Oligodendrocyte Pathology and Early Remyelination

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Oligodendrocytes are susceptible to damage via a number of immune or toxic mechanisms present within the MS lesion. These include cytokines such as TNF-a (38), reactive oxygen or nitrogen species, excitatory amino acids such as glutamate (39), complement components, proteolytic and lipolytic enzymes, T-cell mediated injury via T-cell products (perforin/lymphotoxin) (40), the interaction of Fas antigen with Fas-ligand (41), CD8+ class I MHC-mediated cytotoxicity (42), or persistent viral infection (43). The fate of the oligodendrocyte in active demyelinating lesions is controversial. Some studies suggest an abundance of oligodendrocytes within the active MS lesion (44), whereas others report a partial reduction (45). Several previous studies suggested that the density of oligodendrocytes in actively demyelinating lesions varied between patients (9,46). The more recent availability of new markers to label oligodendrocytes in paraffin embedded formalin-fixed tissue has led to a systematic analysis of the density of oligodendrocytes within over 300 lesions from 113 patients with MS during the early phase of the disease (47). The numbers were correlated with stages of myelin degradation products within macrophages thereby providing a snapshot of the temporal evolution of the lesion. Oligodendrocytes were labeled with PLP mRNA, an early marker of oligodendrocytes actively engaged in myelin synthesis and maintenance, but not present in surviving oligodendrocytes that have lost their myelin sheaths. Cells were also stained with antibodies directed against MOG, which is expressed on the surface of myelin sheaths and terminally differentiated oligodendrocytes late in myelination. MOG is detectable on oligodendrocytes that have survived demyelination following Wallerian degeneration (48).

Two principal groups of oligodendrocyte pathology were identified in these early MS lesions (47). Group I (70% of the cases) was characterized by a variable (minor to moderate) reduction of oligodendrocytes at the active demyelinating plaque edge, with re-appearance of cells within inactive or remyelinated regions. These lesions were associated with prominent remyelination. Although markers for the identification of immature oligodendrocytes were not used, the presence of cells expressing PLP mRNA, but not MOG, suggests that these oligodendrocytes may have been derived from the progenitor pool. Group II (30% of cases) was characterized by extensive destruction of oligodendrocytes at active sites of demyelina-tion in the absence of increased oligodendrocyte numbers in inactive plaque areas. In these lesions, remyelination was sparse or absent. Although there was profound heterogeneity of oligodendrocyte damage between patients, lesions from a single

Remyelination

Figure 6 Electron microscopy of an early multiple sclerosis lesion reveals active demyelina-tion occurring simultaneously with remyelination. A macrophage containing myelin debris is in proximity of both completely demyelinated axons (Ax), as well as thinly remyelinated axons (*). Source: Photo courtesy of Dr. Moses Rodriguez, Mayo Clinic, Rochester, Minnesota, U.S.A.

Figure 6 Electron microscopy of an early multiple sclerosis lesion reveals active demyelina-tion occurring simultaneously with remyelination. A macrophage containing myelin debris is in proximity of both completely demyelinated axons (Ax), as well as thinly remyelinated axons (*). Source: Photo courtesy of Dr. Moses Rodriguez, Mayo Clinic, Rochester, Minnesota, U.S.A.

individual, exactly matched for stage of demyelinating activity, showed very similar oligodendrocyte densities. Furthermore, the extent of early remyelination correlated with oligodendrocyte numbers within the lesion. Remyelination in early MS lesions is also associated with an increased expression of cell death inhibitory proteins such as bcl-2 (49). These studies suggest that early in MS, remyelination may be extensive and may occur simultaneously with demyelination (Figure 6). During the early stage of remyelination (myelin sheath formation), inflammation with prominent macrophage infiltration may be prominent within the lesion. The extent of remyelination at these early stages appears to depend on the availability of oligodendrocytes or their progenitor cells in the lesion. Furthermore, the profound heterogeneity in extent and topography of oligodendrocyte destruction in active demyelinating lesions suggests that myelin, mature oligodendrocytes and possibly oligodendrocyte progenitors, are differentially affected in subsets of MS patients. Different mechanisms of myelin and/or oligodendrocyte injury may be operating in an individual MS patient, and may thereby influence the likelihood of effective remyelination in the MS lesion.

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