Department of Dermatology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
Department of Internal Medicine I, University Hospital Erlangen, University of Erlangen-Nürnberg, Erlangen, Germany.
J Allergy Clin Immunol. 2019 Jan;143(1):201-212.e4. doi: 10.1016/j.jaci.2018.02.041. Epub 2018 Mar 21.
Amylase-trypsin inhibitors (ATIs) in wheat and related cereals are potent activators of myeloid innate immune cells via engagement of TLR4. Furthermore, ATIs have been shown to serve as adjuvants in experimental intestinal inflammatory diseases.
The aim of this study was to analyze whether ATIs are also modifiers of allergic inflammation.
Therefore, CD4 T cells from donors sensitized to grass or birch pollen were stimulated with autologous allergen-pulsed dendritic cells in the presence or absence of ATIs or the control storage protein zein from corn. To analyze allergen-induced gut and lung inflammation, immunodeficient mice were engrafted with PBMCs from these allergic donors plus the respective allergen, and fed with selected diets. Three weeks later, inflammation was induced by rectal or intranasal allergen challenge and monitored by mini endoscopy or airway hyperreactivity, respectively.
Allergen-specific T-cell proliferation and cytokine production was significantly exacerbated by ATIs and not by zein. In vivo, allergen-specific human IgE level was strongly elevated in sera of mice receiving an ATI-containing diet compared with mice that were fed gluten-free and thus ATI-free diet. Importantly, allergen-induced IgE-dependent colitis and airway hyperreactivity were also enhanced in ATI-fed mice. Gut inflammation was further increased in mice receiving an additional ATI injection and even detectable in the absence of the aeroallergen, whereas zein had no such effect. Injection of anti-human TLR4 mAbs or the anti-human IgE mAb omalizumab completely abolished ATI-induced allergic inflammation.
These results underline that wheat ATIs are important nutritional activators and adjuvants of allergy, which might be exploited for nutritional therapeutic strategies.
小麦和相关谷物中的淀粉酶-胰蛋白酶抑制剂（ATIs）通过与 TLR4 结合，成为髓系固有免疫细胞的有效激活剂。此外，ATIs 已被证明在实验性肠道炎症性疾病中作为佐剂。
本研究旨在分析 ATIs 是否也是过敏炎症的修饰物。
因此，从对草或桦树花粉致敏的供体中分离出 CD4 T 细胞，在存在或不存在 ATIs 或来自玉米的对照储存蛋白 zein 的情况下，用自体过敏原脉冲树突状细胞进行刺激。为了分析过敏原诱导的肠道和肺部炎症，将这些过敏供体的 PBMC 与各自的过敏原一起移植到免疫缺陷小鼠中，并给予选定的饮食。3 周后，通过直肠或鼻内过敏原挑战诱导炎症，并分别通过迷你内镜或气道高反应性进行监测。
过敏原特异性 T 细胞增殖和细胞因子产生明显被 ATIs 而非 zein 加剧。在体内，与接受无麸质和无 ATI 饮食的小鼠相比，接受含 ATI 饮食的小鼠血清中过敏原特异性人 IgE 水平显著升高。重要的是，在接受 ATI 喂养的小鼠中，过敏原诱导的 IgE 依赖性结肠炎和气道高反应性也增强。在接受额外 ATI 注射的小鼠中，肠道炎症进一步增加，甚至在不存在气传过敏原的情况下也可检测到，而 zein 则没有这种作用。注射抗人 TLR4 mAb 或抗人 IgE mAb omalizumab 可完全消除 ATI 诱导的过敏炎症。
这些结果强调了小麦 ATIs 是过敏的重要营养激活剂和佐剂，这可能被用于营养治疗策略。
