Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4.
Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4.
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DOI：
10.1084/jem.20102660
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发表时间：
2012-12-17
期刊：
影响因子：
--
通讯作者：
Schuppan D
中科院分区：
文献类型：
--
作者：
Junker Y;Zeissig S;Kim SJ;Barisani D;Wieser H;Leffler DA;Zevallos V;Libermann TA;Dillon S;Freitag TL;Kelly CP;Schuppan D
抗害虫分子，小麦中的α-淀粉酶/胰蛋白酶抑制剂，通过与TLR 4的结合激活先天免疫细胞，引发肠道中的炎症反应。乳糜泻患者摄入小麦、大麦或黑麦会引发小肠炎症。具体而言，这些谷物的储藏蛋白（麸质）在携带HLA-DQ 2或HLA-DQ 8作为主要遗传易感性的个体中引发适应性Th 1介导的免疫应答。这种明确的适应性免疫的作用与乳糜泻中先天免疫的不明确组成部分形成对比。我们鉴定了α-淀粉酶/胰蛋白酶抑制剂（ATI）CM 3和0.19，小麦中的抗害虫分子，作为单核细胞、巨噬细胞和树突状细胞中先天免疫应答的强激活剂。ATI与TLR 4-MD 2-CD 14复合物结合，导致成熟标志物的上调，并引发来自乳糜泻和非乳糜泻患者的细胞以及乳糜泻患者活检组织中促炎细胞因子的释放。TLR 4或TLR 4信号传导缺陷的小鼠在用ATI经口攻击时被保护免于肠道和全身免疫应答。这些发现将谷物ATI定义为乳糜泻的新贡献者。此外，ATI可能会在其他肠道和非肠道免疫疾病中引发炎症和免疫反应。
Pest resistance molecules, α-amylase/trypsin inhibitors from wheat, activate innate immune cells through engagement of TLR4 to elicit inflammatory responses in the intestine. Ingestion of wheat, barley, or rye triggers small intestinal inflammation in patients with celiac disease. Specifically, the storage proteins of these cereals (gluten) elicit an adaptive Th1-mediated immune response in individuals carrying HLA-DQ2 or HLA-DQ8 as major genetic predisposition. This well-defined role of adaptive immunity contrasts with an ill-defined component of innate immunity in celiac disease. We identify the α-amylase/trypsin inhibitors (ATIs) CM3 and 0.19, pest resistance molecules in wheat, as strong activators of innate immune responses in monocytes, macrophages, and dendritic cells. ATIs engage the TLR4–MD2–CD14 complex and lead to up-regulation of maturation markers and elicit release of proinflammatory cytokines in cells from celiac and nonceliac patients and in celiac patients’ biopsies. Mice deficient in TLR4 or TLR4 signaling are protected from intestinal and systemic immune responses upon oral challenge with ATIs. These findings define cereal ATIs as novel contributors to celiac disease. Moreover, ATIs may fuel inflammation and immune reactions in other intestinal and nonintestinal immune disorders.
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影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
适应性免疫细胞缓和最初的先天反应。
影响因子：
82.9
作者：
通讯作者：
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DOI：
10.1073/pnas.0600462103
发表时间：
2006-06-13
影响因子：
11.1
作者：
McGettrick, Anne F.;Brint, Elizabeth K.;O'Neill, Luke A. J.
通讯作者：
O'Neill, Luke A. J.
影响因子：
9.8
作者：
Biesiekierski, Jessica R.;Newnham, Evan D.;Gibson, Peter R.
通讯作者：
Gibson, Peter R.
影响因子：
--
作者：
Fasano, A;Berti, I;Horvath, K
通讯作者：
Horvath, K