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

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.