Antigen

In immunology, an antigen (Ag) is a molecule or molecular

structure, such as may be present on the outside of a pathogen,
that can be bound by an antigen-specific antibody or B-cell
antigen receptor.[1] The presence of antigens in the body
normally triggers an immune response.[2] The Ag abbreviation
stands for an antibody generator.[3]

Antigens are "targeted" by antibodies.[1] Each antibody is

specifically produced by the immune system to match an antigen
after cells in the immune system come into contact with it; this
allows a precise identification or matching of the antigen and the
initiation of an adaptive response.[1][2] The antibody is said to
"match" the antigen in the sense that it can bind to it due to an
adaptation in a antigen-binding fragment of the antibody.[1] In
most cases, an adapted antibody can only react to and bind one
specific antigen; in some instances, however, antibodies may
cross-react and bind more than one antigen.

Antigens are proteins, peptides (amino acid chains) and

polysaccharides (chains of monosaccharides/simple sugars) but
lipids and nucleic acids become antigens only when combined An illustration that shows how antigens
induce the immune system response by
with proteins and polysaccharides.[4]
interacting with an antibody that matches
the molecular structure of an antigen
The antigen may originate from within the body ("self-protein")
or from the external environment ("non-self").[2] The immune
system identifies and attacks "non-self" external antigens and
usually does not react to self-protein due to negative selection of T cells in the thymus.[5]

Vaccines 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. Vaccines for the seasonal flu virus is a common example.[6]

Contents
Etymology
Terminology
Sources
Exogenous antigens
Endogenous antigens
Autoantigens
Neoantigens
Viral antigens
Tumor antigens
Process
 Nativity
Antigenic specificity
See also
References

Etymology
Paul Ehrlich coined the term antibody (in German Antikörper) in his side-chain theory at the end of the 19th
century.[7] In 1899, Ladislas Deutsch (László Detre) (1874–1939) named the hypothetical substances halfway
between bacterial constituents and antibodies "substances immunogenes ou antigenes" (antigenic or
immunogenic substances). He originally believed those substances to be 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 of antisomatogen
(Immunkörperbildner). The Oxford English Dictionary indicates that the logical construction should be
"anti(body)-gen".[8]

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 regions.

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 spp.) it is dispersed over a relatively large number of parasite
antigens.[9]

Antigen-presenting cells present antigens in the form of peptides on histocompatibility molecules. 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).[10]
The antigen cannot elicit the immune response without the help of an immunologic adjuvant.[4] Similarly, the
adjuvant component of vaccines plays an essential role in the activation of the innate immune system.[11][12]

An immunogen is an antigen substance (or adduct) that is able to trigger a humoral (innate) or cell-mediated
immune response.[13] 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.[14]

At the molecular level, an antigen can be characterized by its ability to bind to an antibody's paratopes.
Different antibodies have the potential to discriminate among specific epitopes present on the antigen surface.
A hapten is a small molecule that changes the structure of an antigenic epitope. In order to induce an immune
response, it needs to be attached to a large carrier molecule such as a protein (a complex of peptides). Antigens
are usually carried by proteins and polysaccharides, and less frequently, lipids. This includes parts (coats,
capsules, cell walls, flagella, fimbriae, and toxins) of bacteria, viruses, and other microorganisms. Lipids and
nucleic acids are antigenic only when combined with proteins and polysaccharides. 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. The immune system's response to exogenous antigens is often subclinical. By
endocytosis or phagocytosis, exogenous antigens are taken into the antigen-presenting cells (APCs) and
processed into fragments. APCs then present the fragments to T helper cells (CD4+) by the use of 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 cells, 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 CD8+ T cells recognize them, the T cells secrete various
toxins that cause the lysis or apoptosis of the infected cell. In order to keep the cytotoxic cells from killing cells
just for presenting self-proteins, the cytotoxic cells (self-reactive T cells) are deleted as a result of tolerance
(negative selection). Endogenous antigens include xenogenic (heterologous), autologous and idiotypic or
allogenic (homologous) antigens. Sometimes antigens are part of the host itself in an autoimmune disease.[2]

Autoantigens
An autoantigen is usually a self-protein or protein complex (and sometimes DNA or RNA) that is recognized
by the immune system of patients suffering from 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.[15] 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.[16]

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.[15]

Tumor antigens

Tumor antigens are those antigens that are presented by MHC class I or MHC class II molecules on the
surface of tumor cells. Antigens found only on such cells are called tumor-specific antigens (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 antigens (TAAs). Cytotoxic T lymphocytes that recognize these
antigens may be able to destroy tumor cells.[15]

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.[15]

For human tumors without a viral etiology, novel peptides (neo-epitopes) are created by tumor-specific DNA
alterations.[15]

Process

A large fraction of human tumor mutations is 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.[15]

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.[15]
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 proteasomal processing, transport into
the endoplasmic reticulum, affinity for the relevant MHC class I alleles and gene expression or protein
translation levels.[15]

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.[15]

Nativity

A native antigen is an antigen that is not yet processed by an APC to smaller parts. T cells cannot bind native
antigens, but require that they be processed by APCs, whereas B cells 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.[2][6] Both T cells and B cells are cellular components of adaptive immunity.[2][17]

See also
Antigenic escape
Antitoxin
Conformational epitope
Epitope
Linear epitope
Magnetic immunoassay
Neutralizing antibody
Original antigenic sin
Paul Ehrlich: Magic Bullet
Polyclonal B cell response
Priming (immunology)

References
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