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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

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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 1

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Casein gel zymography of experimental BP lesional skin. Skin samples (12...
Casein gel zymography of experimental BP lesional skin. Skin samples (12 μg/lane) from BALB/c mice injected with PBS (lane 1), control rabbit IgG (lane 2), or pathogenic anti-mBP180 IgG (lanes 3, 6, 8, 10–13) were analyzed by casein gel zymography. Purified murine neutrophil extract (1 μg/lane; lanes 4, 7, and 9) and purified human NE (5 ng/lane; lane 5) were used as a standard. The 29-kDa caseinolytic band comigrating with the NE standard (arrow) was completely inhibited by the serine proteinase inhibitor, PMSF (lanes 8 and 9), but not by the metalloproteinase inhibitor, EDTA (lanes 6 and 7). This activity was also blocked by neutrophil elastase inhibitor, MeoSUC-AAPV-CK (AAPV, lane 11) or α1-PI (lane 12), but not by the CG/chymase inhibitor, GLF (lane 13) or DMSO (lane 10). mNE, murine NE.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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