Acquired, inflammatory leukoencephalopathies
Inflammation may either be related to infection, or indicate the presence of an autoimmune process. Infection of oligodendroglial cells is unusual, and is practically confined to JC virus infection in immunocompromised hosts which results in progressive multifocal leukoencephalopathy (which will be discussed in the CNS Infections lecture). Autoimmune attack on myelin may also be seen in a variety of contexts, but the most important disease in this category is multiple sclerosis.  

The pathologic hallmark of MS is the demyelinative plaque. These basically occur in two forms: inactive, which consists of a well-demarcated area of myelin loss with relative axonal preservation, admixed reactive astrocytes, and perivascular lymphocytes; and acive, which consists of all of these features plus lipid-laden macrophages.

Recently developed techniques have allowed more precise studies of MS plaques, particularly with regard to assessing oligodendrocyte pathology. In these studies, plaque activity is defined by immunocytochemical demonstration of macrophage activation antigens, and oligodendroglial cells are identified by in-situ hybridization for proteolipid protein mRNA and immunocytochemical staining for myelin oligodendrocyte glycoprotein (MOG). On the basis of 82 cases in which brain biopsies from early bouts of the disease were available, 16 autopsy cases of acute MS, and 9 cases of chronic acute MS, several types of MS plaque have been defined:

1. Demyelination with relative sparing of oligodendrocytes and rapid remyelination - this is the expected process when the pathogenetic process is primarily directed against the myelin sheath.
2. Demyelination with complete loss of oligodendrocytes and lack of remyelination - these are most likely due to a pathogenetic mechanism which not only eliminates mature oligodendrocytes but also effectively destroys the progenitor pool.
3. Demyelination with a gradient of oligodendrocyte loss from the active lesion into the plaque center - oligodendrocytes expressing stress proteins while attempting remyelination in the hostile environment of an active plaque may themselves become targeted for destruction.
4. Lesions with oligodendrocyte death occurring in the periplaque white matter outside the zone of active myelin degeneration - in a subgroup of MS patients, oligodendrocyte destruction may lead to secondary demyelination.

These findings suggest that the pathogenetic mechanisms leading to demyelination may be fundamentally distinct in different groups of MS patients, and may have important implications with respect to the design of future therapeutic studies in multiple sclerosis. Practically speaking, however, most MS plaques demonstrate: 2. Demyelination with complete loss of oligodendrocytes and lack of remyelination - these are most likely due to a pathogenetic mechanism which not only eliminates mature oligodendrocytes but also effectively destroys the progenitor pool.

Remyelination
There are two general hypotheses to explain the absence of full remyelination in MS lesions: 1) The presence of an inhibitory local environment may prevent spontaneous repair, and 2) The absence of endogenous cells or factors required for new myelin synthesis may prevent remyelination. Experimental strategies have been designed to either block inhibitory immune responses through immunosuppression, stimulate endogenous oligodendrocyte proliferation and differentiation with growth factors, or directly replace lost oligodendrocytes through glial cell transplantation. Recent studies indicate that oligodendroglial precursor cells are present within chronic MS plaques, which suggests that failure of remyelination is due to molecular abnormalities of chronically demyelinated axons or the microenvironmental imbalances described above.