Sites of prion protein accumulation in scrapie-infected mouse spleen revealed by immune-electron microscopy

Prion protein (PrP) from the brains of animals with transmissible spongifor m encephalopathies is partially protease resistant (PrPres) compared with f ully sensitive PrP (PrPsen) from uninfected brains. In most experimental mo dels, PrPres is a reliable indicator of infectivity, Light microscopic stud ies have suggested that both PrPsen and disease-specific accumulations of P rP are associated with follicular dendritic cells (FDCs), Using immunogold electron microscopy, this study has demonstrated disease-specific accumulat ion of PrP in the spleens of C57 BL mice, 70 days after intracerebral infec tion with the ME7 strain of scrapie and at the terminal stage of disease at 170 days. At both stages, tingible body macrophages contained PrP within l ysosomes and PrP was also detected at the plasmalemma of FDCs, In the light zone of follicles of terminally diseased mice, all FDC dendrites were arra nged in the form of highly reactive or hyperplastic labyrinthine glomerular complexes, within which PrP was consistently seen between FDC processes in association with abundant electron dense material, interpreted as antigen- antibody complexes. Within some glomeruli, fibrillar forms of PrP consisten t with amyloid were seen, At 70 days after challenge, large or hyperplastic labyrinthine complexes were rare and invariably labelled for PrP, However, sparse PrP labelling was also seen on simple FDC processes at this stage, The ubiquitous accumulation of extracellular PrP in complex glomerular dend rites of FDCs in spleens from terminally affected mice, contrasted with sim ple FDC profiles, sparse PrP and limited electron dense deposits in all but a few FDCs of 70-day post-infected mice. This suggests that FDCs continual ly release PrP from the cell surface, where it is associated with trapped a ntigen-antibody complexes and dendritic extension. It is likely that tingib le body macrophages acquire PrP following phagocytosis of PrP within iccoso mes or from the extracellular space around FDC dendrites, These studies wou ld not support an intracellular phase of PrP accumulation in FDCs but show that PrP is produced in excess by scrapie-infected cells from where it is r eleased into the extracellular space. We suggest that PrPsen is involved in dendritic extension or in the process of antibody-antigen trapping, perhap s as part of the binding mechanism for antigen-antibody complexes. (C) Crow n copyright 2000, Reproduced with the permission of Her Majesty's Stationer y Office, Published by John Wiley & Sons, Ltd.