A critical role for neutrophil elastase in experimental bullous pemphigoid.
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.
Liu
Z
Z
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. zhiliu@mcw.edu
Shapiro
S D
SD
Zhou
X
X
Twining
S S
SS
Senior
R M
RM
Giudice
G J
GJ
Fairley
J A
JA
Diaz
L A
LA
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
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