Diss. (sammanfattning) Linköping : Linköpings universitet, 2005. / Härtill 6 uppsatser.

Les eczémas [eczéma allergique de contact (EAC) et l'eczéma atopique (EA)] sont des dermatoses inflammatoires fréquentes des pays industrialisés. Elles sont induites suite au recrutement et à l'activation dans la peau de lymphocytes T spécifiques d'allergènes, qui sont présents dans notre environnement, et qui sont habituellement très bien tolérés par la majoritédes individus exposés. Ce travail de thèse porte sur un aspect novateur de la physiopathologie des eczémas, à savoir : la contribution des lymphocytes T mémoires résidants (LTrm) dans la peau à la chronicité et à la sévérité de ces maladies.Capitalisant sur des modèles précliniques pertinents ainsi que sur des échantillons cliniques prélevés chez les patients, ce travail a permis d'acquérir de nouvelles connaissances : (i) de nombreux LTrm CD8+ spécifiques colonisent les lésions d'eczéma (ii) ils s'accumulent avecla persistance de l'allergène dans la peau, (iii) ils jouent un rôle majeur dans les récidives de la maladie, mais (iv) ils expriment à leur surface divers récepteurs inhibiteurs, tels que PD-1 ou TIM-3, qui empêchent la survenue de réponses allergiques excessives.Ces travaux apportent donc des informations majeures sur la nature unique des LTrm CD8+ spécifiques d'allergènes et des mécanismes qui contrôlent leur réactivation, afin de préserver l'intégrité de la peau et la survenue de réactions chroniques sévères. Le développement des nouvelles stratégies thérapeutiques ciblant la réactivation des LTrm via leurs récepteursinhibiteurs pourrait permettre de restaurer la tolérance chez les individus allergiques / Allergic contact dermatitis (ACD) and atopic dermatitis (AD), also referred to contact or atopic eczema, are frequent skin inflammatory diseases with increasing prevalence and high socioeconomic impact in Western countries. Eczemas are the prototype of skin delayed-type hypersensitivity reactions. Skin lesions are induced by the recruitment and activation in the skin of effector/memory T cells specific for environmental antigens that are innocuous to healthy non-allergic individuals.The aim of this work was to better understand the pathophysiology of eczemas by a comprehensive analysis of the contribution of skin resident memory T cells (Trm) to the chronicity and severity of these diseases.Capitalizing on relevant preclinical eczema models and on clinical samples collected from allergic patients, this work showed that: (i) numerous allergen-specific CD8+Trm colonize the eczema lesion, (ii) they accumulate in the epidermis in response to the long-term persistence of the allergen in the skin, (iii) they are instrumental for the recurrence of eczema, but (iv) theyexpress several inhibitory check point receptors (ICRs, such as PD-1, TIM-3) at their surface, which keep them in check to prevent the development of severe immunopathology.Thus, our work provides important information for considering the unique nature of hapteninduced CD8+ Trm and the mechanisms that prevent their unwanted reactivation and subsequent development of chronic or severe skin allergy. The development of therapeutic strategies targeting the reactivation of skin Trm in situ via their ICRs should open new avenues to restore tolerance in allergic individuals

Submitted by Geandra Rodrigues (geandrar@gmail.com) on 2018-10-10T13:46:10Z No. of bitstreams: 1 ingridpimentelcunhamagalhaesdesouzalima.pdf: 1571962 bytes, checksum: 521511b66ed89adf27b01a59f98c7cfc (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-10-16T13:34:14Z (GMT) No. of bitstreams: 1 ingridpimentelcunhamagalhaesdesouzalima.pdf: 1571962 bytes, checksum: 521511b66ed89adf27b01a59f98c7cfc (MD5) / Made available in DSpace on 2018-10-16T13:34:14Z (GMT). No. of bitstreams: 1 ingridpimentelcunhamagalhaesdesouzalima.pdf: 1571962 bytes, checksum: 521511b66ed89adf27b01a59f98c7cfc (MD5) Previous issue date: 2018-08-24 / O objetivo do presente estudo é avaliar a positividade do teste cutâneo de contato alérgico de leitura tardia para Dermatophagoides pteronyssinus, Dermatophagoides farinae e Blomia tropicalis em pacientes com doenças respiratórias como rinite alérgica e/ou asma com ou sem dermatite atópica. A maioria dos trabalhos existentes nessa área de pesquisa se refere ao emprego desse método diagnóstico na dermatite atópica, mas, neste estudo, a amostra é composta, principalmente, de pacientes com doenças respiratórias. Blomia tropicalis é um ácaro muito incidente no Brasil e só há dois trabalhos que envolvem o emprego deste ácaro da poeira domiciliar típico de países de clima tropical. Os pacientes foram selecionados pela história clínica e foram divididos em dois grupos: I- pacientes com doenças respiratórias, como asma e/ou rinite alérgica, com dermatite atópica e II- pacientes somente com doenças respiratórias. Foi realizado teste cutâneo de leitura imediata e teste de cutâneo de contato alérgico de leitura tardia para os três ácaros no mesmo dia. O teste de contato alérgico foi retirado em 48 horas. A análise estatísitica foi realizada em porcentagens e a tabela 1 apresenta as variáveis por sexo e por grupo estudado. Setenta e quatro pacientes, com idades de 2 a 60 anos, foram incluídos neste estudo; 16 no grupo I e 58 no grupo II. Considerando o teste cutâneo de leitura imediata, o ácaro mais prevalente foi o Dermatophagoides pteronyssinus, seguido pelo Dermatophagoides farinae e Blomia tropicalis. Em relação ao teste cutâneo de contato alérgico de leitura tardia, o ácaro que induziu maior positividade foi o Dermatophagoides farinae (78,4%), seguido pelo Dermatophagoides pteronyssinus (77%) e Blomia tropicalis (52,7%). Comparando o teste cutâneo de leitura imediata com o teste cutâneo de contato alérgico de leitura tardia, 53 pacientes (71,6%) foram positivos para ambos os testes, e 30 (56,6%) foram positivos ao mesmo ácaro. Foram identificados seis pacientes (8%) que tinham história clinica positiva para alergia e só apresentavam positividade no teste cutâneo de contato alérgico de leitura tardia. Estes resultados sugerem que o teste cutâneo de contato alérgico de leitura tardia é relevante e deve ser considerado como um teste diagnóstico adicional, em pacientes com história clínica positiva para doenças respiratórias, com teste cutâneo de leitura imediata negativa. / The aim of this study is to evaluate the positivity rates of atopy patch tests for Dermatophagoides pteronyssinus, Dermatophagoides farinae and Blomia tropicalis in patients with respiratory diseases such as asthma and allergic rhinitis with or without atopic dermatitis. Most studies have been performed with atopic dermatitis patients, but in our study, most of the patients had respiratory conditions. Blomia tropicalis is a mite that is prevalent in tropical areas, such as Brazil, and only two publications include these three mites, which are present in Brazil. The patients’ clinical histories were collected, and the patients were subjected to skin prick and patch tests with the three different house dust mites on the same day. The patch tests were examined 48 hours later, and then, the patients were divided into two groups: I- patients with respiratory diseases, such as asthma and/or rhinitis, and atopic dermatitis and II-patients with only respiratory diseases. The statistical analysis results are presented as percentages, and Table 1 presents the variables by gender and groups studied. A total of 74 patients ranging in age from 2 to 60 years old were included in this study; 16 patients were included in group I and 58 were included in group II. In the skin prick tests, the most prevalent mite that evoked a reaction was Dermatophagoides pterronyssinus, followed by Dermatophagoides farinae and Blomia tropicalis. Regarding the atopy patch tests, the mite that most frequently induced a positive reaction was Dermatophagoides farinae (78.4%), followed by Dermatophagoides pteronyssinus (77%) and Blomia tropicalis (52.7%). A comparison between the skin prick and atopy patch tests revealed that 53 patients (71.6%) were positive on both tests, and 30 (56.6%) patients were positivite for the same mite. We found six patients (8%) who had a positive clinical history of allergy and only exhibited positivity on the atopy patch test. These results suggest that the mite atopy patch test is relevant and should be considered as an additional test for patients with clinical histories of allergic respiratory disease who have negative prick test results.

Contexte : La prévalence de l'asthme et des allergies a augmenté au cours de ces dernières décennies,en particulier chez les enfants et dans le monde occidental. Cette augmentation de la prévalence estdevenue un problème très grave de santé publique et pourrait être liée à une combinaison deprédisposition génétique, de facteurs environnementaux et des changements dans le mode de vie, ycompris les habitudes alimentaires. Cependant, les études épidémiologiques concernant les maladiesallergiques chez l’enfant en relation avec l'alimentation sont rares.Objectifs : Ce travail analyse la littérature récente traitant l'alimentation, les habitudes alimentaires et lanutrition en relation avec les maladies allergiques chez les enfants en tenant compte de la méthodologieutilisée pour évaluer les habitudes alimentaires. En outre, il évalue en premier lieu l'association entre leshabitudes alimentaires et l'asthme et les maladies allergiques et en deuxième lieu la relation entrel'asthme et le surpoids/l’obésité dans l’étude des six villes françaises.Méthodes : MEDLINE/PubMed et Cochrane Database of Systematic Reviews ont été utilisés pour larevue de la littérature concernant l'alimentation et les maladies allergiques. Des études transversales ontété menées à Bordeaux, Clermont-Ferrand, Créteil, Marseille, Reims, Strasbourg sur 7 432 enfantsscolaires, choisis au hasard et âgés de 9-11 ans. Des questionnaires adressés aux parents, basés surl'Enquête internationale sur l'asthme et les allergies dans l'enfance (ISAAC), ont été utilisés pourrecueillir des informations sur les maladies allergiques et les facteurs de risque potentiels, y compris unquestionnaire de fréquence alimentaire pour évaluer les habitudes alimentaires des enfants. Des testscutanés aux allergènes communs ont été effectués afin d'identifier l'existence d'une hypersensibilitéallergique et des tests d’effort ont été effectués pour évaluer l'asthme à l’effort.Résultats : Les apports moyens de 12 principaux produits alimentaires consommés par les élèves ontété calculées et trois profils alimentaires ont été extraits par analyse en composantes principales:l’alimentation proche du régime méditerranéen, l’alimentation à base d’oméga-3 et de poissons gras etl’alimentation non équilibrée. Les risques relatifs des maladies allergiques ont été estimés par des odds7ratios (OR) et le contrôle des facteurs de confusion a été réalisé par des régressions logistiques. Lessifflements, l’asthme et la rhinite sont plus fréquents chez les garçons que chez les filles. En analysemultivariée, l’alimentation à base d’oméga-3 avait un effet protecteur contre l'asthme vie et l’asthmesévère chez les enfants (OR ajusté: 0,77 ; IC 95%: [0,62 -0,96] et OR ajusté: 0,55 ; IC 95%: [0,32 -0,94]respectivement). L’adhérence à une alimentation proche du régime méditerranéen et riche enantioxydants semble avoir un effet protecteur contre les maladies allergiques. Le surpoids et l’obésitéont été positivement associés avec l’asthme vie chez les enfants ne présentant pas de sifflements (ORajusté: 1,98 ; IC 95%: [1,06 -3,70]) et ont été de même associé positivement avec la rhinite vie et larhinite 12 mois chez les enfants présentant des sifflements (OR ajusté: 1,63 ; IC 95%: [1,09 -2,45] etOR ajusté: 2,20 ; IC 95%: [1,13 -4,27] respectivement), mais pas avec l’asthme à l’effort.Conclusion: Dans l'ensemble, l'adhésion à un régime alimentaire sain, y compris les antioxydants et lesoméga-3 semble avoir un effet protecteur sur l'asthme et les allergies chez les enfants. Le surpoids etl’obésité a été associé significativement avec l’asthme chez les enfants non atopiques et la rhiniteallergique chez les enfants atopiques. Des études prospectives longitudinales sont donc nécessaires pourpouvoir évaluer les relations de causalité. / Background: The prevalence of asthma and allergy has risen in recent decades, especially amongchildren and in the Western world. This increase in prevalence has become a serious public healthproblem and might be related to a combination of genetic predisposition, environmental factors, andlifestyle changes, including dietary habits. However, epidemiological studies concerning childhood dietrelatedallergic diseases are scarce.Objectives: This work reviews published literature dealing with diet, dietary patterns and nutrition inrelation with allergic diseases among children taking into account the methodology used to evaluatedietary patterns. Moreover, it assesses primary the association between food patterns and asthma andallergic diseases and secondary the relation between asthma and overweight/obesity in the French SixCities Study.Methods: MEDLINE/PubMed and Cochrane Database of Systematic Reviews were used for theliterature review concerning diet and allergic diseases. Cross-sectional studies were conducted inBordeaux, Clermont-Ferrand, Créteil, Marseille, Reims, and Strasbourg among 7432 randomly selectedschoolchildren aged 9-11 years. Parental questionnaires, based on the International Study on Asthmaand Allergies in Childhood (ISAAC), were used to collect information on allergic diseases and potentialrisk factors including a food frequency questionnaire to evaluate dietary habits. Skin prick testing tocommon allergens was performed to identify the existence of an allergic hypersensitivity and exercisetest was performed to assess Exercise-Induced Asthma (EIA).Results: The mean intakes of 12 main food items were calculated and three food patterns wereextracted by principal component analysis labeled: the Mediterranean-like diet, the diet rich in omega-3fatty acids and the unhealthy diet. Relative risks of allergic diseases were estimated as odds ratios (OR)and confounders control was performed with multiple logistic regressions. Wheezing, asthma andrhinitis were more prevalent in boys than in girls. In the multivariate analysis, diet rich in omega-3 wasprotective for lifetime and severe asthma in children (adjusted OR: 0.77; 95% CI: [0.62 -0.96] and9adjusted OR: 0.55; 95% CI: [0.32 -0.94] respectively). Adherence to the Mediterranean-like diet rich inantioxidants tended to be protective against allergic diseases. Overweight and obesity were positivelyassociated with lifetime asthma in non-wheezing children (adjusted OR: 1,98 ; 95% CI: [1,06 -3,70])and were also positively associated with lifetime and past year allergic rhinitis in wheezing children(adjusted OR: 1.63; 95% CI: [1.09 -2.45] and adjusted OR: 2.20; 95% CI: [1.13 -4.27] respectively), butwere not associated with EIA.Conclusion: Overall, adherence to a healthy diet including antioxidants and omega-3 fatty acids seemsto have a protective effect on asthma and allergy in childhood. Overweight and obesity weresignificantly associated with asthma in non-atopic children and with allergic rhinitis in atopic children.Prospective longitudinal studies should be necessary for evaluation of causal relations.

Background: Evidence-based treatment algorithms, successfully established for asthma, are missing for atopic eczema (AE). Objectives: To investigate whether treatment according to an evidence-based algorithm is an effective and applicable concept for the management of AE. Methods: Based on a systematic literature review, we developed an evidence-based severity-score-oriented treatment algorithm for AE and compared its effectiveness to that of an individualised symptom-oriented treatment (individual therapy) in a randomised controlled trial. Sixty-three participants were randomised to algorithm (n = 32) or individual therapy (n = 31) and treated accordingly for 12 months. Study end points included difference between baseline SCORAD and mean SCORAD under treatment (primary end point), quality of life and treatment utilisation. Analysis was by intention to treat (registration: ClinicalTrials.gov:NCT00148746). Results: No statistically significant differences in clinical or subjective response were observed between groups. Treatment following the algorithm and individual treatment both effectively controlled AE. Mean SCORAD reductions were 47% (95% confidence interval, CI = 38–55; algorithm) and 42% (95% CI = 29–54; individual). Clinical response was paralleled by improved quality of life in both groups. Physicians adhered to the algorithm option in 93% of their treatment decisions. Conclusion: Treatment following an evidence-based algorithm is an effective and applicable concept for the management of AE but does not show clear advantages compared to individualised treatment in a dermatological setting. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Background: Financial constraints challenge evidence of the effectiveness of dermatological inpatient management. Objective: To evaluate the effectiveness of hospitalization in atopic dermatitis and psoriasis regarding initial and sustained benefits. Methods: Prospective study on adults with psoriasis vulgaris (n = 22) and atopic dermatitis (n = 14). At admission, discharge, and 3 months after discharge, validated outcomes of objective and subjective disease severity were assessed by trained investigators. Results: Hospitalization resulted in substantial benefit in quality of life and clinical disease severity. Looking at mean scores, the observed benefit appeared stable until 3-month follow-up. The analysis of individual patient data revealed significant changes in disease severity between discharge and 3-month follow-up with some patients relapsing, others further improving. Reasons for hospitalization and treatment performed were not related to sustained benefit. Conclusions: In psoriasis vulgaris and atopic dermatitis, hospitalization effectively improved quality of life and clinical disease severity. Further research should focus on prognostic factors for sustained improvement. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Background: Pimecrolimus cream 1% is a non-steroid, selective inflammatory cytokine inhibitor indicated for atopic dermatitis (AD). Objective: To compare the safety and efficacy of pimecrolimus cream 1%-based treatment versus conventional therapy in adults with moderate AD. Methods: Patients were randomized to receive pimecrolimus cream 1% (n = 62) or vehicle (n = 68) at the first signs/symptoms of AD, for 24 weeks as required. A moderately potent topical corticosteroid (prednicarbate 0.25% cream) was allowed in both groups to treat flares. Results: Corticosteroids were required on fewer days in the pimecrolimus group, compared with the vehicle group (9.7 vs. 37.8%, p < 0.001). Furthermore, 59.7% of pimecrolimus-treated patients experienced no flares during the study period, compared with 22.1% of vehicle-treated patients (p < 0.001). Pimecrolimus cream 1% was well tolerated throughout the study. Conclusion: For adults with moderate AD, pimecrolimus cream 1% is well tolerated, reduces the incidence of flares, reduces/eliminates corticosteroid use, improves long-term disease control and enhances the patients’ quality of life. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Background: Pimecrolimus cream (Elidel®, SDZ ASM 981), a non-steroid inhibitor of inflammatory cytokines, is effective in the treatment of atopic dermatitis (AD). We assessed whether early treatment of AD signs/symptoms reduces the need for topical corticosteroids. Objective: To investigate the efficacy and safety of pimecrolimus cream 1% in the long-term management of adult AD. Methods: 192 adults with moderate to severe AD were randomised (1:1) for twice daily (b.i.d.) treatment of early signs or symptoms of AD with either pimecrolimus cream 1% or vehicle cream (control group) to prevent progression to flares. Treatment was given as needed for 24 weeks. In the event of flares, a moderately potent corticosteroid (prednicarbate 0.25% cream) was permitted as rescue medication in both groups. The percentage of days on which a topical corticosteroid was used to treat disease flares was the main outcome measure. Results: Corticosteroid medication was used on 14.2% (95% confidence interval, CI: 8.3–21.1) of the days of the 24-week treatment period in the pimecrolimus group and on 37.2% (95% CI: 30.4–44.0) of the days in the control group (p < 0.001). In total, 44.8% (43/96) of patients in the pimecrolimus group did not experience a flare compared with 18.8% (18/96) of patients in the control group. The median time to first flare was 144 days in the pimecrolimus group and 26 days in the control group (p < 0.001). Pimecrolimus treatment was also associated with improvement in signs and symptoms of AD, pruritus, patients’ self-assessment and quality of life. Conclusions: Pimecrolimus cream 1% b.i.d. is an effective, well-tolerated, long-term treatment for AD in adults, substantially reducing the number of flares compared to a conventional therapy and consequently reducing or eliminating the need for corticosteroid treatment. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Allergic manifestations are increasingly common in infants and children. Accumulating evidence suggests that the ‘epidemic’ increase of childhood allergy may be associated with environmental factors such as stress. Although the impact of stress on the manifestation and exacerbation of allergy has been demonstrated, the underlying mechanisms of stress-induced exacerbation are still obscure. A growing number of studies have suggested an altered hypothalamus-pituitary-adrenal (HPA) axis function to stress in allergic children. It is speculated that a dysfunctional HPA axis in response to stress may facilitate and/or consolidate immunological aberrations and thus, may increase the risk for allergic sensitization and exacerbation especially under stressful conditions. In the present review the potential impact of a hyporesponsive as well as a hyperresponsive HPA axis on the onset and chronification of childhood allergy is summarized. Moreover, potential factors that may contribute to the development of an aberrant HPA axis responsiveness in allergy are discussed. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Die Haut ist das größte Organ des Menschen und stellt die primäre Barriere gegen Umwelteinflüsse und Pathogene dar. Eine Dysbalance der Hautbarriere birgt die Gefahr einer nachfolgenden Entzündungsreaktion. Bleibt diese bestehen, können sich Hautkrankheiten wie zum Beispiel die atopische Dermatitis (AD) entwickeln. Verschiedene Zytokine wie Thymic Stromal Lymphopoietin (TSLP) werden bei entzündlichen Hauterkrankungen eine bedeutende Rolle zugeschrieben. Die Bedeutung von TSLP wurde zunächst anhand mehrerer Knockout-Mausstämme untersucht. Hier zeigte sich, dass TSLPR-KO und TNF-TSLPR-DKO Mäuse im Gegensatz zu TNF-KO Mäusen keine bzw. weniger Zeichen einer Entzündungsreaktion in der Haut entwickeln. Die Rolle äußerer Einflüsse auf die TSLP-Produktion wurde anhand eines Irritationsmodells ebenfalls in Mäusen untersucht. Dabei führte die Hautirritation, ausgelöst durch Abtragen der oberen Hautschichten mittels eines Tesa-Abriss, zu einem signifikanten Anstieg von TSLP in der Haut?. Mit Hilfe von Agonisten und Inhibitoren konnte gezeigt werden, dass dieser Irritations-vermittelte TSLP-Anstieg über Interleukin-1 (IL-1) und Protease Activated Receptor 2 (PAR-2) vermittelt wird. In diesem Zusammenhang wurde auch gezeigt, dass die Aktivierung von IL-1- sowie PAR-2-abhängigen Signalwegen zu einer gesteigerten Aktivität des TSLP-Promotors führte. Die Untersuchung der Wirkung verschiedener Mastzellmediatoren auf die TSLP-Expression ergab, dass Tryptase, über die Aktivierung von PAR-2, der wichtigste Mediator für den Anstieg von TSLP nach der Degranulation von Mastzellen ist. Dieses Ergebnis wurde mittels verschiedener in vitro, in vivo und ex vivo Experimentalansätze belegt. So konnte in einem c48/80-abhängigen Degranulationsmodell in Mäusen gezeigt werden, dss PAR-2- sowie Mastzell-KO Mäuse im Vergleich zu Wildtypen nach Injektion von c48/80 signifikant weniger TSLP exprimierten. / The skin is the first line of defense against environmental or microbial pathogens. A deviation of the skin barrier homeostasis by any kind of insult can result in an inflammatory response. The inflammatory response in turn can promote the development of an eczemaincluding atopic eczema. Thymic stromal lymphopoietin (TSLP) due to its pleiotropic nature play an important role in inflammatory disorders. The major aim of this thesis was to better understand the underlying mechanisms of TSLP production in the context of skin irritation and mast cell (MC) mediators and their contribution in the development of atopic dermatitis (AD). The role of TSLP was studied using TSLPR-/- mice. The data show that TSLPR-/- and TNF-/-/TSLPR-/- mice were protected from AD development, by contrast TNF-/- mice exhibited severe AD. The role of exogenous triggers was studied using tape stripping mediated skin irritation mouse models. Skin irritation resulted in significant enhanced TSLP production. TSLP induction was identified to depend on interleukin (IL)-1 and protease activated receptor (PAR)-2 pathways proven by using exogenous activators or inhibitors of these pathways. Moreover, PAR-2 and IL-1 concomitantly promoted NF-κB binding to the human TSLP promoter which in turn resulted in an increased TSLP promoter activity. Additionally, the role of mast cell mediators in the context of TSLP induction was investigated. Tryptase turned out to be the trigger responsible for the enhanced TSLP response by activating the PAR-2 pathway. This finding was proven by employing in vitro, ex vivo and in vivo approaches. In detail PAR-2-/- and MC-/- mice were used in a compound 48/80 (C48/80) dependent MCs degranulation model. PAR-2-/- and MC-/- mice produced significantly less TSLP in comparison to control mice.