A critical role for neutrophil elastase in experimental bullous pemphigoid

Bullous pemphigoid (BP) is an autoimmune skin disease characterized by sube pidermal blisters and autoantibodies against 2 hemidesmosome-associated pro teins, BP180 and BP230. The immunopathologic features of BP can be reproduc ed in mice by passive transfer of anti-BP180 antibodies. Lesion formation i n this animal model depends upon complement activation and neutrophil recru itment. In the present study, we investigated the role of neutrophil elasta se (NE) in antibody-induced blister formation in experimental BP. Abnormall y high levels of caseinolytic activity, consistent with NE, were detected i n extracts of lesional skin and blister fluid of mice injected with anti-BP 180 IgG. The pathogenic anti-BP180 IgG failed to induce subepidermal bliste ring in NE-null (NE-/-) mutant mice. NE-/- mice reconstituted with neutroph ils from wild-type mice became susceptible to experimental BP. Wild-type mi ce given NE inhibitors (alpha 1-proteinase inhibitor and Me-O-Suc-Ala-Ala-P ro-Val-CH2Cl), but not mice given cathepsin G/chymase inhibitors (alpha 1-a ntichymotrypsin or Z-Gly-Leu-Phe-CH2Cl), were resistant to the pathogenic a ctivity of anti-BP180 antibodies. Incubation of murine skin with NE induced BP-like epidermal-dermal detachment. Finally, NE cleaved BP180 in vitro an d in vivo. These results implicate NE directly in the dermal-epidermal clea vage induced by anti-BP180 antibodies in the experimental BP model.