Kinetics of epidermal Langerhans cells.

Langerhans cells are considered to play an important role in the initiation of the immune response. This study was performed in order to analyze the kinetics of the Langerhans cell population under different experimental conditions. Using tritiated thymidine, the number of labeled Langerhans cells (demonstrated by the Leucinaminopeptidase reaction), and of labeled basal keratinocytes was investigated by autoradiography in guinea pig skin in vivo, before and 2, 5 and 8 days after stripping and before and 2, 5 and 8 days after initiation of repeated topical exposures to a 0.25% solution of dinitrochlorobenzene (DNCB). In addition the total number of Langerhans cells per mm2 was determined before and after DNCB treatment of epidermal guinea pig sheet preparations using the ATPase reaction. A total of more than 100,000 cell as of basal keratinocytes was stimulated significantly (by statistical analysis), both by stripping and by application of DNCB. After stripping, however, the increase of the Langerhans cell turnover was found to be secondary to the turnover of basal keratinocytes, whereas after DNCB application the increase in the proliferative activity of Langerhans cells appeared as the primary event in epidermal cellular kinetics.

Failure to detect gliadin or gliadin binding sites in the skin of patients with dermatitis herpetiformis: immunofluorescence, organ culture and autoradiographic studies.

Recent investigations indicate an abnormal binding of gluten or gliadin to lymphocytes or intestinal mucosa cells in gluten sensitive enteropathy. Since dermatitis herpetiformis is closely associated to gluten sensitive enteropathy, similar receptors could also exist in the skin of patients with dermatitis herpetiformis. To prove this hypothesis, skin of normal volunteers and uninvolved skin of 3 patients with dermatitis herpetiformis was investigated for the presence of gliadin and gliadin binding sites. In vivo bound gliadin was not found by direct immunofluorescence using 3 different rabbit antigliadin antisera. In order to test skin for gliadin binding sites, normal sera and autologous dermatitis herpetiformis sera containing 25 mg% gliadin and tritium labeled gliadin, respectively, were used for incubation of normal and dermatitis herpetiformis skin cryocut sections and of normal and dermatitis herpetiformis skin specimens, grown under organ culture conditions. As checked by direct immunofluorescence and autoradiography, there was no specific in vitro binding of gliadin, indicating that gliadin does not fix to normal human or dermatitis herpetiformis skin. Thus, the role of gliadin in the fixation in vivo, of antibodies or immune complexes to skin in dermatitis herpetiformis, remains obscure.

Effect of PUVA treatment on the locomotion of polymorphonuclear leukocytes and mononuclear cells in psoriasis.

Polymorphonuclear leukocyte (PMN) and mononuclear cell (MNC) locomotion was investigated in patients with psoriasis vulgaris before and after treatment with oral photochemotherapy (PUVA) and was found to be significantly increased (PMN: p < 0.001; MNC: p < 0.002) when compared to healthy controls. No significant difference was observed in the locomotion of PMN or MNC before and after PUVA treatment. These results indicate that PMN and MNC locomotion is increased in psoriasis vulgaris and remains unaltered by PUVA treatment.

Bullous pemphigoid, herpes gestationis and linear dermatitis herpetiformis: circulating anti-basement membrane zone antibodies; in vitro studies.

It is well established that suprabasal acantholysis can be produced in tissue culture of normal human skin in the presence of pemphigus IgG autoantibody. In this study, bullous pemphigoid, herpes gestationis and linear dermatitis herpetiformis anti-basement membrane zone antibodies failed to produce dermoepidermal separation in a tissue culture model in spite of the presence of complement. The binding of the antibodies was demonstrated by immunofluorescence and immunoelectron microscopy; ultrastructurally, identical binding sites of anti-basement membrane zone antibodies could be demonstrated in vitro, as has been observed in vivo previously. Tissue culture is a suitable model for studying the binding sites of circulating anti-basement membrane zone antibodies but the functional activity (blister format;on) of these antibodies cannot be assessed thereby.

Mouse model for protoporphyria. II. Cellular and subcellular events in the photosensitivity flare of the skin.

Acute phototoxic reactions were induced by long-wave ultraviolet light (UV-A) in mice with griseofulvin-induced protoporphyria. The clinical response was characterized by erythema, pronounced edema, and purpura. Tracer experiments and electron microscopy revealed pronounced vascular damage and leakage of vascular contents, whereas the epidermis and all other dermal components were intact. There was selective destruction of endothelial cells and damage of the basal lamina of the vessels. This striking vascular injury was absent from nonprotoporphyric UV-A-irradiated mice and from protoporphyric and nonprotoporphyric mice exposed to short-wave ultraviolet light (UV-B). Patients with erythropoietic protoporphyria (EPP) exhibit an identical, selective damage of blood vessels when irradiated with UV-A or sunlight but not with UV-B alone. It is hypothesized that in both murine protoporphyria and EPP, endothelial cells are photosensitized by protoporphyrin circulating in the serum and that photosensitized endothelia represent the primary cellular target of the photochemical reaction induced by UV-A.

Laboratory evidence for impaired cellular immunity in different stages of syphilis.

Abundant evidence suggests that Treponema pallidum (T.p.) escapes humoral immune defence despite the host produces antibodies early in the infection. Since the serologic responses in syphilis have been studied in detail this paper focuses on the cellular immune mechanisms. For this purpose the leukocyte migration inhibition was investigated in 17 patients in different stages of syphilis. Leukocyte migration inhibition assay was performed before, and 7 days, 3 weeks, 2 mo. and 1 yr after start of treatment. Ultrasonicated T.p. were used as antigen corresponding to 5 X 10(6) to 2 X 10(7) Treponema pallida per ml. Controls without antigen, with addition of Concanavalin. A instead of T.p. and using cells of normal volunteers were run. There was no leukocyte migration inhibition before treatment, suggesting nonexistent or depressed cellular immunity in the untreated syphilitic patient. Significant leukocyte migration inhibition, however, was observed as early as 2 days after start of treatment, being most pronounced after 1 week. Hypothetical circulating blocking factors for cellular immune reactions might be present in the untreated syphilitic patient, which become abolished after therapy. Since stimulation with Con A of syphilitic leukocytes gave normal results even before treatment in the syphilitic patient, there might be a specific block of leukocyte migration inhibition against T.p.

Inhibition of the induction of contact hypersensitivity by a UV-mediated epidermal cytokine.

UVB exposure (290-320 nm) of mice has been shown to cause systemic suppression of contact hypersensitivity (CHS). Because UVB radiation hardly penetrates the epidermis, epidermal cells have been anticipated to be the site of the initiation of immunosuppression. Supernatants derived from UV-irradiated BALB/c epidermal cell cultures and a keratinocyte cell line (Pam 212) were evaluated for the ability to induce suppression of CHS after i.v. injection to BALB/c mice. Injection of supernatants derived from UV-treated epidermal cells and Pam 212 cells significantly blocked induction but not elicitation of CHS. In contrast, i.v. application of supernatants derived from unirradiated cells did not inhibit CHS. Using high-performance liquid chromatography gel filtration this mediator was shown to be a low-molecular-weight protein (15-50 kD). Moreover UV-mediated inhibitor production seems to be confined to epidermal cells since neither P 388 macrophages nor L 929 fibroblasts released this inhibitory cytokine. Therefore UV radiation may induce epidermal cells to produce an inhibitor of CHS which is distinct from prostaglandins and leukotrienes and may participate in the regulation of UV-mediated local as well as systemic immunosuppression.

Mouse model for protoporphyria. III. Experimental production of chronic erythropoietic protoporphyria-like skin lesions.

Albino mice were made protoporphyric with griseofulvin according to an established procedure. Photosensitivity flares were elicited once a week throughout a 10-month period, using black light as a source for 410 nm radiation and the flares were monitored by the intravenous injection of vascular tracers and by light and electron microscopy. Each irradiation led to a selective destruction of the endothelial cells of superficial capillaries which was followed by massive vascular leakage. The basal lamina remained largely intact, providing the scaffold for regenerating endothelial cells which deposited new basal lamina material at their periphery. Subsequent exposures to 410 nm radiation reproduced the endothelial damage and subsequent basal lamina formation; multiple irradiations thus resulted in excessive, concentric, tubelike basal lamina deposits around dermal vessels which light microscopically appeared as PAS-positive hyaline material and clinically gave the skin a thickened, waxy appearance. This model thus reproduced the skin of erythropoietic protoporphyria clinically, microscopically, and at the ultrastructural level.

Mouse model for protoporphyria. I. The liver and hepatic protoporphyrin crystals.

Outbred albino mice were rendered protoporphyric by a diet containing 2.5% (weight) of griseofulvin. There was a 5-fold increase in liver weight, hepatocellular degeneration and necrosis, cholestasis, ductular proliferation and cirrhosis. Liver protoporphyrin values were elevated and brown pigment granules were present in hepatocytes, Kupffer cells, and bile ducts. The granules showed red fluorescence, birefringence, and, at the ultrastructural level, consisted of aggregates of needle-like crystals. Crystals isolated from such livers showed solubility and absorption characteristics of protoporphyrin; in vitro recrystallization of protoporphyrin, extracted from protoporphyric mouse livers, yielded crystals identical with those observed in vivo, and commercial protoporphyrin exhibited similar morphologic features. The liver pathology and protoporphyrin crystals observed in these animals are identical to the liver pathology and crystals observed in the human disease, erythropoietic protoporphyria. In this mouse model, protoporphyrin crystals are intimately associated with hepatocellular injury and it appears that their accumulation within hepatocytes leads to hepatocellular destruction. A similar pathogenesis is postulated for the hepatic damage that occurs in some cases of erythropoietic protoporphyria.

Detection of a specific inhibitor of interleukin 1 in sera of UVB-treated mice.

It was recently demonstrated that murine keratinocytes upon irradiation with ultraviolet (UV) light release an immunosuppressive cytokine which blocks the biological activity of interleukin 1 (IL 1). This epidermal cell derived inhibitor (EC-contra IL 1) exhibits a molecular weight of 40 kD and a pI of approximately 9.0. EC-contra IL 1 in vivo possibly may penetrate through the basal lamina and subsequently cause systemic immunosuppression following UV-exposure. In the present study, we tested whether EC-contra IL 1 can also be detected in vivo. Serum samples obtained from total body UV-exposed mice were subjected to HPLC gel filtration and tested for IL 1 inhibitory activity. While a non-specific high molecular weight (300 kD) suppressor factor was detected in sera of both UV-exposed and sham treated control mice, a specific IL 1 inhibitor exhibiting a molecular weight of 40 kD was observed only in sera of UV-exposed mice. This cytokine named serum-contra IL 1 was maximally released 24 h after UV-exposure, exhibited a pI of 9.0, and blocked the activity of natural as well as recombinant interleukin 1 in a dose dependent manner. Serum-contra IL 1 did not suppress interleukin 2 or interleukin 3 and did not inhibit spontaneous cell proliferation. The present biochemical and biologic data suggest that serum-contra IL 1 and EC-contra IL 1 appear to be closely related if not identical. These observations therefore indicate that keratinocytes upon UV-irradiation in vivo release EC-contra IL 1 which may at least partly be responsible for the immunosuppression following UV-exposure.

PUVA suppresses the proliferative stimulus produced by stripping on hairless mice.

Hairless mice were fed with 8-methoxypsoralen by gastric tube and exposed to UVA light to produce threshold phototoxic reactions. 3H-thymidine autoradiography revealed no significant difference of the epidermal labelling index as compared to that of nonirradiated animals (4.8 vs 6.2). Single PUVA exposures performed 2,8,14 and 24 hr after tape stripping lead to suppression of a wave of synchronized DNA synthesis present in nonirradiated control animals. These data demonstrate different reactions of stripped and unstripped epidermis to PUVA exposures and offer indirect evidence for the suppression of DNA synthesis in hyperproliferative skin disorders by PUVA in vivo.

Anthralin minute entire skin treatment. A new outpatient therapy for psoriasis.

Anthralin minute entire skin treatment (AMEST) was developed to improve the efficacy and cosmetic results of anthralin short-contact therapy. In a split comparison study to determine the optimal period of anthralin application, ten minutes of anthralin contact time gave maximum antipsoriatic activity with minimal side effects. Dosimetry variables for AMEST were determined based on the patient's pigmentation type, the erythematous response, the therapeutic effect, and so on. Such treatment of 43 patients resulted in complete clearing in 31 patients (72%), with 90% improvement in two patients (5%) and less than 90% clearing in seven patients (16%). Psoriatic lesions disappeared, leaving no spotty pigmentation that is known to occur following conventional anthralin therapy. The dosimetry variables employed in our study allowed AMEST with minimal skin irritation. Laboratory values did not change significantly during therapy. In addition, AMEST does not involve systemic medication and is easy to perform without special equipment; therefore, it is economic and can be used for outpatients and probably for home treatment.

Photochemotherapy for psoriasis with orally administered methoxsalen.

Photochemotherapy denotes a therapeutic approach that is based on the interaction of light and a photoactive drug. This study describes the efficacy of photochemotherapy, using orally administered methoxsalen and long-wave ultraviolet light in 91 patients with severe, generalized psoriasis. Oral administration of methoxsalen was followed by exposure to a high-intensity long-wave ultraviolet light source, emitting a continuous spectrum between 320 and 390 nm (peak, 365 nm) and an energy of 5.6 to 7.5 mw/sq cm at 15 cm. There was complete clearing of 82 patients (90%), a 90% to 100% clearing in seven (8%), and a satisfactory improvement in two (2%). A paired comparison study in 54 patients showed photochemotherapy to be far more effective than ultraviolet light emitted by fluorescent bulbs or a xenon source. Eighty-five percent of the patients receiving outpatient maintenance treatment have remained in remission for periods up to 400 days.

Decreased DNA repair activity in sunburn cells. A possible pathogenetic factor of the epidermal sunburn reaction.

The pathogenesis of the formation of sunburn cells is unknown. Based on autoradiographic methods the unscheduled DNA repair synthesis of UV-induced thymin dimers was investigated in vivo in sunburn cells and in irradiated but histologically normal stratum spinosum cells. The results show a significant lower number of sparsly labeled cells in the sunburn cell-population (13.2 +/- 2.5; mean) when compared to the population of normal stratum spinosum cells (57.8 +/- 7.5; mean). These data indicate that the population of those epidermal cells, which become manifest as sunburn cells 24 h after UV exposure exhibit a reduced DNA repair of UV induced thymine dimers immediately after UV irradiation. Nuclear factors thus seem to play at least some role in the origin of sunburn cells.

Photoprotective effect of a psoralen-UVA-induced tan.

To determine whether a tan produced by 8-MOP and UVA protects from subsequent solar light irradiation, volunteers were irradiated with unfiltered Xenon arc light before and 10 days after a 1 week's course of four 8-MOP-UVA treatments. Evaluation of the minimal erythema doses and of histological changes before and after 8-MOP-UVA treatment revealed that the 8-MOP-UVA induced tan protected against the erythemogenic and cell damaging effects of Xenon arc light. Unscheduled repair DNA synthesis, used as a measure for UVB-induced DNA damage and repair, was also investigated in skin irradiated with the Xenon arc before and after 8-MOP-UVA induced tanning. Both the number of grains per sparse labeled cell and the number of sparse labeled cells per 1000 cells, were found to be significantly lower in tanned skin; taking decreased unschedules repair DNA synthesis as a measure for decreased DNA-damage, these findings also demonstrate a photoprotective effect of the 8--MOP-UVA induced tan.

Treatment of polymorphous light eruption.

This study was designed in order to prove on a large-scale basis the efficacy of oral photochemotherapy (PUVA) in the prevention of polymorphous light eruption (PLE), to work out indication criteria for PUVA treatment of this disease, and to establish a simple method based on anamnestic data to differentiate UVA from UVB induced PLE. The results obtained in 106 PLE patients (85 UVA-, 21 UVB-induced) demonstrate that: 1) time consuming phototesting for determination of the disease's action spectrum is unnecessary for practical purposes; 2) PUVA-induced tanning under routine conditions represents a potent prophylaxis even in severe cases of PLE; and 3) topical sunscreens ("sunblockers") in the majority of cases are sufficient to protect UVB-promoted PLE, but fail in UVA-induced disease. PUVA thus seems the treatment of choice only in UVA-mediated PLE, the action spectrum of the disease at least in most cases being easily discovered from certain anamnestic data.

Serum uric acid levels in untreated and PUVA-treated patients with psoriasis.

Elevated uric acid serum levels are a frequent finding in psoriasis and, despite some reports to the contrary, it is generally believed that an association does exist between hyperuricemia and psoriasis. It seems a convincing idea that the rapid epidermal turnover in psoriasis might lead to an increased purine breakdown and may thus influence the uric acid serum levels. Consequently, a relationship might well be expected between hyperuricemia and the extent of psoriatic skin involvement. The present study was undertaken in order to prove or disprove such an assumption and to investigate the influence of oral photochemotherapy on the serum uric acid levels in psoriatic subjects.

[Condylomata acuminata]. / Condylomata acuminata.

Condylomata acuminata are benign epitheliomas which are caused by the human papilloma virus. 8 subgroups (variants) of the virus are known up to now. Condylomata acuminata are infectious, the virus being transferred by direct contact with a lesion. Condylomata acuminata are found more often in males than in females and never occur in children prior to the age of two years. The peak incidence is between 19 and 22 years of age. Greatly proliferating condylomata acuminata (type Buschke-Löwenstein) may lead to malignant degeneration. There exists a broad spectrum of topical therapeutic modalities: cytotoxic substances such as podophyllin (10 to 25%), colchicine (8%), 5-fluorouracil (1 to 5%), cryotherapy (solid carbon dioxyde or liquid nitrogen), surgical treatment (excochleation, electrocautery or laser beam. Vaccination therapy may prove successful in certain cases in the future.

[Serum uric levels in patients with psoriasis vulgaris (author's transl)]. / Harnsäurewerte im Serum von Patienten mit Psoriasis vulgaris.

Hyperuicaemia is a frequent finding in psoriasis vulgaris. Enhanced purine catabolism due to the rapid turnover of psoriatric epidermis is thought to be the cause of the raised serum uric acid levels. In the present study serum acid determinations were performed in 197 patients with psoriasis vulgaris. Since no correlation was found between the extent of skin involvement and the incidence of hyperuricaemia, increased epidermopoesis does not seem to be an adequate explanation for hyperuricaemia in psoriasis. An analysis of body weight and serum cholesterol and triglyceride levels in psoriatic patients points to a combination of genetic predisposition and overeating as the causes of hyperuricaemia.

[Genital chlamydial infections]. / Genitale Chlamydieninfektionen.

Chlamydia trachomatis is today the most frequent cause of sexually transmitted diseases. In spite of their usually mild, sometimes even asymptomatic course, urogenital infections with Chlamydia trachomatis can lead to severe complications (infertility, adnexitis) if not treated properly. Clinical features, complications, diagnosis and therapy are discussed in detail.