Completed Research Project

Title / Titel
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Role of complement in prion pathogenesis
Summary / Zusammenfassung
The complement system plays important roles in host defense. Our lab showed that mice deficient for complement factors or receptors were partially or fully protected against spongiform encephalopathy upon intraperitoneal exposure to limiting amounts of prions. We are creating mice deficient for both of the two central complement components, C3 and C4, in order to dissect the role of the complement cascade in prion pathogenesis.
Although intracerebral inoculation of PrPSc most efficiently initiates TSEs in the laboratory, peripheral exposure undoubtedly occurs more commonly in nature. The mechanism by which PrPSc invades the nervous system from peripheral sites, therefore, remains a crucial point of investigation. The immune system plays a paramount role in PrPSc neuroinvasion from the periphery, with accumulation primarily occurring in follicular dendritic cells (FDCs) in lymphoid organs. FDC accumulation of PrPSc requires B cells that, despite being PrP replication deficient, are required for neuroinvasion. This requirement probably relates to the role of B cells in FDC maturation. Both B cells and FDCs express and interact with components of the complement system shown to be important in PrPSc neuroinvasion and pathogenesis. Mice deficient in CD21/35, a complement receptor expressed only on B cells and FDCs that binds cleavage products of the serum complement protein C3, exhibited delayed PrPSc accumulation and disease onset. Mice deficient in C3 displayed a similar phenotype. Interestingly, mice deficient in the serum complement protein C1q demonstrated a much more dramatic phenotype, accumulating no PrPSc and exhibiting no scrapie pathology at low-dose inoculation. We are examining the role of FDC replication of PrPSc in prion pathogenesis and further examines the role of the complement system by clearly defining the role of CD21/35 and C1q in PrPSc accumulation, neuroinvasion, disease onset and progression.
Publications / Publikationen
Klein, M. A., R. Frigg, E. Flechsig, A. J. Raeber, U. Kalinke, H. Bluethmann, F. Bootz, M. Suter, R. M. Zinkernagel, and A. Aguzzi. 1997. A crucial role for B cells in neuroinvasive scrapie. Nature 390:687.

Klein, M. A., P. S. Kaeser, P. Schwarz, H. Weyd, I. Xenarios, R. M. Zinkernagel, M. C. Carroll, J. S. Verbeek, M. Botto, M. J. Walport, H. Molina, U. Kalinke, H. Acha-Orbea, and A. Aguzzi. 2001. Complement facilitates early prion pathogenesis. Nat Med 7:488.

Keywords / Suchbegriffe
Complement, prions, neuroinvasion, CD21, C1q, FDC, C3, C4
Project Leadership and Contacts /
Projektleitung und Kontakte
Isabelle Arrighi (Project Leader)isabelle.arrighi@usz.ch
Mark Zabel (Project Leader)mark.zabel@usz.ch
Prof. A. Aguzziadriano@pathol.uzh.ch
Other Links to external Webpages
http://www.uzh.ch/pathol/neuropathologie/d/index.html
Funding Source(s) /
Unterstützt durch
Others
EMBO
Duration of Project / Projektdauer
Mar 2002 to Feb 2006

© Universität Zürich, 4. Januar 2008, Impressum