Major histocompatibility complex heavy chain accumulation in the endoplasmic reticulum of oligodendrocytes results in myelin abnormalities

The immune cytokine interferon-gamma (IFN-gamma) is believed to be a key ag ent in the pathogenesis of immune-mediated demyelinating disorders. We have examined the possibility that one effect of this cytokine involves overloa ding the endoplasmic reticulum (ER) of oligodendrocytes through the inducti on of major histocompatibility complex (MHC) class I heavy chain (HC) gene expression. For these studies, we have utilized several genetic mouse model s that yield different subcellular localizations of HC in oligodendrocytes. We show that transgenic mice that ectopically express HG in oligodendrocyt es (MBP/MHC class I mice) fail to transport HC past the ER. These mice are hypomyelinated and have a tremoring phenotype. When oligodendrocytes defici ent in beta2 microglobulin (beta 2m), which is required for MHC class I ass embly and transport, were treated with IFN-gamma in vitro, HC was transport ed past the ER to the trans-Golgi network but not onto the cell surface. Wh en an asymptomatic line of mice that expresses MHC class I in the CNS due t o transgene-derived IFN-gamma (MBP/IFN-gamma mice) was crossed onto the bet a 2m-/- background, the resulting mice were asymptomatic. In contrast, incr easing the amount of MHC class I protein transported through the ER in MBP/ MHC class I transgenic mice, by crossing them to the asymptomatic MBP/IFN-g amma mice, exacerbated their phenotype. Taken together, these data indicate that the ER is a sensitive site in oligodendrocytes for accumulation of MH C class I HC and suggest a molecular mechanism for IFN-gamma's deleterious effects on these cells. (C) 2000 Wiley-Liss, Inc.