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The danger model approach to the pathogenesis of the rheumatic diseases.

Pacheco-Tena C, González-Chávez SA - J Immunol Res (2015)

Bottom Line: We assume that tissular dysfunction is a prerequisite for chronic autoimmunity and propose two genetically conferred hypothetical roles for the tissular cells causing the disease: (A) the Impaired cell and (B) the paranoid cell.Both roles are not mutually exclusive.Some examples in human disease and in animal models are provided based on current evidence.

View Article: PubMed Central - PubMed

Affiliation: Facultad de Medicina, Universidad Autónoma de Chihuahua, Circuito No. 1, Nuevo Campus Universitario, 31240 Chihuahua, CHIH, Mexico.

ABSTRACT
The danger model was proposed by Polly Matzinger as complement to the traditional self-non-self- (SNS-) model to explain the immunoreactivity. The danger model proposes a central role of the tissular cells' discomfort as an element to prime the immune response processes in opposition to the traditional SNS-model where foreignness is a prerequisite. However recent insights in the proteomics of diverse tissular cells have revealed that under stressful conditions they have a significant potential to initiate, coordinate, and perpetuate autoimmune processes, in many cases, ruling over the adaptive immune response cells; this ruling potential can also be confirmed by observations in several genetically manipulated animal models. Here, we review the pathogenesis of rheumatic diseases such as systemic lupus erythematous, rheumatoid arthritis, spondyloarthritis including ankylosing spondylitis, psoriasis, and Crohn's disease and provide realistic approaches based on the logic of the danger model. We assume that tissular dysfunction is a prerequisite for chronic autoimmunity and propose two genetically conferred hypothetical roles for the tissular cells causing the disease: (A) the Impaired cell and (B) the paranoid cell. Both roles are not mutually exclusive. Some examples in human disease and in animal models are provided based on current evidence.

No MeSH data available.


Related in: MedlinePlus

The paranoid overstimulated intestinal epithelial cell in Crohn's disease. The deficiency in NOD2 inhibits an anti-inflammatory mechanism that impedes TLR2 from continual signaling if in contact with its bacterial wall ligands. The loss of this compensatory anti-inflammatory mechanism generates uncontrolled inflammation based on a threat that is not real, because the commensal flora does not harm.
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fig4: The paranoid overstimulated intestinal epithelial cell in Crohn's disease. The deficiency in NOD2 inhibits an anti-inflammatory mechanism that impedes TLR2 from continual signaling if in contact with its bacterial wall ligands. The loss of this compensatory anti-inflammatory mechanism generates uncontrolled inflammation based on a threat that is not real, because the commensal flora does not harm.

Mentions: In that regard the risk for infection is not that real. The role of NOD2 as a regulatory molecule is crucial in the GI tract since the perennial and abundant presence of bacterial components which are ligands to NOD, TLR, and other PRR has the potential to trigger a continuous stimulation of the immune elements of the intestinal mucosa. It is possible to assume that defective NOD2 function could explain an impaired regulation of TLR responses specially TLR2 [181]. It is also hypothesized that the inferred immunodeficiency conferred by a defective NOD2 is arguable and that the presence of bacteria or bacterial components in the lamina propria has not been proved to trigger the inflammation in CD. In the other hand, the continuous stimulation of NOD2 with muramyl peptide could tolerize macrophages previously stimulated with either TLR2 or 4 [184, 185]; therefore, defective tolerizing proteins such as NOD2 could induce a perpetual inflammatory status despite; in this case, the threat of infection (i.e., bacterial invasion) is not real (Figure 4).


The danger model approach to the pathogenesis of the rheumatic diseases.

Pacheco-Tena C, González-Chávez SA - J Immunol Res (2015)

The paranoid overstimulated intestinal epithelial cell in Crohn's disease. The deficiency in NOD2 inhibits an anti-inflammatory mechanism that impedes TLR2 from continual signaling if in contact with its bacterial wall ligands. The loss of this compensatory anti-inflammatory mechanism generates uncontrolled inflammation based on a threat that is not real, because the commensal flora does not harm.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4417989&req=5

fig4: The paranoid overstimulated intestinal epithelial cell in Crohn's disease. The deficiency in NOD2 inhibits an anti-inflammatory mechanism that impedes TLR2 from continual signaling if in contact with its bacterial wall ligands. The loss of this compensatory anti-inflammatory mechanism generates uncontrolled inflammation based on a threat that is not real, because the commensal flora does not harm.
Mentions: In that regard the risk for infection is not that real. The role of NOD2 as a regulatory molecule is crucial in the GI tract since the perennial and abundant presence of bacterial components which are ligands to NOD, TLR, and other PRR has the potential to trigger a continuous stimulation of the immune elements of the intestinal mucosa. It is possible to assume that defective NOD2 function could explain an impaired regulation of TLR responses specially TLR2 [181]. It is also hypothesized that the inferred immunodeficiency conferred by a defective NOD2 is arguable and that the presence of bacteria or bacterial components in the lamina propria has not been proved to trigger the inflammation in CD. In the other hand, the continuous stimulation of NOD2 with muramyl peptide could tolerize macrophages previously stimulated with either TLR2 or 4 [184, 185]; therefore, defective tolerizing proteins such as NOD2 could induce a perpetual inflammatory status despite; in this case, the threat of infection (i.e., bacterial invasion) is not real (Figure 4).

Bottom Line: We assume that tissular dysfunction is a prerequisite for chronic autoimmunity and propose two genetically conferred hypothetical roles for the tissular cells causing the disease: (A) the Impaired cell and (B) the paranoid cell.Both roles are not mutually exclusive.Some examples in human disease and in animal models are provided based on current evidence.

View Article: PubMed Central - PubMed

Affiliation: Facultad de Medicina, Universidad Autónoma de Chihuahua, Circuito No. 1, Nuevo Campus Universitario, 31240 Chihuahua, CHIH, Mexico.

ABSTRACT
The danger model was proposed by Polly Matzinger as complement to the traditional self-non-self- (SNS-) model to explain the immunoreactivity. The danger model proposes a central role of the tissular cells' discomfort as an element to prime the immune response processes in opposition to the traditional SNS-model where foreignness is a prerequisite. However recent insights in the proteomics of diverse tissular cells have revealed that under stressful conditions they have a significant potential to initiate, coordinate, and perpetuate autoimmune processes, in many cases, ruling over the adaptive immune response cells; this ruling potential can also be confirmed by observations in several genetically manipulated animal models. Here, we review the pathogenesis of rheumatic diseases such as systemic lupus erythematous, rheumatoid arthritis, spondyloarthritis including ankylosing spondylitis, psoriasis, and Crohn's disease and provide realistic approaches based on the logic of the danger model. We assume that tissular dysfunction is a prerequisite for chronic autoimmunity and propose two genetically conferred hypothetical roles for the tissular cells causing the disease: (A) the Impaired cell and (B) the paranoid cell. Both roles are not mutually exclusive. Some examples in human disease and in animal models are provided based on current evidence.

No MeSH data available.


Related in: MedlinePlus