Parasitische Würmer wie Filarien können das Immunsystem ihres Wirtes modulieren. Diese Immunmodulation schützt nicht nur den Parasiten, sondern kann auch den Wirt vor allergischen Reaktionen schützen. In der vorliegenden Arbeit konnte belegt werden, dass Filariencystatin, ein sezernierter Proteinaseinhibitor des Fadenwurms Acanthocheilonema viteae Th2-assoziierte Entzündungen und die daraus resultierende Atemwegserkrankung im murinen Asthmamodell supprimiert. Diese Effekte von Cystatin beruhen wahrscheinlich auf der Induktion von IL-10 sezernierenden Makrophagen. Dafür spricht, dass sowohl die Depletion von Makrophagen, als auch die Blockierung von IL-10 den schützenden Effekt von Cystatin aufhoben. In einem murinen Dermatitismodell konnte durch Cystatinapplikation die Entzündung der Haut ebenfalls unterbunden werden. Die Verbesserung der atopischen Dermatitis führte zu einem Anstieg von TGF-Beta in den Ekzemregionen. Zusammenfassend belegen die Daten, dass ein einzelnes rekombinantes Helminthenprotein den anti-allergischen Effekt einer Gesamtwurminfektion nachahmen kann. Des weiteren wurde untersucht, ob die Immunmodulation von Helminthen an die Biologie des Wurmes gebunden ist. Der Einfluss einer gastrointestinalen Wurminfektion mit Heligmosomoides polygyrus wurde in Modellen mucosa-assoziierter allergischer Atemwegsentzündung und nicht-mukosa-assoziierter, kutanen Dermatitis untersucht. Im Asthmamodell konnte eine Reduzierung der Inflammation beobachtet werden, im Dermatitis Modell keinerlei Verbesserung des klinischen Bildes. Die Wurminfektion führte zu erhöhten Werten von Foxp3+ regulatorischen T-Zellen (Treg) in peribronchialen Lymphknoten, im Gegensatz dazu konnten keine Treg Zellen in ekzematöser Haut nachgewiesen werden. Diese Ergebnisse sind ein wichtiger Aspekt beim Einsatz von Helminthen zur Behandlung allergischer Erkrankungen, da die Lokalisation des Wurmes ein entscheidender Faktor in Richtung Verbesserung oder Verschlimmerung allergischer Erkrankungen zu sein scheint. / Parasitic worms, like filariae, have the intriguing capacity to modulate immune responses directed against them. This immunomodulation protects the parasite and was found to mediate a negative correlation between parasite infections and the prevalence of allergic disease. In the present study filarial cystatin (Av17), a secreted protease inhibitor of the filarial nematode Acanthocheilonema viteae, was found to suppress Th2-related inflammation and allergic airway responsiveness in mice. These effects of Av17 on allergic airway inflammation were probably due to induction of IL-10 secreting macrophages. Depletion of macrophages as well as blocking of IL-10 by application of anti-IL-10 receptor antibodies, prevented the curative effects and restored allergic airway inflammation. Treatment with cystatin in a model of allergic skin disease, suppressed inflammation, too. The protective effect on atopic dermatitis was accompanied by an increase of TGF-Beta in the eczema region. Hence, the data demonstrate that treatment with a single recombinant helminth protein can exert the anti-allergic effects of helminth infections. Furthermore this study investigated if immunomodulation by helminths is dependent on the biology of the worm. Infection with the gastrointestinal nematode Heligmosomoides polygyrus, was analyzed in models of mucosa-associated airway disease and non-mucosal, cutaneous atopic dermatitis. Infected mice showed reduced signs of allergic airway inflammation but no differences in phenotypical signs of dermatitis. Worm infection was associated with elevated numbers of Foxp3+ regulatory T cells (Treg) in peribronchial lymph nodes in the asthma model, whereas Treg cells were basically absent in eczematous skin. These findings might be an important aspect for future considerations of helminths for treatment of allergic diseases, as localisation of the parasites might be a crucial factor leading to amelioration or aggravation of allergic disease.

Introdução: Eczemas são manifestações inflamatórias da pele. Na infância se destacam a dermatite atópica (DA) e a dermatite de contato (DC). Os testes de contato correspondem a um método auxiliar para diferenciar a dermatite de contato por irritante primário (DCIP) da dermatite de contato alérgica (DCA) e definir a etiologia da DCA. Nos pacientes com DA, têm a faculdade de também auxiliar na identificação de substâncias que possam estar contribuindo para a piora do quadro. Objetivos: verificar a frequência de testes de contato positivos em crianças com hipóteses diagnósticas de DC e de DA associada ou não à DC; obter os principais sensibilizantes nessa faixa etária e comparar os dados obtidos entre os grupos de pacientes com DC e DA. Métodos: Durante o período entre julho de 2007 e agosto de 2009, 62 crianças com idades entre 2 e 12 anos foram submetidas aos testes de contato com a bateria padrão e/ou bateria de cosméticos de testes de contato padronizadas pelo Grupo Brasileiro de Estudos em Dermatite de Contato. As leituras foram realizadas em 48 e 96 horas. Resultados: Entre os 62 pacientes submetidos aos testes de contato, 38 pacientes apresentaram pelo menos um teste de contato positivo e 24, todos negativos. Entre os 44 pacientes com hipótese diagnóstica inicial de DA, 19 tinham DA associada à DCA. Entre os 18 pacientes com hipótese diagnóstica inicial de DC, 12 apresentavam DCA. No total, foram encontrados 76 testes positivos, sendo 53 (70%) relevantes, e 23 (30%) não relevantes com a história clínica do paciente. Os pacientes com DA apresentaram mais testes positivos não relevantes do que os pacientes com hipótese diagnóstica apenas de DC, e essa diferença foi estatisticamente significativa.( 2 = 6,55 e p = 0,01 ). Considerando os testes relevantes com a história clínica, o sulfato de níquel foi o principal sensibilizante com 14 (22,6%) testes positivos, a neomicina foi o segundo sensibilizante mais comum com sete testes positivos (11,3%), e a terceira substância mais comum foi o cloreto de cobalto com quatro (6,4%) testes positivos. Testes não relevantes foram encontrados em 30% do total de substâncias com testes positivos. O timerosol foi positivo em 11 casos, porém em oito pacientes com DA não foram relevantes com a história clínica. Conclusões: Pacientes na faixa etária entre 2 e 12 anos com DA e DC apresentaram testes de contato positivos, e não houve diferenças quanto à frequência dos testes positivos entre esses dois grupos. Os principais sensibilizantes relevantes com a história clínica foram o sulfato de níquel, a neomicina e o cloreto de cobalto, o que está de acordo com vários estudos na literatura. Pacientes com DA apresentaram mais testes falso-positivos que os pacientes com DC, possivelmente por um defeito da barreira cutânea dos pacientes com DA, e maior exposição precoce aos medicamentos tópicos ou emolientes para o controle da DA. Teste de contato em crianças pode ser considerado importante ferramenta para auxiliar no diagnóstico dos eczemas, identificando o agente causador da DC ou de piora nos casos de DA, e deve ser levado em conta em todos esses pacientes / Eczema is a cutaneous inflammatory manifestation in some dermatosis. In children, we highlight atopic dermatitis (AD) and contact dermatitis (CD). Patch tests help to differentiate irritative contact dermatitis (ICD) from allergic contact dermatitis (ACD), and define the etiology of allergic contact dermatitis. In patients with AD, it may also help to identify substances that may contribute to the worsening of this dermatosis. Objectives: To determine the frequency of positive patch tests in children with diagnosis of CD and AD with or without CD; to detect the main sensitizers in this group and compare the results between the groups of patients with CD and AD. Methods: From July 2007 to August 2009, 62 children aged between 2 to 12 years old were patch tested with the Brazilian standard battery of patch tests and cosmetic series. The readings were taken at 48 and 96 hours. Results: Thirty-eight patients had at least one positive patch test reactions and 24, all negative. Among the 44 patients with initial diagnosis of AD, 19 were associated with ACD. Among the 18 patients with initial diagnosis of CD, 12 had ACD. In total, there were 76 positive tests, 53 (70%) relevant, and 23 (30%) not relevant to the patient\'s clinical history. Patients with AD showed more positive tests not relevant than patients with diagnosis of CD only, and this difference was statistically significant. (2 = 6.55 and p = 0.01). Considering the relevant tests, nickel sulphate was the main allergen with 14 (22.6%) positive tests, neomycin was the second with seven positive tests (11.3%), and the third substance was cobalt chloride with four (6.4%) positive tests. Tests not relevant were found in 30% of the total of the positive tests. Thimerosol was positive in 11 cases, but in eight patients with AD were not relevant to the clinical history. Conclusions Patients aged between 2 to 12 years old with AD and CD had positive tests, and there were no differences in the frequency of positive tests between these two groups. The main sensitizers, relevant to the clinical history were nickel sulfate, neomycin and cobalt chloride. This result is consistent with several studies in the literature. Patients with AD showed more false-positive tests than patients with CD, possibly due to a defective skin barrier of AD patients, and earlier exposure to topical emollients and treatments for the control of AD. Patch test in children can be considered an important tool for the diagnosis of eczema, identifying the causative agent of CD or worsening cases of AD, and should be performed in all these patients. The correct interpretation of the patch tests is essential to evaluate the association of ACD in patients with AD and to identify the causative agent of the ACD

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Diss. (sammanfattning) Stockholm : Karol inst., 2004. / Härtill 5 uppsatser.

Introdução: Eczemas são manifestações inflamatórias da pele. Na infância se destacam a dermatite atópica (DA) e a dermatite de contato (DC). Os testes de contato correspondem a um método auxiliar para diferenciar a dermatite de contato por irritante primário (DCIP) da dermatite de contato alérgica (DCA) e definir a etiologia da DCA. Nos pacientes com DA, têm a faculdade de também auxiliar na identificação de substâncias que possam estar contribuindo para a piora do quadro. Objetivos: verificar a frequência de testes de contato positivos em crianças com hipóteses diagnósticas de DC e de DA associada ou não à DC; obter os principais sensibilizantes nessa faixa etária e comparar os dados obtidos entre os grupos de pacientes com DC e DA. Métodos: Durante o período entre julho de 2007 e agosto de 2009, 62 crianças com idades entre 2 e 12 anos foram submetidas aos testes de contato com a bateria padrão e/ou bateria de cosméticos de testes de contato padronizadas pelo Grupo Brasileiro de Estudos em Dermatite de Contato. As leituras foram realizadas em 48 e 96 horas. Resultados: Entre os 62 pacientes submetidos aos testes de contato, 38 pacientes apresentaram pelo menos um teste de contato positivo e 24, todos negativos. Entre os 44 pacientes com hipótese diagnóstica inicial de DA, 19 tinham DA associada à DCA. Entre os 18 pacientes com hipótese diagnóstica inicial de DC, 12 apresentavam DCA. No total, foram encontrados 76 testes positivos, sendo 53 (70%) relevantes, e 23 (30%) não relevantes com a história clínica do paciente. Os pacientes com DA apresentaram mais testes positivos não relevantes do que os pacientes com hipótese diagnóstica apenas de DC, e essa diferença foi estatisticamente significativa.( 2 = 6,55 e p = 0,01 ). Considerando os testes relevantes com a história clínica, o sulfato de níquel foi o principal sensibilizante com 14 (22,6%) testes positivos, a neomicina foi o segundo sensibilizante mais comum com sete testes positivos (11,3%), e a terceira substância mais comum foi o cloreto de cobalto com quatro (6,4%) testes positivos. Testes não relevantes foram encontrados em 30% do total de substâncias com testes positivos. O timerosol foi positivo em 11 casos, porém em oito pacientes com DA não foram relevantes com a história clínica. Conclusões: Pacientes na faixa etária entre 2 e 12 anos com DA e DC apresentaram testes de contato positivos, e não houve diferenças quanto à frequência dos testes positivos entre esses dois grupos. Os principais sensibilizantes relevantes com a história clínica foram o sulfato de níquel, a neomicina e o cloreto de cobalto, o que está de acordo com vários estudos na literatura. Pacientes com DA apresentaram mais testes falso-positivos que os pacientes com DC, possivelmente por um defeito da barreira cutânea dos pacientes com DA, e maior exposição precoce aos medicamentos tópicos ou emolientes para o controle da DA. Teste de contato em crianças pode ser considerado importante ferramenta para auxiliar no diagnóstico dos eczemas, identificando o agente causador da DC ou de piora nos casos de DA, e deve ser levado em conta em todos esses pacientes / Eczema is a cutaneous inflammatory manifestation in some dermatosis. In children, we highlight atopic dermatitis (AD) and contact dermatitis (CD). Patch tests help to differentiate irritative contact dermatitis (ICD) from allergic contact dermatitis (ACD), and define the etiology of allergic contact dermatitis. In patients with AD, it may also help to identify substances that may contribute to the worsening of this dermatosis. Objectives: To determine the frequency of positive patch tests in children with diagnosis of CD and AD with or without CD; to detect the main sensitizers in this group and compare the results between the groups of patients with CD and AD. Methods: From July 2007 to August 2009, 62 children aged between 2 to 12 years old were patch tested with the Brazilian standard battery of patch tests and cosmetic series. The readings were taken at 48 and 96 hours. Results: Thirty-eight patients had at least one positive patch test reactions and 24, all negative. Among the 44 patients with initial diagnosis of AD, 19 were associated with ACD. Among the 18 patients with initial diagnosis of CD, 12 had ACD. In total, there were 76 positive tests, 53 (70%) relevant, and 23 (30%) not relevant to the patient\'s clinical history. Patients with AD showed more positive tests not relevant than patients with diagnosis of CD only, and this difference was statistically significant. (2 = 6.55 and p = 0.01). Considering the relevant tests, nickel sulphate was the main allergen with 14 (22.6%) positive tests, neomycin was the second with seven positive tests (11.3%), and the third substance was cobalt chloride with four (6.4%) positive tests. Tests not relevant were found in 30% of the total of the positive tests. Thimerosol was positive in 11 cases, but in eight patients with AD were not relevant to the clinical history. Conclusions Patients aged between 2 to 12 years old with AD and CD had positive tests, and there were no differences in the frequency of positive tests between these two groups. The main sensitizers, relevant to the clinical history were nickel sulfate, neomycin and cobalt chloride. This result is consistent with several studies in the literature. Patients with AD showed more false-positive tests than patients with CD, possibly due to a defective skin barrier of AD patients, and earlier exposure to topical emollients and treatments for the control of AD. Patch test in children can be considered an important tool for the diagnosis of eczema, identifying the causative agent of CD or worsening cases of AD, and should be performed in all these patients. The correct interpretation of the patch tests is essential to evaluate the association of ACD in patients with AD and to identify the causative agent of the ACD

Background: Birch pollen is an important outdoor allergen able to aggravate symptoms in atopic dermatitis (AD). Specific immunotherapy (SIT), an established procedure for allergic airway diseases, might also represent an attractive therapeutic option for the causal treatment of allergen-triggered cutaneous symptoms in these patients. Studies with house dust mite SIT have already shown beneficial effects in AD patients, whereas the safety and efficacy of SIT with birch pollen extract in AD patients have not been studied so far. The aim of this study was to evaluate for the first time the safety and efficacy of SIT with a depigmented polymerized birch pollen extract in AD patients. Methods: Fifty-five adult patients with moderate-to-severe AD and clinically relevant sensitization to birch pollen received SIT for 12 weeks. SIT was continued during birch pollen season. The assessment of safety, the total SCORAD value, and the Dermatology Life Quality Index (DLQI) were evaluated. Results: The median total SCORAD value was reduced by 34% (p < 0.001) during the course of treatment and the mean DLQI improved by 49% (p < 0.001) despite strong simultaneous birch pollen exposure. Eight patients (14.5%) developed systemic reactions and 19 patients (34.5%) developed local reactions which were of mild intensity in most cases. No patient discontinued the study prematurely due to adverse drug reactions. Coseasonal treatment was well tolerated. Conclusion: SIT with a depigmented polymerized birch pollen extract leads to significant improvement of the SCORAD value and the DLQI in patients suffering from moderate-to-severe AD sensitized to birch pollen. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Contexte : Les dermatoses professionnelles sont l’une des principales causes de pathologies professionnelles en Europe, et dans près de 80% des cas, elles concernent des dermatites de contact professionnelles (DCP). Les DCP comprennent les dermatites allergiques de contact (DAC), les dermatites irritatives de contact (DIC) et les urticaires de contact (UC). En France, les secteurs et nuisances à risque de DCP et les tendances chronologiques de DCP sont très peu documentés. Objectifs : 1) étudier les tendances observées au fil du temps vis-à-vis du nombre de cas de dermatoses professionnelles, des secteurs d’activité concernés et des nuisances mises en cause, 2) mettre en évidence des secteurs ou des postes à risque de dermatoses professionnelles. Méthode : Ce travail de thèse s’appuie sur le réseau français RNV3P (Réseau national de vigilance et de prévention des pathologies professionnelles) qui assure le suivi des évènements de santé liés au travail sur l’ensemble du territoire, en centralisant les informations recueillies dans ses 32 centres de consultations de pathologies professionnelles (CCPP). Les analyses ont porté sur les DAC, les DIC et les UC en lien probable ou certain avec le travail et recensées dans le RNV3P entre 2001 et 2010. L’analyse des évolutions temporelles a été réalisée à partir des rapports de cote de signalement (Reporting Odds-Ratio, ROR). Deux méthodes statistiques ont été utilisées : le coefficient de corrélation de rang de Kendall sur les ROR estimés chaque année et le modèle logistique calculant la variation annuelle des cas. Résultats : Les 5990 cas de DCP notifiés touchent plus fréquemment les femmes, dans des tranches d'âges jeunes. Les principaux secteurs mis en cause pour les trois DCP se distribuent différemment en fonction du sexe et sont, par ordre décroissant de fréquence : santé et action sociale, services personnels, construction, métallurgie et travail des métaux, administrations publiques, services fournis principalement aux entreprises, commerce et réparation automobile, hôtellerie et restauration. Les DCP associées aux cosmétiques (savons ou substances parfumantes) et les biocides augmentent significativement dans le secteur de la santé et de l’action sociale ; les produits de coiffure et les cosmétiques (savons essentiellement) augmentent dans celui des services personnels, essentiellement parmi les coiffeuses. On observe une montée des cas de DAC aux résines époxy dans la construction sur la période et les DIC liées au ciment dans ce secteur ne baissent pas. Les cas de DAC aux métaux augmentent dans le secteur des services fournis aux entreprises (personnels de nettoyage). Nos résultats ont aussi montré une hausse des DAC liées aux isothiazolinones, quel que soit le secteur (+38%) et une baisse des DIC liées à l’action de lavage des mains (utilisation itérative des savons). Par ailleurs, nos données ont objectivé l’impact de mesures réglementaires ou de politiques visant à prévenir les DCP : la mise en place de la directive européenne « Ciment » (2003/53/CE) en 2005 s’est accompagnée d’une réduction de moitié des cas de DAC et une baisse similaire a été observée à partir des données du réseau britannique EPIDERM, confortant nos conclusions ; la campagne de substitution des gants en latex dans le secteur de soins au milieu des années 2000 est suivie d’une réduction significative de la notification des cas d’UC. Conclusion : Ces résultats démontrent, avec l’exemple des dermatoses professionnelles, la capacité du RNV3P à orienter les politiques nationales en matière de prévention des risques professionnels et à en évaluer l’efficacité. / Background: In Europe, occupational skin disease is one of the major causes of work-related diseases, among them occupational contact dermatitis (OCD) accounts for 80% of all cases of OSD reported, but data about sectors and agents at risk remains sparse. Objectives: 1) to study OCD trends in terms of industrial activities and main causal agents, 2) to describe industrial sectors or occupations at risk of OCD. Method: Data were collected from the French National Network of Occupational Disease Surveillance and Prevention (RNV3P) during 2001-2010 period, based on the 32 French Occupational and Environmental Disease Consultation Centres. All allergic contact dermatitis (ACD), irritative contact dermatitis (ICD) and contact urticaria (CU) probably or certainly work-related were included in the study. Trends were examined (i) on annual crude numbers of OCD and (ii) on reported odds-ratios of OCD calculated using logistic regression models. Results: 5990 OCD cases were included and concerned more frequently young age classes among women and older age classes among men. Industrial sectors more commonly involved in OCD concerned in decreasing order: health and social work activities, personal service activities, construction, metal industry, public administrations, other business activities, retail trade and repair of motor vehicles, and hotels and restaurants. According to trend analysis of OCD cases, cosmetics (including soaps and fragrances) and biocides increased significantly in health and social work activities; hairdressing products and cosmetics (mainly soaps) in personal service activities (including primarily hairdressers). In construction sector, ACD due to epoxy resins increased during the study period and concomitantly, ICD attributed to cement did not decrease underlying the lack of prevention in this sector at risk. ACD due to metals increased in other business activities mainly occupied by cleaning staff. We showed a rise of ACD due to isothiazolinone compounds whatever the sector. Besides, we have shown the impact of regulatory measures or prevention campaign on OCD: (i) a significant reduction by almost half in the occurrence of ACD attributed to chromate in cement which coincides with the implementation of the European Cement directive and we obtained similar results to a study based on the UK EPIDERM network; (ii) the effectiveness of latex exposure prevention measures for health care workers since half of 2000s and (iii) the wide use of disinfection with an alcohol-based solution in health and social work activity followed by a significant reduction of ICD due to iterative handwashing with soap. Conclusion: RNV3P data allowed to highlight causal agents involved in sectors most at risk of OCD. These results might help intervention policy in health and safety at work and allergy prevention. They also showed the effectiveness of preventative intervention on OCD, suggesting that RNV3P reporting scheme is useful in France to evaluate intervention policy in health and safety at work.

Mastzellen sind ubiquitär im Bindegewebe vorkommende Zellen, welche eine Vielzahl von Mediatoren physiologischer und pathologischer Prozesse exprimieren. Ihre Zahl ist in gesunden Geweben gering, am höchsten jedoch in der Haut und Schleimhäuten von Nase, Auge und Gastrointestinaltrakt sowie in der Lunge. Die Ergebnisse unserer Arbeitsgruppe zeigen, dass unter pathologischen Bedingungen, insbesondere bei entzündlichen Reaktionen und Erkrankungen des atopischen Formenkreises, die Mastzellzahlen um ein Vielfaches steigen. Dabei werden die Vorläuferzellen des Blutes, welche aus einer CD34+/c-Kit+ hämatopoetischen Stammzelle des Knochenmarkes rekrutiert werden, aktiviert und durch chemotaktisch wirkende Faktoren zur Einwanderung in die Gewebe stimuliert. Unter Verwendung von in vitro Kulturmodellen konnte gezeigt werden, dass diese Vorläuferzellen im Blut die Expression von c-Kit und CD34 herunterregulieren und als Zellpool im peripheren Blut zirkulieren. Nach Aktivierung der Zellen wurde c-Kit wieder nachgewiesen. Die Zellen wandern ins Gewebe ein und differenzieren dort unter Einfluss von Zytokinen, welche durch andere Gewebszellen freigesetzt werden, aus. Es wurden Wechselwirkungen in der Haut zwischen Mastzellen und Fibroblasten, Melanozyten, Keratinozyten und Nervenzellen gezeigt. Als Mittler dieser Wechselwirkungen konnten, neben den in der Literatur beschriebenen Faktoren, von uns SCF, GM-CSF, NGF und andere Neurotrophine zum Beispiel BDNF, NT-3 und NT-4 gezeigt werden. Die Regulation und Freisetzung dieser Faktoren ist bei pathologisch veränderter Haut, wie bei Atopischer Dermatitis, Psoriasis, Haarwachstumsstörungen, Tumoren der Haut und in der Wundheilung verändert. Die Modulation der Expression dieser Faktoren und ihrer Rezeptoren durch verschiedene Therapeutika, wie Glukokortikoide, Antihistaminika, Retinoide und UV-Bestrahlung konnte in verschiedenen Kulturmodellen gezeigt werden. Diese Erkenntnisse können in Zukunft bei der Entwicklung neuer Therapeutika zur Behandlung von verschiedenen Erkrankungen der Haut, Lunge sowie Darm und, da in zunehmendem Maße auch von Mastzellfunktionen in anderen Organen, wie Hirn, Herz, Leber und Niere berichtet wird, auch hier weiterführend beitragen. / Mast cells are ubiquitary connective tissue cells derived from bone marrow CD34+/c-Kit+ stem cells. They are able to produce various regulators of physiological and pathological processes. Normally, they are present in low numbers with highest density in skin and nasal, ophthalmic, gastrointestinal and pulmonary mucosa. The number is increased up to 100-fold in various pathological processes as inflammatory reactions and atopic diseases. During this processes mast cell precursors from peripheral blood are activated, migrate in the tissues by the effects of chemotactically acting factors. In order to elucidate the mechanisms involved in this processes, we established different in vitro cell culture models. Our results suggest that the precursor cells circulating in the peripheral blood do not express c-Kit. When the cells are activated, c-Kit expression is upregulated and the cells are able to migrate in the tissue, where they differentiate influenced by cytokines released from tissue cells. The interaction between mast cells and fibroblasts, melanocytes, keratinocytes and nerve cells were studied. Stem cell factor, GM-CSF, nerve growth factor and other neurotrophins as BDNF, NT-3 and NT-4 could be demonstrated as mediators of this interactions. The regulation and release of these factors are modified in pathological skin diseases as atopic dermatitis, psoriasis, changes in the hair cycle and skin tumors and in wound healing. Modulation of expression of these factors and its receptors by therapeutics as glucocorticoids, antihistamines, retinoids and UV-radiation was shown in different culture models. Our results may contribute to develop new therapeutics for skin, pulmonary and intestinal diseases and give new insights in mast cell functions in brain, liver and kidney.

INTRODUÇÃO: A dermatite atópica (DA) é uma doença cutânea inflamatória, acompanhada por prurido intenso e xerose cutânea. A etiopatogenia da DA é multifatorial, envolvendo fatores genéticos, ambientais e imunológicos, dentre outros. OBJETIVOS: Avaliar a influência das enterotoxinas A e B do Staphylococcus aureus (SEA e SEB) na resposta mediada por células Th17 e Th22 nos indivíduos adultos com DA. MÉTODOS: Foram selecionados 38 pacientes adultos com DA e um grupo controle com 40 indivíduos adultos, pareados por idade e gênero Os métodos utilizados foram: 1) ELISA: dosagem dos níveis séricos de IL-6, IL-17, IL-22 e IL-12p40/IL-23 e em sobrenadantes de culturas de células mononucleares do sangue periférico (PBMC) estimuladas com SEA e SEB; 2) Imuno-histoquímica: análise da expressão de IL-17 em fragmentos de pele; 3) Citometria de fluxo: a) análise das citocinas circulantes em amostras de soro: IL-2, IL-4, IL-5, IL-6, IL-10, TNF, IL-17A e IFN-y b)avaliação das células T CD4+ mono e polifuncionais secretoras de IL-17, IL-22, TNF, IFN-y, MIP-1beta, e expressão do marcador de ativação celular CD38; c) células Th22 e Tc22 estimuladas com SEA e SEB. RESULTADOS: 1) Através do ELISA, a secreção de IL-22 sérica e em PBMC induzidas por SEA e SEB foi significativamente mais elevada, quando comparada ao grupo controle; 2) houve aumento na expressão de IL-17 em amostras de pele de doentes de DA através da imuno-histoquímica; 3) Através da citometria de fluxo, foram detectados: a) níveis séricos de IL-2, 5, 6, 10, 17A e IFN-y elevados no grupo com DA em relação aos controles; houve diferença significativa nos níveis circulantes de IL-17A nos pacientes com DA moderada e grave; b) na avaliação monofuncional das células T CD4+ sob estímulo de SEA/SEB, houve redução da expressão das citocinas IFN-y, IL-17A, IL-22 ou TNF na DA, quando comparadas ao grupo controle; na análise polifuncional das células T CD4+/CD8+, ocorreu redução da resposta na DA em relação aos controles; nos pacientes atópicos encontramos aumento da resposta em situação basal na dependência de CD38, e redução na resposta frente a SEA/SEB na ausência de CD38; c) encontramos resposta reduzida das células Th22, e elevada de células Tc22 frente aos estímulos SEA e SEB, nos pacientes com DA. CONCLUSÕES: O estudo corrobora o papel patogênico das enterotoxinas estafilocócicas na DA. A ativação crônica com superantígenos estafilocócicos pode contribuir com a alta frequência de células T CD4+ CD38+ polifuncionais, e com a resposta polifuncional anérgica, mediadas por células T CD38- / BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin disease with intense itching and xerosis. AD pathogenesis is multifactorial, involving genetic, environmental, and immunological factors, among others. OBJECTIVES: To evaluate the influence of enterotoxins A and B from Staphylococcus aureus (SEA and SEB) in Th17 and Th22 cell response in adults with AD. METHODS: We evaluated 38 adult patients with AD, and a control group of 40 adults, age and gender matched. Assays: 1) ELISA: evaluation of IL-6, IL-17, IL-12p40/IL-23 and IL-22 serum levels and in supernatants of mononuclear cell cultures from peripheral blood (PBMC), stimulated with SEA/SEB; 2) Immunohistochemistry: analysis of IL-17 expression in skin specimens; 3) Flow cytometry: a) analysis of circulating cytokines in serum samples: IL-2, IL-4, IL-5, IL-6, IL-10, TNF, IL-17A and IFN-y b) evaluation of mono and polyfunctional TCD4+ cells that secrete IL-17, IL-22, TNF, IFN-y, MIP-1beta, and expression of the activation marker CD38; c) analysis of Tc22 and Th22 cells stimulated with SEA and SEB. RESULTS: 1) Secretion of IL-22 in the serum and from supernatants of cell cultures from PBMC, stimulated with SEA and SEB were higher in AD patients, when compared to the control group by ELISA; 2) there was an increase of IL-17 expression in skin samples by immunohistochemistry; 3) Flow cytometry showed: a) elevated serum levels of IL-2, 5, 6, 10, 17A and IFN-y in AD, when compared to controls; there was a significant difference in circulating levels of IL-17A in patients with moderate and severe disease; b) monofunctional evaluation of T CD4+ cells under SEA/SEB stimuli showed reduced expression of IFN-y, IL-17A, IL-22 or TNF cytokines in AD, compared to controls; the same was observed for polyfunctional CD4+/CD8+ T cells analysis, exhibiting a diminished response in AD. In atopic patients under basal conditions, there was an augmented CD38- dependent response and reduced pattern to SEA/SEB in the absence of CD38; c) finally, we observed a reduced response of Th22 cells and enhanced Tc22 cells under SEA/SEB stimuli in patients with AD. CONCLUSIONS: This study corroborates the pathogenic role of staphylococcal enterotoxins in AD. Chronic activation with staphylococcal superantigens may contribute to the high frequency of polyfunctional CD4 +CD38+ T cells and with the anergic polyfunctional response mediated by T CD38- T cells

A dermatite de contato alérgica (DCA) ao íon níquel (Ni2+) é uma dermatose inflamatória frequente nos países industrializados. Envolve a ativação de células T específicas ao Ni2+, seguida da proliferação e indução de um perfil misto de citocinas, tanto pró-inflamatórias quanto reguladoras, sugerindo que vários subtipos de células T (helper - Th e citotóxica - Tc) estão envolvidos na resposta imune. Este estudo teve como objetivo a análise das citocinas TNF-alfa, INF-y, IL-2, IL-4, IL-10, IL-13, IL-17 e IL-23 pela técnica de imuno-histoquímica, para tentar identificar a prevalência de um ou mais subtipos de células T (Th/Tc), nos eczemas crônico e agudo de pacientes com DCA ao Ni2+. Avaliamos 20 pacientes (17 mulheres e 3 homens, com idade mediana de 46 anos) apresentando eczema crônico, pelo contato cotidiano do paciente com o Ni2+. Foram coletadas duas biópsias de pele em cada um dos 20 pacientes, a primeira no local do eczema crônico ao Ni2+, antes da aplicação do teste de contato (TC); e a segunda no local do eczema agudo, provocado pelo TC com o sulfato de níquel, 48 horas após sua fixação, nas leituras positivo forte (++) ou positivo muito forte (+++). Foram 160 amostras de eczema agudo e 160 de eczema crônico, perfazendo um total de 320 amostras. Apenas três amostras foram excluídas devido a algum tipo de falha técnica, como, por exemplo, o descolamento dos cortes de pele da lâmina. Para a análise dos dados utilizou-se o software estatístico STATA versão 13. As amostras coradas revelaram resultados positivos para as oito citocinas estudadas, e estas apresentaram valores heterogêneos. Esta heterogeneidade foi medida pelo coeficiente de variação, indicando a variabilidade do conjunto dos dados obtidos. O TNF-alfa, IFN-y, IL-4, IL-13 e IL-17 tiveram prevalência maior no eczema crônico do que no eczema agudo, a IL-2 e IL-23 apresentaram maior prevalência no eczema agudo, em comparação com o eczema crônico e a IL-10 apresentou prevalência similar tanto no eczema agudo quanto no crônico, porém, estas prevalências foram muito baixas, em ambos os eczemas. O TNF-alfa foi a citocina que mais prevaleceu no eczema crônico e a IL-2 foi a mais prevalente no eczema agudo. Porém, estas prevalências foram estatisticamente significantes apenas para a IL-4 e IL-13. Verificamos, nos eczemas crônico e agudo, a presença de um perfil misto de citocinas dos subtipos de células T (Th/Tc), sugerindo que as respostas imunes são expressas ao mesmo tempo. Entretanto, são necessários mais estudos para uma compreensão mais ampla sobre o perfil das citocinas na DCA ao Ni2+, o que poderia levar a novas abordagens terapêuticas / Allergic contact dermatitis (ACD) to nickel (Ni+2) is a inflammatory dermatosis, common in industrialized countries. It involves the activation of nickel-specific T cells, followed by the proliferation and induction of a mixed profile of both proinflammatory and regulatory cytokines, suggesting that several T cell subtypes (helper - Th and cytotoxic - Tc) are involved in the immune response. This study aimed to analyze the cytokines TNF-alfa, INF-y, IL-2, IL-4, IL-10, IL-13, IL-17 and IL-23 using the immunohistochemistry technique in order to try to identify the prevalence of one or more T cell subtypes (Th/Tc) in the chronic and acute eczema of patients with ACD to Ni+2. We evaluated 20 patients (17 women and 3 men, median age of 46 years) with chronic eczema, by the patient\'s daily contact with Ni+2. Two skin biopsies were collected in each of the 20 patients, the first at the site of the chronic eczema to Ni+2, prior to the application of the contact test (CT); and the second at the site of acute eczema caused by CT with nickel sulphate, 48 hours after its fixation in the strong positive (++) or very strong positive (+++) readings. There were 160 samples of acute eczema and 160 of chronic eczema, a total of 320 samples. Only three samples were excluded due to some kind of technical failure, such as detachment of the skin cuts from the microscope slide. Statistical software STATA version 13 was used to analyze the data. The stained samples showed positive results for the eight cytokines studied, and these presented heterogeneous values. This heterogeneity was measured by the coefficient of variation, indicating the variability of the data set obtained. TNF-alfa, IFN-y, IL-4, IL-13 and IL-17 had a higher prevalence in chronic eczema than in acute eczema, IL-2 and IL-23 were more prevalent in acute eczema compared to chronic eczema and IL-10 presented similar prevalence in both acute and chronic eczema, however, a very low prevalence in both eczema. TNF-alfa was the most prevalent cytokine in chronic eczema and IL-2 was the most prevalent in acute eczema. However, these prevalences were statistically significant only for IL-4 and IL-13. In chronic and acute eczema, we observed the presence of a mixed cytokine profile of the T cell subtypes (Th/Tc), suggesting that immune responses are expressed at the same time. However, further studies are needed for a broader understanding of the cytokine profile in ACD to Ni+2, which could lead to new therapeutic approaches