IMGT-ONTOLOGY 2012

Abstract

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).

Keywords: IMGT; IMGT-ONTOLOGY; T cell receptor; antibody; immune repertoire; immunogenetics; immunoglobulin; immunoinformatics.

Figure 1

An example of knowledge at the molecular level: the synthesis of an IG or antibody in humans, described in (Lefranc, 2011a). “gDNA,” “mRNA,” and “protein” are types of molecules (“MoleculeType”) that are involved in the IG or TR synthesis, “germline” and “rearranged” are types of configuration (“ConfigurationType”) [the configuration of C-gene is “undefined” (not shown)]. A molecule entity type characterizes a unique conformation of a molecular component at each step of its biosynthesis, which is defined by a type of molecule, a type of configuration and type(s) of genes. The 10 leafconcepts of “Molecule_EntityType” identified during the IG synthesis (e.g., V-gene, V-D-J-gene, L-V-D-J-C-sequence) are shown. Main steps of the antigen receptor synthesis are indicated with numbers. (1) DNA rearrangements (is_rearranged_into), (2) Transcription (is_transcribed_into), (3) Translation (is_translated_into) (IMGT Repertoire, http://www.imgt.org).

Figure 2

The “Molecule_EntityType” concept with its relations. The “Molecule_EntityType” concept is defined by the “MoleculeType,” “GeneType,” and “ConfigurationType” concepts of identification and has properties identified in the “FunctionalityType” and “StructureType” concepts (IDENTIFICATION axiom). Arrows indicate reciprocal relations “is_defined_by” and “defines,” “_has_,” and “_for_.” Leafconcepts are general (online in blue) or specific of the IG and TR (online in red). The “Molecule_EntityType” concept has 38 leafconcepts (or keywords in the IMGT^® databases and tools). Only a few examples of the “StructureType” leafconcepts (or keywords in the IMGT^® databases and tools) are shown (see details in Lefranc, 2011b).

Figure 3

“ChainType” “highconcept.” The hierarchy of “ChainType” for the identification of IG chains comprises four levels of granularity which are associated with an increasing level of precision: the “MolecularComponentLevelChainType,” the “ReceptorLevelChainType,” the “ClassLevelChainType,” and the “GeneLevelChainType.”

Figure 4

The “ReceptorType” concept with its relations. The “ReceptorType” concept is defined by the “ChainType” concept of identification and has properties identified in the “FormatType”, “SpecificityType,” and “FunctionType” concepts (IDENTIFICATION axiom). The “ChainType” concept is itself defined by the “Molecule_EntityType” and “DomainType” concepts and by concepts of classification organized in a hierarchy (see CLASSIFICATION axiom). Arrows indicate reciprocal relations “is_defined_by” and “defines,” “_has_,” and “_for_” (see details in Lefranc, 2011b). The “ChainType” and “ReceptorType” concepts have different levels of granularity (up to four) and are highconcepts. The reciprocical relations between “ReceptorType” and “Cell_EntityType” concepts are “_has_” and “_for_.” The “Cell_EntityType” (not developped in the current version) is part of the “CellularComponent” concept (Pappalardo et al., 2010).

Figure 5

Prototype or graphical representation of two “Molecule_EntityPrototype” leafconcepts. (A) “V-GENE.” (B) “V-D-J-GENE.” Thirty-nine labels (27 for for “V-GENE” and 33 for “V-D-J-GENE” of which 20 are shared) and 12 relations are necessary and sufficient for a complete description of these prototypes (Lefranc, 2011c).

Figure 6

Concepts of classification for gene and allele nomenclature (generated from the IMGT-ONTOLOGY CLASSIFICATION axiom) (Duroux et al., ; Lefranc, 2011d). (A) Hierarchy of the concepts of classification and their relations (Giudicelli and Lefranc, 1999). The “Locus” concept is a concept of localization (LOCALIZATION axiom). (B) Example of leafconcepts for each concept of classification. They are associated with a “TaxonRank” level, and more precisely for the “Gene” and “Allele” concepts with a leafconcept of “Species” (here, Homo sapiens).

Figure 7

IMGT Collier de Perles for V domain. (A) Ribbon representation of a V-DOMAIN as an example. A similar topology and 3D structure characterize a V-LIKE-DOMAIN. (B) and (C) V-DOMAIN on one layer and on two layers, respectively (Mus musculus VH [8.8.12]). (D) V-LIKE-DOMAIN on two layers (Homo sapiens CD28 [9.9.13]). Amino acids are shown in the one-letter abbreviation. Positions at which hydrophobic amino acids (hydropathy index with positive value: I, V, L, F, C, M, A) and tryptophan (W) are found in more than 50% of analyzed sequences are shown online in blue. All proline (P) are shown online in yellow. The loops BC, C^′C^′′ and FG (corresponding to the CDR-IMGT) are limited by amino acids shown in squares (anchor positions), which belong to the neighboring strands (FR-IMGT). BC loops are represented online in red, C^′C^′′ loops in orange and FG loops in purple. Hatched circles or squares correspond to missing positions according to the IMGT unique numbering for V domain (Lefranc et al., 2003). Arrows indicate the direction of the beta strands and their designations in 3D structures. The IMGT Colliers de Perles on two layers show, in the forefront, the GFCC^′C^′′ strands and, in the back, the ABED strands. The chain identifiers to which the domains belong are 1a3l_H for (A), (B), (C), and 1yjd_C for (D) [IMGT/3Dstructure-DB (Ehrenmann et al., ; Ehrenmann and Lefranc, 2011b)].

Figure 8

IMGT Collier de Perles for G domain. (A) Ribbon representation of two G-DOMAIN as an example. A similar topology and 3D structure characterize the G-LIKE-DOMAIN. (B) G-DOMAIN of MH1: G-ALPHA1 and G-ALPHA2 (Homo sapiens HLA-A*0201). (C) G-DOMAIN of MH2: G-ALPHA and G-BETA (Homo sapiens HLA-DRA*0101 and HLA-DRB1*0101). (D) G-LIKE-DOMAIN of RPI-MH1Like: G-ALPHA1-LIKE and G-ALPHA2-LIKE (Mus musculus CD1D1). Amino acids are shown in the one-letter abbreviation. Hatched circles correspond to missing positions according to the IMGT unique numbering for G domain (Lefranc et al., 2005c). Note that the N-terminal end of a peptide in the cleft would be on the left hand side. The chain identifiers to which the domains belong are 1akj_A for (A) and (B), 1fyt_B for (C) and 1cd1_C for (D) [IMGT/3Dstructure-DB (Ehrenmann et al., ; Ehrenmann and Lefranc, 2011b)].