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Biomedical subjects

Thomas Werfel

Publications and source records attributed to Thomas Werfel.

At least 19 recordsLinked to original sources
PubMed2007

Staphylococcus aureus-derived enterotoxins enhance house dust mite-induced patch test reactions in atopic dermatitis.

BACKGROUND: Up to 65% of Staphylococcus aureus strains isolated from the skin of patients with atopic dermatitis (AD) produce exotoxins with superantigenic properties that may also act as allergens leading to an induction of exotoxin-specific IgE antibodies. Staphylococcal enterotoxin B (SEB) applied epicutaneously in a concentration of 10 micro g/cm(2), i.e. 200 micro g/ml, under occlusion induces cutaneous inflammation in patients with AD and healthy individuals. METHODS: We performed patch tests in 32 adult patients with AD using different concentrations (i.e. 2-200 micro g/ml) of SEA, SEB and house dust mite (HDM) extract (500 micro g/ml). Furthermore, the respective enterotoxins and HDM extract were applied simultaneously to the same patch test site. Specific IgE levels to SEA, SEB and HDM were measured with the CAP FEIA. RESULTS: The rates of patch test reactions to SEA and SEB increased with rising enterotoxin concentrations. There were no differences in the rates of patch test reactions to SEA and SEB between patients sensitized to the corresponding enterotoxin and non-IgE-sensitized patients. The number of patch test reactions to the mixture of enterotoxin and HDM extract was higher than the number of patch test reactions to either the enterotoxins or HDM extract. We identified 11 patients with AD who reacted neither to the enterotoxins nor to HDM extract, but who showed patch test reactions to the mixture. These reactions were not predicted by the presence of enterotoxin- or HDM-specific IgE. CONCLUSIONS: Colonization with exotoxin-producing S. aureus may influence the outcome of patch tests in patients with AD.

Adolescent↗
PubMed2006

Does allergen-specific immunotherapy represent a therapeutic option for patients with atopic dermatitis?

House dust mite (HDM) allergens are perennial indoor allergens, which may play a role as allergic trigger factors in atopic dermatitis (AD). Facilitated by their high enzymatic activity, HDM allergens are capable of penetrating the impaired epidermal skin barrier in patients with AD, gaining access to immune cells. In this way, HDM allergens induce both allergic reactions of the immediate type and allergic reactions of the delayed type, which contribute to impairment of AD. Because allergen reduction achieved by encasing strategies does not always lead to significant improvement of clinical symptoms, specific immunotherapy (SIT) might represent an attractive therapeutic option for long-time treatment of this subgroup of patients with AD. However, systematic studies on the effectiveness of SIT in patients with AD are rare. Furthermore, data on the immunologic changes induced by SIT in patients with AD are not well studied. In this review, we provide an overview of the pathogenic impact of HDM allergens as an example for aeroallergens on the course of AD. In addition, we discuss prophylactic and therapeutic options for the treatment of HDM allergy in patients with AD, including a summary of the current data available on SIT as a potential therapeutic option for patients with AD.

Adolescent↗
PubMed2006

Induction of C3 and CCL2 by C3a in keratinocytes: a novel autocrine amplification loop of inflammatory skin reactions.

The complement fragment-3a (C3a) acts via a G protein-coupled C3aR and is of importance in allergic and inflammatory diseases. Recent studies suggest the presence of complement proteins in the epidermal compartment and synthesis of some of these proteins (C3, factor B, and factor H) by human primary keratinocytes (KCs) during inflammation. However, expression of C3aR and its role in human KCs is not elucidated thus far. In this study, we demonstrate the expression of C3aR on KCs as detected by quantitative real-time RT-PCR and flow cytometry. IFN-gamma and IFN-alpha strongly up-regulated the surface expression of C3aR on KCs among all other cytokines tested. After up-regulation of C3aR by IFN-gamma and IFN-alpha, we observed the induction of five genes (CCL2, CCL5, CXCL8, CXCL10, and C3) after stimulation of KCs with C3a in microarray analysis. We confirmed the induction of C3 and CCL2 at RNA and protein levels. Furthermore, incubation of C3 with skin mast cells tryptase resulted in the generation of C3 fragments with C3a activity. In conclusion, our data illustrate that epidermal KCs express functional C3aR. The increases of C3 and CCL2 synthesis by C3a and C3 activation by skin mast cell tryptase delineates a novel amplification loop of complement activation and inflammatory responses that may influence the pathogenesis of allergic/inflammatory skin diseases.

Autocrine Communication↗
PubMed2006

Human plasmacytoid dendritic cells express receptors for anaphylatoxins C3a and C5a and are chemoattracted to C3a and C5a.

The presence of plasmacytoid dendritic cells (pDC) was recently demonstrated in lesions of inflammatory skin diseases. Since anaphylatoxins or their precursors were also found in such lesions, we investigated a possible interaction between pDC and anaphylatoxins C3a and C5a. pDC precursors isolated from peripheral blood did not express the receptors for C3a and C5a, complement C3a receptor (C3aR) and complement C3a receptor (C5aR). If these pDC precursors were cultured with IL-3, the resultant immature pDC expressed both receptors. Expression of C3aR and C5aR could also be demonstrated on pDC in lesions of cutaneous lupus erythematosus and allergic contact dermatitis. Such pDC were immature since they lacked the expression of the maturation marker CD83. Blood-derived pDC matured with CpG oligonucleotides downregulated the receptors. Immature pDC responded to C3a and C5a (but not C3adesArg) stimulation with increased F-actin polymerization and chemotactic migration. In contrast, interferon alpha production, surface molecule expression, and T-cell stimulatory capacity were not significantly modulated by C3a or C5a. Thus, immature pDC represent another type of antigen-presenting cell that express C3aR and C5aR, and respond to anaphylatoxins with chemotaxis. This might be relevant in the direction of pDC to cutaneous lesions of inflammation, for example, in lupus erythematosus or contact dermatitis.

Anaphylatoxins↗
PubMed2006

Cooking birch pollen-related food: divergent consequences for IgE- and T cell-mediated reactivity in vitro and in vivo.

BACKGROUND: The major birch pollen allergen Bet v 1 cross-reacts with homologous food allergens, resulting in IgE-mediated oral allergy syndromes (OASs). To avoid this food, allergy allergologists and guidebooks advise patients to consume birch pollen-related foods after heating. OBJECTIVE: We sought to evaluate whether cooked Bet v 1-related food allergens induce IgE- and T cell-mediated reactions in vitro and in vivo. METHODS: Recombinant Bet v 1, Mal d 1 (apple), Api g 1 (celery), and Dau c 1 (carrot) were incubated at increasing temperatures. Protein structures were determined by means of circular dichroism. Mediator release was tested in basophil activation assays. PBMCs and Bet v 1-specific T-cell lines with known epitope specificity were stimulated with native and cooked food allergens. Patients with birch pollen allergy who experienced OAS and the exacerbation of atopic dermatitis (AD) on ingestion of fresh apple, celery, or carrot were retested in double-blind, placebo-controlled food challenges with the respective foods in cooked form. RESULTS: In vitro, cooked food allergens lost the capacity to bind IgE and to induce mediator release but had the same potency to activate Bet v 1-specific T cells as native proteins. In vivo, ingestion of cooked birch pollen-related foods did not induce OAS but caused atopic eczema to worsen. CONCLUSION: T-cell cross-reactivity between Bet v 1 and related food allergens occurs independently of IgE cross-reactivity in vitro and in vivo. In patients with AD, the resulting immune reaction can even manifest as late eczematous skin reactions. Therefore the view that cooked pollen-related foods can be consumed without allergologic consequences should be reconsidered. CLINICAL IMPLICATIONS: Symptom-free consumed pollen-related food allergens might cause T cell-mediated late-phase skin reactions in patients with pollen allergy and AD.

Allergens↗
PubMed2006

Critical involvement of IL-12 in IFN-gamma induction by calcineurin antagonists in activated human lymphocytes.

Calcineurin antagonists are known as potent immunosuppressants working particularly on T cells by virtue of their capacity to block nuclear factor of activated T cell (NFAT) activation and translocation to the nucleus. In addition to interleukin (IL)-2 suppression, T helper cell type 1 (Th1) as well as Th2 cytokine transcription is blocked by calcineurin antagonists. Here, we show that calcineurin antagonists such as cyclosporin A (CsA) or tacrolimus can markedly enhance the production of interferon-gamma (IFN-gamma) by human T cells. This increased IFN-gamma production is dependent on T cell receptor (TCR) and CD28 signaling as well as on the presence of IL-12. IL-27, which could mimic the effect of IL-12, was however less potent in inducing IFN-gamma production in the presence of CsA and TCR stimulation. Other cytokines such as IL-23, IL-18, IL-2, or the Th2-related cytokine IL-4 are not able to support a calcineurin antagonist-dependent up-regulation of IFN-gamma. CsA-dependent IFN-gamma production is observable in therapeutic concentrations. The effect is independent of IL-10 or IL-4, as addition of these cytokines could not inhibit the CsA-induced IFN-gamma production. The effect of calcineurin antagonists is associated with an increased c-fos expression and DNA-binding activity of the transcription factor activated protein-1 but not with increased DNA-binding activity of T-bet. Our study further supports the relevance of known calcineurin activities other than NFAT activation. The presented data may help to explain why concomitant infections (resulting in increased IL-12 expression) under therapy with calcineurin antagonists often have a negative impact on the activity of the underlying disease (e.g., autoimmune disease).

CD28 Antigens↗
PubMed2006

Age related, structured educational programmes for the management of atopic dermatitis in children and adolescents: multicentre, randomised controlled trial.

OBJECTIVE: To determine the effects of age related, structured educational programmes on the management of moderate to severe atopic dermatitis in childhood and adolescence. DESIGN: Multicentre, randomised controlled trial. SETTING: Seven hospitals in Germany. PARTICIPANTS: Parents of children with atopic dermatitis aged 3 months to 7 years (n = 274) and 8-12 years (n = 102), adolescents with atopic dermatitis aged 13-18 years (n = 70), and controls (n = 244, n = 83, and n = 50, respectively). INTERVENTIONS: Group sessions of standardised intervention programmes for atopic dermatitis once weekly for six weeks or no education (control group). MAIN OUTCOME MEASURES: Severity of eczema (scoring of atopic dermatitis scale), subjective severity (standardised questionnaires), and quality of life for parents of affected children aged less than 13 years, over 12 months. RESULTS: Significant improvements in severity of eczema and subjective severity were seen in all intervention groups compared with control groups (total score for severity: age 3 months to 7 years - 17.5, 95% confidence intervals - 19.6 to - 15.3 v - 12.2, - 14.3 to - 10.1; age 8-12 years - 16.0, - 20.0 to - 12.0 v - 7.8, - 11.4; - 4.3; and age 13-18 years - 19.7, - 23.7 to - 15.7 v - 5.2, - 10.5 to 0.1). Parents of affected children aged less than 7 years experienced significantly better improvement in all five quality of life subscales, whereas parents of affected children aged 8-12 years experienced significantly better improvement in three of five quality of life subscales. CONCLUSION: Age related educational programmes for the control of atopic dermatitis in children and adolescents are effective in the long term management of the disease.

Adolescent↗
PubMed2006

A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of pemphigus.

OBJECTIVE: To investigate the safety and efficacy of oral methylprednisolone combined with azathioprine sodium or mycophenolate mofetil for the treatment of pemphigus. DESIGN: A prospective, multicenter, randomized, nonblinded clinical trial to compare 2 parallel groups of patients with pemphigus (pemphigus vulgaris and pemphigus foliaceus) treated with oral methylprednisolone plus azathioprine or oral methylprednisolone plus mycophenolate mofetil. Settings Thirteen departments of dermatology in Germany. Patients We included patients with pemphigus vulgaris (n = 33) or pemphigus foliaceus (n = 7) evidenced by clinical lesions suggestive of pemphigus, intraepidermal blistering on histological analysis of skin biopsy specimens, intercellular deposition of IgG within the epidermis, and immunoblot analysis findings for antidesmoglein 3 and/or antidesmoglein 1 autoantibodies. MAIN OUTCOME MEASURES: The cumulative total methylprednisolone doses and rate of remission. Secondary outcome measures were safety profiles and duration of remission. RESULTS: In 13 (72%) of 18 patients with pemphigus receiving oral methylprednisolone and azathioprine, complete remission was achieved after a mean +/- SD of 74 +/- 127 days compared with 20 (95%) of 21 patients receiving oral methylprednisolone and mycophenolate mofetil in whom complete remission occurred after a mean +/- SD of 91 +/- 113 days. The total median cumulative methylprednisolone dose used was 8916 mg (SD, +/-29 844 mg) in the azathioprine group compared with 9334 mg (SD, +/-13 280 mg) in the mycophenolate group. In 6 (33%) of 18 patients treated with azathioprine, grade 3 or 4 adverse effects were documented in contrast to 4 (19%) of 21 patients who received mycophenolate mofetil. Conclusion Mycophenolate mofetil and azathioprine demonstrate similar efficacy, corticosteroid-sparing effects, and safety profiles as adjuvants during treatment of pemphigus vulgaris and pemphigus foliaceus.

Administration, Oral↗
PubMed2006

Proceedings of the 4th Georg Rajka International Symposium on Atopic Dermatitis, Arcachon, France, September 15-17, 2005.

The 4th Georg Rajka International Symposium on Atopic Dermatitis presented a comprehensive view of our current understanding and management of atopic dermatitis (AD). These proceedings highlight contributions related to the history of AD doctrines; genetic and epigenetic background; epidemiology; maturation of the immune system; infection and innate-adaptive immunity; epidermal inflammation, including neurogenic inflammation and pruritus; animal models; skin barrier; evidence-based therapy and education programs; prognostic and severity markers; and allergy testing. Several studies in animal models and human subjects point to impaired skin barrier function as a primary defect that facilitates the effect of environmental factors and immune dysregulation found in AD. The new frontier in AD therapy should, in the near future, reflect our better understanding of the skin barrier. The influence of environmental factors on the skin and other epithelial barriers in the perinatal period needs to be better understood to implement appropriate prevention programs.

Animals↗
PubMed2006

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↗
PubMed2006

IL-13-stimulated human keratinocytes preferentially attract CD4+CCR4+ T cells: possible role in atopic dermatitis.

Skin inflammation in atopic dermatitis (AD) is characterized by the predominant infiltration of T-helper (Th)2-cells in lesional skin. However, the mechanism of recruitment of these cells in lesional skin of AD is not yet fully elucidated. In this study, we investigated the role of IL-13-stimulated human primary keratinocytes (HPKs) in the recruitment of lymphocytes and further delineated the mechanism of enrichment of these cells. In the migration assays, we observed preferential enrichment of CD4(+)CCR4(+) T cells towards IL-13-stimulated HPKs. Interestingly, CD4(+)CCR4(+) T cells from AD showed a higher chemotactic response than those from healthy individuals. We observed a significant increase in the expression of CCL22 in IL-13-stimulated HPKs as compared to unstimulated cells. Blocking of CCL22 in IL-13-stimulated HPKs by a neutralizing antibody resulted in 70-90% inhibition in migration of CD4(+)CCR4(+) T cells. Moreover, IL-13 upregulated IFN-gamma-induced chemokines, CCL2 and CCL5, in HPKs. Taken together, our data suggest that IL-13-stimulated HPKs participate in a positive feedback loop by preferentially enriching Th2-cells in lesional skin of acute AD patients. However, in chronic phase, IL-13 may act in synergy with IFN-gamma resulting in lymphocytes recruitment of a mixed phenotype at the site of inflammation, thus contributing to the chronification of eczema.

CD4-Positive T-Lymphocytes↗
PubMed2006

Interaction of keratinocytes with infiltrating lymphocytes in allergic eczematous skin diseases.

PURPOSE OF REVIEW: Eczematous skin diseases, including atopic dermatitis, are characterized by T-cell infiltration into the epidermal compartment. Whereas an active role of the main constituents of the epidermis, the keratinocytes, has long been neglected, it has become clear in the last decade that they are important, immunological active cells. This review highlights the recent work published between March 2005 and May 2006 that expands our knowledge about keratinocyte-T-cell interactions in epidermal immune responses, with emphasis on the pathogenesis of eczematous skin diseases in humans, mainly atopic dermatitis. RECENT FINDINGS: The cross-talk between T cells and keratinocytes is only partially understood. Recent studies suggest that in certain micromilieu settings, keratinocytes are capable of regulating the response of CD4+, CD8+ as well as regulatory T cells. Keratinocytes, however, respond to T helper type 1 and type 2-derived mediators which often exert synergistic effects on these cells. So far, only very few studies have investigated how T-cell-keratinocyte interaction influences the outcome of inflammatory responses in autologous human systems. SUMMARY: Keratinocytes play an active part during the acute and the chronic phase of eczema by means of cytokine production and surface molecule expression which leads to an inflammatory infiltrate in the upper layers of the skin.

Dermatitis, Allergic Contact↗
PubMed2006

Allergic manifestations of skin diseases--atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease which often becomes manifest in early infancy and is characterized by itchy eczematous lesions with characteristic localization. The cellular infiltrate of allergic eczematous skin diseases (i.e. AD, allergic contact dermatitis) is mainly composed of mononuclear cells. Whereas allergic contact dermatitis is always triggered by allergen-specific T cells, a number of allergic and nonallergic trigger factors appear to be relevant in AD. This article discusses data coming from immunological studies focusing on T-cell responses in AD. The concept of a switch from a T helper type 1 (Th1) to a Th2 cytokine profile in lesional skin of AD is well accepted. Besides CD4+ T lymphocytes, CD8+ cells are likely to play an important role in the pathogenesis of AD. Recent studies point to the induction of apoptosis in keratinocytes by interferon-gamma derived from skin-homing T cells as a further important mechanism for the induction and maintenance of the eczema. Recent clinical studies have confirmed the major role of food allergy and infectious microorganisms as trigger factors of AD. New therapeutic strategies for AD include topical calcineurin inhibitors which were introduced as a new therapeutic principle at the beginning of this decade.

Allergens↗
PubMed2005

Histamine H4 receptor stimulation suppresses IL-12p70 production and mediates chemotaxis in human monocyte-derived dendritic cells.

There is increasing evidence that histamine as an important mediator of immediate type allergic reactions also effects professional APCs. Recent reports showed effects of histamine on human monocyte-derived dendritic cells (MoDC) mediated primarily via histamine H1 receptors (H1R) and H2R. We show here that MoDC also express H3R and H4R at the mRNA and protein level. mRNA of the H3R is down-regulated and mRNA of the H4R is up-regulated during the differentiation from monocytes to MoDC. H4R or H2R stimulation suppressed IL-12p70 production in MoDC. Induction of cAMP was necessary for IL-12p70 inhibition mediated via the H2R. In contrast, H4R stimulation did not affect cAMP production but induced the transcription factor AP-1, and U0126, an inhibitor of AP-1 transactivation and MEK, rescued H4R mediated IL-12p70 suppression. Moreover, MoDC responded to a H4R agonist (and also to a H2R agonist) with increased F-actin polymerization and migration in modified Boyden chamber assays, suggesting a chemotactic effect of histamine via the H2R and the H4R. Thus, H4R stimulation on MoDC results in immunomodulatory and chemotactic effects. Histamine induces chemotaxis and IL-12p70 suppression via different receptors using different signaling pathways, which might be important for the pathogenesis of and therapeutic interventions in allergic diseases.

Cell Differentiation↗
PubMed2005

Long-term control of atopic dermatitis with pimecrolimus cream 1% in infants and young children: a two-year study.

OBJECTIVE AND METHODS: The safety and efficacy of treatment with pimecrolimus cream 1% was evaluated for up to 2 years in infants and young children with atopic dermatitis. Ninety-one patients participated in a 1-year, open-label extension to a 1-year double-blind study. Of these, 76 received pimecrolimus for 2 years. Pimecrolimus was applied twice daily at the first signs or symptoms of the disease until clearance. Outcome measures included the incidence of adverse events and the Eczema Area and Severity Index (EASI). RESULTS: No patient discontinued because of adverse events. The incidence of systemic and skin infections did not increase over time. Over the 2-year period, 2 patients experienced an episode of clinically diagnosed eczema herpeticum. In patients receiving pimecrolimus for 2 years, the mean decrease in EASI score from baseline was 68.7% at 3 months and 70.8% at 24 months. CONCLUSION: Treatment with pimecrolimus cream 1% for up to 2 years was well tolerated and resulted in a marked and sustained improvement of atopic dermatitis.

Administration, Cutaneous↗
PubMed2005

Human keratinocytes respond to interleukin-18: implication for the course of chronic inflammatory skin diseases.

Interleukin (IL)-18 has been described to play a role in several inflammatory skin diseases such as eczema and psoriasis. In this study, we aimed to elucidate keratinocytes as potential targets for IL-18 effects. In human primary keratinocytes expression of IL-18Ralpha as well as responses to IL-18 were determined. In keratinocytes freshly isolated from skin biopsies of lesional atopic dermatitis or psoriasis, we observed a significantly higher expression of the IL-18Ralpha as compared with keratinocytes from normal donors. A marked upregulation was induced in vitro upon stimulation with interferon (IFN)gamma+tumor necrosis factor (TNF)alpha or poly I:C. IL-4 led to downregulation of IL-18Ralpha. IL-18-induced CXCL10/IP-10 production in freshly isolated keratinocytes from lesional psoriasis as well as in cultured normal keratinocytes. Furthermore, IL-18 upregulated major histocompatibility complex (MHC) class II expression on IFNgamma-stimulated keratinocytes. This was of functional significance as verified in coculture experiments with CD4+ T cells in the presence of superantigen. T cells produced significant amounts of IFNgamma after coculture with IL-18-induced MHC class II expressing keratinocytes. In conclusion, we have shown that keratinocytes functionally respond to IL-18 with upregulation of MHC II and production of the chemokine CXCL10/IP-10. These findings further support an important role of IL-18 in inflammatory skin diseases in the epidermal compartment.

CD4-Positive T-Lymphocytes↗