IL-25 and CD4(+) TH2 cells enhance type 2 innate lymphoid cell-derived IL-13 production, which promotes IgE-mediated experimental food allergy.
IL-25 and CD4(+) TH2 cells enhance type 2 innate lymphoid cell-derived IL-13 production, which promotes IgE-mediated experimental food allergy.
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DOI：
10.1016/j.jaci.2015.09.019
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发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Wang YH
中科院分区：
文献类型：
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作者：
Lee JB;Chen CY;Liu B;Mugge L;Angkasekwinai P;Facchinetti V;Dong C;Liu YJ;Rothenberg ME;Hogan SP;Finkelman FD;Wang YH
食物介导的过敏反应已成为一个主要的健康问题。促进胃肠道中饮食过敏原不受控制的 2 型免疫反应的潜在机制仍然难以捉摸。我们研究了改变 IL-25 信号传导是否会增强或减弱对食物过敏原的过敏反应。 iIL-25Tg小鼠（其肠道IL-25持续过度表达）和Il17rb−/−小鼠（其中Il17rb基因表达被破坏）被致敏并用卵清蛋白（OVA）灌胃。我们评估了实验性食物过敏的症状特征，包括腹泻发生率、体温过低发生率、肠道 TH2 免疫反应以及血清 OVA 特异性 IgE 和肥大细胞蛋白酶 (MCPt)-1 的产生。在对摄入的OVA抗原产生过敏反应之前，肠上皮中Il25表达的快速诱导。 iIL-25Tg 小鼠更容易发生实验性食物过敏，而 Il17rb−/− 小鼠则更能抵抗实验性食物过敏。常驻肠道 2 型先天淋巴细胞 (ILC2) 被确定为响应 IL-25 的 IL-5 和 IL-13 的主要产生者。用 Rora−/− 或 Il17rb−/− 骨髓 (BM) 重建受辐射的野生型小鼠，分别导致 ILC2 区室的缺陷或功能障碍，以及对实验性食物过敏的抵抗。重复胃内抗原激发诱导 CD4+TH2 细胞显着增加，从而增强 ILC2 离体和体内产生 IL-25 刺激的 IL-13。最后，重组的 IL-13 缺陷型 ILC2 促进过敏性炎症的能力降低，从而导致对实验性食物过敏的抵抗力增强。摄入的抗原诱导的 IL-25 和 CD4+TH2 细胞增强了 ILC2 衍生的 IL-13 的产生，从而促进 IgE 介导的实验性食物过敏。
Food-mediated allergic reactions have emerged as a major health problem. The underlying mechanisms that promote uncontrolled type-2 immune response to dietary allergens in the gastrointestinal tract remain elusive. We investigated whether altering IL-25 signaling enhances or attenuates allergic responses to food allergens. iIL-25Tg mice, which constitutively overexpress intestinal IL-25, and Il17rb−/− mice, in which the Il17rb gene expression is disrupted, were sensitized and gavage fed with ovalbumin (OVA). We assessed symptomatic characteristics of experimental food allergy, including incidence of diarrhea, incidence of hypothermia, intestinal TH2 immune response, and serum OVA-specific IgE and mast cell protease (MCPt)-1 production. Rapid induction of Il25 expression in the intestinal epithelium preceded the onset of anaphylactic response to ingested OVA antigen. iIL-25Tg mice were more prone, and Il17rb−/− were mice more resistant, to developing experimental food allergy. Resident intestinal type-2 innate lymphoid cells (ILC2s) were identified as the major producers of IL-5 and IL-13 in response to IL-25. Reconstituting irradiated wild-type mice with Rora−/− or Il17rb−/− bone marrow (BM) resulted in a deficiency or dysfunction of the ILC2 compartment, respectively, and resistance to developing experimental food allergy. Repeated intragastric antigen challenge induced a significant increase of CD4+TH2 cells, which enhance IL-25-stimulated IL-13 production by ILC2 ex vivo and in vivo. Finally, reconstituted IL-13–deficient ILC2s had reduced capability to promote allergic inflammation, resulting in the increased resistance to experimental food allergy. IL-25 and CD4+TH2 cells induced by ingested antigens enhance ILC2-derived IL-13 production, thereby promoting IgE-mediated experimental food allergy.