Lesions of Baló ’ s concentric sclerosis are characterized by alternating l ayers of myelinated and demyelinated tissue. The reason for concentric demyelina tion in this variant of multiple sclerosis is unclear. In the present study we i nvestigated the immunopathology in autopsy tissue of 14 patients with acute mult iple sclerosis or fulminant exacerbations of chronic multiple sclerosis with Bal ó - type lesions in the CNS, focusing on the patterns of tissue injury in acti vely demyelinating lesions.We found that all active concentric lesions followed a pattern of demyelination that bears resemblance s to hypoxia- like tissue injury. This was associated with high expression of i nducible nitric oxide synthase in macrophages and microglia. At the edge of acti ve lesions and, less consistently, in the outermost layer of preserved myelin, p roteins involved in tissue preconditioning,such as hypoxia- inducible factor 1 α and heat- shock protein 70, were expressed mainly in oligodendrocytes and t o a lesser degree also in astrocytes and macrophages. Due to their neuroprotecti ve effects, the rim of periplaque tissue, where these proteins are expressed, ma y be resistant to further damage in an expanding lesion and may therefore remain as a layer of preserved myelinated tissue. Lesions of Baló’s concentric sclerosis are characterized by alternating l ayers of myelinated and demyelinated tissues. The reason for concentric demyelina tion in this variant of multiple sclerosis is unclear. In the present study we examined the immunopathology in autopsy tissue of 14 patients with acute multisple sclerosis or fulminant exacerbations of chronic multiple sclerosis with Bal ó - type lesions in the CNS, focusing on the patterns of tissue injury in acti vely demyelinating lesions. We found that all active concentric lesions followed a pattern of demyelination that bears resemblance s This is associated with high expression of i nducible nitric oxide synthase in macrophages and microglia. At the edge of acti ve lesions and, less consistently, in the outermost layer of preserved myelin, p roteins involved in tissue preconditioning , such as hypoxia-inducible factor 1 α and heat-shock protein 70, were expressed mainly in oligodendr Due to their neuroprotecti ve effects, the rim of periplaque tissue, where these proteins are expressed, ma y be resistant to further damage in an expanding lesion and may therefore remain as a layer of preserved myelinated tissue.