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Model to explain how an inflammatory process, topographically unassociated with a pancreatic islet, may initiate beta-cell damage - selectively, but in an immunologically unspecific manner (modified from Bendtzen et al. Clin. Immunol. Newslett. 1988; 9: 72 and Bendtzen. Autoimmunity 1989; 2: 177). Infiltrating mononuclear cells, primarily MØ and NK cells, as well as endothelial cells are potent producers of IL-1b. TNFa and TNFb augment this production and potentiate the damaging effect of IL-1b on beta-cells. IL-6, produced by MNC, endothelial cells and fibroblasts, may contribute to this effect. IFN-gamma and IL-1b increase vascular permeability aiding the accumulation of cytokines within the islet. The inflammatory processes may not involve the entire pancreatic gland, and the amount of IL-1b and the TNFs may not always be sufficient to cause permanent damage to the beta-cells. Furthermore, only a few beta-cells may be damaged during each inflammatory incident, and a certain degree of regeneration of functional beta-cells would be expected. The disease process may therefore proceed stepwise and take months or years to complete (see figure below). IFN-gamma, reinforced by TNFa and IL-1b, may induce MHC class II molecules on the beta-cells, and TNFa also synergizes with IFN-gamma to increase expression of MHC class I molecules on these cells. Although the triggering event(s) in this model are antigenically and otherwise unrelated to the insulin-producing beta-cells, the expression of certain MHC class II haplotypes may confer 'immunogenic' functions upon beta-cells, initiating an autoimmune attack on these cells after cytokine-induced damage. Proposed time-course of IDDM development
The arrows shows four individual attacks on the integrity of pancreatic beta-cells, each causing a partially reversible damage to the total beta-cell mass. At the time of diagnosis, the insulin demand cannot be met by the residual beta-cells. Eventually, a beta-cell-specifc immune attack may participate in the destruction of beta-cells. This model implies that there may be different etiologies involved in human IDDM development - even in the same individual. Adapted from: Bendtzen et al. Clin. Immunol. Newslett. 1988; 9: 72-79, and Bendtzen K. Autoimmunity 1989; 2: 177-189.
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