MOLECULAR IMMUNOPATHOGENESIS OF DEMYELINATING DISEASE

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The central goal of this program project is the analysis of crucial cellular and soluble elements involved with in situ central nervous system (CNS) immune responses. Specific emphasis has been placed on two cell types, the B-cell and the astrocyte, and the immune functions which they may play in inflammatory CNS demyelination. Project No. 1 is concerned with cytokine production by astrocytes, particularly the immunomodulatory cytokine interleukin-6 (lL-6). Studies will focus on the investigation of the cellular and molecular mechanisms involved in astrocyte lL-6 gene expression, and characterize the signaling pathways, cis-acting DNA elements and astrocyte nuclear factors involved in lL-6 induction. Project No. 2 is also examining a mediator of immune responses produced by astrocytes, this being complement proteins. Project No. 2 will define the structural and functional characteristics of complement proteins produced by astrocytes, and analyze the molecular aspects of complement gene expression in response to the cytokine, interferon-gamma (lFN-gamma). Project No. 3 will determine the effects of anti-idiotype (anti-id) in altering humoral and cellular immunity to myelin basic protein (MBP). Both in vitro effects of anti-id on T and B-cells, and in vivo effects in altering murine experimental allergic encephalomyelitis (EAE) will be examined. In addition, possible relationships with multiple sclerosis (MS) will be studied. Project No. 4 will determine the molecular features of ld-bearing monoclonal antibody (MAb), the T-cell receptor (TCR) and MAb anti-lds with which they react. The emphasis will be on ld-anti-ld reactions involving MBP peptides. The objective is to determine is the molecular recognition theory can provide a structural explanation for the reactions of the immune network proposed by Jerne. The unifying theme is to study cellular (T-cells, B-cells, astrocytes) and soluble (cytokines, complement proteins, antibodies) factors involved with in situ CNS immune responses, and the ultimate relationship of these components to inflammatory CNS demyelinating diseases such as MS and EAE.