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M cell-depletion blocks oral prion disease pathogenesis Mucosal Immunology (2012) 5, 216–225; doi:10.1038/mi.2011.68; published online 1 February 2012 D S Donaldson1,6, A Kobayashi1,2,6, H Ohno3, H Yagita4, I R Williams5 and N A Mabbott1 1The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Edinburgh, UK 2Tohoku University Graduate School of Medicine, Sendai, Japan 3Research Center for Allergy and Immunology, RIKEN, Suehiro, Yokohama, Japan 4Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan 5Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA 6These authors contributed equally to this work Correspondence: NA Mabbott, (email@example.com) Received 4 November 2011; Accepted 19 December 2011; Published online 1 February 2012. Abstract Many prion diseases are orally acquired. Our data show that after oral exposure, early prion replication upon follicular dendritic cells (FDC) in Peyer's patches is obligatory for the efficient spread of disease to the brain (termed neuroinvasion). For prions to replicate on FDC within Peyer's patches after ingestion of a contaminated meal, they must first cross the gut epithelium. However, the mechanism through which prions are conveyed into Peyer's patches is uncertain. Within the follicle-associated epithelium overlying Peyer's patches are microfold cells (M cells), unique epithelial cells specialized for the transcytosis of particles. We show that following M cell-depletion, early prion accumulation upon FDC in Peyer's patches is blocked. Furthermore, in the absence of M cells at the time of oral exposure, neuroinvasion and disease development are likewise blocked. These data suggest M cells are important sites of prion uptake from the gut lumen into Peyer's patches.