Alternative IgE isoforms in mast cell function and immune response

肥大细胞功能和免疫反应中的替代 IgE 亚型

• 批准号: 7510491
• 负责人: TAKAYUKI OTA
• 金额: $ 23.74万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-08 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7510491
• 关键词: Adrenal Cortex Hormones; Affect; Affinity; Allergic; Allergic Reaction; Alternative Splicing; Antibodies; Antigens; Asthma; Atopic Dermatitis; Basophils; Binding; Biological; Breathing; Cell Survival; Cell physiology; Cells; Chronic; Clinical; Contact hypersensitivity; Dendritic Cells; Disease; Fc Receptor; Gene Expression; Genes; Goals; Host Defense; Human; Hybridomas; IgE; IgE Receptors; Immediate hypersensitivity; Immune response; Interleukin-3; Liver; Membrane; Messenger RNA; Monoclonal Antibodies; Mus; Passive Cutaneous Anaphylaxis; Pathogenesis; Patients; Play; Preparation; Production; Property; Protein Isoforms; Proteins; RNA Splicing; Race; Recombinant Proteins; Recombinants; Regulation; Rhinitis; Role; Series; Specificity; Stem Cell Factor; Structure; Symptoms; System; Testing; Variant; Work; anti-IgE; crosslink; cytokine; improved; in vivo; innovation; macrophage; mast cell; neutralizing antibody; novel; omalizumab; overexpression; response; tissue culture

DESCRIPTION (provided by applicant): This is an R21 proposal to study the biological significance of IgE isoforms. In humans, two forms of secreted IgE have been identified. These molecules differ at the COOH terminus owing to alternative mRNA splicing. The functional significance of this difference is unclear but the two isoforms appear to differ in abundance in particular disease states. In the mouse system some monomeric IgE preparations have the ability to promote the survival of mast cells. IgEs with this property are called "cytokinergic." This property is not understood, but it requires binding to FceR1 and is distinct from conventional mast cell activation, which requires crosslinking, rather than simple occupancy of FceR1. It is not clear why certain IgEs are cytokinergic while others are not. Obviously, regulation of mast cell survival could have a major impact on chronic allergic conditions. Mouse IgE H-chain mRNA isoforms homologous to those of human have been described, but no protein information has been available. I hypothesize that these two forms, IgE-S1 and IgE-S2, differ in their bioactivities and hence potential pathogenesis. The prediction will be tested that IgE-S2, but not the normally dominant IgE-S1 form, is cytokinergic. Moreover, we will test if the two IgE isoforms differ in their binding to a newly discovered IgE receptor, Fc?R4. It is important to understand the functions of secreted IgE isoforms and to determine if they differentially control allergic reactions. These goals will be approached through the following Specific Aims. 1. To develop recombinant IgE-S1 and -S2 molecules with identical specificities. 2. To produce series of hybridoma cells producing highly cytokinergic IgE. 3. To compare the bioactivities of IgE-S1 and IgE-S2 by in vivo overexpression. PROJECT NARRATIVE: This is an R21 proposal to study the biological significance of IgE isoforms in allergic disorders. IgE plays a key role in allergic disorders, including asthma and atopic dermatitis. We focus on a specific IgE isoform that may particularly exacerbate allergic symptoms. The goal of the project is to define the role of alternative IgE isoforms in vivo and to determine the IgE isoform contribution against the novel Fc receptor, Fc?R4.

描述（由申请人提供）：这是研究IgE同工型生物学意义的R21提案。在人类中，已经确定了两种形式的分泌IgE。由于替代的mRNA剪接，这些分子在COOH末端有所不同。这种差异的功能意义尚不清楚，但是在特定疾病状态下的两种同工型似乎在丰度上有所不同。在小鼠系统中，一些单体IgE制剂具有促进肥大细胞存活的能力。具有该特性的Iges称为“细胞分裂素能”。该特性尚不清楚，但需要与FCER1结合，并且与常规的肥大细胞激活不同，这需要交联，而不是FCER1的简单占用率。目前尚不清楚为什么某些IGE是细胞分裂的，而其他IGE则却不清楚。显然，肥大细胞存活的调节可能会对慢性过敏状况产生重大影响。已经描述了与人类同源的小鼠IgE H链mRNA同工型，但尚无蛋白质信息。我假设这两种形式的IgE-S1和IgE-S2在其生物活性上有所不同，因此潜在的发病机理。预测将测试IgE-S2，但通常不是主要的IgE-S1形式，是细胞分裂的。此外，我们将测试两个IgE同工型与新发现的IgE受体FC？R4的结合是否有所不同。重要的是要了解分泌的IgE同工型的功能，并确定它们是否差异控制过敏反应。这些目标将通过以下特定目标实现。 1。开发具有相同特异性的重组IgE -S1和-s2分子。 2。产生一系列产生高细胞因子能IgE的杂交瘤细胞。 3。通过体内过表达比较IgE-S1和IgE-S2的生物活性。项目叙述：这是R21的建议，旨在研究IgE同工型在过敏性疾病中的生物学意义。 IgE在包括哮喘和特应性皮炎在内的过敏性疾病中起着关键作用。我们专注于特定的IgE同工型，可能特别加剧过敏症状。该项目的目的是定义体内替代IgE同工型的作用，并确定针对新型FC受体FC？R4的IgE同工型贡献。