Class II HLA molecules are required for initiation of an immune response and can act as targets for effector CD4+ T lymphocytes. Therefore, aberrant expression of class II genes has been suggested as a factor in the generation of some organ-specific autoimmune disease. Class II molecules are not normally expressed on certain cell types in the central nervous system (CNS), but can be induced on endothelial cells and astrocytes by several agents. In addition, microglia, which constitutively express class II genes, can be induced to higher levels of expression. The purpose of this project is to understand genetic molecular mechanisms that control the expression of HLA class II genes in the CNS. Current research is examining the effect of positive and negative regulators of class II expression in human glial cells and cell lines derived from glioblastomas. Interleukin-1beta (IL-1beta), normally present in the CNS, suppresses class II induction by interferon-gamma in adult human astrocytes, endothelial cells, and a glioblastoma multiforme cell line. Constitutive class II expression is also inhibited in the glioblastoma by IL-1beta. Such an effect is not observed on class II expression in human microglia. In contrast, infection with measles virus and agents that produce an increase in intracellular levels of cyclic AMP induce class II gene expression. Class II gene enhancer elements and their DNA-binding proteins that are involved in mediating these effects are being examined. Understanding these molecular mechanisms is being explored to investigate the roles of these factors in autoimmunity in the CNS.
