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Galectins in Modulating Immune Responsiveness of IgE-bearing Cells

半乳糖凝集素调节 IgE 细胞的免疫反应

基本信息

批准号：
10651597
负责人：
JOHN T. SCHROEDER
金额：
$ 52.23万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-19 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651597
关键词：
A549 Address Affect Affinity Allergens Allergic Allergic Disease Antigens Asthma Atopic Dermatitis Autoimmunity Basophils Binding Blood Cells Cell Adhesion Cell Line Cells Cellular Structures Child Chronic Data Dendritic Cells Disease Disease susceptibility Epithelial Cells Food Galactose Binding Lectin Galectin 3 Goals Histamine Histamine Release Human Hypersensitivity IgE Immobilization Immune Immune response Immunologic Receptors Impairment Inflammation Mediators Inflammatory Interferon Type I Interferon alpha Interleukin-13 Interleukin-4 Interleukin-6 Investigation Learning Lectin Leukocytes Leukotriene C4 Ligand Binding Link Lung Lupus Nephritis Malignant Neoplasms Mediating Mediator Microspheres Modeling Mus Myelogenous Organ Pathogenesis Pathway interactions Pattern Population Property Proteins Regulation Reporting Signal Pathway Signal Transduction Skin Source Stimulus Symptoms TNF gene TSLP gene Testing Translating United States Urticaria Virus chemical release crosslink cytokine genetic manipulation immunoregulation in vivo insight mast cell mouse model prevent receptor receptor binding response small hairpin RNA wound healing

项目摘要

Allergic diseases are caused by skewed immune responses to otherwise harmless antigens, and, in one form or another, affect up to 25% of the population in the United States, with a disproportionately increase especially among children with asthma and food-related hypersensitivities. The binding of specific IgE to cells bearing high affinity receptors (FcεRI) is hallmark for the pathogenesis of allergic disease in that subsequent interaction with allergen causes cells such as basophils, mast cells, and dendritic cells to release pro-inflammatory mediators and cytokines that promote and/or amplify disease. In particular, crosslinking of IgE/FcεRI triggers basophils to release histamine and LTC4 but also IL-4 and IL-13 – mediators and cytokines central to the allergic diathesis. More recently, these activities have been confirmed and extended in vivo using mouse models, with some showing evidence for an “axis” whereby epithelial cell (EC)-derived cytokines activate basophils to produce IL-4 (& IL-13). In contrast, confirmatory results of these EC cytokines activating human basophils have not been forthcoming. In exploring this translational discrepancy, we serendipitously uncovered a remarkably robust, and potentially unique, mode of EC-dependent activation of human basophils that requires cell-to-cell adhesion and is IgE-dependent. Preliminary data now point to this mode of activation (discovered after co-culturing basophils with A549-lung EC) as being mediated by galectin-3 (Gal-3) –a lectin long known to bind IgE. There is also rationale for yet another level of regulation to this response –one mediated by Gal-9, which also binds IgE with nearly 100- fold greater affinity than does Gal-3 but lacks IgE/FcεRI crosslinking capabilities. Aim 1 studies further characterize the parameters underlying EC-dependent activation of basophils, with the goal of extending Gal-3-dependent activation to include primary human epithelial cells (PHEC). The Gal-3/Gal-9 interplay is also to be addressed in PHEC using genetic manipulation as well as a model whereby microspheres are coated with these galectins. Signaling pathways will also be explored and are thought to differ from those associated with standard anaphylactic release. Aim 2 will test the hypothesis that Gal-3/9 interplay also regulates the activities of other IgE-bearing cells, with preliminary evidence that Gal-3 also induces DC subtypes to secrete large quantities of pro-inflammatory cytokines (i.e. TNF-α/IL-6). Finally, Aim-3 investigates the regulation of Gal3/9 on EC, hypothesizing that their expression is counter-regulated by pro- inflammatory cytokines/mediators vs. innate immune stimuli. Overall, these results could ultimately provide insight into several unexplained IgE-related phenomena for which these IgE-bearing cells and Gal-3 are all implicated, ranging from allergic disease (e.g. asthma, chronic urticaria, and atopic dermatitis) to non- allergic conditions, including autoimmunity (lupus nephritis), cancer, and conceivably wound healing.

过敏性疾病是由免疫系统对无害抗原的扭曲反应引起的

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Basophils from allergy to cancer.

从过敏到癌症的嗜碱性粒细胞。

DOI：
10.3389/fimmu.2022.1056838
发表时间：
2022
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
通讯作者：

Is There a Role for Basophils in Cancer?

DOI：
10.3389/fimmu.2020.02103
发表时间：
2020
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Marone G;Schroeder JT;Mattei F;Loffredo S;Gambardella AR;Poto R;de Paulis A;Schiavoni G;Varricchi G
通讯作者：
Varricchi G

The S1 Subunit of the SARS-CoV-2 Spike Protein Activates Human Monocytes to Produce Cytokines Linked to COVID-19: Relevance to Galectin-3.