A critical role for neutrophil elastase in experimental bullous pemphigoid
Zhi Liu, Steven D. Shapiro, Xiaoye Zhou, Sally S. Twining, Robert M. Senior, George J. Giudice, Janet A. Fairley, Luis A. Diaz
Zhi Liu, Steven D. Shapiro, Xiaoye Zhou, Sally S. Twining, Robert M. Senior, George J. Giudice, Janet A. Fairley, Luis A. Diaz
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A critical role for neutrophil elastase in experimental bullous pemphigoid

Abstract

Bullous pemphigoid (BP) is an autoimmune skin disease characterized by subepidermal blisters and autoantibodies against 2 hemidesmosome-associated proteins, BP180 and BP230. The immunopathologic features of BP can be reproduced in mice by passive transfer of anti-BP180 antibodies. Lesion formation in this animal model depends upon complement activation and neutrophil recruitment. In the present study, we investigated the role of neutrophil elastase (NE) in antibody-induced blister formation in experimental BP. Abnormally high levels of caseinolytic activity, consistent with NE, were detected in extracts of lesional skin and blister fluid of mice injected with anti-BP180 IgG. The pathogenic anti-BP180 IgG failed to induce subepidermal blistering in NE-null (NE–/–) mutant mice. NE–/– mice reconstituted with neutrophils from wild-type mice became susceptible to experimental BP. Wild-type mice given NE inhibitors (α1-proteinase inhibitor and Me-O-Suc-Ala-Ala-Pro-Val-CH2Cl), but not mice given cathepsin G/chymase inhibitors (α1-antichymotrypsin or Z-Gly-Leu-Phe-CH2Cl), were resistant to the pathogenic activity of anti-BP180 antibodies. Incubation of murine skin with NE induced BP-like epidermal-dermal detachment. Finally, NE cleaved BP180 in vitro and in vivo. These results implicate NE directly in the dermal-epidermal cleavage induced by anti-BP180 antibodies in the experimental BP model.

Authors

Zhi Liu, Steven D. Shapiro, Xiaoye Zhou, Sally S. Twining, Robert M. Senior, George J. Giudice, Janet A. Fairley, Luis A. Diaz

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Identification of BP180 degradation products in the lesional skin of exp...
Identification of BP180 degradation products in the lesional skin of experimental BP. Neonatal NE+/+ (lanes 1 and 2) and NE–/– (lane 3) mice were injected intradermally (2.5 mg/g body weight) with control IgG R50 (lane 1) or pathogenic IgG R621 (lanes 2 and 3). Skin biopsies were obtained at 12 hours after IgG injection, and protein extracts (45 μg/lane) were analyzed by immunoblotting using the anti-mBP180 IgG. Degraded BP180 band was present in the lesional skin samples of NE+/+ mice injected with pathogenic IgG (lane 2), but not in the nonlesional skin samples from control IgG-injected NE+/+ (lane 1) or pathogenic IgG-injected NE–/– mice (lane 3).