The role of C5aR2 in the pathogenesis of pemphigoid diseases

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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.