McDermott Jacqueline R, Bartram Ruth E, Knight Pamela A, Miller Hugh R P, Garrod David R, Grencis Richard K
School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7761-6. doi: 10.1073/pnas.1231488100. Epub 2003 Jun 9.
We have investigated the influence of mast cells on the barrier function of intestinal epithelium during nematode infection. Trichinella spiralis infection induces a strong type 2 cytokine-mediated inflammation, resulting in a critical mucosal mastocytosis that is known to mediate expulsion of the parasites from the intestine. The host response to infection is also characterized by an increase in mucosal leakiness. We show here that intestinal epithelial permeability is markedly elevated during infection, with kinetics that mirror the adaptive immune response to primary and secondary infection. Furthermore, we have identified degradation of the tight junction protein, occludin, thereby providing a mechanism for increased paracellular permeability during helminth infection. We further demonstrate by using anti-c-kit antibody and IL-9 transgenic mice that mast cells are directly responsible for increasing epithelial paracellular permeability and that mice deficient in a mast cell-specific protease fail to increase intestinal permeability and fail to expel their parasite burden. These results provide the mechanism whereby mucosal mast cells mediate parasite expulsion from the intestine.
我们研究了线虫感染期间肥大细胞对肠道上皮屏障功能的影响。旋毛虫感染会引发强烈的2型细胞因子介导的炎症反应，导致严重的黏膜肥大细胞增多症，已知该病症可介导寄生虫从肠道排出。宿主对感染的反应还表现为黏膜渗漏增加。我们在此表明，感染期间肠道上皮通透性显著升高，其动力学反映了对初次和二次感染的适应性免疫反应。此外，我们发现紧密连接蛋白occludin降解，从而为蠕虫感染期间细胞旁通透性增加提供了一种机制。我们通过使用抗c-kit抗体和IL-9转基因小鼠进一步证明，肥大细胞直接导致上皮细胞旁通透性增加，而缺乏肥大细胞特异性蛋白酶的小鼠无法增加肠道通透性，也无法排出其体内的寄生虫负荷。这些结果提供了黏膜肥大细胞介导寄生虫从肠道排出的机制。
