Commensal-dependent maturation of the natural IgM repertoire

天然 IgM 库的共生依赖性成熟

基本信息

  • 批准号:
    9307724
  • 负责人:
  • 金额:
    $ 1万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-07-02 至 2017-07-03
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): This proposal will determine how the intestinal microbiota shapes the development of innate-like B cells and the specificities of antibodies represented in the natural IgM (nIgM) repertoire. nIgM plays significant roles in maintenance of immunological homeostasis and the clearance of potentially immunogenic autoantigens represented on apoptotic cells, suppressing the development of autoimmune and allergic diseases. Innate-like B cells are the source of nIgM, and possess specificities for polysaccharide and phospholipid epitopes that are conserved between mammalian antigens and commensal bacteria harbored within the gut, however little is known regarding the impact of microbiota-derived antigens on the development of this subset of antibodies. Observations that innate-like B cells undergo antigen selection in the small intestine lamina propria leading to the differentiation of IgA secreting plasma cells in those tissues, and observations that mice maintained under germ free conditions experience exacerbated diseases in allergy models and in several autoimmune disease models led us to hypothesize that the microbiota plays a previously unappreciated role in shaping the systemic B cell repertoire and the generation of nIgM. We investigated the distribution of B cells specific for the T cell-independent (TI) antigen N-acetyl-D-Glucosamine (GlcNAc) between specific pathogen free and germ free mice and have found substantial evidence that intestinal colonization increases the numbers of B cells and levels of serum antibody specific for GlcNAc, while inducing shifts in the dominant immunoglobulin V-gene used to generate this specificity. To further dissect these interactions, we developed a novel fluorescence-activated cell sorting approach to study the distribution of TI antigens on species of commensal bacteria. Through simultaneous evaluation of the IgA opsonization status of these antigens, we expect to (i) identify immunologically relevant microorganisms bearing specific TI- antigens that interface with humoral immunity in the gut. Using gnotobiotic animal models, wherein germ free mice are reconstituted with flora enriched for particular antigenic determinants with the platform described above, we plan to test the hypothesis that antigen derived from the commensal micoflora leads to selection of B cell clonotypes into the nIgM-producing niche. We plan to test this hypothesis by (ii) evaluating the frequency and phenotype of splenic GlcNAc and Lewis X antigen-specific B cells following microbial reconstitution with bacteria commensal isolates enriched for these antigens, (iii) monitoring the generation of LP, spleen and bone marrow-localized plasma cells, and (iv) monitoring shifts in the B cell clonotypes composing those specificities. These experiments will demonstrate for the first time that interaction with exogenous antigen at peripheral tissues is required for development of a fully competent nIgM repertoire. This work will lead to the development of novel means of classifying the diversity of the intestinal microbiota, and offer valuable insight to the development of the nIgM repertoire value in designing immunotherapies aimed at boosting natural immunity.
 描述(由申请人提供):该提案将确定肠道微生物群如何塑造先天性B细胞的发育以及天然IgM(nIgM)库中代表的抗体的特异性。nIgM在维持免疫稳态和清除凋亡细胞上代表的潜在免疫原性自身抗原,抑制自身免疫性和过敏性疾病的发展中起重要作用。天然样B细胞是nIgM的来源,并且对多糖和磷脂表位具有特异性,所述多糖和磷脂表位在哺乳动物抗原和肠道内窝藏的肠道细菌之间是保守的,然而关于微生物来源的抗原对该抗体子集的发展的影响知之甚少。观察到先天样B细胞在小肠固有层中经历抗原选择,导致这些组织中分泌伊加的浆细胞分化,并且观察到保持在无菌条件下的小鼠在变态反应模型和几种自身免疫性疾病模型中经历了恶化的疾病,这使我们假设微生物群在形成系统性B细胞库和免疫性疾病中起着以前未被认识到的作用。nIgM的生成。我们研究了特异性针对T细胞非依赖性(TI)抗原N-乙酰基-D-氨基葡萄糖(GlcNAc)的B细胞在无特定病原体和无菌小鼠之间的分布,发现了大量证据表明肠道定植增加了B细胞数量和GlcNAc特异性血清抗体水平,同时诱导了用于产生这种特异性的显性免疫球蛋白V基因的变化。为了进一步剖析这些相互作用,我们开发了一种新的荧光激活细胞分选方法来研究TI抗原在细菌物种上的分布。通过同时评价这些抗原的伊加调理作用状态,我们期望(i)鉴定携带特异性TI-抗原的免疫相关微生物,所述TI-抗原与肠道中的体液免疫相互作用。使用无菌动物模型,其中无菌小鼠用上述平台用富集特定抗原决定簇的植物群重建,我们计划测试来源于肠道微生物植物群的抗原导致B细胞克隆型选择进入产生nIgM的小生境的假设。我们计划通过(ii)用富含这些抗原的细菌分离株进行微生物重建后,评价脾脏GlcNAc和刘易斯X抗原特异性B细胞的频率和表型,(iii)监测LP、脾脏和骨髓定位浆细胞的生成,以及(iv)监测构成这些特异性的B细胞克隆型的变化,来检验这一假设。这些实验将首次证明,在外周组织与外源性抗原的相互作用是开发完全胜任的nIgM库所必需的。这项工作将导致开发对肠道微生物群多样性进行分类的新方法,并为nIgM库的开发提供有价值的见解,以设计旨在增强天然免疫力的免疫疗法。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Glycan-Reactive Innate-like B Cells and Developmental Checkpoints.
聚糖反应性先天样 B 细胞和发育检查点。
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

James Stewart New其他文献

Microbiota and B-1 B cell repertoire development in mice
小鼠微生物群与 B-1 B 细胞库的发育
  • DOI:
    10.1016/j.coi.2024.102452
  • 发表时间:
    2024-08-01
  • 期刊:
  • 影响因子:
    5.800
  • 作者:
    James Stewart New;Rodney Glenn King;Jeremy B Foote;John F Kearney
  • 通讯作者:
    John F Kearney

James Stewart New的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('James Stewart New', 18)}}的其他基金

Commensal-dependent maturation of the natural IgM repertoire
天然 IgM 库的共生依赖性成熟
  • 批准号:
    9120659
  • 财政年份:
    2015
  • 资助金额:
    $ 1万
  • 项目类别:

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 1万
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 1万
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 1万
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 1万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 1万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 1万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 1万
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 1万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 1万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 1万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了