The central hypothesis of this proposal is that patients with NF-1 have altered immune systems and activation of chronic inflammation pathways. The presence of NF-1 together with differences in the innate immune system significantly increases the risk of tumor formation. In addition, we hypothesize that variations in the immune system are responsible for the heterogeneous natural history of OPG. Research Strategy: There is no existing data in the literature on the immune system or its function in children with NF-1. In this study, we will generate initial data on circulating markers of inflammation and immunity, to characterize the innate immune system, and to test immune function in this population and appropriate controls. We will measure circulating cytokines, inflammatory markers and components of the immune system in circulating blood of subjects. Patients with NF-1, patients with NF-1 and OPG, and patients without NF-1 who have OPGs will be compared to their unaffected siblings and to each other. Methods: Blood (amount limited by body weight) and urine will be collected for analysis of serum cytokines, inflammation and immune mediators. Both ELISA and Multiplex technologies will be used to assay a panel of circulating cytokines and inflammatory markers. Immunophenotyping and functional assays will be performed. The immune response in the CNS is not homogeneous, and varies depending on the effector molecules released and their cell and signal specificities.We hypothesize that children with NF-1 who develop OPGs have developed tolerance to tumor antigens due to deficient activation and signaling of dendritic cells resulting in an inadequate antitumor immune response. Children with NF-1 have an increased incidence of gliomas, which most frequently involve the optic pathway and hypothalamus. Microglia, which are abundant in mouse and human optic pathway gliomas, respond to stimuli by producing prostaglandins and pro-inflammatory cytokines.2 A number of different cytokines are produced in response to tissue damage, activation of the immune system or the inflammatory response, and the cell and tissue response to cytokines depends upon the presence and number of receptors on each cell. We will collect blood for measurement of immunoglobulin levels and mast cell numbers. In addition, midkine, plasma histamine and serum SCF will be measured using ELISA and Mesoplex technologies. As this is a new study, we are currently in the process of identifying potential participants and collecting samples for analyses.
