BSE, scrapie and new variant Creutzfeldt–Jakob disease are caused by exposure to pathological forms of prion protein (PrPSc). Following amplification in the periphery, PrPSc invades the nervous system by an as-yet-unknown mechanism. Follicular dendritic cells (FDCs) are the major site of PrPSc accumulation outside of the CNS. Indeed, FDCs play a pivotal role in disease progression, as animals lacking FDCs are protected from disease. Under physiological conditions, FDCs ‘fish’ Ags from the circulation and store them in their native form on the cell surface; these trapped Ags are presented to specific B cells for the initiation and maintenance of Ab responses. This Ag-trapping mechanism might occur through Fc receptors or the complement receptors CD21 and/or CD35. Thus, a functional complement cascade and/or Ab system is required for the efficient capture of Ag by FDCs.Two articles by Mabbott et al. 1xTemporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie. Mabbott, N.A. et al. Nat. Med. 2001; 7: 485–487Crossref | PubMed | Scopus (176)See all References1 and Klein et al. 2xComplement facilitates early prion pathogenesis. Klein, M.A. et al. Nat. Med. 2001; 7: 488–492Crossref | PubMed | Scopus (247)See all References2 assess the role of complement and Fc receptors in the progression of murine scrapie. The absence of C3, a crucial component of both the classical and alternative pathways of the complement cascade, significantly delayed disease progression and reduced the burden of PrPSc in the periphery. A deficiency of complement receptors CR1 and CR2 (CD21 and CD35, respectively) had a similar impact on disease progression, suggesting that C3 is responsible for the deposition of PrPSc through complement receptors. Interestingly, the absence of PrPSc-specific Abs and a variety of Fc receptors (FcγRI–FcγRIII) had no influence on the disease. This is consistent with the observation that no anti-PrPSc Abs can be detected in infected animals, probably because the host's immune system remains unresponsive to PrPSc. Nevertheless, it remains possible that the combination of a deficiency in Fc receptors and complement might result in a further reduction in the replication of PrPSc. This is in line with the observation that the requirement for complement for disease progression is not absolute, as high doses of PrPSc were able to induce scrapie with normal kinetics in complement-deficient mice. This is reminiscent of some anti-viral B-cell responses, where complement-dependency can be overcome by high Ag-load.These observations demonstrate a pivotal, albeit not absolute, role for complement in the induction of scrapie, and suggest that temporal elimination of components of the complement cascade might be a potential therapy for infected individuals. The studies also make an interesting case for how infectious agents, including, in this case, the simplest-known agent, can exploit the properties of the immune system for their own purposes. FDCs store native Ags and present them to B cells; to perform this task, they have evolved receptors that bind foreign Ags and mechanisms that protect the Ags from degradation and phagocytosis by other cell types. It is precisely this property of FDCs that is exploited by the scrapie-agent and allows PrPSc not only to persist safely, but even to replicate, within the heart of the immune system. It is hard to believe that all this is achieved by a protein that apparently does not even carry any genetic information!