Division of Immunology, Children's Hospital, Boston, Mass 02115, USA.
J Allergy Clin Immunol. 2011 Mar;127(3):795-805.e1-6. doi: 10.1016/j.jaci.2010.11.009. Epub 2010 Dec 17.
In atopic subjects food ingestion drives the production of IgE antibodies that can trigger hypersensitivity reactions. The IL-4 pathway plays a critical role in this response, and genetic polymorphisms in its components have been linked to allergy.
We sought to test whether an activating mutation in the IL-4 receptor (IL-4R) α chain enhances allergic responses to a food antigen.
F709 mice, in which the IL-4Rα immunoreceptor tyrosine-based inhibitory motif is inactivated, were gavage fed with ovalbumin (OVA). Reactions to OVA challenge and immune responses, including antibody production and T(H)2 responses, were assessed.
F709 mice, but not wild-type control animals, sensitized by means of gavage with OVA and either cholera toxin or staphylococcal enterotoxin B, displayed mast cell activation and systemic anaphylaxis on enteral challenge. Anaphylaxis was elicited even in F709 mice enterally sensitized with OVA alone. Bone marrow chimera experiments established that the increased sensitivity conferred by the F709 genotype was mediated mostly by hematopoietic cells but that nonhematopoietic cells also contributed. F709 mice exhibited increased intestinal permeability to macromolecules. The F709 genotype conferred increased OVA-specific IgE but not IgG1 responses, local and systemic T(H)2 responses, and intestinal mast cell hyperplasia compared with wild-type mice. Anaphylaxis was abrogated in F709 mice lacking IgE or the high-affinity receptor for IgE (FcεRI).
Augmented IL-4Rα signaling confers increased intestinal permeability and dramatically enhanced sensitivity to food allergens. Unlike anaphylaxis to injected antigens, which in rodents can be mediated by either IgE or IgG antibodies, the food-induced response in F709 mice is solely IgE dependent.
在特应性患者中，食物摄入会促使 IgE 抗体的产生，从而引发过敏反应。IL-4 通路在此反应中起着至关重要的作用，其成分中的遗传多态性与过敏有关。
我们旨在测试 IL-4 受体（IL-4R）α链的激活突变是否会增强对食物抗原的过敏反应。
用卵清蛋白（OVA）灌胃 F709 小鼠，该小鼠的 IL-4Rα免疫受体酪氨酸基抑制基序失活。评估对 OVA 挑战的反应和免疫反应，包括抗体产生和 T(H)2 反应。
F709 小鼠，而非野生型对照动物，经灌胃 OVA 并用霍乱毒素或葡萄球菌肠毒素 B 致敏后，在肠内挑战时显示出肥大细胞活化和全身性过敏反应。甚至在 F709 小鼠仅经肠内致敏 OVA 时也会引发过敏反应。骨髓嵌合体实验表明，F709 基因型赋予的敏感性增加主要由造血细胞介导，但非造血细胞也有贡献。F709 小鼠表现出对大分子的肠道通透性增加。与野生型小鼠相比，F709 小鼠表现出增加的 OVA 特异性 IgE 但不是 IgG1 反应、局部和全身 T(H)2 反应以及肠道肥大细胞增生。在缺乏 IgE 或高亲和力 IgE 受体（FcεRI）的 F709 小鼠中，过敏反应被阻断。
增强的 IL-4Rα信号传导赋予增加的肠道通透性和对食物过敏原的显著增强的敏感性。与啮齿动物中注射抗原引起的过敏反应不同，后者可以由 IgE 或 IgG 抗体介导，F709 小鼠中食物诱导的反应仅依赖于 IgE。
