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Front Immunol. 2018 Mar 15;9:488. doi: 10.3389/fimmu.2018.00488. eCollection 2018.

Tissue Destruction in Bullous Pemphigoid Can Be Complement Independent and May Be Mitigated by C5aR2.

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Institute of Systemic Inflammation, University of Lübeck, Lübeck, Germany.
Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, Lübeck, Germany.
Department of Dermatology, University of Lübeck, Lübeck, Germany.
Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany.
Division of Immunobiology, Cincinnati Children's Hospital and College of Medicine, University of Cincinnati, Cincinnati, OH, United States.


Bullous pemphigoid (BP), the most frequent autoimmune bullous disorder, is a paradigmatic autoantibody-mediated disease associated with autoantibodies against BP180 (type XVII collagen, Col17). Several animal models have been developed that reflect important clinical and immunological features of human BP. Complement activation has been described as a prerequisite for blister formation, however, the recent finding that skin lesions can be induced by anti-Col17 F(ab')2 fragments indicates complement-independent mechanisms to contribute to blister formation in BP. Here, C5-/- mice injected with anti-Col17 IgG showed a reduction of skin lesions by about 50% associated with significantly less skin-infiltrating neutrophils compared to wild-type mice. Reduction of skin lesions and neutrophil infiltration was seen independently of the employed anti-Col17 IgG dose. Further, C5ar1-/- mice were protected from disease development, whereas the extent of skin lesions was increased in C5ar2-/- animals. Pharmacological inhibition of C5a receptor 1 (C5aR1) by PMX53 led to reduced disease activity when applied in a prophylactic setting. In contrast, PMX-53 treatment had no effect when first skin lesions had already developed. While C5aR1 was critically involved in neutrophil migration in vitro, its role for Col17-anti-Col17 IgG immune complex-mediated release of reactive oxygen species from neutrophils was less pronounced. Our data demonstrate that complement-dependent and -independent mechanisms coexist in anti-Col17-autoantibody-mediated tissue destruction. C5aR1 and C5aR2 seem to play opposing roles in this process with C5aR1 exerting its primary effect in recruiting inflammatory cells to the skin during the early phase of the disease. Further studies are required to fully understand the role of C5aR2 in autoantibody-mediated skin inflammation.


BP180; autoantibody; dermal–epidermal junction; skin; treatment; type XVII collagen

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