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The article reports that Cyclosporin A (CyA) has been shown to suppress both humoral and cell-mediated immunity by affecting the early steps of T-cell activation.Recent studies have also shown a marked beneficial effect in the treatment of patients with psoriasis. Fish oil may have a limited beneficial effect on psoriasis. Thirteen patients with psoriasis (CyA group) received cyclosporin A alone and seven patients (CyA/EPA + DHA group) received a combination of cyclosporin A and fish oil (6 g EPA + DHA daily) for 3 months. The study suggests that fish oil can modify CyA-associated renal dysfunction in psoriasis patients.

Two girls, sisters aged 4.5 years and 6 months, had experienced serious erythrodermia since birth, with scarcely any hair growth and they exhibited poor growth despite a hypoallergenic diet. On the basis of the dermatological condition ichthyosis linearis circumflexa and microscopic examination of a hair shaft in which trichorrhexis invaginata (bamboo hair) was observed, the diagnosis of Netherton's syndrome was established. In this autosomal recessive hereditary condition there is a defective production or maintenance of the stratum corneum. Apart from the skin and the hair abnormalities there is often an atopic constitution as well. The treatment consists of skin ointments and a high-energy diet due to the loss of protein via the skin.

Recruitment of activated T-cells to the skin is a common feature in a wide variety of inflammatory skin diseases. As CXCR3 activating chemokines CXCL10 (IP-10), CXCL9 (Mig), and CXCL11 (IP-9/I-TAC) specifically attract activated T-cells, this study addressed the question of whether differences in the expression of these chemokines correlate with the site and cellular composition of the skin infiltrates in different types of inflammatory skin disease. Skin biopsies from lichen planus, chronic discoid lupus erythematosus, allergic patch test reactions, psoriasis, and Jessner's lymphocytic infiltration of the skin were investigated for chemokine expression using RNA in situ hybridization, and for the expression of CXCR3 using immunohistochemistry. The results showed differential expression of CXCL10, CXCL9, and CXCL11, which correlated with differences in the localization and cellular composition of the infiltrates. Whereas CXCL10 and CXCL11 were mainly expressed by basal keratinoctyes, CXCL9 mRNA expression was located predominantly in the dermal infiltrates. Correlation with immunohistochemical data suggested that macrophages and activated keratinocytes were the main producers of these chemokines. CXCR3 was expressed by a majority of both CD4+ and CD8+ infiltrating T-cells, suggesting a functional interaction between locally produced chemokines and CXCR3-expressing T-cells. In conclusion, these findings indicate that these CXCR3 activating chemokines play a significant role in the recruitment and maintenance of T-cell infiltrates in the inflammatory skin diseases studied., (Copyright 2001 John Wiley & Sons, Ltd.)

Background: The effectiveness of systemic treatment of psoriasis with fumaric acid esters has been proven, but their mode of action at the cellular and molecular level has not yet been fully elucidated., Objectives: To study the effect of dimethylfumarate (DMF) on the production of the chemokines CXCL1, CXCL8, CXCL9, CXCL10 and CXCL11, formerly known as GROalpha, interleukin-8, Mig, IP-10 and IP-9/I-TAC, respectively, in human keratinocytes and peripheral blood mononuclear cells (PBMC)., Methods: Cultured keratinocytes were stimulated with interferon (IFN) -gamma to produce CXCL9, CXCL10 and CXCL11 and with phorbol myristate acetate to produce CXCL1 and CXCL8 in the absence and presence of DMF (5, 15 and 45 micromol L(-1)). PBMC were stimulated with either IFN-gamma to produce CXCL9 and CXCL10 or lipopolysaccharide to produce CXCL8, in the absence and presence of DMF (5, 15 and 45 micromol L(-1)). RNA preparations from isolated keratinocytes were analysed by Northern blotting; protein production by keratinocytes and PBMC was monitored by an enzyme-linked immunosorbent assay., Results: Northern blot analysis on isolated keratinocyte RNA preparations showed a dose-dependent inhibition of CXCL1, CXCL8, CXCL9, CXCL10 and CXCL11 transcription by DMF. At 45 micromol L(-1) the inhibition was almost complete. In addition, keratinocytes and PBMC showed in the presence of DMF a dose-dependent inhibition of CXCL8, CXCL9 and CXCL10 protein production., Conclusions: These results show the ability of DMF to inhibit the production of chemokines that may be critically involved in the development and perpetuation of psoriatic lesions. This might explain, at least in part, the beneficial effects of treatment with fumaric acid esters in psoriasis patients.

In two young patients with an elevated temperature, a girl aged 6 months and a boy aged 10 months, purpura and oedema were noticed on the face, ears, arms and legs. On one occasion the boy lost blood anally. A histopathological examination revealed leucocytoclastic vasculitis with fibrin deposits. The diagnosis was 'acute haemorrhagic oedema of infancy' (AHOI), a relatively unknown variant of palpable purpura due to leucocytoclastic vasculitis affecting infants and young children (up to two years of age). AHOI is characterised clinically by marked oedema and fever as well as large palpable purpuric and ecchymotic skin lesions in a target-like pattern mainly on the face, ears and extremities. The skin lesions heal spontaneously within one to three weeks and internal organs are rarely affected. This is in contrast to Henoch-Schönlein purpura, which was observed in a 5-year old boy suffering from similar skin lesions on the legs as well as painful joints, in whom IgA deposits were found in the vasculitis. Henoch-Schönlein purpura is clinically characterised by palpable purpura on the extensor surfaces of the legs and on the buttocks, whereas in AHOI larger purpura and ecchymoses are found on the face, ankles and wrists, with far more extensive oedema. There are also histological differences: in AHOI there is more extensive vasculitis with fibrin deposits and IgA deposits are seen in a minority of cases. Awareness of this relatively unknown form of leucocytoclastic vasculitis will assist in making an early diagnosis possible, thereby avoiding unnecessary treatment and concern.

A patient is described who initially presented with pemphigus vulgaris, limited to the oral cavity, and weight loss. Although the various laboratory studies pointed to the diagnosis of paraneoplastic pemphigus (PNP), the underlying neoplasm was not detected until 6 months later, when the patient developed shortness of breath and routine physical examination on admission revealed an abdominal mass, which eventually was proven to be an epithelioid leiomyosarcoma. In spite of radical excision of the tumour and intensive treatment of the dyspnoea, the patient died of respiratory failure 19 months after the PNP had been diagnosed. Early diagnosis of PNP is stressed to possibly prevent fatal pulmonary involvement.

Differentiation between allergic and irritant contact dermatitis reactions is difficult, as both inflammatory diseases are clinically, histologically, and immunohistologically very similar. Previous studies in mice revealed that the chemokine IP-10 is exclusively expressed in allergic contact dermatitis reactions. In the present study, we investigated whether the mRNA expression of IP-10 and the related CXCR3 activating chemokines, Mig and IP-9 are also differentially expressed in human allergic contact dermatitis and irritant contact dermatitis reactions. Skin biopsies from allergic (13 cases) and sodium lauryl sulfate-induced irritant patch test reactions (13 cases), obtained 1-72 h after patch testing, were studied by means of an in situ hybridization technique. Results of chemokine mRNA expression were correlated with clinical scoring, histology, and immunohistochemical data including the proportion of inflammatory cells expressing CXCR3, the receptor for IP-10, Mig, and IP-9, and ICAM-1 and HLA-DR expression on keratinocytes. IP-10, Mig, and IP-9 mRNA were detected in seven of nine allergic contact dermatitis reactions after 24-72 h, but not in sodium lauryl sulfate-induced irritant contact dermatitis reactions. ICAM-1 expression by keratinocytes was only found in allergic contact dermatitis reactions and correlated with chemokine expression. Moreover, up to 50% of the infiltrating cells in allergic contact dermatitis expressed CXCR3, in contrast to only 20% in irritant contact dermatitis reactions. In conclusion, we have demonstrated differences in chemokine expression between allergic contact dermatitis and irritant contact dermatitis reactions, which might reflect different regulatory mechanisms operating in these diseases and may be an important clue for differentiation between allergic contact dermatitis and irritant contact dermatitis reactions.

IFN-gamma-inducible protein-10 (IP-10) is a chemokine, which plays an important role in mediating inflammation by attracting activated T cells, and it has been demonstrated in inflammatory skin diseases and cutaneous T cell lymphomas. Keratinocytes can abundantly produce IP-10 mRNA after IFN-gamma treatment. In this study we explored possibilities to downregulate IP-10 expression using human cultured keratinocytes as a model system. Decreased IP-10 mRNA levels were found using specific inhibitors of protein kinase (PK)-C (H-7 and Calphostin C). Moreover, depletion of PK-C by pretreatment of the cells with phorbol myristate (PMA) also down-regulated IP-10 mRNA expression. In addition, elevated cAMP levels were shown to inhibit IP-10 mRNA expression as could be concluded from experiments with forskolin and W-7, substances which, directly or indirectly, raise the intracellular cAMP level. With Genistein, an inhibitor of tyrosine kinase, the IFN-gamma-induced IP-10 mRNA expression was also found to be diminished. These data suggest that inhibitors of the IP-10 mRNA expression in cultured keratinocytes may be potentially of clinical relevance to suppress inflammatory processes in the skin., (Copyright 1999 Academic Press.)

Pentoxifylline (PTX), a methyl xanthine derivative with phosphodiesterase inhibitory activity, has been shown to have antiinflammatory effects. Previous studies have demonstrated that PTX can suppress TNF alpha production and function, and can inhibit the adhesion of neutrophils and monocytes to endothelial cells. In the present study, we sought to determine whether PTX also interferes with the adhesion of human peripheral blood T lymphocytes to cells of the human dermal endothelial cell line HMEC-1. Using a cell adhesion immunoassay, the effect of different doses of PTX (10(-5)-10(-2) M) on the binding of unactivated or PMA-activated T cells to unstimulated or TNF alpha-stimulated endothelial cells was investigated. In addition, blocking experiments with monoclonal antibodies against pairs of adhesion molecules known to be involved in endothelial cell/T-cell adhesion were performed. Unactivated T cells showed minimal adhesion to unstimulated endothelial cells. PMA-activated T cells showed an eightfold increased binding to TNF alpha-stimulated endothelial cells, which was found to be mediated largely by LFA-1/ICAM-1. PTX inhibited the binding of PMA-activated T cells to TNF alpha-stimulated endothelial cells in a dose-dependent manner. This inhibition was only found when PTX was present during the adhesion assay. A similar inhibition was found when PTX was replaced by isobutylmethylxanthine, another methyl xanthine derivative, or by a combination of two cAMP analogues. The results suggest that interference with T-cell/endothelial cell adhesion, which forms an essential step in the migration of T cells from the peripheral blood into sites of inflammation, may be another explanation for the beneficial effect of PTX in several inflammatory dermatoses.

In many inflammatory dermatoses leukocyte function-associated antigen-1/intercellular adhesion molecule-1 mediated T-cell/keratinocyte adhesion is considered to play an important role. Pentoxifylline (PTX), a methylxanthine derivative widely used for the symptomatic treatment of various vascular disorders, was recently found to have anti-inflammatory effects. PTX can suppress tumor necrosis factor-alpha production and function, and inhibits leukocyte-endothelial cell adherence. The aim of the present study was to investigate whether PTX also interferes with T-cell/keratinocyte binding. Peripheral blood T cells were activated with phorbol myristate acetate and co-incubated with interferon-gamma- or tumor necrosis factor-alpha-stimulated keratinocytes (SVK 14 cells) in the presence or absence of PTX. Using an enzyme-linked immuno cell adhesion assay PTX was found to inhibit T-cell/keratinocyte adhesion in a dose-dependent manner. A similar inhibition was found when PTX was replaced by isobutylmethylxanthine, another methylxanthine derivative, or by a combination of two cyclic adenosine monophosphate analogues. No major effect on T-cell/keratinocyte adherence was observed when PTX was present during the pre-incubation of keratinocyte monolayers with tumor necrosis factor-alpha or interferon-gamma prior to the adhesion assay. In keratinocyte monolayers the interferon-gamma or tumor necrosis factor-alpha induced intercellular adhesion molecule-1 expression could not be inhibited by PTX. However, when PTX was added to short-term organ cultures of normal human skin biopsies, the lipopolysaccharide- and tumor necrosis factor-alpha-induced keratinocyte intercellular adhesion molecule-1 expression was blocked completely. The interferon-gamma-induced ICAM-1 expression was not blocked by PTX. The results presented herein suggest that impaired T-cell/keratinocyte binding may be one of the mechanisms by which PTX exerts a beneficial effect in certain inflammatory dermatoses.

Background: Pemphigus vegetans, a rare form of pemphigus vulgaris, consists of vegetating plaques localized to flexural areas. Two types, the Neumann and the Hallopeau type, are recognized with their own characteristics., Methods: Three patients with pemphigus vegetans were examined, two with Hallopeau type and one with Neumann type. The microscopic and immunofluorescence findings were recorded., Results: Two remarkable features were present. In one case pemphigus vegetans was possibly induced by the use of enalapril. Only in three previous cases has enalapril been described in relation to pemphigus. A second case was associated with a malignant lung tumor, a phenomenon which could not be traced in the literature., Conclusions: Two types of pemphigus vegetans must be distinguished. Induction of pemphigus (also vegetans) is an accepted side effect of captopril. The effect of enalapril on pemphigus is still in debate. To the best of our knowledge, this is the first time that a patient with pemphigus vegetans and a simultaneously occurring internal malignancy is described.

HuGRO, IL-8 and gamma-IP-10 belong to a recently described superfamily of genes encoding a group of cytokines with inflammatory, growth regulating and/or leukocyte chemotactic properties (chemokines). We studied huGRO, IL-8 and gamma-IP-10 gene expression in unstimulated and stimulated (TNF alpha, INF gamma, TNF alpha + IFN gamma, IL-1 beta, PMA and LPS) normal human keratinocytes by Northern blot analysis. The mRNA for none of the three chemokines was detectable in unstimulated keratinocytes, but considerably elevated levels of huGRO and IL-8 mRNA, but not of gamma-IP-10 mRNA, were found in the presence of cycloheximide, indicating that huGRO and IL-8 mRNA, but not gamma-IP-10 mRNA, are constitutively produced. gamma-IP-10 mRNA was exclusively induced by IFN gamma, with a strong and transient rise between 8 and 18 h, and superinduced by the combination of IFN gamma and TNF alpha, indicating marked synergism. Both huGRO and IL-8 mRNA were induced by TNF alpha and PMA (a strong and transient rise between 2 and 8 h), but not by IFN gamma or LPS. The combination of TNF alpha and IFN gamma did not show a synergistic effect. In addition, IL-1 beta transiently upregulated huGRO mRNA but failed to induce IL-8 mRNA. Using specific oligonucleotides for alpha, beta and gamma huGRO, TNF alpha was found to induce all three forms, alpha and beta to an equal extent and gamma to a lesser extent.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcitriol has recently been shown to be effective against psoriasis. However, its mode of action is not exactly known. The present study focused on the influence of calcitriol on growth, differentiation, chemokine mRNA and ICAM-1 mRNA expression of keratinocytes (KC) and on the binding of T-cells to keratinocytes. In vitro studies showed that calcitriol has a strong anti-proliferative effect and induces terminal differentiation. gamma-IP-10 and ICAM-1 mRNA were induced by gamma-IFN, an induction not influenced by calcitriol. Moreover, the functional expression of ICAM-1 on the KC cell surface as measured by a cell adhesion assay, was not influenced either. IL-8 and huGRO mRNAs were constitutively produced in KC, as was demonstrated after incubation with cycloheximide. Up-regulation of both IL-8 and huGRO mRNA by IL-1 alpha was also not affected by calcitriol. It is concluded that calcitriol has a strong antiproliferative activity and does not interfere with KC responsiveness to gamma-IFN and IL-alpha induced chemokine expression or with the adhesion of T-cells to keratinocytes.

Eight patients with psoriasis received low-dose cyclosporin (CyA) treatment for an average period of 12 months (range 4-16 months). There was great variability in minimal effective CyA dose. In 50% of the patients long-term treatment was limited by dose reductions necessitated by side-effects. A considerable impairment of renal function during CyA therapy was found. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured with 125I-iothalamate and 131I-hippuran, respectively. Both at the end of the active treatment period (GFR-CyA and ERPF-CyA), and 4 months after withdrawal of CyA (GFR-4mo and ERPF-4mo), there was sustained renal impairment: GFR-BL = 97 (64-117), GFR-CyA reduction 17.8% (2.2-31.9%) [P < 0.02], GFR-4mo reduction = 9.8% (5.5-21.5%) ml/min/1.73 m2 (P < 0.05 vs. BL); ERPF-BL = 401 (232-607), ERPF-CyA reduction = 10.1% (7.4-27.3%) [P < 0.05], ERPF-4mo reduction = 13.5% (3.0-32.9%) ml/min/1.73 m2 (P < 0.02). Further studies of the effects on renal function during, and after, long-term therapy of psoriasis with low-dose CyA are warranted.