What is an Epitope (Antigenic Determinant)?
An epitope is a specific molecular structure on an antigen's surface that is recognized and bound by antibodies or T cell receptors, serving as the fundamental unit of immune recognition. 1
Core Definition and Recognition
Epitopes are relational entities that require complementary binding sites (paratopes) on immunoglobulin molecules for their operational recognition. 1
The antigenic determinants correspond to those parts of a protein molecule that are specifically recognized by the binding sites of certain immunoglobulin molecules. 1
An epitope must fulfill two functional criteria: (1) specifically stimulate the immune response (either B or T cell mediated), and (2) be acted upon by the products of these protective mechanisms. 2
Types of Epitopes
B Cell Epitopes
Continuous (linear or sequential) epitopes are composed of a single antibody-recognizing element located at a single locus of the primary protein structure. 2
Discontinuous (assembled) epitopes involve more than one physically separated entity brought together by protein folding. 2
B cell epitopes are frequently composed of the side chains (R-groups) of amino acids found at solvent-exposed surfaces. 2
T Cell Epitopes
T cell epitopes are peptides presented on the surface of antigen-presenting cells (macrophages, dendritic cells, and B cells) that are bound to major histocompatibility complex (MHC) proteins. 2
The T cell receptor recognizes this peptide-MHC complex rather than the native antigen structure. 2
Sources of Epitope Antigenicity
Microbial Epitopes
Microbial proteins provide highly antigenic epitopes because they are not covered by central tolerance, and their epitopes efficiently prime immune responses. 3
Conserved microbial products (microbe-associated molecular patterns or MAMPs) deliver potent immunostimulatory signals alongside their antigenic epitopes. 3
Tumor Neoantigens (TNAs)
Non-synonymous point mutations and frameshift mutations in tumor cells create neoepitopes that have poor structural homology to self epitopes, making them highly immunogenic. 3
TNAs partially resemble microbial epitopes and efficiently prime de novo immune responses because they are not covered by central tolerance. 3
Post-Translational Modification (PTM)-Derived Epitopes
Enzymatic and non-enzymatic post-translational modifications can generate antigenic determinants not covered by central tolerance. 3
PTMs that create novel epitopes include phosphorylation, acetylation, glycosylation, citrullination, nitration/nitrosylation, glycation, oxidation, and ubiquitination. 3
PTM-containing epitopes may escape central tolerance because signal transduction cascades regulating enzymatic PTMs are not necessarily activated similarly in the periphery and thymic epithelium during T cell selection. 3
PTM-dependent epitopes have been attributed pathogenic value in autoimmune disorders including diabetes and rheumatoid arthritis. 3
Tumor-Associated Antigens (TAAs)
TAAs are self-antigens expressed by cancer cells that can initiate antitumor immunity, including tissue differentiation antigens (CD19, CD20, gp100, MART-1) and ectopically expressed proteins (carcinoembryonic antigens, cancer/testis antigens, MAGE and SSX protein families). 3
Central tolerance against TAAs is leaky, meaning naïve T cell clones expressing low-affinity TCRs are available and peripheral tolerance can be overcome with robust adjuvanticity. 3
Epitope Boundaries and Specificity
All epitopes have fuzzy boundaries and can only be identified by their ability to bind to certain antibodies. 4
Antigenic cross-reactivity is common because antibodies can recognize a considerable number of related epitopes, which places severe limits on antibody specificity. 4
The delineation of epitopes requires specific criteria for deciding which residues of the antigen are in contact with the paratope and functionally part of the epitope. 1
Clinical Relevance
Epitope Spreading
Epitope spreading refers to the development of an immune response to epitopes distinct from, and non-cross-reactive with, the disease-causing epitope. 5
This diversification allows the immune system to attack multiple targets on a pathogen but may also propagate autoimmunity. 5
Neutralization Epitopes
Neutralization epitopes are a special subclass specifically recognized by antibodies able to neutralize the biological activity of infectious agents and toxins. 1
Identification of neutralization epitopes is critical for synthetic vaccine development because these epitopes should be mimicked to elicit protective immunity. 1
Important Distinction: Antigenicity vs. Immunogenicity
Antigenicity (the ability of an epitope to react with an antibody) must be distinguished from immunogenicity (the ability to induce antibodies in a competent vertebrate host). 4
This distinction is critical because failure to recognize it partly explains why no successful peptide-based vaccines have yet been developed despite accurate epitope identification. 4