The role of C5aR2 in the pathogenesis of pemphigoid diseases

补体系统在类天疱疮(PD)的病变形成中起关键作用。它是将中性粒细胞募集到皮肤中的关键因素，然后导致促炎介质、活性氧物种和蛋白酶的释放，最终降解真皮-表皮连接(DEJ)。最近，我们发现补体通过补体5a受体2(C5aR2)在帕金森病皮肤炎症中的抗炎作用，以及大疱性类天疱疮(BP)患者亚群出现不依赖补体的皮肤炎症的描述，对补体激活在帕金森病中的独特促炎致病作用提出了质疑。本提案将利用tdTomato-C5aR2报告鼠鉴定皮肤和血液中主要的C5aR2表达细胞类型以及它们在帕金森病实验小鼠模型中的功能相关性。这些小鼠将使我们不仅能够监测C5aR2的表达，而且通过将它们与克隆株杂交，来确定不同的C5aR2表达细胞类型的功能相关性。通过使用C5aR2激动剂和拮抗剂对帕金森病小鼠模型的药理干预，我们将研究C5aR2对自身抗体产生和抗体介导的组织破坏的影响。因此，我们将评估C5aR2在PD中的治疗潜力，特别是可能有益的药理学激活。我们将与P3和P7合作，在整个病程中分析补体系统及其调节器的活动状态以及C5aR2在BP患者皮肤和血液中的表达。BP中补体活性的这一特征将被整合到PD的建模中，以及我们在Z2项目中定义PD患者亚组的努力，以便全面了解补体系统在PD中复杂的、部分对立的角色。

The complement system has been shown to be pivotal in lesion formation of pemphigoid diseases (PD). It serves as key element to recruit PMNs into the skin, which then leads to the release of proinflammatory mediators, reactive oxygen species, and proteases, that finally degrade the dermal-epidermal junction (DEJ). Recently, the exclusively proinflammatory pathogenic role of complement activation in PD has been questioned by our finding of antiinflammatory effects of complement, mediated via the complement 5a receptor 2 (C5aR2), in PD skin inflammation, and the description of patient subgroups of bullous pemphigoid (BP) patients developing skin inflammation independent of complement. The present proposal will identify the main C5aR2-expressing cell types in skin and blood and their functional relevance in experimental mouse models of PD using floxed tdTomato-C5aR2 reporter mice. These mice will allow us not only to monitor C5aR2 expression, but also – by crossing them with cre-deleter strains - to identify the functional relevance of distinct C5aR2-expressing cell type. By pharmacological interventions using C5aR2 agonists and antagonists in PD mouse models, we will investigate the impact of C5aR2 on autoantibody production and antibody-mediated tissue destruction. Thereby, we will evaluate the therapeutic potential particularly of the putatively beneficial pharmacological activation of C5aR2 in PDs. In collaboration with P3 and P7, we will profile the state of activity of the complement system and its modulators as well as the expression of C5aR2 in the skin and blood of BP patients throughout the course of disease. This profile of complement activity in BP will be integrated into the modeling of PDs and our effort to define PD patient subgroups in the Z2 project in order to gain comprehensive understanding of the complex, partially opposing roles of the complement system in PDs.