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.

项目概要食物过敏与神经精神疾病和神经退行性疾病有关。食物过敏在脑功能障碍中的作用一直存在争议，这主要是由于病理证据不足和我们和其他人利用食物过敏的动物模型提供了明确的潜在机制。通过证明在其他健康的小鼠中诱发食物过敏，将食物过敏与大脑功能障碍联系起来我们发现，导致与神经炎症和神经活动相关的行为变化。对牛乳清过敏原 β-乳球蛋白（BLG，Bos 5 d）敏感的 C57BL/6J 小鼠没有表现出明显的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之一第二天，过敏原特异性 IgE、炎症细胞因子和趋化因子的血浆水平升高。观察表明，过敏引起的免疫反应仍然存在于致敏个体中，即使在利用这种非过敏性牛的小鼠模型，没有明显的过敏反应。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中持续两周的含乳清饮食，以模拟亚临床患者频繁摄入过敏原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，但我们观察到广泛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大脑肥大和免疫细胞的存在与显着的抑郁样行为有关。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因此，我们研究了 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持续活动而引发的神经炎症在这个项目中，我们将首先评估感觉、运动和/或认知功能是否也存在。受 CMA 相关的大脑脱髓鞘和神经炎症变化的影响，以及是否从饮食中去除过敏原可以逆转大脑和行为的变化（目标 1）。研究过敏原刺激的免疫细胞在神经病理学发展中的作用阐明它们在介导大脑周围过敏性损伤中的作用（目标 2）。肠道屏障的药理保护可防止食物消费过程中异常过敏原进入减少 CMA 诱发的神经病理学（目标 3）。这项研究的结果将填补我们在这方面的知识空白。参与外周到中枢通讯的机制并阐明过敏介导的不利影响慢性炎症会影响大脑功能，促使及早发现过敏症，以防止大脑功能障碍。