NR AOPP
AU Aguzzi,A.
TI The immunobiology of prion diseases
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Oral sessions OS-19
PT Konferenz-Vortrag
AB
Mice deficient in the normal prion protein are resistant to exposure to prion infectivity, and expression of the normal prion protein by neurons is necessary for the development of histological damage1. But how do prions reach the brain after entering the body from peripheral sites? The first portal of entry in the gut may be represented by M-cells2. Neuroinvasion, i.e. the process by which prions march through the body of the host towards the brain, is dependent upon expression of the normal prion protein in a non-hematopoietic extracerebral site3. We therefore developed the hypothesis that neuroinvasion takes place in two distinct steps: first the lymphoreticular system is diffusely colonized by the agent, while at a later time infectivity progresses from lymphoreticular organs to the central nervous system4, probably via sympathetic nerves5,6. There is an absolute requirement for B-lymphocytes in peripheral prion patho-genesis7. Surprisingly, the presence of the normal prion protein is not necessary on B-lymphocytes to enable them to support this process8. The mechanism of action of B lymphocytes may consist of pres-entation of lymphotoxin-ß to follicular dendritic cells9. This paves the way to post-exposure prophylaxis strategies10 that exploit the anti-prion effect of soluble lymphotoxin-ß receptors. Why do follicular dendritic cells accumulate prions? We tested the hypothesis that prion uptake may be complement-mediated. Indeed, certain components of the complement system (C1q, CR1/2) proved to play an important role in pathogenesis11. Finally, we have found that transgenic expression of an anti-PrP antibody heavy chain suffices to confer to mice antiprion protection - a finding that may be relevant to the development of antiprion vaccines12.
1. Brandner, S., Isenmann, S., Raeber, A., Fischer, M., Sailer, A., Kobayashi, Y., Marino, S., Weissmann, C. & Aguzzi, A. Normal host prion protein necessary for scrapie-induced neurotoxic-ity. Nature 379, 339-43 (1996).
2. Heppner, F. L., Christ, A. D., Klein, M. A., Prinz, M., Fried, M., Kraehenbuhl, J. P. & Aguzzi, A. Transepithelial prion transport by M cells. Nat Med 7, 976-7 (2001).
3. Blättler, T., Brandner, S., Raeber, A. J., Klein, M. A., Voigtländer, T., Weissmann, C. & Aguzzi, A. PrP-expressing tissue required for transfer of scrapie infectivity from spleen to brain. Nature 389, 69-73 (1997).
4. Aguzzi, A. & Weissmann, C. Prion research: the next frontiers. Nature 389, 795-798 (1997).
5. Glatzel, M., Flechsig, E., Navarro, B., Klein, M. A., Paterna, J. C., Büeler, H. & Aguzzi, A. Adeno-viral and adeno-associated viral transfer of genes to the peripheral nervous system. Proc Natl Acad Sci U S A 97, 442-7 (2000).
6. 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).
7. Klein, M. A., Frigg, R., Flechsig, E., Raeber, A. J., Kalinke, U., Bluethmann, H., Bootz, F., Suter, M., Zinkernagel, R. M. & Aguzzi, A. A crucial role for B cells in neuroinvasive scrapie. Nature 390, 687-90 (1997).
8. Klein, M. A., Frigg, R., Raeber, A. J., Flechsig, E., Hegyi, I., Zinkernagel, R. M., Weissmann, C. & Aguzzi, A. PrP expression in B lymphocytes is not required for prion neuroinvasion. Nat Med 4, 1429-33 (1998).
9. Montrasio, F., Frigg, R., Glatzel, M., Klein, M. A., Mackay, F., Aguzzi, A. & Weissmann, C. Im-paired prion replication in spleens of mice lacking functional follicular dendritic cells. Science 288, 1257-9 (2000).
10. Aguzzi, A. & Collinge, J. Post-exposure prophylaxis after accidental prion inoculation. Lancet 350, 1519-20 (1997).
11. Klein, M. A., Kaeser, P. S., Schwarz, P., Weyd, H., Xenarios, I., Zinkernagel, R. M., Carroll, M. C., Verbeek, J. S., Botto, M., Walport, M. J., Molina, H., Kalinke, U., Acha-Orbea, H. & Aguzzi, A. Complement facilitates early prion pathogenesis. Nat Med 7, 488-92. (2001).
12. Heppner, F. L., Musahl, C., Arrighi, I., Klein, M. A., Rulicke, T., Oesch, B., Zinkernagel, R. M., Ka-linke, U. & Aguzzi, A. Prevention of Scrapie Pathogenesis by Transgenic Expression of Anti-Prion Protein Antibodies. Science 294, 178-182 (2001).
AD Adriano Aguzzi, Institute of Neuropathology, University of Zürich, Switzerland
SP englisch
PO Deutschland