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Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion

Nature volume 425, pages 957–962 (2003)Cite this article

Abstract

Peripheral infection is the natural route of transmission in most prion diseases1. Peripheral prion infection is followed by rapid prion replication in lymphoid organs, neuroinvasion2 and progressive neurological disease. Both immune cells and nerves are involved in pathogenesis3,4, 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.

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Figure 1: Neuroimmune anatomy of CXCR5-/- and WT mice.
Figure 2: Kinetics of prion disease in CXCR5-/- and WT mice.
Figure 3: Splenic prion replication in CXCR5-/- mice in the absence of LTβR signalling.
Figure 4: FDC localization and prion replication in LTβR-Fc treated mice and bone-marrow chimaeras.

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References

  1. Aguzzi, A., Montrasio, F. & Kaeser, P. S. Prions: health scare and biological challenge. Nature Rev. Mol. Cell Biol. 2, 118–126 (2001)

    Article  CAS  Google Scholar 

  2. Aguzzi, A. Neuro-immune connection in spread of prions in the body? Lancet 349, 742–743 (1997)

    Article  CAS  Google Scholar 

  3. Klein, M. A. et al. A crucial role for B cells in neuroinvasive scrapie. Nature 390, 687–690 (1997)

    Article  ADS  CAS  Google Scholar 

  4. Race, R., Oldstone, M. & Chesebro, B. Entry versus blockade of brain infection following oral or intraperitoneal scrapie administration: role of prion protein expression in peripheral nerves and spleen. J. Virol. 74, 828–833 (2000)

    Article  CAS  Google Scholar 

  5. Eklund, C. M., Kennedy, R. C. & Hadlow, W. J. Pathogenesis of scrapie virus infection in the mouse. J. Infect. Dis. 117, 15–22 (1967)

    Article  CAS  Google Scholar 

  6. Kimberlin, R. H. & Walker, C. A. The role of the spleen in the neuroinvasion of scrapie in mice. Virus Res. 12, 201–211 (1989)

    Article  CAS  Google Scholar 

  7. Prinz, M. et al. Lymph nodal prion replication and neuroinvasion in mice devoid of follicular dendritic cells. Proc. Natl Acad. Sci. USA 99, 919–924 (2002)

    Article  ADS  CAS  Google Scholar 

  8. Klein, M. A. et al. PrP expression in B lymphocytes is not required for prion neuroinvasion. Nature Med. 4, 1429–1433 (1998)

    Article  CAS  Google Scholar 

  9. Montrasio, F. et al. Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science 288, 1257–1259 (2000)

    Article  ADS  CAS  Google Scholar 

  10. Kitamoto, T., Muramoto, T., Mohri, S., Doh-ura, K. & Tateishi, J. Abnormal isoform of prion protein accumulates in follicular dendritic cells in mice with Creutzfeldt-Jakob disease. J. Virol. 65, 6292–6295 (1991)

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Glatzel, M., Heppner, F. L., Albers, K. M. & Aguzzi, A. Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron 31, 25–34 (2001)

    Article  CAS  Google Scholar 

  12. Heinen, E., Bosseloir, A. & Bouzahzah, F. Follicular dendritic cells: origin and function. Curr. Top. Microbiol. Immunol. 201, 15–47 (1995)

    CAS  PubMed  Google Scholar 

  13. Forster, R. et al. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87, 1037–1047 (1996)

    Article  CAS  Google Scholar 

  14. Voigt, I. et al. CXCR5-deficient mice develop functional germinal centers in the splenic T cell zone. Eur. J. Immunol. 30, 560–567 (2000)

    Article  CAS  Google Scholar 

  15. Felten, D. L. & Felten, S. Y. Sympathetic noradrenergic innervation of immune organs. Brain Behav. Immun. 2, 293–300 (1988)

    Article  CAS  Google Scholar 

  16. Carlson, S. L. et al. NGF modulates sympathetic innervation of lymphoid tissues. J. Neurosci. 15, 5892–5899 (1995)

    Article  CAS  Google Scholar 

  17. Prusiner, S. B., Cochran, S. P., Downey, D. E. & Groth, D. F. Determination of scrapie agent titer from incubation period measurements in hamsters. Adv. Exp. Med. Biol. 134, 385–399 (1981)

    Article  CAS  Google Scholar 

  18. Kaeser, P. S., Klein, M. A., Schwarz, P. & Aguzzi, A. Efficient lymphoreticular prion propagation requires prp(c) in stromal and hematopoietic cells. J. Virol. 75, 7097–7106 (2001)

    Article  CAS  Google Scholar 

  19. Fischer, M. et al. Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO J. 15, 1255–1264 (1996)

    Article  CAS  Google Scholar 

  20. Beekes, M., Baldauf, E. & Diringer, H. Sequential appearance and accumulation of pathognomonic markers in the central nervous system of hamsters orally infected with scrapie. J. Gen. Virol. 77, 1925–1934 (1996)

    Article  CAS  Google Scholar 

  21. Oldstone, M. B. et al. Lymphotoxin-α- and lymphotoxin-β-deficient mice differ in susceptibility to scrapie: evidence against dendritic cell involvement in neuroinvasion. J. Virol. 76, 4357–4363 (2002)

    Article  CAS  Google Scholar 

  22. Mackay, F. & Browning, J. L. Turning off follicular dendritic cells. Nature 395, 26–27 (1998)

    Article  ADS  CAS  Google Scholar 

  23. Ansel, K. M. et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406, 309–314 (2000)

    Article  ADS  CAS  Google Scholar 

  24. Hill, A. F., Zeidler, M., Ironside, J. & Collinge, J. Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy. Lancet 349, 99–100 (1997)

    Article  CAS  Google Scholar 

  25. Hilton, D. A., Fathers, E., Edwards, P., Ironside, J. W. & Zajicek, J. Prion immunoreactivity in appendix before clinical onset of variant Creutzfeldt-Jakob disease. Lancet 352, 703–704 (1998)

    Article  CAS  Google Scholar 

  26. Aguzzi, A., Glatzel, M., Montrasio, F., Prinz, M. & Heppner, F. L. Interventional strategies against prion diseases. Nature Rev. Neurosci. 2, 745–749 (2001)

    Article  CAS  Google Scholar 

  27. Hill, A. F. et al. Species-barrier-independent prion replication in apparently resistant species. Proc. Natl Acad. Sci. USA 29, 10248–10253 (2000)

    Article  Google Scholar 

  28. Karrer, U. et al. Antiviral B cell memory in the absence of mature follicular dendritic cell networks and classical germinal centers in TNFR1 - / - mice. J. Immunol. 164, 768–778 (2000)

    Article  CAS  Google Scholar 

  29. Wu, Q. et al. Reversal of spontaneous autoimmune insulitis in nonobese diabetic mice by soluble lymphotoxin receptor. J. Exp. Med. 193, 1327–1332 (2001)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Sigurdson and M. Zabel for critical reading of the manuscript, and R. Zinkernagel for support. This work was supported by grants of the Bundesamt für Bildung und Wissenschaft, the Swiss National Foundation, the NCCR on neural plasticity and repair, and the Migros foundation to A.A. M.P. was a postdoctoral fellow of the Deutsche Forschungsgemeinschaft. M.H. is supported by a generous educational grant of the Catello family and by the Verein zur Förderung des Akademischen Nachwuchses. F.L.H. is supported by the Stammbach Foundation and by the Bonizzi-Theler Foundation.

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Author notes

  1. Marco Prinz

    Present address: Institute of Neuropathology, Georg-August-University Göttingen, Göttingen, Germany

  2. Marco Prinz and Mathias Heikenwalder: These authors contributed equally to this work

Authors and Affiliations

  1. Institute of Neuropathology, University Hospital of Zürich, Schmelzbergstrasse 12, Zürich, CH-8091, Switzerland

    Marco Prinz, Mathias Heikenwalder, Petra Schwarz, Markus Glatzel, Frank L. Heppner & Adriano Aguzzi

  2. Institute of Experimental Immunology, University Hospital of Zürich, Schmelzbergstrasse 12, Zürich, CH-8091, Switzerland

    Tobias Junt

  3. Department of Pathology and Committee on Immunology, The University of Chicago, 5841 S. Maryland, Chicago, Illinois, 60637, USA

    Yang-Xin Fu

  4. Department of Molecular Tumor Genetics and Immunogenetics, Max Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Strasse 10, Berlin, 13092, Germany

    Martin Lipp

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Correspondence to Adriano Aguzzi.

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Prinz, M., Heikenwalder, M., Junt, T. et al. Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. Nature 425, 957–962 (2003). https://doi.org/10.1038/nature02072

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