Die Atherosklerose und ihre Folgen sind für ca. 50% der Todesfälle in den USA, Europa und Japan verantwortlich. Die Prävention der Atherosklerose und ihrer klinischen Manifestationen wie der koronaren Herzkrankheit, der peripheren arteriellen Verschlußkrankheit und des ischämischen Zerebralinsultes sind wichtige Ziele. Das Gen des endothelialen leukozytären Adhäsionsmoleküls-1 (E-Selectin) sollte auf DNA-Polymorphismen untersucht werden, um einen möglichen genetischen Hintergrund von zellulären Interaktionen, die in den atherosklerotischen Prozeß involviert sind, zu untersuchen. Die Häufigkeit der S128R-Mutation der EGF-Domäne des E-Selectins in einem Kollektiv von 53 Patienten mit interventionsbedürftiger koronarer Herzkrankheit, deren durchschnittliches Alter fünfzig Jahre überschreitet, ist mit 13,2% ebenso hoch wie in einer Vergleichsgruppe freiwilliger Probanden (n = 102, Häufigkeit der Mutation: 15,7%). Die beobachtete geringere Frequenz der Mutation in höherem Alter stützt die Hypothese der Assoziation einer vorzeitigen Atherosklerose mit der statistisch signifikant erhöhten Frequenz der S128R-Mutation (Häufigkeit: 29,2%) in einem Patientenkollektiv unter fünzig Jahre (106, 107). Assoziationsanalysen zum Vergleich der Häufigkeiten des DNA-Polymorphismus in Abhängigkeit von den Risikofaktoren (männliches Geschlecht, Myokardinfarkt in der Eigenanamnese, positive Familienanamnese, Nikotinabusus, Hyper- bzw. Dyslipidämie, Diabetes mellitus, Adipositas und arterielle Hypertonie) zeigten keine statistisch signifikante Assoziation. / Atherosclerosis and its pathologic consequences are responsible for 50% of the deaths in the United States, Europe and Japan. The prevention of atherosclerosis and its clinical manifestations such as coronary heart disease, peripheral vascular disease and ischemic cerebral insult are fundamental goals. To contribute to the analysis of the genetic background of atherosclerosis especially endothelial dysfunction we searched for DNA-polymorphisms in the endothelial-leukocyte adhesion molecule-1 (E-selectin). The frequency of the S128R-mutation of the EGF-domain of the E-selectin in a collective of 53 patients with severe, an intervention requiring coronary heart disease (mean age above 50 years) is 13,2%, which is as high as in 102 volunteers (15,7%). The observed lesser frequency of the mutation in higher age supports the hypothesis of an association of premature atherosclerosis with a significant higher frequency of the S128R-mutation (29,2%) in patients with the same severe coronary heart disease under the age of 50. Association studies with risk factors for coronary heart disease (male sex, myocardial infarction, positive family history, cigarette smoking, hyperlipidaemia, low HDL-cholesterol, diabetes mellitus, obesity and hypertension) showed no associations.

No description available.

L’asthme est une maladie inflammatoire chronique des voies aériennes. Chez les individus sensibles, l’inhalation d’allergènes entraine une inflammation pulmonaire se traduisant par des épisodes récurrents de toux, de difficultés respiratoires et une sécrétion de mucus. Des études réalisées chez l’animal ont mis en évidence un rôle crucial des lymphocytes Th2 et des cytokines associées (IL-4, IL-5 et IL-13). Plus récemment, il a été montré que les lymphocytes Th17 participaient à la physiopathologie de l’asthme. La présente étude s’intéresse à une cytokine majoritairement produite par les Th17 : l’IL-22. Différents travaux indiquent que cette cytokine serait impliquée dans l’immunitémucosale où elle exercerait des effets protecteurs ou pro-inflammatoires en fonction du modèle expérimental étudié. En utilisant un modèle murin d’inflammation pulmonaire allergique induite par l’ovalbumine, nous avons montré que l’IL-22 jouait un rôle pro-inflammatoire au cours de l’induction de l’asthme allergique puisque les souris déficientes en IL-22 développent une forme atténuée de la maladie. A l’inverse, nous avons constaté que l’IL-22 avait un effet protecteur dans la phase effectrice, et que cet effet était dépendant de l’IL-17A. Nos travaux mettent donc en lumière une double fonction de l’IL-22 dans l’asthme allergique chez la souris. En parallèle de ce travail, nous nous sommes intéressés au rôle de l’IL-1 et de l’inflammasome NLRP3 dans ce même modèle d’inflammation pulmonaire. Enfin, une troisième étude a permis de mettre en lumière un rôle encore inconnu de l’interleukine-33 dans l’activation des cellules dendritiques au cours de la mise en place de la réponse asthmatique. / Asthma is a heterogenous inflammatory disorder of the airways characterized by chronic airway inflammation, airway hyper-reactivity and by symptoms of recurrent wheezing, coughing and shortness breath. Understanding of the role of allergy and Th2 cells in asthma has benefited from mouse model of allergic asthma. Recently, several studies highlighted Th17 involvement in asthma pathogenesis. In the present study, we investigate the role of IL-22, a Th17-related cytokine, in a mouse model of allergic lung inflammation induced by ovalbumin. First, using IL-22 deficient mice, we demonstrated a pro-inflammatory role of IL-22 during the sensitization phase. In contrast, we observed a protective function of IL-22 during the effective phase. This protective effect of IL-22 seems to be dependent of IL-17. In conclusion, we demonstrate here a dual role of IL-22 in asthma pathogenesis. Since interleukin-1_ is critical for Th17 polarization in human, we also investigated the role of IL-1 signalling and NLRP3 inflammasome in our model of allergic airway inflammation. We showed that NLRP3 inflammasome and IL-1R/IL-1 pathway are critical to induce allergic lung inflammation, even in the absence of adjuvant. Finally, we studied the effect of interleukin-33 on dendritic cells activation and Th2 priming during antigen sensitization and in established asthma.

Contexto: Os mecanismos inflamatórios que determinam a gravidade da bronquiolite viral aguda em criançasainda não estão bem estabelecidos e parecem relacionados à disfunção da resposta imune. Objetivos: Avaliar a associação da interleucina-33 e do receptor ST2 com a gravidade da bronquiolite viral aguda. Métodos: Concentrações de IL-33, ST2, IL- 1ß, TNF?, IL-4, IL-6 e IL-8 foram avaliadas em secreção nasofaríngea e plasma de pacientes com bronquiolite viral aguda em dois momentos da internação hospitalar. A necessidade de ventilação mecânica constituiu o critério de gravidade da doença. Resultados: De janeiro de 2015 a dezembro de 2016, 261 crianças foram internadas com diagnóstico de bronquiolite viral aguda. Setenta e nove crianças foram incluídas no estudo; 33 (41,7%) foram submetidas à ventilação mecânica. Cento e oitenta e dois pacientes (69,7%) foram excluídos pelos seguintes motivos: uso de corticoide > 24h (n=156), múltiplas comorbidades (n=7), falha de recrutamento (n=11) e recusa dos responsáveis (n=8). Não houve associações entre etiologias virais ou presença de coinfecções e gravidade da doença. Verificaram-se detecções mais frequentes da IL-33 em secreção nasofaríngea à admissão hospitalar de pacientes submetidos à ventilação mecânica comparados com aqueles que não necessitaram de ventilação mecânica (50% vs. 13,3%, respectivamente; p<0,001). Observou-se o mesmo para o ST2 (87,5% no grupo submetido à ventilação vs. 40,9% no grupo não submetido à ventilação; p< 0,001). Na análise do quinto dia de internação entre os dois grupos, verificaram-se valores mais elevados em secreção nasofaríngea da IL-6 (mediana 152,6 pcg/ml no grupo submetido à ventilação vs. mediana 14,4 pcg/ml no grupo não submetido à ventilação; p=0,001) e IL-8 (mediana 1113 pcg/ml no grupo submetido à ventilação e mediana 792,2 pcg/ml no grupo não submetido à ventilação; p=0,03). Na comparação em secreção nasofaríngea entre os dois períodos de coleta, pacientes que necessitaram ventilação mecânica apresentaram redução das concentrações de ST2 (mediana 5,63 pcg/ml à admissão e mediana 2,44 pcg/ml no quinto dia de internação hospitalar; p=0,03) e aumento das concentrações de IL-4 (mediana 0,2 pcg/ml à admissão e mediana 6,9 pcg/ml no quinto dia; p<0,01) e IL-8 (mediana 342,9 pcg/ml à admissão e mediana 1.113 pcg/ml no quinto dia; p<0,01). Na análise entre os dois momentos de coleta no grupo não submetido à ventilação, demonstraram-se incrementos das concentrações em secreção nasofaríngea da IL-4 (mediana 0,2 pcg/ml à admissão e mediana 5,3 pcg/ml no quinto dia; p<0,01) e IL-8 (mediana 300,2 pcg/ml à admissão e mediana 792,2 pcg/ml no quinto dia; p<0,01), acompanhados de redução da IL-6 (mediana 86,0 pcg/ml à admissão e mediana 14,4 pcg/ml no quinto dia; p=0,04) e de incremento nas concentrações séricas da IL-33 (mediana 0,186,0 pcg/ml à admissão e mediana 36,2 pcg/ml no quinto dia; p=0,04). Conclusão: Detecções mais frequentes da IL-33 e do receptor ST2 durante a admissão hospitalar e concentrações elevadas de IL-6 e IL-8 em secreção nasofaríngea durante o quinto dia da internação foram associadas à gravidade da bronquiolite viral aguda. Não houve associação entre as etiologias virais ou a presença de coinfecções e a gravidade da doença. / Background: The inflammatory mechanisms influencing the severity of acute viral bronchiolitis in children are still not well established and seem to be caused by an immune dysfunction. Objectives: To assess if interleukin-33 and its receptor, ST2, can be used as clinical severity biomarkers in acute viral bronchiolitis. Methods: Levels of IL-33, ST2, IL-1ß, TNF?, IL-4, IL-6 e IL-8 were analyzed in nasopharyngeal aspirates and blood plasma of patients in two different moments after hospital admission. Severity of disease was defined by the presence of mechanical ventilation. Results: From January 2015 to December 2016, 261 were admitted due to acute viral bronchiolitis. Of the 79 children included in the study, 33 (41,7%) were submitted to mechanical ventilation. One hundred and eighty-two patients (69,7%) were excluded, due to use of corticosteroids (n=156), pre-existing comorbidities (n=7), recruitment failure (n=11) and parents refusal (n=8). No associations between viral etiology or the presence of coinfecctions and severity of disease were observed. IL-33 was more frequently detected in nasopharyngeal aspirates of patients submitted to mechanical ventilation during hospital admission (50% of samples of the mechanically ventilated group vs. 13,3% of the samples of children with no need of ventilator support; p<0,001). The same correlation was observed in ST2 levels (87,5% in the mechanically ventilated group vs. 40,9% of samples of children with no need of ventilator support; p< 0,001). On day five postadmission, an increase in concentrarions of nasopharyngeal aspirates in the mechanically ventilated patients was detected for IL-6 (median 152,6 pcg/ml in the mechanically ventilated group and median 14,4 pcg/ml for the group with no need of ventilator support; p=0,001) and IL-8 (median 1.113 pcg/ml in the mechanically ventilated group and median 792,2 pcg/ml for the group with no need of ventilator support; p=0,03). Between admission and day 5, increases of IL-4 (median 0,2 pcg/ml on admission and median 6,9 pcg/ml on day 5; p<0,01) and IL-8 (median 342,9 pcg/ml on admission and median 1.113 pcg/ml on day 5; p<0,01) levels were detected in nasopharyngeal aspirates, whereas ST2 levels showed a decrease (median 5,63 pcg/ml on admission and median 2,44 pcg/ml on day 5; p=0,03). In the same analysis performed in nasopharyngeal aspirates of patients with no need of ventilation support, an increase in IL-4 (median 0,2 pcg/ml on admission and median 5,3 pcg/ml on day 5; p<0,01) and IL-8 (median 300,2 pcg/ml on admission and median 792,2 pcg/ml on day 5; p<0,01) levels was observed and a decrease in IL-6 levels (median 86,0 pcg/ml on admission and median 14,4 pcg/ml on day 5; p=0,04), along with an increase in IL-33 blood plasma levels (median 0,186 pcg/ml on admission and median 36,2 pcg/ml on day 5; p=0,04) were also shown. Conclusion: More frequent detections of IL-33 and ST2 on the day of admission and higher IL-6 and IL-8 levels in nasopharyngeal aspirates were associated with more severe forms of acute viral bronchiolitis. No correlations between viral etiologies or the presence of coinfecctions and severity of disease were observed.

A citocina IL-33 apresenta papel dual e está envolvida com a resolução ou progressão de inúmeras doenças, além disso, acredita-se que a via IL-33/ST2 esteja envolvida no equilíbrio entre a atividade de osteoclastos e osteoblastos. O objetivo deste estudo foi avaliar o papel do receptor ST2 no desenvolvimento e progressão de lesões periapicais experimentalmente induzidas em camundongos. Lesões periapicais foram induzidas em primeiros molares inferiores de camundongos WT e ST2 knockout (KO). Decorridos 7 e 14 dias, as amostras de mandíbula foram submetidas às análises: determinação da área de lesão periapical em cortes histológicos e do volume por microtomografia computadorizada (&mu;CT); contagem de osteoclastos submetidos ao ensaio de histoenzimologia (TRAP); expressão gênica de marcadores osteogênicos e osteoclastogênicos por q-PCR; quantificação de neutrófilos por ensaio de mieloperoxidases. Os linfonodos foram submetidos à análise da expressão dos fatores transcricionais T-bet, GATA-3, RORc e Foxp-3 por q-PCR. Análise estatística utilizada foi One-way ANOVA, seguido de pós-teste de Bonferroni. Aos 14 dias, observou-se maior extensão da lesão periapical em animais WT que em ST2KO (p<0,05). O tamanho da lesão nos animais ST2KO permaneceu igual em função do tempo. Foi observada maior quantidade de neutrófilos na lesão do grupo WT aos 7 dias, em comparação aos animais ST2KO (p<0,05). Na expressão de T-bet, GATA-3, RORc e Foxp-3 não foram observadas diferenças estatisticamente significantes. O número de osteoclastos contados nos animais ST2KO foi maior que o observado em WT aos 7dias e aos 14 dias (p<0,05). A expressão de Runx2 foi maior no grupo lesão dos animais ST2KO quando comparado a seu respectivo controle. Os outros marcadores relacionados com a formação óssea não apresentaram diferenças estatisticamente significantes. Dentre os marcadores relacionados com a reabsorção óssea, a catepsina K e o MMP-9 apresentaram maior expressão aos 14 dias, na lesão dos animais WT quando comparada à expressão na lesão dos animais ST2KO (p<0,05). Com base nos resultados obtidos no presente estudo, pode-se concluir que na ausência do receptor ST2 as lesões periapicais são menos extensas e embora em maior quantidade, os osteoclastos são menos ativos. Nossos resultados sugerem um importante papel da via IL-33/ST2 na ativação dos osteoclastos e desenvolvimento da lesão periapical. / The IL -33 cytokine presents a dual role and is involved either in the resolution and progression of many diseases. Furthermore, it is believed that this pathway is involved between osteoclast and osteoblast activity balance. The aim of this study was to evaluate the role of ST2 receptor in the development and progression of experimentally induced periapical lesions in mice. Periapical lesions were induced in first molars of WT and ST2 knockout (KO) mice. After 7 and 14 days, jaw samples were subjected to various analysis: determination of periapical lesions area by histology and volume by computed microtomography (&mu;CT); osteoclasts number by TRAP histoenzymology; osteogenic and osteoclastogenic markers expression by q-PCR; neutrophil quantification by myeloperoxidase activity. The expression of transcription factors T-bet, GATA-3, RORC and Foxp-3 in lymph nodes were analysed by q-PCR. Statistical analysis was done by One-way ANOVA and Bonferroni post-test. It was observed a greater extent in periapical lesions of WT compared to ST2KO animals at 14 days (p<0.05). There is no progression in the lesion of ST2KO mice with the time. A larger number of neutrophils in WT group was observed, compared to ST2KO mice evaluated at 7 days (p<0.05). The expression of T-bet, GATA-3, RORc and Foxp-3 were not statistically significant different among the groups. The number of osteoclasts in lesions of ST2KO animals were greater than the observed in WT, at 7 and 14 days (p<0.05). Although, other osteogenic markers showed no statistically significant difference, Runx2 expression in ST2KO was higher in lesion side compared to control side at 14 days. The markers related to bone resorption, cathepsin K and MMP-9, were significantly abrogated in the lesion side of ST2KO mice, at 14 days (p<0.05). Based on the results, it can be concluded that although larger amounts of osteoclast were counted in ST2KO, the lesion was less extensive and osteoclasts less active. It all suggests that the IL-33/ST2 pathway play an important role in osteoclasts activation and periapical lesion development.

A citocina IL-33 apresenta papel dual e está envolvida com a resolução ou progressão de inúmeras doenças, além disso, acredita-se que a via IL-33/ST2 esteja envolvida no equilíbrio entre a atividade de osteoclastos e osteoblastos. O objetivo deste estudo foi avaliar o papel do receptor ST2 no desenvolvimento e progressão de lesões periapicais experimentalmente induzidas em camundongos. Lesões periapicais foram induzidas em primeiros molares inferiores de camundongos WT e ST2 knockout (KO). Decorridos 7 e 14 dias, as amostras de mandíbula foram submetidas às análises: determinação da área de lesão periapical em cortes histológicos e do volume por microtomografia computadorizada (&mu;CT); contagem de osteoclastos submetidos ao ensaio de histoenzimologia (TRAP); expressão gênica de marcadores osteogênicos e osteoclastogênicos por q-PCR; quantificação de neutrófilos por ensaio de mieloperoxidases. Os linfonodos foram submetidos à análise da expressão dos fatores transcricionais T-bet, GATA-3, RORc e Foxp-3 por q-PCR. Análise estatística utilizada foi One-way ANOVA, seguido de pós-teste de Bonferroni. Aos 14 dias, observou-se maior extensão da lesão periapical em animais WT que em ST2KO (p<0,05). O tamanho da lesão nos animais ST2KO permaneceu igual em função do tempo. Foi observada maior quantidade de neutrófilos na lesão do grupo WT aos 7 dias, em comparação aos animais ST2KO (p<0,05). Na expressão de T-bet, GATA-3, RORc e Foxp-3 não foram observadas diferenças estatisticamente significantes. O número de osteoclastos contados nos animais ST2KO foi maior que o observado em WT aos 7dias e aos 14 dias (p<0,05). A expressão de Runx2 foi maior no grupo lesão dos animais ST2KO quando comparado a seu respectivo controle. Os outros marcadores relacionados com a formação óssea não apresentaram diferenças estatisticamente significantes. Dentre os marcadores relacionados com a reabsorção óssea, a catepsina K e o MMP-9 apresentaram maior expressão aos 14 dias, na lesão dos animais WT quando comparada à expressão na lesão dos animais ST2KO (p<0,05). Com base nos resultados obtidos no presente estudo, pode-se concluir que na ausência do receptor ST2 as lesões periapicais são menos extensas e embora em maior quantidade, os osteoclastos são menos ativos. Nossos resultados sugerem um importante papel da via IL-33/ST2 na ativação dos osteoclastos e desenvolvimento da lesão periapical. / The IL -33 cytokine presents a dual role and is involved either in the resolution and progression of many diseases. Furthermore, it is believed that this pathway is involved between osteoclast and osteoblast activity balance. The aim of this study was to evaluate the role of ST2 receptor in the development and progression of experimentally induced periapical lesions in mice. Periapical lesions were induced in first molars of WT and ST2 knockout (KO) mice. After 7 and 14 days, jaw samples were subjected to various analysis: determination of periapical lesions area by histology and volume by computed microtomography (&mu;CT); osteoclasts number by TRAP histoenzymology; osteogenic and osteoclastogenic markers expression by q-PCR; neutrophil quantification by myeloperoxidase activity. The expression of transcription factors T-bet, GATA-3, RORC and Foxp-3 in lymph nodes were analysed by q-PCR. Statistical analysis was done by One-way ANOVA and Bonferroni post-test. It was observed a greater extent in periapical lesions of WT compared to ST2KO animals at 14 days (p<0.05). There is no progression in the lesion of ST2KO mice with the time. A larger number of neutrophils in WT group was observed, compared to ST2KO mice evaluated at 7 days (p<0.05). The expression of T-bet, GATA-3, RORc and Foxp-3 were not statistically significant different among the groups. The number of osteoclasts in lesions of ST2KO animals were greater than the observed in WT, at 7 and 14 days (p<0.05). Although, other osteogenic markers showed no statistically significant difference, Runx2 expression in ST2KO was higher in lesion side compared to control side at 14 days. The markers related to bone resorption, cathepsin K and MMP-9, were significantly abrogated in the lesion side of ST2KO mice, at 14 days (p<0.05). Based on the results, it can be concluded that although larger amounts of osteoclast were counted in ST2KO, the lesion was less extensive and osteoclasts less active. It all suggests that the IL-33/ST2 pathway play an important role in osteoclasts activation and periapical lesion development.

Contexto: Os mecanismos inflamatórios que determinam a gravidade da bronquiolite viral aguda em criançasainda não estão bem estabelecidos e parecem relacionados à disfunção da resposta imune. Objetivos: Avaliar a associação da interleucina-33 e do receptor ST2 com a gravidade da bronquiolite viral aguda. Métodos: Concentrações de IL-33, ST2, IL- 1ß, TNF?, IL-4, IL-6 e IL-8 foram avaliadas em secreção nasofaríngea e plasma de pacientes com bronquiolite viral aguda em dois momentos da internação hospitalar. A necessidade de ventilação mecânica constituiu o critério de gravidade da doença. Resultados: De janeiro de 2015 a dezembro de 2016, 261 crianças foram internadas com diagnóstico de bronquiolite viral aguda. Setenta e nove crianças foram incluídas no estudo; 33 (41,7%) foram submetidas à ventilação mecânica. Cento e oitenta e dois pacientes (69,7%) foram excluídos pelos seguintes motivos: uso de corticoide > 24h (n=156), múltiplas comorbidades (n=7), falha de recrutamento (n=11) e recusa dos responsáveis (n=8). Não houve associações entre etiologias virais ou presença de coinfecções e gravidade da doença. Verificaram-se detecções mais frequentes da IL-33 em secreção nasofaríngea à admissão hospitalar de pacientes submetidos à ventilação mecânica comparados com aqueles que não necessitaram de ventilação mecânica (50% vs. 13,3%, respectivamente; p<0,001). Observou-se o mesmo para o ST2 (87,5% no grupo submetido à ventilação vs. 40,9% no grupo não submetido à ventilação; p< 0,001). Na análise do quinto dia de internação entre os dois grupos, verificaram-se valores mais elevados em secreção nasofaríngea da IL-6 (mediana 152,6 pcg/ml no grupo submetido à ventilação vs. mediana 14,4 pcg/ml no grupo não submetido à ventilação; p=0,001) e IL-8 (mediana 1113 pcg/ml no grupo submetido à ventilação e mediana 792,2 pcg/ml no grupo não submetido à ventilação; p=0,03). Na comparação em secreção nasofaríngea entre os dois períodos de coleta, pacientes que necessitaram ventilação mecânica apresentaram redução das concentrações de ST2 (mediana 5,63 pcg/ml à admissão e mediana 2,44 pcg/ml no quinto dia de internação hospitalar; p=0,03) e aumento das concentrações de IL-4 (mediana 0,2 pcg/ml à admissão e mediana 6,9 pcg/ml no quinto dia; p<0,01) e IL-8 (mediana 342,9 pcg/ml à admissão e mediana 1.113 pcg/ml no quinto dia; p<0,01). Na análise entre os dois momentos de coleta no grupo não submetido à ventilação, demonstraram-se incrementos das concentrações em secreção nasofaríngea da IL-4 (mediana 0,2 pcg/ml à admissão e mediana 5,3 pcg/ml no quinto dia; p<0,01) e IL-8 (mediana 300,2 pcg/ml à admissão e mediana 792,2 pcg/ml no quinto dia; p<0,01), acompanhados de redução da IL-6 (mediana 86,0 pcg/ml à admissão e mediana 14,4 pcg/ml no quinto dia; p=0,04) e de incremento nas concentrações séricas da IL-33 (mediana 0,186,0 pcg/ml à admissão e mediana 36,2 pcg/ml no quinto dia; p=0,04). Conclusão: Detecções mais frequentes da IL-33 e do receptor ST2 durante a admissão hospitalar e concentrações elevadas de IL-6 e IL-8 em secreção nasofaríngea durante o quinto dia da internação foram associadas à gravidade da bronquiolite viral aguda. Não houve associação entre as etiologias virais ou a presença de coinfecções e a gravidade da doença. / Background: The inflammatory mechanisms influencing the severity of acute viral bronchiolitis in children are still not well established and seem to be caused by an immune dysfunction. Objectives: To assess if interleukin-33 and its receptor, ST2, can be used as clinical severity biomarkers in acute viral bronchiolitis. Methods: Levels of IL-33, ST2, IL-1ß, TNF?, IL-4, IL-6 e IL-8 were analyzed in nasopharyngeal aspirates and blood plasma of patients in two different moments after hospital admission. Severity of disease was defined by the presence of mechanical ventilation. Results: From January 2015 to December 2016, 261 were admitted due to acute viral bronchiolitis. Of the 79 children included in the study, 33 (41,7%) were submitted to mechanical ventilation. One hundred and eighty-two patients (69,7%) were excluded, due to use of corticosteroids (n=156), pre-existing comorbidities (n=7), recruitment failure (n=11) and parents refusal (n=8). No associations between viral etiology or the presence of coinfecctions and severity of disease were observed. IL-33 was more frequently detected in nasopharyngeal aspirates of patients submitted to mechanical ventilation during hospital admission (50% of samples of the mechanically ventilated group vs. 13,3% of the samples of children with no need of ventilator support; p<0,001). The same correlation was observed in ST2 levels (87,5% in the mechanically ventilated group vs. 40,9% of samples of children with no need of ventilator support; p< 0,001). On day five postadmission, an increase in concentrarions of nasopharyngeal aspirates in the mechanically ventilated patients was detected for IL-6 (median 152,6 pcg/ml in the mechanically ventilated group and median 14,4 pcg/ml for the group with no need of ventilator support; p=0,001) and IL-8 (median 1.113 pcg/ml in the mechanically ventilated group and median 792,2 pcg/ml for the group with no need of ventilator support; p=0,03). Between admission and day 5, increases of IL-4 (median 0,2 pcg/ml on admission and median 6,9 pcg/ml on day 5; p<0,01) and IL-8 (median 342,9 pcg/ml on admission and median 1.113 pcg/ml on day 5; p<0,01) levels were detected in nasopharyngeal aspirates, whereas ST2 levels showed a decrease (median 5,63 pcg/ml on admission and median 2,44 pcg/ml on day 5; p=0,03). In the same analysis performed in nasopharyngeal aspirates of patients with no need of ventilation support, an increase in IL-4 (median 0,2 pcg/ml on admission and median 5,3 pcg/ml on day 5; p<0,01) and IL-8 (median 300,2 pcg/ml on admission and median 792,2 pcg/ml on day 5; p<0,01) levels was observed and a decrease in IL-6 levels (median 86,0 pcg/ml on admission and median 14,4 pcg/ml on day 5; p=0,04), along with an increase in IL-33 blood plasma levels (median 0,186 pcg/ml on admission and median 36,2 pcg/ml on day 5; p=0,04) were also shown. Conclusion: More frequent detections of IL-33 and ST2 on the day of admission and higher IL-6 and IL-8 levels in nasopharyngeal aspirates were associated with more severe forms of acute viral bronchiolitis. No correlations between viral etiologies or the presence of coinfecctions and severity of disease were observed.

O carcinoma espinocelular (CEC) é um dos cânceres humanos mais incidentes. A despeito do entendimento da fisiopatologia do CEC, as opções terapêuticas ainda são limitadas e o(s) exato(s) mecanismo(s) envolvido(s) na progressão deste tipo de tumor ainda não foi descrito. Estudos recentes mostram a existência de uma associação direta entre a resposta imune TH1 e um melhor prognóstico em pacientes com CEC. Aumento da expressão de componentes do eixo IL-33/ST2 foi demonstrado contribuir para transformação neoplásica em diversos modelos tumorais, incluindo cânceres de estômago e de mama. Trabalho recente do nosso e de outros laboratórios indicam que IL-33 pode impedir a resposta imune TH1 . Baseado nessas observações, a hipótese testada foi que o impedimento da resposta imune pela interação IL-33/ST2 pode contribuir para iniciação e progressão do CEC. Utilizando modelo de carcinogênese química em camundongos WT e deficientes de ST2 (ST2KO), os resultados mostram que a deficiência de ST2 leva a uma notável redução da severidade das lesões 20 semanas após a carcinogênese química, sugerindo que a sinalização ST2 é necessária para o desenvolvimento tumoral neste modelo. Análises do infiltrado inflamatório presente nas lesões em camundongos WT e ST2KO revelaram redução significativa nas percentagens de macrófagos, células T CD4+ e células dendríticas, mas não em células T CD8+, células B e células natural killer (NK) no microambiente tumoral de camundongos ST2KO. Além disso, células NK esplênicas isoladas de camundongos ST2KO exibiram atividade citotóxica aumentada contra células YAC quando comparado com células de camundongos do grupo controle (WT). Os resultados indicam que a via IL-33/ST2 contribui para o desenvolvimento de carcinoma espinocelular recrutando células T CD4+, macrófagos e células dendríticas e reduzindo a citotoxicidade de células NK. / Squamous cell carcinoma (SCC) is the second most common form of skin cancer and is most commonly observed in photo-exposed areas of the body. The mechanism(s) involved in the progression of this tumor are unknown. Recent studies have shown that there is a direct association between a TH1-related immune response and a better prognosis in patients with SCC. Increased expression of the IL33/ST2 axis components has been demonstrated to contribute to neoplastic transformation in several tumor models, including gastric and breast cancer. Recent work from ours and other laboratories indicate that can IL-33 impair TH1-type immune responses. Based on these observations, we hypothesized that TH1-type immune response impairment by IL33/ST2 could contribute to the initiation and progress SCC. We found that ST2 deficiency led to a marked decreased in severity of skin lesions at 20 weeks post-DMBA, suggesting that ST2 signaling is necessary for tumor development in this model. Analysis of tumor lesions in WT and ST2KO mice revealed that lack of ST2 led to a specific and significant reduction in the frequency of macrophages, T CD4+ and dendritic cells, but not CD8+, B and NK cells. In addition, splenic NK cells isolated from DMBA-treated ST2KO mice exhibited increased cytotoxicity activity against YAC cells targets when compared with WT splenic NK cells in the same cytotoxic assay. Altogether, our findings indicate that IL-33/ST2 pathway contributes to the SCC development by recruitment T CD4+ cells, macrophages, and dendritic cells and impairing NK cytotoxicity.

Les vascularites des gros vaisseaux comprennent principalement la maladie de Takayasu et l'artérite à cellules géantes. Elles sont caractérisées par des lésions inflammatoires artérielles, associées à une néo-vascularisation adventitielle importante, une désorganisation architecturale de la paroi artérielle et des lésions fibrotiques, affectant l’aorte et ses principales branches. Ces maladies sont caractérisées par des réponses lymphocytaires Th1 et Th17 excessives et dérégulées. Actuellement, les mécanismes régulant la différenciation lymphocytaire, la réponse endothéliale et l’homéostasie tissulaire en contexte d’inflammation artérielle chronique ne sont pas suffisamment connus. Dans la 1ère partie de nos travaux, nous avons étudié le rôle de l’IL-33, cytokine sécrétée par les cellules endothéliales en cas de nécrose tissulaire, surexprimée dans les vascularites des gros vaisseaux et impliquée dans la régulation de la réponse immune. Nous avons mis en évidence le rôle immunomodulateur de l’IL-33 dans les vascularites des gros vaisseaux. Cette cytokine favorise en effet directement une différenciation Th2 et une augmentation des lymphocytes T régulateurs (Treg). L’IL-33 exerce également son action immunorégulatrice par le biais des mastocytes qui favorisent également une augmentation majeure des Treg en présence d’IL-33, probablement grâce à la sécrétion d’IL-2, essentielle à la survie et l’expansion des Treg et la sécrétion d’indoléamine 2,3 dioxygénase (IDO). L’IL-33 et les mastocytes ont également un rôle paradoxal en contexte inflammatoire, en favorisant les processus de néo-angiogenèse, d’activation endothéliale et d’augmentation de la perméabilité vasculaire, phénomènes participant au recrutement de cellules inflammatoires sur le site lésionnel. L’axe IL-33/ST2 et les mastocytes, via leurs actions pro-Th2, immunorégulatrice, et pro-angiogénique, sont également associés aux processus de réparation tissulaire, qui pourraient s’avérer délétères en cas d’inflammation persistante, en raison du développement de lésions de fibrose. Si l’IL-33 ne semble pas être directement responsable d’une activation ou d’une prolifération fibroblastique au niveau artériel, les mastocytes activés par du sérum de patients ayant une vascularite des gros vaisseaux conduisent en revanche à des modifications du phénotype fibroblastique et induisent une augmentation de production de collagène de type 1 et de fibronectine.Dans la 2ème partie de nos travaux, nous avons mis en évidence des profils de différenciation distincts des lymphocytes T CD4+ dans la maladie de Takayasu et l’artérite à cellules géantes. Nous avons démontré une augmentation des lymphocytes T folliculaires helper (Tfh) circulants dans la maladie de Takayasu. L’augmentation des Tfhc chez les patients ayant une maladie de Takayasu est associée à une augmentation des lymphocytes B circulants et à la présence d’organes lymphoïdes ectopiques aortiques. Les Tfhc des patients Takayasu gardent les propriétés fonctionnelles des lymphocytes Tfh tissulaires, puisqu’ils favorisent la prolifération des lymphocytes B ainsi que leur différenciation en cellules mémoires. Nos résultats suggèrent donc l’implication d’une coopération lymphocytaire B et T centrale dans la physiopathologie de la maladie de Takayasu, qui pourrait être associée à la présence de lymphocytes B auto-réactifs sécrétant des auto-anticorps. / Large vessel vasculitis (LVV) mainly include Takayasu arteritis (TA) and giant cell arteritis (GCA), which are characterized by arterial inflammatory lesions, associated with adventitial neo-angiogenesis and fibrotic lesions. They predominantly involve aorta and its major branches. These diseases are related to unbalanced Th1 and Th17 immune responses. The mechanisms regulating lymphocyte differentiation, endothelial response and tissue homeostasis in arterial inflammatory diseases are not sufficiently known. First, we have studied the role of IL-33, which is a cytokine secreted by endothelial cells in response to tissue necrosis and is involved in the regulation of immune response. We demonstrated the immunomodulatory impact of IL-33 and mast cells in LVV. IL-33 had a direct immunomodulatory impact by increasing Th2 and regulatory T cells in PBMC. IL-33 and MC further enhanced Th2 and regulatory responses by inducing a 6.1 fold increased proportion of Tregs through increased indoleamine 2 3-dioxygenase (IDO) and IL-2 secretion. IL-33 and mast cells also had a paradoxical impact in LVV, by promoting angiogenesis, endothelial activation and vascular permeability. IL-33 and mast cells, through Th2 and regulatory responses and angiogenesis, were associated with tissue repair and arterial fibrosis. Although IL-33 did not appear to directly lead to arterial fibroblast activation and proliferation, mast cells activated by LVV serum induced increased production of type 1 collagen and fibronectin by arterial fibroblasts. In the second part of our work, we have demonstrated distinct differentiation profiles of CD4 + T cells in TA and GCA. We demonstrated an increase in circulating T follicular helper lymphocytes (cTfh), defined as CXCR5+ CD4+ T cells, in TA. The increase of cTfh was associated with an increase in circulating B lymphocytes and the presence of tertiary lymphoid organs in TA aorta. CXCR5+ CD4+ T cells of TA patients helped B cells to differentiate into memory cells, to proliferate and to secrete type G immunoglobulins. Our data provide evidence of the key coordinated role of Tfh and B cells in tertiary lymphoid structures in TA and suggest an antigenic trigger.

La modification post-traductionnelle des chimiokines par la dipeptidyl peptidase-4 (DPP4 ou CD26) régule négativement le trafic des lymphocytes, et son inhibition améliore la migration des lymphocytes T et l'immunité anti-tumorale en préservant la forme fonctionnelle de CXCL10. En étendant ces résultats initiaux aux humains et à un modèle préclinique de carcinome hépatocellulaire, nous avons découvert un nouveau mécanisme par lequel l'inhibition de DPP4 améliore les réponses anti-tumorales par le recrutement des éosinophiles. Plus précisément, l'administration d'inhibiteurs de DPP4 (DPP4i) conduit à des concentrations tumorales plus élevées de CCL11 (ou eotaxine) et à une augmentation de la migration des éosinophiles exprimant CCR3 dans les tumeurs. Un meilleur contrôle de la croissance tumorale a été observé lors du traitement par DPP4i, un effet conservé chez les souris Rag2–/– mais abrogé uniquement lors de la déplétion des éosinophiles ou de l'inhibition de leur dégranulation. Nous avons également démontré que l'expression tumorale d’IL-33 était nécessaire et suffisante pour une réponse anti-tumorale médiée par les éosinophiles et que ce mécanisme contribuait à l'efficacité des inhibiteurs de points de contrôle immunitaires. Ces résultats révèlent un nouveau mécanisme par lequel le contrôle tumoral est médiée par IL-33 et les éosinophiles, mécanisme ici révélé lorsque les mécanismes endogènes de régulation immunitaire par DPP4 sont inhibés. / Dipeptidyl peptidase-4 (DPP4 or CD26)–mediated post-translational modification of chemokines has been shown to negatively regulate lymphocyte trafficking, and its inhibition enhances T cell migration and tumor immunity by preserving functional CXCL10. In extending these initial findings to humans and pre-clinical hepatocellular carcinoma models, we discovered a new mechanism whereby DPP4 inhibition improves anti-tumor responses by eosinophil recruitment. Specifically, administration of DPP4 inhibitors (DPP4i) resulted in higher concentrations of CCL11 (or eotaxin) and increased CCR3-mediated eosinophil migration into mouse tumors. Enhanced tumor control was observed upon treatment with DPP4i, an effect strikingly preserved in Rag2–/– mice, and abrogated only upon depletion of eosinophils or inhibition of their degranulation. We further demonstrated that tumor expression of IL-33 was necessary and sufficient for eosinophil-mediated anti-tumor responses, and that this mechanism contributed to checkpoint inhibitor efficacy. These findings provide new insight into IL-33- and eosinophil-mediated tumor control, revealed when endogenous mechanisms of DPP4 immune regulation are inhibited.