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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目摘要在神经精神病和神经退行性疾病中，食物过敏已隐含。但是，是因果关系食物过敏在脑功能障碍中的作用已引起争议，这主要是由于病理证据不足和清晰的潜在机制。使用食物过敏的动物模型，我们和其他人提供了支持证据通过证明其他健康小鼠诱导食物过敏，将食物过敏和脑功能障碍联系起来导致与神经炎症和神经活性改变有关的行为变化。我们找到了 C57BL/6J小鼠对牛轮过敏原敏感β-乳糖球蛋白（BLG，BOS 5 D），不会暴露明显的公开对急性过敏原挑战的过敏反应，但显示出焦虑状和抑郁症状的行为第二天，血浆特异性IgE的血浆水平升高，炎症细胞因子和趋化因子。这些观察表明，敏感个体中仍然存在过敏诱导的免疫反应，即使在没有明显的过敏反应。利用这种非抗逆性牛的鼠标模型牛奶过敏（CMA），我们通过放置对BLG敏感的小鼠进行了反复的过敏原暴露方案持续饮食持续2周，经常模拟亚临床的人的过敏原消耗量反应。尽管未在过敏原小鼠中检测到过敏反应或食物厌恶的证据，但我们观察到的深层皮质脱髓鞘以及血脑周围星形胶质细胞的血液渗透性增加与明显的抑郁症行为相关的大脑中肥大和免疫细胞的存在。此外，过敏原特异性IgE和其他炎症介质的全身水平保持升高在这些老鼠中。这是我们假设CMA诱导的皮质脱髓鞘和其他神经病理学结果来自由脑浸入白细胞的持续活动而策划的神经炎症。过敏原暴露。在这个项目中，我们将首先评估感觉，运动和/或认知功能是否也是受到与CMA相关的脱髓鞘和神经炎症的影响从饮食中去除过敏原会逆转大脑和行为的变化（AIM 1）。然后我们会研究过敏原刺激的免疫细胞参与神经病理学的发展阐明它们在介导周围的过敏性侮辱中的作用（AIM 2）。最后，我们将测试是否肠屏障的药理保护可防止食物消费期间异常的过敏原入口减少CMA诱导的神经病理学（AIM 3）。这项研究的结果将填补我们在涉及外围到中央交流的机制，并澄清过敏介导的不良影响慢性炎症对大脑功能，促使早期过敏检测以防止脑功能障碍。