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Granulocyte‐derived elastase and gelatinase B are required for dermal–epidermal separation induced by autoantibodies from patients with epidermolysis bullosa acquisita and bullous pemphigoid
Author(s) -
Shimanovich Iakov,
Mihai Sidonia,
Oostingh Gertie J,
Ilenchuk T Toney,
Bröcker EvaB,
Opdenakker Ghislain,
Zillikens Detlef,
Sitaru Cassian
Publication year - 2004
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.1674
Subject(s) - epidermolysis bullosa acquisita , bullous pemphigoid , autoantibody , elastase , epidermolysis bullosa , immunology , pemphigoid , neutrophil elastase , pathology , anchoring fibrils , medicine , chemistry , antibody , basement membrane , inflammation , biochemistry , enzyme
Epidermolysis bullosa acquisita (EBA) and bullous pemphigoid (BP) are two clinically and immunologically distinct autoimmune subepidermal blistering skin diseases associated with IgG autoantibodies against the dermal–epidermal junction. BP antibodies are directed against the hemidesmosomal antigens BP180 and BP230, and those in patients with EBA target type VII collagen, a major component of anchoring fibrils. While the pathogenetic mechanisms of subepidermal blistering in BP have been previously studied using a passive transfer mouse model, the effector pathways of blister formation in EBA are largely unknown. Autoantibodies to type VII collagen and BP180 have recently been shown to induce leucocyte‐mediated subepidermal cleavage in cryosections of human skin. The aim of the present study was to identify human leucocyte protease(s) instrumental in dermal–epidermal separation induced by autoantibodies to type VII collagen and BP180. When incubated with cryosections of human skin pretreated with IgG from patients with EBA or BP but not from patients with anti‐laminin 5 mucous membrane pemphigoid or healthy controls, granulocytes were recruited to the dermal–epidermal junction and induced subepidermal splits. A combination of broad‐range protease inhibitors as well as inhibitors of serine and matrix metalloproteases completely abolished dermal–epidermal separation induced by EBA or BP autoantibodies. When characterizing the proteases involved more specifically, selective inhibition of human leucocyte elastase or gelatinase B/MMP‐9 was also found to result in suppression of blistering. These findings strongly suggest that elastase and gelatinase B are essential for granulocyte‐mediated proteolysis resulting in dermal–epidermal separation in EBA and BP patients' skin. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.