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

Kristine D. Baerwald, Joshua G. Corbin, Brian Popko*

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

The immune cytokine interferon-gamma (IFN-γ) is believed to be a key agent in the pathogenesis of immune-mediated demyelinating disorders. We have examined the possibility that one effect of this cytokine involves overloading the endoplasmic reticulum (ER) of oligodendrocytes through the induction of major histocompatibility complex (MHC) class I heavy chain (HC) gene expression. For these studies, we have utilized several genetic mouse models that yield different subcellular localizations of HC in oligodendrocytes. We show that transgenic mice that ectopically express HC in oligodendrocytes (MBP/MHC class I mice) fail to transport HC past the ER. These mice are hypomyelinated and have a tremoring phenotype. When oligodendrocytes deficient in beta-2 microglobulin (β2m), which is required for MHC class I assembly and transport, were treated with IFN-γ in vitro, HC was transported past the ER to the trans-Golgi network but not onto the cell surface. When an asymptomatic line of mice that expresses MHC class I in the CNS due to transgene-derived IFN-γ (MBP/IFN-γ mice) was crossed onto the β2m-/- background, the resulting mice were asymptomatic. In contrast, increasing 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-γ mice, exacerbated their phenotype. Taken together, these data indicate that the ER is a sensitive site in oligodendrocytes for accumulation of MHC class I HC and suggest a molecular mechanism for IFN-γ's deleterious effects on these cells.

Original languageEnglish (US)
Pages (from-to)160-169
Number of pages10
JournalJournal of Neuroscience Research
Volume59
Issue number2
DOIs
StatePublished - Jan 15 2000

Keywords

  • Demyelinating disorders
  • ER overload
  • Interferon-gamma
  • MHC class I

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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