The underlying mechanisms involved in the pathogenesis of the human demyelinating disease multiple sclerosis (MS) are not well understood. Available evidence indicates that the cause of MS is multifactorial and includes both the genetic background of the host as well as environmental influences. Infection of susceptible strains of mice with the coronavirus mouse hepatitis virus (MHV), a positive-stranded RNA virus, leads to a chronic, progressive, demyelinating disease with many clinical and histologic similarities with MS. Animals often develop partial to complete hind-limb paralysis. Although viral RNA persists in the CNS, the host immune response is thought to be the key factor in contributing to demyelination. T-lymphocytes and macrophages are associated with demyelinating plaque lesions in both MS patients as well as MHV-infected mice. The long range goal of this research proposal is to define the cellular mechanisms mediating demyelination in MHV-infected mice. First, emphasis will be placed on the role of the CD4+ T lymphocytes. These cells appear to be crucial in participating in the demyelinating process most likely by release of soluble factors which activate both inflammatory macrophages and resident glia to release cytotoxic factors. A second goal of this project is to study the signals i.e. chemokines which function in attracting CD4+ T cells as well as macrophages to the CNS to sites of viral persistence. Finally, this proposal will analyze the contributions of cytotoxic factors tumor necrosis factor alpha (TNF-a) and nitric oxide (NO) in MHV-induced demyelination. Together, these studies will provide insight into the complex immunological mechanisms involved in CNS demyelinating disease and allow a better understanding of the pathological mechanisms which exist in human demyelinating disease.
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