Role of Staphylococcus aureus and Host immunity in Allergic Skin Disease

特应性皮炎(AD)是一种慢性炎症性皮肤病，影响15%至30%的儿童 工业化国家约5%的成年人。尽管阿尔茨海默病的发病机制尚不完全 理解，这种疾病被认为是由一种异常的炎症反应介导的。 包括免疫球蛋白E(IgE)的产生在皮肤屏障功能障碍的背景下。损失-- 编码一种促进皮肤的表皮蛋白的微丝蛋白基因的功能突变 障碍，是阿尔茨海默病发生的强烈诱因。因为广告的一个标志是 一种改变的皮肤屏障，对微丝蛋白缺乏增加的机制的理解 阿尔茨海默病的易感性可能为疾病的发病机制提供重要的见解。肥大细胞(MC) 导致包括阿尔茨海默病在内的IgE介导的过敏性疾病。在用IgE和抗原激活时 或微生物刺激时，MC释放其结合在膜上的胞浆颗粒导致 多种在AD发病机制和宿主防御中起重要作用的分子的释放 对抗细菌病原体。值得注意的是，90%以上的阿尔茨海默病患者都患有 皮损皮肤中有金黄色葡萄球菌，而大多数健康人的皮肤中没有 把病原体藏起来。几种葡萄球菌外毒素(SE)可以作为超抗原和/或 AD模型中的抗原。然而，这些SE在疾病发病机制中的作用仍然存在。 不清楚。我们已经鉴定了毒素，这是金黄色葡萄球菌释放的一种多肽，属于这种多肽 苯酚可溶调素(PSM)毒素家族，是MC脱颗粒的有效诱导剂。- 毒素是由致病力agr产生的苯酚可溶性调制素家族的成员。 金黄色葡萄球菌的群体感应。重要的是，从AD患者中发现的金黄色葡萄球菌分离株 产生高水平的毒素。值得注意的是，金黄色葡萄球菌的皮肤定植，而不是突变体 毒素缺乏，促进免疫球蛋白E和IL-4的产生。此外，增强免疫球蛋白E MC缺陷小鼠毒素的产生和皮炎被MC消除并恢复 重建。在本申请中，我们提出了三个具体目标，以了解金黄色葡萄球菌是如何 被包括角质形成细胞在内的皮肤细胞感知，从而在皮肤中诱导炎症和IgE。 此外，我们建议研究将金黄色葡萄球菌毒素和相关的PSM与宿主免疫联系起来。 调节皮肤炎症的信号通路。了解金黄色葡萄球菌毒素和 受AGR群体感应系统调节的相关PSM导致过敏性皮肤病 期望对AD的发病机制和新的AD的发展提供重要的见解 预防和/或治疗AD的治疗方法。

Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects 15 to 30% of children and ~5% of adults in industrialized countries. Although the pathogenesis of AD is not fully understood, the disease is thought to be mediated by an abnormal inflammatory response including immunoglobulin E (IgE) production in the setting of skin barrier dysfunction. Loss-of- function mutations in the Filaggrin gene encoding an epidermal protein that promotes the skin barrier, are strong predisposing factors for the development of AD. Because a hallmark of AD is an altered skin barrier, understanding of the mechanism by which Filaggrin deficiency increases the susceptibility to AD may provide critical insight into disease pathogenesis. Mast cells (MCs) contribute to IgE-mediated allergic disorders including AD. Upon activation with IgE and antigen or microbial stimuli, MCs release their membrane-bound cytosolic granules leading to the release of multiple molecules that are important in the pathogenesis of AD and host defense against bacterial pathogens. Notably, more than 90% of AD patients are colonized with Staphylococcus aureus in the lesional skin whereas the skin of most healthy individuals do not harbor the pathogen. Several Staphylococcal exotoxins (SEs) can act as superantigens and/or antigens in models of AD. However, the role of these SEs in disease pathogenesis remains unclear. We have identified -toxin, a peptide released by S. aureus that belongs to the peptide toxin family of phenol-soluble modulins (PSMs), as a potent inducer of MC degranulation. - toxin is a member of the family of phenol-soluble modulins that is produced by the virulence Agr quorum sensing of S. aureus. Importantly, S. aureus isolates recovered from AD patients produce high levels of -toxin. Notably, skin colonization with S. aureus, but not a mutant deficient in -toxin, promoted IgE and IL-4 production. Furthermore, enhancement of IgE production and dermatitis by -toxin were abrogated in MC-deficient mice and restored by MC reconstitution. In this application, we propose three specific Aims to understand how S. aureus is sensed by skin cells including keratinocytes to induce inflammation and IgE in the skin. Furthermore, we propose studies to link S. aureus -toxin and related PSMs to host immune signaling pathways that mediate skin inflammation. Understanding how S. aureus -toxin and related PSMs regulated by the Agr quorum sensing system contribute to allergic skin disease is expected to provide critical insight into the pathogenesis of AD and the development of new therapeutic approaches to prevent and/or treat AD.