The overall goal of this project is to understand mechanisms of cellular immune reactions in the central nervous system (CNS). The hypothesis to be tested is that prominent surface expression of specific molecules on CNS resident cells, particularly endothelial cells, play critical roles in the pathogenesis of immune-mediated injury. We will use immunohistochemistry at the light and electron microscopic levels to localize specific proteins in the CNS, and in situ hybridization to determine sites of synthesis. (I). Class II major histocompatibility complex (Ia) molecules will be analyze in animal T cell immune response models. In experimental allergic encephalomyelitis (EAE) in inbred strains of mice and their F1 progeny we will determine if there is preferential expression of susceptible parent strain-specific Ia molecules in the in response to different myelin antigens and will develop an in vitro system for a lysis of Ia regulation on conventional and resident CNS antigen-presenting cells. Temporal sequences and cellular localization of resident cell Ia molecules will be analyzed in delayed hypersensitivity reactions to determine if cell surface Ia expression precedes or is a secondary effect of T cell infiltration in situ. (II). Endothelial cell surface molecules will be analyzed in human CNS inflammatory diseases. Effect of HIV-1 infection on endothelial cell expression of major histocompatibility complex molecules will be analyzed in patients with AIDS; HLA-DR-specific mRNA will be identified in multiple sclerosis (MS) and viral encephalitis; and fibronectin, a glycoprotein which enhances mononuclear cell attachment to endothelial cells, will be identified and its site of synthesis determined in MS. (III). Potential contributions to demyelination of antibodies to external surface myelin peptides will be determined by identifying protein sequences localized outer leaflets of CNS myelin which may be targets of immune-mediated injury and the comparing effects of monoclonal antibodies to synthetic peptides of various regions of myelin on clinical course and demyelination in EAE. These studies will provide further insights into regulation and cell surface interactions of molecules which participate in CNS immune responses and may contribute to the development of specific strategies for treatment of inflammatory and demyelinating CNS diseases.
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