Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie.
Following peripheral exposure to transmissible spongiform encephalopathies (TSEs), infectivity usually accumulates in lymphoid tissues before neuroinvasion. The host prion protein (PrPc) is critical for TSE agent replication and accumulates as an abnormal, detergent insoluble, relatively proteinase-resistant isoform (PrPSc) in diseased tissues. Early PrPSc accumulation takes place on follicular dendritic cells (FDCs) within germinal centers in lymphoid tissues of patients with variant Creutzfeldt-Jakob disease (vCJD), sheep with natural scrapie or rodents following experimental peripheral infection with scrapie. In mouse scrapie models, the absence of FDCs blocks scrapie replication and PrPSc accumulation in the spleen, and neuroinvasion is significantly impaired. The mechanisms by which the TSE agent initially localizes to lymphoid follicles and interacts with FDCs are unknown. Antigens are trapped and retained on the surface of FDCs through interactions between complement and cellular complement receptors. Here we show that in mice, both temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays the onset of disease following peripheral infection, and reduces the early accumulation of PrPSc in the spleen. Thus, in the early stages of infection, C3 and perhaps C1q contribute to the localization of TSE infectivity in lymphoid tissue and may be therapeutic targets.
Neuropathogenesis Unit, Institute for Animal Health, Edinburgh, UK.
N A
NA
Mabbott
M E
ME
Bruce
M
M
Botto
M J
MJ
Walport
M B
MB
Pepys
D000818:Animals; D015922:Complement C1q / Q000172:deficiency* / Q000235:genetics; D003176:Complement C3 / Q000172:deficiency*; D020566:Dendritic Cells, Follicular / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018620:PrPSc Proteins / Q000378:metabolism; D012608:Scrapie / Q000209:etiology* / Q000276:immunology* / Q000378:metabolism; D012756:Sheep; D013997:Time Factors
D003176:Complement C3; D018620:PrPSc Proteins; D015922:Complement C1q