Understanding IgE Biology
了解 IgE 生物学
基本信息
- 批准号:10396243
- 负责人:
- 金额:$ 30万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2022-03-09
- 项目状态:已结题
- 来源:
- 关键词:AffinityAllergensAllergicAllergic DiseaseAllergic inflammationAlternative SplicingAnaphylaxisAnatomic ModelsAntibodiesAntigensApoptosisAsthmaB-Cell Antigen ReceptorB-LymphocytesBasophilsBiologicalBiologyBone MarrowBone Marrow AspirationCell DegranulationCell LineageCell Surface ReceptorsCell physiologyCell surfaceCellsComplexDataDevelopmentDistalFoodFood HypersensitivityGene Expression ProfilingGeographyHealthHeavy-Chain ImmunoglobulinsHumanHuman VolunteersHypersensitivityIgEImmunityImmunoglobulin Class SwitchingImmunoglobulin Switch RecombinationImmunoglobulinsIndividualInflammationInflammation MediatorsInterleukin-13Interleukin-4KnowledgeLeadLiteratureLocationLongevityMediatingMembraneMemoryMemory B-LymphocyteMessenger RNAMissionMusNaturePathogenesisPatientsPatternPeripheralPlantsPlasma CellsPlasmablastPlayProcessProductionPropertyProteinsPublic HealthRNA SplicingResearchRoleSignal TransductionSiteSourceStimulusSurfaceSurface ImmunoglobulinsSystemic diseaseTestingTissuesUnited States National Institutes of HealthVariantWorkYangantigen bindingbasecytokinedeep sequencingdensitydisabilityexperimental studygenetic manipulationinsightmast cellpathogenreceptor 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 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 LLPCs 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 cell function; 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 mRNA production away from the mIg splice variant (i.e. the BCR variant) restricts
the number and longevity IgE expressing cells, thus constraining IgE secretion largely to the insult site. 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 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.
项目总结
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:
$ 30万 - 项目类别:
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