S100 PROTEINS IN ALLERGIC INFLAMMATION

该项目将研究过敏的主要效应细胞迁移到炎症部位的新方法，如肺和皮肤，并被一种新的S100蛋白介质局部激活。我们发现了先天免疫系统的一种天然蛋白，存在于急性致死性哮喘患者肺部的巨噬细胞和中性粒细胞中，它激活肥大细胞，导致释放引发哮喘发作的介质。我们已经在培养的人类肥大细胞中发现了这种蛋白质的潜在受体。我们将描述这种受体的化学性质，并证实它在肥大细胞活化中具有重要的功能。由于肥大细胞存在于几乎所有的身体组织中，并且也是宿主对感染和慢性炎症（如风湿性关节炎和牛皮癣）反应的重要介质，我们的研究可能表明它们被激活的新颖和意想不到的方式。过敏性疾病和寄生虫病的另一个关键细胞是嗜酸性粒细胞。我们发现另外两种S100蛋白在正常个体血液中的嗜酸性粒细胞中表达，并且编码这些蛋白的基因受到调节嗜酸性粒细胞在过敏部位迁移和存活的介质的调节。然而，尽管在哮喘患者的肺活检中这些细胞的数量很高，但我们发现这些蛋白质通常不表达。由于S100蛋白之一S100A9最近被发现在其他血细胞迁移到组织中招募它们的信号的能力中起重要作用，我们将研究该蛋白是否调节嗜酸性粒细胞迁移的能力。该项目的研究结果将提供有关过敏机制的新知识，并可能导致设计新的策略来调节这一过程。结果可能有更广泛的影响，适用于其他炎症和传染病。

This project will examine new ways in which the major effector cells of allergy migrate to sites of inflammation, such as the lung and the skin and are activated locally by a novel S100 protein mediator. We have found a natural protein of the innate immune system, present in macrophages and neutrophils in the lungs of patients with acute fatal asthma, which activates mast cells causing release of mediators that trigger asthma attack. We have identified a potential receptor for this protein on human mast cells grown in culture. We will characterise the chemical nature of this receptor and verify that it is functionally important in mast cell activation. Because mast cells reside in almost all body tissues and are also important mediators of host responses to infection and in chronic inflammation such as rheumatoid arthritis and psoriasis, our studies may indicate novel and unexpected ways in which they are activated. Another key cell in allergic and parasitic diseases is the eosinophil. We have found that two other S100 proteins are expressed in eosinophils from the blood of normal individuals and that the genes that encode these proteins are regulated by mediators that regulate eosinophil migration and survival at allergic sites. However although the numbers these cells are high in lung biopsies from patients with asthma, we find that these proteins are generally not expressed. Because one of the S100 proteins, S100A9, was recently found to be important in the ability of other blood cells to migrate to signals that recruit them into tissues, we will examine whether this protein regulates the ability of eosinophils to migrate. Results from this project will provide new knowledge concerning mechanisms of allergy and may lead to the design of novel strategies to regulate the process. Results may have broader ramifications applicable to other inflammatory and infectious diseases.