Anepitope, also known asantigenic determinant, is the part of anantigen that 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 ofprotein antigens are divided into two categories,conformational epitopes andlinear 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 structure of 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 structure of 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 structure residues to adopt the epitope's 3-D conformation.[3][4][5][6][7] 90% of epitopes are conformational.[8]
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]
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 ofIgM class, its binding can upregulate the immune response; if the second antibody is ofIgG class, its binding can downregulate the immune response.[citation needed]
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]
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/orELISA to 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]
Epitopes are often used inproteomics and the study of other gene products. Usingrecombinant DNA techniques 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]
The first epitope-based vaccine was developed in 1985 by Jacob et al.[28] Epitope-based vaccines stimulatehumoral andcellular immune responses 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 silico mapping 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]
Aneoantigenic determinant is an epitope on aneoantigen, which is a newly formedantigen that has not been previously recognized by the immune system.[29] Neoantigens are often associated withtumor antigens and 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,phosphorylation orproteolysis. 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]
^Mahmoudi Gomari, Mohammad; Saraygord-Afshari, Neda; Farsimadan, Marziye; Rostami, Neda; Aghamiri, Shahin; Farajollahi, Mohammad M. (1 December 2020). "Opportunities and challenges of the tag-assisted protein purification techniques: Applications in the pharmaceutical industry".Biotechnology Advances.45: 107653.doi:10.1016/j.biotechadv.2020.107653.PMID33157154.S2CID226276355.
^Briggs S, Price MR, Tendler SJ (1993). "Fine specificity of antibody recognition of carcinoma-associated epithelial mucins: antibody binding to synthetic peptide epitopes".European Journal of Cancer.29A (2):230–7.doi:10.1016/0959-8049(93)90181-E.PMID7678496.
^Craig L, Sanschagrin PC, Rozek A, Lackie S, Kuhn LA, Scott JK (August 1998). "The role of structure in antibody cross-reactivity between peptides and folded proteins".Journal of Molecular Biology.281 (1):183–201.doi:10.1006/jmbi.1998.1907.PMID9680484.
^Steers NJ, Currier JR, Jobe O, Tovanabutra S, Ratto-Kim S, Marovich MA, et al. (June 2014). "Designing the epitope flanking regions for optimal generation of CTL epitopes".Vaccine.32 (28):3509–16.doi:10.1016/j.vaccine.2014.04.039.PMID24795226.
^Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002).Molecular biology of the cell (4th ed.). New York: Garland Science. p. 1401.ISBN978-0-8153-3218-3.
^De Groot, Anne S.; Martin, William (May 2009). "Reducing risk, improving outcomes: Bioengineering less immunogenic protein therapeutics".Clinical Immunology.131 (2):189–201.doi:10.1016/j.clim.2009.01.009.PMID19269256.
^Park HR, Cockrell LM, Du Y, Kasinski A, Havel J, Zhao J, Reyes-Turcu F, Wilkinson KD, Fu H (2008)."Protein–Protein Interactions". In Walker J, Rapley R (eds.).Molecular bio-methods handbook. Springer Protocols Handbooks (2nd ed.). Humana Press. pp. 463–494, See p. 467.doi:10.1007/978-1-60327-375-6.ISBN978-1-60327-374-9.
^Novus, Biologicals."OLLAS Epitope Tag". Novus Biologicals. Retrieved23 November 2011.
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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.
