Immunological databases on the web
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Immunological databases on the web. Ole Lund Center for Biological Sequence Analysis BioCentrum-DTU Technical University of Denmark [email protected] 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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Immunological databases on the web

Ole Lund

Center for Biological Sequence Analysis

BioCentrum-DTU

Technical University of Denmark

[email protected]


Vaccines have been made for 36 of >400 human pathogens

+HPV & Rotavirus

Immunological Bioinformatics, The MIT press.


Deaths from infectious diseases in the world in 2002

www.who.int/entity/whr/2004/annex/topic/en/annex_2_en.pdf


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.


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


Databases Used for Vaccine Design

  • Sequence databases

    • General

    • Sequences of proteins of the immune system

  • Epitope databases

  • Pathogen centered databases

    • HIV

    • mTB

    • Malaria


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/


MHC Class I pathway

Figure by Eric A.J. Reits


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).


Expression of HLA is codominant


Polymorphism and polygeny


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


Human Leukocyte antigen (HLA=MHC in humans) polymorphism - alleles

http://www.anthonynolan.com/HIG/index.html


Logos of HLA-A alleles

O Lund et al., Immunogenetics. 2004 55:797-810


Clustering of HLA alleles

O Lund et al., Immunogenetics. 2004 55:797-810


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


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


HLA Binding Results

KD\PathogenInfluenzaMarburgPoxF. tularensisDengueHantaanLassaWest NileYellow Fever

KD<50424597456759275250

50<KD<500 633942214420214152

KD>50087293863011222935

in progress911464123133

Total201114178761479482153170

  • 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


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


Influenza Peptides positive in ELISPOT

Mingjun Wang et al., submitted


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


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/


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


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


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/


MHC class II pathway

Figure by Eric A.J. Reits


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/


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


Other Resources

  • Gene expression data

  • Localization prediction

    • SignalP


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/


Other Predictions at CBS

  • Training matrix and neural network methods

  • Training of Gibbs sampler


Links to links

  • IEDB’s Links

    • http://immuneepitope.org/hyperlinks.do?dispatch=loadLinks


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