Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Cell. 2010 Jun 25;141(7):1135-45. doi: 10.1016/j.cell.2010.05.009.
It is unclear why disease occurs in only a small proportion of persons carrying common risk alleles of disease susceptibility genes. Here we demonstrate that an interaction between a specific virus infection and a mutation in the Crohn's disease susceptibility gene Atg16L1 induces intestinal pathologies in mice. This virus-plus-susceptibility gene interaction generated abnormalities in granule packaging and unique patterns of gene expression in Paneth cells. Further, the response to injury induced by the toxic substance dextran sodium sulfate was fundamentally altered to include pathologies resembling aspects of Crohn's disease. These pathologies triggered by virus-plus-susceptibility gene interaction were dependent on TNFalpha and IFNgamma and were prevented by treatment with broad spectrum antibiotics. Thus, we provide a specific example of how a virus-plus-susceptibility gene interaction can, in combination with additional environmental factors and commensal bacteria, determine the phenotype of hosts carrying common risk alleles for inflammatory disease.
目前尚不清楚为什么只有一小部分携带常见疾病易感基因风险等位基因的人会患病。在这里，我们证明了特定病毒感染与克罗恩病易感基因 Atg16L1 突变之间的相互作用会在小鼠中引发肠道病理。这种病毒加易感基因的相互作用导致了颗粒包装的异常和潘氏细胞中独特的基因表达模式。此外，对毒性物质葡聚糖硫酸钠诱导的损伤的反应也发生了根本改变，包括类似于克罗恩病某些方面的病理。这些由病毒加易感基因相互作用引发的病理变化依赖于 TNFalpha 和 IFNgamma，并且可以通过使用广谱抗生素来预防。因此，我们提供了一个具体的例子，说明了病毒加易感基因的相互作用如何与其他环境因素和共生细菌一起，决定携带炎症性疾病常见风险等位基因的宿主的表型。
