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Institute for Animal Health, Edinburgh United Kingdom
Following oral exposure, some transmissible spongiform encephalopathy (TSE) agents accumulate first upon follicular dendritic cells (FDCs) in the GALT. Studies in mice have shown that this accumulation is obligatory for the efficient delivery of the TSE agent to the brain. However, which GALTs are crucial for disease pathogenesis is uncertain. Mice deficient in specific GALT components were used here to determine their separate involvement in scrapie agent neuroinvasion from the intestine. In the combined absence of the GALTs and FDCs (lymphotoxin (LT)
–/– mice and LT
–/– mice), scrapie agent transmission was blocked. When FDC maturation was induced in remaining lymphoid tissues, mice that lacked both Peyer’s patches (PPs) and mesenteric lymph nodes (wild-type (WT)
LT–/– mice) or PPs alone (WTLT–/– mice) remained refractory to disease, demonstrating an important role for the PPs. Although early scrapie agent accumulation also occurs within the mesenteric lymph nodes, their presence in WTLT–/– mice did not restore disease susceptibility. We have also shown that isolated lymphoid follicles (ILFs) are important novel sites of TSE agent accumulation in the intestine. Mice that lacked PPs but contained numerous FDC-containing mature ILFs succumbed to scrapie at similar times to control mice. Because the formation and maturation status of ILFs is inducible and influenced by the gut flora, our data suggest that such factors could dramatically affect susceptibility to orally acquired TSE agents. In conclusion, these data demonstrate that following oral exposure TSE agent accumulation upon FDCs within lymphoid tissue within the intestine itself is critically required for efficient neuroinvasion.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Medical Research Council Grant G69/1867 and the Biotechnology and Biological Sciences Research Council.
2 Address for correspondence and reprint requests to Dr. Neil A. Mabbott, Neuropathogenesis Unit, Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh, U.K. E-mail address: neil.mabbott{at}bbsrc.ac.uk
3 Abbreviations used in this paper: TSE, transmissible spongiform encephalopathy; FDC, follicular dendritic cell; GFAP, glial fibrillary acid protein; ILF, isolated lymphoid follicle; iILF, immature ILF; LT, lymphotoxin; LYVE-1, lymphatic vessel endothelial hyaluronic acid receptor-1; mILF, mature ILF; MLN, mesenteric lymph node; pAb, polyclonal Ab; PP, Peyer’s patch; PrP, prion protein; vCJD, variant Creutzfeldt-Jakob disease; WT, wild type.
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