A critical role for neutrophil elastase in experimental bullous pemphigoid
Zhi Liu, … , Janet A. Fairley, Luis A. Diaz
Zhi Liu, … , Janet A. Fairley, Luis A. Diaz
Published January 1, 2000
Citation Information: J Clin Invest. 2000;105(1):113-123. https://doi.org/10.1172/JCI3693.
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Article

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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Figure 3

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Clinical, IF, and histological examination of neonatal NE–/– mice inject...
Clinical, IF, and histological examination of neonatal NE–/– mice injected with rabbit anti-mBP180 IgG. Pathogenic rabbit anti-mBP180 IgG (intradermal injection, 2.5 mg/g body weight) produced extensive epidermal disease in neonatal NE+/+ mice. (a) The skin of these animals showed linear deposition of rabbit IgG (b) and mouse C3 (c) at the BMZ by direct IF. H&E-stained sections from these mice showed a subepidermal vesicle with neutrophilic infiltrate (d). The inset, a higher magnification of d, demonstrates neutrophils at the lesional site of the dermis. In contrast, neonatal NE–/– mice injected intradermally with rabbit anti-mBP180 IgG showed no clinical evidence of skin disease (e). Direct IF studies showed rabbit IgG (f) and mouse C3 (g) deposition at the BMZ, but these animals showed no evidence of subepidermal vesiculation at the light microscopic level (h). The inset, a higher magnification of h, exhibits neutrophils in the dermis. Site of blisters (black arrows in a and e), site of basal keratinocytes (white arrowheads in b, c, f, and g; black arrowheads in d and h), dermis (d), epidermis (e), vesicle (v). Original magnification, b–d and f–h: ×100. Inset (original magnification ×400): neutrophils (black arrowheads).