Immunology

Immunology
SystemImmune
Subdivisions
Genetic (Immunogenetics)
  • Humoral
  • Molecular
Significant diseasesRheumatoid arthritis Inflammation
Significant tests
SpecialistImmunologist

Immunology is a branch of biology and medicine[1] that covers the study of immune systems[2] in all organisms.[3] Immunology charts, measures, and contextualizes the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders (such as autoimmune diseases,[4] hypersensitivities,[5] immune deficiency,[6] and transplant rejection[7]); and the physical, chemical, and physiological characteristics of the components of the immune system in vitro,[8] in situ, and in vivo.[9] Immunology has applications in numerous disciplines of medicine, particularly in the fields of organ transplantation, oncology, rheumatology, virology, bacteriology, parasitology, psychiatry, and dermatology.

The term was coined by Russian biologist Ilya Ilyich Mechnikov,[10] who advanced studies on immunology and received the Nobel Prize for his work in 1908. He pinned small thorns into starfish larvae and noticed unusual cells surrounding the thorns. This was the active response of the body trying to maintain its integrity. It was Mechnikov who first observed the phenomenon of phagocytosis,[11] in which the body defends itself against a foreign body.

Prior to the designation of immunity,[12] from the etymological root immunis, which is Latin for "exempt", early physicians characterized organs that would later be proven as essential components of the immune system. The important lymphoid organs of the immune system are the thymus,[13] bone marrow, and chief lymphatic tissues such as spleen, tonsils, lymph vessels, lymph nodes, adenoids, and liver. However, many components of the immune system are cellular in nature, and not associated with specific organs, but rather embedded or circulating in various tissues located throughout the body. When health conditions worsen to emergency status, portions of immune system organs, including the thymus, spleen, bone marrow, lymph nodes, and other lymphatic tissues, can be surgically excised for examination while patients are still alive.

Classical immunology

Classical immunology ties in with the fields of epidemiology and medicine. It studies the relationship between the body systems, pathogens, and immunity. The earliest written mention of immunity can be traced back to the plague of Athens in 430 BCE. Thucydides noted that people who had recovered from a previous bout of the disease could nurse the sick without contracting the illness a second time.[14] Many other ancient societies have references to this phenomenon, but it was not until the 19th and 20th centuries before the concept developed into scientific theory.

The study of the molecular and cellular components that comprise the immune system, including their function and interaction, is the central science of immunology. The immune system has been divided into a more primitive innate immune system and, in vertebrates, an acquired or adaptive immune system. The latter is further divided into humoral (or antibody) and cell-mediated components.

The immune system has the capability of self and non-self-recognition.[15] An antigen is a substance that ignites the immune response. The cells involved in recognizing the antigen are Lymphocytes. Once they recognize, they secrete antibodies. Antibodies are proteins that neutralize the disease-causing microorganisms. Antibodies do not directly kill pathogens, but instead, identify antigens as targets for destruction by other immune cells such as phagocytes or NK cells.

The (antibody) response is defined as the interaction between antibodies and antigens.[16] Antibodies are specific proteins released from a certain class of immune cells known as B lymphocytes, while antigens are defined as anything that elicits the generation of antibodies (antibody generators). Immunology rests on an understanding of the properties of these two biological entities and the cellular response to both.

It is now getting clear that the immune responses contribute to the development of many common disorders not traditionally viewed as immunologic,[17] including metabolic, cardiovascular, cancer, and neurodegenerative conditions like Alzheimer’s disease. Besides, there are direct implications of the immune system in the infectious diseases (tuberculosis, malaria, hepatitis, pneumonia, dysentery, and helminth infestations) as well. Hence, research in the field of immunology is of prime importance for the advancements in the fields of modern medicine, biomedical research, and biotechnology.

Immunological research continues to become more specialized, pursuing non-classical models of immunity and functions of cells, organs and systems not previously associated with the immune system (Yemeserach 2010).

Clinical immunology

Clinical immunology is the study of diseases caused by disorders of the immune system (failure, aberrant action, and malignant growth of the cellular elements of the system). It also involves diseases of other systems, where immune reactions play a part in the pathology and clinical features.

The diseases caused by disorders of the immune system fall into two broad categories:

Other immune system disorders include various hypersensitivities (such as in asthma and other allergies) that respond inappropriately to otherwise harmless compounds.

The most well-known disease that affects the immune system itself is AIDS, an immunodeficiency characterized by the suppression of CD4+ ("helper") T cells, dendritic cells and macrophages by the Human Immunodeficiency Virus (HIV).

Clinical immunologists also study ways to prevent the immune system's attempts to destroy allografts (transplant rejection).[18]

Clinical Immunology and Allergy is usually a subspecialty of Internal Medicine or Pediatrics. Fellows in Clinical Immunology are typically exposed to many of the different aspects of the specialty and get to treat Allergic conditions, Primary Immunodeficiencies and systemic autoimmune and autoinflammatory conditions. As part of their training fellows may do additional rotations in Rheumatology, Pulmonology, Otorhinolaryngology, Dermatology and the Immunologic lab. [19]

Developmental immunology

The body’s capability to react to antigens depends on a person's age, antigen type, maternal factors and the area where the antigen is presented.[20] Neonates are said to be in a state of physiological immunodeficiency, because both their innate and adaptive immunological responses are greatly suppressed. Once born, a child’s immune system responds favorably to protein antigens while not as well to glycoproteins and polysaccharides. In fact, many of the infections acquired by neonates are caused by low virulence organisms like Staphylococcus and Pseudomonas. In neonates, opsonic activity and the ability to activate the complement cascade is very limited. For example, the mean level of C3 in a newborn is approximately 65% of that found in the adult. Phagocytic activity is also greatly impaired in newborns. This is due to lower opsonic activity, as well as diminished up-regulation of integrin and selectin receptors, which limit the ability of neutrophils to interact with adhesion molecules in the endothelium. Their monocytes are slow and have a reduced ATP production, which also limits the newborn's phagocytic activity. Although, the number of total lymphocytes is significantly higher than in adults, the cellular and humoral immunity is also impaired. Antigen-presenting cells in newborns have a reduced capability to activate T cells. Also, T cells of a newborn proliferate poorly and produce very small amounts of cytokines like IL-2, IL-4, IL-5, IL-12, and IFN-g which limits their capacity to activate the humoral response as well as the phagocitic activity of macrophage. B cells develop early during gestation but are not fully active.[21]

Artist's impression of monocytes

Maternal factors also play a role in the body’s immune response. At birth, most of the immunoglobulin present is maternal IgG. These antibodies are transferred from the placenta to the fetus using the FcRn (neonatal Fc receptor).[22] Because IgM, IgD, IgE and IgA do not cross the placenta, they are almost undetectable at birth. Some IgA is provided by breast milk. These passively-acquired antibodies can protect the newborn for up to 18 months, but their response is usually short-lived and of low affinity.[21] These antibodies can also produce a negative response. If a child is exposed to the antibody for a particular antigen before being exposed to the antigen itself then the child will produce a dampened response. Passively acquired maternal antibodies can suppress the antibody response to active immunization. Similarly, the response of T-cells to vaccination differs in children compared to adults, and vaccines that induce Th1 responses in adults do not readily elicit these same responses in neonates.[21] Between six and nine months after birth, a child’s immune system begins to respond more strongly to glycoproteins, but there is usually no marked improvement in their response to polysaccharides until they are at least one year old. This can be the reason for distinct time frames found in vaccination schedules.[23][24]

During adolescence, the human body undergoes various physical, physiological and immunological changes triggered and mediated by hormones, of which the most significant in females is 17-β-estradiol (an estrogen) and, in males, is testosterone. Estradiol usually begins to act around the age of 10 and testosterone some months later.[25] There is evidence that these steroids not only act directly on the primary and secondary sexual characteristics but also have an effect on the development and regulation of the immune system,[26] including an increased risk in developing pubescent and post-pubescent autoimmunity.[27] There is also some evidence that cell surface receptors on B cells and macrophages may detect sex hormones in the system.[28]

The female sex hormone 17-β-estradiol has been shown to regulate the level of immunological response,[29] while some male androgens such as testosterone seem to suppress the stress response to infection. Other androgens, however, such as DHEA, increase immune response.[30] As in females, the male sex hormones seem to have more control of the immune system during puberty and post-puberty than during the rest of a male's adult life.

Physical changes during puberty such as thymic involution also affect immunological response.[31]

Ecoimmunology and behavioural immunity

Ecoimmunology, or ecological immunology, explores the relationship between the immune system of an organism and its social, biotic and abiotic environment.

More recent ecoimmunological research has focused on host pathogen defences traditionally considered "non-immunological", such as pathogen avoidance, self-medication, symbiont-mediated defenses, and fecundity trade-offs.[32] Behavioural immunity, a phrase coined by Mark Schaller, specifically refers to psychological pathogen avoidance drivers, such as disgust aroused by stimuli encountered around pathogen-infected individuals, such as the smell of vomit.[33] More broadly, "behavioural" ecological immunity has been demonstrated in multiple species. For example, the Monarch butterfly often lays its eggs on certain toxic milkweed species when infected with parasites. These toxins reduce parasite growth in the offspring of the infected Monarch. However, when uninfected Monarch butterflies are forced to feed only on these toxic plants, they suffer a fitness cost as reduced lifespan relative to other uninfected Monarch butterflies.[34] This indicates that laying eggs on toxic plants is a costly behaviour in Monarchs which has probably evolved to reduce the severity of parasite infection.[32]

Symbiont-mediated defenses are also heritable across host generations, despite a non-genetic direct basis for the transmission. Aphids, for example, rely on several different symbionts for defense from key parasites, and can vertically transmit their symbionts from parent to offspring.[35] Therefore, a symbiont that successfully confers protection from a parasite is more likely to be passed to the host offspring, allowing coevolution with parasites attacking the host in a way similar to traditional immunity.

Immunotherapy

The use of immune system components or antigens to treat a disease or disorder is known as immunotherapy. Immunotherapy is most commonly used to treat allergies, autoimmune disorders such as Crohn’s disease and rheumatoid arthritis, and certain cancers. Immunotherapy is also often used in the immunosuppressed (such as HIV patients) and people suffering from other immune deficiencies. This includes regulating factors such as IL-2, IL-10, GM-CSF B, IFN-α.

Diagnostic immunology

The specificity of the bond between antibody and antigen has made the antibody an excellent tool for the detection of substances by a variety of diagnostic techniques. Antibodies specific for a desired antigen can be conjugated with an isotopic (radio) or fluorescent label or with a color-forming enzyme in order to detect it. However, the similarity between some antigens can lead to false positives and other errors in such tests by antibodies cross-reacting with antigens that are not exact matches.[36]

Cancer immunology

The study of the interaction of the immune system with cancer cells can lead to diagnostic tests and therapies with which to find and fight cancer. The immunology concerned with physiological reaction characteristic of the immune state.

Reproductive immunology

This area of the immunology is devoted to the study of immunological aspects of the reproductive process including fetus acceptance. The term has also been used by fertility clinics to address fertility problems, recurrent miscarriages, premature deliveries and dangerous complications such as pre-eclampsia.

Theoretical immunology

Immunology is strongly experimental in everyday practice but is also characterized by an ongoing theoretical attitude. Many theories have been suggested in immunology from the end of the nineteenth century up to the present time. The end of the 19th century and the beginning of the 20th century saw a battle between "cellular" and "humoral" theories of immunity. According to the cellular theory of immunity, represented in particular by Elie Metchnikoff, it was cells – more precisely, phagocytes – that were responsible for immune responses. In contrast, the humoral theory of immunity, held by Robert Koch[37] and Emil von Behring,[38] among others, stated that the active immune agents were soluble components (molecules) found in the organism's "humors" rather than its cells.[39][40][41]

In the mid-1950s, Macfarlane Burnet, inspired by a suggestion made by Niels Jerne,[42] formulated the clonal selection theory (CST) of immunity.[43] On the basis of CST, Burnet developed a theory of how an immune response is triggered according to the self/nonself distinction: "self" constituents (constituents of the body) do not trigger destructive immune responses, while "nonself" entities (e.g., pathogens, an allograft) trigger a destructive immune response.[44] The theory was later modified to reflect new discoveries regarding histocompatibility or the complex "two-signal" activation of T cells.[45] The self/nonself theory of immunity and the self/nonself vocabulary have been criticized,[41][46][47] but remain very influential.[48][49]

More recently, several theoretical frameworks have been suggested in immunology, including "autopoietic" views,[50] "cognitive immune" views,[51] the "danger model" (or "danger theory"),[46] and the "discontinuity" theory.[52][53] The danger model, suggested by Polly Matzinger and colleagues, has been very influential, arousing many comments and discussions.[54][55][56][57]

See also

References

  1. ↑ Fossen C. "What is Biology?". www.ntnu.edu. Retrieved 2018-07-25.
  2. ↑ Villani AC, Sarkizova S, Hacohen N (April 2018). "Systems Immunology: Learning the Rules of the Immune System". Annual Review of Immunology. 36 (1): 813–42. doi:10.1146/annurev-immunol-042617-053035. PMC 6597491. PMID 29677477.
  3. ↑ Janeway's Immunobiology textbook Searchable free online version at the National Center for Biotechnology Information
  4. ↑ "Autoimmune Diseases: Types, Symptoms, Causes and More". Healthline. Retrieved 2018-07-25.
  5. ↑ "Hypersensitivities | Microbiology". courses.lumenlearning.com. Retrieved 2018-07-25.
  6. ↑ "Specific Disease Types | Immune Deficiency Foundation". primaryimmune.org. Retrieved 2018-07-25.
  7. ↑ "Transplant rejection: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2018-07-25.
  8. ↑ Pierce CW, Solliday SM, Asofsky R (March 1972). "Immune responses in vitro. IV. Suppression of primary M, G, and A plaque-forming cell responses in mouse spleen cell cultures by class-specific antibody to mouse immunoglobulins". The Journal of Experimental Medicine. 135 (3): 675–97. doi:10.1084/jem.135.3.675. PMC 2139142. PMID 4536706.
  9. ↑ Miyahara S, Yokomuro K, Takahashi H, Kimura Y (November 1983). "Regeneration and the immune system. I. In vitro and in vivo activation of lymphocytes by liver regeneration and the role of Kupffer cells in stimulation". European Journal of Immunology. 13 (11): 878–83. doi:10.1002/eji.1830131104. PMID 6227489. S2CID 22400759.
  10. ↑ "Ilya Ilyich Mechnikov (Elie Metchnikoff) (1845–1916)". The Embryo Project. Arizona State University.
  11. ↑ "Phagocytosis: Definition, Process, & Examples". Encyclopedia Britannica. Retrieved 2018-07-25.
  12. ↑ "Definition of immunity in English". Oxford Dictionaries.
  13. ↑ Lee DK, Hakim FT, Gress RE (October 2010). "The thymus and the immune system: layered levels of control". Journal of Thoracic Oncology. 5 (10 Suppl 4): S273–76. doi:10.1097/JTO.0b013e3181f20474. PMC 2951290. PMID 20859118.
  14. ↑ Gherardi, E (2007-01-02). "The Concept of Immunity. History and Applications". Immunology Course Medical School, University of Pavia. Archived from the original on 2007-01-02. Retrieved 2018-07-27.
  15. ↑ Rich, Robert R.; Chaplin, David D. (2019). "The Human Immune Response". Clinical Immunology. Principles and Practice (5th ed.). pp. 3–17.e1. doi:10.1016/B978-0-7020-6896-6.00001-6. ISBN 9780702068966. S2CID 88829315.
  16. ↑ Janeway CA, Travers P, Walport M, Shlomchik MJ (2001). "Chapter 9: The Humoral Immune Response". Immunobiology the immune system health & disease (5th ed.). New York: Garland. ISBN 978-0-8153-3642-6.
  17. ↑ "What is immunology? | British Society for Immunology". www.immunology.org. Retrieved 2018-07-21.
  18. ↑ "Transplant rejection: T-helper cell paradigm | British Society for Immunology". www.immunology.org. Retrieved 2019-04-23.
  19. ↑ https://www.royalcollege.ca/rcsite/documents/ibd/clinical-immunology-and-allergy-competencies-e.pdf
  20. ↑ Goldsby RA, Kindt TK (2003). Immunology (5th ed.). San Francisco: W.H. Freeman. ISBN 978-0-7167-4947-9.
  21. 1 2 3 Jaspan HB, Lawn SD, Safrit JT, Bekker LG (February 2006). "The maturing immune system: implications for development and testing HIV-1 vaccines for children and adolescents". AIDS. 20 (4): 483–94. doi:10.1097/01.aids.0000210602.40267.60. PMID 16470112. S2CID 20277590.
  22. ↑ "Neonatal Immunology | British Society for Immunology".
  23. ↑ Glezen WP (December 2001). "Maternal vaccines". Primary Care. 28 (4): 791–806, vi–vii. doi:10.1016/S0095-4543(05)70041-5. PMID 11739030.
  24. ↑ Holt PG, Macaubas C, Cooper D, Nelson DJ, McWilliam AS (1997). Th-1/Th-2 switch regulation in immune responses to inhaled antigens. Role of dendritic cells in the aetiology of allergic respiratory disease. Advances in Experimental Medicine and Biology. Vol. 417. pp. 301–06. doi:10.1007/978-1-4757-9966-8_49. ISBN 978-1-4757-9968-2. PMID 9286377.
  25. ↑ Sizonenko PC, Paunier L (November 1975). "Hormonal changes in puberty III: Correlation of plasma dehydroepiandrosterone, testosterone, FSH, and LH with stages of puberty and bone age in normal boys and girls and in patients with Addison's disease or hypogonadism or with premature or late adrenarche". The Journal of Clinical Endocrinology and Metabolism. 41 (5): 894–904. doi:10.1210/jcem-41-5-894. PMID 127002.
  26. ↑ Verthelyi D (June 2001). "Sex hormones as immunomodulators in health and disease". International Immunopharmacology. 1 (6): 983–93. doi:10.1016/S1567-5769(01)00044-3. PMID 11407317.
  27. ↑ Stimson WH (September 1988). "Oestrogen and human T lymphocytes: presence of specific receptors in the T-suppressor/cytotoxic subset". Scandinavian Journal of Immunology. 28 (3): 345–50. doi:10.1111/j.1365-3083.1988.tb01459.x. PMID 2973658. S2CID 38920551.
  28. ↑ Benten WP, Stephan C, Wunderlich F (June 2002). "B cells express intracellular but not surface receptors for testosterone and estradiol". Steroids. 67 (7): 647–54. doi:10.1016/S0039-128X(02)00013-2. PMID 11996938. S2CID 1056135.
  29. ↑ Beagley KW, Gockel CM (August 2003). "Regulation of innate and adaptive immunity by the female sex hormones estradiol and progesterone". FEMS Immunology and Medical Microbiology. 38 (1): 13–22. doi:10.1016/S0928-8244(03)00202-5. PMID 12900050.
  30. ↑ Kanda N, Tamaki K (February 1999). "Estrogen enhances immunoglobulin production by human PBMCs". The Journal of Allergy and Clinical Immunology. 103 (2 Pt 1): 282–88. doi:10.1016/S0091-6749(99)70503-8. PMID 9949320.
  31. ↑ McFarland RD, Douek DC, Koup RA, Picker LJ (April 2000). "Identification of a human recent thymic emigrant phenotype". Proceedings of the National Academy of Sciences of the United States of America. 97 (8): 4215–20. Bibcode:2000PNAS...97.4215M. doi:10.1073/pnas.070061597. PMC 18202. PMID 10737767.
  32. 1 2 Parker BJ, Barribeau SM, Laughton AM, de Roode JC, Gerardo NM (May 2011). "Non-immunological defense in an evolutionary framework". Trends in Ecology & Evolution. 26 (5): 242–48. doi:10.1016/j.tree.2011.02.005. PMID 21435735.
  33. ↑ "Commentaries on Evolutionary Foundations of Cultural Variation: Evoked Culture and Mate Preferences". Psychological Inquiry. 17 (2): 96–137. 2006. doi:10.1207/s15327965pli1702_2. S2CID 219729311.
  34. ↑ Lefèvre T, Oliver L, Hunter MD, De Roode JC (December 2010). "Evidence for trans-generational medication in nature" (PDF). Ecology Letters. 13 (12): 1485–93. doi:10.1111/j.1461-0248.2010.01537.x. hdl:2027.42/79381. PMID 21040353.
  35. ↑ Koga R, Meng XY, Tsuchida T, Fukatsu T (May 2012). "Cellular mechanism for selective vertical transmission of an obligate insect symbiont at the bacteriocyte-embryo interface". Proceedings of the National Academy of Sciences of the United States of America. 109 (20): E1230–37. doi:10.1073/pnas.1119212109. PMC 3356617. PMID 22517738.
  36. ↑ Miller JJ, Valdes R (February 1991). "Approaches to minimizing interference by cross-reacting molecules in immunoassays". Clinical Chemistry. 37 (2): 144–53. doi:10.1093/clinchem/37.2.144. PMID 1993317.
  37. ↑ "Robert Koch | German bacteriologist". Encyclopedia Britannica. Retrieved 2018-07-25.
  38. ↑ "Emil von Behring: The Founder of Serum Therapy". www.nobelprize.org. Retrieved 2018-07-25.
  39. ↑ Silverstein AM (1989). A history of immunology. San Diego: Academic Press. ISBN 978-0-12-643770-6. OCLC 909269335.
  40. ↑ Tauber AI, Chernyak L (1991). Metchnikoff and the Origins of Immunology. New York: Oxford University Press. ISBN 978-0-19-506447-6. OCLC 22906314.
  41. 1 2 Tauber AI (1994). "The Immune Self: Theory or Metaphor?". Immunology Today. Cambridge: Cambridge University Press. 15 (3): 134–6. doi:10.1016/0167-5699(94)90157-0. OCLC 4930079483. PMID 8172646.
  42. ↑ Jerne NK (November 1955). "The natural-selection theory of antibody selection". Proceedings of the National Academy of Sciences of the United States of America. 41 (11): 849–57. Bibcode:1955PNAS...41..849J. doi:10.1073/pnas.41.11.849. PMC 534292. PMID 16589759.
  43. ↑ Burnet FM (1959). The Clonal Selection Theory of Acquired Immunity. Cambridge: Cambridge University Press.
  44. ↑ Burnet FM (1969). Cellular Immunology: Self and Notself. Cambridge: Cambridge University Press.
  45. ↑ Bretscher P, Cohn M (September 1970). "A theory of self-nonself discrimination". Science. 169 (3950): 1042–49. Bibcode:1970Sci...169.1042B. doi:10.1126/science.169.3950.1042. PMID 4194660. S2CID 26916828.
  46. 1 2 Matzinger P (April 2002). "The danger model: a renewed sense of self" (PDF). Science. 296 (5566): 301–05. Bibcode:2002Sci...296..301M. CiteSeerX 10.1.1.127.558. doi:10.1126/science.1071059. PMID 11951032. S2CID 13615808.
  47. ↑ Pradeu T, Vitanza E (2012). The limits of the self: immunology and biological identity. Oxford: Oxford University Press. ISBN 978-0-19-977528-6. OCLC 793571104.
  48. ↑ Langman RE, Cohn M (June 2000). "A minimal model for the self-nonself discrimination: a return to the basics". Seminars in Immunology. 12 (3): 189–95, discussion 257–344. doi:10.1006/smim.2000.0231. PMID 10910739.
  49. ↑ Clark WR (2008). In defense of self: how the immune system really works. New York: Oxford University Press. ISBN 978-0-19-533663-4. OCLC 917294223.
  50. ↑ Coutinho A, Forni L, Holmberg D, Ivars F, Vaz N (1984). "From an antigen-centered, clonal perspective of immune responses to an organism-centered network perspective of autonomous reactivity of self-referential immune systems". Immunological Reviews. 79: 151–68. doi:10.1111/j.1600-065x.1984.tb00492.x. PMID 6235170. S2CID 46481630.
  51. ↑ Irun C (2000). Tending Adam's garden: Evolving the cognitive immune self. San Diego: Academic Press.
  52. ↑ Pradeu T, Carosella ED (November 2006). "On the definition of a criterion of immunogenicity". Proceedings of the National Academy of Sciences of the United States of America. 103 (47): 17858–61. Bibcode:2006PNAS..10317858P. doi:10.1073/pnas.0608683103. PMC 1693837. PMID 17101995.
  53. ↑ Pradeu T, Jaeger S, Vivier E (October 2013). "The speed of change: towards a discontinuity theory of immunity?" (PDF). Nature Reviews. Immunology. 13 (10): 764–69. doi:10.1038/nri3521. PMID 23995627. S2CID 11366176.
  54. ↑ Janeway CA, Goodnow CC, Medzhitov R (May 1996). "Danger – pathogen on the premises! Immunological tolerance". Current Biology. 6 (5): 519–22. doi:10.1016/S0960-9822(02)00531-6. PMID 8805259. S2CID 14347980.
  55. ↑ Vance RE (2000). "Cutting edge commentary: a Copernican revolution? Doubts about the danger theory". Journal of Immunology. 165 (4): 1725–28. doi:10.4049/jimmunol.165.4.1725. PMID 10925247.
  56. ↑ Matzinger P (May 2012). "The evolution of the danger theory. Interview by Lauren Constable, Commissioning Editor". Expert Review of Clinical Immunology. 8 (4): 311–17. doi:10.1586/eci.12.21. PMC 4803042. PMID 22607177.
  57. ↑ Pradeu T, Cooper EL (2012). "The danger theory: 20 years later". Frontiers in Immunology. 3: 287. doi:10.3389/fimmu.2012.00287. PMC 3443751. PMID 23060876.
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