Contribution to Disease

Damage to oligodendrocytes can occur in a variety of ways, including microbial infections, injury, autoimmunity, genetic defects, inflammation, and exposure to toxins. Although great strides have been made in understanding the core features of many of these demyelinating actions, the molecular events leading to damage of oligodendrocytes and, in many cases, dysmyelation or demyelination are not totally understood.

1. Multiple Sclerosis

Multiple sclerosis (MS) is a major demyelinating disease with pathological features similar to those of the experimental animal model, experimental allergic encephalomyelitis (EAE). Blood vessels in the CNS of MS patients characteristically have inflamed perivascular cuffs containing T lymphocytes and monocytes recruited from peripheral circulation. Although much studied, the cause of oligodendrocyte death in MS is not clear. Some investigators have presented evidence that oligodendrocytes in acute and chronic demyelinated lesions undergo apoptotic death, whereas many others have found evidence of only necrotic cell death. Plaques of demyelination are present in the white matter, with chronic plaques devoid of both oligodendrocytes and myelin, as shown in Fig. 4. Reactive astrocytosis is also a prominent feature of MS lesions.

Many factors have been linked etiologically with MS. CD4+ and CD8+ lymphocytes have both been reported to lyse oligodendrocytes, with CD4+ cells doing so by a non-MHC-restricted mechanism involving perforin release and CD8 + by a MHC-restricted mechanism. Furthermore, gd T lymphocytes found in MS lesions may damage oligodendrocytes by a non-antigen-specific necrotic pathway. Activated macro-phage/microglia also have the capacity to necrotically kill oligodendrocytes. Although oligodendrocyte injury and death can be mediated by both antibody-dependent and antibody-independent complement pathways, as well as by exposure to nitric oxide, none of these factors can clearly be shown to be the sole cause of MS.

2. Human T Cell Lymphotropic Virus, Type 1

Human T cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that causes human adult T cell leukemia. Frequently, however, it causes the demyelinating neurological disease tropical spastic paraparesis (TSP), so named because it was thought only to occur in tropical geographic areas of the world. However, it has been found multiracially, in many countries, and in a wide range of climates. Because TSP occurrence has also been documented in individuals residing in countries with temperate climates, the name TSP is considered a misnomer and it has been proposed that it be called HTLV-1-associated myelopathy (HAM).

Luxol Multiple Sclerosis
Figure 4 Demyelinated plaque occurring in the brain of a patient with multiple sclerosis. Tissue section staining with Luxol fast blue visualizes myelinated areas (dark) and regions devoid of myelin (light).

Symptoms associated with the chronic form of MS are similar to those of TSP/HAM, particularly in those patients exhibiting cerebellar signs. The occurrence of MS is rare in tropical regions, and the few patients from HLTV-l-endemic regions who were tested for HTLV-1 antibodies were negative. However, some individuals in temperate regions originally diagnosed as having MS in reality had TSP/HAM.

3. Progressive Multifocal Leukoencephalopathy

JC virus (JCV), a human polyomavirus closely related to BK virus and simian virus 40 (SV40), is the cause of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML), the only human disease known to be caused by infection with JCV. JCV infects 80% or more of the world's population, with initial infection occurring predominantly during childhood. The target of this ubiquitous virus is the myelin-producing oligodendrocyte. The virions can be detected in the nuclei of infected oligodendrocytes in a dense, crystalline arrangement called inclusion bodies. Prior to the AIDS pandemic, PML was a relatively rare disease affecting primarily immunosuppressed cancer patients with lymphoma or leukemia and transplant recipients receiving immunosuppressive therapy. It has been estimated that PML now occurs in about 5% of HIV-1-infected AIDS patients and is a major cause of death. Treatment of PML has been elusive. Some AIDS patients with PML receiving high-intensity antiretroviral therapy, including protease inhibitors, have shown clinical improvement, probably because the drug treatment regimen improved their general immunocompetence. Other AIDS patients with PML receiving high-intensity antiviral drug therapy showed no survival benefit from the treatment.

4. Other

Altered homeostasis of the neurotransmitter glutamate has also been postulated to cause excitotoxic death of oligodendrocytes. This depends on whether glutamate homeostasis is transiently or chronically altered. For example, exposure to short ischemic periods followed by transient increases in extracelluar glutamate may produce only limited damage to oligodendrocytes that can be repaired through the differentiation of oligodendrocyte precursors. Conversely, extended disturbances in glutamate signals may result in progressive oligodendrocyte cell death that exceeds the intrinsic capacity for oligodendrocyte repair, causing permanent damage to the oligoden-drocyte population.

Toxic factors and genetic defects such as those seen in the leukodystrophies and Pelizaeus Merzbacher disease can also cause dysmyelination or demyelina-tion. Exposure to free radical donors such as superoxide (O;T) or nitric oxide (NO), to free radical generating systems such as catecholamines, heat shock, and irradiation, and to agents that increase intracellular calcium concentrations, such as calcium ionophores, kainite, and myelin basic protein, has also been shown to kill oligodendrocytes.

A small percentage of all gliomas, approximately 5%, are oligodendroglial in lineage. These relatively avascular oligodendrogliomas initially form in the white matter and grow into the gray matter as they progress. The tumors can be grouped into two categories: the low-grade, less aggressive oligodendro-gliomas or the more aggressive, anaplastic oligoden-drogliomas. As a rule, a tumor in the low-grade category tends to be a pure oligodendroglioma, whereas the anaplastic tumors are a mixture of astrocytomas and oligodendrogliomas, also known as oligoastrocytomas. Although oligodendrogliomas are seen mainly in adults, they can also occur infrequently in children. Treatment strategies for oligodendrogliomas include surgical removal, radiation therapy, and chemotherapy.

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