Epitope

Template:Short description An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that binds to the epitope is called a paratope. Although epitopes are usually non-self proteins, sequences derived from the host that can be recognized (as in the case of autoimmune diseases) are also epitopes.<ref>Template:Cite journal</ref>

The epitopes of protein antigens are divided into two categories, conformational epitopes and linear epitopes, based on their structure and interaction with the paratope.<ref>Template:Cite journal</ref> 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 or tertiary 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 the primary 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 the primary structure residues to adopt the epitope's 3-D conformation.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 90% of epitopes are conformational.<ref>Template:Cite journal</ref>

FunctionEdit

T cell epitopesEdit

T cell epitopes<ref>Template:Cite journal</ref> are presented on the surface of an antigen-presenting cell, where they are bound to major histocompatibility complex (MHC) molecules. In humans, professional antigen-presenting cells are specialized to present MHC class II peptides, whereas most nucleated somatic cells present MHC class I peptides. T cell epitopes presented by MHC class I molecules 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,<ref>Template:Cite book</ref> and non-classical MHC molecules also present non-peptidic epitopes such as glycolipids.

B cell epitopesEdit

The part of the antigen that immunoglobulin or antibodies bind to is called a B-cell epitope.<ref name="Sanchez-Trincado et al 2017">Template:Cite journal</ref> B cell epitopes can be divided into two groups: conformational or linear.<ref name="Sanchez-Trincado et al 2017"/> B cell epitopes are mainly conformational.<ref>Template:Cite journal</ref><ref name=Regenmortel2009>Template:Cite book</ref> There are additional epitope types when the quaternary structure is considered.<ref name=Regenmortel2009/> Epitopes that are masked when protein subunits aggregate are called cryptotopes.<ref name=Regenmortel2009/> Neotopes are epitopes that are only recognized while in a specific quaternary structure and the residues of the epitope can span multiple protein subunits.<ref name=Regenmortel2009/> Neotopes are not recognized once the subunits dissociate.<ref name=Regenmortel2009/>

Cross-activityEdit

Epitopes are sometimes cross-reactive. This property is exploited by the immune system in regulation by anti-idiotypic antibodies (originally proposed by Nobel laureate Niels 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.Template:Citation needed

Epitope mappingEdit

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T cell epitopesEdit

MHC class I and II epitopes can be reliably predicted by computational means alone,<ref>Template:Cite journal</ref> although not all in-silico T cell epitope prediction algorithms are equivalent in their accuracy.<ref>Template:Cite journal</ref> There are two main methods of predicting peptide-MHC binding: data-driven and structure-based.<ref name="Sanchez-Trincado et al 2017"/> Structure based methods model the peptide-MHC structure and require great computational power.<ref name="Sanchez-Trincado et al 2017"/> Data-driven methods have higher predictive performance than structure-based methods.<ref name="Sanchez-Trincado et al 2017"/> Data-driven methods predict peptide-MHC binding based on peptide sequences that bind MHC molecules.<ref name="Sanchez-Trincado et al 2017"/> By identifying T-cell epitopes, scientists can track, phenotype, and stimulate T-cells.<ref>Template:Cite journal</ref><ref name="Ahmad Eweida El-Sayed 2016">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

B cell epitopesEdit

There are two main methods of epitope mapping: either structural or functional studies.<ref name="Potocnakova et al 2016">Template:Cite journal</ref> Methods for structurally mapping epitopes include X-ray crystallography, nuclear magnetic resonance, and electron microscopy.<ref name="Potocnakova et al 2016"/> X-ray crystallography of Ag-Ab complexes is considered an accurate way to structurally map epitopes.<ref name="Potocnakova et al 2016"/> Nuclear magnetic resonance can be used to map epitopes by using data about the Ag-Ab complex.<ref name="Potocnakova et al 2016"/> This method does not require crystal formation but can only work on small peptides and proteins.<ref name="Potocnakova et al 2016"/> Electron microscopy is a low-resolution method that can localize epitopes on larger antigens like virus particles.<ref name="Potocnakova et al 2016"/>

Methods for functionally mapping epitopes often use binding assays such as western blot, dot blot, and/or ELISA to determine antibody binding.<ref name="Potocnakova et al 2016"/> Competition methods look to determine if two monoclonal antibodies (mABs) can bind to an antigen at the same time or compete with each other to bind at the same site.<ref name="Potocnakova et al 2016"/> Another technique involves high-throughput mutagenesis, an epitope mapping strategy developed to improve rapid mapping of conformational epitopes on structurally complex proteins.<ref>Template:Cite journal</ref> Mutagenesis uses randomly/site-directed mutations at individual residues to map epitopes.<ref name="Potocnakova et al 2016"/> B-cell epitope mapping can be used for the development of antibody therapeutics, peptide-based vaccines, and immunodiagnostic tools.<ref name="Potocnakova et al 2016"/><ref name="Ahmad Eweida Sheweita 2016">Template:Cite journal</ref>

Epitope tagsEdit

Epitopes are often used in proteomics and the study of other gene products. Using recombinant DNA techniques genetic sequences coding for epitopes that are recognized by common antibodies can be fused to the gene. Following synthesis, 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 are Myc-tag, HA-tag, FLAG-tag, GST-tag, 6xHis,<ref>Template:Cite book</ref> V5-tag and OLLAS.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Peptides can also be bound by proteins that form covalent bonds to the peptide, allowing irreversible immobilisation.<ref>Template:Cite journal</ref> These strategies have also been successfully applied to the development of "epitope-focused" vaccine design.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Epitope-based vaccinesEdit

Template:Main articles The first epitope-based vaccine was developed in 1985 by Jacob et al.<ref name="Parvizpour et al 2020">Template:Cite journal</ref> Epitope-based vaccines stimulate humoral and cellular immune responses using isolated B-cell or T-cell epitopes.<ref name="Parvizpour et al 2020"/><ref name="Ahmad Eweida Sheweita 2016"/><ref name="Ahmad Eweida El-Sayed 2016"/> These vaccines can use multiple epitopes to increase their efficacy.<ref name="Parvizpour et al 2020"/> To find epitopes to use for the vaccine, in silico mapping is often used.<ref name="Parvizpour et al 2020"/> Once candidate epitopes are found, the constructs are engineered and tested for vaccine efficiency.<ref name="Parvizpour et al 2020"/> While epitope-based vaccines are generally safe, one possible side effect is cytokine storms.<ref name="Parvizpour et al 2020"/>

Neoantigenic determinantEdit

A neoantigenic determinant is an epitope on a neoantigen, which is a newly formed antigen that has not been previously recognized by the immune system.<ref>Template:Cite book</ref> Neoantigens are often associated with tumor antigens and are found in oncogenic cells.<ref>Neoantigen. (n.d.) Mosby's Medical Dictionary, 8th edition. (2009). Retrieved February 9, 2015 from Medical Dictionary Online</ref> Neoantigens and, by extension, neoantigenic determinants can be formed when a protein undergoes further modification within a biochemical pathway such as glycosylation, phosphorylation or proteolysis. This, by altering the structure of the protein, can produce new epitopes that are called neoantigenic determinants as they give rise to new antigenic determinants. Recognition requires separate, specific antibodies.Template:Cn