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REVIEWS
The immunobiology of prion diseases
Adriano Aguzzi1, Mario Nuvolone1,2 and Caihong Zhu1
Abstract | Individuals infected with prions succumb to brain damage, and prion infections continue to be inexorably lethal. However, many crucial steps in prion pathogenesis occur in lymphatic organs and precede invasion of the central nervous system. In the past two decades, a great deal has been learnt concerning the cellular and molecular mechanisms of prion lymphoinvasion. These properties are diagnostically useful and have, for example, facilitated preclinical diagnosis of variant CreutzfeldtJakob disease in the tonsils. Moreover, the early colonization of lymphoid organs can be exploited for post-exposure prophylaxis of prion infections. As stromal cells of lymphoid organs are crucial for peripheral prion infection, the dedifferentiation of these cells offers a powerful means of hindering prion spread in infected individuals. In this Review, we discuss the current knowledge of the immunobiology of prions with an emphasis on how basic discoveries might enable translational strategies.
Diseases caused by prions are fatal neurodegenerative conditions that affect humans and several other mammals (TABLE1). The transferral of brain extracts from affected individuals into permissive host species can transmit the disease1. Transmission among humans occurred during the kuru epidemic in Papua New Guinea through cannibalistic rituals2. In addition, more than 450 cases of iatrogenic Creutzfeldt Jakob disease (iCJD) have occurred following pituitary hormone treatment or surgical procedures3. Finally, bovine spongiform encephalopathy (BSE) has affected more than180,000 cattle worldwide (see the http://www.oie.int/en/animal-health-in-the-world/bse-portal/
Web End =BSE Portal on the World Organisation for Animal Health website) and has caused variant CJD (vCJD) in humans4. vCJD was shown to be transmitted through blood or blood derivatives, even from subclinical donors5,6.
According to the protein-only hypothesis, the infectious agent that is, the prion itself consists of scrapie prion protein (PrPSc), which is an assembly of conformers of cellular prion protein (PrPC)7. A PrPSc aggregate can recruit PrPC proteins and can perpetuate its own amplification7 in a similar way to crystal growth and fragmentation8. When this cycle occurs within the central nervous system (CNS) and involves membrane-anchored PrPC at the neuronal surface, a neurotoxic signal is triggered, plausibly through PrPC itself9. This results in the typical spongiform changes that are seen in diseased brains. The recognition of the infectious potential of prion diseases...