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

外周免疫细胞活性在食物过敏引起的神经炎症和脱髓鞘中的作用

• 批准号: 10412267
• 负责人: Kumi Nagamoto-Combs
• 金额: $ 38.27万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-18 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412267
• 关键词: Acetates; Acute; Adoptive Transfer; Adult; Adverse effects; Affect; Allergens; Allergic; Allergic Reaction; Alzheimer' s Disease; Anaphylaxis; Animal Model; Antibodies; Anxiety; Astrocytes; Attenuated; Axon; Behavior; Behavioral; Blood; Blood Circulation; Brain; Brain Pathology; CXCR3 gene; Cattle; Cells; Central Nervous System Diseases; Child; Chronic; Chymase; Clinical; Clinical Research; Cognitive; Cohort Studies; Communication; Consumption; Demyelinations; Dermatologic; Detection; Development; Diagnosis; Diet; Early Diagnosis; Etiology; Excision; Exhibits; Exposure to; Female; Food; Food Aversion; Food Hypersensitivity; Genetic; Goals; Human; Hypersensitivity; Hypertrophy; IgE; Immune; Immune System Diseases; Immune response; Individual; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Ingestion; Integrin alpha4beta1; Intestinal permeability; Intestines; Knowledge; Leukocyte Trafficking; Leukocytes; Link; Mediating; Mental Depression; Mental Health; Milk Hypersensitivity; Moods; Motor; Multiple Sclerosis; Mus; Myelin; Neuraxis; Neurodegenerative Disorders; Oligodendroglia; Outcome Study; PTPRC gene; Pathologic; Peripheral; Permeability; Pharmacology; Plasma; Play; Proteins; Reaction; Regimen; Reporting; Risk Factors; Rodent; Role; Sensory; Serum; Stains; Surface; Symptoms; Tail Suspension; Testing; Tight Junctions; Tolonium chloride; United States; autistic behaviour; behavior change; behavior test; blood-brain barrier permeabilization; brain behavior; brain dysfunction; cell motility; chemokine; cognitive function; cohort; comorbidity; cytokine; diagnostic criteria; dimer; food allergen; food consumption; gastrointestinal; inhibitor; intestinal barrier; male; mast cell; migration; mouse model; neuroinflammation; neuropathology; neuropsychiatric disorder; oligodendrocyte progenitor; prevent; relating to nervous system; remyelination; respiratory; response; stem cells; zonulin

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.

项目摘要 食物过敏与神经精神和神经退行性疾病有关。然而，causative 食物过敏在脑功能障碍中的作用一直存在争议，主要是由于病理学证据不足， 明确的基本机制。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， 将食物过敏和脑功能障碍联系起来， 导致与神经炎症和改变的神经活动相关的行为变化。我们发现 对牛乳清过敏原β-乳球蛋白（BLG，Bos 5 d）致敏的C57 BL/6 J小鼠， 急性过敏原激发后出现过敏反应，但表现出焦虑样和抑郁样行为， 第二天，过敏原特异性IgE和炎性细胞因子和趋化因子的血浆水平升高。这些 观察结果表明，过敏诱导的免疫反应仍然存在于致敏个体中，即使在 没有明显的过敏反应。利用这种非过敏性奶牛的小鼠模型， 牛奶过敏（CMA），我们将BLG致敏的小鼠置于重复的过敏原暴露方案， 含乳清饮食2周，以模拟亚临床过敏症患者频繁食用过敏原。 反应.尽管在喂食过敏原的小鼠中没有发现过敏反应或食物厌恶的证据， 观察到严重的皮质脱髓鞘以及血脑通透性增加，血管周围星形胶质细胞 肥大和免疫细胞的存在与显着的抑郁样行为。 此外，过敏原特异性IgE和其他炎症介质的全身水平仍然升高 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学结果 由于反复的脑浸润白细胞的持续活动而引起的神经炎症 过敏原暴露在这个项目中，我们将首先评估感觉，运动和/或认知功能是否也 受脑中CMA相关脱髓鞘和神经炎性变化的影响， 从饮食中去除过敏原可以逆转大脑和行为的变化（目标1）。然后我们将 研究过敏原刺激的免疫细胞参与神经病理学的发展， 阐明了它们在介导对脑的外周过敏性损伤中的作用（目的2）。最后，我们将测试 肠屏障的药理学保护防止食物消耗期间异常过敏原进入， 减少CMA诱导的神经病理学（目的3）。这项研究的结果将填补我们在知识上的空白， 机制参与外周到中央通信，并澄清过敏介导的不良影响， 慢性炎症对大脑功能的影响，促使早期过敏检测，以防止大脑功能障碍。