Understanding IgE Biology
了解 IgE 生物学
基本信息
- 批准号:10375189
- 负责人:
- 金额:$ 68.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-10 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:AffinityAllergensAllergicAllergic DiseaseAllergic inflammationAlternative SplicingAnaphylaxisAnatomic ModelsAntibodiesAntigensApoptosisB-Cell Antigen ReceptorB-LymphocytesBasophilsBiologicalBiologyBone MarrowBone Marrow AspirationCell DegranulationCell LineageCell Surface ReceptorsCell SurvivalCell surfaceCellsComplexDataDevelopmentDistalEvolutionFoodGene Expression ProfilingGeographyHealthHeavy-Chain ImmunoglobulinsHumanHuman VolunteersHypersensitivityIgEImmunityImmunoglobulin Class SwitchingImmunoglobulin GImmunoglobulin Somatic HypermutationImmunoglobulin Switch RecombinationImmunoglobulinsIndividualInflammationInflammation MediatorsInterleukin-13Interleukin-4KnowledgeLeadLiteratureLocationLongevityMediatingMembraneMemoryMemory B-LymphocyteMessenger RNAMissionMusNaturePathogenesisPatientsPatternPeripheralPlantsPlasma CellsPlasmablastPlayProcessProductionPropertyProteinsPublic HealthRNA SplicingResearchRoleSignal TransductionSiteSourceStimulusStructure of germinal center of lymph nodeSurfaceSurface ImmunoglobulinsSystemic diseaseTestingTissuesUnited States National Institutes of HealthVariantWorkantigen bindingbasecytokinedeep sequencingdensitydisabilityexperimental studygenetic manipulationinsightmast cellmouse modelpathogenreceptor densityresponsetranscriptomics
项目摘要
Project Summary
IgE-mediated allergic disease is a growing problem. The pathogenesis of allergic disease requires that
immunoglobulin (Ig) E (IgE) molecules be produced against what are otherwise usually innocuous substances.
Upon activation in the setting of cytokines such as IL-4 or IL-13, B cells can undergo IgH CSR to IgE. IgE
secreted from B lineage cells can, in the presence of cognate antigen, activate mast cells and basophils to
release potent inflammatory mediators. While IgE responses can lead to protective immunity as a part of a
specialized responses to multicellular pathogens or other noxious threats, they also underlie allergic disease.
Allergic disease can be manifest by localized inflammation, or by multiorgan involvement, including deadly
systemic anaphylactic reactions via IgE-sensitized mast cell degranulation. Thus, the production and
dissemination of IgE play a significant role in dictating the strength and extent of tissue mast cell sensitization.
It is therefore critical to understand not only how B cell IgE production and maturation is controlled, but also the
principles underlying distribution of IgE from point of origin to distal sites throughout the body. The overall
objective of this application is to understand biological aspects of IgE production and dissemination and to gain
insights into how this is influenced in allergic disease. Emerging literature and preliminary data from the
applicant suggest a general hypothesis that biological constraints cooperate to restrict IgE dissemination under
homeostatic conditions, and that accumulation of bone marrow IgE long-lived plasma cells is an aberrancy
underlying systemic manifestations of allergic disease. This hypothesis will be tested by pursuing three specific
aims, which are: 1) to determine the mechanisms of IgE expression dynamics on IgE B cells; 2) to elucidate
mechanisms underlying IgE distribution from point of origin to effector sites; and 3) to characterize IgE plasma
cells in allergic patients. Under the first aim, IgE mRNA splicing and IgE surface density will be genetically
perturbed to examine the hypothesis that splice bias-mediated dilute IgE BCR density limits independent IgE
GC B cell evolution potential. Under the second aim, models of anatomic location-specific allergic challenge
will be deployed to examine the degree to which IgE distribution is locally biased, and the role of naïve
bystander B cells in this process. Under the third aim, bone marrow aspirations from healthy and allergic
individuals will be obtained for IgH isotype-resolved deep sequencing as well as single cell transcriptomics to
elucidate the cellular sources and biological properties of IgE in patients with long-standing severe allergies.
This contribution is significant because it is expected to elucidate a more complete picture of how IgE
responses are regulated. Ultimately, such knowledge has the potential to inform the development of new
strategies that will help to reduce the growing problem of allergic disease.
项目概要
IgE 介导的过敏性疾病是一个日益严重的问题。过敏性疾病的发病机制要求
免疫球蛋白 (Ig) E (IgE) 分子是针对通常无害的物质而产生的。
在 IL-4 或 IL-13 等细胞因子激活后,B 细胞可以经历 IgH CSR 转化为 IgE。免疫球蛋白E
B 谱系细胞分泌的 B 谱系细胞在存在同源抗原的情况下可以激活肥大细胞和嗜碱性粒细胞
释放强效炎症介质。虽然 IgE 反应可以导致保护性免疫,作为免疫反应的一部分
它们是对多细胞病原体或其他有害威胁的专门反应,也是过敏性疾病的基础。
过敏性疾病可以表现为局部炎症,或多器官受累,包括致命的
通过 IgE 致敏的肥大细胞脱颗粒引起全身过敏反应。因此,生产和
IgE 的传播在决定组织肥大细胞致敏的强度和程度方面发挥着重要作用。
因此,不仅了解 B 细胞 IgE 的产生和成熟是如何控制的,而且了解 B 细胞 IgE 的产生和成熟也至关重要。
IgE 从起源点到全身远端部位分布的基本原理。整体
该应用的目的是了解 IgE 产生和传播的生物学方面,并获得
深入了解这对过敏性疾病的影响。新兴文献和初步数据
申请人提出了一个一般性假设,即生物约束在条件下协同限制 IgE 传播
稳态条件下,骨髓 IgE 长寿命浆细胞的积累是一种异常
过敏性疾病的潜在全身表现。这个假设将通过追求三个具体的
目标是: 1) 确定 IgE B 细胞上 IgE 表达动态的机制; 2)阐明
IgE 从起始点到效应位点分布的机制; 3) 表征 IgE 血浆
过敏患者的细胞。在第一个目标下,IgE mRNA 剪接和 IgE 表面密度将在遗传上
不安地检验剪接偏倚介导的稀释 IgE BCR 密度限制独立 IgE 的假设
GC B细胞进化潜力。在第二个目标下,解剖位置特异性过敏挑战模型
将被部署来检查 IgE 分布局部偏差的程度,以及 naïve 的作用
B细胞是这个过程的旁观者。在第三个目标下,健康和过敏者的骨髓穿刺
将获得个体进行 IgH 同种型解析深度测序以及单细胞转录组学,以
阐明长期严重过敏患者 IgE 的细胞来源和生物学特性。
这一贡献意义重大,因为它有望更全面地阐明 IgE 如何
反应受到监管。最终,这些知识有可能为新的开发提供信息
有助于减少日益严重的过敏性疾病问题的策略。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Duane R. Wesemann其他文献
Somatic hypermutation generates antibody specificities beyond the primary repertoire
体细胞高频突变产生超出初级库的抗体特异性。
- DOI:
10.1016/j.immuni.2025.04.014 - 发表时间:
2025-06-10 - 期刊:
- 影响因子:26.300
- 作者:
Teng Zuo;Avneesh Gautam;Shahab Saghaei;Sweta N. Khobragade;Rahaman Ahmed;Azadeh Mahdavinia;Mehrdad Zarghami;Gaspar A. Pacheco;Kenneth Green;Meghan Travers;Nicholas Garcia;Zahra Allahyari;Vishal Rao;Sachin Kumar;Robert Novak;Joyce K. Hwang;Duane R. Wesemann - 通讯作者:
Duane R. Wesemann
IL-4 acts on skin-derived dendritic cells to promote the T<sub>H</sub>2 response to cutaneous sensitization and the development of allergic skin inflammation
- DOI:
10.1016/j.jaci.2024.06.021 - 发表时间:
2024-12-01 - 期刊:
- 影响因子:
- 作者:
Juan Manuel Leyva-Castillo;Mrinmoy Das;Maria Strakosha;Alex McGurk;Emilie Artru;Christy Kam;Mohammed Alasharee;Duane R. Wesemann;Michio Tomura;Hajime Karasuyama;Frank Brombacher;Raif S. Geha - 通讯作者:
Raif S. Geha
Duane R. Wesemann的其他文献
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{{ truncateString('Duane R. Wesemann', 18)}}的其他基金
Cross-Protective Humoral Immunity to Coronavirus
对冠状病毒的交叉保护性体液免疫
- 批准号:
10842888 - 财政年份:2021
- 资助金额:
$ 68.65万 - 项目类别:
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