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{{Short description|Molecule triggering an immune response (antibody production) in the host}}
[[File:Antibody.svg|thumb|255px|An illustration that shows how antigens induce the [[immune system]] response by interacting with an [[antibody]] that matches the [[molecular structure]] of an antigen]]

In [[immunology]], an '''antigen''' ('''Ag''') is a [[molecule]] or molecular [[structure]] or any foreign particulate matter or a pollen grain that can bind to a specific [[antibody]] or [[T-cell receptor]].<ref name="gen">{{cite web |title=Antibody |url= https://www.genome.gov/genetics-glossary/Antibody |publisher=National Human Genome Research Institute, US National Institutes of Health |access-date=13 October 2020 |date=2020}}</ref> The presence of antigens in the body may trigger an [[immune response]].<ref name="mlp">{{cite web |title=Immune system and disorders |url=https://medlineplus.gov/immunesystemanddisorders.html |publisher=MedlinePlus, US National Institute of Medicine |access-date=13 October 2020 |date=28 September 2020}}</ref> The term ''antigen'' originally referred to a substance that is an antibody generator.<ref>{{Cite book|url=https://books.google.com/books?id=gE6o5ZRJUawC&q=antibody+generator&pg=PA10|title=Immunology|last=Male|first=David K.|date=2006|publisher=Elsevier Health Sciences|isbn=978-0323033992|pages=10|language=en}}</ref> Antigens can be [[protein]]s, [[peptide]]s (amino acid chains), [[polysaccharide]]s (chains of monosaccharides/simple sugars), [[lipid]]s, or nucleic acids.<ref name=Abbas>{{cite book |last1=Abbas |first1=Abul K. |last2=Lichtman |first2=Andrew |last3=Pillai |first3=Shiv |title=Cellular and Molecular Immunology |date=2018 |publisher=Elsevier|location=Philadelphia |isbn=978-0-323-52324-0 |chapter=Antibodies and Antigens |edition= 9th }}</ref>

Antigens are recognized by antigen receptors, including antibodies and T-cell receptors. Diverse antigen receptors are made by cells of the immune system so that each cell has a specificity for a single antigen. Upon exposure to an antigen, only the lymphocytes that recognize that antigen are activated and expanded, a process known as [[clonal selection]].<ref name=Abbas/> In most cases, an antibody can only react to and bind one specific antigen; in some instances, however, antibodies may [[cross-reactivity|cross-react]] and bind more than one antigen.

The antigen may originate from within the body ("[[self-protein]]") or from the external environment ("non-self").<ref name=mlp/> The immune system identifies and attacks "non-self" external antigens and usually does not react to [[self-protein]] due to [[central tolerance|negative selection]] of [[T cell]]s in the [[thymus]] and [[B cell]]s in the [[bone marrow]].<ref>{{cite journal|last1=Gallucci|first1=S|last2=Lolkema|first2=M|last3=Matzinger|first3=P|title=Natural adjuvants: endogenous activators of dendritic cells|journal=Nature Medicine|date=November 1999|volume=5|issue=11|pages=1249–55|pmid=10545990|doi=10.1038/15200|s2cid=29090284}}</ref>

[[Vaccine]]s are examples of antigens in an immunogenic form, which are intentionally administered to a recipient to induce the memory function of the [[adaptive immune system]] towards antigens of the pathogen invading that recipient. The vaccine for [[seasonal influenza]] is a common example.<ref name="cdc">{{cite web |title=Antigenic characterization |url=https://www.cdc.gov/flu/about/professionals/antigenic.htm |publisher=US Centers for Disease Control and Prevention |access-date=13 October 2020 |date=15 October 2019}}</ref>

==Etymology==
[[Paul Ehrlich]] coined the term ''[[Antibody#History|antibody]]'' ({{lang-de|Antikörper}}) in his [[side-chain theory]] at the end of the 19th century.<ref>{{cite journal|last=Strebhardt|first=Klaus|author2=Ullrich, Axel|title=Paul Ehrlich's magic bullet concept: 100 years of progress|journal=Nature Reviews Cancer|date=Jun 2008|volume=8|issue=6|pages=473–80|doi=10.1038/nrc2394|pmid=18469827|s2cid=30063909|issn=1474-1768}}</ref> In 1899, [[László Detre (microbiologist)|Ladislas Deutsch (László Detre)]] named the hypothetical substances halfway between bacterial constituents and antibodies "antigenic or immunogenic substances" ({{lang-fr|substances immunogènes ou antigènes}}). He originally believed those substances to be [[Protein precursor|precursors]] of antibodies, just as [[zymogen]] is a precursor of an [[enzyme]]. But, by 1903, he understood that an antigen induces the production of immune bodies (antibodies) and wrote that the word ''antigen'' is a [[Contraction (grammar)|contraction]] of antisomatogen ({{lang|de|Immunkörperbildner}}). The ''[[Oxford English Dictionary]]'' indicates that the logical construction should be "anti(body)-gen".<ref name="Lindenmann">{{cite journal |author=Lindenmann, Jean |title=Origin of the Terms 'Antibody' and 'Antigen' |journal=Scand. J. Immunol.|volume=19 |pages=281–85 |year=1984 |pmid=6374880 |issue=4 |doi=10.1111/j.1365-3083.1984.tb00931.x|s2cid=222200504 }}</ref>

==Terminology==
* [[Epitope]] – the distinct surface features of an antigen, its ''antigenic determinant''. Antigenic molecules, normally "large" biological polymers, usually present surface features that can act as points of interaction for specific antibodies. Any such feature constitutes an epitope. Most antigens have the potential to be bound by multiple antibodies, each of which is specific to one of the antigen's epitopes. Using the "lock and key" metaphor, the antigen can be seen as a string of keys (epitopes) each of which matches a different lock (antibody). Different antibody '''[[idiotypes]]''', each have distinctly formed [[complementarity-determining region]]s.
* [[Allergen]] – A substance capable of causing an [[allergic reaction]]. The (detrimental) reaction may result after exposure via ingestion, inhalation, injection, or contact with skin.
* [[Superantigen]] – A class of antigens that cause non-specific activation of T-cells, resulting in polyclonal T-cell activation and massive [[cytokine]] release.
* [[Tolerogen]] – A substance that invokes a specific immune non-responsiveness due to its [[molecular form]]. If its molecular form is changed, a tolerogen can become an [[immunogen]].
* [[Immunoglobulin]]-binding protein – Proteins such as [[protein A]], [[protein G]], and [[protein L]] that are capable of binding to antibodies at positions outside of the antigen-binding site. While antigens are the "target" of antibodies, immunoglobulin-binding proteins "attack" antibodies.
* T-dependent antigen – Antigens that require the assistance of T cells to induce the formation of specific antibodies.
* T-independent antigen – Antigens that stimulate B cells directly.
* Immunodominant antigens – Antigens that dominate (over all others from a [[pathogen]]) in their ability to produce an immune response. T cell responses typically are directed against a relatively few immunodominant epitopes, although in some cases (e.g., infection with the [[malaria]] pathogen ''[[Plasmodium|Plasmodium spp.]]'') it is dispersed over a relatively large number of parasite antigens.<ref name="pmid12886016">{{cite journal | vauthors = Doolan DL, Southwood S, Freilich DA, Sidney J, Graber NL, Shatney L, Bebris L, Florens L, Dobano C, Witney AA, Appella E, Hoffman SL, Yates JR, Carucci DJ, Sette A | title = Identification of Plasmodium falciparum antigens by antigenic analysis of genomic and proteomic data | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 17 | pages = 9952–57 | date = August 2003 | pmid = 12886016 | pmc = 187898 | doi = 10.1073/pnas.1633254100 | bibcode = 2003PNAS..100.9952D | doi-access = free }}</ref>

[[Antigen-presenting cell]]s present antigens in the form of peptides on [[histocompatibility molecule]]s. The T cells selectively recognize the antigens; depending on the antigen and the type of the histocompatibility molecule, different types of T cells will be activated. For T-cell receptor (TCR) recognition, the peptide must be processed into small fragments inside the cell and presented by a [[major histocompatibility complex]] (MHC).<ref>Parham, Peter. (2009). ''The Immune System'', 3rd Edition, p. G:2, Garland Science, Taylor and Francis Group, LLC.</ref> The antigen cannot elicit the immune response without the help of an [[adjuvant|immunologic adjuvant]].<ref name="ReferenceA">{{cite journal|last1=Gavin|first1=AL|last2=Hoebe|first2=K|last3=Duong|first3=B|last4=Ota|first4=T|last5=Martin|first5=C|last6=Beutler|first6=B|last7=Nemazee|first7=D|title=Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling|journal=Science|date=22 December 2006|volume=314|issue=5807|pages=1936–38|pmid=17185603|doi=10.1126/science.1135299|pmc=1868398|bibcode=2006Sci...314.1936G}}</ref> Similarly, the adjuvant component of vaccines plays an essential role in the activation of the innate immune system.<ref>{{cite journal|last1=Janeway CA|first1=Jr|date=1 November 2013|title=Pillars article: approaching the asymptote? Evolution and revolution in immunology. Cold spring harb symp quant biol. 1989. 54: 1–13|journal=Journal of Immunology|volume=191|issue=9|pages=4475–87|pmid=24141854}}</ref><ref>{{cite journal|last=Gayed|first=PM|date=June 2011|title=Toward a modern synthesis of immunity: Charles A. Janeway Jr. and the immunologist's dirty little secret|journal=The Yale Journal of Biology and Medicine|volume=84|issue=2|pages=131–38|issn=1551-4056|pmc=3117407|pmid=21698045}}</ref>

An immunogen is an antigen substance (or [[adduct]]) that is able to trigger a humoral (innate) or cell-mediated immune response.<ref>Parham, Peter. (2009). ''The Immune System'', 3rd Edition, p. G:11, Garland Science, Taylor and Francis Group, LLC.</ref> It first initiates an innate immune response, which then causes the activation of the adaptive immune response. An antigen binds the highly variable immunoreceptor products (B-cell receptor or T-cell receptor) once these have been generated. Immunogens are those antigens, termed [[immunogenic]], capable of inducing an immune response.<ref>{{cite book|title=Kuby Immunology|publisher=Macmillan|year=2006|isbn=978-1-4292-0211-4|edition= 6th|pages=77}}</ref>

At the molecular level, an antigen can be characterized by its ability to bind to an antibody's [[paratope]]s. Different antibodies have the potential to discriminate among specific epitopes present on the antigen surface. A [[hapten]] is a small molecule that can only induce an immune response when attached to a larger carrier molecule, such as a [[protein]]. Antigens can be proteins, polysaccharides, [[lipid]]s, nucleic acids or other biomolecules.<ref name=Abbas/> This includes parts (coats, capsules, cell walls, flagella, fimbriae, and toxins) of [[bacteria]], [[virus]]es, and other [[microorganism]]s. Non-microbial non-self antigens can include pollen, egg white, and proteins from transplanted tissues and organs or on the surface of transfused blood cells.

==Sources==
Antigens can be classified according to their source.

===Exogenous antigens===
Exogenous antigens are antigens that have entered the body from the outside, for example, by [[inhalation]], [[ingestion]] or [[Injection (medicine)|injection]]. The immune system's response to exogenous antigens is often subclinical. By [[endocytosis]] or [[phagocytosis]], exogenous antigens are taken into the [[antigen-presenting cell]]s (APCs) and processed into fragments. APCs then present the fragments to [[T helper cells]] ([[CD4]]+) by the use of [[MHC class II|class II histocompatibility]] molecules on their surface. Some T cells are specific for the peptide:MHC complex. They become activated and start to secrete cytokines, substances that activate [[cytotoxic T lymphocytes]] (CTL), antibody-secreting [[B cell]]s, [[macrophages]] and other particles.

Some antigens start out as exogenous and later become endogenous (for example, intracellular viruses). Intracellular antigens can be returned to circulation upon the destruction of the infected cell.

===Endogenous antigens===
Endogenous antigens are generated within normal cells as a result of normal cell [[metabolism]], or because of viral or intracellular bacterial [[infection]]. The fragments are then presented on the cell surface in the complex with [[MHC class I]] molecules. If activated [[Cytotoxic T cell|cytotoxic CD8+ T cells]] recognize them, the T cells secrete various [[toxin]]s that cause the [[lysis]] or [[apoptosis]] of the infected cell. In order to keep the cytotoxic cells from killing cells just for presenting [[self-protein]]s, the cytotoxic cells (self-reactive T cells) are deleted as a result of [[Central tolerance|tolerance]] (negative selection). Endogenous antigens include [[xenogenic]] (heterologous), [[autologous]] and [[idiotype|idiotypic]] or [[immunoglobulin allotype|allogenic]] (homologous) antigens. Sometimes antigens are [[Autoimmunity|part of the host itself]] in an [[autoimmune disease]].<ref name=mlp/>

===Autoantigens===
An [[Self-protein|autoantigen]] is usually a [[self-protein]] or protein complex (and sometimes DNA or RNA) that is recognized by the immune system of patients with a specific [[autoimmune disease]]. Under normal conditions, these self-proteins should not be the target of the immune system, but in autoimmune diseases, their associated T cells are not deleted and instead attack.

=== Neoantigens ===
Neoantigens are those that are entirely absent from the normal human genome. As compared with nonmutated self-proteins, neoantigens are of relevance to tumor control, as the quality of the T cell pool that is available for these antigens is not affected by central T cell tolerance. Technology to systematically analyze T cell reactivity against neoantigens became available only recently.<ref name="ss15">{{cite journal| journal=Science |date= April 3, 2015 |volume= 348 |issue= 6230 |pages= 69–74 |doi= 10.1126/science.aaa4971 |title=Neoantigens in cancer immunotherapy |first=Ton N. |last1=Schumacher |first2=Robert D. |last2=Schreiber |pmid=25838375|bibcode= 2015Sci...348...69S |doi-access=free }}</ref> Neoantigens can be directly detected and quantified through a method called MANA-SRM developed by a molecular diagnostics company, Complete Omics Inc., through collaborating with a team in Johns Hopkins University School of Medicine.<ref name="ss16">{{cite journal| journal=Cancer Immunol Res |date= September 16, 2019 |volume= 7 |issue= 11 |pages= 1748–54 |doi= 10.1158/2326-6066.CIR-19-0107 |title=Direct Detection and Quantification of Neoantigens|first=Qing. |last1=Wang |first2=Jacqueline |last2=Douglass |pmid=31527070|pmc= 6825591 }}</ref>

==== Viral antigens ====
For virus-associated tumors, such as [[cervical cancer]] and a subset of [[head and neck cancers]], [[epitopes]] derived from viral open reading frames contribute to the pool of neoantigens.<ref name=ss15/>

====Tumor antigens====
''[[Tumor antigen]]s'' are those antigens that are presented by [[MHC class I]] or [[MHC class II]] molecules on the surface of [[tumor cell]]s. Antigens found only on such cells are called [[tumor-specific antigen]]s (TSAs) and generally result from a tumor-specific [[mutation]]. More common are antigens that are presented by tumor cells and normal cells, called [[tumor-associated antigen]]s (TAAs). [[Cytotoxic T lymphocytes]] that recognize these antigens may be able to destroy tumor cells.<ref name=ss15/>

Tumor antigens can appear on the surface of the tumor in the form of, for example, a mutated receptor, in which case they are recognized by [[B cells]].<ref name=ss15/>

For human tumors without a viral etiology, novel [[peptides]] (neo-epitopes) are created by tumor-specific DNA alterations.<ref name=ss15/>

===== Process=====
A large fraction of human tumor mutations are effectively patient-specific. Therefore, neoantigens may also be based on individual tumor genomes. Deep-sequencing technologies can identify mutations within the protein-coding part of the [[genome]] (the [[exome]]) and predict potential neoantigens. In mice models, for all novel protein sequences, potential MHC-binding peptides were predicted. The resulting set of potential neoantigens was used to assess T cell reactivity. Exome–based analyses were exploited in a clinical setting, to assess reactivity in patients treated by either [[tumor-infiltrating lymphocyte]] (TIL) cell therapy or checkpoint blockade. Neoantigen identification was successful for multiple experimental model systems and human malignancies.<ref name="ss15" />

The false-negative rate of cancer exome sequencing is low—i.e.: the majority of neoantigens occur within exonic sequence with sufficient coverage. However, the vast majority of mutations within expressed genes do not produce neoantigens that are recognized by autologous T cells.<ref name="ss15" />

As of 2015 mass spectrometry resolution is insufficient to exclude many false positives from the pool of peptides that may be presented by MHC molecules. Instead, algorithms are used to identify the most likely candidates. These algorithms consider factors such as the likelihood of [[proteasome|proteasomal]] processing, transport into the [[endoplasmic reticulum]], affinity for the relevant MHC class I [[allele]]s and gene expression or protein translation levels.<ref name="ss15" />

The majority of human neoantigens identified in unbiased screens display a high predicted MHC binding affinity. Minor histocompatibility antigens, a conceptually similar antigen class are also correctly identified by MHC binding algorithms. Another potential filter examines whether the mutation is expected to improve MHC binding. The nature of the central TCR-exposed residues of MHC-bound peptides is associated with peptide immunogenicity.<ref name="ss15" />

===Nativity===
A native antigen is an antigen that is not yet processed by an APC to smaller parts. [[T cell]]s cannot bind native antigens, but require that they be processed by APCs, whereas [[B cell]]s can be activated by native ones.

==Antigenic specificity==
Antigenic specificity is the ability of the host cells to recognize an antigen specifically as a unique molecular entity and distinguish it from another with exquisite precision. Antigen specificity is due primarily to the side-chain conformations of the antigen. It is measurable and need not be linear or of a rate-limited step or equation.<ref name=mlp/><ref name=cdc/> Both [[T cell]]s and [[B cell]]s are cellular components of [[adaptive immune system|adaptive immunity]].<ref name=mlp/><ref name=Abbas/>

==See also==
{{columns-list|colwidth=22em|
* [[Antigenic escape]]
* [[Antitoxin]]
* [[Conformational epitope]]
* [[Epitope]]
* [[Linear epitope]]
* [[Magnetic immunoassay]]
* [[Neutralizing antibody]]
* [[Original antigenic sin]]
* [[Paul Ehrlich#Magic bullet|Paul Ehrlich: Magic Bullet]]
* [[Polyclonal B cell response]]
* [[Priming (immunology)]]
}}

==References==
{{Reflist}}
{{immune system}}
{{Authority control}}
{{二次利用|date=13 December 2022}}
[[Category:Immune system]]
[[Category:Biomolecules]]

Antigen - Revision history