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Antigen
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In immunology, an antigen (Ag) is a molecule, moiety,
foreign particulate matter, or an allergen, such as pollen, that Antigens
can bind to a specific antibody or T-cell receptor.) The ae we
wv
presence of antigens in the body may trigger an immune
response,[2]
‘Antigens can be proteins, peptides (amino acid chains), & enti ne
polysaccharides (chains of simple sugars), lipids, or nucleic
acids 3Il4l antigens exist on normal cells, cancer cells,
parasites, viruses, fungi, and bacteria.[*ll3!
o
CS
Antigens are recognized by antigen receptors, including
antibodies and T-cell receptors.!8) Diverse antigen receptors
are made by cells of the immune system so that each cell has
a specificity for a single antigen.'3] Upon exposure to an
antigen, only the lymphocytes that recognize that antigen are
activated and expanded, a process known as clonal
selection. In most cases, antibodies are antigen-specific, Antibody
meaning that an antibody can only react to and bind one Av illustration that shows how antigens
specific antigen; in some instances, however, antibodies may _'nduce the immune system response by
cross-react to bind more than one antigen, The reaction reid wih an antbody hai matches
between an antigen and an antibody is called the antigen- “YY "OSE SNCANE oF an antigen
antibody reaction.
Antigen can originate either from within the body ("self-protein” or "self antigens") or from the
external environment (“non-self").2) The immune system identifies and attacks "non-self” external
antigens. Antibodies usually do not react with self-antigens due to negative selection of ‘cells in the
thymus and B cells in the bone marrow.!5] The diseases in which antibodies react with self antigens
and damage the body's own cells are called autoimmune diseases.!61
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. The vaccine for seasonal influenza is a common example.7!
Etymology
Paul Ehrlich coined the term antibody (German: Antikérper) in his side-chain theory at the end of the
igth century.8! In 1899, Ladislas Deutsch (L4szl6 Detre) named the hypothetical substances halfway
between bacterial constituents and antibodies “antigenic or immunogenic substances" (French:
substances immunogénes ou antigénes). He originally believed those substances to be precursors ofantibodies, just as a 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 (Immunkérperbildner). The Oxford English Dictionary indicates that
the logical construction should be "anti(body)-gen".[9) The term originally referred to a substance that
acts as an antibody generator.[101
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 lack (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.{"1]
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).!"2] The antigen cannot elicit the immune response without
the help of an immunologic adjuvant.31 similarly, the adjuvant component of vaccines plays an
essential role in the activation of the innate immune system, 4115]
An immunogen is an antigen substance (or adduct) that is able to trigger a humoral (innate) or cell-
mediated immune response.l6! 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.17]
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 can only induce an immune response whenattached to a larger carrier molecule, such as a protein. Antigens can be proteins, polysaccharides,
lipids, nucleic acids or other biomolecules.!4! ‘This includes parts (coats, capsules, cell walls, flagella,
fimbriae, and toxins) of bacteria, viruses, and other microorganisms. 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-seereting 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
xenogenie (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 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 tosystematically analyze T cell reactivity against neoantigens became available only recently.!'*l
Neoantigens can be directly detected and quantified.{"9]
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.8!
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./"81
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.!!8)
For human tumors without a viral etiology, novel peptides (neo-epitopes) are created by tumor-
specific DNA alterations."'8)
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.!"81
The false-negative rate of cancer exome sequencing is low—i.e.: the majority of neoantigens occur
within exonie sequence with sufficient coverage. However, the vast majority of mutations within
expressed genes do not produce neoantigens that are recognized by autologous T cells.("81
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.'8!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."81
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.(21I7) Both T cells and B cells are cellular components of adaptive
immunity, 214]
See also
= Antigenic escape = Neutralizing antibody
= Antitoxin = Original antigenic sin
= Conformational epitope = Paul Ehrlich: Magic Bullet
= Epitope = Polyclonal B cell response
« Linear epitope = Priming (immunology)
= Magnetic immunoassay
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