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Natural sheep scrapie is a prion disease characterized by the accumulation of PrPSc in brain and lymphoid tissues. Previous studies suggested that lymph node macrophages and follicular dendritic cells (FDC) accumulate PrPSc. In this study, lymph nodes were analyzed for the presence of PrPSc and macrophage or FDC markers using dual immunohistochemistry. A monoclonal antibody (mAb) to the C-terminus of PrP reacted with CD172a+ macrophages and CD21+ FDC processes in secondary follicles. However, a PrP N-terminus- specific mAb reacted with CD21+ FDC processes but not CD172a+ macrophages in secondary follicles. Neither the PrP N-terminus nor C-terminus-specific mAb reacted with CD172a+ macrophages in the medulla. These results indicate that lymph node follicular macrophages acquire PrPSc by phagocytosis of CD21+ FDC processes. The results also suggest that follicular macrophages have proteases that process full-length PrPSc to N-terminally truncated PrPSc.