Complement facilitates early prion pathogenesis

New-variant Creutzfeldt-Jakob disease and scrapie are typically initiated b y extracerebral exposure to the causative agent, and exhibit early prion re plication in lymphoid organs(1,2). In mouse scrapie, depletion of B-lymphoc ytes prevents neuropathogenesis after intraperitoneal inoculation(3,4), pro bably due to impaired lymphotoxin-dependent maturation of follicular dendri tic cells(5) (FDCs), which are a major extracerebral prion reservoir(6). FD Cs trap immune complexes with Fc-gamma receptors and C3d/C4b-opsonized anti gens with CD21/CD35 complement receptors. We examined whether these mechani sms participate in peripheral prion pathogenesis. Depletion of circulating immunoglobulins or of individual Fc-gamma receptors had no effect on scrapi e pathogenesis if B-cell maturation was unaffected. However, mice deficient in C3, C1q, Bf/C2, combinations thereof(7,8) or complement receptors(9) we re partially or fully protected against spongiform encephalopathy upon intr aperitoneal exposure to limiting amounts of prions. Splenic accumulation of prion infectivity and PrPSc was delayed, indicating that activation of spe cific complement components is involved in the initial trapping of prions i n lymphoreticular organs early after infection.