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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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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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