Myelin and oligodendrocyte pathology in autoimmune encephalomyelitis, multiple sclerosis, and stroke. a–d Chronic autoimmune encephalomyelitis, induced in DA rat by active sensitization with MOG fusion protein; a massive demyelination is seen in the cerebellar white matter, ×6; b–d oligodendrocytes in different lesion stages of EAE; in the peri-plaque white matter myelin (red) is present and multiple oligodendrocytes with PLP mRNA (black) are seen (b); in the active lesions myelin falls apart, myelin fragments are taken up by macrophages (red granules) and oligodendrocytes are lost (c); in more advanced lesions no macrophages with early myelin degradation products are present; numerous oligodendrocytes re-appear in the lesions, apparently recruited from progenitor cells (black cells), followed by rapid and extensive remyelination; immunocytochemistry for PLP and in situ hybridization for PLP mRNA, ×1000; e–h chronic multiple sclerosis case with extensive remyelination within the CNS; This hemispheric brain section contains 3 active lesions, 4 demyelinated plaques, and 8 remyelinated shadow plaques, ×1.2; f–h double staining for PLP protein (red) and PLP mRNA (black) in one of the active lesions shows a similar pattern as described before in EAE; many oligodendrocytes in the peri-plaque white matter (f); oligodendrocyte loss in the zone of active demyelination (g) and reappearance of oligodendrocytes in the inactive zone, closely adjacent to the zone of activity (h), ×500; i–o myelin changes in the initial stage of a lesion in white matter stroke; LFB shows pale myelin staining (i); the axons, stained with Bielschowsky silver impregnation are largely preserved (k); MAG (l) and CNPase (m) are completely lost from the lesions, while the myelin proteins within the compact sheath (PLP; n) or on the oligodendrocyte surface (MOG; o) are preserved, ×20; p–s acute multiple sclerosis with lesions following a pattern of hypoxia-like tissue injury (Pattern III, [109]). p The section contains areas of initial demyelination (i), early active demyelination (a) and late active or inactive portions (d); q serial section of p, stained by immunocytochemistry for PLP; Only the late active and inactive lesions show loss of PLP; in the active portions (a) a minor loss of PLP reactivity is seen, while in the initial lesions PLP reactivity is the same as in the normal appearing white matter, ×3; r and s edge of an active lesion showing partial preservation of immunoreactivity for MOG (r), but extensive and complete loss of MAG(s), ×20

a–d Detection of oligodendrocytes in paraffin embedded tissue sections. a Mouse cortex, stained by immunocytochemistry for CNPase shows numerous process bearing oligodendrocytes and staining of myelin sheaths, ×120; b high magnification of a CNPase positive oligodendrocyte in the mouse cortex (layer I), showing a small round cell body and few cell processes connected to myelin sheaths, ×1,000; c rat spinal cord stained by in situ hybridization for myelin basic protein mRNA; staining is seen in the cell bodies (e.g., in the gray matter) as well as in oligodendrocyte processes associated with myelin sheaths (dark staining in the white matter), ×50; d rat spinal cord stained by in situ hybridization for proteolipid protein (PLP); the mRNA for PLP is only located within the perinuclear cytoplasm, there is no staining of myelin, ×50; e–h oligodendrocyte pathology in transgenic animals overexpressing proteolipid protein; e and f hemizygous animal, which shows normal myelination, stained by immunocytochemistry for PLP; in the normal animal PLP protein is rarely detected in the cytoplasm of oligodendrocytes; in hemizygous PLP transgenic animals a variable extent of PLP expression is seen in the cytoplasm of oligodendrocytes (e), and this is associated with aberrant formation of myelin-like structures within and adjacent to the cells (f); g–h homozygous animal, which shows extensive dys-myelination; only few oligodendrocytes are preserved, which are connected to myelin sheaths and contain abundant PLP immunoreactivity in their cytoplasm (g); some of the PLP reactive oligodendrocytes show nuclear condensation and fragmentation, consistent with apoptosis (h), ×1,200; i–o neuropathology of progressive multifocal leukoencephalopathy; i multiple small confluent demyelinating lesions in the white and gray matter, giving the impression of a moth eaten pattern of demyelination (×2); k edge of an active demyelinating lesion with numerous macrophages, containing recent (luxol fast blue positive) degradation products; l and m pathologically altered nuclei in PML showing giant nuclei of astrocytes (l) and small oligodendrocyte nuclei with intranuclear inclusion (m); n and o similar nuclei, as shown in l and m contain virus antigen as revealed by immunocytochemistry; ×1,200