Dysmyelination in transgenic mice resulting from expression of class I histocompatibility molecules in oligodendrocytes

Abstract

MAJOR histocompatibility complex (MHC) molecules are not normally expressed in the central nervous system (CNS)^1–3. However, aberrant expression has been observed in multiple sclerosis lesions and could contribute to the destruction of myelin or the myelinating cells known as oligodendrocytes^4,5. The mechanism of cell damage associated with aberrant MHC molecule expression is unclear: for example, overexpression of class I (ref. 6) and class II (refs 7, 8) MHC molecules in pancreatic β cells in transgenic mice leads to nonimmune destruction of the cells and insulin-dependent diabetes mellitus. We have generated transgenic mice that express class I H–2K^b MHC molecules, under the control of the myelin basic protein promoter, specifically in oligodendrocytes. Homozygous transgenic mice have a shivering phenotype, develop tonic seizures and die at 15–22 days. This phenotype, which we term 'wonky', is due to hypomyelination in the CNS, and not to involvement of the immune system. The primary defect appears to be a shortage of myelinating oligodendrocytes resulting from overexpression of the class I MHC molecules.