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Interferon-γ-Induced Oligodendrocyte Cell Death: Implications for the Pathogenesis of Multiple Sclerosis

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Abstract

Background

The histopathology of multiple sclerosis (MS) is characterized by a loss of myelin and oligodendrocytes, relative preservation of axons, and a modest inflammatory response. The reasons for this selective oligodendrocyte death and demyelination are unknown.

Materials and Methods

In light of the T lymphocyte and macrophage infiltrates in MS lesions and the numerous cytokines these cells secrete, the direct influence of cytokines on survival of cultured oligodendrocytes and sensory neurons was investigated. Expression of cytokines in vivo was determined by immunolabeling cryostat sections of snap-frozen tissue containing chronic active lesions from four different patients. The samples were also analyzed for the presence of apoptotic nuclei by in situ labeling of 3′-OH ends of degraded nuclear DNA.

Results

The results showed: (i) interferon-γ (IFNγ) to be a potent inducer of apoptosis among oligodendrocytes in vitro and that this effect can be reversed by leukemia inhibitory factor (LIF); (ii) IFNγ has a minimal effect on the survival of cultured neurons; (iii) IFNγ at the margins of active MS plaques but not in unaffected white matter; (iv) evidence for apoptosis of oligodendrocytes at the advancing margins of chronic active MS plaques.

Conclusions

Injury to a substantial number of oligodendrocytes in MS is the result of programmed cell death rather than necrotic cell death mechanisms. We postulate that IFNγ plays a role in the pathogenesis of MS by activating apoptosis in oligodendrocytes.

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Acknowledgments

Tissue specimens obtained from the National Neurological Research Specimen Bank, VAMC, Los Angeles, CA 90073, which is sponsored by NINDS/NIMH, National Multiple Sclerosis Society, Hereditary Disease Foundation, Comprehensive Epilepsy Program, Tourette Syndrome Association, Dystonia Medical Research Foundation, and Veterans Health Services and Research Administration, Department of Veterans Affairs.

This work was supported in part by grants from the National Institutes of Health. T. Vartanian is a recipient of a Clinical Investigator Development Award from the National Institute of Neurologic Disorders and Stroke.

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Authors and Affiliations

  1. Departments of Neurology and Pathology, Beth Israel Hospital, Boston, Massachusetts, USA

    Timothy Vartanian, You Li, Meijuan Zhao & Kari Stefansson

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  1. Timothy Vartanian
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Contributed by R. Cotran on July 8, 1995.

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Vartanian, T., Li, Y., Zhao, M. et al. Interferon-γ-Induced Oligodendrocyte Cell Death: Implications for the Pathogenesis of Multiple Sclerosis. Mol Med 1, 732–743 (1995). https://doi.org/10.1007/BF03401888

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