The role of peripheral immune cell activity in food-allergy-induced neuroinflammation and demyelination

项目总结 食物过敏与神经精神疾病和神经退行性疾病有关。然而，因果关系 食物过敏在脑功能障碍中的作用一直存在争议，主要是由于缺乏病理证据和 理清根本机制。利用食物过敏的动物模型，我们和其他人提供了支持性证据 通过证明在其他健康的小鼠中诱导食物过敏将食物过敏与脑功能障碍联系起来 导致与神经炎症和神经活动改变相关的行为改变。我们发现了 C57BL/6J小鼠对牛乳清变应原β-乳球蛋白(BLG，BoS5d)致敏，未表现出明显的乳清过敏 对急性过敏原激发的过敏反应，但表现出焦虑和抑郁样行为 过敏原特异性IgE、炎性细胞因子和趋化因子水平升高。这些 观察表明，过敏诱导的免疫反应在致敏个体中仍然存在，即使在 没有明显的过敏反应。利用非过敏性奶牛的小鼠模型 牛奶过敏(CMA)，我们让BLG致敏的小鼠接受反复过敏原暴露方案，方法是将它们 在含乳清饮食2周内模拟亚临床患者频繁的过敏原摄入 反应。虽然在喂食过敏原的小鼠中没有检测到过敏反应或食物厌恶的证据，但我们 观察到皮质深度脱髓鞘以及血脑通透性增加，血管周围星形胶质细胞 他们大脑中的肥大和免疫细胞的存在与显著的抑郁症样行为有关。 此外，全身变应原特异性IgE和其他炎症介质的水平仍然很高。 在这些老鼠身上。因此，我们假设CMA诱导的皮质脱髓鞘和其他神经病理结果 由于反复的脑内白细胞的持续活动而引起的神经炎症 接触过敏原。在这个项目中，我们将首先评估感觉、运动和/或认知功能是否也 受CMA相关的脑脱髓鞘和神经炎性改变的影响，以及是否 从饮食中去除过敏原会逆转大脑和行为的变化(目标1)。到时候我们会的 研究变应原刺激的免疫细胞在神经病理发展中的作用 阐明它们在调节对大脑的外周过敏性侮辱中的作用(目标2)。最后，我们将测试 对肠道屏障的药理保护可防止食物摄入过程中的异常变应原进入 减少CMA诱导的神经病理(目标3)。这项研究的结果将填补我们在 参与外周到中枢沟通的机制，并阐明变态反应介导的不良反应 慢性炎症对大脑功能的影响，促使及早进行过敏检测，以防止大脑功能障碍。

PROJECT SUMMARY Food allergy has been implicated in neuropsychiatric and neurodegenerative disorders. However, the causative role of food allergy in brain dysfunction has been debated, largely due to insufficient pathological evidence and clear underlying mechanisms. Using animal models of food allergy, we and others provided supportive evidence linking food allergy and brain dysfunction by demonstrating that inducing food allergy in otherwise healthy mice resulted in behavior changes associated with neuroinflammation and altered neural activities. We have found that C57BL/6J mice sensitized to a bovine whey allergen, β-lactoglobulin (BLG, Bos 5 d), do not exhibit overt anaphylactic reactions upon acute allergen challenge but showed anxiety-like and depression-like behavior one day after with elevated plasma levels of allergen-specific IgE and inflammatory cytokines and chemokines. These observations indicated that allergy-induced immune responses are still present in sensitized individuals even in the absence of apparent allergic reactions. Taking advantage of this mouse model of non-anaphylactic cow’s milk allergy (CMA), we subjected BLG-sensitized mice to a repeated allergen exposure regimen by placing them on a whey-containing diet for 2 weeks to simulate frequent allergen consumption by individuals with subclinical reactions. Although no evidence of anaphylaxis or food aversion was detected in the allergen-fed mice, we observed profound cortical demyelination as well as increased blood-brain permeability, perivascular astrocyte hypertrophy, and immune cell presence in their brains associated with significant depression-like behavior. Furthermore, the systemic levels of allergen-specific IgE and other inflammatory mediators remained elevated in these mice. Thus, we hypothesize that CMA-induced cortical demyelination and other neuropathologies result from neuroinflammation orchestrated by sustained activities of brain-infiltrating leukocytes due to repeated allergen exposure. In this project, we will first assess whether sensory, motor, and/or cognitive functions are also affected by the CMA-associated demyelination and neuroinflammatory changes in the brain and whether removing the allergen from the diet reverses the changes in the brain and behavior (Aim 1). We will then investigate the involvement of allergen-stimulated immune cells in the development of neuropathologies by clarifying their role in mediating the peripheral allergic insult to the brain (Aim 2). Finally, we will test whether pharmacological protection of the intestinal barrier prevents aberrant allergen entry during food consumption and reduces CMA-induced neuropathologies (Aim 3). The outcomes of this study will fill our knowledge gaps in the mechanism involved in peripheral-to-central communication and clarify the adverse effects of allergy-mediated chronic inflammation on brain function, prompting early allergy detection to prevent brain dysfunction.