Inappropriate Expression of Class Ii Mhc Molecules Can Sensitize Autoreactive T Cells

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The pancreatic beta cells of individuals with insulin-dependent diabetes mellitus (IDDM) express high levels of both class I and class II MHC molecules, whereas healthy beta cells express lower levels of class I and do not express class II at all. Similarly, thyroid acinar cells from those with Graves' disease have been shown to express class II MHC molecules on their membranes. This inappropriate expression of class II MHC molecules, which are normally expressed only on antigen-presenting cells, may serve to sensitize TH cells to peptides derived from the beta cells or thyroid cells, allowing activation of B cells or TC cells or sensitization of TH1 cells against self-antigens.

Other evidence suggests that certain agents can induce some cells that should not express class II MHC molecules to express them. For example, the T-cell mitogen phytohemag-glutinin (PHA) has been shown to induce thyroid cells to express class II molecules. In vitro studies reveal that IFN-7 also induces increases in class II MHC molecules on a wide variety of cells, including pancreatic beta cells, intestinal epithelial cells, melanoma cells, and thyroid acinar cells. It was hypothesized that trauma or viral infection in an organ may induce a localized inflammatory response and thus increased concentrations of IFN-7 in the affected organ. If IFN-7 induces class II MHC expression on non-antigen-presenting cells, inappropriate TH-cell activation might follow, with autoimmune consequences. It is noteworthy that SLE patients with active disease have higher serum titers of IFN-7 than patients with inactive disease. These data suggested that the increase in IFN-7 in these patients may lead to inappropriate expression of class II MHC molecules and thus to T-cell activation against a variety of autoantigens.

An interesting transgenic mouse system implicates IFN-7 and inappropriate class II MHC expression in autoim-munity. In this system, an IFN-7 transgene was genetically engineered with the insulin promoter, so that the transgenic mice secreted IFN-7 from their pancreatic beta cells (Figure 20-9a). Since IFN-7 up-regulates class II MHC expression, these transgenic mice also expressed class II MHC molecules on their pancreatic beta cells. The mice developed diabetes, which was associated with cellular infiltration of lymphocytes and inflammatory cells like the infiltration seen in autoimmune NOD mice and in patients with insulin-dependent diabetes mellitus (Figure 20-9b).

Although inappropriate class II MHC expression on pancreatic beta cells may be involved in the autoimmune reaction in these transgenic mice, other factors also may play a role. For example, IFN-7 is known to induce production of several other cytokines, including IL-1 and TNF. Therefore, the development of autoimmunity in this transgenic system may involve antigen presentation by class II MHC molecules on pancreatic beta cells together with a co-stimulatory signal, such as IL-1, that may activate self-reactive T cells. There is also some evidence to suggest that IL-1, IFN-7, and TNF may directly impair the secretory function of human beta cells.

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