A critical role for neutrophil elastase in experimental bullous pemphigoid.

  • Liu Z
  • Shapiro S
  • Zhou X
 et al. 
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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.

Author-supplied keywords

  • Animals
  • Autoantigens
  • Autoantigens: immunology
  • Autoantigens: physiology
  • Carrier Proteins
  • Collagen
  • Cytoskeletal Proteins
  • Humans
  • Immunoglobulin G
  • Immunoglobulin G: toxicity
  • Leukocyte Elastase
  • Leukocyte Elastase: physiology
  • Mice
  • Mice, Inbred BALB C
  • Nerve Tissue Proteins
  • Non-Fibrillar Collagens
  • Pemphigoid, Bullous
  • Pemphigoid, Bullous: enzymology
  • Pemphigoid, Bullous: etiology
  • Peroxidase
  • Peroxidase: metabolism

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  • Z Liu

  • S D Shapiro

  • X Zhou

  • S S Twining

  • R M Senior

  • G J Giudice

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