Figure 1.
The cascade of prion entry, peripheral replication, neuroinvasion, and neurodegeneration.
After peripheral exposure, prions colonize and replicate in secondary lymphoid organs (SLOs) like spleen, Payer's patches, lymph nodes, and tonsils. FDCs are the main sites accumulating prions in SLOs. B cell-derived LTs and TNF facilitate prion accumulation by supporting development and maintenance of FDCs. Dedifferentiation of FDCs by LTβR-Ig delays neuroinvasion, whereas repetitive immunization accelerates prion pathogenesis. Prions reach the central nervous system (CNS) through autonomic nerves, directly after intracerebral inoculation, or via aerosols through immune-independent pathways. In the brain, prions replicate but are also cleared by microglia after opsonisation by astrocyte-borne Mfge8. Prion deposition comes about when PrPSc production exceeds PrPSc clearance.