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