<p>(a) Natural prion diseases are often acquired <i>via</i> peripheral exposure such as orally, or through skin lesions. How prion reaches its peripheral targets is not known. (b) Direct invasion of the central nervous system might occur with high doses of prion or exposure to neuroinvasive strains. (c) Whereas after exposure to limiting doses of infectivity or less neuroinvasive strains, replication in FDCs in the germinal centers of local lymphoid tissues might be necessary prior to neuroinvasion via closely associated nerve fibers. FDCs are dependent on the presence of B lymphocytes for maturation signals, such as lymphotoxin. (d) Haematogenous spread of infectivity <i>via</i> circulating bone marrow derived cells would not play a role in direct neuroinvasion.</p
