Integrin αEβ7-dependent IgA transcytosis during homeostasis and IBD

稳态和 IBD 期间整合素 αEβ7 依赖性 IgA 转胞吞作用

基本信息

项目摘要

7. Project Summary Inflammatory bowel disease (IBD) arises in genetically-susceptible individuals when the intestinal immune system loses tolerance to unidentified elements of the commensal microbiota. Plasma cell (PC)-derived secretory immunoglobulin A(sIgA) is one of the main mechanisms through which we are able to coexist with our microbiota. Despite this, insufficient emphasis has been placed on understanding the B cell/immunoglobulin A (IgA) system during IBD. Antibodies that block integrins on the cell surface of white cells have become a widely- used strategy for the treatment of IBD. One of these drugs (vedolizumab), specifically blocks integrin α4β7, a molecule which is critical for the traffic of white cells to the intestine. We find that B cells carry this integrin more than T cells in mice and humans and critically depend on this molecule to traffic to intestine. Therefore, mice that lack the β7 integrin chain have an intestinal B cell deficit and a stool IgA deficit that leads to alterations if their intestinal flora and worse IBD in two chronic IBD mouse models. Although this could be attributed to an integrin α4β7 defect, the luminal IgA deficit persists in mice that lack αEβ7 integrin, although in these mice B cells can reach the intestine normally. We recently found a previously undescribed subset of intestinal PC that express αEβ7, localized primarily to the base of the crypts. We propose that certain intestinal PC express αEβ7, which allows them to dock with intestinal epithelial cells and directly relay IgA for its most efficient transport to the intestinal lumen. We believe that this new mode of IgA transport plays a critical role for the maintenance of IgA in intestinal lumen and therefore on the microbial flora during IBD. In the current proposal we will several address important questions that remain unanswered. 1. Where are these cells located and what is their origin? 2. How do they influence the severity of IBD in mice and 3. What is their contribution on the control of the intestinal bacterial flora during IBD. This investigation is significant as it begins to address the role of B cells and their critical dependence on β7 integrins to home to the intestine and maintain the required IgA levels that control certain pathogenic microbes during IBD. Understanding the role of lymphocyte integrins at the interface between the microbiota and its host may lead to a better understanding of how do current anti-integrin therapeutics work and lead to new interventions to prevent the uncontrolled immune response to the microbiota that triggers IBD.
7.项目摘要 炎症性肠病(IBD)发生在遗传易感个体,当肠道免疫功能低下时, 系统失去对共生微生物群中未识别成分的耐受性。浆细胞(PC)源性分泌 免疫球蛋白A(sIgA)是我们能够与我们的人共存的主要机制之一。 微生物群尽管如此,对B细胞/免疫球蛋白A的理解还不够重视 (IgA)系统在IBD期间。阻断白色细胞表面整联蛋白的抗体已成为一种广泛的免疫抑制剂。 采用的治疗IBD的策略。其中一种药物(Vedolizumab)特异性阻断整合素α4β7, 这种分子对于白色细胞进入肠道至关重要。我们发现,B细胞携带这种整合素更多, 比小鼠和人类的T细胞更重要,并且严重依赖这种分子运输到肠道。因此,老鼠 缺乏β7整联蛋白链的人有肠B细胞缺陷和粪便伊加缺陷,如果 肠道植物群和更严重的IBD在两个慢性IBD小鼠模型。尽管这可能归因于 整合素α4β7缺陷,在缺乏αEβ7整合素的小鼠中持续存在管腔伊加缺陷,尽管在这些小鼠中B 细胞可以正常到达肠道。我们最近发现了一个以前未描述的肠道PC亚群, 表达αEβ7,主要定位于隐窝的基部。我们认为某些肠PC表达αEβ7, 这使得它们能够与肠上皮细胞对接,并直接传递伊加,以实现最有效的运输 到肠腔。我们认为这种新的伊加转运方式在维持免疫系统中起着关键作用。 伊加在肠腔中,因此在IBD期间对微生物植物群的影响。在目前的提案中,我们将 有几个问题涉及尚未得到解答的重要问题。1.这些细胞位于何处,它们的 起源?2.它们如何影响小鼠IBD的严重程度和3.他们对控制 IBD期间肠道细菌植物群。这项研究是重要的,因为它开始解决B细胞的作用 以及它们对β7整联蛋白的关键依赖,以归巢到肠道并维持所需的伊加水平, 在IBD期间控制某些病原微生物。了解淋巴细胞整合素在界面的作用 微生物群和宿主之间的联系可能会导致更好地理解目前的抗整合素是如何 治疗有效,并导致新的干预措施,以防止对微生物群的不受控制的免疫反应, 引发炎症性肠病

项目成果

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Jesus Rivera-Nieves其他文献

Jesus Rivera-Nieves的其他文献

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{{ truncateString('Jesus Rivera-Nieves', 18)}}的其他基金

Enhancing Mentoring of Diverse Early Career Researchers
加强对多元化早期职业研究人员的指导
  • 批准号:
    10797836
  • 财政年份:
    2023
  • 资助金额:
    $ 64.37万
  • 项目类别:
Control by Beta 7 integrins of the bacterial triggers of IBD
Beta 7 整合素控制 IBD 细菌触发因素
  • 批准号:
    10481726
  • 财政年份:
    2023
  • 资助金额:
    $ 64.37万
  • 项目类别:
HIV Persistence and Renewal in the Gastrointestinal, Genitourinary and Adipose Tissues
HIV 在胃肠道、泌尿生殖系统和脂肪组织中的持续存在和更新
  • 批准号:
    10488262
  • 财政年份:
    2021
  • 资助金额:
    $ 64.37万
  • 项目类别:
HIV Persistence and Renewal in the Gastrointestinal, Genitourinary and Adipose Tissues
HIV 在胃肠道、泌尿生殖系统和脂肪组织中的持续存在和更新
  • 批准号:
    10364543
  • 财政年份:
    2021
  • 资助金额:
    $ 64.37万
  • 项目类别:
HIV Persistence and Renewal in the Gastrointestinal, Genitourinary and Adipose Tissues
HIV 在胃肠道、泌尿生殖系统和脂肪组织中的持续存在和更新
  • 批准号:
    10675778
  • 财政年份:
    2021
  • 资助金额:
    $ 64.37万
  • 项目类别:
High Dimensional Mass Cytometry Analysis of the Effects of Vedolizumab in Intestinal Cellular Subsets and its Correlation with Clinical Parameters
高维质量流式细胞仪分析维多珠单抗对肠细胞亚群的影响及其与临床参数的相关性
  • 批准号:
    9910384
  • 财政年份:
    2019
  • 资助金额:
    $ 64.37万
  • 项目类别:
Dendritic Cell Regulation by Sphingosine-1-phosphate in Inflammatory Bowel Disease
1-磷酸鞘氨醇对炎症性肠病的树突状细胞调节
  • 批准号:
    10292938
  • 财政年份:
    2018
  • 资助金额:
    $ 64.37万
  • 项目类别:
Dendritic Cell Regulation by Sphingosine-1-phosphate in Inflammatory Bowel Disease
1-磷酸鞘氨醇对炎症性肠病的树突状细胞调节
  • 批准号:
    9562862
  • 财政年份:
    2018
  • 资助金额:
    $ 64.37万
  • 项目类别:
Dendritic Cell Regulation by Sphingosine-1-phosphate in Inflammatory Bowel Disease
1-磷酸鞘氨醇对炎症性肠病的树突状细胞调节
  • 批准号:
    10045948
  • 财政年份:
    2018
  • 资助金额:
    $ 64.37万
  • 项目类别:
Dendritic Cell Manipulation: A Novel Therapeutic for Inflammatory Bowel Disease
树突状细胞操作:炎症性肠病的新疗法
  • 批准号:
    8795668
  • 财政年份:
    2011
  • 资助金额:
    $ 64.37万
  • 项目类别:

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