Pathogenesis of prion diseases: current status and future outlook

Prion diseases are progressive, transmissible neurodegenerative disorders with an invariably fatal outcome. Prions, the infectious agent of prion diseases, accumulate in the central nervous system, in organs of the secondary lymphoid system and in blood.Examples of prion diseases include bovine spongiform encephalopathy (BSE) in cows, scrapie in sheep and goat, chronic wasting disease in deer and elk, and sporadic and variant Creutzfeldt–Jakob disease in humans.Neuronal cytotoxicity of PrPSc depends on the expression of PrPC. Evidence indicates that the conversion of PrPC to PrPSc is deleterious, but the mechanisms of neural degeneration are still unclear.In this article, we describe the role of the immune system in prion diseases and review our current understanding of cellular and molecular mechanisms involved in peripheral prion replication and transport.Several prion diseases are transmitted by peripheral prion uptake (for example, ingestion of prion-contaminated food). After prion uptake, a replication phase occurs in lymphoid tissue before neuroinvasion.In the peripheral regions of the host, the abnormally folded, aggregated PrPSc, is amplified by cells of the immune system (for example, follicular dendritic cells) in the germinal centres, located in B-cell follicles of the spleen or lymph nodes.Depletion of mature follicular dendritic cells delays the development of prion disease following intraperitoneal inoculation. This could form the basis of a post-exposure prophylactic strategy.Recent findings indicate that chronic inflammation can induce the deposition of prion infectivity in organs previously believed to be prion free.