Follicular dendritic cells in scrapie pathogenesis

  • K. L. Brown
  • K. Stewart
  • D. Ritchie
  • H. Fraser
  • W. I. Morrison
  • M. E. Bruce
Part of the Archives of Virology. Supplementa book series (ARCHIVES SUPPL, volume 16)


Scrapie pathogenesis was studied in chimaeric mice that carried the prion protein (PrP) gene only in particular cells of the immune system. These mice were produced by grafting bone marrow from PrP expressing donors into PrP deficient recipients and vice versa. As follicular dendritic cells are not replaced significantly from the bone marrow in adult mice, this procedure resulted in a mismatch in PrP genotype between these cells and bone marrow derived cells such as lymphocytes. Using these models we obtained strong evidence that follicular dendritic cells produced high levels of the normal form of PrP in uninfected mice. Furthermore, the replication of a mouse-passaged scrapie strain in the spleen depended only on the presence of PrP expressing follicular dendritic cells. PrP expression by lymphocytes or other bone marrow derived cells had no influence on replication in spleen or on neuroinvasion in these models. These results indicate that the follicular dendritic cell is a potential target for prophylactic or therapeutic intervention in transmissible spongiform encephalopathies.


Prion Protein Follicular Dendritic Cell Uninfected Mouse Graft Bone Marrow Follicular Dendritic Cell Network 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Blattler T, Brandner S, Raeber AJ, Klein MA, Volgtlander T, Weissmann C, Aguzzi A (1997) PrP-expressing tissue required for transfer of scrapie infectivity from spleen to brain. Nature 389: 69–73PubMedCrossRefGoogle Scholar
  2. 2.
    Bosma GC, Custer RP, Bosma MJ (1983) A severe combined immunodeficiency mutation in the mouse. Nature 301: 527–530PubMedCrossRefGoogle Scholar
  3. 3.
    Brown KL, Stewart K, Ritchie DL, Mabbott NA, Williams A, Fraser H, Morrison WI, Bruce ME (1999) Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells. Nature Med 5: 1308–1312PubMedCrossRefGoogle Scholar
  4. 4.
    Bueler H, Aguzzi A, Sailer A, Greiner R-A, Autenried P, Aguet M, Weissmann C (1993) Mice devoid of PrP are resistant to scrapie. Cell 73: 1339–1347PubMedCrossRefGoogle Scholar
  5. 5.
    Cashman NR, Loertscher R, Nalbantoglu J, Shaw I, Kascsak RJ, Bolton DC, Bendheim PE (1990) Cellular isoform of the scrapie agent protein participates in lymphocyte activation. Cell 61: 185–192PubMedCrossRefGoogle Scholar
  6. 6.
    Fraser H, Brown K (1994) Peripheral pathogenesis of scrapie in normal and immunocompromised mice. Animal Technol 45: 21–23Google Scholar
  7. 7.
    Fraser H, Brown KL, Stewart K, McConnell I, McBride P, Williams A (1996) Replication of scrapie in spleens of SCID mice follows reconstitution with wild-type mouse bone marrow. J Gen Virol 77: 1935–1940PubMedCrossRefGoogle Scholar
  8. 8.
    Fraser H, Farquhar CF (1987) Ionising radiation has no influence on scrapie incubation period in mice. Vet Microbiol 13: 211–223PubMedCrossRefGoogle Scholar
  9. 9.
    Hill AF, Butterworth RJ, Joiner S, Jackson G, Rossor MN, Thomas DJ, Frosh A, Tolley N, Bell JE, Spencer M, King A, Al-Sarraj S, Ironside JW, Lantos PL,Collinge J (1999) Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 353: 183–189PubMedCrossRefGoogle Scholar
  10. 10.
    Kapasi ZF, Burton GF, Shultz LD, Tew JG, Szakal AK (1993) Induction of functional follicular dendritic cell development in severe combined immunodeficiency mice: influence of B and T cells. J Immunol 150: 2648–2658PubMedGoogle Scholar
  11. 11.
    Kimberlin RH, Walker CA (1979) Pathogenesis pf mouse scrapie: dynamics of agent replication in spleen, spinal cord and brain after infection by different routes J Comp Pathol 89: 551–562PubMedCrossRefGoogle Scholar
  12. 12.
    Kitamoto T, Muramoto T, Mohri S, Doh-ura K, Tateishi J (1991) Abnormal isoform of prion protein accumulates in follicular dendritic cells in mice with Creutzfeldt-Jakob disease. J Virol 65: 6292–6295PubMedGoogle Scholar
  13. 13.
    Klein MA, Frigg R, Flechsig E, Raeber AJ, Kalinke U, Bluethmann H, Bootz F, Suter M, Zinkernagel RM, Aguzzi A (1997) A crucial role for B cells in neuro-invasive scrapie. Nature 390: 687–690PubMedGoogle Scholar
  14. 14.
    Klein MA, Frigg R, Raeber AJ, Flechsig E, Hegyi I, Zinkernagel RM, Weissmann C, Aguzzi A (1998) PrP expression in B lymphocytes is not required for prion neuroinvasion. Nature Med 4: 1429–1433PubMedCrossRefGoogle Scholar
  15. 15.
    Kosco MH, Pflugfelder E, Gray D (1992) Follicular dendritic cell-dependent adhesion and proliferation of B cells in vitro. J Immunol 148: 2331–2339PubMedGoogle Scholar
  16. 16.
    Kosco-Vilbois MH, Zentgraf H, Gerdes J, Bonnefoy J-Y (1997) To “ or not to ” a germinal center? Immunol Today 18: 225–230PubMedCrossRefGoogle Scholar
  17. 17.
    Mabbott NA, Brown KL, Manson J, Bruce ME (1997) T-lymphocyte activation and the cellular form of the prion protein. Impiunol 92: 161–165CrossRefGoogle Scholar
  18. 18.
    Manson JC, Clarke AR, McBride PA, McConnell I, Hope J (1994) PrP gene dosage determines the timing but not the final intensity or distribution of lesions in scrapie pathology. Neurodegen 3: 331–340Google Scholar
  19. 19.
    McBride PA, Eikelenboom P, Kraal G, Fraser H, Bruce ME (1992) PrP protein is associated with follicular dendritic cells of spleens and lymph nodes in uninfected and scrapie-infected mice. J Pathol 168: 413–418PubMedCrossRefGoogle Scholar
  20. 20.
    O’Rourke KI, Huff TP, Leathers CW, Robinson MM, Gorham JR (1994) SCID mouse spleen does not support scrapie agent replication. J Gen Virol 75: 1511–1514PubMedCrossRefGoogle Scholar
  21. 21.
    Raeber AJ, Klein MA, Frigg R, Flechsig E, Aguzzi A, Weissmann C (1999) PrP-dependent association of prions with splenic but not circulating lymphocytes of scrapie-infected mice. EMBO J 18: 2702–2706PubMedCrossRefGoogle Scholar
  22. 22.
    Ritchie DL, Brown KL, Bruce ME (1999) Visualisation of PrP prptein and follicular dendritic cells in uninfectced and scrapie infpcted spleen. J Cell Pathol 4: 3–10Google Scholar
  23. 23.
    Tkachuk M, Bolliger S, Ryffel B, Pluschke G, Banks TA, Herren S, Gisler RH, Kosco-Vilbois MH (1998) Crucial role of tumor necrosis factor receptor 1 expression on nonhematopoietic cells for B cell localization within the splenic white pulp. J Exp Med 187: 469–477PubMedCrossRefGoogle Scholar
  24. 24.
    van Keulen LJM, Schreuder BEC, Meloen RH, Mooij-Harkes G, Vromans MEW, Langeveld JPM (1996) Immunohistochemical detection of prion protein in lymphoid tissues of sheep with natural scrapie. J Clin Microbiol 34: 1228–1231PubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2000

Authors and Affiliations

  • K. L. Brown
    • 1
  • K. Stewart
    • 1
  • D. Ritchie
    • 1
  • H. Fraser
    • 1
  • W. I. Morrison
    • 2
  • M. E. Bruce
    • 1
  1. 1.Neuropathogenesis UnitInstitute for Animal HealthEdinburghUK
  2. 2.Institute for Animal HealthCompton, NewburyUK

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