Histamine-Releasing Factor Oligomers in Food Allergy

食物过敏中的组胺释放因子低聚物

• 批准号: 10462489
• 负责人: TOSHIAKI KAWAKAMI
• 金额: $ 63.43万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462489
• 关键词: Affect; Affinity; Allergens; Allergic; Allergic Disease; Allergic Reaction; Allergic inflammation; American; Amino Acids; Anaphylaxis; Animals; Antigens; Atopic Dermatitis; Base Sequence; Basophils; Binding; Binding Sites; Biological; Body Fluids; Cell Cycle Progression; Cells; Characteristics; Complementarity Determining Regions; Complex; Data; Diarrhea; Disease; Disulfides; Embryo; Enzymes; Epithelial Cells; Event; Fab Immunoglobulins; Food; Food Hypersensitivity; Histamine Release; Human; Hypersensitivity; IgE; IgE Receptors; Immunoglobulin G; Immunoglobulins; Incidence; Inflammation; Intestines; Knockout Mice; Knowledge; Link; Liquid substance; Malignant - descriptor; Mediating; Modality; Molecular; Molecular Cloning; Mus; Mutant Strains Mice; Mutation; Nature; Pathogenesis; Pathologic; Patients; Peptide Signal Sequences; Peptides; Phase; Phenotype; Prevalence; Preventive; Protein Disulfide Isomerase; Proteins; Pulmonary Inflammation; Recombinants; Regulation; Research; Research Personnel; Role; Serum; Severities; Small Intestines; Structural Models; System; TPT1 gene; Testing; Therapeutic; X-Ray Crystallography; asthma model; base; cell type; clinical development; crosslink; cytokine; dimer; disulfide bond; experimental study; extracellular; glycosylation; gut inflammation; in vivo; inhibitor; insight; intestinal epithelium; mast cell; monomer; mouse model; mutant; novel; prevent; prophylactic; receptor; tool

PROJECT SUMMARY The prevalence of food allergy has been dramatically increasing for the last few decades. Although studies using murine models of food allergy have greatly advanced our understanding of its pathogenesis, there are still significant knowledge gaps. Histamine-releasing factor (HRF) activate mast cells and basophils in an IgE- dependent manner. As its secretion was found in body fluids during late-phase allergic reactions, HRF has been implicated in allergic diseases. However, whether HRF is involved in allergic diseases had remained enigmatic, although its molecular identity was revealed in 1995. Our 2012 study changed this situation by identifying a subset of IgE and IgG molecules as HRF receptors: mapping of the immunoglobulin (Ig) Fab- binding sites within the HRF molecule led to the discovery of HRF sequence-based inhibitors, N19 and H3 peptides, as well as a monomeric mutant HRF-2CA, all of which blocked HRF-Ig interactions; prophylactic administration of these inhibitors, which targeted mast cells, strongly reduced the incidence of allergic diarrhea and anaphylaxis, as well as the severity of intestinal inflammation in an IgE/FcεRI (high-affinity IgE receptor)/mast cell-dependent mouse model of food allergy. HRF is present as a monomer and disulfide-linked oligomers including a dimer. HRF dimer, but not monomer, has an ability to activate IgE-primed mast cells and basophils and to enhance allergen-triggered activation of these cells. HRF oligomers increased in the small intestine of food allergic animals. Our results collectively suggest that HRF oligomers crosslink IgE-bound FcεRI on intestinal mast cells, leading to their activation, which is required for allergen-induced maximal intestinal type 2 inflammation. Based upon these novel data, we hypothesize that HRF oligomerization and HRF-IgE interactions are two critical events to initiate and amplify intestinal inflammation in food allergy. To test this hypothesis, we will conduct food allergy experiments with novel mutant mice lacking normal HRF dimer (Aim 1), and seek to identify the enzyme system that catalyzes oligomerization of HRF (Aim 2). We will also investigate the effects of HRF oligomerization and N-glycosylation of HRF and IgEs on HRF-IgE interactions, and potential regulation of HRF-IgE interactions at the atomic level during food allergy (Aim 3). Therefore, this study will likely establish a novel paradigm that FcεRI-mediated mast cell activation triggered by antigen is amplified by HRF oligomers that cause a heightened inflammation in food allergy.

项目摘要 在过去的几十年里，食物过敏的患病率急剧增加。尽管研究 使用食物过敏的小鼠模型已经极大地推进了我们对其发病机制的理解， 仍然存在巨大的知识差距。组胺释放因子（HRF）激活IgE-1受体中的肥大细胞和嗜碱性粒细胞。 依赖的方式。由于在后期过敏反应期间在体液中发现HRF分泌物， 与过敏性疾病有关然而，HRF是否参与过敏性疾病的发生， 尽管它的分子身份在1995年被发现，但它仍然是一个谜。我们2012年的研究改变了这种情况， 鉴定IgE和IgG分子的子集为HRF受体：免疫球蛋白（IG）Fab- HRF分子内的结合位点导致了基于HRF序列的抑制剂N19和H3的发现 肽，以及单体突变体HRF-2CA，所有这些都阻断HRF-Ig相互作用;预防性 给予这些针对肥大细胞的抑制剂，大大降低了过敏性腹泻的发生率 和过敏反应，以及IgE/FcεRI（高亲和力IgE）中肠道炎症的严重程度 受体）/肥大细胞依赖性食物过敏小鼠模型。HRF以单体形式存在， 低聚物，包括二聚体。HRF二聚体，而不是单体，具有激活IgE致敏的肥大细胞的能力， 嗜碱性粒细胞，并增强这些细胞的过敏原触发的激活。HRF寡聚体增加，在小 食物过敏动物的肠道。我们的研究结果共同表明，HRF寡聚体交联IgE结合 FcεRI作用于肠肥大细胞，导致其活化，这是过敏原诱导的最大免疫应答所必需的。 肠道2型炎症。基于这些新的数据，我们假设HRF寡聚化和 HRF-IgE相互作用是食物过敏中启动和放大肠道炎症的两个关键事件。到 为了验证这一假设，我们将用缺乏正常HRF的新型突变小鼠进行食物过敏实验 二聚体（目的1），并寻求确定酶系统，催化低聚化的HRF（目的2）。我们将 并研究了HRF寡聚化和HRF和IgE的N-糖基化对HRF-IgE的影响 相互作用，以及食物过敏期间原子水平上HRF-IgE相互作用的潜在调节（目的3）。 因此，本研究将可能建立一种新的范式，即Fcε RI介导的肥大细胞活化由 抗原被HRF寡聚体放大，导致食物过敏中的炎症加剧。

项目成果

Editorial overview: Recent advances in research of IgE-mediated and IgE-independent allergies, an overview.

编辑概述：IgE 介导和 IgE 非依赖性过敏研究的最新进展，概述。

• DOI: 10.1016/j.coi.2021.10.003
• 发表时间: 2021
• 期刊: Current opinion in immunology
• 影响因子: 7
• 作者: Kawakami,Toshiaki;Blank,Ulrich
• 通讯作者: Blank,Ulrich

Cooperative Regulation of the Mucosal Mast Cell-Specific Protease Genes Mcpt1 and Mcpt2 by GATA and Smad Transcription Factors.

GATA和SMAD转录因子对粘膜肥大细胞特异性蛋白酶MCPT1和MCPT2的合作调节。

• DOI: 10.4049/jimmunol.1900094
• 发表时间: 2020-03-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Kasakura K;Nagata K;Miura R;Iida M;Nakaya H;Okada H;Arai T;Arai T;Kawakami Y;Kawakami T;Yashiro T;Nishiyama C
• 通讯作者: Nishiyama C

Novel inhibitors of histamine-releasing factor suppress food allergy in a murine model.

新型组胺释放因子抑制剂可抑制小鼠模型中的食物过敏。

• DOI: 10.1016/j.alit.2021.07.005
• 发表时间: 2022
• 期刊: Allergology international : official journal of the Japanese Society of Allergology
• 作者: Kawakami,Yu;Kurosawa,Yasunori;Oltean,Daniela;Espinosa,LisaYuko;Kim,HwanSoo;Lemersal,Ian;Kawakami,Yuko;Okumura,Shigeru;Maruyama,Toshiaki;Kawakami,Toshiaki
• 通讯作者: Kawakami,Toshiaki

Predictive value of 7S globulin-specific IgE in Japanese macadamia nut allergy patients.

7S 球蛋白特异性 IgE 对日本澳洲坚果过敏患者的预测价值。

• DOI: 10.1016/j.jaip.2021.12.039
• 发表时间: 2022
• 期刊: The journal of allergy and clinical immunology. In practice
• 作者: Yasudo,Hiroki;Ando,Tomoaki;Kitaura,Jiro;Maruyama,Nobuyuki;Narita,Masami;Natsume,Osamu;Uneoka,Kei;Miura,Katsushi;Morita,Yoshinori;Kamei,Anna;Okamoto,Yoko;Shirakawa,Seigo;Kitabayashi,Taeru;Kurihara,Kazuyuki;Nogami,Kazuyoshi;Tak
• 通讯作者: Tak

Histamine-Releasing Factor Is a Novel Alarmin Induced by House Dust Mite Allergen, Cytokines, and Cell Death.

• DOI: 10.4049/jimmunol.2200276
• 发表时间: 2022-11-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Kasakura K;Kawakami Y;Jacquet A;Kawakami T
• 通讯作者: Kawakami T