IMGT : a paradigm for genetics, genome and 3D structure data integration towards Systems Biology

Transcription

1 IMGT : a paradigm for genetics, genome and 3D structure data integration towards Systems Biology Marie-Paule Lefranc University Montpellier 2 Institute of Human Genetics CNRS International Symposium on Biotechnology, ISB2008, 4-8 May, 2008, SFAX, TUNISIA

2 Outline What is the IMGT domain of expertise? Adaptive immune response Why and how has IMGT become a paradigm towards Systems Biology? IMGT-ONTOLOGY axioms and concepts Examples of IMGT tools based on the IMGT-ONTOLOGY concepts IMGT/JunctionAnalysis, IMGT/V-QUEST, IMGT/3Dstructure-DB for antibody engineering and antibody humanization Conclusions and Perspectives

3 IMGT domain: the adaptive immune response Vertebrates Immunoglobulin (IG) T lymphocyte B lymphocyte peptide T cell receptor (TR) MHC Trimolecular complex

4 Bone marrow Blood Lymph nodes, spleen V-D-J and V-J rearrangements Hypermutations, selection

5 Immunoglobulin or antibody IgG The Immunoglobulin FactsBook, 2001

6 Structural domains IG and TR MHC V-DOMAIN C-DOMAIN G-DOMAINs

7 V-DOMAINs: VH and VL VH V-D-J junction VL V-J junction VH VL Side view of the V-DOMAINs View from above the CDRs Mouse(Mus musculus) E5.2Fv CDR3-IMGT= Complementarity determining region ( ) V-J junction ( ) V-D-J junction ( )

8 Immunoglobulin (IG) T cell receptor (TR) V-DOMAIN V-J-REGION Light chain Contribution of the 2 V-DOMAINs to the antigen binding site V-DOMAIN V-D-J-REGION Alpha - Beta Gamma - Delta Heavy chain V-J-REGION V-DJ-REGION Membrane IgM T cell receptor The Immunoglobulin FactsBook, 2001

9 Immunoglobulin IgG IMGT Repertoire,

10 genomic DNA (IGH Locus 14q32) Immunoglobulin (IG) synthesis V D J C 5 3' rearranged DNA mrna 5 3' 2 x different IG per individual IMGT Repertoire,

11 Immunoglobulin (IG) synthesis 15 0 FUNCTIONAL IG GENES HEAVY CHAIN V D J C 5' 3' V J C 5' 3' LIGHT CHAIN x 2 3 x x 5 Kappa 6300 POTENTIAL RECOMBINATIONS POTENTIAL RECOMBINATIONS N-DIVERSITY SOMATIC MUTATIONS x x 4-5 Lambda 5' 3' 5 ' 3' ABOUT 6.3 x 10 6 POSSIBILITIES ABOUT 3.5 x 10 5 POSSIBILITIES 2 x DIFFERENT ANTIBODIES IMGT Repertoire,

12 IMGT IMGT, the international ImMunoGeneTics information system Created in 1989 at Montpellier, France (University Montpellier 2 and CNRS) IMGT is the international reference in immunogenetics and immunoinformatics. IMGT comprises: - 6 databases - 15 on-line tools - more than 10,000 HTML pages of Web resources. IMGT receives requests per month.

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14 Why and how has IMGT become a paradigm towards Systems Biology? IMGT-ONTOLOGY axioms and concepts

15 IMGT-ONTOLOGY IMGT-ONTOLOGY seven axioms: To share, reuse and represent knowledge in Immunogenetics and Life Sciences IDENTIFICATION OBTENTION CLASSIFICATION ORIENTATION DESCRIPTION LOCALIZATION NUMEROTATION Giudicelli and Lefranc, Bioinformatics 1999

16 CLASSIFICATION axiom group is a member of an instance of locus IGLV is a member of human IGL (22q11.2) subgroup is a member of an instance of is ordered in an instance of IGLV2 is a member of is ordered in gene IGLV2-11 is a variant of an instance of is a variant of allele IGLV2-11*02 «Concepts» «Instances»

17 IG and TR: 1538 genes and 2523 alleles from human and mouse

18 CLASSIFICATION axiom The IMGT-ONTOLOGY main concepts of classification include group, subgroup, gene, allele. They allowed to set up the nomenclature for IG and TR genes (V, D, J, C genes). IMGT gene names were approved by HGNC in 1999 and entered in GDB, LocusLink and Entrez Gene (NCBI). IMGT/GENE-DB is the international reference database for IG and TR genes (direct links from Entrez Gene NCBI). WHO-IUIS/IMGT 2007 report (Dev. Comp. Immunol., Immunogenetics).

19 DESCRIPTION axiom PROTOTYPE for a V-GENE L-PART1 V-GENE V-EXON FR1-IMGT FR2-IMGT FR3-IMGT 5 UTR 3 UTR C W C CDR3 -IMGT DONOR-SPLICE V-REGION Label 1 Label 2 V-GENE V-EXON Relations entre Labels FR3-IMGT L-PART1 V-REGION V-REGION CDR3-IMGT DONOR-SPLICE FR1-IMGT CDR3-IMGT

20 An example of V-GENE >X HSVI2 Homo sapiens VI-2 gene for immunoglobulin heavy chain tgagagctcc gttcctcacc atggactgga cctggaggat cctcttcttg gtggcagcag 60 ccacaggtaa aa gaggctccct agtcccagtg atgagaaaga gattgagtcc agtccaggga 120 gatctcatcc acttctgtgt tctctccaca ggagcccact cccaggtgca gctggtgcag 180 tctggggctg aggtgaagaa gcctggggcc tcagtgaagg tctcctgcaa ggcttctgga 240 tacaccttca ccggctacta tatgcactgg gtgcgacagg cccctggaca agggcttgag 300 tggatgggat ggatcaaccc taacagtggt ggcacaaact atgcacagaa gtttcagggc 360 agggtcacca tgaccaggga cacgtccatc agcacagcct acatggagct gagcaggctg 420 agatctgacg acacggccgt gtattactgt gcgagagaca cagtgtgaaa tgaaa acccacatcc 480 tgagggtgtc agaaacccaa gggaggaggc ag L-PART1 L-PART2 V-REGION V-RS 5'UTR V-INTRON 3'UTR 5' 3' DONOR -SPLICE ACCEPTOR -SPLICE 1st-CYS 23 2nd-CYS 104 V-HEPTAMER V-SPACER V-NONAMER

21 IMGT/LIGM-DB D E S C R I P T I O N CLASSIFICATION sequences from 223 species IMGT-ONTOLOGY: 277 IMGT labels for sequences 285 IMGT labels for 3D structures SO (Sequence ontology): 67 IMGT labels

22 DESCRIPTION axiom The IMGT-ONTOLOGY concepts of description comprise the standardized IMGT labels and relations. They have allowed to describe the IG, TR and MHC sequences and 3D structures, whatever the receptor type, the chain type, or the species. They are particularly useful to describe IG, TR, and MHC and their complexes (IG/antigen, TR/pMHC). It is possible to query the IMGT databases (IMGT/LIGM- DB for sequences, IMGT/3Dstructure-DB for 3D structures) with IMGT labels. Sequence Ontology (SO) includes IMGT labels.

23 NUMEROTATION axiom CDR-IMGT lengths [ ] IMGT Collier de Perles Lefranc et al. Dev. Comp. Immunol. 27, (2003)

24 IMGT Web resources: pages HTML IMGT Collier de Perles IMGT Alignment of alleles IMGT Protein Display

25 -om ab -xim ab -zum ab -um ab m urom onab (1986) abcixim ab (1994) daclizum ab (1997) adalim um ab (2002) edrecolom ab (1995) rituxim ab (1997) palivizum ab (1998) panitum um ab (2006) ibritum om ab tiuxetan (2002) basilixim ab (1998) trastuzum ab (1998) tositum om ab (2003) inflixim ab (1998) gem tuzum ab ozogam icin (2000) cetuxim ab (2004) alem tuzum ab (2001) efalizum ab (2003) om alizum ab (2003) bevacizum ab (2004) natalizum ab (2004) nim otuzum ab (2004) ranibizum ab (2006) eculizum ab (2007) certolizum ab pegol (2008)

26 Humanized CAMPATH-1H CAMPATH-1H mutant 1 Mutant 1: S28>F VH domain (V-D-J-REGION) [ ] Mutant 2: alemtuzumab S31>T human rat

27 NUMEROTATION axiom The IMGT-ONTOLOGY concepts of numerotation include IMGT unique numbering and IMGT Collier de Perles for V- DOMAIN (IG and TR). They have been extended to the C-DOMAIN (IG and TR) and G-DOMAIN (MHC). They have allowed to bridge the gap between sequences and 3D structures in IMGT/3Dstructure-DB. They are used for mutations, polymorphisms, CDR-IMGT lengths, contact analysis, potential immunogenicity evaluation and paratope definition. WHO-INN programme requires the CDR-IMGT lengths for antibody.

28 Examples of IMGT tools based on the IMGT-ONTOLOGY concepts IMGT/JunctionAnalysis IMGT/V-QUEST IMGT/3Dstructure-DB

29 Immunoglobulin V-D-J generation of sequence diversity 3 V-REGION N-REGION D-REGION N-REGION 5 J-REGION tgtgcgaaa ga tacc agcatattgtg gtggtgactgctat tcc gatt acaactggttcg actcctgg JUNCTION C A P Y R G D T Y D Y S W tgt tgtgcgccagcg cca tac cggggggtgactactat ggt gac tat gat tac tcc tgg

30 IMGT/JunctionAnalysis: analysis of the IG and TR junctions Yousfi Monod et al. Bioinformatics 20, i379-i385 (2004)

31 The eleven IMGT amino acid classes according to the physicochemical properties Pommié et al. J. Mol Recognit. 17, 17-32, 2004

32 IMGT/JunctionAnalysis: analysis of the IG and TR junctions Yousfi Monod et al. Bioinformatics 20, i379-i385 (2004) Pommié et al. J. Mol Recognit. 17, (2004)

33 IMGT/V-QUEST: analysis of IG and TR sequences

34 Analysis by batches of up to 50 sequences in a single run Giudicelli V. et al.

35 IMGT/3Dstructure-DB: analysis of the 3D structures Kaas Q. et al.

36 Access to atomic pair contacts in IMGT/3Dstructure-DB Click on residue in IMGT Collier de Perles (or in amino acid sequence)

37 Atomic pair contacts in IMGT/3Dstructure-DB

38 Hydrogen bonds (IMGT Collier de Perles on 2 layers)

39 Contacts VH-(Ligand), V-KAPPA-(Ligand) Kaas Q. et al.

40 Contacts VH-(Ligand) Kaas Q. et al

41 Kaas Q. et al

42 CONCLUSIONS and PERSPECTIVES 1. The IMGT-ONTOLOGY axioms and concepts: CLASSIFICATION (nomenclature), DESCRIPTION (labels), NUMEROTATION (IMGT unique numbering, IMGT Colliers de Perles) are acknowledged as the international standards in immunogenetics and immunoinformatics. 2. The WHO-INN programme requires the CDR-IMGT lengths. 3. American and European companies (Centocor Johnson and Johnson USA, Merck USA,..) have adopted the IMGT tools for antibody engineering and antibody humanization. 4. The IMGT-ONTOLOGY axioms are used for a multiscale and systemic approach (system immunobiology). Concepts are currently described at the cell level (EU ImmunoGrid IST projet).

43 Many thanks to the IMGT team at Montpellier, France