danger model

The first major immunologic model was the Self/Non-self Model proposed by Macfarlane Burnet and Frank Fenner in 1949 with later refinement by Burnet.{{cite book | vauthors = Burnet FM, Fenner F |title=The Production of Antibodies |edition=2nd |publisher=Macmillan |location=Melbourne |date=1949}}{{cite book | vauthors = Burnet FM |title=Cellular Immunology: Self and Notself |publisher=Cambridge University Press |location=Cambridge |date=1969}} It theorizes that the immune system distinguishes between self, which is tolerated, and non-self, which is attacked and destroyed. According to this theory, the chief cell of the immune system is the B cell, activated by recognizing non-self structures. Later research showed that B cell activation is reliant on CD4+ T helper cells and a co-stimulatory signal from an antigen-presenting cell (APC). Because APCs are not antigen-specific, capable of processing self structures, Charles Janeway proposed the Infectious Non-self Model in 1989.{{cite journal | vauthors = Janeway CA | title = Approaching the asymptote? Evolution and revolution in immunology | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 54 Pt 1 | issue = 1 | pages = 1–13 | date = 1989-01-01 | pmid = 2700931 | doi = 10.1101/sqb.1989.054.01.003 }} Janeway's theory involved APCs being activated by pattern recognition receptors (PRRs) that recognize evolutionarily conserved pathogen-associated molecular patterns (PAMPs) as infectious non-self, whereas PRRs are not activated by non-infectious self. However, neither of these models are sufficient to explain non-cytopathic viral infections, graft rejection, or anti-tumor immunity.{{cite journal | vauthors = Matzinger P | title = The danger model: a renewed sense of self | journal = Science | volume = 296 | issue = 5566 | pages = 301–305 | date = April 2002 | pmid = 11951032 | doi = 10.1126/science.1071059 | s2cid = 13615808 | citeseerx = 10.1.1.127.558 | bibcode = 2002Sci...296..301M }}

In 1994, Polly Matzinger formulated the danger model, theorizing that the immune system identifies threats to initiate an immune response based on the presence of pathogens and/or alarm signals from cells under stress.{{cite journal | vauthors = Matzinger P | title = Tolerance, danger, and the extended family | journal = Annual Review of Immunology | volume = 12 | issue = 1 | pages = 991–1045 | date = 1994 | pmid = 8011301 | doi = 10.1146/annurev.iy.12.040194.005015 }}{{cite journal | vauthors = Hallenbeck J, Del Zoppo G, Jacobs T, Hakim A, Goldman S, Utz U, Hasan A | title = Immunomodulation strategies for preventing vascular disease of the brain and heart: workshop summary | journal = Stroke | volume = 37 | issue = 12 | pages = 3035–3042 | date = December 2006 | pmid = 17082471 | pmc = 1853372 | doi = 10.1161/01.STR.0000248836.82538.ee }} When injured or stressed, tissues typically undergo non-silent types of cell death, such as necrosis or pyroptosis, releasing danger signals like DNA, RNA, heat shock proteins (Hsps), hyaluronic acid, serum amyloid A protein, ATP, uric acid, and cytokines like interferon-α, interleukin-1β, and CD40L for detection by dendritic cells.{{cite journal | vauthors = Jounai N, Kobiyama K, Takeshita F, Ishii KJ | title = Recognition of damage-associated molecular patterns related to nucleic acids during inflammation and vaccination | journal = Frontiers in Cellular and Infection Microbiology | volume = 2 | pages = 168 | year = 2012 | pmid = 23316484 | pmc = 3539075 | doi = 10.3389/fcimb.2012.00168 | doi-access = free }} In comparison, neoplastic tumors do not induce significant immune responses because controlled apoptosis degrades most danger signals, preventing the detection and destruction of malignant cells.{{cite journal | vauthors = Pradeu T, Cooper EL | title = The danger theory: 20 years later | journal = Frontiers in Immunology | volume = 3 | pages = 287 | date = 2012-01-01 | pmid = 23060876 | pmc = 3443751 | doi = 10.3389/fimmu.2012.00287 | doi-access = free }}

Matzinger's work emphasizes that bodily tissues are the drivers of immunity, providing alarm signals on the location and extent of damage to minimize collateral damage.{{cite journal | vauthors = Matzinger P | title = Friendly and dangerous signals: is the tissue in control? | journal = Nature Immunology | volume = 8 | issue = 1 | pages = 11–13 | date = January 2007 | pmid = 17179963 | doi = 10.1038/ni0107-11 | s2cid = 6448542 | url = https://zenodo.org/record/1233431 }}{{cite journal | vauthors = Matzinger P, Kamala T | title = Tissue-based class control: the other side of tolerance | journal = Nature Reviews. Immunology | volume = 11 | issue = 3 | pages = 221–230 | date = March 2011 | pmid = 21350581 | doi = 10.1038/nri2940 | s2cid = 10809131 | url = https://zenodo.org/record/1233542 }} The adaptive immune system relies on the innate immune system using its antigen-presenting cells to activate B and T lymphocytes for specific antibodies, exemplified by low dendritic cell counts resulting in common variable immunodeficiency (CVID).{{cite journal | vauthors = Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Galicier L, Lepelletier Y, Webster D, Lévy Y, Eibl MM, Oksenhendler E, Hermine O, Kaveri SV | display-authors = 6 | title = Common variable immunodeficiency is associated with defective functions of dendritic cells | journal = Blood | volume = 104 | issue = 8 | pages = 2441–2443 | date = October 2004 | pmid = 15226176 | doi = 10.1182/blood-2004-04-1325 | doi-access = free }} For example, gut cells secrete transforming growth factor beta (TGF-β) during bacterial invasions to stimulate B cell production of Immunoglobulin A (IgA).{{cite journal | vauthors = Bauché D, Marie JC | title = Transforming growth factor β: a master regulator of the gut microbiota and immune cell interactions | journal = Clinical & Translational Immunology | volume = 6 | issue = 4 | pages = e136 | date = April 2017 | pmid = 28523126 | pmc = 5418590 | doi = 10.1038/cti.2017.9 }} Similarly, 30-40% of the liver's T cells are Type I Natural Killer T (NTK) cells, providing Interleukin 4 (IL-4) for an organ-specific response of driving naïve CD4+ T cells to become Type 2 Helper T cells, as opposed to Type 1.{{cite journal | vauthors = Gao B, Jeong WI, Tian Z | title = Liver: An organ with predominant innate immunity | journal = Hepatology | volume = 47 | issue = 2 | pages = 729–736 | date = February 2008 | pmid = 18167066 | doi = 10.1002/hep.22034 | s2cid = 5441697 | doi-access = free }}{{cite journal | vauthors = Yoshimoto T | title = The Hunt for the Source of Primary Interleukin-4: How We Discovered That Natural Killer T Cells and Basophils Determine T Helper Type 2 Cell Differentiation In Vivo | journal = Frontiers in Immunology | volume = 9 | pages = 716 | date = 2018 | pmid = 29740428 | doi = 10.3389/fimmu.2018.00716 | pmc = 5924770 | doi-access = free }}

{{See also|Damage-associated molecular pattern}}

Whereas the danger model proposes non-silent cell death releasing intracellular contents and/or expressing unique signalling proteins to stimulate an immune response, the damage-associated molecular pattern (DAMP) model theorizes that the immune system responds to exposed hydrophobic regions of biological molecules. In 2004, Seung-Yong Seong and Matzinger argued that as cellular damage causes denaturing and protein misfolding, exposed hydrophobic regions aggregate into clumps for improved binding to immune receptors.{{cite journal |vauthors=Seong S, Matzinger P |title=Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses|journal=Nature Reviews Immunology |volume=4 |issue= 6|pages=469–478|year=2004 |pmid=15173835 |doi=10.1038/nri1372|s2cid=13336660}}

Pattern Recognition Receptors (PRRs) are a family of surface receptors on antigen-presenting cells that includes toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors,{{cite journal |vauthors=Tanti JF, Ceppo F, Jager J, Berthou F |year=2012 |title=Implication of inflammatory signaling pathways in obesity-induced insulin resistance |journal=Front Endocrinol (Lausanne) |volume=3 |pages=181 |doi=10.3389/fendo.2012.00181 |pmc=3539134 |pmid=23316186 |doi-access=free}} retinoic acid inducible gene-I (RIG-I)-like receptors{{cite journal |vauthors=Beckham SA, Brouwer J, Roth A, Wang D, etal |year=2012 |title=Conformational rearrangements og RIG-I receptor on formation of a multiprotein: dsRNA assembly |journal=Nucleic Acids Res. |volume=41 |issue=5 |pages=3436–45 |doi=10.1093/nar/gks1477 |pmc=3597671 |pmid=23325848}} and C-type lectin-like receptors (CLRs).{{cite journal |vauthors=Kuroki K, Furukawa A, Maenaka K |year=2012 |title=Molecular recognition of paired receptors in the immune system |journal=Front Microbiol |volume=3 |pages=429 |doi=10.3389/fmicb.2012.00429 |pmc=3533184 |pmid=23293633 |doi-access=free}} They recognize alarmins, a category that includes both DAMPs and PAMPs, to process their antigenic regions for presentation to T helper cells.

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Category:Immunology theories