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The development of autoinflammatory diseases is caused by the dysregulation of innate immune mechanisms. This leads to the development of spontaneous inflammation. Mice lacking adaptor protein PSTPIP2 develop chronic autoinflammatory osteomyelitis due to higher activity of neutrophil granulocytes and their increased production of IL-1β. .β. PSTPIP2 interacts with PEST phosphatases and kinase CSK. These proteins are impor- tant negative regulators of Src family kinases. In this diploma thesis, the role of Src family kinases and the role of their positive regulator phosphatase CD45 in the development of chronic autoinflammatory osteomyelitis was studied. For this purpose, a mouse model of chronic autoinflammatory osteomyelitis (CMO) lacking CD45 was used. These mice deve- lop the disease with delayed kinetics. Bone marrow cells isolated from these mice produce less IL-1β. upon silica activation and have lower phosphorylation of ERK MAP kinase. It isβ. probably caused by higher phosphorylation of the inhibitory tyrosine of Src family kinases resulting in their lower activity. The presence of different immune cell populations in the bone marrow, spleen and blood of these mice was also monitored in these mice. The re- sults of this work contribute to a better understanding of the role of Src family...

In der vorliegenden Arbeit wurde Gewebe aus den Nasennebenhöhlen von Patienten mit Nasenpolypen untersucht. Außerdem wurden Zusammenhänge zwischen den Zellpopulationen und den Angaben zu allergischen Erkrankungen und wiederholtem Auftreten der Polypen analysiert. Es fand sich eine interindividuell unterschiedlich starke Infiltration mit eosinophilen Granulozyten. Es konnten keine Unterschiede in der prozentualen Verteilung von eosinophilen Granulozyten im Polypengewebe bei allergischen/ nichtallergischen Patienten oder Patienten mit/ ohne Rezidiv nachgewiesen werden. Die Untersuchungen erfolgten mit dem Laser Scanning Zytometer (LSC), das mit der Standardmethode, der Begutachtung mittels Lichtmikroskop, verglichen wurde. Mit der beschriebenen Methode erfolgte die Untersuchung von Polypengewebe nach einem speziell für diese Anwendung entwickelten Protokoll. Die Ergebnisse korrelierten gut mit den Ergebnissen der Lichtmikroskopie. Aufgrund der Weiterentwicklung des LSC und der ständig wachsenden Anzahl der Nachweismöglichkeiten der an der Polyposis nasi beteiligten Zytokine stellt das LSC eine ideale Methode für die Erforschung der Pathogenese von chronischen Entzündungen der Nasennebenhöhlen dar.

Les leucocytes sont connus pour jouer des rôles autant bénéfiques que néfastes dans le système nerveux central. La compréhension de leur mécanisme de recrutement est donc importante afin de contrôler leur circulation à travers la barrière hémato-encéphalique. De façon générale, l'adhésion forte est reconnue comme étant une étape clé de ce recrutement. Les principales actrices qui y sont impliquées sont les chimiokines et les intégrines. Cependant, l'identité de ces dernières peut changer selon le tissu, le stimulus et la nature des leucocytes recrutés. Dans ce travail, nous nous sommes intéressé à une population de leucocytes principalement composée de granulocytes : les leucocytes en forme de bâtonnets. Notre objectif principal a été de caractériser le mécanisme d'adhésion de ces cellules, dans le cerveau, en conditions inflammatoires via l'utilisation d'anticorps neutralisants ou d'animaux déficients pour les gènes d'intérêt. Notre hypothèse a été que l'intégrine αMβ2, via sa liaison avec ICAM-1, ainsi que l'une des chimiokines liant CXCR2, sont importantes pour adhésion des granulocytes en réponse à différents produits bactériens (la toxine pertussique (PTX) et le lipopolysaccharide (LPS)) et durant l'encéphalomyélite auto-immune expérimentale (EAE). Afin de valider cette idée, nous avons, dans un premier temps, déterminé si l'expression spatio-temporelle d'ICAM-1 est régulée par la PTX et/ou le LPS et si son absence ainsi que la neutralisation d'αMβ2 influencent le recrutement des granulocytes. En second lieu, nous avons déterminé quel ligand de CXCR2 est le plus fortement exprimé dans ces conditions et vérifié si la neutralisation de cette chimiokine, CXCL1, affecte l'adhésion des granulocytes. Nos résultats ont démontré qu'ICAM-1 peut effectivement être régulée par le LPS et la PTX, qu'en réponse à cette dernière toxine, αMβ2 semble être l'unique intégrine responsable de l'adhésion des leucocytes bâtonnets et qu'elle joue son rôle via, entre autre, ICAM-1. De plus, il s'avère que CXCL1 et CXCR2 sont importants dans l'adhésion des granulocytes en réponse à la PTX et au LPS. Finalement, non seulement la neutralisation de CXCL1 diminue cette même adhésion durant l'EAE, mais réduit également la gravité de la maladie. En conclusion, dans ce projet, nous avons contribué à mieux comprendre le mécanisme de recrutement des granulocytes dans le cerveau sous différentes conditions inflammatoires.

Le sepsis est à l’origine d’une dysfonction immunitaire prolongée responsable d’infections nosocomiales et d’une mortalité tardive élevée. Sa physiologie complexe demeure mal connue et il n’existe aucun traitement spécifique en dehors de l’antibiothérapie et des thérapeutiques de suppléance d’organes. Nous nous sommes intéressés au rôle des cellules myéloïdes dans cette dysfonction immunitaire. Nous avons pu montrer qu’il existe chez les patients atteints de sepsis une augmentation du nombre de cellules suppressives d’origine myéloïde monocytaires (M-MDSC) CD14+HLA-DRlow/- et granulocytaires (G-MDSC) identifiées comme des granulocytes de faible densité CD14-CD15+. Ces cellules sont responsables d’une activité Indoléamine 2,3-dioxygénase (IDO) et arginase 1, et leur déplétion permet de restaurer la prolifération des lymphocytes T in vitro. L’augmentation précoce des G-MDSC prédit la survenue ultérieure d’infections nosocomiales. De même, l’augmentation de l’activité IDO et de l’arginase 1 plasmatique sont associées à un mauvais pronostic. Au total, nous avons pu démontrer que les cellules myéloïdes acquièrent un phénotype suppresseur en partie responsable de l’immunodépression acquise et du pronostic péjoratif chez les patients septiques. Afin de restaurer les capacités immunitaires des patients, les MDSC pourraient devenir une future cible thérapeutique. / Sepsis results in a sustained immune dysfunction responsible for poor prognosis and nosocomial infections. Sepsis physiology remains poorly understood and no treatment exists currently, excepted from antibiotherapy and life-support techniques. We asked if myeloid cells could play a role in this sustained immune dysfunction. We demonstrated that Peripheral CD14+HLA-DRlow/- monocytic-myeloid-derived suppressor cells (MDSCs) and CD14-CD15+ low-density granulocytes identified as granulocytic- (G-)MDSCs were increased in septic patients. In vitro, arginase and IDO activities relied on MDSCs and depletion of both subsets restored T-cell proliferation. The initial proportion of G-MDSC predicted occurrence of nosocomial infections. Similarly, high plasma Indoleamine 2,3-dioxygenase (IDO) activity and arginase 1 level were associated with poor outcome. Altogether, our results demonstrate that myeloid cells acquire suppressive functions during sepsis, partially responsible for the sustained immune dysfunction and poor outcome. MDSCs may become a future therapeutic target to restore the immune capacities of septic patients.

O concentrado de granulócitos é um importante componente para o tratamento de pacientes oncológicos. A doação deste componente é mais complexa do que outras doações de sangue ou hemocomponentes, porque necessita de maiores esforços e assumção de riscos por parte do doador e, também, o uso de equipamento automatizado de aférese. O presente estudo tem o objetivo de aumentar o conhecimento sobre a população de doadores de granulócitos e avaliar a diferença entre suas motivações para realizarem as doações e seu capital social geral comparando com doadores de plaquetas e doadores altruistas de sangue total. Com esses resultados os hemocentros que realizam a coleta de granulócitos não só poderão ter informações mais objetivas que tornem mais eficaz o recrutamento deste tipo de doador e, consequentemente, aumentar a disponibilidade deste componente como também, identificando um perfil semelhante dos doadores de granulócitos na população geral de doadores o banco de sangue poderá fidelizar estes indivíduos e promover doações de sangue mais seguras. O perfil dos doadores de granulócitos foi avaliado a partir de um estudo caso-controle, sendo o grupo casos formado por estes doadores (n=64) e, os controles por doadores de plaquetas (n-64) e de sangue total (n=68), na razão de um caso para dois controles. Doadores de granulócitos são principalmente do sexo masculino e com idade mais avançada do que os controles. Com referência às motivações para doarem, doadores de granulócitos não se diferem substancialmente dos doadores de plaquetas, mas em relação aos doadores de primeira vez de sangue total há diferenças consideráveis principalmente no que diz respeito ao interesse nos resultados dos testes sorológicos. Doadores de sangue total são quase duas vezes mais motivados a doarem pelo recebimento dos resultados comparados aos doadores de granulócitos, bem como também se motivam mais a doarem para tirar o dia de folga do trabalho o que indica um gesto de menor altruísmo destes daodores. O perfil sócio determinante entre os grupos de doadores também se difere, doadores de granulócitos são pessoas efetivamente mais engajadas socialmente comparados aos controles e têm de uma rede comunitária mais coesa e confiável, concordando cerca de duas vezes mais do que doadores de plaquetas que têm vizinhos conhecidos que os ajudaria financeiramente (OR=2,49) ou concordando quatro vezes mais que doadores de sangue total que têm vizinhos conhecidos que estariam sempre prontos a ajudar outros vizinhos (OR=4,02). Concluimos que os resultados indicam que há a necessidade dos bancos de sangue utilizarem novas estratégias de recrutamento para aumentar a conversão de doadores, passando a utilizar, além do recrutamento interno, comunicações mais efetivas que, consigam atingir a população foco com maior eficiência, em locais onde a probabilidade de encontrar doadores mais engajados socialmente é aumentada, como clubes, centros comunitários ou associações / The concentrate of granulocytes is an important component for oncologic patient\'s treatment. Donation of this component is more complex than other blood components donations, because it claims more efforts and risks assumptions by the donor, and also the use of automated apheresis equipment. The present study is aimed to increase knowledge about the granulocyte donors´ population and evaluate differences among their motivations to accomplish donations and their general social capital, comparing with platelets apheresis donors and altruistic whole blood donors. These results may help blood centers, which carry granulocyte collection, not just to achieve much more objective information about these donors, but also to identify similar granulocyte donors´ profile within the general population. Blood banks may be able to achieve fidelity among these individuals and to promote safer blood donations. Granulocyte donors´ profile was evaluated in a case-control study. Cases were formed by granulocytes donors (n=64) and controls by platelet apheresis donors (n-64) and first time whole blood donors (n=68), in a ratio of one case per two controls. Granulocyte donors are mainly male and older than controls. Regarding the motivation to donate, granulocyte donors are not essentially different from platelets donors, but regarding first time whole blood donors, there are considerable differences, especially in respect to test seeking. Moreover, whole blood donors are almost twice more motivated to donate to take a day off at work, which shows a minor altruistic gesture. The determinant social profile among donors´ groups is also different. Granulocyte donors are effectively more social engaged people when compared to controls, and have a much more coherent and trustful community net, assenting about twice more than platelets donors, which have acquainted neighbors that would be ever ready to help other neighbors (OR=4.02). In conclusion, these findings indicate that is necessary to blood centers to use new recruitment strategies to increase donor´s retention. More effective communications procedures, besides internal recruitment, that achieves the target with more efficiency in locals where the probability to find donors more social engaged is increased, as clubs, community centers or associations must be warranted

<p>Hodgkin lymphoma (HL) is characterised histologically by a minority of malignant Hodgkin and Reed-Sternberg (HRS) cells surrounded by benign cells, and clinically by a relatively good prognosis. The treatment, however, leads to a risk of serious side effects. Knowledge about the biology of the disease, particularly the interaction between the HRS cells and the surrounding cells, is essential in order to improve diagnosis and treatment. </p><p>HL patients with abundant eosinophils in the tumours have a poor prognosis, therefore the eosinophil derived protein eosinophil cationic protein (ECP) was studied. Serum-ECP (S-ECP) was elevated in most HL patients. It correlated to number of tumour eosinophils, nodular sclerosis (NS) histology, and the negative prognostic factors high erythrocyte sedimentation rate (ESR) and blood leukocyte count (WBC). A polymorphism in the ECP gene (434(G>C)) was identified and the 434GG genotype correlated to NS histology and high ESR.</p><p>The poor prognosis in patients with abundant eosinophils in the tumours has been proposed to depend on HRS cell stimulation by the eosinophils via a CD30 ligand (CD30L)-CD30 interaction. However, CD30L mRNA and protein were detected in mast cells and the predominant CD30L expressing cell in HL is the mast cell. Mast cells were shown to stimulate HRS cell lines via CD30L-CD30 interaction. The number of mast cells in HL tumours correlated to worse relapse-free survival, NS histology, high WBC, and low blood haemoglobin. </p><p>Survival in patients with early and intermediate stage HL, diagnosed between 1985 and 1992, was generally favourable and comparatively limited treatment was sufficient to produce acceptable results for most stages. The majority of relapses could be salvaged. Patients treated with a short course of chemotherapy and radiotherapy had an excellent outcome.</p><p>In conclusion prognosis is favourable in early and intermediate stages and there are possibilities for further improvements based on the fact that mast cells and eosinophils affect the biology and prognosis of HL.</p>

Hodgkin lymphoma (HL) is characterised histologically by a minority of malignant Hodgkin and Reed-Sternberg (HRS) cells surrounded by benign cells, and clinically by a relatively good prognosis. The treatment, however, leads to a risk of serious side effects. Knowledge about the biology of the disease, particularly the interaction between the HRS cells and the surrounding cells, is essential in order to improve diagnosis and treatment. HL patients with abundant eosinophils in the tumours have a poor prognosis, therefore the eosinophil derived protein eosinophil cationic protein (ECP) was studied. Serum-ECP (S-ECP) was elevated in most HL patients. It correlated to number of tumour eosinophils, nodular sclerosis (NS) histology, and the negative prognostic factors high erythrocyte sedimentation rate (ESR) and blood leukocyte count (WBC). A polymorphism in the ECP gene (434(G&gt;C)) was identified and the 434GG genotype correlated to NS histology and high ESR. The poor prognosis in patients with abundant eosinophils in the tumours has been proposed to depend on HRS cell stimulation by the eosinophils via a CD30 ligand (CD30L)-CD30 interaction. However, CD30L mRNA and protein were detected in mast cells and the predominant CD30L expressing cell in HL is the mast cell. Mast cells were shown to stimulate HRS cell lines via CD30L-CD30 interaction. The number of mast cells in HL tumours correlated to worse relapse-free survival, NS histology, high WBC, and low blood haemoglobin. Survival in patients with early and intermediate stage HL, diagnosed between 1985 and 1992, was generally favourable and comparatively limited treatment was sufficient to produce acceptable results for most stages. The majority of relapses could be salvaged. Patients treated with a short course of chemotherapy and radiotherapy had an excellent outcome. In conclusion prognosis is favourable in early and intermediate stages and there are possibilities for further improvements based on the fact that mast cells and eosinophils affect the biology and prognosis of HL.

O concentrado de granulócitos é um importante componente para o tratamento de pacientes oncológicos. A doação deste componente é mais complexa do que outras doações de sangue ou hemocomponentes, porque necessita de maiores esforços e assumção de riscos por parte do doador e, também, o uso de equipamento automatizado de aférese. O presente estudo tem o objetivo de aumentar o conhecimento sobre a população de doadores de granulócitos e avaliar a diferença entre suas motivações para realizarem as doações e seu capital social geral comparando com doadores de plaquetas e doadores altruistas de sangue total. Com esses resultados os hemocentros que realizam a coleta de granulócitos não só poderão ter informações mais objetivas que tornem mais eficaz o recrutamento deste tipo de doador e, consequentemente, aumentar a disponibilidade deste componente como também, identificando um perfil semelhante dos doadores de granulócitos na população geral de doadores o banco de sangue poderá fidelizar estes indivíduos e promover doações de sangue mais seguras. O perfil dos doadores de granulócitos foi avaliado a partir de um estudo caso-controle, sendo o grupo casos formado por estes doadores (n=64) e, os controles por doadores de plaquetas (n-64) e de sangue total (n=68), na razão de um caso para dois controles. Doadores de granulócitos são principalmente do sexo masculino e com idade mais avançada do que os controles. Com referência às motivações para doarem, doadores de granulócitos não se diferem substancialmente dos doadores de plaquetas, mas em relação aos doadores de primeira vez de sangue total há diferenças consideráveis principalmente no que diz respeito ao interesse nos resultados dos testes sorológicos. Doadores de sangue total são quase duas vezes mais motivados a doarem pelo recebimento dos resultados comparados aos doadores de granulócitos, bem como também se motivam mais a doarem para tirar o dia de folga do trabalho o que indica um gesto de menor altruísmo destes daodores. O perfil sócio determinante entre os grupos de doadores também se difere, doadores de granulócitos são pessoas efetivamente mais engajadas socialmente comparados aos controles e têm de uma rede comunitária mais coesa e confiável, concordando cerca de duas vezes mais do que doadores de plaquetas que têm vizinhos conhecidos que os ajudaria financeiramente (OR=2,49) ou concordando quatro vezes mais que doadores de sangue total que têm vizinhos conhecidos que estariam sempre prontos a ajudar outros vizinhos (OR=4,02). Concluimos que os resultados indicam que há a necessidade dos bancos de sangue utilizarem novas estratégias de recrutamento para aumentar a conversão de doadores, passando a utilizar, além do recrutamento interno, comunicações mais efetivas que, consigam atingir a população foco com maior eficiência, em locais onde a probabilidade de encontrar doadores mais engajados socialmente é aumentada, como clubes, centros comunitários ou associações / The concentrate of granulocytes is an important component for oncologic patient\'s treatment. Donation of this component is more complex than other blood components donations, because it claims more efforts and risks assumptions by the donor, and also the use of automated apheresis equipment. The present study is aimed to increase knowledge about the granulocyte donors´ population and evaluate differences among their motivations to accomplish donations and their general social capital, comparing with platelets apheresis donors and altruistic whole blood donors. These results may help blood centers, which carry granulocyte collection, not just to achieve much more objective information about these donors, but also to identify similar granulocyte donors´ profile within the general population. Blood banks may be able to achieve fidelity among these individuals and to promote safer blood donations. Granulocyte donors´ profile was evaluated in a case-control study. Cases were formed by granulocytes donors (n=64) and controls by platelet apheresis donors (n-64) and first time whole blood donors (n=68), in a ratio of one case per two controls. Granulocyte donors are mainly male and older than controls. Regarding the motivation to donate, granulocyte donors are not essentially different from platelets donors, but regarding first time whole blood donors, there are considerable differences, especially in respect to test seeking. Moreover, whole blood donors are almost twice more motivated to donate to take a day off at work, which shows a minor altruistic gesture. The determinant social profile among donors´ groups is also different. Granulocyte donors are effectively more social engaged people when compared to controls, and have a much more coherent and trustful community net, assenting about twice more than platelets donors, which have acquainted neighbors that would be ever ready to help other neighbors (OR=4.02). In conclusion, these findings indicate that is necessary to blood centers to use new recruitment strategies to increase donor´s retention. More effective communications procedures, besides internal recruitment, that achieves the target with more efficiency in locals where the probability to find donors more social engaged is increased, as clubs, community centers or associations must be warranted

Background: Leukocytes in peripheral blood (PB) are prognostic biomarkers in head and neck squamous cell carcinoma cancer patients (HNSCC-CPs), but differences between HNSCC-CPs and healthy adults (HAs) are insufficiently described. Methods: 10-color flow cytometry (FCM) was used for in-depth immunophenotyping of PB samples of 963 HAs and 101 therapy-naïve HNSCC-CPs. Absolute (AbsCC) and relative cell counts (RelCC) of leukocyte subsets were determined. A training cohort (TC) of 43 HNSCC-CPs and 43 HAs, propensity score (PS)-matched according to age, sex, alcohol, and smoking, was used to develop a score consecutively approved in a validation cohort (VC). Results: Differences in AbsCC were detected in leukocyte subsets (p < 0.001), but had low power in discriminating HNSCC-CPs and HAs. Consequently, RelCC of nine leukocyte subsets in the TC were used to calculate 36 ratios; receiver operating characteristic (ROC) curves defined optimum cut-off values. Binary classified data were combined in a score based on four ratios: monocytes-to-granulocytes (MGR), classical monocytes-to-monocytes (clMMR), monocytes-to-lymphocytes (MLR), and monocytes-to-T-lymphocytes (MTLR); ≥3 points accurately discriminate HNSCC-CPs and HAs in the PS-matched TC (p = 2.97 × 10−17), the VC (p = 4.404 × 10−178), and both combined (p = 7.74 × 10−199). Conclusions: RelCC of leukocyte subsets in PB of HNSCC-CPs differ significantly from those of HAs. A score based on MGR, clMMR, MLR, and MTLR allows for accurate discrimination.