Pathogenesis of Lupus Dermatitis

狼疮性皮炎的发病机制

• 批准号: 7885460
• 负责人: Ram Raj Singh
• 金额: $ 38.12万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-06 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7885460
• 关键词: Ablation; Adopted; Age; Animals; Antigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Backcrossings; Binding; Cell Count; Cell Line; Cell surface; Cells; Characteristics; Chronic; Cicatrix; Cutaneous; Data; Defect; Dendritic Cells; Dermatitis; Dermis; Detection; Development; Diphtheria Toxin; Disease; Epidermis; Exhibits; Galactosylceramides; Glycolipids; Goals; Human; Immigration; Immune; Immune system; Immunity; Impairment; In Vitro; Inbred MRL lpr Mice; Inflammation; Inflammatory; Injection of therapeutic agent; Knock-in Mouse; Knowledge; Langerhans cell; Lesion; Link; Lupus; Lymphatic; Lymphoid; Mediating; Modeling; Morbidity - disease rate; Mus; Organ; Pathogenesis; Patients; Peripheral; Physiological; Public Health; Role; Severities; Side; Skin; Systemic Lupus Erythematosus; T-Cell Receptor; T-Lymphocyte; Testing; Time; Tissues; Vaccination; Work; antigen binding; autoreactive T cell; base; cell motility; chemokine; cytokine; diphtheria toxin receptor; enhanced green fluorescent protein; improved; in vivo; killer T cell; langerin; lymph nodes; migration; novel; prevent; promoter; public health relevance; reconstitution; restoration; skin lesion

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.

描述（由申请人提供）：全身性红斑狼疮（SLE）是一种自身免疫性疾病，其特征是许多器官炎症。皮炎是SLE最常见的表现之一，需要持续治疗以控制病变。狼疮性皮炎会导致患者的疤痕和毁容。关于其发病机理知之甚少。发生多器官炎症的MRL-LPR和MRL+/+小鼠已用于研究SLE的机制。我们采用了这种模型来研究狼疮性皮炎的发病机理。皮肤具有一种专门的免疫系统，其中包括称为兰格汉细胞（LC）的专门树突状细胞和称为树突状表皮T细胞（DETC）的专门的34个T细胞。 LCS和DETC并排放在皮肤中。目前尚不清楚这两个免疫细胞如何在体内相互作用，以及这些相互作用的损害是否有助于狼疮性皮炎的发展。 LCS不断迁移以将皮肤抗原带到皮肤排水淋巴结，据信它们可耐受性T细胞并预防自身免疫性。在我们的初步数据的指导下，我们假设LC迁移受损是驱动狼疮性皮炎发展的主要机制。为了检验这一假设，我们将首先使用新产生的langerin（Lang）-EGFP敲入MRL小鼠在狼疮性皮炎中的LC迁移能力，该小鼠表达由langerin启动子驱动的增强绿色荧光蛋白[EGFP]，从而可以清楚地检测LC。为了评估LC在狼疮性皮炎发展中的作用，我们将使用新生成的langdtr.EGFP敲入MRL小鼠，其中LC可以以特定时间的方式消融。这些小鼠将用于检验特定假设，即LC迁移受损会导致狼疮性皮炎的发展。然后，我们将开始描述狼疮中LC迁移受损的机制。在我们的初步数据的指导下，我们将检验以下假设：CD1D调节LC迁移和狼疮性皮炎的发育，尽管通过激活Skin 34 DETC，而不是刺激天然杀伤T细胞的传统作用。我们将研究34个DETC实际上是否代表了CD1D反应性T细胞的新型子集，并且CD1D结合糖胶质会增加34个发病c，改善LC迁移和改善狼疮性皮炎。我们在此应用中的目标是了解皮肤中各种免疫细胞如何相互作用以调节免疫介导的炎症的发展。获得的知识将对开发新疗法的发展具有重大影响，从而通过驻留在组织中的专门34个T细胞来增强器官特异性免疫。公共卫生相关性：狼疮性皮炎是对皮肤的自身免疫性介导的损害，这可能会导致严重的疤痕，毁容和发病率。该应用将调查狼疮性皮炎发展的机制。特别是，该应用将集中在皮肤树突状细胞的病理生理作用上，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。