A sensitive immunohistochemical procedure was used to investigate the presence of prion protein (PrP) in the ileal Peyer's patch of PrP-genotyped lambs, including scrapie-free lambs and lambs naturally and experimentally exposed to the scrapie agent. The tyramide signal amplification system was used to enhance the sensitivity of conventional immunohistochemical procedures to show that PrP was widely distributed in the enteric nervous plexus supplying the gut wall. In scrapie-free lambs, PrP was also detected in scattered cells in the lamina propria and in the dome and interfollicular areas of the Peyer's patch. In the follicles, staining for PrP was mainly confined to the capsule and cells associated with vascular structures in the light central zone. In lambs naturally exposed to the scrapie agent, staining was prominent in the dome and neck region of the follicles and was also found to be associated with the follicle-associated epithelium. Similar observations were made in lambs that had received a single oral dose of scrapie-infected brain material from sheep with a homologous and heterologous PrP genotype 1 and 5 weeks previously. These studies show that the ileal Peyer's patch in young sheep may be an important site of uptake of the scrapie agent and that the biology of this major gut-associated lymphoid tissue may influence the susceptibility to oral infection in sheep. Furthermore, these studies suggest that homology or heterology between PrP genotypes or the presence of PrP genotypes seldom associated with disease does not impede uptake of PrP.

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Disease-associated prion protein (PrP d ) in the enteric nervous system (ENS) of 20-to 24-monthold Suffolk sheep in the late subclinical and early clinical phase of scrapie was studied. Sites in the alimentary tract extending from the forestomachs and abomasum to the colon from scrapie-affected sheep (PrP ARQ/ARQ ) and scrapie-resistant sheep (PrP ARR/ARQ and PrP ARR/ARR ) were examined.PrP d was found only in scrapie-affected sheep and was most prominent in the ENS when abundant deposits of PrP d were also present in adjacent lymphoid nodules. Immunolabelling with the nerve fibre markers PgP 9.5 and neuron-specific enolase and the satellite cell marker glial fibrillary acidic protein revealed the extensive ganglionated networks of the myenteric and submucosal plexi. Fewer nerve fibres were present in the lamina propria, T-cell dominated interfollicular areas and dome regions of Peyer's patches. A substantial network of nerve fibres was detected in many lymphoid nodules of both the scrapie-affected and scrapie-resistant sheep. Nerve fibres were also detected within the capsule of lymphoid nodules. Electron microscopy revealed the presence of nerves in the lymphoid nodules, showing a close association with follicular dendritic cells, lymphocytes and tingible body macrophages. In demonstrating that lymphoid nodules in the Peyer's patches of scrapie-affected sheep possess a substantial network of nerve fibres, the present study shows that nodules provide close contact between nerve fibres and cell populations known to contain abundant PrP d , including follicular dendritic cells and tingible body macrophages, and that gut-associated lymphoid nodules in sheep may represent an important site for neuroinvasion. INTRODUCTIONScrapie is a fatal neurodegenerative disease of sheep and goats that is characterized by the accumulation of a protease-resistant conformer of the cellular prion protein PrP C , which is considered identical to the infectious agent (Prusiner, 1982). The uptake of the scrapie agent from the alimentary tract is the most likely natural route of infection but the processes involved in the movement of the invading agent from the gut lumen to the central nervous system (CNS) are only partially understood. While the early accumulation of disease-associated PrP (PrP d ) in lymphoid tissues has been shown to facilitate neuroinvasion (Lasmézas et al., 1996), it is probably the involvement of peripheral nerves that represents the final common pathway for neuroinvasion in vivo (Race et al., 2000). Studies in PrPknockout mice have shown that a non-haematopoietic PrPpositive cell-type is required for neuroinvasion, arguing against a central role for haematogenous routes of infection (Race et al., 2000). It has also been shown that neuroinvasion can occur without the involvement of lymphoid tissues and bypass the spinal cord to enter the CNS via the vagus nerve and dorsal motor nucleus of the vagus (Beekes et al., 1998). Indeed, the vagus nerve would appear to be the primary route for the transfer of infectivit...

The distribution of disease-associated prion protein (PrP) was investigated in eight animals (20-24 months of age) from a flock of Suffolk sheep that had experienced frequent cases of natural scrapie over a period of several years. Tissue from the central nervous system (CNS), alimentary tract, peripheral nervous system and lymphoreticular system was examined by histopathology and immunohistochemistry. The lymphoid tissues were subjected further to histoblot and immunofluorescence examination.

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