Project 2: Innate Immune Pathways in Food-induced Anaphylaxis

项目 2：食物引起的过敏反应中的先天免疫途径

• 批准号: 10635815
• 负责人: Supinda Bunyavanich
• 金额: $ 5.16万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-06 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10635815
• 关键词: Address; Allergen Immunotherapy; Allergens; Allergic; Allergic Reaction; Allergy to peanuts; Anaphylaxis; Antigen-Antibody Complex; Antigens; Arachis hypogaea; Basophils; Binding; Blood; Blood Platelets; Blood specimen; CD34 gene; Cells; Child; Circulation; Clinical; Coculture Techniques; Complex; Data; Dose; Double-Blind Method; Enteroendocrine Cell; Enzyme-Linked Immunosorbent Assay; Exposure to; FCGR3B gene; Flow Cytometry; Food; Food Hypersensitivity; G-Protein-Coupled Receptors; GPR35 gene; Gastrointestinal tract structure; Gene Expression Profiling; Histamine; Hour; Human; Hydroxyindoleacetic Acid; IgE; Immune; Immunoglobulin G; Immunotherapy; In Vitro; Individual; Innate Immune Response; Interruption; Intervention; Intestines; Ligands; Macrophage; Mass Spectrum Analysis; Measures; Mediating; Mediator; Mus; Natural Immunity; Neutrophil Activation; Neutrophil Infiltration; Oral; Pathogenesis; Pathway interactions; Patients; Peripheral; Phenotype; Placebo Control; Placebos; Plasma; Platelet Activating Factor; Prevention; Proteins; Reaction; Role; Serotonin; Serotonin Production; Serum; Severities; Source; Testing; Whole Blood; absorption; cohort; crosslink; food challenge; genetic signature; high dimensionality; immune activation; in vivo; innate immune mechanisms; innate immune pathways; mast cell; mouse model; neutrophil; novel; peripheral blood; prevent; programs; receptor; response; transcriptome sequencing

SUMMARY – Project 2 Food allergy is mediated by IgE triggering of mast cells and basophils. We found that peanut-specific IgE and basophil activation test could distinguish allergic from sensitized individuals, but had no utility in predicting reaction severity during double blind placebo controlled food challenges (DBPCFC). Distinguishing mild from potentially severe reactions would be of major clinical benefit. Transcriptional profiling identified a neutrophil signature that was associated not only with reactions to peanut, but also with severity of reactions. Flow cytometry profiling identified a significant increase in circulating neutrophils post-challenge, and preliminary data shows a change in neutrophil phenotype consistent with activation. Although neutrophils have been shown to be activated by IgG-allergen complexes, it is unlikely that there would be significant immune complex formation due to the low dose of peanut exposure. Neutrophils have been shown to be responsive to serotonin metabolites, and in preliminary data we demonstrate that activation of whole blood with peanut induces serotonin release. Human mast cells (and potentially basophils) produce low levels of serotonin, but platelets are a major source of serotonin in the circulation and can release it upon activation. We have previously shown that platelets form complexes with basophils in blood from peanut allergic individuals upon exposure to peanut. We hypothesize that basophil-platelet complexes are responsible for the release of serotonin, which then activates neutrophils in the context of food allergy. We will test this hypothesis with three specific aims. The first aim will use spectral flow cytometry and RNA sequencing to examine neutrophil and other innate immune activation during DBPCFC. The second aim will examine the release of serotonin and serotonin metabolites during reactions and test the role of serotonin and metabolites in neutrophil activation. The third aim will examine the contribution of basophil platelet complexes to the production of serotonin in response to peanut exposure. Successful completion of these aims will reveal novel innate immune mechanisms of severe reactions to peanut, leading the way to new interventions for the prevention of severe peanut allergy.

摘要-项目2 食物过敏是由IgE触发肥大细胞和嗜碱性粒细胞介导的。我们发现花生特异性IgE和 嗜碱性粒细胞活化试验可区分过敏和致敏个体，但对预测过敏和致敏个体的预后无意义。 双盲安慰剂对照食物激发（DBPCFC）期间的反应严重程度。区分轻度和 潜在的严重反应将具有重大的临床益处。转录谱鉴定出一种中性粒细胞 这不仅与对花生的反应有关，而且与反应的严重程度有关。流 细胞计数分析确定了攻击后循环中性粒细胞的显著增加，并且初步 数据显示中性粒细胞表型的变化与活化一致。虽然中性粒细胞已经 虽然显示被IgG-变应原复合物激活，但不太可能存在显著的免疫复合物， 由于低剂量的花生暴露而形成。中性粒细胞对血清素有反应 代谢物，并在初步数据中，我们证明，活化全血与花生诱导， 血清素释放人类肥大细胞（以及潜在的嗜碱性粒细胞）产生低水平的血清素，但血小板 是血液循环中血清素的主要来源，激活后可释放血清素。我们先前已经表明 花生过敏个体暴露于花生后，血小板与血液中的嗜碱性粒细胞形成复合物。 我们假设嗜碱性粒细胞-血小板复合物负责释放血清素， 在食物过敏的情况下激活中性粒细胞。我们将以三个具体目标来检验这一假设。的 第一个目标将使用光谱流式细胞术和RNA测序来检查中性粒细胞和其他先天免疫细胞， 在DBPCFC期间激活。第二个目标将检查血清素和血清素代谢物的释放 在反应过程中，并测试血清素和代谢物在中性粒细胞活化中的作用。第三个目标将 研究嗜碱性粒细胞血小板复合物对花生产生血清素的作用 exposure.这些目标的成功实现将揭示重症肌无力的新的先天免疫机制。 研究人员正在研究对花生的过敏反应，为预防严重花生过敏的新干预措施开辟道路。