A novel pathway that controls production of IgE in B cells

过敏是人类健康的一个主要问题。在过去的几十年里，过敏的发生率急剧上升，现在超过10%的欧洲人口受到过敏的影响。过敏是由特定激活的B细胞产生的免疫球蛋白同型E(IgE)引发的。免疫球蛋白与肥大细胞结合，肥大细胞释放导致急性过敏反应的介质化合物。因此，对B细胞产生IgE的基本了解是最终了解过敏的关键。我们已经确定了一种蛋白质，SWAP-70，它调节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约10%。我们之前的数据显示了SWAP-70的核定位及其与核蛋白的相互作用。我们最近的数据显示，SWAP-70参与了IL4触发的核过程，这是产生IgE所特需的。具体地说，染色质免疫沉淀实验表明，SWAP-70与一个关键的启动子区域有关，即启动B细胞转换生成IgE所必需的区域。在这里，SWAP-70控制STAT6和BCL6之间的平衡，STAT6支持ie激活，从而促进IgE合成，而bcl6则抑制ie激活。我们的新假设是，SWAP-70通过控制STAT6-BCL6拮抗作用来支持IgE的产生。这项提议旨在阐明SWAP-70在核进程中的确切作用，它与ie区的联系，以及它与bcl6和STAT6的相互作用。实现这些目标应该使我们能够定义一种新的重要的B细胞IgE产生控制途径，具有潜在的与过敏相关的长期医学意义。

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.