Steen Lisby

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.

Experimental systemic contact dermatitis from nickel: a dose–response study

Systemic contact dermatitis is usually seen as flare‐up of previous dermatitis or de novo dermatitis similar to allergic contact dermatitis. Although systemic contact dermatitis from medicaments is a well‐established entity, the existence of clinically relevant systemic reactions to oral nickel exposure, in particular systemic reactions to nickel in the daily diet, remains controversial. Several studies have shown that oral exposure to nickel can induce systemic contact dermatitis in nickel‐sensitive individuals. In most of these studies, however, the exposure dose of nickel used has been considerably higher than the nickel content in the normal daily diet. The aim of the current investigation was to study dose–response dependency of oral exposure to nickel. In a double‐blind, placebo‐controlled oral exposure trial, 40 nickel‐sensitive persons and 20 healthy (non‐nickel‐sensitive) controls were given nickel sulfate hexahydrate in doses similar to and greater than the amount of nickel ingested in the normal Danish daily diet. The nickel content in urine and serum before and after oral exposure was measured to determine nickel uptake and excretion. The influence of the amount of nickel ingested on the clinical reactions to oral exposure and on nickel concentrations in serum and urine was evaluated. Among nickel‐sensitive individuals, a definite dose–response dependency was seen, following oral exposure to nickel. 7 of 10 nickel‐sensitive individuals had cutaneous reactions to oral exposure to 4.0 mg nickel, an amount approximately 10 times greater than the estimated normal daily dietary intake of nickel. 4 of 10 nickel‐sensitive individuals had cutaneous reactions to 1.0 mg nickel, a dose which is close to the estimated maximum amount of nickel contained in the daily diet. 4 of 10 nickel‐sensitive individuals reacted to 0.3 mg nickel or to the amount equivalent to that contained in a normal daily diet, and 1 of 10 reacted to a placebo. None of the 20 healthy controls had cutaneous reactions to 4.0 mg nickel or to a placebo. Prior to oral exposure, there was no measurable difference in the amount of nickel in the urine or serum of nickel‐sensitive persons and healthy controls. Following the oral challenge, the nickel content in the urine and serum of both nickel‐sensitive and healthy control individuals was directly related to the dose of nickel ingested.

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.

UV‐induced DNA damage in human keratinocytes: Quantitation and correlation with long‐term survival

Abstract:  Ultraviolet (UV) radiation has a major role in the pathogenesis of skin cancer due to its capacity to induce immunosuppression and DNA damage in cells. In this study, we describe the use of a novel extra‐long polymerase chain reaction (XL‐PCR) assay for detection of UV‐inducible DNA lesions in a human keratinocyte line (HaCaT cells). Ultraviolet B (UVB), in doses from 4 to 50 mJ/cm2 resulted in a linear increase in the number of DNA lesions in the genome [range 0.3 ± 0.2 lesions−3.6 ± 0.7 lesions (mean ± SD)/10 kb]. At lower doses of UVB (<10 mJ/cm2), 89 ± 13% lesions were repaired within 24 h of culture. At higher doses, more lesions remained unrepaired, but the repair efficacy expressed as a proportion of repaired lesions to the total amount of DNA lesions remained constant in the range 0–50 mJ/cm2. Moreover, we demonstrated a correlation between the dose of UV and cell survival. The D37 (dose that reduced clonogenic survival to 37%) of UVB equaled 19 mJ/cm2, corresponding to the introduction of 1.4 lesions/10 kb. In contrast to UVB, UVA1 irradiation neither induced measurable DNA damage nor induced cell death in the doses up to 15 J/cm2. In conclusion, the non‐radioactive extra‐long (XL)‐based real‐time (RT)‐PCR assay system can be used to quantify the UV‐induced DNA damage in intact cells. The DNA lesions detected by this assay are mainly induced by short‐waved radiation in the UVB range, and unrepaired DNA lesions cause keratinocyte death or permanent cell‐cycle block.

THE CELLULAR IMMUNE RESPONSE TO HUMAN PAPILLOMAVIRUS INFECTION

This review will concentrate on the human cellular immune response associated with the HPV infection

Phenotype, Ultrastructure, and Function of CD1+DR+ Epidermal Cells that Express CD36 (OKM5) in Cutaneous T‐Cell Lymphoma

This study investigated the phenotype and function of different antigen‐presenting cells (APC) present within the epidermis of patients with cutaneous T‐cell lymphoma (CTCL). Involved epidermis of CTCL compared with uninvolved was found to contain increased numbers of CDI + DR+ APC. This population was heterogeneous and comprised both leucocytes of a novel CD1+DR+CD36 (OK.M5)+ phenotype and CD1+DR+CD36− indeterminate/Langerhans cells. The CD1+DR+CD36+ leucocytes did not express TcR‐1, CD5, CD 15. or CD22, and only a minor population expressed CD11, demonslrating that they were neither T nor B cells, and did not belong lo the major CD11+ (OKM1+) blood monocyte population. Electron microscopy of purified CD36+ lesional epidermal cells (EC) demonstrated that they lacked Birbeck granules found on CD1+‐selected Langerhans cells, and most cells exhibited features of indeterminate cells or macrophages.

Antigen‐Presenting Activity of Non‐Langerhans Epidermal Cells in Contact Hypersensitivity Reactions

Despite the critical role of the Langerhans cells in the induction of contact hypersensitivity reactions, non‐Langerhans antigen‐presenting cells in already sensitized individuals may play a role in the elicitation phase of a contact hypersensitivity reaction, following epicutaneous challenge with antigens, the number of CD1+ DR+ epidermal Langerhans cells increased in a time‐dependent way and. concomitantly. CD1−OKM5+ DR+ epidermal non‐Langerhans cells appeared. In parallel with this, the capacity of epidermal cells to present both alloantigens and auto, nominal antigens increased, and 4 days after initiation of the contact hypersensitivity reactions 33–53% of the epidermal antigen‐presenting capacity was due to CD1− non‐Langerhans antigen‐presenting cells. Thus, contact hypersensitivity skin reactions are accompanied by the appearance of non‐Langerhans antigen‐presenting cells capable of presenting both alloantigens and auto/nominal antigens.

Activation of Reactive Versus Malignant T Cells in Cutaneous T Cell Lymphoma: Role of Abnormal Antigen Presenting Cells and T Cell Activating Molecules

We review our data suggesting that interactions between reactive and malignant T cells in lesions of cutaneous T cell lymphoma (CTCL) may play a role in the biology of CTCL. T cell receptor gene rearrangement (TCRGR) analysis allows the identification of the malignant clone on the basis of the unique size of the TCR gene fragments after enzyme digestion. We identified the malignant clone by TCRGR analysis of DNA extracts from lesionai skin of patients with CTCL, mycosis fungoides type, and compared the TCRGR pattern to that of T cell clones established from lesionai skin of the same patients. We found that each clone demonstrated a TCRGR pattern unique from the others and different from that of the malignant clone identified in the lesion. These data established that a polyclonal population of tumor infiltrating lymphocytes (TEL) are present in the lesion (and potentially regulating the malignant clone), and also suggest that the malignant clone and the TIL’s may have different activation requirements. Intralesional activation of malignant or TIL clones may be induced by abnormal antigen presenting cells (APC’s) in the lesion. We showed that lesionai CDla+ cells (Langerhans cells;LC), purified on immunomagnetic beads, demonstrated ultrastructural abnormalities such as hyperconvoluted nuclei and significant melanophagocytosis. In addition, these LC demonstrated strong expression of CD36, CD11c and CD1c, markers normally more highly expressed on dermal perivascular dendritic cells, in addition to expression of molecules present on normal LC, such as HLA-DR and CDla. Although these modulated LC are hyperstimulatory for autologous T cells, it is not yet clear whether they are stimulating the malignant clone or the TIL’s in the lesion. The balance between progression versus indolence may be related to complex interactions between the cells of the malignant clone, TIL’s, and APC’s.