Basement membrane zone proteins, epithelial integrins and TGF-β system in reepithelialization, dermatitis herpetiformis and psoriasis : modulation by isotretinoin, betamethasone and calcipotriol
1University of Oulu, Faculty of Medicine, Department of Dermatology and Venereology
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|Persistent link:|| http://urn.fi/urn:isbn:951425712X
|Publish Date:|| 2000-07-10
|Thesis type:||Doctoral Dissertation
|Defence Note:||Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in Auditorium 3 of the University Hospital of Oulu, on September 1st, 2000, at 12 noon.
Docent Ilkka Harvima
Docent Matti Kallioinen
TGF-βs are cytokines that signal through the receptor complex of type I and type II receptors. Hemidesmosome (BP180, BP230, plectin/HD1, α6β4 integrin), anchoring filaments (laminin 5), and anchoring fibrils (collagen VII) form a hemidesmosomal adhesion complex that provides stable adherence of keratinocytes to the epidermal basement membrane. Nidogen, collagen IV, and laminins are components of the basement membrane, integrins are cell adhesion molecules, and tenascin-C is a matrix protein.
The expression of TGF-β receptors I and II was studied in normal epidermis and lesional and non-lesional psoriatic epidermis by immunohistochemistry. TGF-β1 and TGF-β2 in suction blister fluid and serum were determined by enzyme-linked immunoassay. Suction blister fluid and serum samples were obtained from acne patients before and after oral isotretinoin treatment. Suction blister fluid samples were also obtained from healthy volunteers in two age groups from a control site and a betamethasone-pretreated site. The expression of BP180, BP230, plectin/HD1, α6 integrin, β4 integrin, laminin 5, collagen VII, collagen IV, nidogen, laminin α3 chain, and laminin β1g1 chains was studied in uninvolved dermatitis herpetiformis skin by the immunofluorescence technique. The ultrastructure of the hemidesmosomal inner plaque was studied in uninvolved dermatitis herpetiformis skin by electron microscopy. The suction blister method was used to study intact blisters, open wounds (=blister roofs removed right after blister induction) and calcipotriol-pretreated open wounds in healthy volunteers. The reepithelialization rate and the expression of BP180, BP230, plectin/HD1, β4 integrin, laminin 5, collagen VII, laminin α5 chain, laminin β1 chain, tenascin-C, αvβ5 integrin, β5 integrin, α5 integrin, and α9 integrin during reepithelialization were studied by haematoxylin and eosin stainings and the immunofluorescence technique. BP180, BP230, and plectin/HD1 expression were analyzed by body site to exclude regional variation.
In normal epidermis, TGF-β receptors I and II were detected in the basal epidermis. Diffusion calculations suggest that circulation is likely to be a major source of TGF-β for TGF-β receptors in the basal epidermis. Downregulation of TGF-β receptors I and II was seen in lesional psoriatic epidermis, suggesting that hyperproliferating lesional epidermis may have lost TGF-β-mediated growth inhibition. Isotretinoin did not affect the serum TGF-β1 or TGF-β2 levels, but caused a 19% local increase in suction blister fluid TGF-β1. Betamethasone caused a 17% decrease in suction blister fluid TGF-β1, presumably due to glucocorticoid-induced vasoconstriction. Modulation of the interstitial fluid TGF-β1 concentration may be one mechanism by which isotretinoin and betamethasone mediate their effects in skin. Immunoreactivity for BP230 and plectin/HD1 was decreased in the basement membrane zone in uninvolved dermatitis herpetiformis skin in a significant proportion of the patients, suggesting distinct molecular changes in BP230 and plectin/HD1. This may be a factor contributing to blister formation. Reepithelialization rate was considerably slower in intact blisters than in open wounds and was not affected by calcipotriol. BP230 and plectin/HD1 appeared earlier in intact blisters than in open wounds. Reepithelialization took place on a continuous laminin sheath in intact blisters, but the laminin sheath in open wounds was partially discontinuous. It was a novel finding that integrin αvβ5 and integrin β5 antibodies showed divergent distributions in regenerating epidermis. The present results suggest that, in some bullous diseases, removal of the blister roof could accelerate blister healing, calcipotriol treatment does not delay wound epithelialization, a continuous laminin sheath may inhibit reepithelialization, and the formation of the hemidesmosomal inner plaque at the leading edge takes place earlier in the more slowly reepithelializing intact blisters than in open wounds.
Acta Universitatis Ouluensis. D, Medica
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