Epitope
Anepitope,also known asantigenic determinant,is the part of anantigenthat is recognized by theimmune system,specifically byantibodies,B cells,orT cells.The part of an antibody that binds to the epitope is called aparatope.Although epitopes are usuallynon-self proteins,sequences derived from the host that can be recognized (as in the case of autoimmune diseases) are also epitopes.[1]
The epitopes ofproteinantigens are divided into two categories,conformational epitopesandlinear epitopes,based on their structure and interaction with the paratope.[2]Conformational and linear epitopes interact with the paratope based on the 3-D conformation adopted by the epitope, which is determined by the surface features of the involved epitope residues and the shape ortertiary structureof other segments of the antigen. A conformational epitope is formed by the 3-D conformation adopted by the interaction of discontiguous amino acid residues. In contrast, a linear epitope is formed by the 3-D conformation adopted by the interaction of contiguous amino acid residues. A linear epitope is not determined solely by theprimary structureof the involved amino acids. Residues that flank such amino acid residues, as well as more distant amino acid residues of the antigen affect the ability of theprimary structureresidues to adopt the epitope's 3-D conformation.[3][4][5][6][7]90% of epitopes are conformational.[8]
Function
[edit]T cell epitopes
[edit]T cellepitopes[9]are presented on the surface of anantigen-presenting cell,where they are bound tomajor histocompatibility complex(MHC) molecules. In humans,professional antigen-presenting cellsare specialized to presentMHC class IIpeptides, whereas most nucleatedsomatic cellspresent MHC class I peptides. T cell epitopes presented byMHC class Imolecules are typically peptides between 8 and 11 amino acids in length, whereas MHC class II molecules present longer peptides, 13–17 amino acids in length,[10]and non-classical MHC molecules also present non-peptidic epitopes such asglycolipids.
B cell epitopes
[edit]The part of the antigen that immunoglobulin or antibodies bind to is called a B-cell epitope.[11]B cell epitopes can be divided into two groups: conformational or linear.[11]B cell epitopes are mainly conformational.[12][13]There are additional epitope types when the quaternary structure is considered.[13]Epitopes that are masked when protein subunits aggregate are calledcryptotopes.[13]Neotopes are epitopes that are only recognized while in a specific quaternary structure and the residues of the epitope can span multiple protein subunits.[13]Neotopes are not recognized once the subunits dissociate.[13]
Cross-activity
[edit]Epitopes are sometimes cross-reactive. This property is exploited by the immune system in regulation by anti-idiotypic antibodies (originally proposed by Nobel laureateNiels Kaj Jerne). If an antibody binds to an antigen's epitope, the paratope could become the epitope for another antibody that will then bind to it. If this second antibody is of IgM class, its binding can upregulate the immune response; if the second antibody is of IgG class, its binding can downregulate the immune response.[citation needed]
Epitope mapping
[edit]T cell epitopes
[edit]MHC class I and II epitopes can be reliably predicted by computational means alone,[14]although not all in-silico T cell epitope prediction algorithms are equivalent in their accuracy.[15]There are two main methods of predicting peptide-MHC binding: data-driven and structure-based.[11]Structure based methods model the peptide-MHC structure and require great computational power.[11]Data-driven methods have higher predictive performance than structure-based methods.[11]Data-driven methods predict peptide-MHC binding based on peptide sequences that bind MHC molecules.[11]By identifying T-cell epitopes, scientists can track, phenotype, and stimulate T-cells.[16][17][18][19]
B cell epitopes
[edit]There are two main methods of epitope mapping: either structural or functional studies.[20]Methods for structurally mapping epitopes includeX-ray crystallography,nuclear magnetic resonance,andelectron microscopy.[20]X-ray crystallography of Ag-Ab complexes is considered an accurate way to structurally map epitopes.[20]Nuclear magnetic resonance can be used to map epitopes by using data about the Ag-Ab complex.[20]This method does not require crystal formation but can only work on small peptides and proteins.[20]Electron microscopy is a low-resolution method that can localize epitopes on larger antigens like virus particles.[20]
Methods for functionally mapping epitopes often use binding assays such aswestern blot,dot blot,and/orELISAto determine antibody binding.[20]Competition methods look to determine if twomonoclonal antibodies(mABs) can bind to an antigen at the same time or compete with each other to bind at the same site.[20]Another technique involves high-throughputmutagenesis,an epitope mapping strategy developed to improve rapid mapping of conformational epitopes on structurally complex proteins.[21]Mutagenesis uses randomly/site-directed mutations at individual residues to map epitopes.[20]B-cell epitope mapping can be used for the development of antibody therapeutics, peptide-based vaccines, and immunodiagnostic tools.[20][22]
Epitope tags
[edit]Epitopes are often used inproteomicsand the study of other gene products. Usingrecombinant DNAtechniques genetic sequences coding for epitopes that are recognized by common antibodies can be fused to the gene. Followingsynthesis,the resulting epitope tag allows the antibody to find the protein or other gene product enabling lab techniques for localisation, purification, and further molecular characterization. Common epitopes used for this purpose areMyc-tag,HA-tag,FLAG-tag,GST-tag,6xHis,[23]V5-tag and OLLAS.[24]Peptides can also be bound by proteins that form covalent bonds to the peptide, allowing irreversible immobilisation.[25]These strategies have also been successfully applied to the development of "epitope-focused" vaccine design.[26][27]
Epitope-based vaccines
[edit]The first epitope-based vaccine was developed in 1985 by Jacob et al.[28]Epitope-based vaccines stimulatehumoralandcellular immuneresponses using isolated B-cell or T-cell epitopes.[28][22][17]These vaccines can use multiple epitopes to increase their efficacy.[28]To find epitopes to use for the vaccine,in silicomapping is often used.[28]Once candidate epitopes are found, the constructs are engineered and tested for vaccine efficiency.[28]While epitope-based vaccines are generally safe, one possible side effect is cytokine storms.[28]
Neoantigenic determinant
[edit]Aneoantigenic determinantis an epitope on aneoantigen,which is a newly formedantigenthat has not been previously recognized by the immune system.[29]Neoantigens are often associated withtumor antigensand are found in oncogenic cells.[30]Neoantigens and, by extension, neoantigenic determinants can be formed when a protein undergoes further modification within a biochemical pathway such asglycosylation,phosphorylationorproteolysis.This, by altering the structure of the protein, can produce new epitopes that are called neoantigenic determinants as they give rise to newantigenic determinants.Recognition requires separate, specificantibodies.[citation needed]
See also
[edit]- Cryptotope
- Epitope binning
- Mimotope
- Odotope
- Polyclonal B cell response
- Protein tag
- TimeSTAMP protein labelling
References
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- ^abcdefParvizpour, Sepideh; Pourseif, Mohammad M.; Razmara, Jafar; Rafi, Mohammad A.; Omidi, Yadollah (June 2020). "Epitope-based vaccine design: a comprehensive overview of bioinformatics approaches".Drug Discovery Today.25(6): 1034–1042.doi:10.1016/j.drudis.2020.03.006.PMID32205198.S2CID214629963.
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External links
[edit]- Antibodies bind to conformational shapes on the surfaces of antigens (Janeway Immunobiology Section 3.8)
- Antigens can bind in pockets or grooves, or on extended surfaces in the binding sites of antibodies (Janeway Immunobiology Figure 3.8)
Epitope prediction methods
[edit]- Rubinstein ND, Mayrose I, Martz E, Pupko T (September 2009)."Epitopia: a web-server for predicting B-cell epitopes".BMC Bioinformatics.10:287.doi:10.1186/1471-2105-10-287.PMC2751785.PMID19751513.
- Rubinstein ND, Mayrose I, Pupko T (February 2009). "A machine-learning approach for predicting B-cell epitopes".Molecular Immunology.46(5): 840–847.doi:10.1016/j.molimm.2008.09.009.PMID18947876.
- Saravanan V, Gautham N (October 2015). "Harnessing Computational Biology for Exact Linear B-Cell Epitope Prediction: A Novel Amino Acid Composition-Based Feature Descriptor".Omics.19(10): 648–658.doi:10.1089/omi.2015.0095.PMID26406767.
- Singh H, Ansari HR, Raghava GP (2013)."Improved method for linear B-cell epitope prediction using antigen's primary sequence".PLOS ONE.8(5): e62216.Bibcode:2013PLoSO...862216S.doi:10.1371/journal.pone.0062216.PMC3646881.PMID23667458.
Epitope databases
[edit]- MHCBN: A database of MHC/TAP binder and T-cell epitopes
- Bcipep: A database of B-cell epitopes
- SYFPEITHI – First online database of T cell epitopes
- IEDB – Database of T and B cell epitopes with annotation of recognition context – NIH funded
- ANTIJEN – T and B cell epitope database at the Jenner institute, UK
- IMGT/3Dstructure-DB – Three-dimensional structures of B and T cell epitopes with annotation of IG and TR – IMGT, Montpellier, France
- SEDB: A Structural Epitope Database – Pondicheery University, DIT funded
- Epitopesat the U.S. National Library of MedicineMedical Subject Headings(MeSH)