[Influence of immunovac-VP-4 therapy on innate immunity effectors in patients with darier erythema annulare centrifugum].

AIM: Detection of features of functioning ofinnate and adaptive immunity pathways in patients with Darier erythema annulare centrifugum (EAC). MATERIALS AND METHODS: 14 EAC patients aged 14 - 52 years were examined. The patients were ranked based on therapy variant. The first group consisted of 6 patients who had received Immunovac-VP-4 (Immunovac) against the background of basic therapy; the second group (4 patients) received cagocel against the background of basic therapy; the third group (4 patients) received only basic therapy; the group of healthy individuals consisted of 15 individuals. All the patients had the level ofcytokines in blood sera determined by solid-phase EIA by using Biosource (Austria) test-systems. Evaluation of TLR expression in peripheral blood mononuclear lymphocytes and keratinocytes was carried out by flow cytometry method by using monoclonal antibodies (Catlag Laboratories, USA) against the corresponding antigens; evaluation of content of lymphocyte subpopulations in blood was carried out by using monoclonal antibodies by flow cytometry method on FacsCalibur flow cytometer (Becton Dickinson, USA). RESULTS: Immunotherapy by Immunovac and cagocel facilitated the increase of CD3+, CD4+, CD8+. Immunovac facilitated a significant increase ofinitially low values ofCD25+, CD95+ and normalization of CD72+; normalization of IgM level. Immunovac increased the level of serum IL-2, induced the increase of IFN-gamma synthesis in contrast to cagocel and basic therapy, the administration of those caused its decrease. TGF-beta increased during the course of Immunovac immunotherapy and decreased during basic therapy. In the course of basic therapy a significant increase of initially high level ofcytokine IL-I beta was observed. CONCLUSION: Immunovac therapy resulted in correction of content of lymphocyte populations, sera cytokines, facilitating the normalization of immunocompetent cell proliferation processes, activation of NK-cells, macrophages and at the same time suppression of DTH reactions. Immunovac facilitated the enhancement ofTLR3, 9 expression in the skin that indicates the inclusion ofintracellular receptor mechanisms of innate immunity.

Platelet and cardiac function in Darier's disease.

ATP2A2, the gene that is abnormal in Darier's disease, encodes SERCA2, a calcium pump that is expressed in many tissues. The wide expression of SERCA2 might suggest that ATP2A2 mutations would cause a multisystem disease. There is however, no evidence of consistent extracutaneous manifestations of Darier's disease. We have conducted preliminary studies in patients with Darier's disease, in two extracutaneous systems in which SERCA2 is known to be important, in order to investigate whether subtle defects have been overlooked. We found no evidence for altered cardiac function in 10 patients using two-dimensional, colour and Doppler echocardiography. There were no consistent defects in platelet function in 12 patients, using bleeding time and aggregation studies. We conclude that the skin is sensitive to defects in SERCA2 function to which other systems appear robust.

Mapping of the Darier's disease gene by serogenetic markers: results in two large British kindreds.

The authors have carried out genetic linkage studies in 57 subjects from two large kindreds of Darier's disease, using a range of serological and biochemical polymorphisms of known chromosomal location. In these kindreds, about 7% of the genome has been excluded for close linkage to the Darier's disease gene. However, one family showed positive lod scores for linkage with the Duffy blood locus (1p13); lod scores were negative in the other family, but in the combined families the total score for this marker was still positive and does not completely exclude linkage.

Abnormal essential fatty acid metabolism in Darier's disease.

Fatty acid levels in plasma and erythrocyte cell membranes were determined in 13 Danish patients with Darier's disease and 21 Danish controls. Concentrations of the main dietary essential fatty acids, linoleic acid (18:2n-6) and alpha-linolenic acid (18:3n-3), were consistently modestly above normal; concentrations of the delta 6-desaturase metabolites of both linoleic and alpha-linolenic acids, however, were consistently and often significantly below normal. These results suggest that the capacity of the enzyme delta 6-desaturase activity is inadequate in patients with Darier's disease.

Patients with dermatitis herpetiformis, acne, psoriasis and Darier's disease have low epidermal zinc concentrations.

Zinc concentration was determined in epidermis, papillary dermis and serum in patients with dermatitis herpetiformis, acne or psoriasis and in two small groups of patients with ichthyosis vulgaris and Darier's disease. Except in ichthyosis vulgaris the zinc level in epidermis was decreased in all these disorders. The mean serum zinc concentration was, however, significantly decreased only in men with dermatitis herpetiformis. There was no correlation between the concentration of zinc in epidermis or dermis and that in serum. The decreased epidermal zinc concentration indicates that many of the patients have a zinc deficiency in spite of a "normal" serum zinc value. Supplementation of zinc might therefore be of value in patients with these disorders.

Vitamin E deficiency in phrynoderma cases from Sri Lanka.

Phrynoderma cases were identified in a village close to Colombo in Sri Lanka. The alpha-tocopherol level in plasma was 3.3 +/- 0.6 mumol/L among the phrynoderma patients (n = 11) and 13.0 +/- 2.3 mumol/L among the control subjects (p less than 0.002). A test on glutathione reductase activity in erythrocytes revealed a stronger riboflavin deficiency among patients than among control subjects (p less than 0.005). No significant differences were found between the groups with regard to plasma levels of retinol, retinol-binding protein, vitamin B-12, folic acid, thiamin, selenium, zinc, or essential fatty acid pattern. Primary malnutrition may partly explain the deficiency of alpha-tocopherol and riboflavin observed in phrynoderma cases.

[Augmentation of the phagocytic activity of monocytes in patients with Darier's disease by the oral administration of retinoic acid]. / Aumento de la actividad fagocigótica de monocitos de pacientes con enfermedad de Darier por administración oral de ácido retinoico.

Other tissue involvement has been described in Darier's disease, eg: susceptibility to infection. In order to know if this susceptibility is due to abnormal phagocytosis and if this can revert by administration of retinoic acid (RA), blood monocyte-derived macrophages, from four individuals with Darier's disease were obtained prior and after administration of RA to determine in them morphological, cytochemical and phagocytic activity changes. It was observed that phagocytosis was diminished and RA administration increased it, without changes in enzyme distribution. This modification of phagocytosis could be due to a reordenation of cytoskeleton.

Etretinate: effect of milk intake on absorption.

Since etretinate, an aromatic retinoid useful in the treatment of psoriasis and other skin disorders is lipid-soluble, it may be poorly absorbed in the absence of a fat load. We therefore studied serum concentrations of etretinate and its major metabolite (Ro 10-1670) after the controlled administration of etretinate. After an overnight fast, 6 Darier's disease and 4 psoriatic patients received a 1 mg/kg morning dose of etretinate with water or 1 pint of whole milk (fat load). There was a 260% increase (p less than 0.0005) in the mean of each patient's increase in the baseline-corrected peak serum concentration of etretinate after administration with milk (115 +/- 15 micrograms/dl) compared to after administration with water (32 +/- 4 micrograms/dl). Over a 24-h period there was an overall 296 +/- 26% (p less than 0.0005) increase in serum etretinate after administration with milk compared to water in 5 patients with Darier's disease. In contrast to the serum etretinate, there was a 17% mean decrease (p less than 0.025) in the corrected peak serum concentration of Ro 10-1670 in all 10 patients after administration of etretinate with milk compared to water. The net result of these alterations is that the mean corrected serum concentration of etretinate is higher than Ro 10-1670 at all time points measured after milk administration. In contrast, after administration of etretinate with water the major retinoid in the serum is Ro 10-1670. Establishing the clinical significance of these alterations may require controlled clinical trials.

High-dose vitamin A therapy for Darier's disease.

Three patients with Darier's disease were treated with 1 X 10(6) IU of orally administered vitamin A daily for 14 days. In all patients, 50% to 80% improvement in the skin lesions was noted. Desquamation was minimal, and side effects consisted of drowsiness, mild frontal headache, dry lips and dry nose. During therapy, all patients had a transient, mild increase in the serum triglyceride level, and two patients had a minimal increase in the serum cholesterol concentration.

Darier's disease and vitamin A. Concentrations of retinoids in serum and epidermis of untreated patients.

Blood samples and skin biopsy specimens from 13 male patients with Darier s disease (DD) and 11 healthy male controls were analyzed for carotene, retinol (vitamin A), dehydroretinol (vitamin A2), and retinol-binding protein (RBP). The serum carotene level was lower in the patients than in the controls, but the vitamin A and RBP levels did not differ from those of the controls regardless of the severity of the disease. The RBP could be visualized by immunofluorescence microscopy in the epidermis of both unaffected and lesional skin of patients with DD. In the epidermis of patients with DD (uninvolved and lesional), the carotene content was similar to that of the controls. The retinol content was probably higher than in the controls. By contrast, the dehydroretinol concentration was normal in the uninvolved skin but markedly higher than normal in the lesions, especially in the severe cases. The abnormal distribution of retinoids in DD may reflect localized disturbances of epidermal vitamin A metabolism rather than a defect in serum vitamin A transport.

The influence of 'Tigason' (Ro 10-9359) on the serum lipoproteins in man.

Eight patients with psoriasis or Darier's disease were studied during 1-3 months of 'Tigason' treatment (0.7-0.8 mg/kg body weight). The levels of triglycerides and cholesterol in whole serum and in different lipoprotein fractions were repeatedly determined. Before treatment all lipid values were within the normal range. During treatment the values changed gradually and five of the eight patients developed pathological VLDL triglyceride concentrations. A significant increase of VLDL cholesterol and a decrease in the HDL cholesterol was also noted. Until more information is available, prolonged treatment periods with 'Tigason' should perhaps be avoided, at least in high risk patients.

[Kyrle's disease (hyperketarosis follicularis et parafollicularis): local and systemic therapy with vitamin A acid (retinoic acid)]. / Morbus Kyrle (Hyperkeratosis follicularis et parafollicularis): lokale und systemische Therapie mit Vitamin-A-Säure (Retinoic Acid)

The cause of Kyrle's disease (hyperkeratosis follicularis et parafollicularis) is unknown. The prognosis is very poor indeed; there is no specific treatment. The normal ranges of serum retinol and carotene were investigated in 10 healthy females. In a female patient suffering from Kyrle's disease, the serum level of retinol was found in the lower part of the normal range. Striking improvement has been noted when the patient was treated systemically with vitamin A acid (retinoic acid) which was associated with elevation of serum levels of retinol and carotene. When this form of therapy was withdrawn, recurrence of the skin lesions was observed and the serum levels of retinol and carotene declined to a level similar to that before the treatment. The administration of vitamin A acid was resumed, and with rising levels of retinol and carotene the skin condition again improved. Several possibilities regarding the treatment of Kyrle's disease as well as the mode of action of vitamin A acid are discussed.

Plasma vitamin A levels in the hyskeratoses.

No significant difference was found between the plasma vitamin A levels of patients with dyskeratoti skin disease and those of comparable control subjects.