Danger model

The Danger model is a theory of how the immune system works. It is based on the idea that the immune system does not distinguish between self and non-self, but rather between things that might cause damage and things that will not.

Function of T helper cells: Antigen-presenting cells (APCs) present antigen on their Class II MHC molecules (MHC2). Helper T cells recognize these, with the help of their expression of CD4 co-receptor (CD4+). The activation of a resting helper T cell causes it to release cytokines and other stimulatory signals (green arrows) that stimulate the activity of macrophages, killer T cells and B cells, the latter producing antibodies. The stimulation of B cells and macrophages succeeds a proliferation of T helper cells.

Brief History of Immunologic Models

The first immunologic model was called the Self Non-self model and was suggested by Burnet and Frank Fenner in 1949,^[1] and refined over the years.^[2] It supposes that the immune system distinguishes between self, which is tolerated, and between non-self, which is attacked and destroyed. According to this theory the chief cell of the immune system is the B lymphocyte, which is activated when it recognizes any non-self structure. Later it was discovered that in order to become activated, the B lymphocyte needs help from a CD4+ T helper cell, and that this T helper cell in turn also required a co-stimulatory signal from an antigen-presenting cell (APC) to be activated. The Self Non-self model developed according to these findings. Because APC cells are not antigen specific and are also capable of processing self structures, in 1989 Charles Janeway proposed a new theory, the so-called Infectious Non-self Model.^[3] It is based on the idea that APCs are activated via pattern recognition receptors (PRRs) which recognize evolutionary distant conserved patterns. These pathogen-associated molecular patterns (PAMPs) on such organisms as bacteria are recognized as infectious non-self, whereas PRRs are not activated by non-infectious self. However, none of these models can explain non-cytopathic virus infections, graft rejection or anti-tumor immunity.^[4]

The Danger Model

In 1994^[5] a new immunologic model was suggested by Polly Matzinger. She suggested that the immune system does not distinguish between self and nonself, but discriminates between dangerous and safe by recognition of pathogens or alarm signals from injured or stressed cells and tissues.^[6]

According to this theory, the most important for stimulation of immune response are normal tissues. When tissue cells are distressed because of injury, infection and so on, they start to secrete or express on their surface so called "Danger signals". "Danger signals" are also thrown out to extracellular space in the case that stressed cell dies by immunologic not-silent cell death such as necrosis or pyroptosis (as opposed to apoptosis, controlled cell death). This model also dictates that despite their potential immunogenicity tumors do not induce significant immune responses which could destroy malignant cells. According to the danger model, the immune surveillance system fails to detect tumor antigens because transformed cells do not send any danger signals which could activate dendritic cells and initiate an immune response. "Danger signals" are normal intracellular molecules, simply they are not in extracellular space among physiological conditions. The danger model has evolved over the years.^[7] "Danger signals" include DNA, RNA, heat shock proteins (Hsps), hyaluronic acid, serum amyloid A protein, ATP, uric acid and also cytokines like interferon alfa, interleukin-1β, CD40L and so on.^{[4] [6][8]}

The Damage-associated molecular pattern (DAMP) Model

"Danger model" suggests that, upon cellular necrosis, cryptic molecules in normal cells might be liberated from the cytoplasm into tissue microenvironment, or new molecules are expressed on the surface of killed cells, or new molecules are synthesized by cells undergoing necrosis. In comparison, "DAMP model" ^[9] suggests that any none-functional molecules (regardless of their cellular location; extracellular or intracellular) which were denatured, oxidized, or having disintegrated quaternary structures might have unique biophysical patterns such as low water-solubility or stretch of polyanion on their surface.

Pattern recognition receptor for Danger signal, DAMP and PAMP

"Danger signals" and DAMPs are together with pathogen-associated molecular patterns (PAMPs) called alarmins and they are recognized by pattern recognition receptors (PRRs) of APC cells. PRRs include Toll-like receptors (TLR), nucleotide oligomerization domain (NOD)-like receptors,^[10] retinoic acid inducible gene-I (RIG-I)-like receptors^[11] and C-type lectine-like receptors.^[12] They are not only at the surface of these cells, but we can find them in cytoplasm and incorporated in the membrane of endolysosomes. Stimulation of PRRs leads to activation of APC cell to process antigen, upregulate expression of costimulatory molecules and present antigen to T helper cells.^[6]

The Danger model has brought a new sight of adaptive and innate immunity. In the past the innate immunity was suggested as a minor part of immune system and to opposite the adaptive part was thought to be the most important and the most effective one. According to danger theory there is no adaptive immunity without the innate part. Because APCs type of cells, like dendritic cells, are essential for activation of T lymphocytes and B lymphocytes, which after activation produce specific antibodies. In the case of dendritic cells deficiency, like in common variable immunodeficiency (CVID), patients suffer by hypogammaglobulinemia and by primary or secondary defects in T-cell functions.^[4][13]

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