A novel pathway that controls production of IgE in B cells

过敏症是人类健康的一个主要问题。在过去的几十年里，过敏症的发病率大幅增加，现在超过10%的欧洲人口受到过敏症的影响。过敏是由特异性激活的B细胞产生的免疫球蛋白同种型E（IgE）引发的。IgE与肥大细胞结合，肥大细胞释放介体化合物，引起急性过敏反应。因此，对B细胞中IgE产生的基本理解是最终理解过敏的关键。我们已经鉴定了一种调节B细胞中IgE产生的蛋白SWAP-70。在SWAP-70缺陷型小鼠和培养的原代Swap-70-/- B细胞中，IgE产生降低至野生型水平的约10%。我们以前的数据显示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IL 4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与一个关键的启动子区域，即，这是必不可少的启动开关的B细胞产生IgE。在这里，SWAP-70控制STAT 6和BCL 6之间的平衡，STAT 6支持Ie激活并因此支持IgE合成，BCL 6抑制Ie激活。我们的新假设是SWAP-70通过控制STAT 6-BCL 6拮抗作用支持IgE产生。该提案旨在阐明SWAP-70在该核过程中的确切作用，其与Ie区域的关联以及其与BCL 6和STAT 6的相互作用。实现这些目标应该使我们能够确定一个新的和重要的途径，IgE生产控制在B细胞与潜在的长期医疗影响方面的过敏。

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.