Pathogenesis of Lupus Dermatitis

描述(申请人提供)：系统性红斑狼疮(SLE)是一种自身免疫性疾病，以多个器官的炎症为特征。皮炎是系统性红斑狼疮最常见的表现之一，需要持续的治疗来控制皮损。狼疮性皮炎会导致患者的疤痕和毁容。对其发病机制知之甚少。MRL-LPR和MRL/小鼠多器官炎症模型已被用于SLE发病机制的研究。我们采用这个模型来研究狼疮性皮炎的发病机制。皮肤有一个专门的免疫系统，其中包括专门的树突状细胞，称为朗格汉斯细胞(LC)和专门的34个T细胞，称为树突状表皮T细胞(DETC)。LCS和DETC并排存在于皮肤中。目前尚不清楚这两种免疫细胞在体内是如何相互作用的，以及这些相互作用中的损害是否有助于狼疮性皮炎的发展。LC不断地迁移，携带皮肤抗原到皮肤引流的淋巴结，在那里它们被认为能耐受皮肤反应性T细胞，并防止自身免疫。根据我们的初步数据，我们假设LC迁移障碍是推动狼疮性皮炎发展的主要机制。为了验证这一假设，我们将首先使用新产生的由langerin启动子驱动的表达增强型绿色荧光蛋白[EGFP]的Langerin(Lang)-EGFP敲入MRL小鼠来评估LC在狼疮性皮炎易感小鼠中的迁移能力，这使得可以清楚地检测到LC。为了评估LC在狼疮性皮炎发生发展中的作用，我们将使用新产生的Lang-DTR.eGFP敲入MRL小鼠，在这些小鼠中LC可以以特定时间的方式消融。这些小鼠将被用来检验LC迁移受损有助于狼疮性皮炎发展的特定假设。然后我们将开始描述狼疮患者LC迁移受损的潜在机制。在我们初步数据的指导下，我们将检验CD1d调节狼疮性皮炎LC迁移和发展的假设，尽管CD1d是通过激活皮肤34DETC而不是传统的刺激自然杀伤T细胞的作用来调节LC的迁移和发展。我们将调查34DETC实际上是否代表CD1d反应性T细胞的一个新亚群，CD1d结合糖脂增加34DETC，改善LC迁移，并改善狼疮性皮炎。我们在这项应用中的目标是了解皮肤中的各种免疫细胞如何相互作用来调节免疫介导性炎症的发展。所获得的知识将对开发通过驻留在组织中的特化34 T细胞来提高器官特异性免疫的新疗法具有重大意义。公共卫生相关性：狼疮性皮炎是一种自身免疫介导的皮肤损害，可导致严重的疤痕、毁容和发病率。这项应用将调查狼疮性皮炎的发生机制。特别是，该应用将侧重于皮肤树突状细胞的病理生理作用，这将对疫苗接种和其他涉及皮肤的炎症性疾病具有重要意义。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by inflammation in many organs. Dermatitis is one of the most common manifestations of SLE, which requires constant treatment to control lesions. Lupus dermatitis can cause scarring and disfigurement in patients. Little is known about its pathogenesis. MRL-lpr and MRL+/+ mice that develop multi-organ inflammation have been used to study mechanisms of SLE. We have adopted this model to investigate pathogenesis of lupus dermatitis. Skin has a specialized immune system that includes specialized dendritic cells called Langerhans cells (LC) and specialized 34 T cells called dendritic epidermal T cells (DETC). LCs and DETC reside side by side in the skin. It is unclear how these two immune cells interact in vivo and whether impairments in these interactions contribute to the development of lupus dermatitis. LCs constantly migrate to carry skin antigens to skin draining lymph nodes, where they are believed to tolerize skin-reactive T cells and prevent autoimmunity. Guided by our preliminary data, we hypothesize that impaired migration of LC is a major mechanism that drives the development of lupus dermatitis. To test this hypothesis, we will first assess the migratory capacity of LC in lupus dermatitis-prone mice using newly generated Langerin (Lang)-eGFP knock-in MRL mice that express enhanced green fluorescent protein [eGFP] driven by a langerin promoter, which allows a clear detection of LC. To evaluate the role of LC in the development of lupus dermatitis, we will use newly generated Lang- DTR.eGFP knock-in MRL mice in which LC can be ablated in a time-specific manner. These mice will be used to test the specific hypothesis that impaired LC migration contributes to the development of lupus dermatitis. We will then begin to delineate mechanisms underlying impaired LC migration in lupus. Guided by our preliminary data, we will test the hypothesis that CD1d regulates LC migration and development of lupus dermatitis although through activation of skin 34 DETC and not in a traditional role of stimulating natural killer T cells. We will investigate whether 34 DETC in fact represent a novel subset of CD1d-reactive T cells, and CD1d-binding glycolipids increase 34 DETC, improve LC migration, and ameliorate lupus dermatitis. Our goal in this application is to understand how various immune cells in the skin interact to regulate the development of immune-mediated inflammation. The knowledge gained will have major implications for the development of new therapies to boost organ-specific immunity via specialized 34 T cells that reside in tissues. PUBLIC HEALTH RELEVANCE: Lupus dermatitis is an autoimmune-mediated damage to skin, which can cause significant scarring, disfigurement and morbidity. This application will investigate mechanisms involved in the development of lupus dermatitis. In particular, the application will focus on patho-physiological roles of skin dendritic cells, which will have important implications for vaccination and other inflammatory diseases that involve skin.