The IL-1 system in psoriatic skin: IL-1 antagonist sphere of influence in lesional psoriatic epidermis.

The epidermal expression of IL-1 in psoriasis is clearly altered, but data are still incomplete and poorly understood. To thoroughly study the IL-1 system in psoriasis, we semiquantitatively analyzed the expression of all currently characterized IL-1 isoforms and their receptors in parallel in both lesional (PP) and nonlesional psoriatic (PN) epidermis. Immunostaining of skin sections showed that IL-1alpha, located in the basal keratinocytes of normal control (NN) and PN epidermis, was significantly decreased to negligible levels in PP epidermis. IL-1 receptor antagonist (IL-1ra) and IL-1R type II (IL-1RII) were both significantly overexpressed in mutually exclusive compartments of PP epidermis, the suprabasal and basal compartment, respectively. A significant inverse correlation was found between the expressions of IL-1alpha and these two IL-1 antagonists, which may be inherent to the accelerated terminal differentiation of the psoriatic keratinocyte. In situ hybridization of IL-1(R) mRNAs confirmed the staining results. Levels of IL-1ra mRNA, however, were not increased in PP epidermis, suggesting that the overexpression of IL-1ra protein may be explained at the level of translation. The more sensitive PCR demonstrated a clearly increased expression of IL-1beta mRNA in PP epidermal cells (EC), which may be related to the inflammatory response in psoriasis. IL-1RI mRNA was clearly present in both PP and NN EC. The mRNA levels of the secreted IL-1ra isoform, but not intracellular IL-1raI and II, and IL-1RII were elevated in PP EC and paralleled those of IL-1beta. In summary, this study provides a defined phenotype of the complete epidermal IL-1 system in psoriasis; it shows that the expressions of IL-1(R) isoforms are coordinately altered, resulting in a predominance of IL-1 antagonists, which may represent a negative feedback response to IL-1 agonists, leading to a decreased IL-1 responsiveness.

Allergy to carbamazepine: parallel in vivo and in vitro detection.

PURPOSE: Five to 20% of patients discontinue antiepileptic drug (AED) therapy because of adverse reactions. Careful reintroduction, however, may be considered if true drug allergy can be ruled out. Definitive assessment of such immunologically mediated reactions requires demonstration of either specific antibodies or sensitized lymphocytes. METHODS: We investigated whether skin patch tests (PTs) and in vitro lymphocyte proliferation assays (LPAs) were suitable for detection of allergy to carbamazepine (CBZ) and the possibly cross-reactive oxcarbazepine (OCBZ). Data of 65 patients displaying a wide range of possibly allergic side effects to CBZ were available for analysis. Data of CBZ users without any side effects and healthy volunteers served as controls. Both PTs and LPAs were done with CBZ, OCBZ and three metabolites [CBZ-10,11-epoxide (CBZ-E), 10-monohydroxy-CBZ (MHD), and 10,11-dihydroxy-CBZ (DIOL)]. RESULTS: Positive PTs with CBZ were seen in 20% and with OCBZ in 14% of the patients. Positive LPA results with CBZ and OCBZ, respectively, were found in 40 and 19%. Both tests were positive in 14 and 7% of the patients. Cross-reactivity to OCBZ was seen in -40% of CBZ-reactive patients in both PTs and LPAs. CONCLUSION: These data illustrate the additional value of LPAs in the detection of CBZ allergy while showing that a major part of side effects to CBZ and OCBZ is not immunologically mediated, according to PTs and LPAs.

Exfoliative dermatitis due to immunologically confirmed carbamazepine hypersensitivity.

A 6-year-old Caucasian girl experienced a generalized erythematous skin rash during carbamazepine therapy. Over the next four days the eruption worsened into erythroderma with fever and generalized lymphadenopathy. Routine laboratory studies revealed increased serum levels of liver enzymes and eosinophilia. Immunologic reactivity to the anticonvulsant carbamazepine and its analogs was investigated both in vivo and in vitro by patch tests and lymphocyte proliferation assays, respectively.

Suggestive evidence for bromocriptine-induced pleurisy.

Pleurisy of initially unknown origin was found in a patient who was treated with bromocriptine for Parkinson's disease for 6 years. At presentation, bilateral pleural thickening existed that caused severe restriction of pulmonary function. There were an elevated erythrocyte sedimentation rate, polyclonal hypergammaglobulinaemia, increased levels of acute phase proteins and anaemia. After withdrawal of the bromocriptine the patient's complaints as well as the laboratory parameters markedly improved. Further loss of pulmonary function did not occur. However, the pleural thickening did not resolve, not even upon subsequent corticosteroid treatment, probably due to fibrosis. Together, these findings strongly suggest a causative role of bromocriptine. The results of the laboratory studies suggested an immunopathogenetic mechanism, but in vitro lymphocyte-proliferation studies and skin patch tests with bromocriptine were negative. Bromocriptine should be considered as a cause of pleurisy. The drug must be stopped immediately upon the occurrence of pleural thickening in order to prevent impairment of pulmonary function. In addition, periodic laboratory and X-ray studies in patients on long-term bromocriptine treatment should be considered.

Enhanced production of biologically active interleukin-1 alpha and interleukin-1 beta by psoriatic epidermal cells ex vivo: evidence of increased cytosolic interleukin-1 beta levels and facilitated interleukin-1 release.

The expression of interleukin (IL)-1 is altered in psoriatic lesions. However, little is known about the actual production of IL-1 alpha and IL-1 beta by psoriatic epidermal cells (EC). We monitored IL-1 in the extracellular, the membrane and the intracellular compartment of freshly isolated EC from untreated lesional psoriatic (PP) and normal healthy (NN) skin during non-stimulated short-term cultures, representing a psoriasis model ex vivo. Cytokines were measured using bioassays combined with neutralizing antibodies and enzyme-linked immunosorbent assay in parallel. PP EC released significantly increased amounts of biologically active IL-1 alpha and IL-1 beta in a ratio of 3:1, whereas NN EC only released IL-1 alpha. Also, the release of IL-6, but not of TNF-alpha, by PP EC was significantly increased. Membrane-associated IL-1 activity, analyzed using glutaraldehyde-fixed EC, was low and not unique to PP EC. The cytosol of PP EC contained significantly increased levels of immunoreactive IL-1 beta. Furthermore, PP EC displayed loss of membrane integrity, as determined by trypan blue exclusion and release of cytosolic lactate dehydrogenase. This facilitated release of intracellular IL-1. Depletion of CD45+ cells showed that intraepidermal leukocytes did not contribute to the production of IL-1. Our observations show that resident PP EC express enhanced IL-1 production ex vivo, which is due to an increased cytosolic IL-1 beta content and facilitated IL-1 release. This study provides the first evidence that PP EC can produce bioactive IL-1 beta.

Hyposensitization in nickel allergic contact dermatitis: clinical and immunologic monitoring.

BACKGROUND: In allergic contact dermatitis (ACD) previously sensitized T cells cause skin damage. If an ubiquitous allergen such as nickel is involved, no effective treatment is available. Down-regulation of this allergic response has been described after antigen presentation in the absence of adequate costimulatory signals. UV exposure can enhance such hyposensitization. OBJECTIVE: The aim of this study was to establish the capability of a hyposensitization procedure to induce antigen-specific tolerance. METHODS: Twenty-one patients with nickel ACD were randomly assigned to either a hyposensitized or control group. A schedule consisting of UVB treatment and subcutaneous nickel sulfate administration (hyposensitization) or UVB only (control) was applied. During the ensuing 2 years, several clinical and immunologic features were monitored. RESULTS: During UVB treatment we observed a significant clinical improvement in both groups that persisted in the hyposensitized group. Except for increased slope variances of specific lymphocyte proliferation in time, no clear changes were seen in the immunologic findings. CONCLUSION: Despite significant clinical improvement induced by UVB, hyposensitization did not induce significant changes in the immunologic findings in patients with nickel ACD.