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An integrated approach to epitope analysis II: A system for proteomic-scale prediction of immunological characteristics.

Bremel RD, Homan EJ - Immunome Res (2010)

Bottom Line: These are characterized as coincident epitope groups (CEGs).A desktop application with interactive graphic capability is shown to be a useful platform for development of prediction and visualization tools for epitope mapping at scales ranging from individual proteins to proteomes from multiple strains of an organism.The possible functional implications of the patterns of peptide epitopes observed are discussed, including their implications for B-cell and T-cell cooperation and cross presentation.

View Article: PubMed Central - HTML - PubMed

Affiliation: 1ioGenetics LLC, 3591 Anderson Street, Madison, WI 53704, USA. robert_bremel@iogenetics.com.

ABSTRACT

Background: Improving our understanding of the immune response is fundamental to developing strategies to combat a wide range of diseases. We describe an integrated epitope analysis system which is based on principal component analysis of sequences of amino acids, using a multilayer perceptron neural net to conduct QSAR regression predictions for peptide binding affinities to 35 MHC-I and 14 MHC-II alleles.

Results: The approach described allows rapid processing of single proteins, entire proteomes or subsets thereof, as well as multiple strains of the same organism. It enables consideration of the interface of diversity of both microorganisms and of host immunogenetics. Patterns of binding affinity are linked to topological features, such as extracellular or intramembrane location, and integrated into a graphical display which facilitates conceptual understanding of the interplay of B-cell and T-cell mediated immunity.Patterns which emerge from application of this approach include the correlations between peptides showing high affinity binding to MHC-I and to MHC-II, and also with predicted B-cell epitopes. These are characterized as coincident epitope groups (CEGs). Also evident are long range patterns across proteins which identify regions of high affinity binding for a permuted population of diverse and heterozygous HLA alleles, as well as subtle differences in reactions with MHCs of individual HLA alleles, which may be important in disease susceptibility, and in vaccine and clinical trial design. Comparisons are shown of predicted epitope mapping derived from application of the QSAR approach with experimentally derived epitope maps from a diverse multi-species dataset, from Staphylococcus aureus, and from vaccinia virus.

Conclusions: A desktop application with interactive graphic capability is shown to be a useful platform for development of prediction and visualization tools for epitope mapping at scales ranging from individual proteins to proteomes from multiple strains of an organism. The possible functional implications of the patterns of peptide epitopes observed are discussed, including their implications for B-cell and T-cell cooperation and cross presentation.

No MeSH data available.


Related in: MedlinePlus

Predicted and experimentally mapped epitope regions for two proteins from Staphylococcus aureus COL (NC_002951). Graphic overlay using proteome-wide standardization of scoring metrics. Blue line is the predicted population phenotypic MHC-II binding. This is computed as described in the methods for fourteen MHC-II alleles permuted as dizygotic combinations within a window ± 4 of the amino acid position indicated. The orange line is the predicted B-cell epitope probability for the particular amino acid being within a B-cell epitope. Actual computed data points are plotted along with the line that is the result of smoothing with a polynomial filter [49]. Blue horizontal bands are the regions of high probability MHC II binding phenotype and orange horizontal bars are high probability predicted B-cell epitope regions. The percentile probabilities used as the threshold are as described in the text and is indicated in the number within the box at the left. The red diamonds (or groups thereof) are experimentally mapped regions of Ig binding. The experimental mapping is described in more detail in Additional File 3 Table S3a. (A) LPXTG cell wall surface anchor protein, IsdB (GI:57651738) [51]. (B) ABC transporter, ATP-binding protein (GI:57651892) [52].
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Figure 6: Predicted and experimentally mapped epitope regions for two proteins from Staphylococcus aureus COL (NC_002951). Graphic overlay using proteome-wide standardization of scoring metrics. Blue line is the predicted population phenotypic MHC-II binding. This is computed as described in the methods for fourteen MHC-II alleles permuted as dizygotic combinations within a window ± 4 of the amino acid position indicated. The orange line is the predicted B-cell epitope probability for the particular amino acid being within a B-cell epitope. Actual computed data points are plotted along with the line that is the result of smoothing with a polynomial filter [49]. Blue horizontal bands are the regions of high probability MHC II binding phenotype and orange horizontal bars are high probability predicted B-cell epitope regions. The percentile probabilities used as the threshold are as described in the text and is indicated in the number within the box at the left. The red diamonds (or groups thereof) are experimentally mapped regions of Ig binding. The experimental mapping is described in more detail in Additional File 3 Table S3a. (A) LPXTG cell wall surface anchor protein, IsdB (GI:57651738) [51]. (B) ABC transporter, ATP-binding protein (GI:57651892) [52].

Mentions: To evaluate our observations alongside the experimental findings of others, we identified a number of publications which provide characterization of epitopes within five Staph. aureus proteins, documenting both predicted B-cell epitopes and MHC binding. In Additional File 3, Table S3a we tabulate the correlation between our observations of CEGs and the experimental findings for these. Much of the data pre-dates genome sequencing projects and thus reconciling the literature with Genbank is challenging. For example, in some cases peptides were reported with amino acid numbering without consideration of the signal peptide cleavage in the Genbank proteome repository. In some cases, such as with the staphylococcal toxins, the cleavage is substantially distal from the starting methionine. Figure 6 shows the graphical plots with the published experimental results overlaid for two proteins; additional plots are found in Additional File 3, Figure 3c and Figure 3d. We caution that our plots show the permuted human population average positions for MHC-II binding; publications may report on experimental results derived from single HLA or mouse MHCs. Overall there is remarkable correlation. Where the most detailed fine epitope mapping is compared to our prediction the mapped contact points either overlap or are within 5 aa. In other cases where mapping is not so detailed the overlapping is extensive. We have predicted additional high affinity MHC-I and MHC-II binding peptides not identified in the literature.


An integrated approach to epitope analysis II: A system for proteomic-scale prediction of immunological characteristics.

Bremel RD, Homan EJ - Immunome Res (2010)

Predicted and experimentally mapped epitope regions for two proteins from Staphylococcus aureus COL (NC_002951). Graphic overlay using proteome-wide standardization of scoring metrics. Blue line is the predicted population phenotypic MHC-II binding. This is computed as described in the methods for fourteen MHC-II alleles permuted as dizygotic combinations within a window ± 4 of the amino acid position indicated. The orange line is the predicted B-cell epitope probability for the particular amino acid being within a B-cell epitope. Actual computed data points are plotted along with the line that is the result of smoothing with a polynomial filter [49]. Blue horizontal bands are the regions of high probability MHC II binding phenotype and orange horizontal bars are high probability predicted B-cell epitope regions. The percentile probabilities used as the threshold are as described in the text and is indicated in the number within the box at the left. The red diamonds (or groups thereof) are experimentally mapped regions of Ig binding. The experimental mapping is described in more detail in Additional File 3 Table S3a. (A) LPXTG cell wall surface anchor protein, IsdB (GI:57651738) [51]. (B) ABC transporter, ATP-binding protein (GI:57651892) [52].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2991286&req=5

Figure 6: Predicted and experimentally mapped epitope regions for two proteins from Staphylococcus aureus COL (NC_002951). Graphic overlay using proteome-wide standardization of scoring metrics. Blue line is the predicted population phenotypic MHC-II binding. This is computed as described in the methods for fourteen MHC-II alleles permuted as dizygotic combinations within a window ± 4 of the amino acid position indicated. The orange line is the predicted B-cell epitope probability for the particular amino acid being within a B-cell epitope. Actual computed data points are plotted along with the line that is the result of smoothing with a polynomial filter [49]. Blue horizontal bands are the regions of high probability MHC II binding phenotype and orange horizontal bars are high probability predicted B-cell epitope regions. The percentile probabilities used as the threshold are as described in the text and is indicated in the number within the box at the left. The red diamonds (or groups thereof) are experimentally mapped regions of Ig binding. The experimental mapping is described in more detail in Additional File 3 Table S3a. (A) LPXTG cell wall surface anchor protein, IsdB (GI:57651738) [51]. (B) ABC transporter, ATP-binding protein (GI:57651892) [52].
Mentions: To evaluate our observations alongside the experimental findings of others, we identified a number of publications which provide characterization of epitopes within five Staph. aureus proteins, documenting both predicted B-cell epitopes and MHC binding. In Additional File 3, Table S3a we tabulate the correlation between our observations of CEGs and the experimental findings for these. Much of the data pre-dates genome sequencing projects and thus reconciling the literature with Genbank is challenging. For example, in some cases peptides were reported with amino acid numbering without consideration of the signal peptide cleavage in the Genbank proteome repository. In some cases, such as with the staphylococcal toxins, the cleavage is substantially distal from the starting methionine. Figure 6 shows the graphical plots with the published experimental results overlaid for two proteins; additional plots are found in Additional File 3, Figure 3c and Figure 3d. We caution that our plots show the permuted human population average positions for MHC-II binding; publications may report on experimental results derived from single HLA or mouse MHCs. Overall there is remarkable correlation. Where the most detailed fine epitope mapping is compared to our prediction the mapped contact points either overlap or are within 5 aa. In other cases where mapping is not so detailed the overlapping is extensive. We have predicted additional high affinity MHC-I and MHC-II binding peptides not identified in the literature.

Bottom Line: These are characterized as coincident epitope groups (CEGs).A desktop application with interactive graphic capability is shown to be a useful platform for development of prediction and visualization tools for epitope mapping at scales ranging from individual proteins to proteomes from multiple strains of an organism.The possible functional implications of the patterns of peptide epitopes observed are discussed, including their implications for B-cell and T-cell cooperation and cross presentation.

View Article: PubMed Central - HTML - PubMed

Affiliation: 1ioGenetics LLC, 3591 Anderson Street, Madison, WI 53704, USA. robert_bremel@iogenetics.com.

ABSTRACT

Background: Improving our understanding of the immune response is fundamental to developing strategies to combat a wide range of diseases. We describe an integrated epitope analysis system which is based on principal component analysis of sequences of amino acids, using a multilayer perceptron neural net to conduct QSAR regression predictions for peptide binding affinities to 35 MHC-I and 14 MHC-II alleles.

Results: The approach described allows rapid processing of single proteins, entire proteomes or subsets thereof, as well as multiple strains of the same organism. It enables consideration of the interface of diversity of both microorganisms and of host immunogenetics. Patterns of binding affinity are linked to topological features, such as extracellular or intramembrane location, and integrated into a graphical display which facilitates conceptual understanding of the interplay of B-cell and T-cell mediated immunity.Patterns which emerge from application of this approach include the correlations between peptides showing high affinity binding to MHC-I and to MHC-II, and also with predicted B-cell epitopes. These are characterized as coincident epitope groups (CEGs). Also evident are long range patterns across proteins which identify regions of high affinity binding for a permuted population of diverse and heterozygous HLA alleles, as well as subtle differences in reactions with MHCs of individual HLA alleles, which may be important in disease susceptibility, and in vaccine and clinical trial design. Comparisons are shown of predicted epitope mapping derived from application of the QSAR approach with experimentally derived epitope maps from a diverse multi-species dataset, from Staphylococcus aureus, and from vaccinia virus.

Conclusions: A desktop application with interactive graphic capability is shown to be a useful platform for development of prediction and visualization tools for epitope mapping at scales ranging from individual proteins to proteomes from multiple strains of an organism. The possible functional implications of the patterns of peptide epitopes observed are discussed, including their implications for B-cell and T-cell cooperation and cross presentation.

No MeSH data available.


Related in: MedlinePlus