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* Institute for Neuropathology, University Hospital of Zürich, Zürich, Switzerland;
Institute of Neuropathology, Georg-August University, Göttingen, Germany;
Department of Immunology, Duke University Medical Center, Durham, NC 27710; and
Department of Pathology, University of Utah, Salt Lake City, UT 84132
We have studied the role of CD21/35, which bind derivatives of complement factors C3 and C4, in extraneural prion replication and neuroinvasion. Upon administration of small prion inocula, CD21/35–/– mice experienced lower attack rates and delayed disease over both wild-type (WT) mice and mice with combined C3 and C4 deficiencies. Early after inoculation, CD21/35–/– spleens were devoid of infectivity. Reciprocal adoptive bone marrow transfers between WT and CD21/35–/– mice revealed that protection from prion infection resulted from ablation of stromal, but not hemopoietic, CD21/35. Further adoptive transfer experiments between WT mice and mice devoid of both the cellular prion protein PrPC and CD21/35 showed that splenic retention of inoculum depended on stromal CD21/35 expression. Because both PrPC and CD21/35 are highly expressed on follicular dendritic cells, CD21/35 appears to be involved in targeting prions to follicular dendritic cells and expediting neuroinvasion following peripheral exposure to prions.
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1 M.D.Z. was supported by the Human Frontiers in Science Foundation Long-Term Fellowship and the Volkswagen Foundation. M.H. was supported by grants of the Bonizzi-Theler Foundation, the Schweizer MS Foundation, and the Prof. Max-Cloëtta Foundation. A.A. was supported by the Volkswagen Foundation, the Swiss National Foundation, and the Ernst-Jung Foundation.
2 Address correspondence and reprint requests to Dr. Mark D. Zabel at the current address: Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 1619 Campus Delivery, Fort Collins, CO 80523-1619; E-mail address: mark.zabel{at}colostate.edu or Dr. Adriano Aguzzi, Institute of Neuropathology, Department of Pathology, Universitätspital Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland; E-mail address: adriano.aguzzi{at}usz.ch
3 Abbreviations used in this paper: TSE, transmissible spongiform encephalopathy; PK, proteinase K; FDC, follicular dendritic cell; BM, bone marrow; dpi, days postinoculation; SCEPA, scrapie cell assay in endpoint format; WT, wild type; IHC, immunohistochemistry; MBA, mouse bioassay; i.c., intracerebral; NaPTA, sodium phosphotungstic acid; IF, immunofluorescence stain; PrP, prion protein; PrPC, cellular prion protein; PrPSc, scrapie-associated, misfolded prion protein.
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