Lymph nodal prion replication and neuroinvasion in mice devoid of follicular dendritic cells

Follicular Dendritic Cell Dedifferentiation by Treatment with an Inhibitor of the Lymphotoxin Pathway Dramatically Reduces Scrapie Susceptibility

“…For example, severe combined immunodeficient (SCID) mice and mice deficient in tumor necrosis factor alpha, LT␣, LT␤, or LT␤R all lack mature FDCs in lymphoid tissues, but a proportion develop disease after inoculation with a high or moderate dose of scrapie (17,31,39,42,48,51). In the permanent absence of FDCs, a study by Prinz et al (51) suggests that macrophages are plausible candidates for scrapie replication and neuroinvasion from lymphoid organs. However, neuroinvasion after inoculation with a high dose of scrapie possibly also occurs after direct uptake of infectivity by nerve terminals at the site of inoculation or after transport to peripheral nerves by DCs (2).…”

“…The most likely explanation for these observations is that, in the absence of FDCs at the time of scrapie challenge, trace amounts of infectivity from the inoculum persist in the host in a cell or compartment that is not affected by LT␤R blockade. Macrophages have been proposed as candidate cells for TSE accumulation in the absence of FDCs (51). The extended survival time in LT␤R-treated mice could simply be related to the time required for FDC networks to restore and initiate replication of the inocula.…”

Current Concepts and Controversies in Prion Immunopathology

“…This hypothesis is strengthened by the fact that even in wild-type lymph nodes, bright PrP signals outside FDC networks colocalized with a subset of ER-TR9-and MOMA-1-positive cells (Prinz et al, 2002).…”

“…We found that ablation of LTβR signaling prevents peripheral pathogenesis (Montrasio et al, 2000;Prinz et al, 2002), whereas ablation of TNFR1 signaling prevents prion pathogenesis in spleen but not in lymph nodes, despite the absence of FDCs. Moreover we have investigated some of the preconditions of transepithelial passage of prions, identifying M cells as a plausible candidate for the mucosal portal of prion infection.…”

“…As described repeatedly (Klein et al, 1997;Kaeser et al, 2001;Prinz et al, 2002), B-cell-deficient mice were entirely resistant to ip-administered prions, whereas TNF/LT-deficient mice were partially resistant. These findings differ from those reported by Mabbott and colleagues (2000) and suggest that the importance of B lymphocytes in prion pathogenesis might go beyond their role in FDC maintenance.…”