Role of Class II MHC Antigens in Neurologic Diseases

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DESCRIPTION (provided by applicant): MHC class II molecules are expressed in the central nervous system (CNS) during a number of neurologic disorders and demyelinating disease. In a majority of these diseases, T cells are generally absent in the affected CNS. To address the importance of class II MHC in CNS disorders, we have characterized two models of demyelination that exhibit class II MHC hyper-expression on microglial cells. Characterizations of these disease models show that the deletion of class II MHC caused the alleviation of overt symptoms, reduced neuropathology/demyelination, reduced microglial activation/proliferation and reduced production of inflammatory cytokines. Most intriguingly, the role of class II MHC is unaffected by the absence of T cells in RAGb mice, but dependent on an intact class II MHC cytoplasmic tail. This caused us to propose that class II may serve an in vivo role in signal transduction, distinct from its conventional biologic role in antigen presenting. The Aims are: 1.Analyze a transgenic mouse strain, H-2M for its response to cuprizone treatment. If conventional antigen processing is not important, then the deletion of H-2M should not affect cuprizone-induced demyelination. 2.Analyze how class II MHC and T cells affect the remyelination process. Recent studies in our laboratory have demonstrated that inflammatory cytokines are necessary for optimal remyelination. The presence of MHC class II causes enhanced cytokine expression, therefore it is timely to determine the role of MHC during remyelination, and if lymphocytes are involved in this process. 3. Determine novel mediators of class II MHC-mediated signaling. We will determine if recently discovered mediators of class II signaling, cell activation and proliferation are affected in microglia/macrophages. 4. Identify genes that are activated upon class II MHC engagement. in a microglial-macrophage line by Affy metrix screening, and assess the status of these genes in the cuprizone model.