Germinal Center Function in Prion Disease

Transmissible spongiform encephalopathies (TSEs) are a family of invariably fatal infectious neurological diseases that occur in many large mammalian species, characterized by the progressive conversion of the normal cellular prion protein (PrPC) into a protease-resistant pathological form (PrPSc). Although transmission has traditionally been associated with the consumption of infected food products, it is now clear that transplants of blood or other organs can result in prion disease creating significant public health implications. <P> Neural cells are the primary target of prion pathogenesis, but immune cells also form an important reservoir of PrPSc. Specifically, follicular dendritic cells (FDCs) and B cells in germinal centers are the earliest identifiable source of PrPSc propogation, and recent data has extended these reservoirs to include any tissue demonstrating B-lymphoid nodules as a result of chronic inflammation. Our research has focused on defining the importance of recirculating B cells in prion pathogenesis. <P>We have previously described two equally represented but phenotypically distinct subsets of B cells in the peripheral blood of sheep, and additional data from our laboratory has clearly demonstrated a disruption in the differentiation and phenotype of these two B cell subsets in response to scrapie infection. To map the mechanisms involved, we have developed a series of ovine FDC cell lines that retain and potentially replicate PrPSc in vitro, as well as supporting normal B cell proliferation. <P>It is the broad, long term goal of this proposal to foster the growth of immunology research in South Dakota by defining molecular mechanisms involved in the regulation of B cell differentiation in prion infected germinal centers. It is the focus of this application to define the molecular mechanisms occurring in germinal centers during prion replication. To this end, we will (a) Define pathways of normal B cell differentiation in our in vitro coculture system; (b) Map changes in these pathways associated with prion infection and (c) introduce undergraduate students to basic research methodologies in Immunology and Prion science. In addition to providing important baseline data on the local immunological effects of prion infection, we will enhance the education of South Dakota Undergraduate students in two areas of biomedical research of significant need to the United States. <P>Blood is known to be infectious in prion diseases. To address this concern, individuals at risk for harboring human prion disease are now excluded from donating blood, resulting in a drop of 500,000 units per year in American Blood Banks, many of whom are likely uninfected potential donors. The focus of this application is to examine the role that blood-borne B lymphocytes play in prion diseases, which may directly lead to development of new methods to screen or purify blood supplies and continue to safeguard the US Blood Supply.