期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2002
卷号：99
期号：2
页码：919-924
DOI：10.1073/pnas.022626399
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Variant Creutzfeldt-Jakob disease and scrapie are typically initiated by extracerebral exposure to prions, and exhibit early prion accumulation in germinal centers. Follicular dendritic cells (FDCs), whose development and maintenance in germinal centers depends on tumor necrosis factor (TNF) and lymphotoxin (LT) signaling, are thought to be indispensable for extraneural prion pathogenesis. Here, we administered prions intraperitoneally to mice deficient for TNF and LT signaling components. LT-/-, LT{beta}-/-, LT{beta}R-/-, and LT-/- x TNF-/- mice resisted infection and contained no infectivity in spleens and lymph nodes (when present). However, TNFR1-/-, TNFR2-/-, and some TNF-/- mice developed scrapie similarly to wild-type mice. High prion titers were detected in lymph nodes, but not spleens, of TNFR1-/- and TNF-/- mice despite absence of FDCs and germinal centers. Transfer of TNFR1-/- fetal liver cells into lethally irradiated Prnp0/0 mice restored infectivity mainly in lymph nodes. Prion protein (PrP) colocalized with a minority of macrophages in tumor necrosis factor receptor (TNFR) 1-/- lymph nodes. Therefore, prion pathogenesis can be restricted to lymphoreticular subcompartments, and mature follicular dendritic cells are dispensable for this process. Macrophage subsets are plausible candidates for lymphoreticular prion pathogenesis and neuroinvasion in the absence of FDCs, and may represent a novel target for postexposure prophylaxis.
