S.A. Büchner

Mu-Opiate Receptor and Beta-Endorphin Expression in Nerve Endings and Keratinocytes in Human Skin

We have previously shown that human epidermal keratinocytes express a functionally active µ-opiate receptor, which adds a new dimension to the recently developed research in neuroimmunodermatology and neurogenic inflammation in skin diseases. Human keratinocytes specifically bind and also produce β-endorphin, the endogenous µ-opiate receptor ligand. Using confocal imaging microscopy, we could now demonstrate that µ-opiate receptors are not only expressed in keratinocytes, but also on unmyelinated peripheral nerve fibers in the dermis and epidermis. Some of the peripheral nerve fibers also express the ligand β-endorphin. The keratinocytes positive for β-endorphin staining are clustered around the terminal ends of the unmyelinated nerve fibers. Therefore the opiate receptor system seems to be crucial in the direct communication between nerves and skin. The keratinocytes can influence the unmyelinated nerve fibers in the epidermis directly via secreting β-endorphin. On the other hand, nerve fibers can also secrete β-endorphin and influence the migration, differentiation and probably also the cytokine production pattern of keratinocytes.

HAARARTIGE HYPERKERATOSEN BEI EINEM NIERENTRANSPLANTIERTEN. EINE NEUE CYCLOSPORIN-NEBENWIRKUNG

ZusammenfassungWir berichten über einen 31jährigen nierentransplantierten Patienten, der unter Cyclosporin A eine ungewöhnliche Talgdrüsenhyperplasie entwickelte, begleitet von einer disseminierten, follikulär gebundenen, spikeartigen Hyperkeratose. Die Hautveränderungen waren besonders ausgeprägt im Gesicht und an den Streckseiten der Extremitäten. Stellenweise imponierte eine haarartige Hyperkeratose mit echter Haarneubildung. Die Histologie dieser Veränderungen zeigte eine stark vermehrte Keratinisation der Haarfollikel mit der Bildung von haarähnlichen „Spikes“, welche teilweise isoliert und in Verbindung mit echten Körperhaaren vorkamen. Aufgrund dieser Eigenschaft lassen sich differentialdiagnostisch die morphologisch sehr ähnliche „Disseminated Spiked Hyperkeratosis“ und andere filiforme Keratosen abgrenzen. Erstmals wird in der vorliegenden Arbeit dieser haarähnliche Aufbau auch mittels rasterelektronenmikroskopischer Aufnahmen dargestellt. Die Talgdrüsenfollikel zeigten eine z.T. zystische Ausweitung, wie sie bereits früher beschrieben worden ist, mit hier ebenfalls stark vermehrter Einlagerung von Keratinmassen. Dieser Fall zeigt, a) daß die beobachteten Hautveränderungen wahrscheinlich der alleinigen Wirkung von Cyclosporin A zuzuordnen und b), daß sie vermutlich dosisabhängig sind.SummaryWe report a 31-year-old renal transplant patient treated with cyclosporin A who developed an unusual sebaceous gland hyperplasia accompanied by a disseminated follicular spiny hyperkeratosis. Those alterations were most evident on his face and limbs. In some locations hairy hyperkeratosis with authentic hair neogenesis was found. The histology of these alterations showed a marked hyperkeratosis of the hair follicles with formation of hair-like spikes either alone or in connection with hairs. The presence of true hairs distinguishes our case from the morphologically similar disseminated spiked hyperkeratosis and other spiny keratinization disorders. Scanning electron microscopy helped to demonstrate the hair-like structure of these keratoses. Some of the sebaceous glands showed cystic widening of their lumina, which were filled with abundant amorphous eosinophilic material, a finding similar to earlier observations. Our case demonstrates that these skin alterations should be classified as side effects of cyclosporin A and that they are apparently dose-dependent.

Lack of effect after local treatment with a new ciclosporin formulation in recalcitrant erosive oral lichen planus

We treated 7 patients with recalcitrant enoral lichen planus (Lp) with a new hydrophilic ciclosporin (CS) formulation during 8 weeks. The preparation with proven in vivo percutaneous absorption was designed for topical use and contained 100 mg CS/g formulation. The patients applied a cumulative daily dose of about 126 mg CS. We did not see the previously reported clinically impressive response with our CS formulation. No CS was detected in the blood of our patients. We conclude that percutaneous absorption of CS is not the key event to the clinical responses. Clinical benefit after CS in enoral Lp seems rather to the clinical responses. Clinical benefit after CS in enoral Lp seems rather to be related to a systemic effect of the drug.

Segmental Manifestation of Darier Disease

Darier disease is an autosomal dominant disorder which may occasionally become manifest in a segmental form. Two clinical phenotypes with a different genetic background have been elaborated in recent years. More than 50 patients with isolated linear disease expression have been documented. In this phenotype the skin outside the segmental affection is absolutely normal. Such a phenotype is explained by a postzygotic mutation with somatic mosaicism which was labeled as type 1 manifestation of segmental forms in autosomal skin disorders. A patient with classical type 1 segmental Darier disease is presented. On the other hand, only 3 patients with Darier disease showing a segmental manifestation in combination with a diffuse distribution have so far been observed. These cases correspond to the recently described type 2 manifestation of segmental forms of autosomal dominant disorders. We describe a fourth patient with type 2 segmental Darier disease. The genetic explanation of such a phenotype is possible with the assumption that a germline mutation for the disease exists but, in addition, a postzygotic mutation is needed resulting in loss of heterozygosity. Hence, in a circumscribed region a homozygous or hemizygous state of the mutation is apparent which can explain the enhanced severity of the segmental manifestation.

Delayed-Type Hypersensitivity to Cow’s Milk Protein in Melkersson-Rosenthal Syndrome: Coincidence or Pathogenetic Role?

BACKGROUND Intolerance to cows milk protein is frequently seen in children and rarely in adults. Non-IgE-mediated hypersensitivity to cows milk protein has been suspected in children based on in vitro evidence. Food intolerance may play a pathogenetic role in some cases of Melkersson-Rosenthal syndrome, which is often of unknown origin. OBJECTIVE We describe an adult female patient who developed a Melkersson-Rosenthal syndrome and at the same time was found to have in vivo and in vitro evidence of a delayed-type hypersensitivity to cows milk protein. METHODS Allergic and immunologic examinations, including skin prick tests, patch tests, serology, lymphocyte transformation tests and biopsies were performed. RESULTS A positive patch test to alpha-lactalbumin, a positive lymphocyte transformation test to whole cows milk and an immunohistology with infiltration of CD4+ and CD8+ T cells were found. CONCLUSIONS There is a possible pathogenetic relation between delayed-type hypersensitivity to cows milk protein and Melkersson-Rosenthal syndrome in the patient presented.

Clinical Controversy on the Effect of Topical Ciclosporin: What Is the Target Site?

In recent years attempts have been made to treat T-cell-mediated skin diseases with topical therapeutics. Based on clinical data on the local treatment of recalcitrant erosive lichen planus (LP) with ciclosporin (CS) we discuss in vitro and in vivo studies on percutaneous absorption of CS, drug localization and drug metabolism in the skin as well as clinical data. Clinically relevant immunosuppressive activity depends not only on drug distribution in the target organ skin. The inhibition of T cell response is also dependent upon T cell subsets involved and the activation stage of the T cell. There are different proportions in T cell subpopulations during different evolutional stages of LP. Thus responsiveness to therapy with this drug may depend on the disease activity. Furthermore lymphocyte migration throughout various organs in the body including skin depend on a variety of molecular and cellular interactions. Whether local CS is sufficient to inhibit these interactions or to inactivate already activated T cells remains unclear. Assuming that the T lymphocyte is the target site for CS, local therapy reaches only a small fraction of the T cell population. This may be insufficient, and a systemic inhibition of helper/inducer T lymphocyte function is needed for successful therapy. With CS and with other drugs it seems that percutaneous absorption is not the only key to variable clinical responses to topical therapy.

Erythema chronicum migrans: Evidence for Cellular Immune Reaction in the Skin Lesion

Skin biopsy specimens from 9 patients with erythema chronicum migrans (ECM) were studied immunohistochemically using a series of monoclonal antibodies. In biopsy specimens taken from the erythematous peripheral portion of ECM the perivascular infiltrates were composed predominantly of LEU-4+ T cells. LEU-3a + helper/inducer T cells were more numerous than LEU-2a + cytotoxic/suppressor T cells. Of particular interest was the high number of LEU-6+ Langerhans cells in the epidermis and dermis of specimens taken from the erythematous portion of ECM as well as from the noninflammatory skin outside the erythema. The presence of LEU-6+ Langerhans cells and T cells in the ECM lesions suggests that, apart from humoral factors, a cell-mediated immune response directed against Borrelia burgdorferi antigen is important as well in the pathogenesis of this disease.

Follicular mucinosis associated with mycosis fungoides.

We report a patient who developed erythematous indurated plaques with alopecia on the face and multiple well-demarcated infiltrated scaling lesions on the trunk and extremities. Skin biopsy showed a mucinous degeneration of the follicular outer root sheaths and sebaceous glands consistent with the diagnosis of follicular mucinosis. A histologic examination of a specimen from the left forearm showed microscopic changes of mycosis fungoides. The present case confirms the need of multiple skin biopsies in the evaluation of patients with follicular mucinosis.

Pili trianguli et canaliculi : a distinctive hair shaft defect leading to uncombable hair

Uncombable hair syndrome refers to a clinical disorder characterized by scalp hairs arranged in bundles in all directions that resist to brush and comb. Several entities may lead to spun-glass hair. As a rule the syndrome becomes obvious during the first years of life. The hair is normal in quantity, and increased fragility is not a common feature. The hair is often dry with silvery blond color. Under the light microscope the hairs may appear normal. Scanning electron microscopy shows a characteristic triangular, kidney- or heat-shaped diameter with typical longitudinal canalicular deformation. We present a 9-year-old girl with the typical clinical features of pili trianguli et canaliculi. Investigation by scanning electron microscopy confirmed the diagnosis. In addition the girl had enamel defects of the teeth and nail abnormalities that classify for a subtype of ectodermal dysplasia.

Acrodermatitis chronica atrophicans involving the face. Evidence for Borrelia burgdorferi infection confirmed by DNA amplification.

In a female patient with increasing redness of the hands and face, proteins of Borrelia burgdorferi were detected in a biopsy of the ear by DNA amplification. Although acrodermatitis chronica atrophicans has been documented to be caused by B. burgdorferi, this is the first case with proven spirochetal presence in the skin of the head. After 2 weeks of intravenous therapy with ceftriaxone marked improvement of discoloration of the skin was noted.