Atopic skin is associated with a lack of phosphatidylcholine-sphingomyelin transacylase activity.
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Acyltransferases↗
Biomedical subjects
Torsten Zuberbier
Publications and source records attributed to Torsten Zuberbier.
Human mast cells in the neurohormonal network: expression of POMC, detection of precursor proteases, and evidence for IgE-dependent secretion of alpha-MSH.
Human mast cells have been shown to release histamine in response to the neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH), but it is unknown whether these cells express proopiomelanocortin (POMC) or POMC-derived peptides. We therefore examined highly purified human skin mast cells and a leukemic mast cell line-1 (HMC-1) for their ability to express POMC and members of the prohormone convertase (PC) family known to process POMC. Furthermore, we investigated whether these cells store and secrete alpha-MSH. Reverse transcriptase-PCR (RT-PCR) analysis revealed that both skin mast cells and HMC-1 cells express POMC mRNA and protein. Expression of the POMC gene at the RNA level in HMC-1 cells could be confirmed by Northern blotting. Transcripts for both PC1 and furin convertase were detectable in skin-derived mast cells and HMC-1 cells, as shown by RT-PCR. In contrast, PC2 transcripts were detected only in skin mast cells, whereas transcripts for paired basic amino acid converting enzyme 4 (PACE4) were present only in HMC-1 cells. Radioimmunoassays performed on cell lysates and cell culture supernatants from human skin-derived mast cells disclosed immunoreactive amounts of alpha-MSH in both fractions. Stimulation with an anti-IgE antibody significantly reduced intracellular alpha-MSH and increased extracellular levels, indicating IgE-mediated secretion of this neuropeptide. Our findings show that human mast cells are active players in the cutaneous POMC system. Mast cell-derived alpha-MSH may contribute to cutaneous hyperpigmentation as seen in patients with urticaria pigmentosa. Moreover, IgE-dependent release of alpha-MSH suggests an immunomodulatory role of this neurohormone during inflammatory and allergic reactions of the skin.
Cell Line, Tumor↗
Patient perspectives on the management of atopic dermatitis.
BACKGROUND: Atopic dermatitis (AD) is increasingly common, with a point prevalence of more than 30% in some countries, and is characterized by visible skin lesions and intense itching. OBJECTIVE: The International Study of Life with Atopic Eczema (ISOLATE) is the first large-scale study to assess the effect of AD on the lives of patients and society, how patients and caregivers manage the condition, and how well patients and caregivers currently believe that AD is controlled. METHODS: Two thousand two patients (>13 years) and caregivers of children (2-13 years) with moderate-to-severe AD randomly selected from 8 countries underwent standardized telephone interviews using questions developed in collaboration with national eczema patient groups and physicians. RESULTS: During each year, patients spend, on average, 1 of 3 days in flare. The majority of patients receive prescription topical corticosteroids to treat flares; however, 49% of respondents are concerned about using these agents. On average, patients and caregivers delay initiating treatment for 7 days after onset of a flare. Only 24% of patients and caregivers feel confident they can manage AD flares adequately. Seventy-five percent of caregivers and patients feel that being able to effectively control AD would be the single most important improvement to their or their child's quality of life. The avoidable secondary economic cost of AD is estimated at 2 billion Euro per year across the European Union. CONCLUSION: ISOLATE highlights the need to improve patients' control of AD to reduce the significant effect this condition has on the patient and society. CLINICAL IMPLICATIONS: ISOLATE shows that patients with AD are untreated for half the time they are in flare, and thus there is an urgent need for physicians to ensure that the patients are educated and confident in using medication as prescribed to gain disease control.
Adolescent↗
Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report.
There are remarkable differences in the diagnostic and therapeutic management of atopic dermatitis practiced by dermatologists and pediatricians in different countries. Therefore, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology nominated expert teams who were given the task of finding a consensus to serve as a guideline for clinical practice in Europe as well as in North America. The consensus report is part of the PRACTALL initiative, which is endorsed by both academies.
Adult↗
Baseline and stimulated turnover of cell surface c-Kit expression in different types of human mast cells.
The receptor tyrosine kinase c-Kit is fundamental to mast cell (MC) development and maintenance. Its regulation can occur at various levels, but nothing is known about how this is accomplished in normal human tissue MC. Likewise, the baseline turnover of c-Kit has not been addressed yet. We used mature MC from human skin, along with the MC lines LAD-2 and HMC-1 and treated them with stem cell factor (SCF), cycloheximide, actinomycin D (AD) and combinations thereof, and determined expression levels of c-Kit and other surface receptors by flow cytometry. Ligand-induced internalization of c-Kit was found to be a universal mechanism and detectable in all MC subtypes. By Western blot analysis of LAD-2 cells, c-Kit was found to nearly disappear 3 h after the addition of SCF to slowly recover thereafter. Investigations into the baseline turnover of c-Kit expression revealed that c-Kit is strongly affected by the inhibition of de novo translation in all MC subsets, while a suppression of transcription had a weaker effect and displayed greater cell-to-cell variation. Only a minor impact on other cell surface receptors (CD29, CD50 and CD54) was noted. On combined treatment, cycloheximide, AD and SCF displayed additive effects, resulting in a complete disappearance of c-Kit from the cell surface. In conclusion, c-Kit represents a rapidly cycling cell surface receptor. It is not only immediately internalized upon binding of its ligand, but it is also heavily affected by the inhibition of translation or transcription when viewed against an average background. Interestingly, c-Kit regulation seems largely independent of the MC subtype.
Antigens, CD↗
Sublingual immunotherapy.
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Administration, Sublingual↗
Frequency of atopic dermatitis and relevance of food allergy in adults in Germany.
Many factors may aggravate atopic dermatitis. The aim of this study was to determine the frequency of atopic dermatitis in an unselected population sample and to evaluate the role of food allergy. Patients with atopic dermatitis were recruited from the population in Berlin, Germany, using a postal questionnaire. Skin prick tests for allergens were performed, followed by food challenges. A total of 1739 questionnaires was returned. In all, 23.5% of patients stated that they had atopic dermatitis, and 146 persons (8.4%) fulfilled our atopic dermatitis criteria after a detailed telephone interview. Of these, 111 were examined, and 28 (1.6%) were identified as currently suffering from atopic dermatitis. Twenty-seven patients were further evaluated: 9/27 were found to be skin prick test negative, 19/27 were skin prick test positive either to pollen and/or food allergens. Nine of 27 were challenged with the suspected food allergen: 1/9 showed a worsening of the eczema, 3/9 had oral symptoms, and 5/9 were negative. In conclusion, only 20% of adults with a positive history of atopic dermatitis show active eczema lesions at a given time point. The data indicate that most individuals with atopic dermatitis were sensitized against pollen allergens and according to that, pollen-associated food allergens. A non-selected AD patient cohort does not frequently suffer from clinically relevant pollen-associated food allergy.
Adolescent↗
Evidence for a restricted rather than generalized stimulatory response of skin-derived human mast cells to substance P.
To resolve the controversy regarding substance P (SP) mediated stimulation of mast cells (MC), we demonstrate that SP triggers histamine release from purified human skin MC (sMC), but contrast to stimulation via FcepsilonRI, does not effect the production of TNF-alpha or IL-8. Conversely, both anti-IgE and SP are suppressive in terms of IL-6. By quantitative RT-PCR, the amount of templates at baseline (per 25 ng total RNA) is 2178 (IL-6), 2,665 (IL-8) and 94 (TNF-alpha), and remains unaltered by SP. Contrast to sMC, LAD2 MC respond to SP with stronger histamine release and robust TNF-alpha production in an only partially neurokinin-1R mediated manner, while histamine release of sMC is chiefly mediated by this receptor. We conclude that human sMC are responsive to SP in a selective manner by eliciting degranulation without the induction of cytokines and that SP-triggered cytokine production varies among MC subtypes, likely through differences in signaling mechanisms.
Cell Line, Tumor↗
Bivalent effect of UV light on human skin mast cells-low-level mediator release at baseline but potent suppression upon mast cell triggering.
Ultraviolet (UV) irradiation is an established treatment for inflammatory skin diseases, although the precise mode of action is still unclear. Activating and suppressive effects on mast cell (MC) mediator release have been described. The aim of this study was to investigate systematically the effects of UVB, UVA-1, and psoralen plus UVA-1 at therapeutic doses on skin-derived human MC. Baseline and stimulated release of histamine, tryptase, and of interleukin (IL)-6, IL-8 and tumor necrosis factor-alpha (TNF-alpha) were examined. In resting MC, UV light induced a slight, yet significant histamine release corresponding to enhanced surface levels of lysosome-associated membrane proteins (LAMP). In contrast, UV pre-treatment caused a marked suppression of the anti-IgE-induced histamine release, accompanied by a diminished, anti-IgE-mediated increase in LAMP expression. The secretion of IL-6, IL-8, and TNF-alpha was inhibited in resting and activated MC, suggesting a different mode of action. Regarding the importance of MC in a variety of allergic and inflammatory processes, our data show a high susceptibility of this cell type towards UV light, which seems to partially depend on the state of cellular activation. Immunosuppressive effects predominate in activated MC, thus corresponding with the beneficial effects in inflammatory diseases, whereas in resting MC, both stimulatory and inhibitory effects are observed.
Cytokines↗
[Therapy of atopic eczema with calcineurin inhibitors].
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Adolescent↗
The European Competence Network on Mastocytosis (ECNM).
The European Competence Network on Mastocytosis (ECNM) is a Europe-wide, multinational cooperative approach attempting to improve recognition, diagnosis, and therapy of mastocytosis. The network is composed of local centers, physicians, and scientists who have dedicated their work to patients with mastocytosis. However, because of the rarity and complexity of the disease, each single component in the network alone would fail to meet important demands and to reach solid conclusions in this field of applied medicine. The ECNM represents an attempt to overcome this restriction as a cooperative multicenter platform that should serve as an important basis for the development of new therapeutic strategies and diagnostic concepts, and for the standardization of techniques used to determine diagnostic and prognostic parameters. Moreover, using future central databases and registries, a suitable infrastructure for the development of co-operative multicenter clinical trials will be established. In addition, the ECNM is dedicated to provide the best available information about the disease to patients and physicians.
Clinical Competence↗
[Screening procedures in the family practice. What is the new fast allergy test?].
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Adult↗
Comparative cytokine profile of human skin mast cells from two compartments--strong resemblance with monocytes at baseline but induction of IL-5 by IL-4 priming.
Although known as heterogenous, mast cells (MC) are believed to induce allergic inflammation, partially by secretion of T helper cell type 2 (Th2) cytokines. We show here that MC purified from two human skin compartments produce cytokines that are primarily associated with inflammation and innate immunity [interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor alpha (TNF-alpha)]. Although these are detectable even without stimulation, immunoglobulin (Ig)E receptor cross-linking is able to enhance only TNF-alpha production, but phorbol 12-myristate 13-acetate additionally promotes IL-1beta and IL-8. With the exception of TNF-alpha, the presence of serum has a positive impact on cytokine production. Although IL-13 transcripts (but not those for IL-4 and -5) are produced by skin MC, all Th2 cytokines remain undetectable in the supernatants or lysates of MC from foreskin and breast skin by all treatments. Therefore, rather than sharing similarity with Th2 cells, the cytokine profile of skin MC at baseline resembles that of monocytes. Of note, MC precultured in the presence of IL-4 [alone or plus stem cell factor (SCF)] before anti-IgE stimulation, acquired the ability to produce IL-5, and IL-1beta was concomitantly suppressed. Additionally, strong up-regulation of IL-6 by SCF was observed, which was inhibited by IL-4. In summary, we present a detailed analysis of the cytokine array of human skin MC immediately upon isolation; demonstrate that MC from different skin compartments, although producing the same pattern of cytokines, display quantitative differences in several aspects; and provide further evidence that MC possess a proinflammatory capacity, which can, however, be altered by microenvironmental stimuli, substantiating the marked plasticity of the cells.
Culture Media↗
Ultraviolet irradiation induces apoptosis in human immature, but not in skin mast cells.
As diverse pruritic cutaneous diseases respond to ultraviolet treatment, we have examined whether ultraviolet light is capable of inducing apoptosis in mast cells. Human mast cell line 1 (HMC1) derived from a patient with malignant mastocytosis and purified skin mast cells were irradiated with single doses of ultraviolet B or ultraviolet A1, or pretreated with 8-methoxypsoralen prior to ultraviolet A1 exposure. After 0 to 48 h of incubation, the percentage of apoptotic and dead cells was assessed. In HMC1 cells, morphologic features of apoptosis were further evaluated by electron microscopy. All ultraviolet treatment induced apoptosis of HMC1 cells in a time- and dose-dependent manner. Apoptosis was associated with activation of caspase-3, release of cytochrome C, cleavage of poly(ADP-ribose)-polymerase, and nuclear accumulation of p53. In contrast, resting skin mast cells were resistant to ultraviolet light induced apoptosis. After incubation with stem cell factor and interleukin-4 for 2 wk, however, slowly proliferating skin mast cells also underwent apoptosis in response to ultraviolet light. In conclusion, these data demonstrate that ultraviolet light directly affects mast cells, but mainly aims at the proliferating mast cells as found in mastocytosis and mast cell dependent pruritic diseases, where increased numbers are observed due to the recruitment mast cell precursors from the blood.
Apoptosis↗
[Diagnosis of allergies].
Various distinct forms of allergic reactions are known (Type I-IV) that demand the appropriate choice of diagnostic procedures. In light of the fact that allergic patients have been offered numerous diagnostic procedures which have proved inappropriate or whose efficacy has not been confirmed, the present review focuses on proven procedures that are in accordance with current guideline recommendations.
Allergy and Immunology↗
Hypersensitivity reactions to oxaliplatin: cross-reactivity to carboplatin and the introduction of a desensitization schedule.
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Antineoplastic Agents↗
Aromatic components of food as novel eliciting factors of pseudoallergic reactions in chronic urticaria.
BACKGROUND: Pseudoallergic reactions (PARs) against both additives and natural foods have been reported to elicit chronic urticaria, but in natural food the responsible ingredients are largely unknown. OBJECTIVE: The study was aimed at identifying novel pseudoallergens in food and focused on evaluating tomatoes, white wine, and herbs as frequently reported food items eliciting wheal responses in urticaria. METHODS: In 33 patients with chronic urticaria and PARs to food (proved by means of elimination diet and subsequent re-exposure with provocation meals), oral provocation tests were performed with field-grown tomatoes, organically grown white wine (whole food, steam distillates, and residues), oily extracts from herbs, and food additives. In addition, skin biopsy specimens from patients were studied for in vitro mast-cell histamine release with tomato distillate alone or on subsequent stimulation with anti-IgE, substance P, and C5a. RESULTS: Seventy-six percent of patients reacted to whole tomato (steam distillate, 45%; residue, 15%), 50% to food additives, 47% to herbs, and 44% to whole wine (extract, 27%; residue, 0%). Histamine, protein, and high levels of salicylate were only found in residues. The tomato distillate was further analyzed by means of mass spectroscopy, identifying low molecular-weight aldehydes, ketones, and alcohol as major ingredients. In vitro histamine release was not caused by tomato extract itself but was enhanced by means of subsequent stimulation with substance P and C5a but not by anti-IgE. CONCLUSION: Aromatic volatile ingredients in food are novel agents eliciting PARs in chronic urticaria. Histamine, salicylate, and a direct mast-cell histamine release are not involved in this reactivity to naturally occurring pseudoallergens.
Adolescent↗
Role of adverse reactions to food in urticaria and exercise-induced anaphylaxis.
In urticaria, adverse reactions to food are only a frequent finding in the subset of patients with chronic continuous urticaria. Mostly these reactions are of pseudoallergic nature, directed against artificial additives as well as naturally occurring aromatic components. IgE-mediated allergic reactions are a rare cause in acute urticaria as well as in recurrent chronic urticaria. In other types of urticaria, e.g. physical urticaria, food plays hardly any role as an eliciting agent with the exception of ice-cold drinks in cold urticaria. By contrast, exercise-induced anaphylaxis is frequently food-dependent. Two subtypes are distinguished: unspecific food-dependent exercise-induced anaphylaxis (FDEIA), where the filling of the stomach independently of the kind of food ingested prior to exercise is responsible for the symptoms. In specific FDEIA, an IgE-mediated food allergy causes symptoms only in combination with exercise. In the latter group, wheat is an important allergen.
Anaphylaxis↗