title: 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 (alpha1-proteinase inhibitor and Me-O-Suc-Ala-Ala-Pro-Val-CH(2)Cl), but not mice given cathepsin G/chymase inhibitors (alpha1-antichymotrypsin or Z-Gly-Leu-Phe-CH(2)Cl), 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.affiliation: Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. zhiliu@mcw.edu
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.forename: S D
authors.initials: SD
authors.lastname: Shapiro
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.forename: S S
authors.initials: SS
authors.lastname: Twining
authors.forename: R M
authors.initials: RM
authors.lastname: Senior
authors.forename: G J
authors.initials: GJ
authors.lastname: Giudice
authors.forename: J A
authors.initials: JA
authors.lastname: Fairley
authors.forename: L A
authors.initials: LA
authors.lastname: Diaz
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology / Q000502:physiology; D002352:Carrier Proteins; D003094:Collagen; D003598:Cytoskeletal Proteins; D000071821:Dystonin; D006801:Humans; D007074:Immunoglobulin G / Q000633:toxicity; D019272:Leukocyte Elastase / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009419:Nerve Tissue Proteins; D024041:Non-Fibrillar Collagens; D010391:Pemphigoid, Bullous / Q000201:enzymology / Q000209:etiology*; D009195:Peroxidase / Q000378:metabolism; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D002352:Carrier Proteins; D003094:Collagen; D003598:Cytoskeletal Proteins; D000071821:Dystonin; D007074:Immunoglobulin G; D019272:Leukocyte Elastase; D009419:Nerve Tissue Proteins; D024041:Non-Fibrillar Collagens; D009195:Peroxidase; D000097805:Collagen Type XVII; C486268:DST protein, human; C095667:Dst protein, mouse