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Background: Filaggrin (Flg) and hornerin (Hrnr) share similar structural and functional features. Both proteins have been implicated as essential proteins for skin barrier maintenance. Loss-of-function mutations of these genes constitute a risk factor for atopic dermatitis and eczema-related asthma. Furthermore, both FLG and HRNR protein levels are downregulated in patients with atopic dermatitis. Thus, mice deficient for Flg and Hrnr provide a novel model to study skin barrier impairment and the susceptibility for cutaneous inflammation. Methods: By using appropriate targeting vectors and breeding strategies, we established a homozygous FlgHrnr double-deficient (FlgHrnr −/− ) mouse model lacking both genes including the intergenomic sequence. Results: Neonates appeared normal, but developed a transient scaly phenotype with overall flaky appearance, but no overt skin phenotype in adulthood, thereby reflecting a subclinical barrier defect seen in humans. Structurally, FlgHrnr −/− mice displayed a markedly reduced granular layer and a condensed cornified layer. Functionally, FlgHrnr −/− mice showed permeability abnormalities and metabolic aberrations regarding the production of natural moisturizing factors (NMFs) in the stratum corneum. Surprisingly, although the immune system revealed no aberrations under steady-state conditions, FlgHrnr −/− mice are predisposed to mount an allergic contact dermatitis, especially at hapten threshold levels eliciting allergic reactions. Conclusions: Together, our FlgHrnr −/− mouse model nicely reflects the epicutaneous sensitization susceptibilities and inflammatory reactions to environmental insults in humans with impaired skin barrier functions.

Background Studies on patch testing with workplace materials and evaluation of current occupational relevance of positive patch test reactions are scarce in patients with occupational dermatitis (OD). Objectives To identify frequent sensitizations with occupational relevance and to determine the value of patch testing with workplace materials in OD patients. Patients and methods Results and clinical data of 654 patients with suspected OD patch tested between 2013 and 2017 were analysed. Results Occupational allergic contact dermatitis was diagnosed in 113 (17.3%) patients. Mechanics had the widest range of occupational sensitizations. Sensitization to epoxy resin was rated occupationally relevant in almost all handicraft trades. Among positive patch test reactions to workplace products, those to water-based metal working fluids and leave-on cosmetic products were most frequent. Despite frequent testing, protective gloves only rarely elicited positive reactions. Preservatives and rubber compounds were most frequently identified as currently occupationally relevant. Conclusions Rubber allergy is occupationally relevant especially in healthcare workers and cleaners. Generally, preservatives including formaldehyde releasers are important allergens in OD patients. Leave-on cosmetic products must not be forgotten as allergen sources. Patch testing both workplace materials and standardized test preparations has a complementary value and is beneficial for the diagnostic work-up of OD patients.

Background The Atopic Dermatitis (AD) TREATgermany registry was initiated by the German Society for Dermatology (DDG) in 2011 to evaluate the ‘real‐life’ situation of health care for patients with AD. Objectives Interim data analysis on baseline characteristics as well as current and prescribed systemic treatments of the TREATgermany registry patients. Methods Patients (≥18 years) with moderate‐to‐severe AD [objective (o)SCORAD > 20], or with current or previous anti‐inflammatory systemic treatment for AD within 24 months, were included and are followed up over at least 24 months. To assess clinical signs, the eczema area severity index (EASI, 0–72), the oSCORAD (0–83) and the Investigator Global Assessment (IGA; 6‐point scale) were used. The disease severity was globally scored by the patients [Patient Global Assessment (PGA); six‐step Likert scale]. Disease symptoms were assessed by the patient‐oriented eczema measure (POEM, 0–28) and numeric rating scales (NRS, 0–10). Health‐related quality of life was measured using the dermatological life quality index (DLQI, 0–30). Results A total of 612 patients were recruited across 32 sites between 06/2016 and 01/2019 (mean age: 42.6 ± 14.2 years; mean oSCORAD: 40.8 ± 16.3). The mean POEM score was 16.3 ± 7.5. Pruritus was rated highest among subjective symptoms (NRS: 5.4 ± 2.7). The mean DLQI value was 11.3 ± 7.5. The frequency of arterial hypertension was lower (20.8%) compared with the general population, whilst this was higher for depression (10%). More than 60% of the patients had received systemic glucocorticosteroids, and 36.8% had received cyclosporine A prior to inclusion. Dupilumab was the leading substance documented as either ‘current’ (12.1%) or ‘prescribed’ (31.4%) at baseline. Conclusions These ‘real‐life’ data clearly demonstrate the substantial disease burden. Most of TREATgermany patients were already treated with or prescribed dupilumab at baseline. Moreover, current findings indicate the urgent need for further alternative agents in order to achieve a perceptible improvement of quality of life of patients with moderate‐to‐severe AD.

Background: Clinical registries may provide high-quality evidence on the use and effectiveness of therapeutic interventions under real-life conditions. Adults with moderate-to-severe atopic eczema (atopic dermatitis [AD]) are enrolled into TREATgermany and prospectively followed over at least 2years. This paper analyses the association between dermatological quality of life and work limitations.Materials and Methods: Treatment modalities and abroad set of physician- and patient-reported outcome measures are documented using validated instruments to assess clinical disease severity (EASI [Eczema Area and Severity Index], objective SCORAD [objective-SCORing Atopic Dermatitis]), quality of life (DLQI [Dermatology Life Quality Index]), symptoms (POEM [Patient-oriented Eczema Measure]), global disease severity, as well as patient satisfaction and work limitations including presenteeism (WLQ [Work Limitation Questionnaire]). From 06/2016 until 12/2017, 241 individuals (mean age 43 +/- 15years, 38.6% female) were enrolled at 19recruitment centers;69% of the patients were employed.Results: Employed persons had DLQI and WLQ scores of 10.6 +/- 6.9points and 17.7 +/- 18.1%, respectively. Mean presenteeism was substantial accounting for 9.2%. With coefficients of 0.39 and 0.33 WLQ and presenteeism scores significantly correlate with DLQI (p

Background Metalworkers occupationally exposed to metals, tools, metalworking fluids (MWFs), technical oils, gloves, skin care products etc. frequently suffer from occupational dermatitis (OD). Objectives To investigate occupational exposure and to identify relevant occupational sensitizers in metalworkers with OD, and to evaluate suitability of current German patch test recommendations for this occupational group. Patients and methods As part of the OCCUDERM project, occupational exposure of 230 metalworkers with suspected OD patch tested in the departments of dermatology in Gottingen and Osnabruck (both Lower Saxony, Germany) in 2012-2017 was recorded by questionnaire. These data, as well as results, of patch testing with standardized allergens and with workplace material were analysed. Results Metalworking fluids and skin care products were the most important exposures. Among MWF allergens, most frequently sensitizations to formaldehyde and formaldehyde releasers, colophony/abietic acid and monoethanolamine were observed. Sensitization to methylisothiazolinone (MI) was frequent, probably as part of the general European epidemic of contact allergy to MI in leave-on cosmetics. Sensitization to glove ingredients only played a minor role. Conclusions The known occupational allergen spectrum could largely be confirmed. In order not to miss relevant sensitizations, patch testing with material from the patients' workplaces in parallel to baseline and MWF series is recommended. Sensitizations diagnosed could not always be linked to particular occupational exposures.

Background: Clinical registries may provide high quality evidence on the use and effectiveness of therapeutic interventions under real-life conditions. Adults with moderate-to-severe AD are enrolled into TREATgermany and prospectively followed over at least 2 years. The paper analyses the association between dermatological quality of life and work limitations. Materials and methods: Treatment modalities and a broad set of physician and patient reported outcome measures are documented using validated instruments to assess clinical disease severity (EASI, objective SCORAD), quality of life (DLQI), symptoms (POEM), global disease severity, as well as patient satisfaction and work limitations including presentism (WLQ). From 06/2016 until 12/2017. 241 individuals (mean age 43 +/- 15 years. 38.6% female) were enrolled at 19 recruitment centers. 69% of them were currently employed. Results: Employed persons had DLQI and WLQ scores of 10.4 +/- 6.9 points and 17.7 +/- 18.1%, respectively. Mean presentism was substantial accounting for 9.2%. With coefficients of 0.39 and 0.33 WLQ and presentism scores significantly correlate with DLQI (p < 0.000). Bootstrapped regression models showed that the limitations in coping with work requirements increase by 1.7% as DLQI increases by one point. Lower quality of life due to AD is most strongly associated with limitations in the area of physical and performance requirements in general. Presentism decreases by 0.5% as DLQI increases by one point. Conclusion: Moderate-to-severe AD has substantial adverse economic impact with mean productivity loss of patients of almost 10%. Future analyses from TREATgermany will address the impact of innovative treatment modalities on quality of life and work productivity of patients with moderate-to-severe AD., Hintergrund: Klinische Register tra- gen zur Evidenzbasierung der Gesund- heitsversorgung und zur Umsetzung von Forschungsergebnissen in die Praxis bei. TREATgermany schließt Erwachsene mit moderater bis schwerer Neurodermitis (AD) mit prospektiver Beobachtung über min- destens 2 Jahre ein. Der Beitrag zeigt ers- te Ergebnisse zum Zusammenhang von krankheitsbezogener Lebensqualität und Leistungseinschränkungen im Beruf. Ma- terial und Methoden: Dokumentiert werden objektive und subjektive Outcomes mit vali- dierten Messinstrumenten: klinischer Schwe- regrad (EASI, oSCORAD), Lebensqualität (DLQI), Symptome (POEM), globaler Schweregrad (IGA/PGA), Patientenzufrie- denheit und berufsbezogene Leistungsein- schränkungen (WLQ) inkl. Präsentismus (Produktivitätsverlust bei der Arbeit) so- wie der Therapieverlauf. 06/2016 – 12/2017 wurden 241 Patienten (Alter 43 ± 15 Jahre; 38,6% Frauen) in deutschlandweit 19 Zent- ren eingeschlossen, 69% waren berufstätig. Ergebnisse: Erwerbstätige hatten DLQI- und WLQ-Mittelwerte von 10,4 ± 6,9 Punkten bzw. 17,7 ± 18,1%. Der mittlere Präsentis- mus betrug 9,2%. Mit r = 0,39 und 0,33 kor- relierten die WLQ- und Präsentismus-Scores signifikant mit dem DLQI (p < 0,001). Eine geringere Lebensqualität war am stärks- ten mit körperlichen und allgemeinen Leis- tungseinschränkungen im Beruf assoziiert. Regressionsmodelle zeigten einen Zuwachs von Limitationen bei der Bewältigung von Arbeitsanforderungen um 1,7% und des Prä- sentismus um 0,5% mit der Zunahme des DLQI um einen Punkt. Diskussion: eine mo- derate bis schwere AD hat negative wirt- schaftliche Auswirkungen mit einem mittle- ren Produktivitätsverlust der Patienten von fast 10%. Weitere Analysen sollten den Ein- fluss innovativer Behandlungsmethoden auf Lebensqualität und Arbeitsproduktivität in den Fokus rücken.

Filaggrin (Flg) and hornerin (Hrnr) share similar structural and functional features. Both proteins have been implicated as essential proteins for skin barrier maintenance. Loss-of-function mutations of these genes constitute a risk factor for atopic dermatitis and eczema-related asthma. Furthermore, both FLG and HRNR protein levels are downregulated in patients with atopic dermatitis. Thus, mice deficient for Flg and Hrnr provide a novel model to study skin barrier impairment and the susceptibility for cutaneous inflammation.By using appropriate targeting vectors and breeding strategies, we established a homozygous FlgHrnr double-deficient (FlgHrnrNeonates appeared normal, but developed a transient scaly phenotype with overall flaky appearance, but no overt skin phenotype in adulthood, thereby reflecting a subclinical barrier defect seen in humans. Structurally, FlgHrnrTogether, our FlgHrnr

Das atopische Ekzem des Kindesalters ist mit einer stadiengerechten topischen Therapie in der Mehrheit der Falle gut behandelbar. Herausforderungen stellen die schweren Verlaufsformen mit rezidivierenden Superinfektionen, das Management assoziierter Nahrungsmittelallergien sowie die psychosozialen Aspekte einer chronischen Erkrankung im Familienkontext dar. In dieser Altersgruppe liegt ein besonderer Fokus auf der Pravention – primar und im Hinblick auf die Entwicklung weiterer Erkrankungen des atopischen Formenkreises. In einigen dieser Bereiche haben sich in den letzten Jahren neue Aspekte ergeben, die das praktische Management des atopischen Ekzems im Kindesalter verandert haben oder in Zukunft verandern konnten.

Bacterial infections of the skin are often seen by dermatologists. The majority of infections are caused by the gram-positive bacteria Staphylococcus aureus and Streptococcus pyogenes. These induce blistering/erosive (impetigo, ecthymata) and abceeding (folliculitis) infections of the skin, respectively. Owing to their differences in virulence factors and host immunity, these strains can lead to varying presentations and courses of the infections. This review focuses on impetigo, folliculitis, perianal streptococcal dermatitis, and ecthymata.

Zusammenfassung Die uberwiegende Zahl der malignen Melanome („schwarzer Hautkrebs”) treten an der sichtbaren Haut auf. Werden sie rechtzeitig erkannt, ist die Behandlung nach Exzision mit Sicherheitsabstand abgeschlossen. Dagegen haben Patienten mit metastasiertem Melanom trotz neuer Therapien weiterhin eine sehr schlechte Prognose. Daher hat die Fruherkennung beim malignen Melanom einen sehr hohen Stellenwert. Der „weise Hautkrebs” ist aufgrund des geringen Metastasierungsrisikos prognostisch deutlich gunstiger, jedoch konnen auch hier durch fruhzeitige Behandlung eingreifende Therapien vermieden werden. Der Artikel gibt praktische Hinweise, auf welche Hautveranderungen Therapeuten bei ihren Patienten achten sollten.

larvae and usually occurs on the trunk or buttocks. Migration is less irregular and produces broad, less clearly demarcated tracks on the extremities (progressing up to 5 cm per hour, hence the name lar-va currens) and usually disappears rapidly. This guideline does not address larva currens. Cutaneous larva migrans should also be distinguished from the symptom “creeping eruption” which is a migrating subcutaneous swelling with redness and urticaria of the overlying skin. It occurs, for instance, in gnathostomiasis, cuta-neous paragonimiasis (

Bestimmte Dermatosen konnen von vorangehenden oder parallel bestehenden Infektionen ausgelost oder verschlechtert werden. Die Psoriasis vulgaris etwa kann Folge einer Streptococcus-pyogenes-Infektion sein, der Lichen ruber durch Hepatitis-C-Viren ausgelost werden.

Silikon ist ein in der Medizin vielfach eingesetztes Material und spielt unter anderem in der plastischen Rekonstruktion eine grose Rolle. Die Anwendung von Silikon kann jedoch fur den Patienten erhebliche, teils nicht abschatzbare Konsequenzen haben, von Schwellungen und Rotungen im Bereich der Injektionsstelle uber regionale Lymphadenopathie bis hin zur Entwicklung schwerer Hautlasionen, auch fern des Applikationsortes, wie im hier geschilderten Fall einer Patientin, die wenige Jahre nach Silikoninjektion in beide Gesashalften massive Ulzerationen gesasabwarts entwickelte. Daruber hinaus sind Systemreaktionen wie intrapulmonale Granulome, Embolien und assoziierte Pneumonien moglich. Auch ein Zusammenhang mit der Entwicklung von Autoimmunerkrankungen und Neoplasien wird diskutiert. Therapiemoglichkeiten bestehen in der operativen Entfernung des Materials sowie antiinflammatorischen Lokal- und Systemtherapien. Erstere ist jedoch angesichts einer diffusen Verteilung von Silikon haufig nicht vollstandig moglich, fur Zweitere fehlen Erfahrungswerte, vor allem im Langzeitverlauf. Flussiges Silikon zur kosmetischen Injektion ist daher weder in Europa noch in den USA zugelassen. Aber auch bei der Verwendung von Silikonimplantaten sollte stets eine sorgfaltige vorherige Abwagung und Aufklarung sowie eine Durchfuhrung nur durch fachlich geschultes Personal erfolgen. Daruber hinaus empfehlen sich regelmasige Nachsorgeuntersuchungen sowohl bei Implantattragern als auch jenen Patienten, denen in der Vergangenheit flussiges Silikon injiziert wurde.

International audience; The mechanisms of the harmful cardiovascular effects of small particulate matter are incompletely understood. Endothelial progenitor cells (EPCs) predict outcome of patients with vascular disease. The aim of our study was to examine the effects of diesel exhaust particles (DEP) on EPC and on the associated vascular damage in mice. C57Bl/6 mice were exposed to DEP. 2 μg DEP/day was applicated intranasally for 3 weeks. Exposure to DEP reduced DiLDL/lectin positive EPC to 58.4 ± 5.6% (p < 0.005). Migratory capacity was reduced to 65.8 ± 3.9% (p < 0.0001). In ApoE(-/-) mice, DEP application reduced the number of EPC to 75.6 ± 6.4% (p < 0.005) and EPC migration to 58.5 ± 6.8% (p < 0.005). Neoangiogenesis was reduced to 39.5 ± 14.6% (p < 0.005). Atherogenesis was profoundly increased by DEP treatment (157.7 ± 18.1% vs. controls, p < 0.05). In cultured human EPC, DEP (0.1-100 μg/mL) reduced migratory capacity to 25 ± 2.6% (p < 0.001). The number of colony-forming units was reduced to 8.8 ± 0.9% (p < 0.001) and production of reactive oxygen species was elevated by DEP treatment (p < 0.001). Furthermore, DEP treatment increased apoptosis of EPC (to 266 ± 62% of control, p < 0.05). In a blood-brain barrier model, DEP treatment impaired endothelial cell integrity during oxygen-glucose deprivation (p < 0.001). Diesel exhaust particles impair endothelial progenitor cell number and function in vivo and in vitro. The reduction in EPC was associated with impaired neoangiogenesis and a marked increase in atherosclerotic lesion formation.

T cells exercise their full impact on target cells through a combination of secreted cytokines. The recently described T helper cell subset Th22 is characterized by a combinatorial secretion of IL-22 and TNF-α. Here, we demonstrate that IL-22 increases the TNF-α-dependent induction and secretion of several immune-modulatory molecules such as initial complement factors C1r and C1s, antimicrobial peptides S100A7 and HBD-2 (human β defensin 2), and antimicrobial chemokines CXCL-9/-10/-11 in primary human keratinocytes. The synergism of IL-22 and TNF-α is transmitted intracellularly by MAP kinases and downstream by transcription factors of the AP-1 family. The induction of innate immunity is relevant in an in vitro infection model, where keratinocytes stimulated with Th22 supernatants or recombinant IL-22 plus TNF-α effectively inhibit the growth of Candida albicans and maintain survival of epithelia. Accordingly, the combinatorial stimulation of keratinocytes with IL-22 and TNF-α most efficiently conserves the integrity of the epidermal barrier in a three-dimensional skin infection model as compared with IFN-γ, IL-17, IL-22 or TNF-α alone. In summary, we demonstrate that IL-22 and TNF-α represent a potent, synergistic cytokine combination for cutaneous immunity.

The endocannabinoid system (ECS) consists of two cannabinoid (CB) receptors, namely CB(1) and CB(2) receptor, and their endogenous (endocannabinoids) and exogenous (cannabinoids, e.g. delta-9-tetrahydrocannabinol (THC)) ligands which bind to these receptors. Based on studies suggesting a role of THC and the ECS in inflammation, the objective of this study was to examine their involvement in type I hypersensitivity using a murine model of allergic airway inflammation. THC treatment of C57BL/6 wildtype mice dramatically reduced airway inflammation as determined by significantly reduced total cell counts in bronchoalveolar lavage (BAL). These effects were greatest when mice were treated during both, the sensitization and the challenge phase. Furthermore, systemic immune responses were significantly suppressed in mice which received THC during sensitization phase. To investigate a role of CB(1/2) receptors in this setting, we used pharmacological blockade of CB(1) and/or CB(2) receptors by the selective antagonists and moreover CB(1)/CB(2) receptor double-knockout mice (CB(1)(-/-)/CB(2)(-/-)) and found neither significant changes in the cell patterns in BAL nor in immunoglobulin levels as compared to wildtype mice. Our results indicate that the activation of the ECS by applying the agonist THC is involved in the development of type I allergies. However, CB(1)/CB(2) receptor-independent signalling seems likely in the observed results.

Model organisms like the mouse are important tools to learn more about gene function in man. Within the last 20 years many mutant mouse lines have been generated by different methods such as ENU mutagenesis, constitutive and conditional knock-out approaches, knock-down, introduction of human genes, and knock-in techniques, thus creating models which mimic human conditions. Due to pleiotropic effects, one gene may have different functions in different organ systems or time points during development. Therefore mutant mouse lines have to be phenotyped comprehensively in a highly standardized manner to enable the detection of phenotypes which might otherwise remain hidden. The German Mouse Clinic (GMC) has been established at the Helmholtz Zentrum München as a phenotyping platform with open access to the scientific community (www.mousclinic.de; [1]). The GMC is a member of the EUMODIC consortium which created the European standard workflow EMPReSSslim for the systemic phenotyping of mouse models (http://www.eumodic.org/[2]).

Primary human keratinocytes and immortalized HaCaT cells were analysed for their capacity to bind purified staphylococcal protein A (SpA). Co-incubation with FITC-labelled SpA led to a dose-depending attachment. Pull-down experiments with cellular extracts revealed the TNFα receptor I (TNF RI) as binding partner on keratinocytes. Thus, we next looked for expression of this receptor in human epidermis and cultured keratinocytes. TNF RI is strongly expressed on all keratinocytes analysed, both at the mRNA and protein level and activation by SpA at optimal doses of 50-100 μg/ml resulted in the phosphorylation of the TNF RI downstream kinases MEK1/2, JNK1/2, and p38 subsequently leading to translocation of the p65 NF kappa B subunit and AP-1 into the nucleus. This translocation was then followed by increased expression of IL-8 and COX-2, two known NF kappa B-induced pro-inflammatory genes. To further test the relevance of our findings, we analysed in vitro production of over 100 strains isolated from atopic eczema showing that more than 85% of the tested strains produced extracellular SpA in substantial amounts. Thus, besides superantigens, haemolysins, and other cell wall components, Staphylococcus aureus exerts pro-inflammatory stimuli on human keratinocytes through the production of SpA signalling through TNF RI.

Background Prior to the discovery of filaggrin (FLG) mutations, evidence for an impaired skin barrier in atopic dermatitis (AD) has been documented, and changes in ceramide profile, altered skin pH and increased trans-epidermal water loss (TEWL) in patients with AD have been reported. Until now, no studies have analysed stratum corneum (SC) lipids combined with skin barrier parameters in subjects of known FLG genotype. Methods A cohort of 49 German individuals genotyped for the most common FLG mutations (R501X, 2282del4) had SC samples taken for lipid analysis by high-performance thin layer chromatography. In addition, TEWL, erythema, skin hydration and pH were measured. In 27 of the 49 individuals, a 24-h irritation patch test with sodium lauryl sulphate was performed. For the analysis, both the AD group and the control group were stratified by FLG mutation status (FLGmut/FLGwt). Results In the FLGmut AD group, significantly lower levels of ceramide 4 and significantly higher levels of ceramide 7 were observed when compared to both healthy control groups. However, ceramide 7 levels also significantly differed between FLGwt AD and FLGwt controls, as did ceramide 1 levels. No significant differences were observed for ceramide 2, 3, 5 and 6. FLGmut individuals had significantly higher skin pH values than individuals not carrying FLG mutations. Patients with AD with FLG mutations had significantly higher erythema compared to patients with AD without FLG mutations. Conclusion Our results confirm previous observations of altered ceramide levels in AD, which however appear to show no clear relationship with FLG mutations.

To cite this article: Mahachie John JM, Baurecht H, Rodriguez E, Naumann A, Wagenpfeil S, Klopp N, Mempel M, Novak N, Bieber T, Wichmann H-E, Ring J, Illig T, Cattaert T, Van Steen K, Weidinger S. Analysis of the high affinity IgE receptor genes reveals epistatic effects of FCER1A variants eczema risk. Allergy 2010; 65: 875–882. Abstract Background: High levels of total and allergen-specific IgE levels are a key feature in allergic diseases. The high-affinity receptor for IgE, which is composed of one alpha (FCER1A), one beta (FCER1B), and two gamma (FCER1G) subunits, represents the central receptor of IgE-induced reactions. In a genome-wide association scan, we recently identified associations between functional FCER1A variants and total serum IgE levels. Previous studies had reported linkage and association of FCER1B variants with IgE and atopic traits. The FCER1G gene has not yet been investigated with regard to atopy. Filaggrin (FLG) is the strongest known risk gene for eczema, in particular the allergic subtype of eczema. Methods: We investigated the association of FCER1A, FCER1B, and FCER1G variants with IgE in a large population-based cohort (n = 4261) and tested for epistatic effects using the model-based multifactor dimensionality reduction (MB-MDR) method. In addition, we investigated a potential interaction between FLG and FCER1A variants in a large collection of eczema cases (n = 1018) and population controls. Results: Three strongly correlated FCER1A polymorphisms were significantly associated with total and specific IgE levels as well as allergic sensitization. No associations were seen for FCER1B and FCER1G. After adjustment for FLG effects, a significant epistatic effect of the FCER1A variants rs10489854 and rs2511211 on eczema risk was detected. Conclusions: These results suggest that FCER1A variants by themselves and in combination influence IgE levels and act synergistically to influence eczema risk.

Gender differences in the development and prevalence of human diseases have long been recognized. Immense interest grows in the understanding of the role of sex hormones in the homeostasis of immunity. Asthma predominates in boys before puberty and this gender preference reverses after puberty and in adulthood, when adult women tend to have a more severe disease, often recalcitrant to treatment. Atopic eczema in preschool children shows insignificant gender difference or male preponderance in different studies, with more adult females suffering from atopic eczema. The limited data on the prevalence of immediate hypersensitivity to hymenoptera venom show controversial results. Discrepancy exists regarding the gender difference in food allergy, with females reporting significantly more allergic reactions in questionnaire studies. In general, adverse reactions to nonionic iodinated radiocontrast media are more commonly observed in females. The course of allergic diseases varies unpredictably during pregnancy, whereas hormone replacement therapy in postmenopausal women usually has a favorable influence on the course of asthma. Experiments in rodents confirm an effect of estrogens on mast cell activation and allergic sensitization, while progesterone is shown to suppress histamine release but potentiate IgE induction. Dehydroepiandrosterone may antagonize the production of Th2 cytokines but the effect of testosterone and the other androgens remains less defined. Actual data from human studies are lacking.

Because of the increasing incidence of resistance to beta-lactam antibiotics, dermatologists will be increasingly confronted with methicillin-resistant S. aureus (MRSA) strains which display a great variability of their virulence factors. In view of the high mortality of systemic MRSA infections (estimated 700-1.500 deaths per year in Germany), dermatologists should be well aware of the various aspects of diagnosis, therapy and prevention of this problem bacteria. Adequate screening measures must be in place to identify high-risk patients and institute appropriate prophylactic measures and therapy. If only colonization is present, topical antiseptic measures are sufficient. If an infection is present, either systemic or topical therapeutic approaches may be indicated. We review the role of MRSA infection and colonization in skin diseases.

B-Zellen sind fur die Ausbildung einer humoralen Immunantwort verantwortlich. Sie proliferieren und differenzieren in den sekundaren lymphatischen Organen. IgE ist das Schlusselmolekul allergischer Erkrankungen vom Typ I und wird von B-Zellen nach Stimulation uber CD40 und IL-4/IL-13 produziert. Zahlreiche Molekule aus der Steroidhor-monrezeptorfamilie konnen die IgE-Produktion hemmen und stellen interessante therapeutische Zielstrukturen der Zukunft dar.

Specific immunotherapy (SIT) protocols for nutritional allergens have only recently been established with a focus on oral allergy syndrome because of pollen cross-reacting antibodies. For these patients, a substantial number of studies have been published suggesting benefits from SIT. The situation in true anaphylaxis to food allergens such as peanut allergy is more complex, and therapeutic strategies are based on individual protocols rather than controlled studies. However, in defined cases, SIT represents a promising approach for a durable protection from life-threatening risks after accidental ingestion. Keywords: allergen-specific immunotherapy, food allergy, long-term effect

Background Patients with atopic diseases are characterized by high levels of specific IgE production. However, little is known about the composition of their B-cell repertoires. Objectives We sought to analyze the complete PBMC-derived IgE repertoire and to compare clonal expansions between different patients. Methods We have analyzed the IgE-bearing B-cell receptor repertoire in highly atopic patients (>1000 IU/mL) using quantitative RT-PCR, complementarity determining region 3 spectratyping, and sequence analysis. Three representative patients were additionally followed during anti-IgE therapy. Results Atopic patients exhibited 100 to 1000 times more IgE-specific transcripts than control individuals. These patients used a variable region of the heavy immunoglobulin chain (VH) e repertoire highly similar to their IgM and IgG repertoires, with preference of VH3b, VH4, VH3a, and VH1 segments. Each patient harbored individual clonal expansions, most probably as correlation of allergen-specific IgE production. Common expansions within the complementary determining region 3 shared by several individuals with similar sensitization patterns were found in spectratyping analysis. However, these antigen-driven expansions showed differences on the sequence level. In omalizumab-treated patients the clinical improvement was paralleled by a clear increase in the ratio of IgG/IgE transcripts. Conclusion The IgE repertoire in atopic patients follows the VH use patterns seen for other immunoglobulins and seems to preferentially recruit individual rearrangements rather than public expansions. Clinical implications The detailed analysis of the IgE B-cell repertoire is highly suitable to follow changes in IgE uses during different therapy modalities.

Background: Regulatory T cells (T-reg cells) have been described as an important cell population in the UV treatment of inflammatory skin diseases. Methods: We have treated five patients with generalized atopic eczema (AE) using medium-dose (15 cycles of 50 J/cm2, total dose of 750 J/cm2) UVA1 therapy and have analyzed the skin-infiltrating T-cellular subsets before and after therapy. Skin biopsies were split for immunohistochemistry and Real-time PCR and analyzed for CD4, Fox-P3, GATA-3, and IL-10 transcription as well as for CD3, CD4, CD152, Fox-P3, and GITR staining. Results: In all the investigated patients, we observed a good clinical response to UVA1. As described previously, the number of epidermal T cells slightly declined after irradiation. However, we did not observe a general decrease in T cell numbers. Within the population of T cells, no specific difference in the kinetics of Fox-P3-positive cells and Fox-P3-specific mRNA was noted as compared with GATA-3 positive T cells. These results were paralleled by RT-PCR for IL-10 and staining for CD152, a surface molecule that has been described for T-reg cells. Conclusion: In our hands, the clinical benefit of UVA1 treatment in AE patients does not seem to be due to a preferential survival/proliferation of T-reg cells.

Summary Background Toll-like receptor (TLR) agonists are widely used as adjuvants in specific immune therapy protocols for patients with atopic disposition. Monocyte-derived dendritic cells (mDCs) are thought to be important target cells for these compounds. Objectives To compare surface markers, TLR expression, TLR functionality after ligand stimulation, and genetic polymorphisms in the TLR 2-, 3-, and 4-genes in mDCs from atopic vs. non-atopic patients. Methods mDCs from highly atopic individuals (total serum IgE >1000 IU/mL) and healthy control persons (total serum IgE

Background B cells play a central role in IgE-mediated allergies. In damaged airway epithelium, they are exposed directly to aeroallergens. We aimed to assess whether direct exposure of B cells to pollen constituents affects allergic sensitization. Methods B cells from murine splenocytes and from blood samples of healthy donors were incubated for 8 days under Th2-like conditions with aqueous ragweed pollen extracts (Amb-APE) or its constituents. Secreted total IgM, IgG, and IgE was quantified by ELISA. Additionally, birch, grass, or pine-pollen extracts were tested. The number of viable cells was evaluated by ATP measurements. B-cell proliferation was measured by CFSE staining. IgE class switch was analyzed by quantitation of class switch transcripts. In an OVA/Alum i.p.-sensitization mouse model, Amb-APE was intranasally instilled for 11 consecutive days. Results Upon Th2 priming of murine B cells, ragweed pollen extract caused a dose-dependent increase in IgE production, while IgG and IgM were not affected. The low-molecular-weight fraction and phytoprostane E1 (PPE1) increased IgE production, while Amb a 1 did not. PPE1 enhanced IgE also in human memory B cells. Under Th1 conditions, Amb-APE did not influence immunoglobulin secretion. The IgE elevation was not ragweed specific. It correlated with proliferation of viable B cells, but not with IgE class switch. In vivo, Amb-APE increased total IgE and showed adjuvant activity in allergic airway inflammation. Conclusions Aqueous pollen extracts, the protein-free fraction of Amb-APE, and the pollen-contained substance PPE1 specifically enhance IgE production in Th2-primed B cells. Thus, pollen-derived nonallergenic substances might be responsible for B-cell-dependent aggravation of IgE-mediated allergies.

Patients with atopic dermatitis (AD) tend to have greatly elevated levels of serum immunoglobulin E (IgE). However, the role of IgE in the pathogenesis of AD is debated. This investigator-initiated open-label pilot study evaluates an anti-IgE-treatment approach by combining extracorporeal immunoadsorption and anti-IgE antibody omalizumab in 10 patients with severe, therapy-refractory AD. IgE levels decreased after immunoadsorption and decreased continuously in all patients during anti-IgE therapy. The reverse trend was observed during 6 months follow-up without treatment. In parallel with these observations, an improvement in AD was observed during the treatment period, with aggravation during follow-up. Further research is needed, based on the principle of reducing IgE levels in order to improve clinical symptoms, using a combination anti-IgE treatment approach, adjusted according to IgE levels.

Die Kolonisierung mit Staphylococcus aureus der lasionalen und nicht lasionalen Haut der Patienten mit atopischem Ekezm (AE) ist einer der wichtigsten Einflussfaktoren bezuglich des Schweregrads und der Haufigkeit von Exazerbationen der Erkrankung. Atopische Haut ist besonders anfallig fur die Besiedelung mit S. aureus. Die Kolonisierung fuhrt zu einer dauernden Stimulation des Immunsystems der Patienten mit AE, insbesondere durch Staphylokok-kensuperantigene. Dies hat ein verstarktes Einwandern von T-Lymphozyten in die Haut sowie eine vermehrte IgE-Synthese zur Folge. Weiter ist in der Haut von Patienten mit AE die Produktion von hautspezifischen, antibakteriell wirksamen Peptiden wie LL-37, HBD-2 und HBD-3 vermindert. Die therapeutische Kontrolle der Besiedelung durch Staphylokokken ist daher eine wichtige Saule im Rahmen eines Therapiekonzepts des AE.

Background Microbial skin colonization with Staphylococcus aureus is known to play an important role in atopic eczema (AE). Recently, an antibacterial effect of silver-coated textiles on S. aureus colonization has been demonstrated. Objectives To investigate clinical efficacy and functionality of silver-coated textiles in AE, a multicentre, double-blind, placebo-controlled trial was conducted. Patients/methods From November 2001 to August 2002, 68 consecutive outpatients clinically diagnosed with generalized AE were included in the study. Inclusion criteria were the clinical diagnosis of AE with a moderate severity as measured by the scoring of atopic dermatitis (SCORAD) index with at least 20. Patients were instructed to wear either silver-coated (verum, 35 patients + 2 dropouts) or cotton garments (placebo, 22 patients + 9 dropouts) directly on the skin for 2 weeks. Only basic skin care and ongoing therapy with topical steroids or oral antihistamines was permitted. Clinical severity was assessed using the ‘SCORAD’ before, during and at the end of study. Quality of life (QOL), wearing comfort (WC) and functionality (FU) of study clothes were measured in parallel. Patients documented their subjective and objective symptoms daily. Results In the verum group, eczema improved significantly after 1 week with further enhancement until the end of study ( P = 0.03 and P < 0.001). Silver-coated textiles were comparable to cotton in WC and FU. Pruritus and self-assigned skin condition improved significantly more than with placebo ( P < 0.001 and P = 0.003). Conclusions In conclusion, silver-coated textiles are able to improve objective and subjective symptoms of AE significantly within 2 weeks, showing a good wearing comfort and functionality comparable to cotton.