The cascade of prion entry, peripheral replication, neuroinvasion, and neurodegeneration.

<p>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 PrP^Sc production exceeds PrP^Sc clearance.