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Chapter 14 : Prionoses and the Immune System

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Abstract:

Transmissible spongiform encephalopathies (TSEs), prion diseases (or prionoses) are fatal neurodegenerative diseases of humans and animals. The TSEs are unique in that they can have three distinct etiologies. They can occur sporadically; be inherited in an autosomal dominant fashion; or, as in the majority of ruminant TSEs, be transmitted by an infectious agent. This chapter discusses the role of the immune system in prion pathogenesis and prion diagnostics, as well as active and passive therapeutic approaches to prion diseases. Prion infections still represent a fascinating biological phenomenon and stimulate interdisciplinary research efforts at the interface between neuroscience, biochemistry, immunology, and other related disciplines. Recent studies have indicated that both macrophages and FDCs are capable of localized production of the complement components C1 and C4, which may be activated by the increased disease-associated prion protein (PrP) to result in further deposition on FDCs in a cyclical amplification pattern. A focus of prion science has been on the deposition and amplification of PrP within lymphoid tissues, it is important to note that cells of the immune system are migratory, continually recirculating between the blood and the tissues via the lymph. A number of techniques that are currently in development focus on identification of low levels of PrP in lymphoid tissues for antemortem diagnostics.

Citation: Richt J, Young A. 2011. Prionoses and the Immune System, p 173-181. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch14

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Figures

Image of FIGURE 1
FIGURE 1

Prion replication. The infectious agent in prion diseases contains no nucleic acid and information appears to be stored in the structure of PrP. Prion aggregates can grow by incorporating new prion protein (PrP) and inducing it to refold into the pathological prion form, PrP The precise stoichiometry of the replication process remains uncertain.

Citation: Richt J, Young A. 2011. Prionoses and the Immune System, p 173-181. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch14
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Image of FIGURE 2
FIGURE 2

Accumulation of prions in germinal centers. PrP concentrates and amplifies on the surface of follicular dendritic cells (FDCs), where it may serve as a continued source of systemic infection of the lymphoreticular system. During this process, PrP complexes may interact both with FDCs and the surrounding B cells, although there are no documented defects in B-cell proliferation associated with prion infection. In contrast, effects of prion infection on germinal center architecture are documented, although there is no apparent dysfunction within the immune system.

Citation: Richt J, Young A. 2011. Prionoses and the Immune System, p 173-181. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch14
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Image of FIGURE 3a
FIGURE 3a

Comparison of the delivery of protein antigen and PrP to lymph node germinal centers. (A) Antigen is delivered to the follicular dendritic cells (FDCs) of germinal centers in at least one of two ways. Early delivery appears to occur as a cell-free, soluble antigen, likely complexed with complement; it is delivered passively via the afferent lymph to the germinal center, where it binds to complement receptors on the surface of FDCs. Over the first day, antigen may also be delivered by specialized “antigen transport cells” (dendritic cells) to the margins of the germinal center, where it is then shuttled to the surface of the FDCs. These cell-surface complexes then directly stimulate B-cell proliferation and maturation of the immune response, and some are released in the form of membrane vesicles or iccosomes where they may further stimulate B cells and tingible body macrophages. (B) PrP is delivered to the FDCs of germinal centers either cell-free or associated with dendritic cells; it directly stimulates activation of the classical pathway of complement. It may then follow normal delivery mechanisms to reach the FDCs of germinal centers. Unlike other antigens, however, PrP appears to be retained and potentially amplified on the surface of the FDCs, where it may serve as a continued reservoir of infection.

Citation: Richt J, Young A. 2011. Prionoses and the Immune System, p 173-181. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch14
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Image of FIGURE 3b
FIGURE 3b

Comparison of the delivery of protein antigen and PrP to lymph node germinal centers. (A) Antigen is delivered to the follicular dendritic cells (FDCs) of germinal centers in at least one of two ways. Early delivery appears to occur as a cell-free, soluble antigen, likely complexed with complement; it is delivered passively via the afferent lymph to the germinal center, where it binds to complement receptors on the surface of FDCs. Over the first day, antigen may also be delivered by specialized “antigen transport cells” (dendritic cells) to the margins of the germinal center, where it is then shuttled to the surface of the FDCs. These cell-surface complexes then directly stimulate B-cell proliferation and maturation of the immune response, and some are released in the form of membrane vesicles or iccosomes where they may further stimulate B cells and tingible body macrophages. (B) PrP is delivered to the FDCs of germinal centers either cell-free or associated with dendritic cells; it directly stimulates activation of the classical pathway of complement. It may then follow normal delivery mechanisms to reach the FDCs of germinal centers. Unlike other antigens, however, PrP appears to be retained and potentially amplified on the surface of the FDCs, where it may serve as a continued reservoir of infection.

Citation: Richt J, Young A. 2011. Prionoses and the Immune System, p 173-181. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch14
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