IL-12 family cytokines IL-23 and IL-27 play an important role linking innate and adaptive immunity, and regulating T-cell responses. The production of IL-12, a structurally similar cytokine, is decreased in chronic HIV infection; therefore IL-23 and IL-27 may also be influenced by HIV infection. I hypothesized that HIV inhibits LPS-induced IL-23 and IL-27 production in human MDMs by suppressing the activation of signalling pathways regulating their expression. In vitro HIV-infection of MDMs did not have any effect on basal secretion of IL-23 or IL-27; however, HIV inhibited LPS-induced production of IL-12/23 p40 and IL-23 p19, and IL-27 EBI3 and IL-27 p28 mRNA expression, and IL-23, IL-12/23 p40 and IL-27 secretion. In order to evaluate the molecular mechanisms by which HIV inhibits IL-23 and IL-27 in LPS-stimulated MDMs, the signalling pathways regulating their expression were evaluated. The PI3K, p38 MAPK, and JNK MAPK pathways were found to positively regulate LPS-induced IL-27 secretion. Interestingly, in vitro HIV infection inhibited LPS-induced p38 and JNK MAPK activation in MDMs. In summary, I have shown that HIV inhibits IL-23 and IL-27 production in LPS-stimulated MDMs and that HIV may inhibit LPS-induced IL-27 production through the inhibition of p38 and JNK MAPK activation. It is currently unknown whether PKCs regulate LPS-induced IL-23 or IL-27 in human monocytes/macrophages. I demonstrated that classical PKCs differentially regulate LPS-induced IL-23 and IL-27 secretion within THP-1 cells, primary monocytes, and MDMs. Classical PKCs were found to positively regulate LPS-induced IL-12/23 p40 and IL-27 p28 mRNA expression and IL-12/23 p40, IL-23, and IL-27 secretion in primary human monocytes. Similarly, the classical PKCs were found to positively regulate IL-27 p28 mRNA expression and IL-27 secretion in THP-1 cells. However, classical PKCs did not regulate LPS-induced IL-27 production in MDMs, or LPS-induced IL-23 production in THP-1 cells. Overall, this demonstrates that classical PKCs differentially regulate LPS-induced IL-23 and IL-27 production in different myeloid cells.

L'axe IL-12-IFN-γ joue un rôle important dans l'immunité anti-mycobactérienne. J'ai identifié et étudié une cohorte de 137 patients présentant un déficit autosomique récessif complet d'IL12RB1 qui code la sous-unité β1 des récepteurs de l'IL-12 et de l'IL-23. Ces patients sont issus de 101 familles provenant de 30 pays. Ils présentent une grande diversité génétique avec 52 allèles mutants différents. Le phénotype cellulaire avec un défaut complet de réponse à l'IL-12 est homogène chez tous les patients. Les phénotypes cliniques sont eux très hétérogènes allant de l'absence d'infection jusqu'au décès. Il s'agit en grande majorité d'infections mycobactériennes (BCG, mycobactéries environnementales et tuberculose) et/ou à salmonelles. La candidose est aussi retrouvée associée à ce défaut chez un grand nombre de patients. L'axe IL-23-IL-17 participe à la différentiation et à l'activation des lymphocytes T CD4+ dits de type Th17. les cytokines et les mécanismes contrôlant la différentiation de ces cellules sont peu connus. J'ai étudié le développement des lymphocytes producteurs d'IL-17 chez des patients porteurs de défauts génétiques affectant la voie du TGF-β (patients TGFBR1, TGFBR2 et TGFB1), de l'IL-1β (patients IRAK4 et MYD88), de l'IL-6 (patients STAT3) et de l'IL-23 (patients IL12B et IL12RB1). Pour cela, j'ai quantifié la production et la sécrétion d'IL-17 dans deux modèles expérimentaux ex vivo et in vitro. Les patients IL12B-/- et IL12RB1-/-, et de façon plus drastique les patients STAT3-/- présentent une diminution des lymphocytes producteurs d'IL-17, ce qui suggère l'importance de ces molécules dans la différentiation et l'expansion des cellules Th17 in vivo

Interleukin-12 (IL-12) ist ein zentrales Zytokin in der Entwicklung einer protektiven, zellulären Typ 1-Immunantwort. Es ist aus einer p40- und einer p35-Untereinheit aufgebaut. Es stimuliert NK- und T-Zellen zur Ausschüttung großer Mengen IFN-gamma und setzt so eine Typ 1-Immunantwort in Gang. Die p40-Untereinheit des IL-12 kommt auch in anderen biologisch wirksamen Verbindungen wie beispielsweise als Monomer, Homodimer oder als IL-23 (in Verbindung mit einer p19-Untereinheit) vor. Während das Homodimer in der vorliegenden Arbeit als reiner Antagonist zu IL-12 zu wirken scheint, wurden für IL-23 bereits zu IL-12 agonistische Wirkungen demonstriert. Im Mittelpunkt der vorliegenden Arbeit stand die Erarbeitung p40-abhängiger Wirkungen unter Ausschluß der Effekte von IL-12, d. h. möglicherweise IL-23-abhängiger Effekte. In den vorliegenden Untersuchungen wurde mit gendeletierten Mäusen gearbeitet, so dass IL-12 in diesen Systemen keine Rolle spielen kann sondern nur die p40-Proteine außer IL-12. Im Infektionsmodell mit Salmonella Enteritidis wurden p35-gendeletierte (p35-/--) und p40-/--Mäuse verwendet. Durch eine Induktion der p40-Expression waren Unterschiede auf die Wirkung der p40-Proteine zurückzuführen. Es zeigte sich, dass p40-Proteine durch die Induktion einer IFN-gamma Produktion eine Verbesserung der Abtötung intrazellulärer Pathogene bewirkten. Dadurch gelang in den p35-/--Mäusen die Eindämmung der systemischen Infektion besser und diese Mäuse überlebten länger als die p40-/--Mäuse. In Tumormodellen mit dem Lewis-Lungenkarzinom und dem Melanom B16 wurden p35/40-/--Mäuse, welche keine p40-Proteine bilden können, mit der für p40 kodierenden DNA gentherapiert. Durch diese lokale Gentherapie kam es zu einer Reduktion des Tumorwachstums. In immunhistologischen Untersuchungen war eine Rekrutierung von Makrophagen und eine Hemmung der Angiogenese im Tumorbereich sichtbar. Lokale und systemische Proteintherapien mit dem Homodimer oder IL-23 hatten keinen Effekt auf das Wachstum des Tumors, was auf die Existenz eines weiteren noch unbekannten heterodimeren p40-Proteins hindeutet. In vitro konnte gezeigt werden, dass IL-23 die IFN-gamma-Produktion durch Splenozyten induziert und dieser Effekt durch das Homodimer antagonisiert werden kann. Interessanterweise kann es in primären Milzzellkulturen auch IL-12 antagonisieren. Eine In-vitro-Infektion führte zu einer p40-abhängigen IFN-gamma-Produktion, die auch durch das Homodimer antagonisiert werden konnte. Während die Effekte der p40-Proteine im Infektionsmodell möglicherweise auf IL-23 zurückgeführt werden können und diese Effekte auch durch In-vitro-Untersuchungen gestützt werden, muss nach den Ergebnissen im Tumormodell auf die Existenz eines weiteren, bisher unbekannten p40-Proteines, p40-x, geschlossen werden. / Interleukin-12 (IL-12) is a key cytokine in the development of a protective cellular Th1 immune response. It consists of a p40 and a p35 subunit. Following stimulation with IL-12, NK and T cells produce large amounts of IFN-gamma resulting in a type 1 immune response. The p40 subunit of IL-12 is also part of other biologically active proteins such as monomeric or homodimeric p40 or the heterodimeric IL-23 (in combination with a p19 subunit). While in this study the homodimeric p40 appears to antagonize IL-12, IL-23 was demonstrated to have agonistic effects. The aim of this study was to investigate p40-dependent effects which can be observed independently of IL-12, i.e. potential effects mediated by IL-23. For the experiments mutant mice were used so that IL-12 dependent mechanisms could not play a role but only p40-dependent proteins excluding IL-12. In a Salmonella Enteritidis infection model p35-gene deleted (p35-/-) and p40-/- mice were used. As the expression of p40 is induced by bacterial antigen, differences between the strains were caused by the p40 protein. During the infection p40 proteins induced IFN-gamma production thus improving the killing of intracellular pathogens. This resulted in a better control of the systemic infection and longer survival periods of the p35-/- mice as compared to p40-/- mice. For the experiments in the tumor model using the Lewis-Lung carcinoma and the Melanoma B16 as tumors, p35/40-/- mice which are unable to produce any p40 proteins, received gene therapy with DNA encoding for p40. This local gene therapy resulted in a reduced tumor growth. Immunohistochemical examination revealed an infiltration of the tumor tissue with macrophages and a reduced neoangiogenesis within the tumor. This effect could not be achieved by local administration of IL-23 or the p40-homodimer as a protein, indicating the existence of an as yet unknown heterodimeric p40 protein. In vitro experiments showed that IL-23 induces IFN-gamma production by splenocytes and this effect can be antagonized by the homodimer. Interestingly, IL-23 is also able to antagonize IL-12 in primary splenocyte cultures. In vitro infection with Salmonella resulted in an p40-dependent IFN-gamma production that could also be antagonized by the homodimer. The protective effects in the infection model might be caused by IL-23, which is supported by the in vitro results. On the other hand, in the tumor model IL-23 does not seem to be the player and it must be concluded that the protective effects are caused by an other as yet unknown p40-dependent protein p40-x.

nÃo hà / O objetivo do estudo foi investigar o perfil de produÃÃo de IL-6 em pacientes com tuberculose pulmonar ativa e avaliar o papel funcional do polimorfismo -174G>C do gene de IL-6 na produÃÃo sistÃmica desta citocina. Um total de 63 pacientes e 99 controles foi estudado, sendo 38 pacientes [25(65,8%) masculinos] e 63 controles [51 (81%) masculinos] para a dosagem de IL-6, enquanto, 42 pacientes [25 (60%) masculinos] e 79 controles [62(78,5%) masculinos] para o estudo do polimorfismo. Os pacientes foram selecionados dos centros de referÃncia da rede estadual de saÃde: Dona LibÃnia, Hospital de Messejana, Hospital de Maracanaà e Hospital Geral Dr. CÃsar Cals. O grupo controle foi selecionado no HEMOCE. Foi realizado teste de ELISA para a dosagem sÃrica de IL-6. O DNA genÃmico foi extraÃdo de sangue perifÃrico e o polimorfismo de IL-6 foi estudado por reaÃÃo de polimerase em cadeia utilizando iniciadores seqÃÃncia especÃficos. A dosagem sÃrica de IL-6 se mostrou elevada nos pacientes portadores de tuberculose em relaÃÃo aos controles (mediana = 4,3 pg/mL versus 0,5 pg/mL, p<0,001), porÃm nÃo exibiu diferenÃa entre os grupos de doentes sensÃveis e os resistentes ao tratamento especÃfico. Em relaÃÃo ao estudo funcional do polimorismo de IL-6, foi observado um robusto aumento dos nÃveis de IL-6 nos doentes portadores do genÃtipo GG (mediana=4,1 pg/mL, variaÃÃo 0,5-12,0 pg/mL), em relaÃÃo aos portadores dos genÃtipos GC e CC, sendo que nestes se observou uma expressÃo de IL-6 semelhante a dos controles (mediana=0,6 pg/mL, variaÃÃo 0,0-2,8 pg/mL), conferindo significÃncia estatÃstica com p=0,04. A relevÃncia deste estudo à mostrar in vivo o papel funcional do polimorfismo de IL-6 na tuberculose. Em conclusÃo, o genÃtipo GG de pacientes com tuberculose pulmonar ativa determina produÃÃo aumentada de IL-6. / The aim of this study was to investigate the profile of IL-6 production in patients with active pulmonary tuberculosis and to evaluate the functional role of polymorphism -174G>C in the systemic production of this cytokine. A total of 63 patients and 99 controls were studied. Among them 38 patients [25(65.8%) males] and 63 controls [51(81%) males] were studied for the IL-6 dosage. Moreover, 42 patients [25(60%) males] and 79 controls [62(78.5%) males] were studied for the -174G>C polymorphism. Patients were selected from Dona LibÃnia Center; Messejana Hospital, Maracanau Hospital and Dr. Cesar Cals General Hospital. The control group was selected from HEMOCE. An ELISA test was performed to measure IL-6 in peripheral blood. The genomic DNA was extracted from peripheral blood and IL-6 polymorphism was studied by polymerase chain reaction using sequence-specific primers. The IL-6 dosage showed an increase in patients with tuberculosis in relation to controls (An increase in IL6 dosage was found in patients with tuberculosis in relation to controls) (median= 4.3 pg/mL vs 0.5 pg/mL, p<0.001), but no difference was observed in drug-sensitive patients in comparison to drug-resistant ones. The genotype distribution showed no difference between patients and controls. In relation to the functional study, the IL-6 levels pointed out a significant increase in patients presenting GG genotype (median=4.1 pg/mL, range 0.5-12.0 pg/mL), in relation to GC and CC careers; these two latter genotypes presented similar IL-6 production as in healthy individuals with median=0.6 pg/mL, range 0.0-2.8 pg/mL, corroborating statistical significance with p=0.04. The relevance of this study is to show in vivo the functional role of IL-6 polymorphism in active pulmonary tuberculosis. Conclusion, the GG genotype in patients with pulmonary tuberculosis determines an increase in IL-6 systemic production.

The canine transmissible venereal tumor (CTVT) is unique in various aspects, and the principal is that the tumoral cells are not originated from the hos t. Recent findings showed that the CTVT is a transplantable tumor that first appeared in a dog ancestor approximately 10000 years ago. The tumoral cells propagate mainly through coitus, develop a s a graft, and have the capability of installing themselves by mechanisms of escape from the host's immunologic response. This specific response involves cellular and humoral immunity and varies according to some factors not yet very elucidated. Beyond the well-known role of fi ghting the tumor cells, the inflammatory response also plays an involuntary and paradoxical role, w hich results in the promotion of tumor growth by releasing vasculogenic, antiapoptotic, and cellular growth- promoting substances. The fact that tumors can benefit from the inf lammatory response makes the investigation of the mechanisms involved important for the development of new therapies focused on the modulation of the inflammatory response to control the tumor development. The aim of this work is to better understand the mechanisms behind tumora l growth by the measurement of the levels of pro-inflammatory (IL-1, IL-6, TNF- α and INF- γ ) and anti- inflammatory (IL-10) cytokines and the C-reactive protein (CRP) ove r the treatment of dogs naturally infected with CTVT. The quantification of the cytokines and CRP was performed in the animals' serum from samples obtained at the moments of the diagnosis and pre-therapy, immediately before chemotherapy, and after the confirmation of the cure of each animal. According to therapy response, two groups were identified, R, were t he tumor was resistant to therapy and NR, which was susceptible. A cure probability was define d in relation to time of treatment and tumor response to vincristin. In group R all parameter s varied significantly: The expression of pro-inflammatory cytokines and CRP were higher, and of I L-10, lower, comparing to group NR. For pro-inflammatory cytokines, this difference was ma intained until cure. Statistical analysis was able to detect correlations betwee n all variables, demonstrating the participation of cytokines during tumor evolution. The role of inflammati on has been postulated and, although the mechanisms remain unclear, a correlation of chronic i nflammation and cancer susceptibility has been demonstrated. Because CTVT is a tumor of foreign cells, it is a suitable model to investigate the mechanisms involved in tumor maintenance and deve loping, as well as the associated immune response. / O tumor venéreo transmissível canino (TVTc) é um tumor único em vários aspectos, sendo o principal, o fato de as células tumorais não serem originárias do animal acometido. Resultados de pesquisas recentes demonstraram que o TVTc é um tumor transplantável que surgiu em ancestrais do cão doméstico há aproximadamente 10000 anos. As células, que se propagam principalmente pelo coito, se desenvolvem como um enxerto e apresentam a capacidade de se implantar através de mecanismos de escape à resposta imunológica do hospedeiro. Essa resposta envolve a imunidade celular e humoral e varia de acordo com fatores não totalmente elucidados. Além do conhecido papel na resposta imune com o objetivo de combater tumores, a resposta inflamatória desempenha um papel involuntário e paradoxal que resulta na promoção do crescimento tumoral pela liberação de substâncias vasculogênicas, antiapoptóticas e promotoras de crescimento celular. O fato de que os tumores possam se beneficiar da resposta inflamatória torna necessárias pesquisas visando o desenvolvimento de terapias direcionadas à modulação da resposta inflamatória para o controle do desenvolvimento tumoral. Dessa forma, o objetivo deste estudo foi compreender melhor os mecanismos envolvidos no desenvolvimento do tumor através da mensuração dos níveis das citocinas pró-inflamatórias (IL- 1, IL-6, TNF-α e INF-γ) e da anti-inflamatória (IL-10) e de uma proteína de fase aguda da inflamação, a Proteína C-reativa (PCR) durante o tratamento de cães naturalmente infectados pelo TVTc. A quantificação das citocinas e da PCR foi realizada no soro dos animais a partir de amostras obtidas no diagnóstico e pré-terapia, imediatamente antes de cada nova aplicação 9 quimioterápica e no momento em que o animal era considerado curado. A partir da resposta à quimioterapia foram caracterizados grupos de animais de acordo com os tumores resistentes (R) e não-resistentes (NR). Foi estabelecida a probabilidade de cura em relação ao tempo de terapia, de acordo com o tipo de tumor. No grupo R, foi observada variação significativa em todos os parâmetros, sendo a expressão das citocinas pró-inflamatórias e da PCR, mais elevadas e a expressão da IL-10 inferior em relação à expressão observada em amostras dos animais do grupo NR. No caso das citocinas pró-inflamatórias e da PCR, essa diferença se manteve até a cura dos animais, diferindo da IL-10, cujas concentrações foram similares nos dois grupos ao final do tratamento. A análise estatística realizada detectou a presença de correlações entre as variáveis, demonstrando a participação das citocinas durante o processo de evolução tumoral. O papel da inflamação no desenvolvimento do câncer foi postulado, apesar de os mecanismos moleculares não terem sido elucidados, sabe-se que a inflamação crônica eleva a probabilidade do desenvolvimento de tumores. Pelo fato de o TVTc ser um tumor de células estranhas ao organismo, seu estudo é importante para verificar os mecanismos relacionados com a manutenção e desenvolvimento dos tumores, bem como da resposta imune associada.

IL-12 family cytokines IL-23 and IL-27 play an important role linking innate and adaptive immunity, and regulating T-cell responses. The production of IL-12, a structurally similar cytokine, is decreased in chronic HIV infection; therefore IL-23 and IL-27 may also be influenced by HIV infection. I hypothesized that HIV inhibits LPS-induced IL-23 and IL-27 production in human MDMs by suppressing the activation of signalling pathways regulating their expression. In vitro HIV-infection of MDMs did not have any effect on basal secretion of IL-23 or IL-27; however, HIV inhibited LPS-induced production of IL-12/23 p40 and IL-23 p19, and IL-27 EBI3 and IL-27 p28 mRNA expression, and IL-23, IL-12/23 p40 and IL-27 secretion. In order to evaluate the molecular mechanisms by which HIV inhibits IL-23 and IL-27 in LPS-stimulated MDMs, the signalling pathways regulating their expression were evaluated. The PI3K, p38 MAPK, and JNK MAPK pathways were found to positively regulate LPS-induced IL-27 secretion. Interestingly, in vitro HIV infection inhibited LPS-induced p38 and JNK MAPK activation in MDMs. In summary, I have shown that HIV inhibits IL-23 and IL-27 production in LPS-stimulated MDMs and that HIV may inhibit LPS-induced IL-27 production through the inhibition of p38 and JNK MAPK activation. It is currently unknown whether PKCs regulate LPS-induced IL-23 or IL-27 in human monocytes/macrophages. I demonstrated that classical PKCs differentially regulate LPS-induced IL-23 and IL-27 secretion within THP-1 cells, primary monocytes, and MDMs. Classical PKCs were found to positively regulate LPS-induced IL-12/23 p40 and IL-27 p28 mRNA expression and IL-12/23 p40, IL-23, and IL-27 secretion in primary human monocytes. Similarly, the classical PKCs were found to positively regulate IL-27 p28 mRNA expression and IL-27 secretion in THP-1 cells. However, classical PKCs did not regulate LPS-induced IL-27 production in MDMs, or LPS-induced IL-23 production in THP-1 cells. Overall, this demonstrates that classical PKCs differentially regulate LPS-induced IL-23 and IL-27 production in different myeloid cells.

BACKGROUND: Recently, it is found that T-helper (Th) 22 cells are involved in different types of autoimmune and tumor diseases. But, till now, no study has been carried out to understand the involvement of these cells in cervical cancer (CC). METHODS: Flow cytometry was used to determine the expression of interferon gamma (IFN-gamma), Interleukin-22 (IL-22), IL-17 in the peripheral blood of healthy controls (HC), CIN and cervical cancer patients. From peripheral blood mononuclear cells (PBMCs), mRNA expression levels of Aryl hydrocarbon receptor (AHR), RAR-related orphan receptor C (RORC), TNF-alpha and IL-6 were respectively determined. Using the method of ELISA, plasma concentrations of IL-22, IL-17 and TNF-alpha were examined. RESULTS: Th22 and Th17 cells were elevated in CC and CIN patients. Th1 cells and the plasma concentrations of IL-22 in CC patients were significantly increased compared with HC. In CC patients, an increased prevalence of Th22 cells was associated with lymph node metastases. There was a positive correlation between Th22 and Th17 cells, but an approximately negative correlation between Th22 and Th1 cells in CC patients. The mRNA expression of RORC, TNF-alpha and IL-6 was significantly high in CC patients. CONCLUSIONS: Our results indicate that there is a higher circulatory frequency of Th22, Th17 and Th1 cells in CC which may conjointly participate in the pathogenesis and growth of CC.

No description available.

Les neutrophiles produisent plusieurs médiateurs peptidiques contribuant à l'inflammation lors de la réponse immunitaire contre les agents infectieux. Ces médiateurs sont encodés par des gènes dont la transcription est strictement régulée. Alors que ces facteurs de transcription sont bien connus, les voies de signalisation causant l'activation transcriptionnelle, ainsi que l'initiation de la traduction des chimiokines, sont moins bien caractérisées chez les neutrophiles humains. En conséquence, nous avons caractérisé le rôle de la PI3K dans cette réponse. L'inhibition de la PI3K par le LY294002 a considérablement réduit la sécrétion de chimiokines. La nucléofection de dominant-négatifs des sous-unités de la PI3K dans la lignée cellulaire PLB-985 différenciée en neutrophiles a confirmé ces résultats. D'autre part, le LY294002 a drastiquement inhibé l'expression génique de certaines chimiokines sans influencer l'activation des facteurs de transcription. Ceci a aussi été confirmé par la double nucléofection des dominants-négatifs et de promoteurs couplés à la luciférase. Ainsi, la PI3K affecte sélectivement la transcription de certaines chimiokines et module la traduction puisque le LY294002 inhibe la phosphorylation de protéines impliquées dans l'initiation de la traduction. Puisque les mécanismes contrôlant l'initiation de la traduction sont à peu près inconnus chez les neutrophiles, nous avons donc étudié la contribution de MNK I. Le CGP57380, un inhibiteur de MNK I, a fortement réduit la sécrétion de chimiokines. Ces données ont été confirmées par la nucléofection d'un dominant-négatif de MNK I dans la lignée cellulaire PLB-985 différenciée en neutrophiles. De plus, le CGP57380 n'influence pas l'expression génique des chimiokines. L'utilisation d'une coiffe synthétique mimant celle des ARNms nous a permis de déterminer que MNK I n'y est pas recrutée. Par contre, le CGP57380 diminue la phosphorylation de protéines impliquées dans le contrôle de l'initiation de la traduction. Nos résultats montrent que MNK I participe au contrôle de la traduction des chimiokines. Pour terminer, nous avons étudié la contribution de l'IL- 18 à la production de chimiokines. Nous avons tout d'abord détecté l'expression de l'IL- 18 en ARNm et au niveau protéique. De plus, bien que l'ARNm de l'IL- 18 soit inductible en réponse à plusieurs stimuli inflammatoires, seul le LPS peut induire sa sécrétion. Les neutrophiles sécrètent de façon constitutive l'IL-18 BP, l'inhibiteur naturel de l'IL-18, bien que cette sécrétion ne soit pas modulable. L'IL- 18 sécrété en réponse au LPS agit de façon autocrine sur les neutrophiles. En effet, le blocage de l'IL- 18 réduit considérablement l'expression et la sécrétion des chimiokines. En accord avec ces données, l'ajout d'IL-18 exogène induit l'expression et la sécrétion de plusieurs chimiokines en activant une signalisation intracellulaire semblable aux autres stimuli inflammatoires déjà étudiés. Dans leur ensemble, nos résultats dévoilent de nouvelles interactions entre l'IL-18 et les neutrophiles. En conclusion, les travaux présentés dans cette thèse ont montré que les stimuli inflammatoires utilisent en partie la voie de la PI3K au niveau de la transcription; et, au niveau de la traduction, les kinases MNK I et PI3K pour induire la production de chimiokines par les neutrophiles humains. Ces molécules de signalisation pourraient donc représenter des cibles prometteuses pour des interventions thérapeutiques visant à abaisser la production de chimiokines dans des pathologies chroniques dans lesquelles les neutrophiles et leurs produits jouent un rôle prédominant.

<p>Within the field of immunology, the existence of autoimmune diseases presents a unique set of challenges. The immune system typically protects the host by identifying foreign pathogens and mounting an appropriate response to eliminate them. Great strides have been made in understanding how foreign pathogens are identified and responded to, leading to the development of powerful immunological tools, such as vaccines and a myriad of models used to study infectious diseases and processes. However, it is occasionally possible for host tissues themselves to be inappropriately identified as foreign, prompting an immune response that attempts to eliminate the host tissue. The immune system has processes in place, referred to as selection, designed to prevent the development of cells capable of recognizing the self as foreign. While a great deal of work has been invested in understanding these processes, many concrete answers remain elusive. </p><p>Our laboratory, which focuses on understanding the roles of E and Id proteins in lymphocyte development, has established the Id3 knockout mouse as a model of autoimmune disease. Id3 knockout mice develop a disease reminiscent of human Sj&#1255;gren's Syndrome, an autoimmune disease that progressively damages the salivary and lachrymal glands. Continued study of this model has yielded interesting results. These include the identification of CD4+ T cells as initiators of disease as well as the identification of the cytokine Interleukin 13 (IL-13) as a potential causative agent. However, the source of IL-13, its true role as a causative agent of disease, as well as the developmental basis for its elevated expression remained elusive. </p><p>To this end, I utilized a reporter gene that enabled me to detect cells producing IL-13 as well as test the effects of IL-13 deletion on disease progression. Using this system, I was able to identify both CD4+ T cells and &#947;&#948; T cells as major sources of IL-13. I was also able to determine that elimination of IL-13 in Id3 knockout mice was sufficient to block the development of disease symptoms, reinforcing the hypothesis that IL-13 is a causative agent in disease initiation. Finally, I attempted to better characterize the phenotype of cells producing IL-13. These experiments indicated that the T cell receptor (TCR) repertoire of Id3 knockout mice is markedly different than that of wild-type (WT) mice. Furthermore, cells bearing certain TCRs appeared to express IL-13 at dramatically different rates, indicating that certain TCRs may be predisposed to IL-13 particular effector fates.</p> / Dissertation