Development of Intestinal Polyreactive IgA B Cells
Development of Intestinal Polyreactive IgA B Cells
批准号:
10078246
负责人:
ALBERT S. BENDELAC
金额:
$49.84万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-01-17 至 2023-12-31
关键词:
AddressAffinityAntibodiesAntibody AffinityAntibody ResponseAntibody SpecificityAntigensAutoimmuneAutoimmunityB cell differentiationB cell repertoireB-Cell DevelopmentB-LymphocytesBacterial AntigensBindingBone MarrowCRISPR/Cas technologyCell CompartmentationCell LineageCellsDevelopmentDiseaseEpitopesEquilibriumFlagellinGene Expression ProfilingGenerationsGenesHIVHomeostasisHumanImmune responseImmunityImmunoglobulin AImmunoglobulin MImmunologicsImmunologyIn VitroInflammatoryInflammatory Bowel DiseasesInfluenzaIntestinesKnock-inKnock-in MouseKnowledgeMicrobeModelingMucous MembraneMutationPatternPeripheralPhenotypePhysiologicalPlasma CellsPolysaccharidesPopulationProductionPropertyRiskRoleSelf ToleranceSignal TransductionSiteSomatic MutationSpecificityStructureSurfaceSystemT-LymphocyteTestingVaccine DesignVaccinescommensal bacteriacommensal microbesimprovedin vivointestinal homeostasismicrobialmicrobiotaneutralizing monoclonal antibodiesnovelnovel strategiesoral vaccinepathobiontpathogenresponsetool
中文摘要
在稳态条件下,大部分肠道肠道微生物群被伊加抗体包被,
但是对付细菌抗原的巨大多样性的策略和机制,
仍然难以捉摸汇聚的研究表明,稳态伊加反应采用高度多反应性,
库结合广泛但不同的微生物群亚群。这些抗体反应是在
有限的T细胞帮助,具有低的体细胞突变率和很少的亲和力成熟。这种新视角
与粘膜免疫刺激引起的T细胞依赖性、高亲和力抗体应答的经典范例相反,
病原体,病原体和疫苗,并提供了一个简单的免疫解决方案的挑战,
微生物抗原复杂性。它还提出了几个基本问题,包括如何多反应
特异性是在伊加库中产生和选择的,以及它们如何与其他特异性共存或重叠。
免疫反应和疾病。该项目通过以下方式解决这些问题:(i)生成
使用CRISPR/Cas9技术的多反应性伊加基因敲入小鼠,以(ii)了解
多反应性伊加前体B细胞的分化和(iii)研究多反应性伊加在
肠内和肠外挑战背景下的克隆水平。这些研究将澄清一个主要的差距,
我们对多反应性B细胞库的理解,解决了对现有抗体教条的挑战,
具体性和宽容性,并发展新的知识、概念和工具,以更好地了解
肠道免疫、炎症性肠病和口服疫苗。
英文摘要
A large fraction of the intestinal commensal microbiota is coated with IgA antibodies in homeostatic conditions,
but the strategy and the mechanisms deployed to confront the immense diversity of bacterial antigens have
remained elusive. Converging studies indicate that homeostatic IgA responses employ a highly polyreactive
repertoire to bind broad but distinct subsets of microbiota. These antibody responses develop in the presence
of limited T cell help, with low rate of somatic mutations and little affinity maturation. This new perspective
contrasts with the classical paradigm of T cell-dependent, high-affinity antibody responses elicited by mucosal
pathobionts, pathogens and vaccines, and provides a simple immunological solution to the challenge of
microbiota antigenic complexity. It also raises several fundamental issues, including how polyreactive
specificities are generated and selected in the IgA repertoire, and how they coexist or overlap with other
immune responses during homeostasis and disease. This project addresses these issues by (i) generating
polyreactive IgA knock-in mice using CRISPR/Cas9 technology to (ii) understand the development and
differentiation of polyreactive IgA precursor B cells and (iii) to study the function of polyreactive IgA at the
clonal level in the context of intestinal and extraintestinal challenges. These studies will clarify a major gap in
our understanding of polyreactive B cell repertoires, address a challenge to existing dogmas of antibody
specificity and tolerance, and develop new knowledge, concepts and tools for a better understanding of
intestinal immunity, inflammatory bowel diseases and oral vaccines.
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负责人:ALBERT S. BENDELAC
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依托单位:
Development of Intestinal Polyreactive IgA B Cells
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依托单位:
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资助金额:$38.39万
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财政年份:2014
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依托单位:
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负责人:ALBERT S. BENDELAC
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依托单位:
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财政年份:2013
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负责人:ALBERT S. BENDELAC
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依托单位:
Allergic inflammation in genetic models of lung ILC2 deficiency
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财政年份:2013
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负责人:ALBERT S. BENDELAC
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依托单位:
Control of lymphoid effector programs by the E3 ligase cullin 3
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资助金额:$29.7万
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财政年份:2013
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负责人:ALBERT S. BENDELAC
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依托单位:
Control of lymphoid effector programs by the E3 ligase cullin 3
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资助金额:$29.7万
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财政年份:2013
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负责人:ALBERT S. BENDELAC
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依托单位:
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资助金额:$6.48万
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财政年份:2008
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负责人:ALBERT S. BENDELAC
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依托单位:
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财政年份:2008
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负责人:ALBERT S. BENDELAC
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依托单位:
Glycolipid Presentation by CD1d
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依托单位:
Glycolipid Presentation by CD1d
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Glycolipid Presentation by CD1d
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财政年份:2003
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依托单位:
Glycolipid Presentation by CD1d
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海外基金