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IL-25 as a master regulator of extrafollicular benign IgE

IL-25 作为滤泡外良性 IgE 的主要调节因子

基本信息

批准号：
9893651
负责人：
Rebecca Kelley Martin
金额：
$ 38.02万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-03 至 2021-03-31
项目状态：
已结题

项目摘要

Project Summary We have recently found that B1 cells make large amounts of IgE post-helminth infection and that the B1 cell IgE acts contrary to B2 antigen (Ag)-specific IgE. B1 cell IgE prevents mast cell degranulation through competition for the FcεRI. Recently published data also shows that this “benign” B1 cell IgE blocks B2 cell IgE- mediated egg suppression. This B1 cell IgE production assists the helminth in immune evasion and benefits life and reproduction. Further, we show that the helminth-induced alarmin, IL-25, is responsible for the induction of B1 IgE production in vivo. These findings will be further investigated with the following three aims. In Aim 1, using a newly developed mouse that makes FLAG-tagged secreted IgE, we will determine the relative levels of B1 cell vs B2 cell IgE seen post helminth infection. V(D)J region sequencing will be examined for B1 cells and B2 cells before and after helminth infection. B1 cell IgE will be examined for its protective effects after helminth infection in allergic airway models. Aim 2 will examine the mechanism of IL-25 B1 IgE enhancement. Using the FLAG-IgE system the levels of IgE made by IL-25R-/- B1 cells when reconstituting with WT B2 cells will be compared. IL-25R expression analysis on the B1 cell compartments will be assessed. IL-25 signaling in B1 cells will be examined, particularly with respect to STAT5 and STAT3 induction. Aim 3 will move into the human system where preliminary data shows IL-25R on a portion of B cells that produce IgE in response to IL-25 isolated from tonsil. The surface phenotype of the IL25R+ B cell will be more completely characterized and compared to published “B1-like” human B cell markers. PBMC and cord blood B1 cells will be assessed for IL-25/IL-25R signaling. We will additionally examine B cells in PBMC from allergic vs non- allergic individuals to determine if there are differences in the levels of the IL25R+ B cells in the two populations, which could indicate a bias towards allergic sensitivity. A better understanding of non-specific IgE induction could ultimately translate into more effective allergic disease treatments.

项目摘要我们最近发现B1细胞在蠕虫感染后产生大量IgE， IgE的作用与B2抗原（Ag）特异性IgE相反。B1细胞IgE通过以下途径阻止肥大细胞脱粒竞争FcεRI。最近发表的数据也表明，这种“良性”的B1细胞IgE阻断B2细胞IgE- 介导的卵抑制。这种B1细胞IgE的产生有助于蠕虫的免疫逃避，生命和繁殖。此外，我们发现蠕虫诱导的alarmin，IL-25，是负责体内诱导B1 IgE产生。这些调查结果将进一步调查，目的有三。在目标1中，使用新开发的产生FLAG标记的分泌型IgE的小鼠，我们将确定蠕虫感染后观察到的B1细胞与B2细胞IgE的相对水平。将检查V（D）J区测序 B1细胞和B2细胞感染蠕虫前后的变化。将检查B1细胞IgE的保护性在过敏性气道模型中蠕虫感染后的作用。目的2探讨IL-25 B1 IgE的作用机制增强用FLAG-IgE系统检测IL-25 R-/- B1细胞重组时产生的IgE水平将与WT B2细胞进行比较。将评估B1细胞区室的IL-25 R表达分析。将检查B1细胞中的IL-25信号传导，特别是关于STAT 5和STAT 3诱导。目标3 初步数据显示IL-25 R位于产生IgE的部分B细胞上对从扁桃体分离的IL-25的应答。IL 25 R + B细胞的表面表型将更完整表征并与公开的“B1样”人B细胞标志物进行比较。PBMC和脐带血B1细胞将评估IL-25/IL-25 R信号传导。我们还将检查过敏性与非过敏性患者PBMC中的B细胞。过敏个体，以确定在两个个体中IL 25 R + B细胞的水平是否存在差异。人群，这可能表明对过敏敏感性的偏见。更好地了解非特异性IgE 诱导最终可以转化为更有效的过敏性疾病治疗。