Alternative C5 - convertases promote skin inflammation in experimental pemphigoid disease
MOUSAVI S. 1, F. DABIRI S. 3, KAMAGUCHI M. 1, IZUMI K. 1, DRÄGER S. 2, SCHMIDT-JIMÉNEZ L. 1, KASPRICK A. 1, PATZELT S. 1, EMTENANI S. 1,2, PIGORS M. 1, BIEBER K. 1, SCHMIDT E. 1,2, LUDWIG R. 1,2
1 Lübeck Institute for Experimental Dermatology, University of Lübeck, Lübeck, Germany; 2 Department of Dermatology, Allergology and Venereology, University of Lübeck, Lübeck, Germany; 3 Islamic Azad University, Pharmaceutical Sciences Branch, Tehran, Iran
Pemphigoid diseases (PDs) comprise a group of blistering skin conditions in which autoantibodies against basal keratinocyte antigens cause loss of cell adhesion to the dermal-epidermal junction (DEJ). The deposition of linear IgG and C3 deposits are diagnostic hallmarks of PD. Blockade of the C5/C5aR1 axis has previously been identified as a key driver of skin inflammation in experimental murine PD. However, the functional importance of C3 in PD has not been conclusively addressed. We here, using antibody transfer-induced PD models in C3-deficient mice, demonstrate that in three pre-clinical PD models, namely epidermolysis bullosa acquisita (EBA), bullous pemphigoid (BP), and mucous membrane pemphigoid (MMP), experimental PD develops independently of C3. This indicates that C5a in these model conditions can be proteolytically generated independently of C3. Thus, we next addressed the contribution of alternative C5-convertases using the antibody transfer-induced EBA mouse model. EBA was induced in neutrophil-elastase (NE) deficient mice and in (WT) mice treated with the thrombin inhibitor argatroban, both considered alternative C5 convertases. While in NE-deficient mice, EBA, MMP and BP developed like in wild-type littermate controls, blockade of thrombin led to a significant reduction of clinical disease severity in antibody transfer-induced EBA. The degree of reduction in clinical disease activity was not as pronounced when compared to mice deficient in the C5/C5aR1-axis. Thus, additional alternative pathways for C5a generation are most likely operative. Experiments addressing the contribution of elastase and thrombin in established MMP and BP mouse models are ongoing. Preliminary data suggest that thrombin is also required for MMP induction. In summary, we here provide evidence that skin inflammation in experimental PD can develop independent of C3, and that C5a is, at least partially, generated by thrombin.