Perspectives in Diabetes MHC Molecules and P-Cell Destruction Immune and Nanimmune Mechanisms

Hyperexpression of major histocompatibility complex (MHC) molecules by islet cells is a prominent, early feature of islet pathology in insulin-dependent diabetes mellitus and concomitant with p-cell failure after exposure of islets to specific cytokines or viruses. The transgenic expression of a class I MHC gene (H-2Kb) in the p-cells of either syngeneic or allogeneic mice leads to p-cell failure by a nonimmune mechanism. Several class II MHC transgenes, with one exception, have the same effect, but the expression of other transgenes that have products that are membrane proteins is not necessarily detrimental. Class I MHC molecules have been shown to interact directly with other membrane proteins. The inappropriate expression of MHC molecules could therefore interfere with key cellular functions. We postulate that the hyperexpression of MHC molecules in the p-cell, e.g., in response to viruses, is a primary, nonimmune mechanism of p-cell failure that precedes a secondary autoimmune response. Diabetes 38:815-18,1989