Ultraviolet-A1 phototherapy modulates Th1/Th2 and Tc1/Tc2 balance in patients with systemic lupus erythematosus.

OBJECTIVE: Ultraviolet-A1 (UVA1) phototherapy is effective for a variety of dermatological diseases. We examined the effectiveness and reliability of low-dose UVA1 phototherapy (60 kJ/m2/treatment) in patients suffering from systemic lupus erythematosus (SLE). We studied the changes in immunological parameters. METHODS: The patients received a 9-week course of phototherapy according to the following regimen: five times a week during the first 3 weeks, three times a week during the second 3 weeks and twice during the last 3 weeks. Among other things, we analysed the proportions of T helper 1 (Th1), Th2, T cytotoxic (Tc1) and Tc2 cell populations in the peripheral blood of patients by flow cytometric detection of intracytoplasmic interferon gamma (IFN-gamma) and interleukin 4 (IL-4). RESULTS: Our study showed the improvement of clinical symptoms determined by the subjective clinical disease activity scoring and the SLE Disease Activity Index (SLEDAI). By the end of UVA1 phototherapy, the mean value of SLEDAI had decreased from 7.2+/-5.6 to 0.9+/-1.8, which was significant (P = 0.005). Immunological investigations detected a decrease in the frequency of IFN-gamma-producing Th1 and Tc1 cells and a decrease in the Th1/Th2 and Tc1/Tc2 ratios after UVA1 therapy. CONCLUSION: According to the literature, IFN-gamma has a pathogenic role in the development of SLE. We observed a decreased proportion of IFN-gamma-secreting cells, which we think is presumably one of the beneficial effects of UVA1 therapy. On the basis of our study, UVA1 phototherapy does seem to be an effective adjuvant in the treatment of SLE patients.

[Porphyria cutanea tarda and hepatitis C virus]. / Porphyria cutanea tarda és hepatitis C-vírus.

The development of clinically overt porphyria cutanea tarda (PCT) can be attributed to joint effects of genetic predisposition and environmental factors. Regarding exogen factors, studies from several countries published in the last years gave an account of significantly higher frequency of chronic hepatitis C virus (HCV) infection in PCT patients compared to the normal population. At the Department of Dermatology of University of Debrecen the prevalence of positive anti-HCV antibodies has been found in approximately 55% of PCT patients diagnosed from 1990 to 1999, which is comparable to the average prevalence rate seen in Southern-European countries. The majority of male patients were anti-HCV positive and consumed regularly alcohol, whereas every female patient had taken contraceptives. Liver enzymes were only slightly elevated in the majority of the patients and liver biopsy had to be performed only in three patients duo to chronic hepatitis. Our findings emphasise how important the screening of PCT patients for anti-HCV antibody considering that it might be important quo ad vitam for young men.

Low doses of UVB or UVA induce chromosomal aberrations in cultured human skin cells.

Chromosomal defects are frequently present in malignant and premalignant skin disorders; however, it is not known whether ultraviolet radiation from sunlight plays a role in their induction. To obtain information on the ability of ultraviolet A and ultraviolet B to induce chromosomal aberrations, cultured melanocytes and fibroblasts were exposed to physiologic doses of ultraviolet A or ultraviolet B and, for comparison, to gamma rays. As a measure of chromosomal aberrations, the formation of micronuclei was determined. To obtain sufficient statistical data on induced micronuclei and cell kinetics, a flow cytometry method has been modified and applied. The flow cytometry method analysis is based on staining the DNA with ethidium bromide and the cell membranes with 1,6-diphenyl-1,3,5,-hexatriene. We observed dose-dependent micronuclei formation after gamma or ultraviolet B irradiation in both cell types and also for ultraviolet A in fibroblasts. The yield of micronuclei induced in fibroblasts by ultraviolet A was only a factor 15 smaller than that induced by ultraviolet B (313 nm). The results indicate that 10 kJ per m2 (equivalent to 1 minimal erythema dose) of ultraviolet B and 150 kJ per m2 of ultraviolet A (0.2 minimal erythema dose) can induce 1% of micronuclei in fibroblasts, equivalent to the induction due to 0.6 Gy of gamma radiation. In conclusion, physiologic doses of sunlight can induce chromosomal aberrations at a level comparable with that observed after exposure to approximately 1 Gy of ionizing radiation. Therefore, sunlight can be considered a potential inducer of chromosomal aberrations in skin cells, which may contribute to skin carcinogenesis.

bcl-2 vs p53 protein expression and apoptotic rate in human nonmelanoma skin cancers.

BACKGROUND: A failure in the apoptotic response after severe genomic damage could facilitate cell transformation and tumor development, and a constitutive overexpression of either p53 or bcl-2 protein in nonapoptotic tumor cells could signify a defective bax-mediated apoptosis. OBJECTIVES: To investigate whether a negative correlation occurs between these 2 proteins in nonmelanoma skin cancer and whether overexpression of either protein is associated with a low rate of spontaneous apoptosis. DESIGN: Immunohistochemical study of nonmelanoma skin cancer archive material. SETTING: University referral center. PATIENTS: White patients with tumors on sun-exposed skin areas (ie, 17 basal cell carcinomas and 22 squamous cell carcinomas). MAIN OUTCOME MEASURES: Positivity for p53 and bcl-2 were scored semiquantitatively on 4 levels, and the percentages of apoptotic cells were determined. RESULTS: A significant negative correlation between p53 and bcl-2 expression was found in the basal cell carcinomas, but not in the squamous cell carcinomas, largely attributable to the low level of bcl-2 staining in the squamous cell carcinomas. Squamous cell carcinomas have a significantly higher number of apoptotic cells than basal cell carcinomas: 1.1% vs 0.6%, respectively. This spontaneous apoptosis decreases with increasing bcl-2 (in basal cell carcinoma), whereas it does not appear to be related to p53 level expression. CONCLUSIONS: These results indicate that a disturbance in either p53 or bcl-2 suffices to enhance skin tumor formation by suppressing apoptosis; bcl-2 appears to reduce the rate of spontaneous apoptosis, but an aberrant p53 expression does not, and this factor may solely affect the apoptosis from exogenous genotoxicity.

Porphyria cutanea tarda and chronic lymphoid leukemia.

A case of a familial porphyria cutanea tarda (PCT-II) is reported in which the clinically overt form of PCT was provoked by factors relating to chronic lymphoid leukemia (CLL). Typical lesions of PCT developed on a 55-year-old woman after several blood transfusions and chlorambucil treatment. Besides these provoking factors, cytomegalovirus (CMV) infection was diagnosed. Erythrocyte uroporphyrinogen decarboxylase activity was about 50% of normal in the patient and in her two children. This case supports the suggestion that development of PCT in patients with hematological disorders is more than coincidental but may in fact be provoked by exogenous factors relating to the treatment of leukemia.

Formation of DNA adducts in the skin of psoriasis patients, in human skin in organ culture, and in mouse skin and lung following topical application of coal-tar and juniper tar.

Preparations of coal-tar and juniper tar (cade oil) that are used in the treatment of psoriasis are known to contain numerous potentially carcinogenic polycyclic aromatic hydrocarbons (PAH). Evidence of covalent binding to DNA by components of these mixtures was sought in a) human skin biopsy samples from 12 psoriasis patients receiving therapy with these agents, b) human skin explants maintained in organ culture and treated topically with the tars, and c) the skin and lungs of mice treated with repeated doses of the formulations following the regimen used in the clinic. DNA was isolated from the human and mouse tissues and digested enzymically to mononucleotides. 32P-Post-labeling analysis revealed the presence of aromatic DNA adducts in the biopsy samples at levels of up to 0.4 fmol total adducts/microgram DNA. Treatment of human skin in organ culture produced similar levels of adducts, while treatment with dithranol, a non-mutagenic therapeutic agent, resulted in chromatograms indistinguishable from those from untreated controls. In mouse skin, coal-tar ointment and juniper tar gave similar DNA adduct levels, with a similar time-course of removal: maximum levels (0.5 fmol/microgram DNA) at 24 h after the final treatment declined rapidly to 0.05 fmol/microgram at 7 d, thereafter declining slowly over the succeeding 25 d. However, while coal-tar ointment produced only very low levels of adducts in mouse lung (less than 0.03 fmol/microgram DNA), juniper tar produced adducts at a high level (0.7 fmol/microgram DNA) that were persistent in this tissue. These results provide direct evidence for the formation of potentially carcinogenic DNA damage in human and mouse tissue by components of these therapeutic tar preparations.

Poly(ADP-ribose)-synthesis and excision repair in light sensitive skin disorders.

Several data suggest a relationship of poly(ADP-ribose) (PAR) synthesis to DNA repair and the influence of some trace elements on the semiconservative and unscheduled DNA synthesis (UDS). Previously we found certain alterations in the UV-light induced UDS and in the contents of trace elements in the lymphocytes of patients with light sensitive skin disorders. In the recent study in polymorphic light eruption, cutaneous porphyrias and xeroderma pigmentosum the PAR synthesis and zinc, copper and manganese contents in the chromatin of the lymphocytes (measured by neutron activation analysis) were investigated. UV induced PAR synthesis was generally lower in the cells of polymorphic light eruption and especially in xeroderma pigmentosum with a reduced repair capacity whereas in cutaneous porphyrias no difference was observed. Some correlations occurred between the contents of trace elements studied and UDS as well in each group tested. It seems that PAR investigations throw new light upon our understanding of the pathomechanism of photodermatoses.

Determination of zinc, copper, manganese, and iron in blood from patients with light-sensitive skin diseases.

It is known that some trace elements have an influence on the repair of UV light induced DNA damage. We have detected certain alterations in the excision repair of patients with photodermatoses. In these investigations of screening character the levels of zinc, copper, manganese, and iron were measured by means of atomic absorption spectrophotometry in the whole blood of 31 patients with polymorphic light eruption and 27 patients with cutaneous porphyrias. In active stage of polymorphic light eruption decreased zinc, copper, and iron concentrations and an increased manganese content were found. In remission only the zinc level was lower. In the active stage of cutaneous porphyrias a decreased zinc and iron content as well as an increased manganese level could be detected. A presumable connection between the findings and the rate of the excision repair is discussed.

A study on cell-mediated immunity in polymorphic light eruption.

Polymorphic light eruption (PLE) can be defined as a delayed abnormal response to sunlight. In this paper some features of the presumable immune response were studied in 55 patients with PLE and the results were compared with the findings available in 58 cases with porphyria cutanea tarda (PCT). The mean intracutaneous reactivity index measured by skin tests of delayed type was normal in both diseases. The number of the active and total E-rosette-forming peripheral lymphocytes was significantly lower in the active stage of PLE whereas in remission normal values were found. In active PCT only the number of the total E-rosette-forming cells was decreased. The percentage of lymphocytes with so-called dot-like alpha-naphthyl acetate esterase enzyme reaction was reduced significantly in the active stage of PLE whereas in remission their number was normal. Changes observed in PLE seem to be functional and suggest the involvement of T lymphocytes in some phases of the hypersensitive cutaneous reaction induced by sunlight.