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Scrapie Pathogenesis: The Role of Complement C1q in Scrapie Agent Uptake by Conventional Dendritic Cells¹

Adriana Flores-Langarica^*, Yasmine Sebti^*, Daniel A. Mitchell, Robert B. Sim and Gordon G. MacPherson^2,*

^* Sir William Dunn School of Pathology, Medical Research Council Immunochemistry Unit, Biochemistry Department, University of Oxford, Oxford; and Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry United Kingdom

Mice lacking complement components show delayed development of prion disease following peripheral inoculation. The delay could relate to reduced scrapie prion protein (PrP^Sc) accumulation on follicular dendritic cells (DCs). However conventional DCs (cDCs) play a crucial role in the early pathogenesis of prion diseases and complement deficiency could result in decreased PrP^Sc uptake by cDCs in the periphery. To explore this possibility, we cultured murine splenic or gut-associated lymph node cDCs with scrapie-infected whole brain homogenate in the presence or absence of complement. Uptake decreased significantly if the serum in the cultures was heat-inactivated. Because heat inactivation primarily denatures C1q, we used serum from C1q^–/– mice and showed that PrP^Sc uptake was markedly decreased. PrP^Sc internalization was saturable and temperature-dependent, suggesting receptor-mediated uptake. Furthermore, uptake characteristics differed from fluid-phase endocytosis. Immunofluorescence showed colocalization of C1q and PrP^Sc, suggesting interaction between these molecules. We evaluated the expression of several complement receptors on cDCs and confirmed that cDCs that take up PrP^Sc express one of the C1q receptors, calreticulin. Our results show that C1q participates in PrP^Sc uptake by cDCs, revealing a critical role for cDCs in initial prion capture, an event that takes place before the PrP^Sc accumulation within the follicular DC network.

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 This work was supported by Contract F00D-CT-2006-023144 from the European Community ImmunoPrion project. D.A.M. is a Research Council U.K. Fellow.

² Address correspondence and reprint requests to Dr. Gordon G. MacPherson, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE Oxford, U.K. E-mail address: gordon.macpherson{at}path.ox.ac.uk

³ Abbreviations used in this paper: TSE, transmissible spongiform encephalopathy; cDC, conventional dendritic cell; FDC, follicular dendritic cell; MLN, mesenteric lymph node; PrP, prion protein; PP, Peyer’s patch; WBH, whole brain homogenate; MFI, mean fluorescence intensity.