Abstract
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.
Highlights
Type XVII collagen (Col17), termed BP180, is a component of the dermal–epidermal junction (DEJ) and target antigen in various subepidermal blistering autoimmune disorders, the most frequent being bullous pemphigoid (BP) [1,2,3,4]
The neonatal mouse model based on the passive transfer of rabbit antimurine collagen type XVII IgG has vigorously been explored by the group of Liu and Diaz that highlighted the pathogenic importance of, e.g., complement activation, inflammatory cells such as neutrophils, mast cells, and macrophages, and the release of proteolytic enzymes at the DEJ in this model [(8), reviewed in Ref. [10]]
Complement activation appeared to be pivotal in this model as shown by several lines of evidence: C5- and C4-deficient (−/−) mice were completely protected against the pathogenic effect of anti-mCol17 IgG, and pharmacological inhibition of C1q as well as complement depletion by cobra venom prevented skin lesions in the neonatal mouse model of BP [11, 12]
Summary
Type XVII collagen (Col17), termed BP180, is a component of the dermal–epidermal junction (DEJ) and target antigen in various subepidermal blistering autoimmune disorders, the most frequent being bullous pemphigoid (BP) [1,2,3,4]. Complement activation appeared to be pivotal in this model as shown by several lines of evidence: C5- and C4-deficient (−/−) mice were completely protected against the pathogenic effect of anti-mCol IgG, and pharmacological inhibition of C1q as well as complement depletion by cobra venom prevented skin lesions in the neonatal mouse model of BP [11, 12] In this model, factor B (CFB)−/− mice developed delayed and less intense blistering and the C5a receptor 1 (C5aR1) on mast cells was shown to be critical for the formation of skin lesions [12, 13]. In neonatal mice, the injection of F(ab′) fragments of BP patients’ IgG and rabbit anti-hCOL17 IgG resulted in skin fragility questioning the impact of complement activation for lesion formation in BP [15]
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