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.

Figure 1

Basic comparison of the postulates between the self-non-self- (SNS-) model and the danger model (DM). In the SNS-mode, the triggering stimulus is the antigen which is by definition foreign, or, if endogenous, it is mistaken as foreign; once the antigen specific cells have been primed, the persistence of the immune response depends on the perpetual presence of an antigen and for the case of an autoantigen on its expression where it can be detected and processed by antigen presenting cells to T-cells; the severity of the immune reactions depends on the nature and amount of the antigen and the type of immune response it settles on. In the case of the DM the initial step is a scenario of disturbance within the tissues which can be explained by both biological or physical aggressions, the disturbed tissular cell signals to the local antigen presenting cells, and, as the aggression becomes more chronic the tissular cell communicates directly to T- or B-cells; the perpetuating cycle for the case of chronic autoimmune diseases relies on the repeated disturbance of the tissular cells by the annoying stimuli and self-proteins are recognized eventually as antigens due to the enhanced antigenic presentation costimulation upregulated by the soluble factors released by the stressed tissular cells. The severity of the immune reaction depends on the intensity and frequency of the disturbance that the stimuli infringe in the tissular cells.

Figure 2

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.

Figure 3

The hypoxic impaired fibroblast in RA. The hypoxia in the rheumatoid synovium induces several phenotypic changes in the fibroblasts; it not only enhances the synthesis of proinflammatory cytokines and metalloproteases, but also induces the glycolysis pathways upregulating the enzymes, which become antigenic because they are abundant in a stressed scenario and eventually are presented by the local APC.

Figure 4

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.