The human T-lymphotropic virus type I (HTLV-I), the first human retrovirus to be characterized, is associated with adult T-cell leukaemia and a chronic progressive disease of the central nervous system termed tropical spastic paraparesis, or HTLV-I-associated myelopathy. Only 1% of individuals infected with HTLV-I develop clinical disease however. The various manifestations of an HTLV-I infection may be related to differences in the genetic backgrounds of individuals, infection with variant strains of HTLV-I, differences in viral tropism or host immune response to the virus. Whereas the humoral response to HTLV-I is well characterized, little is known about the human cellular immune response, such as the production of cytotoxic T lymphocytes. Here we report the presence of high levels of circulating HTLV-I-specific cytotoxic T lymphocytes in patients with HTLV-I associated neurological disease but not in HTLV-I seropositive individuals without neurological involvement. These cytotoxic T lymphocytes are CD8+, HLA class I- restricted and predominantly recognize the HTLV-I gene products encoded in the regulatory region pX. These findings suggest that HTLV-I-specific cytotoxic T lymphocytes may contribute to the pathogenesis of associated neurological disorders associated with HTLV-I.
Primary demyelination in the central nervous system results from damage to the myelin sheath or oligodendroglia and can be produced by a variety of mechanisms, including metabolic disturbances, toxicities, infection, and autoimmunity. The major human demyelinating disease affecting the central nervous system is multiple sclerosis (MS). Although the etiology of MS is not known, existing data indicate that both genetic and environmental factors contribute to pathogenesis. Experimental allergic encephalomyelitis (EAE) is induced by immunization of genetically susceptible animals with myelin proteins. This is mediated by autoimmune T cells. Characterization of MHC restriction, fine specificity of antigen recognition, and T cell receptor (TCR) usage by encephalitogenic T cells has resulted in highly specific immunotherapies. Both HLA and TCR genes have been linked to susceptibility for MS which is widely believed to be mediated by T cells that recognize an as yet unidentified autoantigen. Because of the advances in the understanding and treatment of EAE, recent research in MS has been focused on the characterization of cellular immune responses against myelin components. The results of these studies are reviewed and the potential implications of these findings for the pathogenesis and future therapy of MS are examined.
Magnetic resonance imaging is a highly sensitive method for the detection of the lesions of multiple sclerosis and renders possible the study and the evolution of early lesions. Previous reports on magnetic resonance imaging following gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) injection demonstrated that new lesions can be recognized by contrast enhancement. The pathological basis of these observations is uncertain. We have had the opportunity to study at autopsy the brain of a patient with chronic progressive multiple sclerosis who suffered acute worsening leading to death. Magnetic resonance imaging performed 10 days and 4 weeks prior to death showed new Gd-DTPA-enhanced lesions in the posterior hemispheric white matter adjacent to the lateral ventricles. Light microscopic examination of these areas demonstrated them to be fresh lesions comprising intense inflammatory activity and dense perivascular cuffs within an edematous lesion center and a striking parenchymal mononuclear cell infiltration at the margins of the lesions. Lesions that were demonstrated by increased signal on T2-weighted images, but were not enhanced following administration of Gd-DTPA, were all of the chronic type, either inactive or active. None of these showed the intense inflammatory activity of the acute lesions and most displayed fibrous astrogliosis.
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