The multiple roles of the C5a/C5aR-axes in AIBD
Epidermolysis Bullosa Acquisita (EBA) is an AIBD caused by auto-antibodies against type VII collagen. Such antibodies induce an inflammatory cascade eventually resulting in the generation of C5a, which recruits and activates neutrophils. Such neutrophils secrete proteolytic enzymes, which lead to dermal-epidermal separation and blister formation. Previously, we found that C5a receptor 1 (C5aR1) deficiency protects from skin blistering in a passive model of EBA. This finding demonstrates a critical role for C5aR in the effector phase of the autoimmune disease (Karsten et al. Nat Med 2012). In collaboration with the Lübeck Institute of Experimental Dermatology (R. Ludwig), we recently established in our lab an active model of EBA, in which cutaneous inflammation is induced by active immunization with a fragment of collagen type VII. This fragment shows sequence homology with the type A like domain 2 of the von-Willebrand-factor (vWFA2). In this model we aim to define the role of the C5a/C5aR axes and their cross-talk with Fc-gamma receptors (FcγRs) for disease initiation including the formation of pathogenic vWFA2-specific IgG auto-antibodies. We perform such studies in close collaboration with the Köhl laboratory.
Role of C5aR2 in bullous pemphigoid: The role of C5aR2 in AIBDs has not yet been addressed. In collaboration with Enno Schmidt (LIED), we have therefore recently examined C5aR2-deficient mice in a passive bullous pemphigoid (BP) mouse model. Deficiency in C5ar2 significantly aggravated skin inflammation, indicating a protective role of this receptor in the effector phase of PDs (Karsten et al. Front Immunol 2018). The mechanisms of this protective role of C5aR2 in AIBD are still unknown. Likewise, it is still elusive whether the protective effects mediated via C5aR2 can be harnessed for therapeutic purposes. In this project, we aim to elucidate the role of C5aR2 in the regulation of AIBD-driven skin inflammation and its potential as therapeutic target in the treatment of AIBDs.
Figure 1: Steps involved in the pathogenesis of EBA in the skin. 1) Binding of IgG auto-antibodies to the dermal-epidermal junction zone, 2) complement activation, 3) activation of endothelial cells and 4) recruitment of effector cells (e.g. neutrophils) into the skin 5-6) FcgR-mediated activation of effector cells and 7) release of proteases and ROS causing 8) blister formation. (with courtesy of R. Ludwig, Lübeck Institute of Experimental Dermatology (LIED))