Antigen Mechanisms

In immunology, an antigen is a molecule capable of inducing an immune response (to produce an antibody) in the host organism. (1) Sometimes antigens are part of the host itself in an autoimmune disease. (2)

The term antigen originally described a structural molecule that binds specifically to an antibody. It was expanded to refer to any molecule or a linear molecular fragment that can be recognized by highly variable antigen receptors (B-cell receptor or T-cell receptor) of the adaptive immune system.

Antigens are “targeted” by antibodies. Each antibody (immune response) 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 a tailored response.

The antibody is said to “match” the antigen in the sense that it can bind to it. In most cases, an adapted antibody can only react to and bind one specific antigen; in some instances, however, antibodies may cross-react to and bind more than one antigen. (Ibid.).

Moreover, an antigen can be a molecule that binds to Ag-specific receptors, but cannot induce an immune response in the body by itself. (3)

Antigens are usually peptides (amino acid chains), polysaccharides (chains of monosaccharides/simple sugars) or lipids. In general, saccharides and lipids (as opposed to peptides) qualify as antigens but not as immunogens since they cannot elicit an immune response on their own. Furthermore, for a peptide to induce an immune response (activation of T-cells by antigen-presenting cells) it must be a large enough size, since peptides too small will also not elicit an immune response.

The antigen may originate from within the body (“self-antigen”) or from the external environment (“non-self”).

The immune system usually does not react to self-antigens under normal homeostatic conditions due to negative selection of T cells in the thymus and is supposed to identify and attack “non-self” invaders from the outside world or modified/harmful substances present in the body under distressed conditions. (4) 

Antigen presenting cells present antigens in the form of peptides on histocompatibility molecules. The T cell/T lymphocyte (a subtype of white blood cell), of the adaptive immune system, selectively recognize the antigens. (See the Intitute’s vide on T cells attacking cancer cells) Depending on the antigen and the type of the histocompatible 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). (5)

Furthermore,  the antigen cannot elicit the immune response without the help of an immunologic adjuvant. (3)

This is how the  the adjuvant component of vaccines can play an essential role in the activation of the innate immune system. (6-7)

An immunogen is an antigen substance (or adduct) that is able to trigger a humoral (innate) or cell-mediated immune response (8) 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. (9)

At the molecular level, an antigen can be characterized by its ability to bind to an antibody’s variable Fab region. 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. (Ibid). 

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. Vaccines are examples of antigens in an immunogenic form, which are intentionally administered to a recipient to induce the memory function of adaptive immune system toward the antigens of the pathogen invading that recipient.


Antigens can be classified according to their source, each of which has its own mechanisms of action.

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.


An autoantigen is usually a normal 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 antigens should not be the target of the immune system, but in autoimmune diseases, their associated T cells are not deleted and instead attack.


Neoantigens are those that are entirely absent from the normal human genome. As compared with nonmutated self-antigens, 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. (13)

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. (Ibid).

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. (Ibid).

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

Mechanisms of Action

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. (Ibid)

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. (10-13)

Native Antigens

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. (Ibid). (14)

Antigenic escape

Antigenic escape occurs when the immune system is unable to respond to an infectious agent. This means that the response mechanisms a host’s immune system normally utilizes to recognize and eliminate a virus or pathogen is no longer able to do so. This process can occur in a number of different mechanisms of both genetic and environmental nature.(14) Such mechanisms include homologous recombination, and manipulation and resistance of the host’s immune responses. (15)

Different antigens are able to escape through a variety of mechanisms. For example, the African trypanosome parasites are able to clear the host’s antibodies, as well as resist lysis and inhibit parts of the innate immune response. (16) Another bacteria, Bordetella pertussis, is able to escape the immune response by inhibiting neutrophils and macrophages from invading the infection site early on.[4] One cause of antigenic escape is that a pathogen’s epitopes (the binding sites for immune cells) become too similar to a person’s naturally occurring MHC-1 epitopes. The immune system becomes unable to distinguish the infection from self-cells.

Antigenic escape is not only crucial for resistance of a host’s natural immune response, but also for the resistance against vaccinations. The problem of antigenic escape has greatly deterred the process of creating new vaccines. Because vaccines generally cover a small ratio of strains of one virus, the recombination of antigenic DNA that lead to diverse pathogens allows these invaders to resist even newly developed vaccinations. (18)] Some antigens may even target pathways different than those the vaccine had originally intended to target. (17) Recent research on many vaccines, including the malaria vaccine, has focused on how to anticipate this diversity and create vaccinations that can cover a broader spectrum of antigenic variation. (18)

Text under construction


Antitoxin: An antitoxin is an antibody with the ability to neutralize a specific toxin. Antitoxins are produced by certain animals, plants, and bacteria. Although they are most effective in neutralizing toxins, they can kill bacteria and other microorganisms. Antitoxins are made within organisms, but can be injected into other organisms, including humans. This procedure involves injecting an animal with a safe amount of a particular toxin. Then, the animal’s body makes the antitoxin needed to neutralize the toxin. Later, the blood is withdrawn from the animal. When the antitoxin is obtained from the blood, it is purified and injected into a human or other animal, inducing passive immunity. To prevent serum sickness, it is often best to use antitoxin generated from the same species (e.g. use human antitoxin to treat humans).

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: Polysaccharides (usually) 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.[12]

Priming:The first contact of a T or B cell with its specific antigen is called priming and causes differentiation into effector T or B cells (cytotoxic, cytokine, antibody).Priming of naïve T cells requires dendritic cell antigen presentation. Priming of naive CD8 T cells generates cytotoxic T cells  capable of directly killing pathogen-infected cells. CD4 cells develop into a diverse array of effector cell types depending on the nature of the signals they receive during priming. CD4 effector activity can include cytotoxicity, but more frequently it involves the secretion of a set of cytokines that directs the target cell to make a particular response. This activation of naive T cell is controlled by a variety of signals.

Polyclonal B cell response is a natural mode of immune response exhibited by the adaptive immune systemof mammals. It ensures that a single antigen is recognized and attacked through its overlapping parts, called epitopes, by multiple clones of B cell. In the course of normal immune response, parts of pathogens (e.g. bacteria) are recognized by the immune system as foreign (non-self), and eliminated or effectively neutralized to reduce their potential damage. Such a recognizable substance is called an antigen. The immune system may respond in multiple ways to an antigen; a key feature of this response is the production of antibodies by B cells (or B lymphocytes) involving an arm of the immune system known as humoral immunity. The antibodies are soluble and do not require direct cell-to-cell contact between the pathogen and the B-cell to function.

Reference and Precision Notes

  1.  harbour B, Johnson A, Lewis J, et al. (2002). “24. The Adaptive Immune System”. Molecular Biology of the Cell (4th ed.). New York: Garland Science.
  2.  US National Library of Medicine. Retrieved 2015-07-30.
  3. Gavin, AL; Hoebe, K; Duong, B; Ota, T; Martin, C; Beutler, B; Nemazee, D (22 December 2006). “Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling”. Science. 314 (5807): 1936–8. doi:10.1126/science.1135299. PMC 1868398Freely accessible. PMID 17185603.
  4. Gallucci, S; Lolkema, M; Matzinger, P (November 1999). “Natural adjuvants: endogenous activators of dendritic cells”. Nature Medicine. 5 (11): 1249–55. doi:10.1038/15200. PMID 10545990.
  5. Parham, Peter. (2009). The Immune System, 3rd Edition, pg. G:2, Garland Science, Taylor and Francis Group, LLC.
  6. Janeway CA, Jr (1 November 2013). “Pillars article: approaching the asymptote? Evolution and revolution in immunology. Cold spring harb symp quant biol. 1989. 54: 1–13”. Journal of Immunology. 191 (9): 4475–87. PMID 24141854.
  7.  Gayed, PM (June 2011). “Toward a modern synthesis of immunity: Charles A. Janeway Jr. and the immunologist’s dirty little secret”. The Yale Journal of Biology and Medicine. 84 (2): 131–8. ISSN 1551-4056. PMC 3117407Freely accessible. PMID 21698045.
  8.  Parham, Peter. (2009). The Immune System, 3rd Edition, pg. G:11, Garland Science, Taylor and Francis Group, LLC.
  9.  Kuby Immunology (6th ed.). Macmillan. 2006. p. 77. ISBN 978-1-4292-0211-4.
  10.  Strebhardt, Klaus; Ullrich, Axel (Jun 2008). “Paul Ehrlich’s magic bullet concept: 100 years of progress”. Nature Reviews Cancer. 8 (6): 473–480. doi:10.1038/nrc2394. ISSN 1474-1768. PMID 18469827.
  11.  Lindenmann, Jean (1984). “Origin of the Terms ‘Antibody’ and ‘Antigen'”. Scand. J. Immunol. 19 (4): 281–5. doi:10.1111/j.1365-3083.1984.tb00931.x. PMID 6374880. Retrieved 2008-10-31.
  12.  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 (August 2003). “Identification of Plasmodium falciparum antigens by antigenic analysis of genomic and proteomic data”. Proceedings of the National Academy of Sciences of the United States of America. 100 (17): 9952–7. doi:10.1073/pnas.1633254100. PMC 187898Freely accessible. PMID 12886016.
  13.  Schumacher, Ton N.; Schreiber, Robert D. (April 3, 2015). “Neoantigens in cancer immunotherapy”. Science. 348 (6230): 69–74. doi:10.1126/science.aaa4971. PMID 25838375.
  14. Allen, Clint; Clavijo, Paul; Waes, Carter; Chen, Zhong (2015). “Anti-Tumor Immunity in Head and Neck Cancer: Understanding the Evidence, How Tumors Escape and Immunotherapeutic Approaches”. Cancers.
  15. Hanada, Katsuhiro; Yamaoda, Yoshio (2014). “Genetic Battle between Helicobacter pylori and humans. The Mechanism Underlying Homologous Recombination in Bacteria, Which Can Infect Human Cells”. Microbes and Infection. doi:10.1016/j.micinf.2014.08.001
  16.  Cnops, Jennifer; Magez, Stefan; De Trez, Carl (2015). “Escape Mechanisms of African Trypanosomes: Why Trypanosomosis Is Keeping Us Awake”. Parasitology. 142: 417–427. doi:10.1017/s0031182014001838.
  17. Barnett, Timothy; Lim, Jin; Soderholm, Amelia; Rivera-Hernandes, Tania; West, Nicholas; Walker, Mark (2015). “Host-Pathogen Interaction During Bacterial Vaccination”. Current Opinion in Immunology. 36: 1–7. doi:10.1016/j.coi.2015.04.002.
  18. Barry, Alyssa; Arnott, Alicia (2014). “Strategies for Designing and Monitoring Malaria Vaccines Targeting Diverse Antigens”. Frontiers in Immunology. 5. doi:10.3389/fimmu.2014.00359

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