Key Points
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Prion diseases are fatal, transmissible, neurodegenerative conditions of sporadic, infectious, iatrogenic or genetic origin. The infectious agent is termed a prion and consists of or coincides with scrapie prion protein (PrPSc), which is a misfolded conformer of cellular prion protein (PrPC).
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Besides enabling prion replication and mediating prion-induced neurotoxicity, the ubiquitously expressed, membrane-anchored PrPC is involved in myelin maintenance under physiological conditions. Numerous other functions have been attributed to PrPC, including many within the immune system, but they have not been mechanistically elucidated and some are controversial.
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In acquired prion diseases, prions are often first found in lymphoid tissues, mainly in association with follicular dendritic cells (FDCs). From lymphoid tissues, prions exploit nerves of the autonomic nervous system to reach the central nervous system (CNS), where they have their toxic effect.
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Lymphoid tissue inducer cells and B cells instruct perivascular stromal cells to form mature FDCs through tumour necrosis factor receptor 1 and lymphotoxin-β receptor signalling. Interference with these pathways can temporally deplete FDCs and retard neuroinvasion in experimental models of peripheral exposure to prions, so this can represent a post-exposure prophylaxis approach.
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Prion infection does not induce an apparent peripheral immune response but activates microglia and astrocytes in the CNS. Microglia phagocytose prions, thereby playing a protective part in the disease development.
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Immunotherapy, including both active and passive immunization, provides the potential to combat prion disease. However, great caution should be taken because of the striking toxicity of certain PrP-specific antibodies.
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 Creutzfeldt–Jakob 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.
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Acknowledgements
We apologize to all those colleagues whose work was discussed without proper quotation owing to space constraints. We thank T. P. Johnson for critically reading our manuscript. A.A. is the recipient of an Advanced Grant of the European Research Council and is supported by grants from the European Union (PRIORITY and NEURINOX), the Swiss National Foundation, the Foundation Alliance BioSecure, the Novartis Research Foundation and the Clinical Research Priority Program (KFSP) of the University of Zurich, Switzerland. M.N. received grants from Collegio Ghislieri (Pavia, Italy) and the Foundation for Research at the Medical Faculty of the University of Zurich.
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Glossary
- Protein-only hypothesis
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Introduced by Griffith and formally enunciated by Prusiner, it states that prions are unconventional infectious agents that are devoid of informational nucleic acids and that uniquely consist of an infectious, pathogenic protein.
- Prion
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The aetiological agent of prion disease; prion is short for proteinaceous infectious particle.
- Scrapie prion protein
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(PrPSc). The pathological version of prion protein that is present in the central nervous system and other tissues of patients with transmissible spongiform encephalopathies. It is believed to differ from cellular PrP only in terms of post-translational modifications.
- Cellular prion protein
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(PrPC). The physiological version of prion protein, which is present in the central nervous system and other tissues under normal circumstances.
- Prion diseases
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Also known as transmissible spongiform encephalopathies (TSEs). These are a group of transmissible neurodegenerative diseases that affect humans and various mammals.
- Prion strains
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Natural sources or isolates of prions that, when inoculated into genetically homogeneous hosts, induce a prion disease with peculiar clinical, histological and biochemical features.
- Propagons
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Proteinaceous aggregates that are capable of seeding a self-perpetuating reaction of templated nucleation within a biological system. Propagons are not necessarily identical to scrapie prion proteins but might represent a subset of prion protein conformations, some of which might not be resistant to proteolysis. Propagons could, in principle, have specific post-translational modifications.
- Prionoids
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Self-aggregating proteins that are capable of transmitting between cells within one organism, but not from one organism to another. Amyloid-β, tau, huntingtin and amyloid A protein are examples of prionoids. Synuclein was thought to be a prionoid, but recent evidence suggests that it might behave like a bona fide prion.
- Follicular dendritic cells
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(FDCs). Stromal cells derived from platelet-derived growth factor receptor-β (PDGFR)+ perivascular precursors and localized in lymphoid follicles. FDCs trap and retain immune complexes to stimulate an immune response. FDCs also express milk fat globule epidermal growth factor 8 (MFGE8) to facilitate the removal of apoptotic cells in secondary lymphoid organs.
- Mastitis
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Inflammation occurring in the mammary gland. It can be caused by infection or by blockage of milk ducts.
- M2 phenotype
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Activated macrophages or microglia that show phagocytic behaviour and express factors such as interleukin-4 (IL-4), IL-10 and arginase 1.
- M1 phenotype
-
Activated macrophages or microglia that show pro-inflammatory features and express factors such as interleukin-1β, tumour necrosis factor and inducible nitric oxide synthase.
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Aguzzi, A., Nuvolone, M. & Zhu, C. The immunobiology of prion diseases. Nat Rev Immunol 13, 888–902 (2013). https://doi.org/10.1038/nri3553
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DOI: https://doi.org/10.1038/nri3553
