Epidermolysis bullosa acquisita (EBA) is a rare blistering skin disease induced by autoantibodies directed against type VII collagen (COL7). Transfer of antibodies against murine COL7 (mCOL7) into mice mimics the effector phase of EBA and results in a subepidermal blistering phenotype. Activation of the complement system, and especially the C5a/C5aR1 axis driving neutrophil activation, are critical for EBA pathogenesis. However, the role of the alternative C5a receptor, C5aR2, which is commonly thought to be more immunosuppressive, in the pathogenesis of EBA is still elusive. Therefore, we sought to delineate the functional relevance of C5aR2 during the effector phase of EBA. Unexpectedly, C5aR2-deficient (C5ar2–/–) mice showed an attenuated disease phenotype, suggesting a pathogenic contribution of C5aR2 to disease progression. In vitro, C5ar2–/– neutrophils exhibited significantly reduced (Ca2+)i flux, reactive oxygen species release, and migratory capacity when activated with immune complexes or exposed to C5a. These functions were completely absent when C5ar1–/– neutrophils were activated. Moreover, C5aR2 deficiency more than tripled FcγRIIb expression on neutrophils thus lowering the A/I ratio of FcγRs and impeding the sustainment  of inflammation. Collectively, we demonstrate here a pro-inflammatory contribution of C5aR2 to the pathogenesis of antibody-induced tissue damage in experimental EBA.

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