Glaysher Bridget R, Mabbott Neil A
Neuropathogenesis Unit, Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh, United Kingdom.
J Immunol. 2007 Mar 15;178(6):3757-66. doi: 10.4049/jimmunol.178.6.3757.
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 LTbeta(-/-) 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-->LTbeta(-/-) 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-->LTbeta(-/-) 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.
经口暴露后，一些传染性海绵状脑病（TSE）病原体首先在肠道相关淋巴组织（GALT）的滤泡树突状细胞（FDC）上积聚。对小鼠的研究表明，这种积聚对于将TSE病原体有效递送至大脑是必不可少的。然而，哪些GALT对疾病发病机制至关重要尚不确定。本文使用缺乏特定GALT成分的小鼠来确定它们在羊瘙痒病病原体从肠道进行神经侵袭过程中的各自作用。在同时缺乏GALT和FDC的情况下（淋巴毒素（LT）α基因敲除小鼠和LTβ基因敲除小鼠），羊瘙痒病病原体的传播被阻断。当在其余淋巴组织中诱导FDC成熟时，既缺乏派尔集合淋巴结（PP）又缺乏肠系膜淋巴结的小鼠（野生型（WT）→LTα基因敲除小鼠）或仅缺乏PP的小鼠（WT→LTβ基因敲除小鼠）对疾病仍具有抗性，这表明PP具有重要作用。尽管早期羊瘙痒病病原体也在肠系膜淋巴结中积聚，但在WT→LTβ基因敲除小鼠中肠系膜淋巴结的存在并未恢复疾病易感性。我们还表明，孤立淋巴滤泡（ILF）是TSE病原体在肠道中积聚的重要新部位。缺乏PP但含有大量含FDC的成熟ILF的小鼠与对照小鼠在相似时间内死于羊瘙痒病。由于ILF的形成和成熟状态是可诱导的且受肠道菌群影响，我们的数据表明这些因素可能会显著影响口服获得性TSE病原体的易感性。总之，这些数据表明，经口暴露后，肠道自身淋巴组织内FDC上TSE病原体的积聚是有效神经侵袭的关键要求。
