGT has important applications in medical research (autoimmune diseases, AIDS, leukemias, lymphomas, myelomas), biotechnology related to antibody engineering (phage displays, combinatorial libraries) and thera-peutic approaches (graft, immunotherapy). IMGT is freely available at http://imgt.cines.fr.
PMCID: PMC165532  PMID: 12520009
7.  IMGT, the International ImMunoGeneTics database. 
Nucleic Acids Research  1998;26(1):297-303.
IMGT, the international ImMunoGeneTics database, is an integrated database specialising in Immunoglobulins (Ig), T cell Receptors (TcR) and Major Histocompatibility Complex (MHC) of all vertebrate species, created by Marie-Paule Lefranc, CNRS, Montpellier II University, Montpellier, France (lefranc@ligm.crbm.cnrs-mop.fr). IMGT includes three databases: LIGM-DB (for Ig and TcR), MHC/HLA-DB and PRIMER-DB (the last two in development). IMGT comprises expertly annotated sequences and alignment tables. LIGM-DB contains more than 23 000 Immunoglobulin and T cell Receptor sequences from 78 species. MHC/HLA-DB contains Class I and Class II Human Leucocyte Antigen alignment tables. An IMGT tool, DNAPLOT, developed for Ig, TcR and MHC sequence alignments, is also available. IMGT works in close collaboration with the EMBL database. IMGT goals are to establish a common data access to all immunogenetics data, including nucleotide and protein sequences, oligonucleotide primers, gene maps and other genetic data of Ig, TcR and MHC molecules, and to provide a graphical user friendly data access. IMGT has important implications in medical research (repertoire in autoimmune diseases, AIDS, leukemias, lymphomas), therapeutical approaches (antibody engineering), genome diversity and genome evolution studies. IMGT is freely available at http://imgt.cnusc.fr:8104
PMCID: PMC147225  PMID: 9399859
8.  IMGT, the international ImMunoGeneTics database 
Nucleic Acids Research  2000;28(1):219-221.
IMGT, the international ImMunoGeneTics database (http://imgt.cines.fr:8104 ), is a high-quality integrated database specialising in Immunoglobulins (Ig), T cell Receptors (TcR) and Major Histocompatibility Complex (MHC) molecules of all vertebrate species, created in 1989 by Marie-Paule Lefranc, Université Montpellier II, CNRS, Montpellier, France (lefranc@ ligm.igh.cnrs.fr ). At present, IMGT includes two databases: IMGT/LIGM-DB, a comprehensive database of Ig and TcR from human and other vertebrates, with translation for fully annotated sequences, and IMGT/HLA-DB, a database of the human MHC referred to as HLA (Human Leucocyte Antigens). The IMGT server provides a common access to expertized genomic, proteomic, structural and polymorphic data of Ig and TcR molecules of all vertebrates. By its high quality and its easy data distribution, IMGT has important implications in medical research (repertoire in autoimmune diseases, AIDS, leukemias, lymphomas), therapeutic approaches (antibody engineering), genome diversity and genome evolution studies. IMGT is freely available at http://imgt.cines.fr:8104 . The IMGT Index is provided at the IMGT Marie-Paule page (http://imgt.cines.fr:8104/textes/IMGTindex.html ).
PMCID: PMC102442  PMID: 10592230
9.  Immunoglobulins: 25 Years of Immunoinformatics and IMGT-ONTOLOGY 
Biomolecules  2014;4(4):1102-1139.
IMGT®, the international ImMunoGeneTics information system® (CNRS and Montpellier University) is the global reference in immunogenetics and immunoinformatics. By its creation in 1989, 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 IgSF and MhSF superfamilies. IMGT® has been built on the IMGT-ONTOLOGY axioms and concepts, which bridged the gap between genes, sequences and three-dimensional (3D) structures. The concepts include the IMGT® standardized keywords (identification), IMGT® standardized labels (description), IMGT® standardized nomenclature (classification), IMGT unique numbering and IMGT Colliers de Perles (numerotation). IMGT® comprises seven databases, 15,000 pages of web resources and 17 tools. IMGT® tools and databases provide a high-quality analysis of the IG from fish to humans, for basic, veterinary and medical research, and for antibody engineering and humanization. They include, as examples: IMGT/V-QUEST and IMGT/JunctionAnalysis for nucleotide sequence analysis and their high-throughput version IMGT/HighV-QUEST for next generation sequencing, IMGT/DomainGapAlign for amino acid sequence analysis of IG domains, IMGT/3Dstructure-DB for 3D structures, contact analysis and paratope/epitope interactions of IG/antigen complexes, and the IMGT/mAb-DB interface for therapeutic antibodies and fusion proteins for immunological applications (FPIA).
doi:10.3390/biom4041102
PMCID: PMC4279172  PMID: 25521638
IMGT; immunogenetics; immunoinformatics; IMGT-ONTOLOGY; IMGT Collier de Perles; immunoglobulin; immune repertoire; IMGT unique numbering; next generation sequencing; antibody humanization
10.  Common and Well-Documented HLA Alleles: 2012 Update to the CWD Catalogue 
Tissue antigens  2013;81(4):194-203.
We have updated the catalogue of common and well-documented (CWD) HLA alleles to reflect current understanding of the prevalence of specific allele sequences. The original CWD catalogue designated 721 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, and –DPB1 loci in IMGT/HLA Database release 2.15.0 as being CWD. The updated CWD catalogue designates 1122 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1 and –DPB1 loci as being CWD, and represents 14.3% of the HLA alleles in IMGT/HLA Database release 3.9.0. In particular, we identified 415 of these alleles as being “common” (having known frequencies) and 707 as being “well-documented” on the basis of ~140,000 sequence-based typing observations and available HLA haplotype data. Using these allele prevalence data, we have also assigned CWD status to specific G and P designations. We identified 147/151 G groups and 290/415 P groups as being CWD. The CWD catalogue will be updated on a regular basis moving forward, and will incorporate changes to the IMGT/HLA Database as well as empirical data from the histocompatibility and immunogenetics community. This version 2.0.0 of the CWD catalogue is available online at cwd.immunogenomics.org, and will be integrated into the Allele Frequencies Net Database, the IMGT/HLA Database and National Marrow Donor Program’s bioinformatics web pages.
doi:10.1111/tan.12093
PMCID: PMC3634360  PMID: 23510415
allele prevalence; common allele; CWD; HLA; sequence based typing; well-documented allele
11.  Immunoglobulin and T Cell Receptor Genes: IMGT® and the Birth and Rise of Immunoinformatics 
IMGT®, the international ImMunoGeneTics information system®1, (CNRS and Université Montpellier 2) is the global reference in immunogenetics and immunoinformatics. By its creation in 1989, 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. IMGT® has been built on the IMGT-ONTOLOGY axioms and concepts, which bridged the gap between genes, sequences, and three-dimensional (3D) structures. The concepts include the IMGT® standardized keywords (concepts of identification), IMGT® standardized labels (concepts of description), IMGT® standardized nomenclature (concepts of classification), IMGT unique numbering, and IMGT Colliers de Perles (concepts of numerotation). IMGT® comprises seven databases, 15,000 pages of web resources, and 17 tools, and provides a high-quality and integrated system for the analysis of the genomic and expressed IG and TR repertoire of the adaptive immune responses. Tools and databases are used in basic, veterinary, and medical research, in clinical applications (mutation analysis in leukemia and lymphoma) and in antibody engineering and humanization. They include, for example IMGT/V-QUEST and IMGT/JunctionAnalysis for nucleotide sequence analysis and their high-throughput version IMGT/HighV-QUEST for next-generation sequencing (500,000 sequences per batch), IMGT/DomainGapAlign for amino acid sequence analysis of IG and TR variable and constant domains and of MH groove domains, IMGT/3Dstructure-DB for 3D structures, contact analysis and paratope/epitope interactions of IG/antigen and TR/peptide-MH complexes and IMGT/mAb-DB interface for therapeutic antibodies and fusion proteins for immune applications (FPIA).
doi:10.3389/fimmu.2014.00022
PMCID: PMC3913909  PMID: 24600447
IMGT; immunogenetics; immunoinformatics; IMGT-ONTOLOGY; IMGT Collier de Perles; immunoglobulin; T cell receptor; major histocompatibility
12.  IMGT/3Dstructure-DB and IMGT/DomainGapAlign: a database and a tool for immunoglobulins or antibodies, T cell receptors, MHC, IgSF and MhcSF 
Nucleic Acids Research  2009;38(Database issue):D301-D307.
IMGT/3Dstructure-DB is the three-dimensional (3D) structure database of IMGT®, the international ImMunoGenetics information system® that is acknowledged as the global reference in immunogenetics and immunoinformatics. IMGT/3Dstructure-DB contains 3D structures of immunoglobulins (IG) or antibodies, T cell receptors (TR), major histocompatibility complex (MHC) proteins, antigen receptor/antigen complexes (IG/Ag, TR/peptide/MHC) of vertebrates; 3D structures of related proteins of the immune system (RPI) of vertebrates and invertebrates, belonging to the immunoglobulin and MHC superfamilies (IgSF and MhcSF, respectively) and found in complexes with IG, TR or MHC. IMGT/3Dstructure-DB data are annotated according to the IMGT criteria, using IMGT/DomainGapAlign, and based on the IMGT-ONTOLOGY concepts and axioms. IMGT/3Dstructure-DB provides IMGT gene and allele identification (CLASSIFICATION), region and domain delimitations (DESCRIPTION), amino acid positions according to the IMGT unique numbering (NUMEROTATION) that are used in IMGT/3Dstructure-DB cards, results of contact analysis and renumbered flat files. In its Web version, the IMGT/DomainGapAlign tool analyses amino acid sequences, per domain. Coupled to the IMGT/Collier-de-Perles tool, it provides an invaluable help for antibody engineering and humanization design based on complementarity determining region (CDR) grafting as it precisely defines the standardized framework regions (FR-IMGT) and CDR-IMGT. IMGT/3Dstructure-DB and IMGT/DomainGapAlign are freely available at http://www.imgt.org.
doi:10.1093/nar/gkp946
PMCID: PMC2808948  PMID: 19900967
13.  IMGT, the international ImMunoGeneTics database. 
Nucleic Acids Research  1999;27(1):209-212.
IMGT, the international ImMunoGeneTics database (http://imgt.cnusc. fr:8104), is a high-quality integrated database specialising in Immunoglobulins (Ig), T cell Receptors (TcR) and Major Histocompatibility Complex (MHC) molecules of all vertebrate species, created in 1989 by Marie-Paule Lefranc, Université Montpellier II, CNRS, Montpellier, France (lefranc@ligm.igh.cnrs.fr). IMGT comprises three databases: LIGM-DB, a comprehensive database of Ig and TcR, MHC/HLA-DB, and PRIMER-DB (the last two in development); a tool, IMGT/DNAPLOT, developed for sequence analysis and alignments; and expertised data based on the IMGT scientific chart, the IMGT repertoire. By its high quality and its easy data distribution, IMGT has important implications in medical research (repertoire in autoimmune diseases, AIDS, leukemias, lymphomas), therapeutic approaches (antibody engineering), genome diversity and genome evolution studies. IMGT is freely available at http://imgt.cnusc. fr:8104
PMCID: PMC148137  PMID: 9847182
14.  IMGT®, the international ImMunoGeneTics information system® 
Nucleic Acids Research  2008;37(Database issue):D1006-D1012.
IMGT®, the international ImMunoGeneTics information system® (http://www.imgt.org), was created in 1989 by Marie-Paule Lefranc, Laboratoire d'ImmunoGénétique Moléculaire LIGM (Université Montpellier 2 and CNRS) at Montpellier, France, in order to standardize and manage the complexity of immunogenetics data. The building of a unique ontology, IMGT-ONTOLOGY, has made IMGT® the global reference in immunogenetics and immunoinformatics. IMGT® is a high-quality integrated knowledge resource specialized in the immunoglobulins or antibodies, T cell receptors, major histocompatibility complex, of human and other vertebrate species, proteins of the IgSF and MhcSF, and related proteins of the immune systems of any species. IMGT® provides a common access to standardized data from genome, proteome, genetics and 3D structures. IMGT® consists of five databases (IMGT/LIGM-DB, IMGT/GENE-DB, IMGT/3Dstructure-DB, etc.), fifteen interactive online tools for sequence, genome and 3D structure analysis, and more than 10 000 HTML pages of synthesis and knowledge. IMGT® is used in medical research (autoimmune diseases, infectious diseases, AIDS, leukemias, lymphomas and myelomas), veterinary research, biotechnology related to antibody engineering (phage displays, combinatorial libraries, chimeric, humanized and human antibodies), diagnostics (clonalities, detection and follow-up of residual diseases) and therapeutical approaches (graft, immunotherapy, vaccinology). IMGT is freely available at http://www.imgt.org.
doi:10.1093/nar/gkn838
PMCID: PMC2686541  PMID: 18978023
15.  An Integrated Tool to Study MHC Region: Accurate SNV Detection and HLA Genes Typing in Human MHC Region Using Targeted High-Throughput Sequencing 
PLoS ONE  2013;8(7):e69388.
The major histocompatibility complex (MHC) is one of the most variable and gene-dense regions of the human genome. Most studies of the MHC, and associated regions, focus on minor variants and HLA typing, many of which have been demonstrated to be associated with human disease susceptibility and metabolic pathways. However, the detection of variants in the MHC region, and diagnostic HLA typing, still lacks a coherent, standardized, cost effective and high coverage protocol of clinical quality and reliability. In this paper, we presented such a method for the accurate detection of minor variants and HLA types in the human MHC region, using high-throughput, high-coverage sequencing of target regions. A probe set was designed to template upon the 8 annotated human MHC haplotypes, and to encompass the 5 megabases (Mb) of the extended MHC region. We deployed our probes upon three, genetically diverse human samples for probe set evaluation, and sequencing data show that ∼97% of the MHC region, and over 99% of the genes in MHC region, are covered with sufficient depth and good evenness. 98% of genotypes called by this capture sequencing prove consistent with established HapMap genotypes. We have concurrently developed a one-step pipeline for calling any HLA type referenced in the IMGT/HLA database from this target capture sequencing data, which shows over 96% typing accuracy when deployed at 4 digital resolution. This cost-effective and highly accurate approach for variant detection and HLA typing in the MHC region may lend further insight into immune-mediated diseases studies, and may find clinical utility in transplantation medicine research. This one-step pipeline is released for general evaluation and use by the scientific community.
doi:10.1371/journal.pone.0069388
PMCID: PMC3722289  PMID: 23894464
16.  IMGT/3Dstructure-DB and IMGT/StructuralQuery, a database and a tool for immunoglobulin, T cell receptor and MHC structural data 
Nucleic Acids Research  2004;32(Database issue):D208-D210.
IMGT/3Dstructure-DB and IMGT/Structural-Query are a novel 3D structure database and a new tool for immunological proteins. They are part of IMGT, the international ImMunoGenetics information system®, a high-quality integrated knowledge resource specializing in immunoglobulins (IG), T cell receptors (TR), major histocompatibility complex (MHC) and related proteins of the immune system (RPI) of human and other vertebrate species, which consists of databases, Web resources and interactive on-line tools. IMGT/3Dstructure-DB data are described according to the IMGT Scientific chart rules based on the IMGT-ONTOLOGY concepts. IMGT/3Dstructure-DB provides IMGT gene and allele identification of IG, TR and MHC proteins with known 3D structures, domain delimitations, amino acid positions according to the IMGT unique numbering and renumbered coordinate flat files. Moreover IMGT/3Dstructure-DB provides 2D graphical representations (or Collier de Perles) and results of contact analysis. The IMGT/StructuralQuery tool allows search of this database based on specific structural characteristics. IMGT/3Dstructure-DB and IMGT/StructuralQuery are freely available at http://imgt.cines.fr.
doi:10.1093/nar/gkh042
PMCID: PMC308776  PMID: 14681396
17.  IMGT, the international ImMunoGeneTics information system®: a standardized approach for immunogenetics and immunoinformatics 
Immunome Research  2005;1:3.
IMGT, the international ImMunoGeneTics information system®, was created in 1989 by the Laboratoire d'ImmunoGénétique Moléculaire (LIGM) (Université Montpellier II and CNRS) at Montpellier, France. IMGT is a high quality integrated knowledge resource specialized in immunoglobulins (IG), T cell receptors (TR), major histocompatibility complex (MHC) of human and other vertebrates, and related proteins of the immune system (RPI) of any species which belong to the immunoglobulin superfamily (IgSF) and to the MHC superfamily (MhcSF). IMGT consists of five databases, ten on-line tools and more than 8,000 HTML pages of Web resources. IMGT provides a common access to standardized data from genome, genetics, proteome and three-dimensional structures. The accuracy and the consistency of IMGT data are based on IMGT-ONTOLOGY, a semantic specification of terms to be used in immunogenetics and immunoinformatics. IMGT-ONTOLOGY comprises six main concepts: IDENTIFICATION, CLASSIFICATION, DESCRIPTION, NUMEROTATION, ORIENTATION and OBTENTION. Based on these concepts, the controlled vocabulary and the annotation rules necessary for the immunogenetics data identification, classification, description and numbering and for the management of IMGT knowledge are defined in the IMGT Scientific chart. IMGT is the international reference in immunogenetics and immunoinformatics for medical research (repertoire analysis of the IG antibody sites and of the TR recognition sites in autoimmune and infectious diseases, AIDS, leukemias, lymphomas, myelomas), veterinary research (IG and TR repertoires in farm and wild life species), genome diversity and genome evolution studies of the adaptive immune responses, biotechnology related to antibody engineering (single chain Fragment variable (scFv), phage displays, combinatorial libraries, chimeric, humanized and human antibodies), diagnostics (detection and follow up of residual diseases) and therapeutical approaches (grafts, immunotherapy, vaccinology). IMGT is freely available at .
doi:10.1186/1745-7580-1-3
PMCID: PMC1312312  PMID: 16305737
IMGT; antibody; immunoglobulin; T cell receptor; superfamily; MHC; HLA; ontology; database; information system; knowledge resource; immunoinformatics; immunogenetics; Collier de Perles; three-dimensional; 3D structure; polymorphism; annotation
18.  Strategies to work with HLA data in human populations for histocompatibility, clinical transplantation, epidemiology and population genetics: HLA-NET methodological recommendations 
HLA-NET (a European COST Action) aims at networking researchers working in bone marrow transplantation, epidemiology and population genetics to improve the molecular characterization of the HLA genetic diversity of human populations, with an expected strong impact on both public health and fundamental research. Such improvements involve finding consensual strategies to characterize human populations and samples and report HLA molecular typings and ambiguities; proposing user-friendly access to databases and computer tools and defining minimal requirements related to ethical aspects. The overall outcome is the provision of population genetic characterizations and comparisons in a standard way by all interested laboratories. This article reports the recommendations of four working groups (WG1-4) of the HLA-NET network at the mid-term of its activities. WG1 (Population definitions and sampling strategies for population genetics’ analyses) recommends avoiding outdated racial classifications and population names (e.g. ‘Caucasian’) and using instead geographic and/or cultural (e.g. linguistic) criteria to describe human populations (e.g. ‘pan-European’). A standard ‘HLA-NET POPULATION DATA QUESTIONNAIRE’ has been finalized and is available for the whole HLA community. WG2 (HLA typing standards for population genetics analyses) recommends retaining maximal information when reporting HLA typing results. Rather than using the National Marrow Donor Program coding system, all ambiguities should be provided by listing all allele pairs required to explain each genotype, according to the formats proposed in ‘HLA-NET GUIDELINES FOR REPORTING HLA TYPINGS’. The group also suggests taking into account a preliminary list of alleles defined by polymorphisms outside the peptide-binding sites that may affect population genetic statistics because of significant frequencies. WG3 (Bioinformatic strategies for HLA population data storage and analysis) recommends the use of programs capable of dealing with ambiguous data, such as the ‘gene[rate]’ computer tools to estimate frequencies, test for Hardy–Weinberg equilibrium and selective neutrality on data containing any number and kind of ambiguities. WG4 (Ethical issues) proposes to adopt thorough general principles for any HLA population study to ensure that it conforms to (inter)national legislation or recommendations/guidelines. All HLA-NET guidelines and tools are available through its website http://hla-net.eu.
doi:10.1111/j.1744-313X.2012.01113.x
PMCID: PMC3533781  PMID: 22533604
19.  Quantitative Predictions of Peptide Binding to Any HLA-DR Molecule of Known Sequence: NetMHCIIpan 
PLoS Computational Biology  2008;4(7):e1000107.
CD4 positive T helper cells control many aspects of specific immunity. These cells are specific for peptides derived from protein antigens and presented by molecules of the extremely polymorphic major histocompatibility complex (MHC) class II system. The identification of peptides that bind to MHC class II molecules is therefore of pivotal importance for rational discovery of immune epitopes. HLA-DR is a prominent example of a human MHC class II. Here, we present a method, NetMHCIIpan, that allows for pan-specific predictions of peptide binding to any HLA-DR molecule of known sequence. The method is derived from a large compilation of quantitative HLA-DR binding events covering 14 of the more than 500 known HLA-DR alleles. Taking both peptide and HLA sequence information into account, the method can generalize and predict peptide binding also for HLA-DR molecules where experimental data is absent. Validation of the method includes identification of endogenously derived HLA class II ligands, cross-validation, leave-one-molecule-out, and binding motif identification for hitherto uncharacterized HLA-DR molecules. The validation shows that the method can successfully predict binding for HLA-DR molecules—even in the absence of specific data for the particular molecule in question. Moreover, when compared to TEPITOPE, currently the only other publicly available prediction method aiming at providing broad HLA-DR allelic coverage, NetMHCIIpan performs equivalently for alleles included in the training of TEPITOPE while outperforming TEPITOPE on novel alleles. We propose that the method can be used to identify those hitherto uncharacterized alleles, which should be addressed experimentally in future updates of the method to cover the polymorphism of HLA-DR most efficiently. We thus conclude that the presented method meets the challenge of keeping up with the MHC polymorphism discovery rate and that it can be used to sample the MHC “space,” enabling a highly efficient iterative process for improving MHC class II binding predictions.
Author Summary
CD4 positive T helper cells provide essential help for stimulation of both cellular and humoral immune reactions. T helper cells recognize peptides presented by molecules of the major histocompatibility complex (MHC) class II system. HLA-DR is a prominent example of a human MHC class II locus. The HLA molecules are extremely polymorphic, and more than 500 different HLA-DR protein sequences are known today. Each HLA-DR molecule potentially binds a unique set of antigenic peptides, and experimental characterization of the binding specificity for each molecule would be an immense and highly costly task. Only a very limited set of MHC molecules has been characterized experimentally. We have demonstrated earlier that it is possible to derive accurate predictions for MHC class I proteins by interpolating information from neighboring molecules. It is not straightforward to take a similar approach to derive pan-specific HLA-DR class II predictions because the HLA class II molecules can bind peptides of very different lengths. Here, we nonetheless show that this is indeed possible. We develop an HLA-DR pan-specific method that allows for prediction of binding to any HLA-DR molecule of known sequence—even in the absence of specific data for the particular molecule in question.
doi:10.1371/journal.pcbi.1000107
PMCID: PMC2430535  PMID: 18604266
20.  IMGT/GeneInfo: T cell receptor gamma TRG and delta TRD genes in database give access to all TR potential V(D)J recombinations 
BMC Bioinformatics  2006;7:224.
Background
Adaptative immune repertoire diversity in vertebrate species is generated by recombination of variable (V), diversity (D) and joining (J) genes in the immunoglobulin (IG) loci of B lymphocytes and in the T cell receptor (TR) loci of T lymphocytes. These V-J and V-D-J gene rearrangements at the DNA level involve recombination signal sequences (RSS). Whereas many data exist, they are scattered in non specialized resources with different nomenclatures (eg. flat files) and are difficult to extract.
Description
IMGT/GeneInfo is an online information system that provides, through a user-friendly interface, exhaustive information resulting from the complex mechanisms of T cell receptor V-J and V-D-J recombinations. T cells comprise two populations which express the αβ and γδ TR, respectively. The first version of the system dealt with the Homo sapiens and Mus musculus TRA and TRB loci whose gene rearrangements allow the synthesis of the αβ TR chains. In this paper, we present the second version of IMGT/GeneInfo where we complete the database for the Homo sapiens and Mus musculus TRG and TRD loci along with the introduction of a quality control procedure for existing and new data. We also include new functionalities to the four loci analysis, giving, to date, a very informative tool which allows to work on V(D)J genes of all TR loci in both human and mouse species. IMGT/GeneInfo provides more than 59,000 rearrangement combinations with a full gene description which is freely available at .
Conclusion
IMGT/GeneInfo allows all TR information sequences to be in the same spot, and are now available within two computer-mouse clicks. This is useful for biologists and bioinformaticians for the study of T lymphocyte V(D)J gene rearrangements and their applications in immune response analysis.
doi:10.1186/1471-2105-7-224
PMCID: PMC1482724  PMID: 16640788
21.  IPD—the Immuno Polymorphism Database 
Nucleic Acids Research  2012;41(Database issue):D1234-D1240.
The Immuno Polymorphism Database (IPD), http://www.ebi.ac.uk/ipd/ is a set of specialist databases related to the study of polymorphic genes in the immune system. The IPD project works with specialist groups or nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The IPD project stores all the data in a set of related databases. IPD currently consists of four databases: IPD-KIR, contains the allelic sequences of killer-cell immunoglobulin-like receptors, IPD-MHC, a database of sequences of the major histocompatibility complex of different species; IPD-HPA, alloantigens expressed only on platelets; and IPD-ESTDAB, which provides access to the European Searchable Tumour Cell-Line Database, a cell bank of immunologically characterized melanoma cell lines. The data is currently available online from the website and FTP directory. This article describes the latest updates and additional tools added to the IPD project.
doi:10.1093/nar/gks1140
PMCID: PMC3531162  PMID: 23180793
22.  IFN-γ production in response to in vitro stimulation with collagen type II in rheumatoid arthritis is associated with HLA-DRB1*0401 and HLA-DQ8 
Arthritis Research  1999;2(1):75-84.
IFN-γ was measured in supernatants after in vitro stimulation of peripheral blood mononuclear cells with collagen type II (CII), purified protein derivative or influenza virus. IFN-γ production in response to CII was similar in rheumatoid arthritis (RA) patients and healthy control individuals. The IFN-γ response to purified protein derivative and influenza virus was lower in RA patients, reflecting a general T-cell hyporesponsiveness in RA. After recalculating the response to CII taking this hyporesponsiveness into account the CII response was higher in RA patients, and was associated with human leucocyte antigen (HLA)-DRB1*0401 and HLA-DQA1*0301-DQB1*0302 (HLA-DQ8). Rheumatoid arthritis patients with elevated serum levels of immunoglobulin (Ig)G anti-CII antibodies had lower CII-induced IFN-γ production than patients with low anti-CII levels. The relative increase in CII-reactivity in RA patients as compared with healthy control individuals, and the association of a higher response with RA-associated HLA haplotypes, suggest the existence of a potentially pathogenic cellular reactivity against CII in RA.
Introduction:
Despite much work over past decades, whether antigen-specific immune reactions occur in rheumatoid arthritis (RA) and to what extent such reactions are directed towards joint-specific autoantigens is still questionable. One strong indicator for antigenic involvement in RA is the fact that certain major histocompatibility complex (MHC) class II genotypes [human leucocyte antigen (HLA)-DR4 and HLA-DR1] predispose for the development of the disease [1]. In the present report, collagen type II (CII) was studied as a putative autoantigen on the basis of both clinical and experimental data that show an increased frequency of antibodies to CII in RA patients [2,3,4] and that show that CII can induce experimental arthritis [5].
It is evident from the literature that RA peripheral blood mononuclear cells (PBMCs) respond poorly to antigenic stimulation [6,7,8], and in particular evidence for a partial tolerization to CII has been presented [9]. The strategy of the present work has accordingly been to reinvestigate T-cell reactivity to CII in RA patients, to relate it to the response to commonly used recall antigens and to analyze IFN-γ responses as an alternative to proliferative responses.
Aims:
To study cellular immune reactivity to CII in patients with RA and in healthy control individuals and to correlate this reactivity to HLA class II genotypes and to the presence of antibodies to CII in serum.
Methods:
Forty-five patients who met the 1987 American College of Rheumatology classification criteria for RA [10] and 25 healthy control individuals of similar age and sex were included. Twenty-six of these patients who had low levels of anti-CII in serum were randomly chosen, whereas 19 patients with high anti-CII levels were identified by enzyme-linked immunosorbent assay (ELISA)-screening of 400 RA sera.
Heparinized blood was density gradient separated and PBMCs were cultured at 1 × 106/ml in RPMI-10% fetal calf serum with or without antigenic stimulation: native or denatured CII (100 μ g/ml), killed influenza virus (Vaxigrip, Pasteur Mérieux, Lyon, France; diluted 1 : 1000) or purified protein derivative (PPD; 10 μ g/ml). CII was heat-denatured in 56°C for 30 min.
Cell supernatants were collected after 7days and IFN-γ contents were analyzed using ELISA. HLA-DR and HLA-DQ genotyping was performed utilizing a polymerase chain reaction-based technique with sequence-specific oligonucleotide probe hybridization. Nonparametric statistical analyses were utilized throughout the study.
Results:
PBMCs from both RA patients and healthy control individuals responded with inteferon-γ production to the same degree to stimulation with native and denatured CII (Fig. 1a), giving median stimulation indexes with native CII of 4.6 for RA patients and 5.4 for healthy control individuals, and with denatured CII of 2.9 for RA patients and 2.6 for healthy control individuals. RA patients with elevated levels of anti-CII had a weaker IFN-γ response to both native and denatured CII than did healthy control individuals (P = 0.02 and 0.04, respectively).
Stimulation with the standard recall antigens PPD and killed influenza virus yielded a median stimulation index with PPD of 10.0 for RA patients and 51.3 for healthy control individuals and with influenza of 12.3 for RA patients and 25.7 for healthy, control individuals. The RA patients displayed markedly lower responsiveness to both PPD and killed influenza virus than did healthy control individuals (Fig. 1b). IFN-γ responses to all antigens were abrogated when coincubating with antibodies blocking MHC class II.
The low response to PPD and killed influenza virus in RA patients relative to that of healthy control individuals reflects a general downregulation of antigen-induced responsiveness of T cells from RA patients [6,7,8]. That no difference between the RA group and the control group was recorded in CII-induced IFN-γ production therefore indicates that there may be an underlying increased responsiveness to CII in RA patients, which is obscured by the general downregulation of T-cell responsiveness in these patients. In order to address this possibility, we calculated the fraction between individual values for the CII-induced IFN-γ production and the PPD-induced and killed influenza virus-induced IFN-γ production, and compared these fractions. A highly significant difference between the RA and healthy control groups was apparent after stimulation with both native CII and denatured CII when expressing the response as a fraction of that with PPD (Fig. 2a). Similar data were obtained using killed influenza virus-stimulated IFN-γ values as the denominator (Fig. 2b).
When comparing the compensated IFN-γ response to denatured CII stimulation between RA patients with different HLA genotypes, highly significant differences were evident, with HLA-DRB1*0401 patients having greater CII responsiveness than patients who lacked this genotype (Fig. 3a). HLA-DQ8 positive patients also displayed a high responsiveness to CII as compared with HLA-DQ8 negative RA patients (Fig. 3b). These associations between the relative T-cell reactivity to denatured CII and HLA class II genotypes were not seen in healthy control individuals. Similar results were achieved using influenza as denominator (P = 0.02 for HLA-DRB1*0401 and P = 0.01 for HLA-DQ8).
Discussion:
No reports have previously systematically taken the general T-cell hyporesponsiveness in RA into account when investigating specific T-cell responses in this disease. In order to address this issue we used the T-cell responses to PPD and killed influenza virus as reference antigens. This was made on the assumption that exposure to these antigens is similar in age-matched and sex-matched groups of RA patients and healthy control individuals. The concept of a general hyporesponsiveness in RA T cells has been documented in several previous reports, in which both nominal antigens [6,7,8] and mitogens [11,12,13] have been used. The fact that a similar functional downregulation in RA PBMCs was obtained with both PPD and killed influenza virus as reference antigens strengthens the validity of our approach.
We identified an association between the IFN-γ response to CII and HLA-DRB1*0401 and HLA-DQ8 in the RA patient group, which is of obvious interest because both these MHC class II alleles have been associated with high responsiveness to CII in transgenic mice that express these human MHC class II molecules [14,15]. There was no association between high anti-CII levels and shared epitope (HLA-DRB1*0401 or HLA-DRB1*0404).
Conclusion:
CII, a major autoantigen candidate in RA, can elicit an IFN-γ response in vitro that is associated with HLA-DRB1*0401 and HLA-DQ8 in RA patients. This study, with a partly new methodological approach to a classical problem in RA, has provided some additional support to the notion that CII may be a target autoantigen of importance for a substantial group of RA patients. Continued efforts to identify mechanisms behind the general hyporesponsiveness to antigens in RA, as well as the mechanisms behind the potential partial anergy to CII, may provide us with better opportunities to study the specificity and pathophysiological relevance of anti-CII reactivity in RA.
PMCID: PMC17806  PMID: 11219392
collagen type II; human leucocyte antigen-DR; IFN-γ; rheumatoid arthritis; T cell
23.  IMGT-ONTOLOGY 2012 
Immunogenetics is the science that studies the genetics of the immune system and immune responses. Owing to the complexity and diversity of the immune repertoire, immunogenetics represents one of the greatest challenges for data interpretation: a large biological expertise, a considerable effort of standardization and the elaboration of an efficient system for the management of the related knowledge were required. IMGT®, the international ImMunoGeneTics information system® (http://www.imgt.org) has reached that goal through the building of a unique ontology, IMGT-ONTOLOGY, which represents the first ontology for the formal representation of knowledge in immunogenetics and immunoinformatics. IMGT-ONTOLOGY manages the immunogenetics knowledge through diverse facets that rely on the seven axioms of the Formal IMGT-ONTOLOGY or IMGT-Kaleidoscope: “IDENTIFICATION,” “DESCRIPTION,” “CLASSIFICATION,” “NUMEROTATION,” “LOCALIZATION,” “ORIENTATION,” and “OBTENTION.” The concepts of identification, description, classification, and numerotation generated from the axioms led to the elaboration of the IMGT® standards that constitute the IMGT Scientific chart: IMGT® standardized keywords (concepts of identification), IMGT® standardized labels (concepts of description), IMGT® standardized gene and allele nomenclature (concepts of classification) and IMGT unique numbering and IMGT Collier de Perles (concepts of numerotation). IMGT-ONTOLOGY has become the global reference in immunogenetics and immunoinformatics for the knowledge representation of immunoglobulins (IG) or antibodies, T cell receptors (TR), and major histocompatibility (MH) proteins of humans and other vertebrates, proteins of the immunoglobulin superfamily (IgSF) and MH superfamily (MhSF), related proteins of the immune system (RPI) of vertebrates and invertebrates, therapeutic monoclonal antibodies (mAbs), fusion proteins for immune applications (FPIA), and composite proteins for clinical applications (CPCA).
doi:10.3389/fgene.2012.00079
PMCID: PMC3358611  PMID: 22654892
IMGT; immunogenetics; immunoinformatics; IMGT-ONTOLOGY; immunoglobulin; antibody; T cell receptor; immune repertoire
24.  IMGT/GeneInfo: enhancing V(D)J recombination database accessibility 
Nucleic Acids Research  2004;32(Database issue):D51-D54.
IMGT/GeneInfo is a user-friendly online information system that provides information on data resulting from the complex mechanisms of immunoglobulin (IG) and T cell receptor (TR) V(D)J recombinations. For the first time, it is possible to visualize all the rearrangement parameters on a single page. IMGT/GeneInfo is part of the international ImMunoGeneTics information system® (IMGT), a high-quality integrated knowledge resource specializing in IG, TR, major histocompatibility complex (MHC), and related proteins of the immune system of human and other vertebrate species. The IMGT/GeneInfo system was developed by the TIMC and ICH laboratories (with the collaboration of LIGM), and is the first example of an external system being incorporated into IMGT. In this paper, we report the first part of this work. IMGT/GeneInfo_TR deals with the human and mouse TRA/TRD and TRB loci of the TR. Data handling and visualization are complementary to the current data and tools in IMGT, and will subsequently allow the modelling of V(D)J gene use, and thus, to predict non-standard recombination profiles which may eventually be found in conditions such as leukaemias or lymphomas. Access to IMGT/GeneInfo is free and can be found at http://imgt.cines.fr/GeneInfo.
doi:10.1093/nar/gkh041
PMCID: PMC308775  PMID: 14681357
25.  IMGT/LIGM-DB, the IMGT® comprehensive database of immunoglobulin and T cell receptor nucleotide sequences 
Nucleic Acids Research  2005;34(Database issue):D781-D784.
IMGT/LIGM-DB is the IMGT® comprehensive database of immunoglobulin (IG) and T cell receptor (TR) nucleotide sequences from human and other vertebrate species. It was created in 1989 by LIGM, Montpellier, France and is the oldest and the largest database of IMGT®. IMGT/LIGM-DB includes all germline (non-rearranged) and rearranged IG and TR genomic DNA (gDNA) and complementary DNA (cDNA) sequences published in generalist databases. IMGT/LIGM-DB allows searches from the Web interface according to biological and immunogenetic criteria through five distinct modules depending on the user interest. For a given entry, nine types of display are available including the IMGT flat file, the translation of the coding regions and the analysis by the IMGT/V-QUEST tool. IMGT/LIGM-DB distributes expertly annotated sequences. The annotations hugely enhance the quality and the accuracy of the distributed detailed information. They include the sequence identification, the gene and allele classification, the constitutive and specific motif description, the codon and amino acid numbering, and the sequence obtaining information, according to the main concepts of IMGT-ONTOLOGY. They represent the main source of IG and TR gene and allele knowledge stored in IMGT/GENE-DB and in the IMGT reference directory. IMGT/LIGM-DB is freely available at .
doi:10.1093/nar/gkj088
PMCID: PMC1347451  PMID: 16381979

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