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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 sun-burned defective DNA repairer keratinocyte in SLE. The exposure of the keratinocyte DNA to UV radiation infringes DNA damage, which cannot be normally repaired because of faulty enzymes. DNA repairing proteins are upregulated and therefore presented as antigens; in the stressed context costimulatory molecules are upregulated and an autoimmune response toward nucleoproteins is settled. Repetitive cycles of UV radiation perpetuate the immune process because the tissue is harmed again and releases danger mediators.
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fig2: The sun-burned defective DNA repairer keratinocyte in SLE. The exposure of the keratinocyte DNA to UV radiation infringes DNA damage, which cannot be normally repaired because of faulty enzymes. DNA repairing proteins are upregulated and therefore presented as antigens; in the stressed context costimulatory molecules are upregulated and an autoimmune response toward nucleoproteins is settled. Repetitive cycles of UV radiation perpetuate the immune process because the tissue is harmed again and releases danger mediators.

Mentions: DNA damage is an everyday fact and it induces inflammation [94–96] but also a DNA reparative response [97–100]. In physiological conditions, damaged DNA is repaired and the consequent inflammation fades; however, in a defective DNA repairing scenario (i.e., impaired keratinocyte), a perpetual inflammatory status could be eventually settled. Repeated efforts from the keratinocyte to maintain its DNA integrity and physiological function eventually fail. A defective repairing pathway could be compensated by others, and the repairing proteins will be upregulated beyond physiological levels that altogether with the cell stress scenario will make great antigenic candidates out of them. Once the tolerogenic nature of the tissue is lost and the danger signals spread up, an unspecific mononuclear infiltrate lies around immune activated keratinocytes, and the role of the immune competent cells is far from being understood; likely those cells are just answering the call; the caller has the structure to congregate them (Figure 2).


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

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

The sun-burned defective DNA repairer keratinocyte in SLE. The exposure of the keratinocyte DNA to UV radiation infringes DNA damage, which cannot be normally repaired because of faulty enzymes. DNA repairing proteins are upregulated and therefore presented as antigens; in the stressed context costimulatory molecules are upregulated and an autoimmune response toward nucleoproteins is settled. Repetitive cycles of UV radiation perpetuate the immune process because the tissue is harmed again and releases danger mediators.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: The sun-burned defective DNA repairer keratinocyte in SLE. The exposure of the keratinocyte DNA to UV radiation infringes DNA damage, which cannot be normally repaired because of faulty enzymes. DNA repairing proteins are upregulated and therefore presented as antigens; in the stressed context costimulatory molecules are upregulated and an autoimmune response toward nucleoproteins is settled. Repetitive cycles of UV radiation perpetuate the immune process because the tissue is harmed again and releases danger mediators.
Mentions: DNA damage is an everyday fact and it induces inflammation [94–96] but also a DNA reparative response [97–100]. In physiological conditions, damaged DNA is repaired and the consequent inflammation fades; however, in a defective DNA repairing scenario (i.e., impaired keratinocyte), a perpetual inflammatory status could be eventually settled. Repeated efforts from the keratinocyte to maintain its DNA integrity and physiological function eventually fail. A defective repairing pathway could be compensated by others, and the repairing proteins will be upregulated beyond physiological levels that altogether with the cell stress scenario will make great antigenic candidates out of them. Once the tolerogenic nature of the tissue is lost and the danger signals spread up, an unspecific mononuclear infiltrate lies around immune activated keratinocytes, and the role of the immune competent cells is far from being understood; likely those cells are just answering the call; the caller has the structure to congregate them (Figure 2).

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