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Immunological databases on the web

Immunological databases on the web. Ole Lund Center for Biological Sequence Analysis BioCentrum-DTU Technical University of Denmark lund@cbs.dtu.dk. Vaccines have been made for 36 of >400 human pathogens. +HPV & Rotavirus. Immunological Bioinformatics, The MIT press.

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Immunological databases on the web

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  1. Immunological databases on the web Ole Lund Center for Biological Sequence Analysis BioCentrum-DTU Technical University of Denmark lund@cbs.dtu.dk

  2. Vaccines have been made for 36 of >400 human pathogens +HPV & Rotavirus Immunological Bioinformatics, The MIT press.

  3. Deaths from infectious diseases in the world in 2002 www.who.int/entity/whr/2004/annex/topic/en/annex_2_en.pdf

  4. Pathogenic Viruses 1st column: log10 of the number of deaths caused by the pathogen per year2nd column: DNA Advisory Committee (RAC) classificationDNA Advisory Committee guidelines [RAC, 2002] which includes those biological agents known to infect humans, as well as selected animal agents that may pose theoretical risks if inoculated into humans. RAC divides pathogens intofour classes.Risk group 1 (RG1). Agents that are not associated with disease in healthy adult humansRisk group 2 (RG2). Agents that are associated with human disease which is rarely serious and for which preventive or therapeutic interventions are often availableRisk group 3 (RG3). Agents that are associated with serious or lethal human disease for which preventive or therapeutic interventions may be available (high individual risk but low community risk)Risk group 4 (RG4). Agents that are likely to cause serious or lethal human disease for which preventive or therapeutic interventions are not usually available (high individual risk and high community risk)3rd column: CDC/NIAID bioterror classificationclassification of the pathogens according to the Centers for Disease Control and Prevention (CDC) bioterror categories A–C, where category A pathogens are considered the worst bioterror threats4th column: Vaccines availableA letter indicating the type of vaccine if one is available (A: acellular/adsorbet; C: conjugate; I: inactivated; L: live; P: polysaccharide; R: recombinant; S staphage lysate; T: toxoid). Lower case indicates that the vaccine is released as an investigational new drug (IND)).5th column: G: Complete genome is sequenced Data derived from /www.cbs.dtu.dk/databases/Dodo.

  5. Need for new vaccine technologies • The classical way of making vaccines have in many cases been tried for the pathogens for which no vaccines exist • Need for new ways for making vaccines

  6. Databases Used for Vaccine Design • Sequence databases • General • Sequences of proteins of the immune system • Epitope databases • Pathogen centered databases • HIV • mTB • Malaria

  7. Sequence Databases • Used to study sequence variability of microbes • Sequence conservation • Positive/negative selection • Examples • Swissprot http://expasy.org/sprot/ • GenBank http://www.ncbi.nlm.nih.gov/Genbank/

  8. MHC Class I pathway Figure by Eric A.J. Reits

  9. The binding of an immunodominant 9-mer Vaccinia CTL epitope, HRP2 (KVDDTFYYV) to HLA-A*0201. Position 2 and 9 of the epitopes are buried deeply in the HLA class I molecule. Figure by Anne Mølgaard, peptide (KVDDTFYYV) used as vaccine by Snyder et al. J Virol 78, 7052-60 (2004).

  10. Expression of HLA is codominant

  11. Polymorphism and polygeny

  12. The MHC gene region http://www.ncbi.nlm.nih.gov/mhc/MHC.fcgi?cmd=init&user_id=0&probe_id=0&source_id=0&locus_id=0&locus_group=0&proto_id=0&banner=1&kit_id=0&graphview=0

  13. Human Leukocyte antigen (HLA=MHC in humans) polymorphism - alleles http://www.anthonynolan.com/HIG/index.html

  14. Logos of HLA-A alleles O Lund et al., Immunogenetics. 2004 55:797-810

  15. Clustering of HLA alleles O Lund et al., Immunogenetics. 2004 55:797-810

  16. Databases of Sequences of Proteins of Immune system • Used to study variability of the human genome • Anthony Nolan Database (IMGT/HLA sequences) • http://www.anthonynolan.com/HIG/ • IMmunoGeneTics HLA (IMGT/HLA) database • Sequences of HLA, antibody and other molecules • http://imgt.cines.fr/ • dbMHC • Clinical data and sequences related to the immune system • http://www.ncbi.nlm.nih.gov/gv/mhc/main.cgi?cmd=init

  17. Peptide-MHC complex Incubation Development Determination of peptide-HLA binding • Step I: Folding of MHC class I molecules in solution b2m Heavy chain peptide • Step II: Detection of de novo folded MHC class I molecules by ELISA C Sylvester-Hvid et al., Tissue Antigens. 2002 59:251-8

  18. HLA Binding Results KD\PathogenInfluenza Marburg Pox F. tularensis Dengue Hantaan Lassa West Nile Yellow Fever KD<50 42 45 97 45 67 59 27 52 50 50<KD<500 63 39 42 21 44 20 21 41 52 KD>500 87 29 38 6 30 11 22 29 35 in progress 9 1 1 4 6 4 12 31 33 Total 201 114 178 76 147 94 82 153 170 • 1215 peptides received • 1114 tested for binding • 827 (74%) bind with KD better than 500nM • 484 (43%) bind with KD better han 50 nM Søren Buus Lab

  19. ELISPOT assay • Measure number of white blood cells that in vitro produce interferon-g in response to a peptide • A positive result means that the immune system has earlier reacted to the peptide (during a response to a vaccine/natural infection) SLFNTVATL SLFNTVATL SLFNTVATL SLFNTVATL SLFNTVATL SLFNTVATL Two spots

  20. Influenza Peptides positive in ELISPOT Mingjun Wang et al., submitted

  21. Peters B, et al. Immunogenetics. 2005 57:326-36, PLoS Biol. 2005 3:e91.

  22. Epitope Databases • Used to find regions that can be recognized by the immune system • General Epitope Databases • IEDB General epitope database • http://immuneepitope.org/home.do • AntiJen (MHC Ligand, TCR-MHC Complexes, T Cell Epitope, TAP , B Cell Epitope molecules and immunological Protein-Protein interactions) • http://www.jenner.ac.uk/AntiJen/ • FIMM (MHC, antigens, epitopes, and diseases) • http://research.i2r.a-star.edu.sg/fimm/

  23. More Epitope Databases • SYFPEITHI • Natural ligands: sequences of peptides eluded from MHC molecules on the surface of cells • http://www.syfpeithi.de/ • MHCBN: Immune related databases and predictors • http://www.imtech.res.in/raghava/mhcbn/ • http://bioinformatics.uams.edu/mirror/mhcbn/ • HLA Ligand/Motif Database: Discontinued • MHCPep: Static since 1998, replaced by FIMM

  24. Prediction of HLA binding • Many methods available, including: • bimas, syfpeithi, Hlaligand, libscore, mapppB, mapppS,mhcpred, netmhc, pepdist, predbalbc, predep, rankpep, svmhc • See links at: • http://immuneepitope.org/hyperlinks.do?dispatch=loadLinks • Recent benchmark: • http://mhcbindingpredictions.immuneepitope.org/internal_allele.html

  25. B cell Epitope Databases • Linear • IEDB, Bcipep, Jenner, FIMM, BepiPred • HIV specific database • http://www.hiv.lanl.gov/content/immunology/ab_search • Conformational • CED: Conformational B cell epitopes • http://web.kuicr.kyoto-u.ac.jp/~ced/

  26. MHC class II pathway Figure by Eric A.J. Reits

  27. Pathogen Centered Databases • HIV • http://www.hiv.lanl.gov/content/index • Influenza • http://www.flu.lanl.gov/ • Tuberculosis • http://www.sanger.ac.uk/Projects/M_tuberculosis/ • POX • http://www.poxvirus.org/

  28. Reviews • Tong JC, Tan TW, Ranganathan S. Methods and protocols for prediction of immunogenic epitopes. Brief Bioinform. 2006 Oct 31 • Web based Tools for Vaccine Design (Lund et al, 2002) • http://www.cbs.dtu.dk/researchgroups/immunology/webreview.html

  29. Other Resources • Gene expression data • Localization prediction • SignalP

  30. Immunological resources at CBS • Web servers • CTL epitopes • http://www.cbs.dtu.dk/services/NetCTL/ • MHC binding • http://www.cbs.dtu.dk/services/NetMHC/ • http://www.cbs.dtu.dk/services/NetMHCII/ • http://www.cbs.dtu.dk/services/NetMHCpan/ • Proteasome processing • http://www.cbs.dtu.dk/services/NetChop-3.0/ • B-cell epitopes • http://www.cbs.dtu.dk/services/BepiPred/ • http://www.cbs.dtu.dk/services/DiscoTope/ • Plotting of epitopes relative to reference sequence • http://www.cbs.dtu.dk/services/EpiPlot-1.0/ • Analysis of human immunoglobulin VDJ recombination • http://www.cbs.dtu.dk/services/VDJsolver/ • Geno-pheno type association based mapping of binding sites • http://www.cbs.dtu.dk/services/SigniSite/ • PhD/master course in Immunological Bioinformatics, June, 2008 • http://www.cbs.dtu.dk/courses/27685.imm/

  31. Other Predictions at CBS • Training matrix and neural network methods • Training of Gibbs sampler

  32. Links to links • IEDB’s Links • http://immuneepitope.org/hyperlinks.do?dispatch=loadLinks

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