Role of T cell activation in the pathogenesis of psoriasis.
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Cyclosporine↗
Biomedical subjects
D M Carter
Publications and source records attributed to D M Carter.
Cyclosporine in psoriasis treatment. Inhibition of keratinocyte cell-cycle progression in G1 independent of effects on transforming growth factor alpha/epidermal growth factor receptor pathways.
Cyclosporine, an immunosuppressive drug, is effective in the treatment of recalcitrant psoriasis. Previous work suggested that keratinocyte hyperproliferation and inflammation are linked in psoriasis and that immune mechanisms participate in the pathogenesis of psoriasis. Transforming growth factor (TGF) alpha may be an important regulatory factor of epidermal growth as overproduction of TGF-alpha is associated with epidermal hyperplasia in psoriatic plaques and epidermal growth factor receptors are overexpressed in psoriatic epithelium. In this study, the effects of cyclosporine on cultured human keratinocytes were examined. Cyclosporine specifically inhibited keratinocyte cell-cycle progression in the G1 phase without causing keratinocytes to terminally differentiate. Cyclosporine did not decrease the expression of TGF-alpha or epidermal growth factor receptors. These results suggest that the effects of cyclosporine on psoriatic skin are unrelated to direct effects on autocrine growth regulation of keratinocytes via TGF-alpha production or of epidermal growth factor receptor modulation.
Chemokine CXCL10↗
The ultrastructural defect in conjunctiva from a case of recessive dystrophic epidermolysis bullosa.
The predominant feature in the several forms of epidermolysis bullosa is the formation of cutaneous bullous lesions arising after minimal mechanical trauma. Ocular involvement has been noted as a complication. To our knowledge to date, only four investigators have correlated clinical eye disease with light microscopic findings. Ultrastructure of the ocular lesions has not been described previously. We present four cases of recessive dystrophic epidermolysis bullosa emphasizing their associated ocular complications. Diagnosis was confirmed by skin biopsy specimen and in one patient by demonstrating light and electron microscopic findings in eyelid skin. This tissue exhibited ultrastructural recessive cutaneous lesions; namely, bullous separation occurring below the basal lamina and absence of anchoring fibrils in both bullous and nonbullous areas. By electron microscopy, the conjunctiva in this patient exhibited an absence of clear anchoring fibrils that were numerous in control tissue. This defect may increase the susceptibility of the conjunctiva to minor mechanical trauma, resulting in the bullous and cicatricial changes seen clinically.
Aged↗
Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa. A consensus report by the Subcommittee on Diagnosis and Classification of the National Epidermolysis Bullosa Registry.
Inherited epidermolysis bullosa encompasses a number of diseases, with the common finding of blister formation after minor mechanical trauma to the skin. In some forms significant, if not eventually fatal, extracutaneous disease activity may occur. In recent years application of newer technologies has contributed substantially to an overall understanding of this collection of inherited diseases. Concurrently, many new phenotypes have been recognized, in part the result of ongoing prospective patient registries in the United States and abroad. Unfortunately, this has resulted in a massive literature that may appear to be confounded by seemingly excessive or arbitrary subdivision of epidermolysis bullosa variants. With these concerns in mind a subcommittee was established by the National Epidermolysis Bullosa Registry to summarize the current literature and to make recommendations as to the best clinical and laboratory criteria for the practical diagnosis and subclassification of patients with inherited epidermolysis bullosa.
Epidermolysis Bullosa↗
Hypertriglyceridemia in patients with psoriasis treated with cyclosporine.
Eight patients received cyclosporine at doses of 2.0 to 7.5 mg/kg/day. Seven of these patients had increased fasting plasma triglyceride levels with cyclosporine therapy compared with pretreatment values, which peaked after 1 month of therapy. Four patients experienced elevations in fasting triglycerides, over the upper limits for age- and sex-matched controls, which were at least two times higher than their baseline values. It was striking that all four of these patients had previously had hypertriglyceridemia while using etretinate and three of these patients had preexisting hypertriglyceridemia before both etretinate and cyclosporine therapy. Triglyceride elevation did not correlate with cyclosporine levels. Thus cyclosporine, similar to etretinate, unmasks a latent tendency for mild to moderate hypertriglyceridemia. Fasting triglyceride levels should be monitored during cyclosporine therapy, especially after 1 to 2 months of use, and in patients with preexisting increased triglycerides and/or a history of etretinate use.
Adult↗
Synergistic effects of epidermal growth factor (EGF) and insulin-like growth factor I/somatomedin C (IGF-I) on keratinocyte proliferation may be mediated by IGF-I transmodulation of the EGF receptor.
The epidermal growth factor (EGF) receptor pathway is an important mediator of keratinocyte growth in vitro and both receptor and ligand components of this pathway are abnormally expressed in hyperproliferative epidermis. The purpose of this study was to examine interactions between the EGF receptor pathway and the insulin-like growth factor I/somatomedin C (IGF-I) receptor pathway in modulating the growth of cultured normal human keratinocytes. Short-term growth of keratinocytes in a chemically defined medium demonstrated that neither EGF nor IGF-I alone could support significant keratinocyte spreading or proliferation, but that a combination of EGF with IGF-I or high-dose insulin could. IGF-I or high-dose insulin transmodulates keratinocyte EGF receptor expression via the IGF-I receptor in a dose- and time-dependent manner, increasing EGF receptor binding an average of 1.8 times up to a maximum of fourfold without altering EGF binding affinity. Staining of normal human epidermis with an IGF-I receptor specific monoclonal antibody demonstrates that IGF-I receptors localize to the basal proliferative cell compartment, suggesting that IGF-I receptor and EGF receptor pathway interactions may play a role in the regulation of epidermal growth and in the pathogenesis of hyperproliferative skin diseases.
Cell Division↗
Effects of oxygen tension on the growth and pigmentation of normal human melanocytes.
The effects of oxygen tension on human melanocyte growth, tyrosinase activity, and melanin production were assessed. Melanocytes, seeded at 10(4) cells/cm2, were grown in modified Eagle's medium (MEM) with 5% fetal bovine serum (FBS) and 10 ng/ml 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Flasks were equilibrated with gas mixtures containing 5% CO2 and various partial pressures of oxygen (PO2 7-620 mm Hg) and kept in incubators, which were electronically maintained at the desired oxygen tensions. Melanocytes grew best at PO2 from 6-34 mm Hg. Growth was reduced by 30% at PO2 142 mm Hg, and even more at O2 tensions greater than 230 mm Hg. A PO2 of 603 mm Hg was cytotoxic. Tyrosinase activity (assayed by the method of Pomerantz) was 300 microU/mg protein at PO2 7-34 mm Hg. At PO2 235 and 355 mm Hg tyrosinase activity decreased to about 100 microU/mg protein. The apparent Km for tyrosine was unchanged in melanocytes cultured at all experimental oxygen tensions. The Vmax, however, was decreased at the higher oxygen tensions (PO2 235 mm Hg). At PO2 6-135 mm Hg the melanin content was proportional to tyrosinase activity. At cytostatic oxygen tensions (PO2 235 and 355 mm Hg) the intracellular melanin content increased somewhat, although tyrosinase activity was decreased. Low oxygen tension is favorable for both melanocyte proliferation and tyrosinase activity.
Cell Division↗
Increased dermal expression of platelet-derived growth factor receptors in growth-activated skin wounds and psoriasis.
Platelet-derived growth factor (PDGF) is a potent mitogenic and chemotactic factor for fibroblasts and other cell types. PDGF effects are mediated by binding of PDGF to dimeric PDGF receptors possessing intrinsic tyrosine kinase activity. We examined the expression pattern of PDGF receptors in cryostat sections of normal and growth-activated human skin using a monoclonal antibody, PR7212, specific for the beta subunit of the PDGF receptor. PDGF receptors were expressed at low levels in normal skin, with only occasional staining of dermal connective tissue cells. In contrast, PDGF receptor expression was greatly elevated in the dermis of growth-activated skin from 15 chronic wounds and 10 psoriatic lesions. PDGF receptors were increased in dermal fibroblasts and in dermal blood vessels in both conditions. Immunoblot analysis confirmed the increased expression of beta-subtype PDGF receptors in psoriatic lesional tissue. PDGF receptors were not detected in normal or growth-activated epidermis. Differential expression of PDGF receptors could regulate increased proliferation of vascular and connective tissue cells observed in psoriasis and chronic wounds.
Antibodies, Monoclonal↗
Junctional epidermolysis bullosa keratinocytes in culture display adhesive, structural, and functional abnormalities.
An unusual, elongated, refractile cell morphology was observed in keratinocytes cultured from three patients with non-lethalis forms of junctional epidermolysis bullosa (JEB). To determine whether these changes might be related to altered cell adhesion, keratinocyte strains established from one patient were examined for adhesive, structural, and functional characteristics. JEB keratinocytes expressed keratin tonofilaments, as determined by staining with AE1 monoclonal antibodies and direct observation of tonofilaments by electron microscopy. JEB keratinocytes showed diminished cell-substratum adhesions, judged by interference reflection microscopy. Areas of diminished cell-substratum adhesion corresponded to F-actin-rich cell adhesions (focal adhesions) and not to cellular areas that abundantly express hemidesmosomal antigens. Analysis of cell-substratum adhesion by electron microscopy revealed extensive areas of cell-substratum separation in JEB keratinocytes that were not present in normal keratinocytes maintained in serum-free medium. Normal keratinocytes displayed numerous regions of focal contact between the ventral plasma membrane and the culture substratum, but these structures were not seen in JEB keratinocytes. Bundled actin filaments (stress fibers) were greatly diminished in expected regions of cell-substratum adhesion in JEB keratinocytes and, instead, displayed disorganized individual filaments. The growth rate of JEB keratinocytes was quite slow in culture, with a population doubling time of 2.7 d versus 1.5 d for normal keratinocytes under identical conditions. JEB keratinocytes also displayed a reduced ability to aggregate into colonies upon exposure to medium with increased extracellular calcium. JEB keratinocytes thus display adhesive, structural, and functional abnormalities that suggest this cell type may be central to the pathogenesis of junctional epidermolysis bullosa. Study of affected keratinocytes could be important to characterize associated molecular pathologies.
Actins↗
Mupirocin-resistant Staphylococcus aureus after long-term treatment of patients with epidermolysis bullosa.
In a long-term, open study, 47 patients with epidermolysis bullosa were treated with topical 2% mupirocin (Bactroban) ointment to decrease bacterial infection and promote wound healing. This antibiotic is effective against gram-positive but not gram-negative organisms. No significant adverse effects were noted, although some patients have been treated for more than 4 years. We sought evidence in this patient population for the appearance of bacterial strains with decreased sensitivity to mupirocin. In five patients cultures from nonhealing wounds revealed Staphylococcus aureus resistance to mupirocin. Four of these patients were given oral antibiotics to which S. aureus was sensitive; they improved clinically, and cultures of their wounds became negative for pathogens.
Adult↗
Occlusive hydrocolloid dressings decrease keratinocyte population growth fraction and clinical scale and skin thickness in active psoriatic plaques.
Clinical studies suggest a therapeutic role for occlusion in the treatment of psoriasis. Previous studies, using multiparameter RNA/DNA flow cytometric analysis of epidermal suspensions obtained from active plaques, demonstrated increased keratinocyte growth fraction which reversed with successful medical treatment. Because keratinocyte growth fraction reflected disease activity, it was used in this study in addition to clinical evaluations in order to determine the efficacy of occlusion in the treatment of psoriatic plaques. In each of 9 patients, scale, skin thickness and erythema were compared in one occluded and one control plaque using an analog scale. Both scale and skin thickness, but not erythema, were decreased after 2 weeks of occlusion. However after 10 weeks, no additional differences were seen when compared with assessments made after 2 weeks, suggesting that the benefits of occlusive therapy occurred early. After 10 weeks of occlusion, the keratinocyte growth fraction was significantly decreased in occluded plaques. This study demonstrates that occlusion plays a synergistic role with other therapeutic modalities in ameliorating psoriatic plaques.
Bandages, Hydrocolloid↗
Role of growth factors, cytokines, and their receptors in the pathogenesis of psoriasis.
Psoriasis is characterized by epidermal hyperplasia, altered epidermal maturation, and local accumulation of acute and chronic inflammatory cells. Keratinocyte hyperplasia in psoriasis may be explained in part by overproduction of growth factors or cytokines which stimulate epidermal proliferation and by altered metabolism of growth-factor receptors in affected skin. Psoriatic epidermis displays overproduction of TGF-alpha and interleukin-6 (IL-6), factors produced by keratinocytes and other cell types in psoriatic skin. TGF-alpha and IL-6 are mitogens for normal human keratinocytes and act via specific receptors. The TGF-alpha receptor (EGF receptor) is overexpressed in psoriatic epithelium and its altered expression could be caused in part by gamma interferon which prevents normal receptor down-regulation in response to EGF binding. Several phenotypic features of the psoriatic keratinocyte, including growth activation and expression of HLA-DR, gamma-IP-10, ICAM-1, and other molecules, are best explained as resulting from the combined effects of TGF-alpha, IL-6, and gamma interferon (and possibly other cytokines) on epidermal keratinocytes. The multiple histologic features of psoriasis, including epidermal hyperplasia and accumulation of acute and chronic inflammatory cells, may be mediated by defined growth factors and cytokines that are produced in psoriatic skin and affect the function of diverse cell types.
Animals↗
Physiological and pharmacological effects of zinc on immune response.
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Antigens, Surface↗
Recessive dystrophic epidermolysis bullosa skin displays a chronic growth-activated immunophenotype. Implications for carcinogenesis.
Epidermolysis bullosa represents a grouping of inherited skin diseases characterized by epidermal fragility and frequently wounded skin. The recessive dystrophic subtype of epidermolysis bullosa (RDEB) is characterized by extensive dermal scarring after healing of repeated epidermal injuries and by an unusually high incidence of squamous cell carcinoma occurring in chronically wounded skin. In contrast, the simplex form of epidermolysis bullosa usually heals without scarring and does not predispose to malignant neoplasms of the skin. The differences in scarring and the neoplastic potential of these two forms of epidermolysis bullosa prompted us to investigate growth activation and differentiation characteristics in epidermal keratinocytes in individuals with these disorders. The expression of filaggrin, involucrin, cytokeratins, and the growth activation marker psi-3 was examined by immunohistochemistry in skin biopsy specimens from four individuals with epidermolysis bullosa simplex and six individuals with RDEB. Previous experiments using this technique have demonstrated that these antibodies are good markers for identifying growth-activated keratinocytes in wounded and hyperplastic epidermis. All biopsy specimens of healed wounds in skin from patients with RDEB showed epidermis that reacted with antibodies to filaggrin, involucrin, specific cytokeratins, and psi-3 in a growth-activated pattern. This growth-activated phenotype was maintained in keratinocytes from previously wounded skin that had been healed for more than 2 years. The RDEB growth-activated phenotype detected by immunohistochemistry was not associated with microscopically detectable epidermal hyperplasia. In contrast, all cases of epidermolysis bullosa simplex examined showed an epidermal phenotype similar to that of keratinocytes in normal skin. Thus, healing with dermal scar formation in RDEB is associated with a persistent growth-activated immunophenotype of epidermal keratinocytes. This chronic growth activation state or failure of cells to differentiate in a normal fashion may be directly linked to the high incidence of squamous cell cancers in individuals with RDEB.
Adolescent↗
Epidermolysis bullosa: when the skin falls apart.
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Epidermolysis Bullosa↗
Actinic DNA damage and the pathogenesis of cutaneous malignant melanoma.
The near epidemic of melanoma and non-melanoma skin cancer in the United States and certain other industrialized nations is attributable to cutaneous exposure to sunlight more than to any other factor. Chronic exposure to UV irradiation and a high total cumulative dose may be less deleterious than are periodic bursts of large amounts of sun exposure leading to severe sunburn. Such an exposure pattern is characteristic of individuals such as office workers whose outdoor activities are irregular rather than daily, as with farmers or fisherman. Although UV irradiation is injurious to many cellular elements, the mechanisms underlying UV-mediated skin cancer are thought to be most likely related to DNA damage to cutaneous cells. Various types of UV-induced DNA damage have been identified, and they differ in biologic significance. Damage which is apt to be most cytotoxic is probably less effective as an inducer of skin cancer than is more subtle damage, which is tolerated but can initiate malignant transformation. Repair of DNA damage involves specific cellular activities which vary in their effectiveness in restoring cutaneous cell function to normal. Other biologic effects of UV irradiation may contribute to the development of skin cancer through effects on such defenses as pigmentation and the immune response. Sun-induced damage to DNA, however, is apparently necessary. Biologic consequences of dangerous environmental exposure to UV irradiation can be modulated by changes in life-style, the depth of the ozone layer, use of sunscreens, and possibly by hormones or their synthetic analogs.
DNA↗
Nonmelanoma skin cancers in the elderly.
This article discusses the relationship between aging and development of nonmelanoma skin cancer. Possible age-related risk factors for development of such cancers are cumulative exposure to ultraviolet irradiation from the sun, decreased DNA repair capacity, decreased immunosurveillance, reduced melanocyte density, and altered dermal matrix. Clinical features of basal-cell carcinoma, squamous-cell carcinoma, and keratoacanthoma are discussed.
Aged↗
The effect of ultraviolet B radiation treatments on calcium excretion and vitamin D metabolites in kidney stone formers.
Several factors could explain the effect of warm, sunny weather on kidney stone formation. To determine the role of sun exposure, we used a light box to administer artificial ultraviolet B radiation during the winter months in New York City. Eleven male stone formers and 7 age- and sex-matched controls received 10 UVB light exposures over a two-week period while maintaining a 400 mg calcium diet. 25-OH vitamin D levels increased significantly (p less than 0.001) in both patients (25.9 +/- 9.8 to 51.6 +/- 14.1 ng/ml) and controls (21.3 +/- 7.1 to 49.6 +/- 3.1 ng/ml). However, 1,25 dihydroxyvitamin D levels rose in the patients (50.8 +/- 14.8 to 55.9 +/- 13.1 pg/ml) but fell (60.1 +/- 6.5 to 49.4 +/- 3.1 pg/ml) in the controls. Only 2 of the 11 patients but all of the controls demonstrated this down regulation of 1,25 dihydroxyvitamin D levels (p less than 0.002). 24,25 dihydroxyvitamin D levels tended to rise in both groups but parathyroid hormone levels were unchanged. There was a trend, which did not reach statistical significance, for parameters of calcium excretion to increase after UVB radiation. 24-hour urinary calcium excretion rose 24% from 140 to 173 mg in the patients and 31% from 113 to 148 mg in the controls. The ratio of calcium/creatinine following a one gram calcium load showed a small increase after UVB radiation from 0.17 to 0.20 in patients and 0.118 to 0.124 in the controls. However, no correlation could be discerned between changes in vitamin D metabolite concentrations and changes in urinary calcium.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗