Regulation of Immune Responses by IgE and Mast Cells

IgE 和肥大细胞对免疫反应的调节

• 批准号: 7846424
• 负责人: Hans C Oettgen
• 金额: $ 1.12万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846424
• 关键词: Adoptive Transfer; Allergens; Allergic; Animals; Antibodies; Antigens; Bone Marrow; Breathing; Cell Count; Cell physiology; Chemicals; Complex; Contact Dermatitis; Cutaneous; Data; Dendritic Cells; Dermal; Disease; Goals; Haptens; IgE; IgE Receptors; Immune; Immune response; Individual; Injection of therapeutic agent; Interleukin-6; Irritants; Laboratories; Langerhans cell; Link; Lung; Lymphoid Tissue; Measures; Mediating; Membrane; Modeling; Mucous Membrane; Mus; Occupational Asthma; Pathway interactions; Patients; Phase; Production; Reaction; Regulation; Reporting; Research Personnel; Role; Signal Pathway; Signal Transduction; Skin; System; T-Lymphocyte; TNF gene; Testing; Tissues; airway inflammation; cytokine; environmental allergen; in vivo; intradermal injection; lymph nodes; mast cell; methacholine; mutant; programs; receptor expression; reconstitution; research study; response; trafficking

DESCRIPTION (provided by applicant): Patients with allergic diseases invariably have elevated IgE levels. The acquisition of specific immune sensitivity to allergens in these same individuals is linked to their cumulative environmental allergen exposure. These associations suggest that IgE may promote allergic sensitization. Recent data from this laboratory have established such a function for IgE antibodies in contact sensitivity responses, where they enhance immune sensitization to epicutaneously-applied chemical haptens using a mechanism that requires their interaction with mast cells via FcEepsilonRI. Preliminary studies have shown that responses to contact sensitizers are markedly impaired in IgE-/- and mast cell-deficient (W/W') mice as well as animals lacking FcepsilonRI. IgE antibodies support the production of cytokines by mast cells in irritant-exposed skin in an antigen-independent manner consistent with monomeric IgE signaling. The skin of both mast cell- and IgE-deficient animals has abnormally low levels of TNF, a mast cell cytokine previously shown to be critical in contact sensitivity. Intradermal injection of TNF completely restores the contact sensitivity responses of IgE-/- and W/W' mice. Pulmonary responses to contact sensitizers are also IgE-dependent. These findings give rise to the hypothesis that IgE primes dermal mast cells for irritant-induced production of TNF and IL-6 and that these mast cell-derived cytokines activate tissue dendritic cells to drive effective immune sensitization. This hypothesis will be examined with the following aims: I. The contact sensitivity system will be used to establish the effects of mast cells and of mast cell-derived cytokines TNF and IL-6 on dermal dendritic cells and Langerhans cells. ll. The "priming" function of IgE antibodies for mast cell responses to chemical irritants and secretagogues and the mechanism of monomeric IgE signaling will be characterized in cultured mast cells and in vivo. III. A murine model of occupational asthma will be used to examine the roles of IgE antibodies, mast cells, IL-6 and TNF in the induction of airway inflammation following inhalation of contact sensitizers.

描述（由申请人提供）：过敏性疾病患者的IgE水平总是升高。在这些相同的个体中获得对过敏原的特异性免疫敏感性与他们累积的环境过敏原暴露有关。这些关联表明IgE可能促进过敏性致敏。来自该实验室的最新数据已经确定了IgE抗体在接触敏感性反应中的这种功能，其中它们使用需要它们通过Fc ε RI与肥大细胞相互作用的机制来增强对表皮应用的化学半抗原的免疫致敏性。 初步研究表明，在IgE-/-和肥大细胞缺陷（W/W '）小鼠以及缺乏Fc ε RI的动物中，对接触致敏剂的反应明显受损。 IgE抗体支持暴露于刺激物的皮肤中的肥大细胞以与单体IgE信号传导一致的抗原非依赖性方式产生细胞因子。肥大细胞和IgE缺陷动物的皮肤中TNF水平异常低，这是一种肥大细胞细胞因子，此前已被证明对接触敏感性至关重要。皮内注射TNF完全恢复IgE-/-和W/W'小鼠的接触敏感性反应。 肺对接触致敏剂的反应也是IgE依赖性的。这些发现提出了这样的假设，即IgE引发真皮肥大细胞刺激诱导产生TNF和IL-6，这些肥大细胞衍生的细胞因子激活组织树突状细胞，以驱动有效的免疫致敏。这一假设将按照以下目标进行审查： I.接触敏感性系统将用于确定肥大细胞和肥大细胞衍生的细胞因子TNF和IL-6对真皮树突状细胞和朗格汉斯细胞的影响。 ll.肥大细胞对化学刺激物和促分泌素的反应的IgE抗体的“引发”功能和单体IgE信号传导的机制将在培养的肥大细胞和体内表征。 三.职业性哮喘的小鼠模型将用于检查IgE抗体、肥大细胞、IL-6和TNF在吸入接触致敏剂后诱导气道炎症中的作用。

项目成果

Lyn kinase controls basophil GATA-3 transcription factor expression and induction of Th2 cell differentiation.

• DOI: 10.1016/j.immuni.2009.02.008
• 发表时间: 2009-04-17
• 期刊: IMMUNITY
• 影响因子: 32.4
• 作者: Charles, Nicolas;Watford, Wendy T.;Ramos, Haydee L.;Hellman, Lars;Oettgen, Hans C.;Gomez, Gregorio;Ryan, John J.;O'Shea, John J.;Rivera, Juan
• 通讯作者: Rivera, Juan

Basophils are rapidly mobilized following initial aeroallergen encounter in naïve mice and provide a priming source of IL-4 in adaptive immune responses.

在首次接触气源性过敏原的小鼠中，嗜碱性粒细胞会迅速动员起来，并在适应性免疫反应中提供 IL-4 的启动来源。

• 发表时间: 2014
• 期刊: Journal of biological regulators and homeostatic agents
• 影响因子: 3.2
• 作者: Poddighe,D;Mathias,CB;Freyschmidt,EJ;Kombe,D;Caplan,B;Marseglia,GL;Oettgen,HC
• 通讯作者: Oettgen,HC

Beyond immediate hypersensitivity: evolving roles for IgE antibodies in immune homeostasis and allergic diseases.

• DOI: 10.1111/j.1600-065x.2011.01024.x
• 发表时间: 2011-07
• 期刊: Immunological reviews
• 影响因子: 8.7
• 作者: Burton OT;Oettgen HC
• 通讯作者: Oettgen HC

Immunoglobulin E antibodies enhance pulmonary inflammation induced by inhalation of a chemical hapten.

免疫球蛋白 E 抗体可增强吸入化学半抗原引起的肺部炎症。

• DOI: 10.1111/j.1365-2222.2008.03140.x
• 发表时间: 2009
• 期刊: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
• 作者: Mathias,CB;Freyschmidt,E-J;Oettgen,HC
• 通讯作者: Oettgen,HC