The role of leukotriene B4 and its receptor BLT1 in the pathogenesis of the prototypical organ-specific autoimmune disease epidermolysis bullosa acquisita

白三烯 B4 及其受体 BLT1 在典型器官特异性自身免疫性疾病大疱性表皮松解症发病机制中的作用

• 批准号: 238897420
• 负责人: Professor Dr. Christian David Sadik
• 金额: --
• 依托单位: Klinik für Dermatologie, Allergologie und Venerologie (Hautklinik)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/238897420?language=en
• 关键词: role; leukotriene; B4; its; receptor

Sequential lipid-cytokine-chemokine cascades orchestrating the recruitment of immune cells to inflammatory sites are a hallmark of the effector phase of the immune response. Herein, leukotriene B4 (LTB4) is often the lipid mediator initiating these cascades. Accordingly, inhibition of LTB4 or its receptor BLT1 protects from inflammation in diverse models of autoimmune disease. This role of LTB4/BLT1 was elaborated in most detail for autoantibody-induced arthritis. In this mouse model, LTB4 is required to act as chemoattractant initiating neutrophil recruitment.Epidermolysis bullosa acquisita (EBA) is a prototypical bullous autoimmune disease of the skin caused by autoantibodies against type VII collagen, present in the anchoring fibrils at the dermal-epidermal junction. In 2005 a research group at the Department of Dermatology in Lübeck described a mouse model of EBA, in which the formation of immune complexes at the dermal-epidermal junction initiates the recruitment of neutrophils to the skin, which in turn induce dermal-epidermal separation, the signature lesion of EBA, by radical oxygen species (ROS) release. The mechanisms inducing the release of ROS from neutrophils in this model, however, are still unknown. Recent in vitro experiments of the applicant suggest that LTB4 may be required. Although high levels of LTB4 can be found in blister fluid of bullous pemphigoid patients, another autoimmune disease similar to EBA, the role of LTB4/BLT1 in autoimmune skin diseases has not been addressed. The first-time applicant of this proposal was instrumental in elucidating the role and regulation of LTB4 in neutrophil recruitment in arthritis and in contriving the paradigm of lipid-cytokine-chemokine cascades as drivers of inflammation, which was spearheaded by Prof. Lusters lab at the Massachusetts General Hospital in Boston, where the applicant was working for 3.5 years. In the last 6 months, the applicant, funded by the DFG, learned to conduct the EBA mouse model in Prof. Zillikens lab in Lübeck. He has generated preliminary data indicating a major role of leukotrienes in the pathogenesis of EBA. The major hypothesis of the present proposal is that LTB4 is required for EBA, and that neutrophils are both its major source, and its major cellular target. Furthermore, it is hypothesized that in EBA, LTB4 acts in a bimodal way of action and mediates two pivotal effects on neutrophils by first acting as a chemoattractant initiating the recruitment of the first neutrophils into the dermis, and later by activating neutrophils in the dermis to release ROS and induce dermal-epidermal separation.In this project the overall requirement for LTB4/BLT1 in the EBA mouse model will be determined and the essential cellular sources and targets of LTB4 will be identified. Additionally, the molecular mechanisms LTB4 engages to drive skin inflammation will be precisely defined. These data will clarify the role of LTB4 in autoimmune bullous diseases of the skin.

连续的脂质-细胞因子-趋化素级联反应协调免疫细胞到炎症部位的募集是免疫反应效应阶段的标志。在此，白三烯B4(LTB4)通常是启动这些级联反应的脂质介体。因此，抑制LTB4或其受体BLT1可以在不同的自身免疫性疾病模型中保护炎症。在自身抗体诱导的关节炎中，LTB4/BLT1的这种作用被最详细地阐述。在这个小鼠模型中，需要LTB4作为趋化剂来启动中性粒细胞的募集。获得性大疱性表皮松解症是一种典型的大疱性自身免疫性疾病，由针对VII型胶原的自身抗体引起，存在于真皮-表皮交界处的锚定纤维中。2005年，L贝克皮肤科的一个研究小组描述了一种皮肤萎缩性痴呆的小鼠模型，在该模型中，在真皮-表皮交界处形成的免疫复合体启动中性粒细胞在皮肤上的募集，进而通过释放自由基氧物种(ROS)导致皮肤-表皮分离，这是EBA的标志性病变。然而，在这个模型中，诱导中性粒细胞释放ROS的机制仍然不清楚。申请人最近的体外实验表明，可能需要LTB4。尽管在另一种类似于EBA的自身免疫性疾病--大疱性类天疱疮患者的疱液中可以发现高水平的LTB4，但LTB4/BLT1在自身免疫性皮肤病中的作用尚未得到解决。这项提案的首次申请者在阐明LTB4在关节炎中性粒细胞招募中的作用和调节方面发挥了重要作用，并设计了脂质-细胞因子-趋化素级联作为炎症驱动因素的范例，该范例由波士顿马萨诸塞州总医院的卢斯特斯教授带头，申请者在那里工作了3.5年。在过去的6个月里，申请者在DFG的资助下，在L的Zillikens教授实验室学习了EBA小鼠模型的操作。他已经产生了初步数据，表明白三烯在EBA的发病机制中起着重要作用。本提案的主要假设是LTB4是EBA所必需的，中性粒细胞既是其主要来源，也是其主要细胞靶点。此外，假设在EBA中，LTB4以双峰作用方式起作用，首先作为趋化剂启动中性粒细胞在真皮中的募集，然后通过激活真皮中的中性粒细胞释放ROS并诱导真皮-表皮分离，从而介导对中性粒细胞的两个关键作用。在本项目中，将确定EBA小鼠模型对LTB4/BLT1的总体需求，并确定LTB4的基本细胞来源和靶点。此外，LTB4参与驱动皮肤炎症的分子机制将得到精确定义。这些数据将阐明LTB4在皮肤自身免疫性大疱性疾病中的作用。