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Dermatophyten-Infektionen der Haut und der Nägel sind weltweit verbreitet, sie unterscheiden sich je nach geographischer Region und verändern sich im Laufe der Zeit. Ziel dieser Studie war es, das epidemiologische Profil von Dermatophyten in Deutschland zu erfassen, wobei ein Schwerpunkt auf dem Vergleich von Kindern und Erwachsenen lag.Für diese retrospektive multizentrische Studie wurden die Befunde mykologischer Dermatophytenkulturen aus dem Zeitraum 01/2014 bis 12/2016 nach identifiziertem Erreger, Alter und Geschlecht der Patienten sowie Krankheitsbild ausgewertet.Von 1136 Infektionen (Kinder: n = 88, Erwachsene: n = 1.048) wurden 50,8 % klinisch als Onychomykose klassifiziert, gefolgt von Tinea pedis (34,6 %), Tinea corporis (16,2 %), Tinea manus (16,2 %), Tinea capitis (2,5 %) und Tinea faciei (1,2 %). Der häufigste Erreger war Trichophyton (T.) rubrum (78,6 %), gefolgt von T. interdigitale (14,3 %), T. benhamiae (3,2 %), T. mentagrophytes (2,1 %) und Microsporum canis (1,7 %). Das Erregerspektrum unterschied sich insbesondere bei Tinea corporis und Tinea capitis zwischen Kindern und Erwachsenen mit einem breiteren Erregerspektrum bei den Kindern. Nur selten wurde Trichophyton tonsurans als Ursache für Tinea corporis (2,7 %) oder Tinea capitis (3,3 %) identifiziert.Für die optimale Auswahl eines geeigneten Therapieregimes sollten die Unterschiede bei den Erregern und der Häufigkeit von Pilzinfektionen zwischen den Altersgruppen berücksichtigt werden.

Hintergrund: Die chronische Urtikaria (CU) ist eine häufige und für viele Patienten stark belastende Erkrankung. Die aktuelle Urtikaria-Leitlinie beschreibt die evidenzbasierte Diagnostik und Therapie der CU. Darüber hinaus treten jedoch oftmals Fragen im praktischen Alltag auf, die durch die Leitlinie nicht beantwortet werden. Methoden: Im Mai 2020 fand ein digitales Treffen deutscher Urtikaria-Experten statt, in dem praxisrelevante Aspekte der Behandlung der CU erörtert und unterstützende Hilfestellungen für den klinischen Behandlungsalltag formuliert wurden. Die resultierenden Hinweise dieses Dokumentes fokussieren auf praktische Fragen und der hierzu verfügbaren Literatur und Erfahrungen der Teilnehmer. Ergebnisse: Die Diagnose einer CU kann in kurzer Zeit mittels gründlicher Anamnese, einer körperlichen Untersuchung und einer laborchemischen Basisdiagnostik gestellt werden. Hierzu werden in dieser Arbeit praktische Empfehlungen für den Praxisalltag gegeben. Eine erweiterte Diagnostik ist nur in wenigen Fällen indiziert und sollte grundsätzlich parallel zu einer effektiven Therapie erfolgen. Generell gilt, dass die CU immer auf gleiche Weise zu therapieren ist, unabhängig davon, ob Quaddeln, Angioödeme oder beides auftreten. Eine symptomatische Therapie sollte nach dem von den Leitlinien empfohlenen Stufenschema erfolgen. Die vorliegende Publikation gibt hierzu praktische Hinweise für Fragen in der Praxis, wie zum Beispiel dem Vorgehen in der aktuellen COVID-19-Pandemie, dem kardialen Risiko unter höher dosierten H 1-Antihistaminika, der Selbstapplikation von Omalizumab sowie dem Impfen unter Omalizumab-Therapie. Zusätzlich zu den Behandlungsempfehlungen werden Themen wie die Dokumentation in der Praxis und Familienplanung bei Urtikaria besprochen. Diskussion: Diese unterstützenden Behandlungsempfehlungen dienen als Ergänzung zu den aktuellen Leitlinien der CU und geben beim Umgang mit Patienten mit CU eine Hilfestellung für den Praxisalltag. Ziel ist es, dass Patienten, die unter einer CU leiden, mithilfe einer optimalen Therapie eine vollständige Beschwerdefreiheit erreichen. Zusatzmaterial online: Zu diesem Beitrag sind unter 10.1007/s15007-021-4772-2 für autorisierte Leser zusätzliche Dateien abrufbar.

Background Chronic urticaria (CU) is a common disease which represents a considerable burden for many patients. The current urticaria guideline describes the evidence-based diagnosis and treatment of CU. In addition, however, questions often arise in everyday practice that are not addressed by the guideline. Methods In May 2020, a digital meeting with German urticaria experts was held, in which practical aspects of CU treatment were discussed and supporting aids for everyday clinical treatment formulated. The resulting advice in this document focus on practical questions and the available literature and experiences of the participants. Results The diagnosis of CU can be made in a short time by means of a thorough anamnesis, a physical examination, and a basic laboratory chemical diagnosis. For this purpose, practical recommendations for everyday practice are given in this paper. An extended diagnosis is only indicated in a few cases and should always be carried out in parallel with an effective therapy. In general, CU should always be treated in the same way, regardless of whether wheals, angioedema or both occur. Symptomatic therapy should be carried out according to the treatment steps recommended by the guidelines. This publication provides practical advice on issues in everyday practice, such as the procedure in the current coronavirus disease 2019 (COVID-19) pandemic, the cardiac risk under higher dosed H1 antihistamines, the self-administration of omalizumab as well as vaccination under omalizumab therapy. In addition to treatment recommendations, topics such as documentation in the practice and family planning with urticaria will be discussed. Discussion These supporting treatment recommendations serve as an addendum to the current CU guideline and provide support in dealing with CU patients in everyday practice. The aim is to ensure that patients suffering from CU achieve complete freedom of symptoms with the help of an optimal therapy.

Background/objectives Para-phenylenediamine, a dye frequently added to henna tattoos to create the black color, is a potent contact allergen. Severe contact dermatitis may arise within days even after the first application. Our objective was to develop a method for rapid and complete removal of para-phenylenediamine-containing black henna tattoos from the skin, an important problem many physicians are confronted with, but for which no simple method exists. Methods A database search revealed polyethylene glycol 400, described in removal of ortho-phenylenediamine from contaminated skin. We therefore investigated its use in removal of the structurally related ortholog para-phenylenediamine present in black henna tattoos. Results A protocol was established involving repeated cycles of rinsing of the skin with polyethylene glycol 400 solution. In 5 patients, one of whom had already developed a severe blistering contact dermatitis and another a mild erosive dermatitis, black henna tattoos were successfully removed. Removal was completed in a single session of 1 hour or less, depending on tattoo size, with a maximum of 6 rinse cycles. Conclusions We provide a simple and safe method for rapid and effective removal of black henna tattoos. This procedure requires no special equipment and can be applied in virtually any setting.

BACKGROUND Hereditary angioedema (HAE) is a group of genetic diseases characterized by recurrent, painful and potentially lethal tissue swelling. The most common form results from mutations in the SERPING1 gene, leading to reduced function of complement 1 inhibitor (C1-INH). Rarer forms with normal C1-INH may arise from mutations in the coagulation factor F12 gene, but mostly the genetic background is unknown. Recently, a novel HAE mutation in the plasminogen (PLG) gene was shown. PATIENTS AND METHODS We analyzed the various clinical manifestations of HAE in 14 related patients using clinical data, biochemical analysis for C1-INH and C4 as well as gene sequencing. RESULTS Patients' symptoms were assigned to two different forms of HAE. In ten patients suffering from swelling of the lips or tongue but not of the extremities, a mutation in the PLG gene (c.988A>G) was found whereas in the only four patients with swelling of the gastrointestinal tract and extremities, a mutation in the SERPING1 gene (c.1480C>T) was identified. In two cases this was additional to PLG c.988A>G. CONCLUSIONS This unique finding of two different HAE-specific mutations in a large family not only explains the divergent phenotypes but also supports a genotype-phenotype correlation showing that abdominal attacks and swelling of the extremities are common with HAE-C1-INH but unusual with HAE-PLG.

Eosinophilic fasciitis (EF) and generalized morphea (GM) are rare and difficult-to-treat sclerosing skin diseases which may occur in association with hematologic disorders. We present a 66-year-old man with EF and associated Waldenström macroglobulinemia who received combination therapy with rituximab (375mg/m2 every other week, gradually extended to every eight weeks), prednisolone (1.25-30mg/d), and methotrexate (7.5-15mg/w). Three months after rituximab initiation, his skin condition improved steadily accompanied by a significant improvement in joint mobility with only mild and transitory flares (observation period: 59 months under treatment with rituximab). To date, there are five case reports on rituximab treatment of EF/GM with an association to hypergammaglobulinemia in three of those cases. Therapy effected significant improvement in four patients. Our case adds to the hitherto limited evidence that rituximab may be a promising therapeutic strategy for EF/GM in association with hypergammaglobulinemia.

Bei Skabies im Kindesalter ist ein adäquates Management unverzichtbar, um einer verlängerten Krankheitsdauer vorzubeugen und die weitere Ausbreitung der Erkrankung zu verhindern. Noch fehlen die Daten, die die topische Anwendung von Permethrin 5 % bei Säuglingen unter zwei Monaten unterstützen; die Anwendung in dieser Altersgruppe ist daher ein Off-Label-Use.Um Sicherheit und Wirksamkeit der topischen Therapie mit Permethrin-Creme in dieser Altersgruppe zu untersuchen, ermittelten wir an Skabies erkrankte Säuglinge, die jünger als zwei Monate waren. Die Diagnosestellung der Skabies erfolgte aufgrund der charakteristischen Symptomatik und der pathognomischen Befunde in der Dermatoskopie. Wir untersuchten die Wirksamkeit und Sicherheit der angewendeten Therapien.Sieben Skabies-Patienten unter zwei Monaten wurden mit Permethrin-Creme 5 % behandelt. Bei vier Patienten wurde die topische Therapie aufgrund einer unvollständigen Remission oder dem Wiederauftreten der Hautveränderungen bis zu dreimal wiederholt.Die Permethrin-Therapie wurde von allen sieben Säuglingen gut vertragen, auch bei mehrmaliger Anwendung. Unsere Ergebnisse bestätigen, dass die Anwendung von Permethrin-Creme 5 % bei Säuglingen unter zwei Monaten sicher ist.

Background and objectives Proper management of infantile scabies is indispensable in order to prevent prolonged duration and spread of the disease. Data are still lacking that support topical treatment with permethrin 5 % cream in infants under two months of age, and application remains off-label for this age group. Patients and methods We identified infants younger than two months who suffered from scabies in order to evaluate the safety and efficacy of topical treatment with permethrin cream in this age group. Diagnosis of scabies was based on the typical symptoms and pathognomonic features as determined with dermoscopy. We analyzed the efficacy and safety of the therapies that were applied. Results Seven scabies patients under two months of age were treated with permethrin 5 % cream. Topical therapy was repeated up to three times in four patients due to incomplete resolution or recurrence of skin lesions. Conclusions Permethrin therapy was well tolerated in all seven infants, even when conducted several times. Our results confirm that the use of permethrin 5 % cream in children younger than two months of age is safe.

Background and objective Dermatophyte infections of the skin and nails are common worldwide and vary between geographical areas and over time. The aim of this study was to determine the epidemiological profile of dermatophytes in Germany with a focus on comparing children with adults. Patients and methods In this retrospective multicenter study, mycological dermatophyte culture results in the period 01/2014 to 12/2016 were analyzed according to identified pathogen, age and gender of patients, and type of disease. Results Of 1,136 infections (children: n = 88, adults: n = 1,048), 50.8 % were clinically classified as onychomycosis, followed by tinea pedis (34.6 %), tinea corporis (16.2 %), tinea manus (16.2 %), tinea capitis (2.5 %), and tinea faciei (1.2 %). The most frequent pathogen was Trichophyton (T.) rubrum (78.6 %), followed by T. interdigitale (14.3 %), T. benhamiae (3.2 %), T. mentagrophytes (2.1 %), and Microsporum canis (1.7 %). The fungal spectrum differed particularly in tinea corporis and tinea capitis between children and adults with a more diverse pathogen spectrum in children. Trichophyton tonsurans was rarely identified as cause for tinea corporis (2.7 %) or tinea capitis (3.3 %). Conclusions Differences in pathogens and frequency of fungal infections between age groups should be considered for optimal selection of the appropriate therapeutic regimen.

Die Pathogenese des chronischen und akuten Pruritus ist bislang noch nicht vollstandig geklart. Interaktionen von Neuronen mit transienten und residenten Zellen der Haut scheinen jedoch eine wichtige Rolle in der Regulation des Pruritus einzunehmen. Neuronale Zellen, die spezifische Rezeptoren exprimieren und Neuromediatoren ausschutten, sind dabei aktiv beteiligt. Durch die freigesetzten Mediatoren konnen Immunzellen wie Mastzellen und eosinophile Granulozyten aktiviert werden, die bei vielen Hauterkrankungen mit chronischem Pruritus im entzundlichen Infiltrat in der Haut vorliegen. Mastzellen und eosinophile Granulozyten exprimieren Rezeptoren fur Neuromediatoren und setzen selbst Neuromediatoren und Zytokine frei, die wiederum zu einer Aktivierung von peripheren Nervenfasern fuhren. Beispielsweise konnen Mastzellen und eosinophile Granulozyten Neurotrophine wie „nerve growth factor“ (NGF) und „brain-derived neurotrophic factor“ (BDNF) sowie Zytokine wie IL-31 freisetzen. NGF, BDNF und IL-31 korrelieren bei Patienten mit chronisch entzundlichen Hauterkrankungen wie der atopischen Dermatitis mit der Krankheitsschwere und teilweise mit dem Pruritus der Patienten. Ferner fuhren NGF, BDNF und IL-31 zu einem vermehrten Nervenfaserwachstum. Es scheint also, dass das Zusammenspiel zwischen transienten und residenten Zellen in der Haut mit peripheren Nervenfasern, Mastzellen und eosinophilen Granulozyten eine wichtige Rolle in der gegenseitigen Aktivierung spielt, wobei noch nicht ganzlich klar ist, wie diese neurobiologischen Zusammenhange zu einer Induktion von Pruritus fuhren konnen.

Allergische Kontaktekzeme konnen im Kindesalter auftreten. Bei einem klinischen Verdacht auf ein allergisches Kontaktekzem sollte ein Epikutantest durchgefuhrt werden. In der vorliegenden Arbeit wurden Daten von 116.742 Patienten, die von 2005 bis 2014 in den Zentren des Informationsverbundes Dermatologischer Kliniken epikutan getestet wurden, analysiert. Es wurden insgesamt 925 Kinder im Alter von 0 bis 12 Jahren getestet. Wenn mindestens 700 getestete Individuen in dieser Gruppe berucksichtigt wurden, fanden sich am haufigsten Sensibilisierungen gegenuber Nickelsulfat (8,5 %), Duftstoff-Mix I (5,5 %) und Kolophonium (3,4 %), wobei diese Sensibilisierungen in der Erwachsenengruppe fur Nickelsulfat mit 15,5 % und Duftstoff-Mix I mit 8,4 % haufiger auftraten, wahrend die Sensibilisierungshaufigkeit fur Kolophonium mit 3,7 % vergleichbar war. Im Vergleich zeigten sich fur die Gruppe der Jugendlichen mit und ohne Beruf gleichfalls haufig positive Testungsergebnisse gegenuber Nickelsulfat (11,1 und 13,6 %) sowie Kobalt(II)-chlorid (6,3 und 6,0 %) wahrend die Sensibilisierungsfrequenzen gegenuber Duftstoff-Mix I mit je 3,9 und 3,4 % im Vergleich zu der Erwachsenenkontrollgruppe (8,4 %) geringer waren. Sowohl in der Kinder- als auch der Jugendlichengruppe fanden sich nicht selten Sensibilisierungen gegenuber Paratoluylendiamin und Paraphenylendiamin, wobei hier zu berucksichtigen ist, dass die Testungen insgesamt weniger haufig (weil nur bei Verdacht) durchgefuhrt wurden. Die Daten zeigen, dass das Sensibilisierungsprofil bei Kindern und Jugendlichen im Vergleich zu Erwachsenen vergleichbar ist, sich aber die relativen Haufigkeiten fur einzelne Allergene unterscheiden. Der Nachweis von Sensibilisierungen gegenuber Paraphenylendiamin im Kindes- und Jugendlichenalter steht moglicherweise im Zusammenhang mit aktuellen Trends wie Tatowierungen.

Sarcoidosis is a rare, systemic disease that is characterized by the formation of granulomas in various organs, including the skin. As the etiology remains unknown, the treatment of sarcoidosis is challenging. We present a 47-year-old female patient with progressive, multi-organ sarcoidosis who had a complete clinical improvement of the skin lesions, a moderate reduction in pulmonary opacities on chest X-ray, a marked subjective improvement in general status and pulmonary efficiency and a marked reduction in serum angiotensin-converting enzyme and soluble interleukin-2 receptor after 6 months of therapy with fumaric acid esters. The present case and similar reports in the literature highlight the probable efficacy of fumaric acid esters in the treatment of sarcoidosis and other non-infectious, granulomatous diseases.

Background Most data on chronic spontaneous urticaria (CSU) originate from highly selected patient populations treated at specialized centres. Little is known about CSU patient characteristics and the burden of CSU in routine clinical practice. AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) is an ongoing global study designed to assess chronic urticaria in the real-life setting. Objective To describe the baseline characteristics of the first 1539 German AWARE patients with H1-antihistamine-refractory CSU. Methods This prospective non-interventional study included patients (18-75 years) with a diagnosis of H1-antihistamine-refractory CSU for > 2 months. Baseline demographic and disease characteristics, comorbidities, and pharmacological treatments were recorded. Quality of life (QoL) was assessed using the dermatology life quality index (DLQI), chronic urticaria QoL questionnaire (CU-Q(2)oL), and angioedema QoL questionnaire (AE-QoL, in cases of angioedema). Previous healthcare resource utilization and sick leave data were collected retrospectively. Results Between March and December 2014, 1539 patients were assessed in 256 sites across Germany. The percentage of females, mean age, and mean body mass index were 70%, 46.3 years, and 27 kg/m(2), respectively. The mean urticaria control test score was 7.9, one in two patients had angioedema, and the most frequent comorbidities were chronic inducible urticaria (CIndU;24%), allergic rhinitis (18.2%), hypertension (18.1%), asthma (12%), and depression (9.5%). Overall, 57.6% of patients were receiving at least one pharmacological treatment including second-generation H1-antihistamines (46.3%), first-generation H1-antihistamines (9.1%), and corticosteroids (15.8%). The mean DLQI, total CU-Q(2)oL, and total AE-QoL scores were 8.3, 36.2, and 46.8, respectively. CSU patients reported frequent use of healthcare resources, including emergency services (29.7%), general practitioners (71.9%), and additional allergists or dermatologists (50.7%). Conclusions and Clinical Relevance This study reveals that German H1-antihistamine-refractory CSU patients have high rates of uncontrolled disease, angioedema, and comorbid CIndU, are undertreated, have impaired QoL, and rely heavily on healthcare resources.

Summary An 11-month-old boy was brought to our clinic with superinfected, sharply-defined, symmetrical, erythematous macules and vesicles, some with yellowish-brownish crusts, on the cheeks, fingers, and in the diaper region. The suspected impetigo contagiosa had failed to respond to both topical antiseptic therapy and systemic antibiotics. Because of the unusual clinical picture and course, we measured the serum zinc level. A significantly reduced level of 2 μmol/l (normal range 9.2–18.4 μmol/l) was identified. Initial skin lesions had appeared one week after weaning (5th week after birth). Since the age of 8 months the infant had also had recurrent diarrhea. Two weeks after zinc-histidine substitution, the diarrhea ceased and skin lesions slowly disappeared. Molecular genetic testing for the SLC39A4 (zinc transporter) gene revealed compound heterozygosity for the previously unidentified mutations c.1465_1474+4del (p.?) and c.295G>A (p.Ala99Thr). The parents are healthy heterozygous gene carriers. The same compound heterozygosity was later detected in the newborn brother of our patient shortly after birth. A zinc deficiency could therefore be identified and treated before symptoms occurred. The inherited autosomal recessive zinc transporter deficiency is termed acrodermatitis enteropathica. Lifelong zinc substitution is recommended. A differential diagnosis can be difficult because bacterial and fungal superinfection is common in zinc deficiency. Precise diagnosis requires testing family members for the gene.

Background Pyoderma gangraenosum is an immune-mediated, inflammatory, neutrophilic dermatosis of unknown etiology, which represents one of the extraintestinal manifestations of inflammatory bowel disease. It is a rare disease that occurs in less than 1% of patients with inflammatory bowel disease and with the same ratio in patients with Crohn's disease and ulcerative colitis.

The vanilloid receptor subtype 1 (VR1)/(TRPV1), binding capsaicin, is a non-selective cation channel that recently has been shown in human keratinocytes in vitro and in vivo. However, a description of VR1 localization in other cutaneous compartments in particular cutaneous nerve fibers is still lacking. We therefore investigated VR1 immunoreactivity as well as mRNA and protein expression in a series (n = 26) of normal (n = 7), diseased (n = 13) [prurigo nodularis (PN) (n = 10), generalized pruritus (n = 1), and mastocytosis (n = 2)], and capsaicin-treated human skin (n = 6). VR1 immunoreactivity could be observed in cutaneous sensory nerve fibers, mast cells, epidermal keratinocytes, dermal blood vessels, the inner root sheet and the infundibulum of hair follicles, differentiated sebocytes, sweat gland ducts, and the secretory portion of eccrine sweat glands. Upon reverse transcriptase-polymerase chain reaction and Western blot analysis, VR1 was detected in mast cells and keratinocytes from human skin. In pruritic skin of PN, VR1 expression was highly increased in epidermal keratinocytes and nerve fibers, which was normalized after capsaicin application. During capsaicin therapy, a reduction of neuropeptides (substance P, calcitonin gene-related peptide) was observed. After cessation of capsaicin therapy, neuropeptides re-accumulated in skin nerves. In conclusion, VR1 is widely distributed in the skin, suggesting a major role for this receptor, e.g. in nociception and neurogenic inflammation.

Zusammenfassung Hintergrund und Fragestellung: Teebaumol, ein Destillationsprodukt der Blatter des australischen Teebaumes Melaleuca alternifolia, erfreut sich zunehmender Beliebtheit als Alternativheilmittel fur die Behandlung diverser Hauterkrankungen. Das Ol ist ein Gemisch aus zahlreichen allergologisch relevanten Substanzen wie Monoterpenen und Sesquiterpenen. In dieser multizentrischen Studie sollte evaluiert werden, ob die Zunahme des Verbrauches von Teebaumol zu einer Sensibilisierungshaufigkeit in Deutschland und Osterreich gefuhrt hat, die die Aufnahme in die Standardreihe rechtfertigen wurden. Patienten und Methode: Fur die Epikutantestung wurde ein standardisiertes Teebaumol, 5 % in Diethylphthalat (DEP), verwendet. Getestet wurden konsekutive Ekzem-Patienten von 11 Hautkliniken in Deutschland und Osterreich. Die Ablesung erfolgte nach zwei und drei Tagen gemas den Empfehlungen der Deutschen Kontaktallergiegruppe (DKG). Ergebnisse: Von insgesamt 3 375 getesteten Patienten reagierten 36 (1,1 %) positiv auf Teebaumol. Die Sensibilisierungshaufigkeit zeigte grose geographische Unterschiede von 2,3 % (Dortmund), 1,7 % (Buxtehude), 1,1 % (Essen), 0,7 % (Graz) bis 0 % (Berlin, Wien). 14/36 Patienten (38,9 %) zeigten auch eine positive Reaktion auf Terpentin. Schlusfolgerung: Fur einzelne Testzentren ist Teebaumol ein wichtiges Allergengemisch. Bei anamnestischen Hinweisen uber die Anwendung teebaumolhaltiger Produkte sollte es getestet werden. Angesichts der grosen regionalen Unterschiede in der Sensibilisierungshaufigkeit ist die Aufnahme in die Standardreihe noch nicht zu empfehlen. Summary Background and aim: Tea tree oil, a distillation product of the Australian tea tree (Melalence alternitolia) is increasingly used as an alternative remedy for various dermatological diseases. Tea tree oil contains several allergenic monoterpenes and sesquiterpenes. In this multicenter study it was evaluated, whether the increasing use of tea tree oil has lead to an increased frequency of sensitization in Germany and Austria which would justify its inclusion into the standard series. Patients and method: For patch testing a standardized tea tree oil was used, dissolved 5 % in diethylphtalate (DEP). Consecutive patients of 11 dermatological departments in Germany and Austria were tested. Readings were taken on day 2 and 3 according to the guidelines of the German Contact Dermatitis Research Group (DKG). Results: 5 % tea tree oil was positive in 36/3375 patients (1.1 %). Sensitization frequencies showed great regional variations and ranged from 2.3 % (Dortmund), 1.7 % (Buxtehude), 1.1 % (Essen), 0.7 % (Graz), to 0 % (Berlin, Vienna). 14/36 patients (38.9 %) also showed a positive patch test reaction to oil of turpentine. Conclusion: Our results show that tea tree oil is an important contact allergen for some centers. It should be tested, if medical history suggests its previous use. Considering the great regional differences in frequencies of sensitization its inclusion into the standard series is not recommended yet.

Shiitake an edible asian mushroom nowadays becomes popular in european cooking, too. Allergic diseases to shiitake occur as contact dermatitis, alveolitis or asthma. Consuming of raw shiitake causes toxicodermia. Along with this disease papules develop. The polysaccharide lentina probably is the responsible toxin. Within seven months, we found three patients developing skin lesions after eating this mushroom. A 45 years old patient who often prepared and consumed meals containing shiitake, showed recurrent erythematous papules on his face. A prick to prick test with a shiitake mushroom showed an immediate converting into a delayed reaction. Two other patients developed skin eruptions after eating raw shiitake. One of them had eaten fried shiitake before without any problems. Prick to prick tests with Shiitake turned out to be negative in both cases. At the side of testing, 24 hrs later a delayed reaction with severely itching papules developed. The first case is supposed to be an allergic reaction whether the two other cases may rather be a toxicodermia, because of their history and clinical symptoms. However, the positive skin tests in these two cases would suggest other possible mechanisms. Further studies are necessary to clarify theses different phenomenon.

Until recently, mast cells have been viewed primarily as harmful because of their key role as effector cells of allergic and potentially lethal anaphylactic reactions. Their contribution to human health appeared instead to be limited to the elimination of parasites. There is, however, growing evidence for additional beneficial functions of mast cells, particularly regarding the initiation of acquired immune reactions. Thus, mast cells can phagocytize diverse particles, take up antigens, and express a number of receptors, particularly MHC class I and II antigens, ICAM-1 and -3, CD43, CD80, CD86 and CD40L which allow them to interact with T and B lymphocytes. They can also secrete numerous cytokines that induce and enhance recruitment and functions of lymphocytes. Finally, there is good evidence that mast cells present e.g. pollen and bacterial antigens, respond to bacterial superantigens, but fail to react to endogenously produced antigens or superantigens. Mast cells can also activate B cells directly to produce IgE, but this activity and the ability to produce IL-4 or IL-13 is restricted primarily to basophil leukocytes and mucosal mast cells. Finally, recent evidence attributes a pivotal role to the cells in natural immunity to bacteria. There is also emerging evidence that mast cells can downmodulate the immune response. While these data require further clarification, the basic ability of mast cells to initiate innate and acquired immune reactions can no longer be questioned.

H1-type antihistamines have recently been reported to inhibit cytokine secretion from human and murine mast cells and basophils. In order to confirm and expand these studies, we have compared several H1-blockers and the H2-blocker ranitidine for their effect on TNF-alpha, IL-3, 6, 8 and GM-CSF release from human leukemic mast (HMC-1) and basophilic (KU812) cells, compared to dexamethasone. Cells were stimulated for 24 h with phorbol myristate acetate (25 ng/ml) and calcium ionophore A 23187 (2.5x10(-7) M) alone or with the drugs added at 10(-4) to 10(-15) M, and production of cytokines was measured by ELISA. All antihistamines caused a dose-dependent inhibition of TNF-alpha release from HMC-1 cells, with maximal effects at 10(-12) M for azelastine, 10(-9) M for loratadine and cetirizine, and 10(-8) M for ranitidine. The inhibitory potency of H1-blockers on cytokines from HMC-1 cells was TNF-alpha >IL-8> or =IL-6> or =IL-3, with no significant effects on GM-CSF. In KU812 cells which failed to secrete TNF-alpha and GM-CSF, the sequence was IL-6 >IL-8 after preincubation. Dexamethasone inhibited all cytokines, but ranitidine only TNF-alpha and IL-3. Antihistamines had no effect on calcium flux in resting or stimulated cells. At the mRNA level, inhibition was only seen with KU812 cells and IL-8 in the presence of azelastine at 10-(10) M. These data show thus distinct inhibitory patterns for different antihistamines during cytokine production from human mast cells and basophils which may contribute to the anti-inflammatory effects of these drugs during treatment of allergic diseases.

Mast cells have been implicated in various diseases that are accompanied by neovascularization. The exact mechanisms by which mast cells might mediate an angiogenic response, however, are unclear and therefore, we have investigated the possible expression of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in the human mast cell line HMC-1 and in human skin mast cells. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that mast cells constitutively express VEGF121, VEGF165, and VEGF189. After a prolonged stimulation of cells for 24 h with phorbol 12-myristate 13-acetate (PMA) and the ionophore A23187, an additional transcript representing VEGF206was detectable, as could be verified by sequence analysis. These results were confirmed at the protein level by Western blot analysis. When the amounts of VEGF released under unstimulated and stimulated conditions were compared, a significant increase was detectable after stimulation of cells. Human microvascular endothelial cells (HMVEC) responded to the supernatant of unstimulated HMC-1 cells with a dose-dependent mitogenic effect, neutralizable up to 90% in the presence of a VEGF-specific monoclonal antibody. Flow cytometry and postembedding immunoelectron microscopy were used to detect VEGF in its cell-associated form. VEGF was exclusively detectable in the secretory granules of isolated human skin mast cells. These results show that both normal and leukemic human mast cells constitutively express bioactive VEGF. Furthermore, this study contributes to the understanding of the physiological role of the strongly heparin-binding VEGF isoforms, since these were found for the first time to be expressed in an activation-dependent manner in HMC-1 cells.

The factors that control migration of mast cells to sites of inflammation and tissue repair remain largely undefined. Whereas several recent studies have described chemotactic factors that induce migration of murine mast cells, only stem cell factor (SCF ) is known to induce migration of human mast cells. We report here that the anaphylatoxins C3a and C5a are chemotactic factors for the human mast cell line HMC-1, human cord blood-derived mast cells (CBMC) and cutaneous mast cells in vitro. The presence of an extracellular matrix protein, laminin, was required for chemotaxis in response to complement peptides. Migration of mast cells towards C3a and C5a was dose-dependent, peaking at 1 μg/mL (100 nmol/L), and was inhibited by specific antibodies. Pretreatment with pertussis toxin inhibited the anaphylatoxin-mediated migration of HMC-1 cells, indicating that Gi proteins are involved in complement-activated signal transduction pathways in human mast cells. Both C3a and C5a also induced a rapid and transient mobilization of intracellular free calcium ([Ca2+]i ) in HMC-1 cells. Besides SCF, other chemotactic factors tested, such as interleukin-3, nerve growth factor, transforming growth factor β, RANTES (regulated upon activation, normal T cell expressed and secreted), monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3, macrophage inflammatory protein-1α (MIP-1α), and MIP-1β, failed to stimulate migration of human mast cells. In summary, these findings indicate that C3a and C5a serve as chemotaxins for human mast cells. Anaphylatoxin-mediated recruitment of mast cells might play an important role in hypersensitivity and inflammatory processes.

Mast cells are well known effector cells not only in allergic but also in diverse acute and chronic inflammatory diseases. We have shown previously that these cells produce a broad spectrum of cytokines which might contribute to mast cell-dependent pathology. In the present study, we have investigated the influence of four potent glucocorticoids, methylprednisolone-aceponate, methylprednisolone-17-propionate, prednicarbate, and betametasone valerate (105M-10-9M), on the IL-1Β, IL-3, IL-8, and tumor necrosis factor Α secretion of the HMC-1 mast cell line as measured by ELISA. All four glucocorticoids caused a comparable dose- and time-dependent inhibition of cytokine release from HMC-1 cells stimulated for 24 h with phorbol 12-myristate 13-acetate 25 ng/ml and calcium ionophore 2 × 10-7M. These results shed further light on the mechanisms involved in antiinflammatory effects of glucocorticoids in allergic inflammation.

Mast cells and basophils are central effector cells of allergic reactions and are involved in inflammatory diseases. These cell types produce an array of mediators including a broad spectrum of cytokines. In order to examine whether antiallergic drugs modulate the release of these mediators, we have investigated the influence of dexamethasone and decarboethoxy-loratadine (DEL), the active metabolite of the H1-blocking agent loratadine, on the release of IL-6 and IL-8 by the human mast cell line HMC-1 and the human basophilic cell line KU812 by ELISA. Dexamethasone (10(-6)-10(-11) M) or Del (10(-5)-10(-14) M) were added to the cells either 1 h prior to or simultaneously with PMA and Ca-ionophore A23187. When preincubated with the cells, DEL dose-dependently suppressed IL-6 release by up to 40% and IL-8 release by up to 50%. Dexamethasone potently suppressed secretion of both cytokines if simultaneously added to the cells with the stimuli by up to 60% and after preincubation by up to 80%. Since both antihistamines and glucocorticoids are used for treatment of allergic diseases, the findings reported here indicate that these drugs may modulate allergic reactions via inhibition of cytokine release from mast cells and basophils.

Autoimmune bullous skin disorders are induced by autoantibodies against distinct adhesion complexes of the epidermal and dermal-epidermal junction. Since most of these disorders are characterized by a severe, potentially lethal course,they require long-term immunosuppressive treatment to reduce the de novo synthesis of pathogenic autoantibodies by B lymphocytes. Rituximab, a chimeric monoclonal antibody against CD20 on B lymphocytes, has shown promise in several case reports or cohort studies in the treatment of paraneo-plastic pemphigus,refractory cases of pemphigus vulgaris and foliaceus and in other autoimmune bullous disorders. Treatment with rituximab leads to depletion of pathogenic B-cells which may last up to 12 months resulting in a reduction of plasma cells secreting pathogenic autoantibodies. Rituximab is usually administered in an adjuvant setting at a dose of 375 mg/m(2) i.v.in weekly intervals for four consecutive weeks in addition to the standard immunosuppressive treatment. The present consensus statement of German-speaking dermatologists, rheumatologists and oncologists summarizes and evaluates the current evidence for the use and mode of application of rituximab in autoimmune bullous skin disorders.

In order to further evaluate the role of cytokines in the induction of atopic pruritus, leukocytes from 10 atopic eczema patients or 10 nonallergic controls were stimulated in vitro with mite or birch pollen antigen for 1 and 4 days. Subjects were prick-tested with the supernatants, and whealing and itching were evaluated 20 and 60 min later. The supernatants were also examined for the contents of GM-CSF, IL-2, IL-6 and IL-8 by ELISA and TNFα. Two hours prior to testing, the antihistamine cetirizine (20 mg) or a placebo tablet were given to the patients according to a randomized, double-blind study protocol. After pricking with antigen-stimulated leukocyte supernatants, 6 of 10 patients but no controls reacted mostly at 20 min with whealing and/or pruritus. In the cetirizine-treated group, no decrease in these skin reactions was seen compared to placebo. Analysis for cytokines showed increased levels of IL-8 in allergen-stimulated samples, with no correlation to the induction of itching or whealing by these supernatants. IL-6 levels were low and variable, and GM-CSF, IL-2 and TNFα levels were always below standard values. These data show that leukocytes selectively release IL-8 in response to in vitro antigen stimulation. They furthermore provide additional support for the concept that as yet to be identified products play a role in atopic pruritus.

Mast cells derive from bone marrow stem cells, are ubiquitously distributed resident tissue cells, and are particularly frequent in the lamina propria of epithelial organs, including the skin. The cells are characterized and distinguishable from other cells by their electrondense cytoplasmatic granules, their contents of mediators like histamine, heparin and tryptase, and by their surface receptors for SCF (c-kit) and IgE (the high affinity IgE receptor, FcɛRI). Basophils which belong to the granulocytic series of the bone marrow and reside primarily in peripheral blood, are often grouped with mast cells since they share many properties with these cells except for their morphology and their lack of tryptase and c-kit. Mast cells also have a number of properties in common with other tissue resident and infiltrating inflammatory cells like the receptors c-kit on melanocytes, FceRI on Langerhans cells, and C3bR, C5aR and FcγRIII on monocytes and granulocytes. Furthermore, like most inflammatory cells, they are able to produce a broad range of mediators including leukotrienes, platelet activating factor (PAF) and cytokines. While mast cells have traditionally been viewed as primary effector cells of immediate type allergic reactions, their potential role in diverse other immunological and inflammatory processes has become more and more apparent in recent years (for review, see [1]).

The chemokine interleukin-8 (IL-8) mediates infiltration and adhesion of neutrophils during inflammatory processes. We have previously shown that this cytokine can be produced and released by normal and leukemic human mast cells (HMC-1 cells). To assess whether and to what extent this cytokine is stored intracellularly, we investigated production and localization of IL-8 at the single-cell level by combined use of flow cytometry (FACS) and immunoelectron microscopy. Conditions necessary for optimal fixation and permeabilization of HMC-1 cells were determined by measuring changes in cell-specific light scatter parameters and by estimating cellular uptake of propidiumiodide (PI). In this way, we were able to detect IL-8 with a monoclonal antibody in stimulated cells that were microwave-fixed with a combination of paraformaldehyde (4%) and glutaraldehyde (0.1%), followed by permeabilization with saponin (0.025%). FACS analysis revealed time-dependent synthesis of IL-8 with at most 50% positively stained cells at 8–12 hr after stimulation. For pre-embedding immunogold electron microscopy, cells were treated according to the protocol established by flow cytometry. IL-8 was found to be located in specific cytoplasmic, electron-dense granules of stimulated HMC-1 cells. These results confirm and extend our previous findings by demonstrating IL-8 expression in HMC-1 cells at the single-cell level. In addition, we propose that quantitative FACS can be reliably used in a timesaving manner to establish appropriate conditions for pre-embedding immunoelectron microscopy of intracellular antigens.

Since glucocorticoid effects on inflammatory processes may be mediated via modulation of cytokine release, different types of myelomonocytic cells were stimulated in vitro with lipopolysaccharide (50 ng/ml) or phorbol myristate acetate (25 ng/ml) plus the ionophore A23187, 2 x 10(-7) M, and release of interleukin (IL)-1 beta, IL-8 and tumor necrosis factor (TNF)-alpha was measured after 24 h by ELISA. Peripheral blood mononuclear cells from two allergic and two normal human donors released similarly large quantities of IL-8 and lower amounts of IL-1 beta and TNF-alpha. This also held for myelomonocytic cell lines, with THP-1 cells being most active, followed by U-937 and HL-60 cells. All potent glucocorticoids studied caused a dose-dependent inhibition of cytokine release from donor cells, being most marked for IL-1 beta and lowest for IL-8. Inhibition of cytokine release was also noted with U-937 cells, with clear differences in potency between the glucocorticoids, whereas release was enhanced in all experiments with THP-1 cells. These results were confirmed with Northern blot analysis. Modulating effects of glucocorticoids on cytokine release are thus complex, and are particularly dependent on the cell type studied.

Since mast cells and basophils are thought to play a central role in several types of cutaneous inflammatory and allergic reactions, and since interleukin-6 (IL-6) is an important mediator in these processes, we have studied the ability of the human mast cell line HMC-1, the human basophilic cell line KU812, and human skin mast cells to produce IL-6. All three cell types proved to be potent sources of this cytokine after appropriate stimulation. Transcription of IL-6 mRNA was first detectable 2 h after stimulation with the ester phorbol myristate acetate (PMA) and the calcium ionophore A23187 in both cell lines, as evidenced by semiquantitative reverse transcriptase polymerase chain reaction analysis. Whereas resting cells did not produce IL-6 protein, PMA/A23187-stimulated cells released immunoreactive and biologically active IL-6, as demonstrated and quantitated by enzyme-linked immunosorbent assay and by the use of TEPC 1033 cells, an IL-6-dependent murine plasmacytoma cell line. Stimulated KU812 cells secreted sevenfold more IL-6 (up to 15 ng/ml) than HMC-1 cells (up to 2.4 ng/ml). Immunoblotting of HMC-1- and KU812 cell-derived IL-6 revealed several IL-6 forms in the molecular weight range of 21 to 30 kDa. Immunoelectron microscopic studies of human skin biopsies provided evidence that unstimulated mast cells do not contain preformed IL-6 but accumulate IL-6 in cytoplasmic and extruded granules after IgE-dependent stimulation. These findings suggest that IL-6 secreted by human mast cells and basophils potentially contributes to allergic, other immunologically mediated and nonspecific inflammatory responses.

Psoriasis is a chronic inflammatory skin disease in which epidermal hyperplasia results from the release of cytokines by infiltrating type 1 T cells. Up- regulation of endogenous interleukin-10 controls type 1 skin responses in animal models; however, interleukin-10 production is low in psoriatic lesions. Consistent with an important role of interleukin-10 in psoriasis, we and colleagues have recently demonstrated clinical efficacy of subcutaneous administration of recombinant interleukin-10 to affected patients. Here, we studied the effects of interleukin-10 on disease-related inflammatory pathways. Patients were treated with recombinant interleukin-10 over 6 wk in an open-label phase II clinical trial. Tissue was obtained before and after therapy and examined by histology/immunohistochemistry, in situ hybridization, and quantitative real-time reverse transcription-polymerase chain reaction. Ten of 14 patients showed a marked reduction of the clinical disease activity. The clinical response was associated with a significant decrease of cutaneous T cell infiltration and the lesional expression of type 1 cytokines interferon-gamma and tumor necrosis factor-alpha. Interleukin-10 inhibited the epidermal interleukin-8 pathway by downregulating the expression of interleukin-8, its receptor CXCR2, and its inducer interleukin-17, and partially reversed the aberrant keratinocyte maturation defining psoriatic epidermal pathology. Remarkably, there was evidence that genetic factors are involved in the response to interleukin-10 as individual variations in the downregulation of tumor necrosis factor-alpha were related to the presence of polymorphisms in the tumor necrosis factor-alpha promoter. These data suggest that excessive production of type 1 cytokines in human skin disease can be counter-regulated by the administration of recombinant interleukin-10. Genotypic analysis may help to identify patients that will preferentially respond to interleukin-10 therapy.

Mast cells are important players in innate immunity and mediate allergic responses. Upon stimulation, they release biologically active mediators including histamine, cytokines and lysosomal hydrolases. We used permeabilized rat basophilic leukaemia cells as model to identify R-SNAREs (soluble NSF (N-ethylmaleimide-sensitive fusion protein)) mediating exocytosis of hexosaminidase from mast cells. Of a complete set of recombinant mammalian R-SNAREs, only vesicle associated membrane protein (VAMP8)/endobrevin consistently blocked hexosaminidase release, which was also insensitive to treatment with clostridial neurotoxins. Thus, VAMP8, which also mediates fusion of late endosomes and lysosomes, plays a major role in hexosaminidase release, strengthening the view that mast cell granules share properties of both secretory granules and lysosomes.

Mast cells generate and release histamine during anaphylactic reactions, and there is pharmacological evidence that histamine regulates this process via specific receptors. Therefore, we examined human leukemic (HMC-1) and normal skin mast cells for the expression of all four currently known histamine receptors. Both cell types expressed H2 and H4 receptors at mRNA and protein levels, whereas H3 receptor specific mRNA and receptor protein was undetectable. Similarly, immunohistochemistry of cutaneous tissue showed an absence of H3 receptor in these cells. Despite transcription of mRNA, H1 receptor protein was only moderately expressed in HMC-1 cells and was virtually absent in skin mast cells. Furthermore, only H1, H2, and H4 receptors were detectable by Western blot analysis of HMC-1 cells. Radiolabeled histamine binding was strongly inhibited only by H2 (ranitidine)- and H3/H4 (FUB 108)-specific antagonists. Histamine-induced increase of cAMP was inhibited by the H2 receptor antagonist famotidine, whereas induction of IP3 was not observed, making signaling via the H1 receptor unlikely. These data show that human mast cells constitutively express primarily H2 and H4 receptors and that H2 receptors are functionally linked to cellular processes. They provide new insights into the mechanisms that govern auto- and paracrine histamine-induced mast cell functions.