Altogether, these results indicate an important role for C5a-C5aR1-axis activation in the development of BP and could be an interesting target for intervention. Although previous pre-clinical studies are encouraging, these experiments were all performed in mice which makes it difficult to translate these data to humans. We also discuss potential therapeutic approaches targeting key complement components, pathways and pathogenic complement-mediated events. studies indeed demonstrated direct pathogenic effects of auto-antibodies and F(ab)2 fragments leading to depletion of BP180 in cultured keratinocytes (18, 19, 21). Although complement-independent mechanisms are likely to exist, the contradictory results between different studies could also be explained by the differences Cl-amidine in target epitopes on COL17 in the models used, antibody concentration, antibody affinity, or the clonality of antibodies in each experiment (19). Importantly, conflicting results are observed between the humanized and non-humanized models and could (in part) be explained by the lower murine complement fixating and activating capacities of the transferred human auto-antibodies compared to mouse and/or rabbit antibodies (22). Open in a separate window Figure 2 A case of bullous pemphigoid. Histology shows a subepidermal blister (A) accompanied by specific linear C3c deposition along the Cl-amidine BMZ visualized by direct HSF immunofluorescence (B). Figure (in part) adapted from Giang et al. (2). Liu et al. further characterized complement in BP and found that neutrophil depletion protected against the development of BP in wildtype mice, while injection of C5a or IL-8 in C5-KO mice regained susceptibility for BP (23). Moreover, absence of C5aR1-expression on mast cells demonstrated similar protection against BP development, despite complement activation and the presence of neutrophils. It was found that in the BP mouse model, extensive mast cell degranulation occurs that precedes the influx of neutrophil infiltration and subepidermal blister formation. These findings reveal that complement-dependent neutrophil recruitment in BP acts, at least in part, via C5aR1-induced mast cell degranulation (12, 24). Recently, this hypothesis was further investigated by Karsten et al. who confirmed the protection of C5aR1-KO mice against BP, whereas C5aR2-KO animals were more susceptible for disease development. As a proof of principle, prophylactic treatment with a C5aR1-inhibitor PMX53 in mice also led to reduced disease activity (17). Altogether, these results indicate an important role for C5a-C5aR1-axis activation in the development of BP and could be an interesting target for intervention. Although previous pre-clinical studies are encouraging, these experiments were all performed in mice which makes it difficult to translate these data to humans. However, Romeijn et al. showed in a large patient study comprising 300 patients with BP, that complement C3c was deposited in the majority of (peri)lesional skin biopsies. More interestingly, the extent of deposition was correlated with clinical and serological disease activity, strengthening the crucial role of complement in this disease (25). Besides the deposition of complement in the skin, Chiorean et al. recently found that functional complement-activation capacity of autoantibodies in BP also correlates with severity of skin disease and autoantibody titers (26). Mucous Membrane Pemphigoid Mucous membrane pemphigoid (MMP) is an AIBD. The disease represents a spectrum, which affects both skin and mucosa, especially the oral and ocular mucous membranes. Cutaneous lesions Cl-amidine manifest as tense blisters that, when ruptured, heal slowly and usually Cl-amidine result in scarring. Histopathology reveals a subepidermal blister and a lymphocytic infiltrate in the upper dermis with eosinophils and sometimes neutrophils. DIF shows IgG- and C3c-deposition along the BMZ, but also IgA-, IgM-, and fibrin-deposition can be found (27, 28). Various autoantigens have been found in MMP including BP180 (BPAG2), BP230 (BPAG1), laminin 332, 6/4 integrin, and laminin 6 (29). Early DIF studies have found deposition of C3, C1q, C4, FB, and properdin along the BMZ (28). Experimental models that passively transferred rabbit anti-laminin 5 (laminin 332) produced subepidermal blisters with the same clinical, histologic, and immunopathologic features of MMP. However, blistering could not be prevented in C5-deficient mice, indicating that the Cl-amidine terminal complement pathway is not involved in.