049 Dual inhibition of the complement factor C5 and leukotriene B4by the bifunctional soft tick-derived lipocalin Coversin synergizes in suppressing disease in a murine model of bullous pemphigoid-like epidermolysis bullosa acquisita

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The treatment of autoimmune diseases still relies on immunosuppression and is associated with severe side-effects. The development of drugs abrogating pathogenic pathways more specifically is, therefore, most desirable. In nature, such specificity is exemplified, e.g., by the soft-tick-derived lipocalin Coversin, which locally suppresses immune responses by simultaneously inhibiting the complement factor C5 and leukotriene B4 (LTB4). C5a, a proteolytic fragment of C5, and LTB4have been highlighted as critical drivers of skin inflammation in pemphigoid diseases (PDs), a group of autoimmune blistering skin diseases. Here, we demonstrate that both Coversin and its mutated form L-Coversin, which only inhibits LTB4, dose-dependently attenuate disease in a model of bullous pemphigoid-like epidermolysis bullosa acquisita (BP-like EBA).Coversin, however, reduces disease more effectively than L-Coversin, indicating that inhibition of C5 and that of LTB4 synergize in their suppressing effects in that model. Further supporting a similar therapeutic potential of Coversin and L-Coversin in humans, we show that C5a and LTB4are both present in the blister fluid of BP patients in quantities inducing the recruitment of granulocytes and that their receptors C5aR1 and BLT1, respectively, are abundant specifically in lesional skin. Collectively, our results highlight Coversin and L-Coversin as potential therapeutics for PDs.