RESUMO
Exposure to ultraviolet-B radiation impairs cellular immune responses. This immunosuppression seems to be associated with Langerhans cell migration. DNA damage appears to play a key role because enhanced nucleotide excision repair, a pathway essential for elimination of ultraviolet-B-induced DNA lesions, strongly counteracts immunosuppression. To determine the effect of DNA repair on ultraviolet-B-induced local immunosuppression and Langerhans cell disappearance, three mouse strains carrying different defects in nucleotide excision repair were compared. XPC mice, which were defective in global genome repair, were as sensitive to ultraviolet-B-induced local suppression of contact hypersensitivity to picryl chloride as their wild-type littermates. CSB mice, defective in transcription-coupled repair, were far more sensitive for immunosuppression as were XPA mice, defective in both transcription-coupled repair and global genome repair. Only a moderate depletion of Langerhans cells was observed in XPC mice and wild-type littermates. Ultraviolet-B-induced Langerhans cell depletion was enhanced in CSB and XPA mice. Hence, the major conclusion is that local immunosuppression is only affected when transcription-coupled DNA repair is impaired. Furthermore, a defect in transcription-coupled repair was linked to enhanced ultraviolet-B-induced Langerhans cell depletion. In combination with earlier experiments, it can be concluded that Langerhans cell disappearance is related to ultraviolet-B-induced local but not to systemic immunosuppression.
Assuntos
Reparo do DNA/imunologia , Sistema Imunitário/efeitos da radiação , Células de Langerhans/citologia , Células de Langerhans/efeitos da radiação , Animais , Biomarcadores , Movimento Celular/imunologia , Proteínas de Ligação a DNA/genética , Relação Dose-Resposta à Radiação , Sistema Imunitário/imunologia , Células de Langerhans/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T/genética , Transcrição Gênica/imunologia , Raios Ultravioleta/efeitos adversos , Proteína de Xeroderma Pigmentoso Grupo ARESUMO
Ultraviolet B radiation can suppress cellular immunity. One of the mechanisms related to this immunosuppression is the disappearance of Langerhans cells from the epidermis. The aim of this study was to establish the mechanism of ultraviolet B-induced Langerhans cell disappearance in healthy individuals. The two most likely mechanisms for Langerhans cell disappearance are apoptosis and migration. Apoptosis was assessed in vivo by exposing buttock skin of 10 healthy volunteers to six minimal erythema doses of ultraviolet B. Only very few apoptotic Langerhans cells could be observed in sections from the ultraviolet B-exposed skin. Migration of Langerhans cells cannot be established in skin sections and suction blisters were therefore raised in an attempt to trap migrating Langerhans cells in the sub-basal membrane blister fluid. Blisters were raised on the flexor side of the lower arm of 30 healthy volunteers at several time points after exposure of the skin to six minimal erythema doses of ultraviolet B. Blister fluid was collected and blister roofs were removed to check for Langerhans cell disappearance. Langerhans cells were detected in the blister fluid of the ultraviolet B-exposed skin and not of the unexposed skin. The number of Langerhans cells in the blister fluid peaked at about 18 h after ultraviolet exposure, which coincided with the largest depletion of Langerhans cells in the blister roof. A fraction (20-30%) of the Langerhans cells in the blister fluid stained positive for DNA damage (cyclobutyl pyrimidine dimers), showing that they originated from the epidermis. Ultraviolet B-induced Langerhans cell disappearance appears to be mainly attributable to migration.
Assuntos
Apoptose/imunologia , Movimento Celular/imunologia , Epiderme/patologia , Células de Langerhans/patologia , Adulto , Antígenos CD1/análise , Vesícula/patologia , Caspase 3 , Caspases/metabolismo , Dano ao DNA , Epiderme/efeitos da radiação , Feminino , Humanos , Marcação In Situ das Extremidades Cortadas , Células de Langerhans/química , Células de Langerhans/efeitos da radiação , Masculino , Pessoa de Meia-Idade , Dímeros de Pirimidina/análise , Sucção , Raios UltravioletaRESUMO
The glucagonoma syndrome is a rare disease in which a typical skin disorder, necrolytic migratory erythema, is often one of the first presenting symptoms. Weight loss and diabetes mellitus are two other prevalent characteristics of this syndrome. Necrolytic migratory erythema belongs to the recently recognized family of deficiency dermatoses of which zinc deficiency, necrolytic acral erythema and pellagra are also members. It is typically characterized on skin biopsies by necrolysis of the upper epidermis with vacuolated keratinocytes. In persistent hyperglucagonemia, excessive stimulation of basic metabolic pathways results in diabetes mellitus at the expense of tissue glycogen stores, and muscle and fat mass. Multiple (essential) nutrient and vitamin B deficiencies develop, which contribute to the dermatosis. In addition, glucagonomas may produce various other products, like pancreatic polypeptide, that add to the catabolic effects of glucagon.
Assuntos
Eritema/etiologia , Glucagonoma/complicações , Neoplasias Pancreáticas/complicações , Adolescente , Idoso , Eritema/patologia , Glucagonoma/diagnóstico por imagem , Humanos , Masculino , Neoplasias Pancreáticas/diagnóstico por imagem , Síndrome , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Disturbances in UV-induced Langerhans cell migration and T helper (T(H)) 2 cell responses could be early steps in the pathogenesis of PLE. OBJECTIVE: To establish whether UV-B exposure induces aberrant cytokine expression in the uninvolved skin of patients with polymorphous light eruption (PLE). DESIGN: Immunohistochemical staining and comparison of microscopic sections of skin irradiated with 6 times the minimal dose of UV-B causing erythema and the unirradiated skin of patients with PLE and of healthy individuals. SETTING: University Medical Center (Dutch National Center for Photodermatoses). Patients Patients with PLE (n = 6) with clinically proven pathological responses to UV-B exposure and normal erythemal sensitivity. Healthy volunteers (n = 5) were recruited among students and hospital staff. MAIN OUTCOME MEASURES: Expression of cytokines related to Langerhans cell migration (interleukin [IL] 1, IL-18,and tumor necrosis factor [TNF] alpha); T(H)2 responses (IL-4 and IL-10); and T(H)1 responses (IL-6, IL-12, and interferon gamma). Double staining was performed for elastase (neutrophils), tryptase (mast cells), and CD36 (macrophages). RESULTS: The number of cells expressing IL-1beta and TNF-alpha was reduced in the UV-B-exposed skin of patients with PLE compared with the skin of healthy individuals (P<.05 for TNF-alpha). No differences were observed in the expression of T(H)1-related cytokines but fewer cells expressing IL-4 infiltrated the epidermis of patients with PLE 24 hours after irradiation (P =.03). After UV exposure TNF-alpha, IL-4, and, to a lesser extent, IL-10 were predominantly expressed by neutrophils. CONCLUSIONS: The reduced expression of TNF-alpha, IL-4, and IL-10 in the UV-B-irradiated skin of patients with PLE appears largely attributable to a lack of neutrophils, and is indicative of reduced Langerhans cell migration and reduced T(H)2 skewing. An impairment of these mechanisms underlying UV-B-induced immunosuppression may be important in the pathogenesis of PLE.
Assuntos
Citocinas/metabolismo , Transtornos de Fotossensibilidade/imunologia , Pele/imunologia , Raios Ultravioleta , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Masculino , Pessoa de Meia-Idade , Pele/efeitos da radiação , Fator de Necrose Tumoral alfa/metabolismoRESUMO
In women, acne can be successfully treated with oral contraceptives. This article focuses on the results of clinical studies on the treatment of acne with oral contraceptives. From the literature, 12 such studies could be traced over the last 10 years. Most of the studies were multicenter, randomized, and double blind. Five studies were placebo controlled. All of these studies were analyzed and compared with each other. Statistically, all placebo-controlled studies showed a better result with the active treatment, than with the placebo. However, the placebo groups also showed an improvement in the acne lesions. In seven studies, two oral contraceptives were compared for their effect on acne vulgaris. All oral contraceptives studied showed a beneficial effect on the severity of acne. It can be concluded, based on these studies, that all oral contraceptives have a more or less beneficial effect on mild to moderate acne in women. Comparing the various clinical trials, ethinylestradiol/drospirenone is as good as ethinylestradiol/cyproterone, which is slightly better than ethinylestradiol/desogestrel and ethinylestradiol/gestodene. Ethinylestradiol/chlormadinone is slightly better than ethinylestradiol/levonorgestrel, which is as effective as ethinylestradiol/norethindrone, which is far better than the placebo. Ethinylestradiol/norgestimate is better than placebo.
Assuntos
Acne Vulgar/tratamento farmacológico , Anticoncepcionais Orais Combinados/uso terapêutico , Acne Vulgar/patologia , Ensaios Clínicos como Assunto , Anticoncepcionais Orais Combinados/administração & dosagem , Feminino , Humanos , Resultado do TratamentoRESUMO
Ultraviolet light exposure can impair immune responses that are not restricted to the exposed skin but is also found at other sites, i.e. systemic immunosuppression. Therefore, we investigated the UV-induced modulating effects on vaccination against hepatitis B in a mouse model. Two different mouse strains, BALB/c and C57B1/ 6, were vaccinated intramuscularly against hepatitis B. Mice were exposed to different doses of ultraviolet B (UVB) for five consecutive days on shaved back skin before the vaccination. Vaccination against hepatitis B induced cellular (delayed-type hypersensitivity [DTH] and lymphocyte stimulation test) as well as humoral immune responses in both mouse strains. The DTH responses in C57BB1/6 mice were statistically significantly higher compared with BALB/c mice. UVB exposure induced a dose-dependent suppression of cellular immunity in both strains of mice. C57B1/6 mice seemed to be more susceptible to this suppression. Anti-hepatitis B surface antibodies (total-Ig) were only marginally suppressed after UVB exposure. IgG2a and interferon-gamma levels, both indicators for Th1 immune response, were suppressed in both mouse strains after UVB exposure. In summary, UVB exposure induced a dose-dependent suppression of both cellular and humoral immune responses after hepatitis B vaccination, although the suppressive effects on humoral immunity were limited to IgG2a production. Susceptibility to UVB-induced immunomodulation depended on the strain of mice and their predilection for developing different T cell responses.
Assuntos
Vacinas contra Hepatite B/farmacologia , Vacinas contra Hepatite B/efeitos da radiação , Raios Ultravioleta , Animais , Anticorpos Antivirais/sangue , Formação de Anticorpos/efeitos da radiação , Hipersensibilidade Tardia , Imunoglobulina G/sangue , Ativação Linfocitária/efeitos da radiação , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Especificidade da EspécieRESUMO
Urocanic acid (UCA) is a major UV-absorbing chromophore in the epidermis and has been suggested to act as one of the initiators of UV-induced immunosuppression. cis-UCA, the isomer from UCA that is formed upon UV exposure, has been shown to impair some cellular immune responses. cis-UCA levels were determined in a study in which the influence of ultraviolet B (UVB) exposure on immune responses after hepatitis B vaccination in human volunteers was established. A significant increase in cis-UCA levels was found in the skin of UVB-exposed volunteers compared with controls. cis-UCA levels, calculated as the percentage of the total UCA amount, in UVB-exposed volunteers correlated significantly with the cumulative UVB dose received in 5 consecutive days, i.e. the higher the UVB dose (J/m2), the higher the cis-UCA levels (until a cis-UCA plateau was reached in the so-called photostationary state). Correlations between skin cis-UCA levels and immune responses were determined, and they revealed no statistically significant correlations among lymphocyte proliferation responses after either mitogenic stimulation or stimulation with recall antigens. No correlation was found between cis-UCA levels and hepatitis B-specific antibody titers. However, we found a statistically significant negative correlation between cis-UCA levels and hepatitis B-specific lymphocyte proliferation responses when volunteers were irradiated with UVB before hepatitis B vaccination. In other words, volunteers with high cis-UCA levels caused by UVB exposure showed lower cellular immune responses against hepatitis B antigen after hepatitis B vaccination.
Assuntos
Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Adulto , Estudos de Casos e Controles , Vacinas contra Hepatite B/administração & dosagem , Humanos , Tolerância Imunológica/efeitos da radiação , Imunidade Celular/efeitos da radiação , Fotobiologia , Pele/imunologia , Pele/metabolismo , Ácido Urocânico/metabolismo , Vacinas Sintéticas/administração & dosagemRESUMO
A new oral contraceptive has been developed that contains a unique progestogen, drospirenone (DRSP), and that has both antiandrogenic and antimineralocorticoid activity. Our objective was to compare the effect of 30 microg ethinyl estradiol (EE)/3 mg DRSP (EE/DRSP; Yasmin, Schering AG, Berlin, Germany) with that of 35 microg EE/2 mg cyproterone acetate (EE/CPA; Diane-35, Schering AG, Berlin, Germany) on mild-to-moderate cases of acne. Diane-35 is used worldwide (it is not on the market in the United States and Japan) as a hormone treatment for acne, with additional contraceptive benefits. This multicenter, double-blind, randomized study was completed over 9 treatment cycles. A total of 128 women with mild-to-moderate facial acne, with or without seborrhea and/or hirsutism, were randomized. Treatment with either EE/DRSP or EE/CPA was assigned in a 2:1 ratio. Acne lesions, sebum production, and hair growth on the upper lip, chin, and chest were assessed, as well as levels of total and free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG), and luteinizing hormone (LH). At study completion, dermatologists, gynecologists, and subjects gave their overall assessment of the effect of treatment on acne. After 9 treatment cycles, the median total acne lesion count was reduced markedly by 62.5% in the EE/DRSP group and 58.8% in the EE/CPA group. A comparison of the 2 groups revealed that EE/DRSP was at least as effective as EE/CPA. Both preparations also reduced sebum production and hair growth on the upper lip and chin. A 3-fold increase in the levels of SHBG was observed in both treatment groups, and levels of androgens and LH decreased. Treatment differences were not seen. Subjective evaluation of the effect of treatment on facial acne by dermatologists, gynecologists, and the subjects themselves indicated an excellent or good improvement for most subjects in both groups. EE/DRSP has been shown to be as effective for treating mild-to-moderate acne as a preparation containing EE/CPA. This new preparation may provide useful hormone therapy for women with androgen-dependent disorders who also require contraception.
Assuntos
Acne Vulgar/tratamento farmacológico , Androstenos/administração & dosagem , Anticoncepcionais Orais Combinados/uso terapêutico , Ciproterona/administração & dosagem , Dermatite Seborreica/tratamento farmacológico , Dermatoses Faciais/tratamento farmacológico , Acne Vulgar/patologia , Adolescente , Adulto , Antagonistas de Androgênios/administração & dosagem , Dermatite Seborreica/patologia , Método Duplo-Cego , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Etinilestradiol/administração & dosagem , Dermatoses Faciais/patologia , Feminino , Alemanha , Humanos , Países Baixos , Congêneres da Progesterona/administração & dosagem , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Pimozide is widely used in psychiatry for chronic psychoses, schizophrenia, the syndrome of Gilles de la Tourette and to a certain extent, also in dermatology. The only dermatological indication is for delusions of parasitosis. Though there is a good rationale for using pimozide in this disease, the majority of the studies on pimozide in dermatology are uncontrolled trials and case reports.
Assuntos
Antipsicóticos/farmacologia , Pimozida/farmacologia , Antipsicóticos/efeitos adversos , Antipsicóticos/química , Antipsicóticos/uso terapêutico , Interações Medicamentosas , Pimozida/efeitos adversos , Pimozida/química , Pimozida/uso terapêuticoRESUMO
BACKGROUND: Treatment of early-stage mycosis fungoides (MF) consists of topical steroids, phototherapy (UVB), photochemotherapy (psoralen plus UVA [PUVA]), topical nitrogen mustard, or total skin electron-beam irradiation. It has been reported that the same effective UVB dose is safer than PUVA regarding carcinogenicity and produces fewer side effects. Narrowband UVB (311 nm) results in less irritation and erythema and is more effective compared with broadband UVB. OBJECTIVE: Our purpose in this retrospective study was to analyze the response to treatment, relapse-free interval, and irradiation dose in 56 patients with early-stage MF (stage Ia and Ib). A total of 21 patients were treated with narrowband UVB (311 nm); 35 patients were treated with PUVA. RESULTS: Narrowband UVB treatment led to complete remission in 17 of 21 patients (81%), partial remission in 4 of 21 (19%), and none showed progressive disease. PUVA treatment led to complete remission in 25 of 35 patients (71%), partial remission in 10 of 35 (29%), and none showed progressive disease. The mean relapse-free interval for patients treated with UVB was 24.5 months (range, 2-66 months) and for patients treated with PUVA, 22.8 months (range, 1-43 months). CONCLUSION: Narrowband UVB therapy for patients with early-stage MF is an effective treatment modality. It has several advantages over treatment with broadband UVB and PUVA. When treating patients with early-stage MF it may be beneficial to start with narrowband UVB therapy and, if there is progression or no response, switch to PUVA therapy.