The Danger Model Approach to the Pathogenesis of the Rheumatic Diseases

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.

High prevalence of autoimmune disease in the rare inflammatory bone disorder sternocostoclavicular hyperostosis: survey of a Dutch cohort

“…An interesting hypothetical framework that may explain the association between inflammation and autoimmunity can be found in the proposed immunological “danger theory”, which emphasizes that autoimmune disease can be provoked by cellular damage (“danger”) signals [ 29 , 30 ]. Within this context, it could be speculated that in SCCH patients, prolonged exposure to low-grade inflammation combined with an inadequate clearance of self-antigens from cellular debris may be associated with a state of increased susceptibility to autoimmune disease in general.…”

Serum levels of HSP70 and other DAMP proteins can aid in patient diagnosis after traumatic injury

“…HSP70 is released into the extracellular environment and binds to Toll-like receptors (TLR2 and TRL4) to trigger pro-inflammatory responses by upregulation of adhesion molecules, co-stimulatory molecules, and cytokine and chemokine secretion (Prohászka et al 2002;Asea et al 2000b). BDanger theory^has significantly extended our understanding of these responses (de Haan et al 2013;Pacheco-Tena & González-Chávez 2015;LeRoux et al 2015;Heil & Land 2014). Endogenous danger signals such as HSP70 released from necrotic or stressed cells, called DAMPs (Bianchi 2007;Harris & Raucci 2006), share structural and functional similarities with molecules released from invading microorganisms, called pathogen-associated *Correlation is significant at the 0.05 level (2-tailed); **Correlation is significant at the 0.01 level (2-tailed) (Seong & Matzinger 2004;Hirsiger et al 2012).…”

DNA Damage and Deficiencies in the Mechanisms of Its Repair: Implications in the Pathogenesis of Systemic Lupus Erythematosus

“…The accumulation of apoptotic cells results in an excessive presentation of autoantigens and production of autoantibodies. Under normal conditions, UV-damaged DNA is sensed and repaired by the activation of complex multiprotein pathways, whose function is to maintain the integrity of DNA, adequate genome functionality, and cellular homeostasis [ 36 ]. The fact that several proteins are involved in specific roles in multistep processes widens the chances for dysfunction; besides, many of the proteins involved in genome stability have functional influencing polymorphisms.…”