NR AWYD
AU Glaysher,B.R.; Mabbott,N.A.
TI Role of the GALT in scrapie agent neuroinvasion from the intestine
QU Journal of Immunology 2007 Mar 15; 178(6): 3757-66
PT comparative study; journal article; research support, non-u.s. gov't
AB 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)alpha(-/-) mice and LTß(-/-) 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) -> LTalpha(-/-) mice) or PPs alone (WT -> LTß(-/-) 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 WT -> LTß(-/-) 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.
IN Wenn Prionen über den Verdauungstrakt aufgenommen werden, dann wird die Empfänglichkeit für eine Infektion entscheidend auch von Darm-assoziiertem lymphoidem Gewebe (GALT) beeinflusst. Glaysher und Mabbott inokulierten mit Maus-adaptierter Scrapie-Infektiosität oral Mäuse, denen bestimmte Komponenten des GALT fehlten, um die Bedeutung dieser Komponenten zu ermitteln. Fehlten normalen Hausmäusen die Peyerplatten, dann waren sie resistent gegen orale Inokulationen. Wenn aber Hausmäuse ohne Peyerplatten in ihren isolierten lymphoiden Follikeln über viele follikuläre dendritische Zellen verfügten, dann waren sie für orale Inokulationen doch empfänglich. Da aber die Bildung und Reifung der isolierten lymphoiden Follikeln induzierbar ist und von der Darmflora abhängt, muss es in diesem Bereich eine ganze Reihe vom Prionprotein unabhängige Faktoren mit erheblichem Einfluss auf die Empfänglichkeit für orale Inokulationen mit TSE geben.
MH Administration, Oral; Animals; Dendritic Cells, Follicular/*immunology/pathology; Immunity, Mucosal/drug effects/genetics; Intestines/*immunology/pathology; Lymphotoxin-alpha/deficiency/immunology; Lymphotoxin-beta/deficiency/*immunology; Mice; Mice, Knockout; Peyer's Patches/*immunology/pathology; PrPsc Proteins/immunology/*pharmacology; Scrapie/genetics/*immunology/transmission
AD Bridget R. Glaysher, Neil A. Mabbott (neil.mabbott@bbsrc.ac.uk), Neuropathogenesis Unit, Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh, United Kingdom
SP englisch
PO USA