# IMGT, a system and an ontology that bridge biological and computational spheres in bioinformatics.

Marie-Paule Lefranc, Véronique Giudicelli, Laëtitia Regnier, Patrice Duroux

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Marie-Paule Lefranc, Véronique Giudicelli, Laëtitia Regnier, Patrice Duroux. IMGT, a system and an ontology that bridge biological and computational spheres in bioinformatics.. Briefings in Bioinformatics, 2008, 9 (4), pp.263-275. 10.1093/bib/bbn014. hal-00357138

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# IMGT, a system and an ontology that bridge biological and computational spheres in bioinformatics

Marie-Paule Lefranc, Véronique Giudicelli, Laetitia Regnier and Patrice Duroux

Submitted: 9th January 2008; Received (in revised form): 13th February 2008

## Abstract

IMGT®, the international ImMunoGeneTics information system (http://imgt.cines.fr), is the reference in immuno- genetics and immunoinformatics. IMGT standardizes and manages the complex immunogenetic data that include the immunoglobulins (IG) or antibodies, the T cell receptors (TR), the major histocompatibility complex (MHC) and the related proteins of the immune system (RPI), which belong to the immunoglobulin superfamily (IgSF) and the MHC superfamily (MhcSF). The accuracy and consistency of IMGT data and the coherence between the different IMGT components (databases, tools and Web resources) are based on IMGT-ONTOLOGY, the first ontology for immu- nogenetics and immunoinformatics. IMGT-ONTOLOGY manages the immunogenetics knowledge through diverse facets relying on seven axioms, ‘IDENTIFICATION’, ‘DESCRIPTION’, ‘CLASSIFICATION’, ‘NUMEROTATION’, ‘LOCALIZATION’, ‘ORIENTATION’ and ‘OBTENTION’, that postulate that objects, processes and relations have to be identified, described, classified, numerotated, localized, orientated, and that the way they are obtained has to be determined. These axioms constitute the Formal IMGT-ONTOLOGY, also designated as IMGT-Kaleidoscope. These axioms have been essential for the conceptualization of the molecular immunogenetics knowledge and for the creation of IMGT. Indeed all the components of the IMGT integrated system have been developed, based on standardized concepts and relations, thus allowing IMGT to bridge biological and computational spheres in bioinfor- matics. The same axioms can be used to generate concepts for multi-scale level approaches at the molecule, cell, tissue, organ, organism or population level, emphasizing the generalization of the application domain. In that way the Formal IMGT-ONTOLOGY represents a paradigm for the elaboration of ontologies in system biology.

**Keywords:** IMGT; immunoinformatics; immunogenetics; ontology; information system; systems biology

## INTRODUCTION

IMGT®, the international ImMunoGeneTics information system (http://imgt.cines.fr) [1], is the international reference in immunogenetics and immunoinformatics. Created in 1989 at the

Laboratoire d'ImmunoGénétique Moléculaire (LIGM) by Marie-Paule Lefranc (Université Montpellier 2 and CNRS) in Montpellier, France, IMGT provides a high-quality integrated knowledge resource, specialized in the immunoglobulins (IG)

Corresponding author. Marie-Paule Lefranc, IMGT, Laboratoire d'ImmunoGénétique Moléculaire, LIGM, UPR CNRS 1142, IGH, 141 rue de la Cardonille, 34396 Montpellier Cedex 5, France. Tel: +33 (0)4 99 61 99 65; Fax: +33 (0)4 99 61 99 01; E-mail: Marie-Paule.Lefranc@igh.cnrs.fr

**Marie-Paule Lefranc**, PhD, is Professor at the Université Montpellier 2 and Head of the Laboratoire d'ImmunoGénétique Moléculaire at the Institut de Génétique Humaine CNRS. She is Director of IMGT, the international ImMunoGeneTics information system (http://imgt.cines.fr) that she created in 1989, at Montpellier, France.

**Véronique Giudicelli**, PhD, Engineer in Bioinformatics, has developed IMGT/GENE-DB, the IMGT genome database, and IMGT/V-QUEST, the IMGT tool for the analysis of the IG and TR sequences. She is in charge of the bioinformatic developments of IMGT, the international ImMunoGeneTics information system.

**Laetitia Regnier**, Engineer in Bioinformatics is in charge of the improvement of the annotations in IMGT/LIGM-DB and of the quality assurance in IMGT, the international ImMunoGeneTics information system.

**Patrice Duroux**, PhD, Research Engineer in informatics, is in charge of the computing management of IMGT, the international ImMunoGeneTics information system, at the Laboratoire d'ImmunoGénétique Moléculaire, Institut de Génétique Humaine CNRS, Montpellier, France.
<figure><img src="image_2.png" /><figcaption>**Figure 1:** IMGT databases and tools with their interactions according to the genetic, genomic and/or structural approaches (http://imgt.cines.fr).</figcaption></figure>

or antibodies, T cell receptors (TR), major histo-compatibility complex (MHC) of human and other vertebrates and related proteins of the immune system (RPI), which belong to the immunoglobulin superfamily (IgSF) and to the MHC superfamily (MhcSF) of any species. The IMGT information system consists of databases (three of sequences, one of genes and one of three-dimensional (3D) structures) and interactive tools for sequence, genome and 3D structure analysis, which interact together according to genetic, genomic and structural approaches [2] (Figure 1). Moreover, IMGT provides Web resources

comprising more than 10 000 HTML pages of synthesis (IMGT Repertoire), knowledge (IMGT Scientific chart, IMGT Biotechnology page, IMGT Medical page, IMGT Veterinary page, IMGT Education and IMGT Index) and external links (IMGT Immunoinformatics page, IMGT Bloc-notes and IMGT other accesses) [1, 2].

The accuracy and the consistency of the IMGT data, as well as the coherence between the different IMGT components (databases, tools and Web resources) are based on IMGT-ONTOLOGY, the first ontology for immunogenetics and
<figure><img src="image_3.png" /><figcaption>**Figure 2:** An example of biological knowledge at the molecular level: the synthesis of an IG or antibody in humans. A human being may potentially synthesize 10¹² different antibodies [5]. (1) DNA rearrangements (is_rearranged_into); (2) Transcription (is_transcribed_into); (3) Translation (is_translated_into).</figcaption></figure>

immunoinformatics [3]. The standardization rules, defined in the IMGT Scientific chart, are based on the IMGT-ONTOLOGY concepts that were developed to solve the complexity of the immunogenetics knowledge and that, interestingly, were defined in an unprecedented approach, and before the term ‘ontology’ became commonly used in biology and bioinformatics [3]. The IMGT-ONTOLOGY concepts are generated from the seven axioms of the Formal IMGT-ONTOLOGY or IMGT-Kaleidoscope: ‘IDENTIFICATION’, ‘DESCRIPTION’, ‘CLASSIFICATION’, ‘NUMEROTATION’, ‘LOCALIZATION’, ‘ORIENTATION’ and ‘OBTENTION’ [4]. These axioms postulate that the approach to manage biological data and to represent knowledge in biology comprises various facets [4].

Immunogenetics, the science that studies the genetics of the immune responses, has shown a considerable expansion in biomedical fields since the last decades. It has highlighted the complex mechanisms by which B cells and T cells are at the origin of the extreme diversity of antigen receptors, the main actors of the adaptive immune responses, that comprise the IG or antibodies, and the TR

(10¹² different IG and 10¹² different TR per individual, in humans) [5, 6]. These mechanisms include in particular DNA rearrangements [7] and, for the IG, somatic hypermutations [5, 6]. The IMGT-ONTOLOGY axioms and concepts have allowed the representation, at the molecular level, of immunogenetics knowledge related to the genome, transcriptome, proteome, genetics and 3D structures. In this article, we review some of the major IMGT-ONTOLOGY concepts that allow to bridge the gap between the biological and computational spheres in bioinformatics.

## IDENTIFICATION AXIOM: IMGT STANDARDIZED KEYWORDS

### An example of biological knowledge

The IG synthesis is a key example of biological knowledge. An IG or antibody is composed of two identical IG-Heavy chains associated with two identical IG-Light chains, kappa or lambda (Figure 2). In humans, the IG heavy genes (locus IGH), IG kappa genes (locus IGK) and IG lambda genes (locus IGL) are located on the chromosomes 14 (14q32.3), 2 (2p11.2) and 22 (22q11.2), respectively.
<figure><img src="image_4.png" /><figcaption>**Figure 3:** Main IMGT-ONTOLOGY concepts of identification generated from the IDENTIFICATION axiom and their relations with concepts generated from the DESCRIPTION, CLASSIFICATION and NUMEROTATION axioms, at the molecular level.</figcaption></figure>

The synthesis of an IG requires rearrangements of the IGH, IGK and IGL genes during the differentiation of the B lymphocytes [5, 6]. In the human genome (genomic DNA or gDNA), four types of genes code the IG (and TR): variable (V), diversity (D), joining (J) and constant (C) genes. The configuration of the V-gene, D-gene and J-gene is identified as ‘germline’ (Figure 2), the configuration of the C-gene is ‘undefined’. During the differentiation of the B lymphocytes in the bone marrow, the genomic DNA is rearranged first in the IGH locus, and then in the IGK and IGL loci. The rearrangements in the IGH locus lead to the junction of a D-gene and a J-gene to form a D-J-gene, and then to the junction of a V-gene to the D-J-gene to form a V-D-J-gene. The rearrangements in the IGK or IGL loci lead to the junction of a V-gene and a J-gene to form a V-J-gene. The configuration of these genes is identified as ‘rearranged’. After transcription and

maturation of the pre-messenger by splicing, the messenger RNA (mRNA) L-V-D-J-C-sequence and L-V-J-C-sequence (L for leader) are obtained and then translated into the heavy chain (IG-Heavy) and the light chain (IG-Light) of an IG (or antibody) (Figure 2).

## Concepts of identification

In a first step, biological objects, processes and relations require to be identified in order to be entered into IMGT. The IDENTIFICATION axiom [4] has generated the IMGT-ONTOLOGY concepts of identification that were necessary to define the IMGT standardized keywords and their relations [3, 8]. At the molecular level, four major concepts were defined: ‘MoleculeEnt Type’, ‘MoleculeReceptorType’, ‘ChainType’ and ‘DomainType’ (Figure 3).
### 'MoleculeEnt Type' concept

In Figure 2, 10 molecular entities can be identified: V-gene, D-gene, J-gene, C-gene, V-D-J-gene, V-J-gene, L-V-D-J-C-sequence, L-V-J-C-sequence, V-D-J-C-sequence and V-J-C-sequence. They represent instances of the 'MoleculeEnt Type' concept. This concept that includes 21 instances, allows to identify any coding molecule of the genome, transcriptome and proteome. These instances are defined by the instances of three other concepts of identification: 'MoleculeType' ('gDNA', 'mRNA', 'cDNA', 'protein'), 'GeneType' ['conventional', 'variable' (V), 'diversity' (D), 'joining' (J) and 'constant' (C)], and 'ConfigurationType' ('undefined' for conventional and C genes, 'germline' for unrearranged V, D and J genes and 'rearranged' for V, D and J genes after DNA rearrangements [5, 6]). Three instances, 'gene', 'nt-sequence' and 'AA-sequence', respectively, identify the gDNA, mRNA and protein ('MoleculeType') of a conventional gene ('GeneType') in undefined configuration ('ConfigurationType'). The nt-sequence instance is also valid for cDNA. Eighteen instances identify the IG and TR, including the 10 ones shown in Figure 2. For example, the instance 'V-gene' identifies a 'gDNA' containing a 'V' gene, in 'germline' configuration. The instance 'L-V-J-C-sequence' identifies a sequence of 'mRNA' or 'cDNA' containing 'V', 'J' and 'C' genes, with V and J in 'rearranged' configuration. The eight instances not shown in Figure 2 correspond to partial rearrangements or to sterile transcripts [4].

Once a 'MoleculeEnt Type' concept instance has been identified, it is possible to define two properties: its structure and its functionality, defined by the instances of two other concepts of identification. The 'StructureType' concept allows to identify entities with a classical organization ('regular'), from those that have been modified either naturally *in vivo* ('orphon', 'processed orphon', 'unprocessed orphon', 'unspliced', 'partially spliced', etc.) or artificially *in vitro* ('chimeric', 'humanized', 'transgene', etc.). The 'Functionality' concept includes five instances, three of them, 'functional', 'ORF' (open reading frame) and 'pseudogene' identify the functionality of 'MoleculeEnt Type' instances in undefined or germline configuration (conventional genes, C genes, germline V, D and J genes), whereas the two others 'productive' and 'unproductive' identify the functionality of 'MoleculeEnt Type' instances in rearranged configuration (rearranged V, D and

J genes, fusion genes resulting from translocations or obtained by biotechnology and/or molecular engineering).

### 'MoleculeReceptorType' concept

The 'MoleculeReceptorType' concept identifies the type of protein receptor, defined by its chain composition [4]. Thus, IG is an instance of the 'MoleculeReceptorType' concept, defined as comprising four chains, two IG-Heavy and two IG-Light chains, identical two by two and covalently linked (Figure 4).

Once a 'MoleculeReceptorType' concept instance has been identified, it is possible to define its properties such as structure, specificity and function by instances of other concepts of identification. Thus, instances of the 'Specificity' concept identify the antigen recognized by an antigen receptor (IG or TR). The instances of that concept (several hundreds at the present time) can be connected on the one hand, with the 'Epitope' concept that identifies the part of the antigen recognized by the antigen receptor and, on the other hand, with the 'Paratope' concept that identifies the part of the antigen receptor (IG or TR), which recognizes and binds to the antigen [9]. Instances of the 'Function' concept identify the dual function of the antigen receptors [5].

### 'ChainType' and 'DomainType' concepts

The two IG-Heavy and two IG-Light chains of an IG are instances of the 'ChainType' concept (Figure 2). The 'ChainType' concept identifies the type of chain. It is one of the most important concepts of identification for the standardization of genome, transcriptome and proteome data in system biology. Indeed, an instance of the 'ChainType' concept is defined not only by an instance of the 'MoleculeEnt Type' (for instance V-J-sequence) but also by an instance of a concept of classification and by a definition in domains, which bridges the gap with 3D structures.

By its relation with the concepts of classification, the 'ChainType' concept contains a hierarchy of concepts that identify the chain type at different levels of granularity. The finest level of granularity, the 'GeneLevelChainType' concept, identifies the chain type by reference to the gene(s), which code(s) the chain (reciprocal relations 'is_coded_by' and 'codes'). The number of instances of the 'GeneLevelChainType' concept depends on the number of functional genes and ORF per haploid
<figure><img src="image_5.png" /><figcaption>**Figure 4:** Concepts of identification. The different representations (A), (B), (C) and (D) of an IG or antibody (here, an IgG) allow to identify the 'ChainType' (IG-Heavy, IG-Light) and the 'DomainType' (VH, CH1, CH2, CH3, VL, CL), and in (D), the 'MoleculeEnt Type' (V-J-C-sequence, V-D-J-C-sequence) (IDENTIFICATION axiom). The IG-Heavy of an IgM or an IgE would have a CH4 and no hinge. Based on (D), a schematized Y shape is frequently used to represent an IG.</figcaption></figure>

genome in a given species (in the case of the IG and TR, it is the number of functional and ORF constant genes, which is taken into account). If only the functional genes are considered, the instances of this concept correspond to the isotypes.

A chain type instance can also be defined by its constitutive structural units ('DomainType' concept). A domain is a chain subunit characterized by its 3D structure and, by extension, its amino acid sequence and the nucleotide sequence that encodes it. The 'DomainType' concept may theoretically comprise many instances, but so far only the instances that have been carefully characterized by LIGM have been entered in IMGT-ONTOLOGY. The 'DomainType' concept has currently three instances, V type domain (variable domains of the IG and TR and V-like domains of other IgSF proteins), C type domain (constant domains of the IG and TR and C-like domains of other IgSF proteins) and G type

domain (groove domains of the MHC and G-like domains of other MhcSF proteins) [10–14].

DESCRIPTION AXIOM: IMGT
STANDARDIZED LABELS

In a second step, once entered in IMGT, biological objects, processes and relations require to be described. The DESCRIPTION axiom [4] has generated the IMGT-ONTOLOGY concepts of description that were necessary to define the IMGT standardized labels (written in capital letters) and their relations [3, 8].

'MoleculeEnt TypePrototype' concept

Each one of the 21 instances of the ‘Molecule_ EntityType’ concept (IDENTIFICATION axiom) is linked to an instance of the ‘MoleculeEnt TypePrototype’ concept (DESCRIPTION axiom),
<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /><figcaption>**Figure 5:** Concepts of description. (A) V-J-GENE and (B) V-D-J-GENE instances of the 'MoleculeEntiyPrototype' concept graphically representated with their labels (DESCRIPTION axiom). Twenty-seven labels and 10 relations are necessary and sufficient for a complete description of these instances [4]. (C) VH and VL domains encoded by the V-D-J-REGION (of V-D-J-GENE) and by the V-J-REGION (of V-J-GENE).</figcaption></figure>

by the reciprocal relations ‘is_described_by’ and ‘describes’. Each instance of the ‘MoleculeEntiy Prototype’ concept can be described with its constitutive motifs, which belong to other concepts of description. Figure 5 shows as examples the graphical representation of the V-D-J-GENE and V-J-GENE instances with their constitutive motifs and their encoded VH and VL domains.

A set of 10 relations is necessary and sufficient
to compare the localization of the motifs of an

instance of the concept 'MoleculeEntiyPrototype'
(Table 1). These relations are part of the concepts
of localization (LOCALIZATION axiom) (IMGT
Index, http://imgt.cines.fr).

The ontology for sequences and 3D structures has
been the focus of IMGT for many years. More than
500 standardized labels were defined [221 for the
nucleotide sequences (http://imgt.cines.fr/cgi-bin/
IMGTlect.jv?query=7) [15] and 285 for the 3D
structures [9] (http://imgt.cines.fr/textes/IMGT
<table><caption>**Table 1:** Relations for sequence description (LOCALIZATION axiom)</caption><thead><tr><td>Relation</td><td>Reciprocal relation</td></tr></thead><tbody><tr><td>'adjacent_at_its_5_prime_to'</td><td>'adjacent_at_its_3_prime_to'</td></tr><tr><td>'included_withSame_5_prime_in'</td><td>'includes_withSame_5_prime'</td></tr><tr><td>'included_withSame_3_prime_in'</td><td>'includes_withSame_3_prime'</td></tr><tr><td>'overlaps_at_its_5_prime_with'</td><td>'overlaps_at_its_3_prime_with'</td></tr><tr><td>'included_in'</td><td>'includes'</td></tr></tbody></table>

ScientificChart/SequenceDescription/IMGT3Dlabel def.html)]. Prototypes represent the organizational relationship between labels and give information on the order and expected length (in number of nucleotides) of the labels [3]. This provides rules to verify the manual annotation, and to design automatic annotation tools such as IMGT/LIGMotif and IMGT/Automat [16]. Annotation of sequences and 3D structures with these labels constitutes the main part of the expertise. Interestingly, 64 IMGT specific labels defined for nucleotide sequences have been entered in the newly created Sequence Ontology (SO) (http://song.sourceforge.net/) [17] to describe specific IG and TR gene organization (http://imgt.cines.fr/textes/IMGTindex/ontology.html).

The 'MoleculeEntiyPrototype' concept is fundamental in IMGT-ONTOLOGY as relations between its instances allow the representation of the knowledge related to the complex mechanisms of IG and TR gene rearrangements and chain synthesis [5, 6]. The relation 'is_rearranged_into' is specific to the synthesis of the IG and TR. The relations 'is_transcribed_into' and 'is_translated_into' are general for molecular biology. These three relations allow the organization of the various instances of the 'MoleculeEntiyPrototype' concept during the synthesis of the IG and the TR, and in a more general way for the expression of any protein. They allow in addition, by more specific relations, to take into account the alternative transcripts, the protein isoforms and the post-translational modifications.

## CLASSIFICATION AXIOM: IMGT STANDARDIZED GENE NAMES

In IMGT, biological objects, processes and relations require to be classified. The CLASSIFICATION axiom [4] has generated the IMGT-ONTOLOGY concepts of classification that were necessary to set

up the IMGT standardized nomenclature for the genes and alleles [3, 8].

## Group, subgroup, gene and allele

The objective was initially to provide immunologists and geneticists with a standardized nomenclature per locus and per species, which allows extraction and comparison of data for the complex B and T cell antigen receptor molecules, most of the instances of the 'MoleculeEntiyType' concept containing more than one gene (three for V-J-C, four for V-D-J-C) (Figure 2). Moreover, the IG and TR genes belong to highly polymorphic multigene families. A major contribution of IMGT-ONTOLOGY was to set the principles of their classification and to propose a standardized nomenclature [5, 6] (Figure 6).

The 'Group' concept classifies a set of genes that belong to the same multigene family, within the same species or between different species. For the IG and TR, the set of genes is identified by an instance of the 'GeneType' concept (V, D, J or C). The 'Subgroup' concept classifies a subset of genes that belong to the same group, and which, in a given species, share at least 75% of identity at the nucleotide sequence level (and in the germline configuration for the V, D and J genes). The 'Gene' concept classifies a unit of DNA sequence that can be potentially transcribed and/or translated (this definition includes the regulatory elements in 5' and 3', and the introns, if present). The instances of the 'Gene' concept are gene names. In IMGT-ONTOLOGY, a gene name is composed of the name of the species (instance of the Taxon 'Species' concept) and of the gene symbol, for example, *Homo sapiens* IGHV1-2. By extension, orphans and pseudogenes are also instances of the 'Gene' concept. The 'Allele' concept classifies a polymorphic variant of a gene. The instances of the 'Allele' concept are allele names. Alleles identified by the mutations of the nucleotide sequence are classified by reference to allele *01. Full description of mutations and allele name designations are currently recorded for the core sequences (V-REGION, D-REGION, J-REGION, C-REGION). They are reported in Alignment tables, in IMGT Repertoire (http://imgt.cines.fr) and in IMGT/GENE-DB [18].

## International IMGT gene nomenclature

The IMGT gene nomenclature was approved at the international level by Human Genome Organisation (HUGO) Nomenclature Committee HGNC in
<figure><img src="image_9.png" /><figcaption>**Figure 6:** Concepts of classification for gene and allele nomenclature (CLASSIFICATION axiom). (A) Hierarchy of the concepts of classification and their relations. (B) Examples of concept instances for each concept of classification. The concepts instances are associated with an instance of the 'Taxon' concept (IDENTIFICATION axiom), and more precisely for the 'Gene' and 'Allele' concepts with an instance of the 'Species' concept (here, *Homo sapiens*). The 'Locus' concept is a concept of localization (LOCALIZATION axiom).</figcaption></figure>

1999 [19]. The IMGT IG and TR gene names are the official references for the genome projects and, as such, were entered in Genome Database (GDB) and in LocusLink at the National Center for Biotechnology Information (NCBI) in 1999–2000, in Entrez Gene (NCBI) [20] when this gene database superseded LocusLink and in IMGT/GENE-DB [18]. The IMGT IG and TR gene names are the official references for the World Health Organization-International Union of Immunological Societies (WHO-IUIS) Nomenclature Subcommittee for IG and TR [21, 22] and for the genome projects and, as such, have been integrated in the MapViewer at NCBI and, in 2006, in the Ensembl server at the European Bioinformatics Institute (EBI).

## IMGT reference sequences and analysis tools

IMGT reference sequences have been defined for each allele of each gene based on one or, whenever possible, several of the following criteria: germline sequence, first published sequence, longest sequence, mapped sequence. They are listed in the germline gene tables of the IMGT Repertoire (http://imgt.cines.fr) and are available in IMGT/GENE-DB [18]. The IMGT Protein displays show the translated sequences of the alleles *01 of the functional or ORF genes [5, 6]. IMGT/DomainGapAlign identifies the closest IG and TR (V, J and C), MHC and RPI genes from amino acid sequences [9]. The IMGT/V-QUEST tool allows to identify the closest germline V and J genes and alleles

from user IG and TR nucleotide sequences by comparison with the IMGT reference directory sets, whereas the IMGT/JunctionAnalysis tool analyses precisely the V-J and V-D-J junctions and identifies the closest D genes and alleles [23, 24]. These tools are widely used for the IG and TR repertoire analysis in normal and pathological situations [25]. They are recommended by the European Research Initiative on Chronic lymphocytic leukemia CLL (ERIC) for IGHV mutational status analysis in CLL [26].

## NUMEROTATION AXIOM: IMGT UNIQUE NUMBERING

In IMGT, biological objects, processes and relations require to be numeroted. The NUMEROTATION axiom [4] has generated the IMGT-ONTOLOGY concepts of numerotation, and among them, the flagship of IMGT: the IMGT unique numbering [10–14] and its two-dimensional (2D) graphical representation or IMGT Collier de Perles [5, 6, 27, 28] (Figure 7). These concepts were recently reviewed [29] and are only briefly described here.

### IMGTunique numbering

A uniform numbering system for IG and TR sequences of all species has been established to facilitate sequence comparison and cross-referencing between experiments from different laboratories whatever the antigen receptor (IG or TR),
<figure><img src="image_10.png" /><figcaption>**Figure 7:** Concepts of numerotation. Ribbon representations and IMGT Colliers de Perles for V type, C type and G type domains, based on the IMGTunique numbering (NUMEROTATION axiom). (A) V type IgSF domain [12]. (B) C type IgSF domain [13]. (C) G type MhcSF domain [14]. Amino acids are shown in the one-letter abbreviation. Hatched circles correspond to missing positions according to the IMGTunique numbering.</figcaption></figure>

the chain type or the species [10–14]. Structural and
functional domains of the IG and TR chains
comprise the V-DOMAIN (9-strand beta-
sandwich framework), which corresponds to the
V-J-REGION or V-D-J-REGION and is coded by

two or three genes [5, 6] and the constant domain or
C-DOMAIN (7-strand beta-sandwich framework),
which corresponds to the C-REGION (CL of
IG-Light) or is part of it (CH1, CH2 and CH3
of IG-Heavy) (Figure 4). In the IMGT unique
numbering, conserved amino acids from frameworks
always have the same number whatever the IG or
TR domain, and whatever the species they come
from. As examples: cysteine 23 (B-STRAND),
tryptophan 41 (C-STRAND), leucine (or other
hydrophobic amino acid) 89 (E-STRAND) and
cysteine 104 (F-STRAND) [12, 13].

The IMGT unique numbering has been extended to the V-LIKE-DOMAINs and to the C-LIKE-DOMAINs of IgSF proteins other than IG and TR [12, 13]. More recently, the IMGT unique numbering has also been defined for the groove domain or G-DOMAIN (four beta-strands and one alpha-helix) of the MHC class I and II chains [14, 30, 31] and for the G-LIKE-DOMAINs of MhcSF proteins other than MHC [14]. The IMGT unique numbering has made possible standardized comparisons of the sequences and structures of the V type (V-set) and C type (C-set) IgSF domains [32–34] and of the G type (G-set) MhcSF domains [35, 36], whatever the species, the receptor or the chain type.

IMGT Collier de Perles

IMGT Colliers de Perles can be drawn from user
amino acid sequences, after being gapped according
to the IMGT unique numbering (for example with
IMGT/DomainGapAlign), using the IMGT/
Collier-de-Perles tool on the IMGT Web site at
http://imgt.cines.fr. The IMGT Colliers de Perles
are used in antibody humanization design based on
complementarity determining regions (CDR) graft-
ing, to precisely define the CDR-IMGT to be
grafted, and in antibody engineering [37, 38]. IMGT
Colliers de Perles statistical profiles for the human
expressed IGHV, IGKV and IGLV repertoires were
established [39], they help to identify potential
immunogenic residues at given positions in chimeric
or humanized antibodies [37]. In IMGT/
3Dstructure-DB, IMGT Colliers de Perles give
access to the IMGT Residue@Position cards,
which provide the atom contact types and atom
contact categories [9]. They bridge the gap between
linear amino acid sequences and 3D structures, as
illustrated by the display of hydrogen bonds (for V
and C type domains) [9] and pMHC contact sites
(for G type domains) [9, 30, 31].

IMPACT AND PERSPECTIVES

The concepts of IMGT-ONTOLOGY led to the
setting up of international standards: gene and allele

nomenclature by the WHO-IUIS/IMGT Nomen-
clature Committees, and standardized monoclonal
antibody definitions by the WHO-International
Nonproprietary Names (INN) Programme. The
IMGT IG and TR genes names are used in the
genome databases at NCBI (Entrez Gene), EBI
(Ensembl) and Wellcome Trust Sanger Institute
(UK). Many research laboratories, including phar-
maceutical companies, journals, European and
American networks and scientific societies advocate
the use of the IMGT databases and tools, as they
provide the international standards for nomenclature,
description and numerotation (IMGT Scientific
chart, http://imgt.cines.fr), based on the IMGT-
ONTOLOGY concepts [3, 4, 40]. In December
2007, the Antibody Society has acknowledged
IMGT as the molecular informatics framework in
antibody engineering and antibody humanization.
Indeed, IMGT standardized results represent a
crucial step in the evaluation of homologies between
monoclonal antibodies and their closest germline
human counterparts and hence their possible immu-
nogenicity [37].

Beyond these direct applications, the IMGT
concepts are used for the exchange and the sharing
of knowledge in very diverse academic and industrial
fields of research: (i) fundamental and medical
research (repertoire analysis of the IG antibody sites
and of the TR recognition sites in normal and
pathological situations such as autoimmune diseases,
infectious diseases, AIDS, leukaemias, lymphomas,
myelomas), (ii) veterinary research (IG and TR
repertoires in farm and wild life species), (iii) genome
diversity and genome evolution studies of the
adaptive immune responses, (iv) structural evolution
of the IgSF and MhcSF proteins, (v) molecular
biotechnology related to antibody engineering and
antibody therapeutics (scFv, phage displays, combi-
natorial libraries, chimeric, humanized and human
antibodies), (vi) diagnostics (clonalities, detection and
follow-up of residual diseases) and (vii) therapeutical
approaches (grafts, immunotherapy, vaccinology).

The concepts of IMGT-ONTOLOGY are
available, for the users of IMGT and the biologists
in general, in natural language in IMGT Scientific
chart (http://imgt.cines.fr) [8], and have been
formalized for programming purpose in IMGT-ML
(XML Schema) [41]. IMGT-ONTOLOGY is
being implemented in Protégé and OBO-Edit to
facilitate the export in formats such as OWL,
and to link, whenever possible, the concepts of
IMGT-ONTOLOGY to those of other ontol-
ogies in biology such as the Gene Ontology (GO)
[42], and in immunology, such as the Immunome
Epitope database and Analysis Resource (IEDB) [43]
and other Open Biomedical Ontologies (OBO)
(http://obo.sourceforge.net).

The huge amount of immunological experimental
data continues to grow exponentially and necessitates
to be managed and analysed computationally. This
is the goal of immunoinformatics, a science that
implments the bioinformatics methodologies to
answer these needs. At the same time, standardized
representation of genomic, genetic, proteomic and
3D structural data is required to organize immuno-
genetics knowledge towards system biology and for
the modelling and a better understanding of the
immune system. As the same axioms can be used to
generate concepts for multi-scale level approaches,
the Formal IMGT-ONTOLOGY represents a para-
digm for the elaboration of ontologies in system
biology, which requires to identify, to describe, to
classify, to numerate, to localize, to orientate and to
determine the obtaining and evolution of biological
knowledge from molecule to population, in time and
space. In that perspective, IMGT-ONTOLOGY
represents a key component in the elaboration and
setting up of standards of the European ImmunoGrid
project (http://www.immunogrid.org/) whose aim is
to define the essential concepts for modelling of the
immune system.

Key Points

* The Formal IMGT-ONTOLOGY or IMGT-Kaleidoscope comprises seven axioms that postulate that biological objects, processes and relations have to be identified, described, classified, numerotated, localized, orientated and that the way they are obtained has to be determined.

* The 'IDENTIFICATION' axiom of the Formal IMGT-ONTOLOGY and the generated concepts of identification allowed to define the IMGT standardized keywords and their relations.

* The 'DESCRIPTION' axiom of the Formal IMGT-ONTOLOGY and the generated concepts of description allowed to define the IMGT standardized labels and their relations.

* The 'CLASSIFICATION' axiom of the Formal IMGT-ONTOLOGY and the generated concepts of classification allowed to set up the IMGT standardized nomenclature for the genes and alleles that is the international reference.

* The 'NUMEROTATION' axiom of the Formal IMGT-ONTOLOGY and the generated concepts of numerotation allowed to set up the IMGT unique numbering for V, C and G type domains and their graphical representation or IMGT Collier de Perles.

Acknowledgements

We thank Chantal Ginestoux for the figures. We are grateful to Gérard Lefranc for helpful discussion and to the IMGT team for its expertise and constant motivation. This work was funded by Centre National de la Recherche Scientifique CNRS; Ministère de l'Enseignement Supérieur et de la Recherche MESR (ACI-IMPBIO IMP82-2004, Université Montpellier 2 Plan Pluri-Formation); Région Languedoc-Roussillon; Agence Nationale de la Recherche ANR BYOSIS (ANR-06-BYOS-0005-01); European Union ImmunoGrid project (IST-2004-0280069).

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