Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion

Marco Prinz, Mathias Helkenwalder, Tobias Junt, Petra Schwarz, Markus Glatzel, Frank L. Heppner, Yang Xin Fu, Martin Lipp, Adriano Aguzzi

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171 Scopus citations

Abstract

Peripheral infection is the natural route of transmission in most prion diseases. Peripheral prion infection is followed by rapid prion replication in lymphoid organs, neuroinvasion and progressive neurological disease. Both immune cells and nerves are involved in pathogenesis, but the mechanisms of prion transfer from the immune to the nervous system are unknown. Here we show that ablation of the chemokine receptor CXCR5 juxtaposes follicular dendritic cells (FDCs) to major splenic nerves, and accelerates the transfer of intraperitoneally administered prions into the spinal cord. Neuroinvasion velocity correlated exclusively with the relative locations of FDCs and nerves: transfer of CXCR5-/- bone marrow to wild-type mice induced perineural FDCs and enhanced neuroinvasion, whereas reciprocal transfer to CXCR5-/- mice abolished them and restored normal efficiency of neuroinvasion. Suppression of lymphotoxin signalling depleted FDCs, abolished splenic infectivity, and suppressed acceleration of pathogenesis in CXCR5 -/- mice. This suggests that prion neuroimmune transition occurs between FDCs and sympathetic nerves, and relative positioning of FDCs and nerves controls the efficiency of peripheral prion infection.

Original languageEnglish (US)
Pages (from-to)957-962
Number of pages6
JournalNature
Volume425
Issue number6961
DOIs
StatePublished - Oct 30 2003

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    Prinz, M., Helkenwalder, M., Junt, T., Schwarz, P., Glatzel, M., Heppner, F. L., Fu, Y. X., Lipp, M., & Aguzzi, A. (2003). Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. Nature, 425(6961), 957-962. https://doi.org/10.1038/nature02072