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==History of immunologic models==
==History of immunologic models==


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.<ref>{{cite book |author=Burnet FM|author2=Fenner F |title=The Production of Antibodies |edition=2nd |publisher=Macmillan |location=Melbourne |date=1949}}</ref><ref>{{cite book |author=Burnet FM |title=Cellular Immunology: Self and Notself |publisher=Cambridge University Press |location=Cambridge |date=1969}}</ref> 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 (biology)|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 cell|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.<ref>{{Cite journal|last=Janeway|first=C. A.|date=1989-01-01|title=Approaching the asymptote? Evolution and revolution in immunology|journal=Cold Spring Harbor Symposia on Quantitative Biology|volume=54|pages=1–13|issn=0091-7451|pmid=2700931|doi=10.1101/sqb.1989.054.01.003|issue=1}}</ref> Janeway's theory involved APCs being activated by [[pattern recognition receptor]]s (PRRs) that recognize evolutionarily conserved [[pathogen-associated molecular pattern]]s (PAMPs) as infectious non-self, whereas PRRs are not activated by non-infectious self. However, neither of these models are sufficient to explain [[cytopathic effect|non-cytopathic]] [[virus|viral]] infections, [[graft rejection]], or [[cancer immunology|anti-tumor immunity]].<ref name=matzinger>{{cite journal |author=Matzinger P|title=The danger model: a renewed sense of self|journal=Science |volume=296| issue=5566|pages=301–5|year=2002 |pmid=11951032 |doi=10.1126/science.1071059|bibcode=2002Sci...296..301M |citeseerx=10.1.1.127.558|s2cid=13615808}}</ref>
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.<ref>{{cite book |author=Burnet FM|author2=Fenner F |title=The Production of Antibodies |edition=2nd |publisher=Macmillan |location=Melbourne |date=1949}}</ref><ref>{{cite book |author=Burnet FM |title=Cellular Immunology: Self and Notself |publisher=Cambridge University Press |location=Cambridge |date=1969}}</ref> 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 cell|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.<ref>{{Cite journal|last=Janeway|first=C. A.|date=1989-01-01|title=Approaching the asymptote? Evolution and revolution in immunology|journal=Cold Spring Harbor Symposia on Quantitative Biology|volume=54|pages=1–13|issn=0091-7451|pmid=2700931|doi=10.1101/sqb.1989.054.01.003|issue=1}}</ref> Janeway's theory involved APCs being activated by [[pattern recognition receptor]]s (PRRs) that recognize evolutionarily conserved [[pathogen-associated molecular pattern]]s (PAMPs) as infectious non-self, whereas PRRs are not activated by non-infectious self. However, neither of these models are sufficient to explain [[cytopathic effect|non-cytopathic]] [[virus|viral]] infections, [[graft rejection]], or [[cancer immunology|anti-tumor immunity]].<ref name=matzinger>{{cite journal |author=Matzinger P|title=The danger model: a renewed sense of self|journal=Science |volume=296| issue=5566|pages=301–5|year=2002 |pmid=11951032 |doi=10.1126/science.1071059|bibcode=2002Sci...296..301M |citeseerx=10.1.1.127.558|s2cid=13615808}}</ref>


==Danger model==
==Danger model==


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.<ref>{{Cite journal|last=Matzinger|first=P|date=1994|title=Tolerance, Danger, and the Extended Family|journal=Annual Review of Immunology|language=en|volume=12|issue=1|pages=991–1045|doi=10.1146/annurev.iy.12.040194.005015|pmid=8011301}}</ref><ref name=hallenbeck>{{cite journal |vauthors=Hallenbeck J, Del Zoppo G, Jacobs T, Hakim A, etal |title=Immunomodulation strategies for preventing vascular disease of the brain and heart: workshop summary |journal=Stroke |volume=37| issue=12|pages=3035–42|year=2006 |pmid=17082471 |doi=10.1161/01.STR.0000248836.82538.ee |pmc=1853372}}</ref> 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 protein]]s (Hsps), [[hyaluronic acid]], [[serum amyloid A]] protein, [[Adenosine triphosphate|ATP]], [[uric acid]], and [[cytokine]]s like [[interferon-α]], [[IL1B|interleukin-1β]], and [[CD40L]] for detection by [[Dendritic cell|dendritic cells]].<ref name="matzinger" /><ref name="hallenbeck" /><ref name="jounai">{{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=Front Cell Infect Microbiol |volume=2|pages=168|year=2012|pmid=23316484|doi=10.3389/fcimb.2012.00168 |pmc=3539075|doi-access=free}}</ref> 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.<ref>{{Cite journal|last1=Pradeu|first1=Thomas|last2=Cooper|first2=Edwin L.|date=2012-01-01|title=The danger theory: 20 years later|journal=Frontiers in Immunology|volume=3|pages=287|doi=10.3389/fimmu.2012.00287|issn=1664-3224|pmc=3443751|pmid=23060876|doi-access=free}}</ref>
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.<ref>{{Cite journal|last=Matzinger|first=P|date=1994|title=Tolerance, Danger, and the Extended Family|journal=Annual Review of Immunology|language=en|volume=12|issue=1|pages=991–1045|doi=10.1146/annurev.iy.12.040194.005015|pmid=8011301}}</ref><ref name=hallenbeck>{{cite journal |vauthors=Hallenbeck J, Del Zoppo G, Jacobs T, Hakim A, etal |title=Immunomodulation strategies for preventing vascular disease of the brain and heart: workshop summary |journal=Stroke |volume=37| issue=12|pages=3035–42|year=2006 |pmid=17082471 |doi=10.1161/01.STR.0000248836.82538.ee |pmc=1853372}}</ref> 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 protein]]s (Hsps), [[hyaluronic acid]], [[serum amyloid A]] protein, [[Adenosine triphosphate|ATP]], [[uric acid]], and [[cytokine]]s like [[interferon-α]], [[IL1B|interleukin-1β]], and [[CD40L]] for detection by [[Dendritic cell|dendritic cells]].<ref name="matzinger" /><ref name="hallenbeck" /><ref name="jounai">{{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=Front Cell Infect Microbiol |volume=2|pages=168|year=2012|pmid=23316484|doi=10.3389/fcimb.2012.00168 |pmc=3539075|doi-access=free}}</ref> 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.<ref>{{Cite journal|last1=Pradeu|first1=Thomas|last2=Cooper|first2=Edwin L.|date=2012-01-01|title=The danger theory: 20 years later|journal=Frontiers in Immunology|volume=3|pages=287|doi=10.3389/fimmu.2012.00287|issn=1664-3224|pmc=3443751|pmid=23060876|doi-access=free}}</ref>

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.<ref>{{Cite journal |last=Matzinger |first=P |date=2007 |title=Friendly and dangerous signals: is the tissue in control? |url=https://zenodo.org/record/1233431 |journal=Nature Immunology |language=en |volume=8 |issue=1 |pages=11–13 |doi=10.1038/ni0107-11 |pmid=17179963 |s2cid=6448542}}</ref><ref>{{Cite journal |vauthors=Tirumlai K, Matzinger P |date=2011 |title=Tissue-based class control: the other side of tolerance |url=https://zenodo.org/record/1233542 |journal=Nature Reviews Immunology |language=en |volume=11 |issue=3 |pages=221–30 |doi=10.1038/nri2940 |pmid=21350581 |s2cid=10809131}}</ref> 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|common variable immunodeficiency (CVID)]].<ref name="bayry">{{cite journal |vauthors=Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Galicier L, etal |year=2004 |title=Common variable immunodeficiency is associated with defective functions of dendritic cells |journal=Blood |volume=104 |issue=8 |pages=2441–3 |doi=10.1182/blood-2004-04-1325 |pmid=15226176}}</ref> For example, gut cells secrete [[Transforming growth factor beta|transforming growth factor beta (TGF-β)]] during bacterial invasions to stimulate B cell production of [[Immunoglobulin A|Immunoglobulin A (IgA)]].<ref>{{Cite journal |last=Bauché |first=David |last2=Marie |first2=Julien C |date=2017-04-07 |title=Transforming growth factor β: a master regulator of the gut microbiota and immune cell interactions |url=http://doi.wiley.com/10.1038/cti.2017.9 |journal=Clinical & Translational Immunology |volume=6 |issue=4 |pages=e136 |doi=10.1038/cti.2017.9 |issn=2050-0068 |pmc=PMC5418590 |pmid=28523126}}</ref> Similarly, 30-40% of the liver's T cells are [[Natural killer T cell|Type I Natural Killer T (NTK)]] cells, providing [[Interleukin 4|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.<ref>{{Cite journal |last=Gao |first=Bin |last2=Jeong |first2=Won-Il |last3=Tian |first3=Zhigang |date=2007-12-31 |title=Liver: An organ with predominant innate immunity |url=https://onlinelibrary.wiley.com/doi/10.1002/hep.22034 |journal=Hepatology |language=en |volume=47 |issue=2 |pages=729–736 |doi=10.1002/hep.22034}}</ref><ref>{{Cite journal |last=Yoshimoto |first=Tomohiro |date=2018 |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 |url=https://www.frontiersin.org/articles/10.3389/fimmu.2018.00716 |journal=Frontiers in Immunology |volume=9 |doi=10.3389/fimmu.2018.00716/full |issn=1664-3224}}</ref>


==Damage-associated molecular pattern (DAMP) model==
==Damage-associated molecular pattern (DAMP) model==
{{See also|Damage-associated molecular pattern}}
{{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 their initial 2004 proposal, [[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.<ref>{{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}}</ref>
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.<ref>{{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}}</ref>


== Pattern Recognition Receptors (PRRs) ==
== Pattern Recognition Receptors (PRRs) ==


[[pattern recognition receptor|Pattern Recognition Receptor]]s (PRRs) are a family of surface receptors on [[antigen-presenting cell|antigen-presenting cells]] that includes [[Toll-like receptor|toll-like receptors (TLRs)]], [[NOD-like receptor|nucleotide oligomerization domain (NOD)-like receptors]],<ref name="tanti">{{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}}</ref> [[RIG-I-like receptor|retinoic acid inducible gene-I (RIG-I)-like receptor]]s<ref name="beckham">{{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}}</ref> and [[C-type lectin-like receptor|C-type lectin-like receptors (CLRs)]].<ref name="kuroki">{{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}}</ref> They recognize alarmins, a category that includes both DAMPs and PAMPs, processing their [[Antigen|antigenic regions]] for presentation to [[T helper cell|Helper T cells]].<ref name=hallenbeck />
Pattern Recognition Receptors (PRRs) are a family of surface receptors on antigen-presenting cells that includes [[Toll-like receptor|toll-like receptors (TLRs)]], [[NOD-like receptor|nucleotide oligomerization domain (NOD)-like receptors]],<ref name="tanti">{{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}}</ref> [[RIG-I-like receptor|retinoic acid inducible gene-I (RIG-I)-like receptor]]s<ref name="beckham">{{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}}</ref> and [[C-type lectin-like receptor|C-type lectin-like receptors (CLRs)]].<ref name="kuroki">{{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}}</ref> They recognize alarmins, a category that includes both DAMPs and PAMPs, to process their [[Antigen|antigenic regions]] for presentation to T helper cells.<ref name=hallenbeck />
==Cellular control of immunity==

The danger model is a new perspective on [[adaptive immune system|adaptive]] and [[innate immune system|innate immunity]]. In the past innate immunity was suggested to be a minor part of the [[immune system]] — in contrast, adaptive immunity was thought to be the most important and effective part of the immune system. According to the danger model there is no adaptive immunity without the innate part. This is because [[antigen-presenting cell|APC]]s like [[dendritic cell]]s are essential for activation of [[T lymphocyte]]s and [[B lymphocyte]]s, which after activation produce specific [[antibody|antibodies]]. In the case of dendritic cell deficiency, like in [[common variable immunodeficiency]] (CVID), patients suffer from [[hypogammaglobulinemia]] and from primary or secondary defects in T-cell functions.<ref name=matzinger /><ref name=bayry>{{cite journal |vauthors=Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Galicier L, etal |title=Common variable immunodeficiency is associated with defective functions of dendritic cells |journal=Blood |volume=104| issue=8|pages=2441–3|year=2004 |pmid=15226176 |doi=10.1182/blood-2004-04-1325}}</ref>

According to Matzinger,<ref>{{Cite journal|last=Matzinger|first=P|date=2007|title=Friendly and dangerous signals: is the tissue in control?|journal= Nature Immunology|language=en|volume=8|issue=1|pages=11–13|doi=10.1038/ni0107-11|pmid=17179963|s2cid=6448542|url=https://zenodo.org/record/1233431}}</ref><ref>{{Cite journal|vauthors=Tirumlai K, Matzinger P| date=2011|title=Tissue-based class control: the other side of tolerance|journal=Nature Reviews Immunology|language=en|volume=11|issue=3|pages=221–30|doi=10.1038/nri2940| pmid=21350581| s2cid=10809131| url=https://zenodo.org/record/1233542}}</ref> even more important players in immunity are the normal bodily tissues. Rather than passive receivers of immunity, they are key controllers. They not only initiate immune responses by sending out alarm signals, they also influence the type of response that ensues to ensure that the response is effective in that environment and that it doesn't do much bystander damage. Some types of immune responses can destroy a tissue, so tissues communicate with cells of the immune system to ensure that these destructive types of response are only used in extreme circumstances. They do this by secreting certain cytokines (the gut and the eye secrete TGFbeta, for example, which instructs B cells to make IgA, the appropriate antibody for these organs); or by inviting certain tissue-resident lymphocytes to take up residence (e.g 40% of T cells residing in the liver are NK1 T cells, a specialized set that secretes the cytokine, IL-4, which tends to suppress harmful Th1 responses).

==References==
==References==
{{reflist|2}}
{{reflist|2}}

Revision as of 17:47, 9 January 2023

Function of T helper cells: Antigen-presenting cells (APCs) present antigens on their Class II MHC molecules (MHC2). Helper T cells recognize these by expressing the CD4 co-receptor. The activation of a resting helper T cell causes it to release cytokines and other signals (green arrows) that stimulate the activity of macrophages, killer T cells, and B cells, the last of which produces antibodies. The proliferation of Helper T cells stimulates B cells and macrophages.

The danger model of the immune system proposes that it differentiates between components that are capable of causing damage, rather that distinguishing between self and non-self.

History of immunologic models

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.[1][2] 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.[3] 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.[4]

Danger model

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.[5][6] 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.[4][6][7] 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.[8]

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.[9][10] 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).[11] For example, gut cells secrete transforming growth factor beta (TGF-β) during bacterial invasions to stimulate B cell production of Immunoglobulin A (IgA).[12] 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.[13][14]

Damage-associated molecular pattern (DAMP) model

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.[15]

Pattern Recognition Receptors (PRRs)

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,[16] retinoic acid inducible gene-I (RIG-I)-like receptors[17] and C-type lectin-like receptors (CLRs).[18] They recognize alarmins, a category that includes both DAMPs and PAMPs, to process their antigenic regions for presentation to T helper cells.[6]

References

  1. ^ Burnet FM; Fenner F (1949). The Production of Antibodies (2nd ed.). Melbourne: Macmillan.
  2. ^ Burnet FM (1969). Cellular Immunology: Self and Notself. Cambridge: Cambridge University Press.
  3. ^ Janeway, C. A. (1989-01-01). "Approaching the asymptote? Evolution and revolution in immunology". Cold Spring Harbor Symposia on Quantitative Biology. 54 (1): 1–13. doi:10.1101/sqb.1989.054.01.003. ISSN 0091-7451. PMID 2700931.
  4. ^ a b Matzinger P (2002). "The danger model: a renewed sense of self". Science. 296 (5566): 301–5. Bibcode:2002Sci...296..301M. CiteSeerX 10.1.1.127.558. doi:10.1126/science.1071059. PMID 11951032. S2CID 13615808.
  5. ^ Matzinger, P (1994). "Tolerance, Danger, and the Extended Family". Annual Review of Immunology. 12 (1): 991–1045. doi:10.1146/annurev.iy.12.040194.005015. PMID 8011301.
  6. ^ a b c Hallenbeck J, Del Zoppo G, Jacobs T, Hakim A, et al. (2006). "Immunomodulation strategies for preventing vascular disease of the brain and heart: workshop summary". Stroke. 37 (12): 3035–42. doi:10.1161/01.STR.0000248836.82538.ee. PMC 1853372. PMID 17082471.
  7. ^ Jounai N, Kobiyama K, Takeshita F, Ishii KJ (2012). "Recognition of damage-associated molecular patterns related to nucleic acids during inflammation and vaccination". Front Cell Infect Microbiol. 2: 168. doi:10.3389/fcimb.2012.00168. PMC 3539075. PMID 23316484.
  8. ^ Pradeu, Thomas; Cooper, Edwin L. (2012-01-01). "The danger theory: 20 years later". Frontiers in Immunology. 3: 287. doi:10.3389/fimmu.2012.00287. ISSN 1664-3224. PMC 3443751. PMID 23060876.
  9. ^ Matzinger, P (2007). "Friendly and dangerous signals: is the tissue in control?". Nature Immunology. 8 (1): 11–13. doi:10.1038/ni0107-11. PMID 17179963. S2CID 6448542.
  10. ^ Tirumlai K, Matzinger P (2011). "Tissue-based class control: the other side of tolerance". Nature Reviews Immunology. 11 (3): 221–30. doi:10.1038/nri2940. PMID 21350581. S2CID 10809131.
  11. ^ Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Galicier L, et al. (2004). "Common variable immunodeficiency is associated with defective functions of dendritic cells". Blood. 104 (8): 2441–3. doi:10.1182/blood-2004-04-1325. PMID 15226176.
  12. ^ Bauché, David; Marie, Julien C (2017-04-07). "Transforming growth factor β: a master regulator of the gut microbiota and immune cell interactions". Clinical & Translational Immunology. 6 (4): e136. doi:10.1038/cti.2017.9. ISSN 2050-0068. PMC 5418590. PMID 28523126.{{cite journal}}: CS1 maint: PMC format (link)
  13. ^ Gao, Bin; Jeong, Won-Il; Tian, Zhigang (2007-12-31). "Liver: An organ with predominant innate immunity". Hepatology. 47 (2): 729–736. doi:10.1002/hep.22034.
  14. ^ Yoshimoto, Tomohiro (2018). "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". Frontiers in Immunology. 9. doi:10.3389/fimmu.2018.00716/full. ISSN 1664-3224.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  15. ^ Seong S, Matzinger P (2004). "Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses". Nature Reviews Immunology. 4 (6): 469–478. doi:10.1038/nri1372. PMID 15173835. S2CID 13336660.
  16. ^ Tanti JF, Ceppo F, Jager J, Berthou F (2012). "Implication of inflammatory signaling pathways in obesity-induced insulin resistance". Front Endocrinol (Lausanne). 3: 181. doi:10.3389/fendo.2012.00181. PMC 3539134. PMID 23316186.
  17. ^ Beckham SA, Brouwer J, Roth A, Wang D, et al. (2012). "Conformational rearrangements og RIG-I receptor on formation of a multiprotein: dsRNA assembly". Nucleic Acids Res. 41 (5): 3436–45. doi:10.1093/nar/gks1477. PMC 3597671. PMID 23325848.
  18. ^ Kuroki K, Furukawa A, Maenaka K (2012). "Molecular recognition of paired receptors in the immune system". Front Microbiol. 3: 429. doi:10.3389/fmicb.2012.00429. PMC 3533184. PMID 23293633.
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