Homogeneity of active demyelinating lesions in established multiple sclerosis.

OBJECTIVE: Four different patterns of demyelination have been described in active demyelinating lesions of multiple sclerosis (MS) patients that were biopsied shortly after disease onset. These patterns were suggested to represent heterogeneity of the underlying pathogenesis. The aim of this study was to determine whether lesion heterogeneity also exists in an unselected collection of autopsy material from patients with established MS. METHODS: All MS brain tissue available in the VU Medical Center was assessed for the presence of active demyelinating lesions using magnetic resonance imaging-guided sampling and immunohistochemistry. Tissue blocks containing active demyelinating lesions were evaluated for the presence of complement and antibody deposition, oligodendrocyte apoptosis, differential loss of myelin proteins, and hypoxia-like damage using histology, immunohistochemistry, and confocal microscopy. Blocks with active demyelinating lesions were compared with blocks with active (nondemyelinating) and inactive lesions. RESULTS: Complement and antibodies were consistently associated with macrophages in areas of active demyelination. Preferential loss of myelin proteins, extensive hypoxia-like damage, and oligodendrocyte apoptosis were absent or rare. This pattern was observed in all tissue blocks containing active demyelinating lesions; lesion heterogeneity between patients was not found. INTERPRETATION: The immunopathological appearance of active demyelinating lesions in established MS is uniform. Initial heterogeneity of demyelinating lesions in the earliest phase of MS lesion formation may disappear over time as different pathways converge in one general mechanism of demyelination. Consistent presence of complement, antibodies, and Fcgamma receptors in phagocytic macrophages suggests that antibody- and complement-mediated myelin phagocytosis is the dominant mechanism of demyelination in established MS.

The blood-brain barrier in cortical multiple sclerosis lesions.

The blood-brain barrier (BBB) is composed mainly of specialized endothelial cells characterized by the presence of intercellular tight junctions. Additionally, perivascular cells, astrocytes, and surrounding basement membranes determine BBB integrity. BBB disruption is an early phenomenon in the formation of new white matter multiple sclerosis (MS) lesions; however, knowledge of the extent of BBB changes in gray matter MS lesions is lacking. Here, we studied several markers for BBB integrity in well-characterized brain tissue of patients with MS. Plasma protein leakage was enhanced in white matter lesions compared with that in normal-appearing white matter, whereas plasma protein leakage was absent in gray matter lesions. White matter lesions showed irregular basement membranes and parenchymal depositions of collagen type IV, whereas purely gray matter lesions lacked basement membrane alterations. Similarly, we observed no evidence for astrogliosis and tight junction changes in cortical MS lesions. Although BBB dysfunction is a common feature of white matter MS lesions, cortical MS lesions lack markers for BBB disruption or astrogliosis. Our data may indicate that BBB breakdown is not a critical event in the formation of gray matter MS lesions.

The pathology of multiple sclerosis is location-dependent: no significant complement activation is detected in purely cortical lesions.

Complement activation is known to occur in white matter multiple sclerosis (MS) lesions. It is thought to mediate oligodendrocyte/myelin damage and to be a marker of pathologic heterogeneity among individuals. Less is known about complement deposition in the gray matter in MS. The aim of this study was to characterize the presence and distribution of complement activation products in cortical MS lesions. Immunohistochemical staining was performed on cryostat sections from the brains of 22 MS patients and 5 nonneurologic control patients obtained at autopsy. Deposition of the complement activation products C1q, C3d, and C5b-9 (membrane attack complex) was detected on and within macrophages/microglia and astrocytes and in blood vessel walls in white matter MS lesions. C3d and C4d were detected along myelin sheaths at the edge of the lesions. In the gray matter part of combined gray matter/white matter lesions complement activation was less frequent, but increased immunopositivity was detected for C3d on blood vessels, and for C3d and C4d on myelin at the border of lesions, when compared with control areas. In contrast, in the purely cortical lesions, the extent of complement deposition in general was low. In conclusion, the role of complement in MS pathogenesis seems lesion location-dependent.