In immunology, an antigen (Ag), or antibody generator, is any substance which provokes an adaptive immune response. That is to say, an antigen is a molecule that also induces an immune response in the body. An antigen is often foreign or toxic to the body (for example, a bacterium) which, once in the body, attracts and is bound to a respective and specific antibody. Each antibody is specifically designed to deal with certain antigens because of variation in the antibody's complementarity determining regions (a common analogy used to describe this is the fit between a lock and a key). Paul Ehrlich coined the term antibody (in German Antikörper) in his side-chain theory at the end of 19th century. The term antigen originally came from ANTIbody GENerator (see section History).
The antigen may originate from within the body ("self") or from the external environment ("non-self"). The immune system is usually non-reactive against "self" antigens under normal conditions and is supposed to identify and attack only "non-self" invaders from the outside world or modified/harmful substances present in the body under distressed conditions.
Cells present their antigenic structures to the immune system via a histocompatibility molecule. Depending on the antigen presented and the type of the histocompatibility molecule, several types of immune cells can become activated. Antigen was originally a structural molecule that binds specifically to the antibody, but the term now also refers to any molecule or molecular fragment that can be recognized by highly variable antigen receptors (B-cell receptor or T-cell receptor) of the adaptive immune system. For T-Cell Receptor (TCR) recognition, it must be processed into small fragments inside the cell and presented to a T-cell receptor by major histocompatibility complex (MHC). Antigen by itself is not capable to elicit the immune response without the help of an Immunologic adjuvant. The essential role of the adjuvant component of vaccines in the activation of innate immune system is so-called immunologist's dirty little secret as originally described by Charles Janeway.
An immunogen is in analogy to the antigen a substance (or a mixture of substances) that is able to provoke an immune response if injected to the body. An immunogen is able to initiate an indispensable innate immune response first, later leading to the activation of the adaptive immune response, whereas an antigen is able to bind the highly variable immunoreceptor products (B-cell receptor or T-cell receptor) once these have been produced. The overlapping concepts of immunogenicity and antigenicity are, therefore, subtly different. According to current textbook notions:
Immunogenicity is the ability to induce a humoral and/or cell-mediated immune response
Antigenicity is the ability to combine specifically with the final products of the immune response (i.e. secreted antibodies and/or surface receptors on T-cells). Although all immunogenic molecules are also antigenic, the reverse is not true.
At the molecular level, an antigen can be characterized by its ability to be bound by the variable Fab region of an antibody. Note also that different antibodies have the potential to discriminate between specific epitopes present on the surface of the antigen (as illustrated in the Figure). Hapten is a small molecule that changes the structure of an antigenic epitope. In order to induce an immune response, it has to be attached to a large carrier molecule such as protein. Antigens are usually proteins and polysaccharides, less frequently also lipids. This includes parts (coats, capsules, cell walls, flagella, fimbrae, and toxins) of bacteria, viruses, and other microorganisms. Lipids and nucleic acids are antigenic only when combined with proteins and polysaccharides. Non-microbial exogenous (non-self) antigens can include pollen, egg white, and proteins from transplanted tissues and organs or on the surface of transfused blood cells. Vaccines are examples of antigens in an immunogenic form, which are to be intentionally administered to induce the memory function of adaptive immune system toward the antigens of the pathogen invading the recipient.
- Epitope – The distinct molecular surface features of an antigen capable of being bound by an antibody (a.k.a. antigenic determinant). Antigenic molecules, normally being "large" biological polymers, usually present several surface features that can act as points of interaction for specific antibodies. Any such distinct molecular feature constitutes an epitope. Therefore, most antigens have the potential to be bound by several distinct antibodies, each of which specific to a particular epitope. Using the "lock and key" metaphor, the antigen itself can be seen as a string of keys – any epitope being a "key" – each of which matching a different lock. Different antibody idiotypes, each having distinctly formed complementarity determining regions, correspond to the various "locks" that can match "the keys" (epitopes) presented on the antigen molecule.
- 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 – These proteins are capable of binding to antibodies at positions outside of the antigen-binding site. That is, whereas antigens are the "target" of antibodies, immunoglobulin-binding proteins "attack" antibodies. Protein A, protein G, and protein L are examples of proteins that strongly bind to various antibody isotypes.
- T-dependent antigen – T-dependent antigens are usually proteins. They require an assistance of T cells to induce the formation of specific antibodies.
- T-independent antigen – T-independent antigens are usually polysaccharides stimulating B cells directly.
- Immunodominant antigens are the ones that dominate (over all others from a pathogen) in their ability to produce an immune response. It is commonly assumed that T cell responses are directed against a relatively few immunodominant epitopes, although at least in some cases (e.g., infection with the malaria pathogen Plasmodium spp.) it is dispersed over a relatively large number of parasite antigens.
Origin of the term antigen
In 1899, Ladislas Deutsch (Laszlo 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".
Origin of antigens
Antigens can be classified in order of their class.
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. Cytokines are substances that can activate cytotoxic T lymphocytes (CTL), antibody-secreting B cells, macrophages, and other particles.
Some antigens start out as exogenontigens, and later become endogenous (for example, intracellular viruses). Intracellular antigens can again be released back into circulation upon the destruction of the infected cell.
Endogenous antigens are antigens that have been generated within previously 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 begin to 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, self-reactive T cells are deleted from the repertoire as a result of tolerance (also known as negative selection). Endogenous antigens include xenogenic (heterologous), autologous and idiotypic or allogenic (homologous) antigens.
An autoantigen is usually a normal protein or complex of proteins (and sometimes DNA or RNA) that is recognized by the immune system of patients suffering from a specific autoimmune disease. These antigens should not be, under normal conditions, the target of the immune system, but, due mainly to genetic and environmental factors, the normal immunological tolerance for such an antigen has been lost in these patients.
Tumor antigens or neoantigens are those antigens that are presented by MHC I or MHC II molecules on the surface of tumor cells. These antigens can sometimes be presented by tumor cells and never by the normal ones. In this case, they are called tumor-specific antigens (TSAs) and, in general, result from a tumor-specific mutation. More common are antigens that are presented by tumor cells and normal cells, and they are called tumor-associated antigens (TAAs). Cytotoxic T lymphocytes that recognize these antigens may be able to destroy the tumor cells before they proliferate or metastasize.
Tumor antigens can also be on the surface of the tumor in the form of, for example, a mutated receptor, in which case they will be recognized by B cells.
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.
Antigen(ic) 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 a measurement, although the degree of specificity may not be easy to measure, and need not be linear or of the nature of a rate-limited step or equation.
- Conformational epitope
- Linear epitope
- Magnetic immunoassay
- Neutralizing antibody
- Original antigenic sin
- Paul Ehrlich: Magic Bullet
- Polyclonal B cell response
- Priming (immunology)
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- Antigen Retrieval Protocol
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