92-kD gelatinase is produced by eosinophils at the site of blister formation in bullous pemphigoid and cleaves the extracellular domain of recombinant 180-kD bullous pemphigoid autoantigen.

Abstract

Eosinophils are prominent in bullous pemphigoid (BP), and proteases secreted from these and other inflammatory cells may induce disruption of the basement membrane. We used in situ hybridization and immunohistochemistry to localize the sites of 92-kD gelatinase expression in BP lesions. In all samples (20/20), a strong signal for gelatinase mRNA was detected only in eosinophils and was most pronounced where these cells accumulated at the floor of forming blisters. No other cells were positive for enzyme mRNA. Both eosinophils and neutrophils, however, contained immunoreactive 92-kD gelatinase indicating that active expression occurred only in eosinophils. Degranulated eosinophils were also seen near blisters, and as demonstrated by gelatin zymography, immunoblotting, and ELISA, 92-kD gelatinase protein was prominent in BP blister fluid. No other gelatinolytic activity was specifically detected in BP fluid, and only small amounts of 92-kD gelatinase were present in suction blister fluids. As demonstrated in vitro, 92-kD gelatinase cleaved the extracellular, collagenous domain of recombinant 180-kD BP autoantigen (BP180, BPAG2, HD4, type XVII collagen), a transmembrane molecule of the epidermal hemidesmosome. Our results suggest that production and release 92-kD gelatinase by eosinophils contributes significantly to tissue damage in BP.

The α5 Chain of Type IV Collagen Is the Target of IgG Autoantibodies in a Novel Autoimmune Disease with Subepidermal Blisters and Renal Insufficiency

“…Eosinophils could play a crucial role in the dermal-epidermal separation through the release of their enzymatic mediators (20). Accordingly, this could explain why in patients with the X-linked Alport syndrome with mutations in the ␣5(IV) collagen gene no major skin lesions have been reported.…”

Human IgG1 Monoclonal Antibody against Human Collagen 17 Noncollagenous 16A Domain Induces Blisters via Complement Activation in Experimental Bullous Pemphigoid Model

“…The major pathogenic epitope of BP autoantibodies is present at the extracellular noncollagenous 16A (NC16A) domain, which has distinctive diversity among different species (10)(11)(12). Deposition of anti-hCOL17 autoantibodies at the BMZ triggers sequential inflammatory cascades, including complement activation, degranulation of dermal mast cells, infiltration of eosinophils and neutrophils, and subepidermal blister formation elicited by proteinases derived from the inflammatory cells (13)(14)(15)(16)(17).…”

Bullous Pemphigoid, Mucous Membrane Pemphigoid and Pemphigus Vulgaris: An Update on Pathobiology

“…Blister fluid and lesional biopsies from BP patients show high levels of proteolytic enzymes, such as NE and MMP-9, which in turn degrade both extracellular matrix proteins and the extracellular domain of BP180 [50]. Mouse models deficient in NE or MMP-9 are resistant to the disease [51,52].…”