Ole Baadsgaard

Decrease in nickel sensitization in a Danish schoolgirl population with ears pierced after implementation of a nickel‐exposure regulation

Summary Background To reduce the skin nickel exposure of the population the Danish Ministry of Environment issued a regulation that was implemented in 1992, and the European Union countries have recently adopted an expanded regulation.

Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model.

Psoriasis is a chronic inflammatory disease of the skin characterized by epidermal hyperplasia, dermal angiogenesis, infiltration of activated T cells, and increased cytokine levels. One of these cytokines, IL-15, triggers inflammatory cell recruitment, angiogenesis, and production of other inflammatory cytokines, including IFN-gamma, TNF-alpha, and IL-17, which are all upregulated in psoriatic lesions. To investigate the role of IL-15 in psoriasis, we generated mAbs using human immunoglobulin-transgenic mice. One of the IL-15-specific antibodies we generated, 146B7, did not compete with IL-15 for binding to its receptor but potently interfered with the assembly of the IL-15 receptor alpha, beta, gamma complex. This antibody effectively blocked IL-15-induced T cell proliferation and monocyte TNF-alpha release in vitro. In a human psoriasis xenograft model, antibody 146B7 reduced the severity of psoriasis, as measured by epidermal thickness, grade of parakeratosis, and numbers of inflammatory cells and cycling keratinocytes. These results obtained with this IL-15-specific mAb support an important role for IL-15 in the pathogenesis of psoriasis.

Cyclosporine in dermatology

Cyclosporine is a potent immunosuppressive agent with no appreciable effect on the bone marrow and a selective inhibitory effect on helper T cells. Oral cyclosporine was first used to prevent organ rejection but also has been reported to be effective in other disorders. In cutaneous diseases that respond to oral cyclosporine helper T cells appear to be involved in their pathogenesis. This article reviews the cutaneous diseases that have been treated with cyclosporine and its pharmacology and side effects. Two significant adverse side effects are renal dysfunction and hypertension, both of which are reversible when short-term low-dose (less than 5 mg/kg per day) oral cyclosporine is discontinued. Lymphoma is unlikely in an otherwise healthy patient who has received low-dose oral cyclosporine for limited periods. The use of oral cyclosporine in any patient should be carefully considered in terms of the risk/benefit ratio and needs to be carried out under close medical supervision. In view of the limited experience with cyclosporine in dermatology, whenever possible its use should be confined to formal clinical studies with established protocols and guidelines. Further controlled studies need to be performed to evaluate the efficacy of low-dose cyclosporine in many dermatoses and its side-effect profile, particularly over the long term.

Association of TNFA gene polymorphism at position -308 with susceptibility to irritant contact dermatitis.

Abstract Mechanisms underlying susceptibility to skin irritants are not clearly understood. Cytokines play a key role in inflammation, and functional polymorphisms in cytokine genes may affect responses to irritants. We investigated the relationship between polymorphism in the tumor necrosis factor (TNF) α-chain gene and responses to irritants. Volunteers (n=221) tested with sodium dodecyl sulfate (SDS) and benzalkonium chloride (BKC) were divided into responders and nonresponders and high and low irritant-threshold groups. DNA was assayed for the TNF-308 polymorphism by a polymerase chain reaction-restriction fragment length polymorphism method. There was a significant increase in the A allele (P=0.030) and AA genotype (P=0.023) in both the SDS low irritant-threshold group and in SDS responders (A allele P=0.022, AA genotype P=0.048). In the BKC low irritant-threshold group, we found a significant increase in the A allele (P=0.002) and AA genotype (P=0.016). Individuals with a low threshold to both irritants demonstrated a significant increase (P=0.002) in the A allele. This is the first description of a nonatopic genetic marker for irritant susceptibility in normal individuals. Genotyping for theTNF-308 polymorphism may thus contribute to screening of individuals deemed at risk of developing irritant contact dermatitis.

Release of nickel ions from stainless steel alloys used in dental braces and their patch test reactivity in nickel‐sensitive individuals

Nickel ions leached in sufficient quantities from nickel‐containing alloys may induce nickel sensitization or elicit allergic contact dermatitis. Nickel‐containing stainless steel alloys are generally considered safe for nickel‐sensitive individuals to use. The study summarized in this paper investigated 3 parameters. First, the release of nickel was estimated in artificial saliva and sweat from 4 different stainless steel alloys frequently used in dental braces. Second, in a pilot study, oral mucosa cells harvested from 3 dental patients before and after the attachment of dental braces were analysed for possible nickel content. Third, patch test reactivity of the 4 stainless steel alloys was tested on 31 nickel‐sensitive subjects. All 4 stainless steel alloys released small amounts of nickel ions into artificial saliva (<0·13 µg/cm2/week) and artificial sweat (<0·05 µg/cm2/week), but no measurable amounts of nickel were found in any of the oral mucosa samples. None of the 31 nickel‐sensitive subjects reacted to patch testing with the 4 stainless steel alloys, indicating that these stainless steel alloys would be safe to use in direct and prolonged contact with the skin.

Lymphocytes and macrophages of the epidermis and dermis in lesional psoriatic skin, but not epidermal Langerhans cells, are depleted by treatment with cyclosporin A

SummarySince cyclosporin A (CsA) is an immuno-suppressive agent, its beneficial effect in psoriasis suggests that immune cells may play a role in the pathogenesis and resolution of psoriasis. To determine early effects of CsA in psoriasis, we quantitated immune cells using double immunofluorescence microscopy on biopsy specimens obtained prior to therapy and after 3,7, and 14 days of CsA therapy. CsA therapy resulted in significant reductions in the absolute number of immune cells (including T cells, monocytes/macrophages, and antigen presenting cells) contained within psoriatic skin. The effect was rapid, with over one-half of the reduction in the density of HLe1+ (human leukocyte antigen-1 positive or bone marrow derived) cells, including T cells, activated T cells, monocytes, and Langerhans cells (LCs), occurring within 3 days. Despite the overall reduction in the numbers of immunocytes in the skin, the proportion of T cells, Langerhans cells, and monocytes in relation to the total number of immune cells was unchanged with therapy, reflecting equally proportional losses of each subtype. Dermal CD1+DR+ cells (putative Langerhans cells), which are not found in normal skin but are present in lesional psoriasis skin, were virtually cleared from the papillary dermis after CsA therapy. Although absolute numbers of epidermal Langerhans cells, defined as cells expressing both CD1 (T6) and DR molecules (CD1+DR+), were also reduced after CsA, epidermal non-Langerhans CD1-DR+ cells (macrophages, activated T cells, DR- keratinocytes) demonstrated a proportionally greater decrease, with the ratio of CD1+DR+ Langerhans cells/non-Langerhans CD1-DR+ epidermal cells changing from a mean of 0.82 at baseline to 1.92 at day 14. Thus, early in the course of therapy, CsA appears to be effective at clearing CD1-DR+ cells while leaving LC relatively intact in the epidermis.

Dose response and time course for induction of T6− DR+ human epidermal antigen-presenting cells by in vivo ultraviolet A, B, and C irradiation

In vivo ultraviolet (UV) exposure of human skin abrogates the antigen-presenting function of T6+ DR+ Langerhans cells and induces the appearance of antigen-presenting T6- DR+ epidermal melanophages. UV-exposed epidermal cells containing T6- DR+ epidermal antigen-presenting cells, in contrast to unexposed epidermal cells containing T6+ DR+ Langerhans cells, potently activate autoreactive regulatory T cells in the absence of exogenous antigens. Autoreactive T cells may be important for regulation of other immune responses such as those which occur in photosensitive lupus erythematosus and in immune surveillance of UV-induced skin cancers. It is therefore imperative to determine the factors that govern their appearance in the skin. It was found that UVB and UVC, but not UVA, induced a dose-dependent appearance of T6- DR+ epidermal melanophages. The optimal time of appearance was 2 or 3 days after UVB and UVC exposure. In contrast, UVA was a poor inducer of T6- DR+ cells at all doses and all time points tested. Although UVA was a poor inducer of T6- DR+ epidermal cells, UVA radiation resulted in depletion of T6+ DR+ Langerhans cells from the epidermis, as did UVB and UVC radiation. This differential effect of UV wave bands on the immunocompetent cells in human skin may be related to the greater potential of UVB exposure to induce skin cancers and to exacerbate systemic lupus erythematosus.

Calcipotriol inhibits the proliferation of hyperproliferative CD29 positive keratinocytes in psoriatic epidermis in the absence of an effect on the function and number of antigen-presenting cells.

The aim of this study was to elucidate some of the possible mechanisms of action of the vitamin D analogue calcipotriol in vivo. Calcipotriol is finding increasing use in the treatment of psoriasis, but the primary target cell in vivo has not yet been identified. We treated psoriatic patients and healthy volunteers with calcipotriol and placebo ointment for 4 and 7 days, and obtained epidermal cell suspensions from treated areas. Epidermal cells were cocultured with autologous T cells, isolated from peripheral blood, in the absence or the presence of a classical antigen or a superantigen. In both psoriatic and normal skin, calcipotriol treatment did not alter the capacity of epidermal antigen‐presenting cells to stimulate the proliferation of autologous T cells, either in the absence or in the presence of exogenous antigen. Epidermal cell suspensions were analysed further by staining for infiltrating leucocytes (CD45+) and Langerhans cells (CD1a+). Flow cytometric analyses showed that calcipotriol did not alter the number of CD45+ cells or Langerhans cells in psoriatic skin. These results indicate that calcipotriol does not alter either the number or the function of epidermal antigen‐presenting cells in psoriatic epidermis. In contrast, we found that calcipotriol significantly inhibited the proliferation of epidermal cells isolated from psoriatic skin after in vivo treatment, as determined by propidium iodide staining and flow cytometry. More specifically, we stained for CD29+ keratinocytes and found an even more significant reduction in proliferative capacity. This cell type contains the population of hyperproliferative keratinocytes in psoriatic epidermis. In conclusion, calcipotriol seems to act via an inhibitory effect on hyperproliferative basal keratinocytes of psoriatic epidermis, rather than via an effect on infiltrating leucocytes, including antigen‐presenting cells.

CDw60, which identifies the acetylated form of GD3 gangliosides, is strongly expressed in human basal cell carcinoma

The monoclonal antibody UM4D4, assigned to the CDw60 cluster of differentiation, identities an epilope expressed on a subset of normal T cells, some malignant T cells, melanocytes, malignant melanoma cells and hyperproliferative psoriatic keratinocytes. CDw60 antibodies bind to the acetylated form of GD3 gangliosides. These gangliosides have been implicated in the control of cellular proliferation. Because the acetylated form of GD3 has been demonstrated in basal cell carcinomas, we determined whether the CDw60 epitope was expressed in basal cell carcinomas (n= 24) and squamous cell carcinomas (n= 2). Biopsies of these tumours were sectioned on a cryostat, and stained with anti‐CDw60 using a sensitive indirect immunoperoxidase technique. A mean of 74±4% (mean ± SEM) of the basal cell carcinoma cells expressed CDw60. In contrasl, CDw60 expression in normal skin was confined to melanocytes and a few scattered keratinocytes at the basal cell layer. CDw60 expression in basal cell carcinomas was highly upregulated at the tumour front in most of the lesions, whereas the squamous cell carcinomas showed uniform CDw60 expression in all areas.

Increased expression of Fas on human epidermal cells after in vivo exposure to single‐dose ultraviolet (UV) B or long‐wave UVA radiation

Summary Background  Apoptosis has been proposed to act as an important mechanism for eliminating keratinocytes that have been irreversibly damaged by ultraviolet (UV) irradiation. One way to induce apoptosis in keratinocytes is through activation of the cell surface receptor Fas (CD95), either with the ligand (FasL) or directly with UV radiation.