A novel pathway that controls production of IgE in B cells

控制 B 细胞 IgE 产生的新途径

• 批准号: 265594313
• 负责人: Professor Dr. Rolf Jessberger
• 金额: --
• 依托单位: Institut für Physiologische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/265594313?language=en
• 关键词: novel; pathway; controls; production; IgE

Allergies constitute a major human health problem. The incidence of allergies strongly increased over the past few decades, with now more than 10 % of the European population affected by allergies. Allergies are triggered by the immunoglobulin isotype E (IgE) produced by specifically activated B cells. IgE binds to mast cells, which release mediator compounds that cause the acute allergic reaction. Thus, the basic understanding of IgE production in B cells is key to eventually understanding allergies. We have identified a protein, SWAP-70, which regulates IgE production in B cells. In SWAP-70 deficient mice and in cultured, primary Swap-70-/- B cells, IgE production is reduced to about 10 % of wild-type levels. Our previous data showed SWAP-70 nuclear localization and its interaction with nuclear proteins. Our recent data show that SWAP-70 is involved in IL4 triggered nuclear processes specifically required for IgE production. Specifically, chromatin immunoprecipitation experiments suggest that SWAP-70 associates with a critical promotor region, Ie, which is essential for initiating the switch of B cells to generate IgE. Here, SWAP-70 controls the balance between STAT6, which supports Ie activation and thus IgE synthesis, and BCL6, which inhibits Ie activation. Our new hypothesis is that SWAP-70 supports IgE production through control of the STAT6-BCL6 antagonism. This proposal aims at elucidating the precise role of SWAP-70 in this nuclear process, its association with the Ie region, and its interactions with BCL6 and STAT6. Achieving these aims should allow us to define a new and important pathway of IgE production control in B cells with potential long-term medical implications with respect to allergies.

过敏是人类健康的一大问题。在过去的几十年里，过敏的发病率急剧上升，现在有超过10%的欧洲人口受到过敏的影响。过敏是由特异性激活的B细胞产生的免疫球蛋白E （IgE）引起的。IgE与肥大细胞结合，释放引起急性过敏反应的介质化合物。因此，对B细胞中IgE产生的基本了解是最终理解过敏的关键。我们已经确定了一种蛋白质SWAP-70，它可以调节B细胞中IgE的产生。在SWAP-70缺陷小鼠和培养的原代SWAP-70 -/- B细胞中，IgE的产生减少到野生型水平的10%左右。我们之前的数据显示SWAP-70的核定位及其与核蛋白的相互作用。我们最近的数据表明SWAP-70参与了IL4触发的IgE产生所需的核过程。具体而言，染色质免疫沉淀实验表明SWAP-70与一个关键启动子区域Ie相关，该区域对于启动B细胞产生IgE的开关至关重要。在这里，SWAP-70控制STAT6和BCL6之间的平衡，STAT6支持Ie激活并因此合成IgE， BCL6抑制Ie激活。我们的新假设是SWAP-70通过控制STAT6-BCL6的拮抗作用来支持IgE的产生。本研究旨在阐明SWAP-70在这一核过程中的确切作用，它与Ie区的关联，以及它与BCL6和STAT6的相互作用。实现这些目标将使我们能够确定B细胞中IgE产生控制的一个新的和重要的途径，这对过敏有潜在的长期医学意义。