The Effects of Host Age on the Transport of Complement-Bound Complexes to the Spleen and the Pathogenesis of Intravenous Scrapie Infection

Infections with variant Creutzfeldt-Jakob disease (vCJD) have almost exclusively occurred in young patients but the reasons for this age distribution are uncertain. Our data suggest that the pathogenesis of many peripherally acquired transmissible spongiform encephalopathy (TSE) agents is less efficient in aged individuals. Four vCJD cases linked to transfusion of vCJD-contaminated blood or blood products have been described. Three cases occurred in eldery patients implying that intravenous exposure is more efficient in aged individuals than other peripheral routes. To test this hypothesis, young (6-8 wk old) and aged mice (600 days old) were injected intravenously with a TSE agent. In aged and young mice the intravenous route was more efficient than other peripheral routes of TSE agent exposure. However, in aged mice disease pathogenesis was significantly reduced. Although most aged mice failed to develop clinical disease during their lifespans, many showed histopathological signs of TSE disease in their brains. Thus, the effects of age on intravenous TSE pathogenesis may lead to significant levels of sub-clinical disease in the population. After peripheral exposure many TSE agents accumulate upon follicular dendritic cells (FDC) in lymphoid tissues before they infect the brain. In aged spleens PrPC expression and TSE agent accumulation upon FDC were reduced. Furthermore, the splenic marginal zone microarchitecture was substantially disturbed adversely affecting the delivery of immune complexes to FDC. This study is the first to suggest that the effects of ageing on the microarchitecture that the function of the splenic marginal zone significantly influence the pathogenesis of an important pathogen.