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1

Duchesnes, Cecile Emmanuelle. "Molecular characterisation of the chemokine receptor CCR3". Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.407171.

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Brasseit, Jennifer. "Mutagenese und funktionelle Charakterisierung des humanen CCR3-Rezeptors". [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:352-opus-61848.

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Joubert, Philippe. "Expression and function of chemokine receptors on airway smooth muscle cells". Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103385.

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Asthma is a respiratory disease that affects 2.5-3 million Canadians. This condition is characterized by a Th2-driven immune response that implicates the infiltration of eosinophils and remodelling of the airways. In the last decade, airway smooth muscle cells (ASMC) have became the subject of intense research in the field of inflammatory lung diseases including asthma. It is known that ASMC respond to a wide variety of inflammatory mediators such as cytokines and chemokines. Function of ASMC in the context of asthma has extended beyond its traditional role of a structural cell. Indeed, it is believed that they can participate in the initiation and the perpetuation of the inflammatory response that takes place in the airway of asthmatic subjects. The general aim of this work was to investigate the role of ASMC in the pathogenesis of asthma. More specifically, we studied the expression of two C-C chemokine receptors, CCR3 and CCR1 in the context of asthma.
For the first time, this work describes the expression of chemokine receptors by ASMC. We have shown that eotaxin, an important chemokine in asthma, induces migration of ASMC through the activation of CCR3. Although CCR3 expression is not regulated by Th2 cytokines in vitro, ASMC isolated from asthmatic patients expressed intrinsically higher levels of the surface receptor when compared to controls. We also describe the expression of CCR1 by ASMC, a receptor involved in airway remodelling in an animal model of asthma. We reported the expression of CCR1 mRNA in biopsies obtained from mild, moderate and severe asthmatics and showed that mild group express the highest level of CCR1. We also confirmed that ASMC express the receptor in vivo and showed that stimulation of this receptor with its ligands induces intra-cellular calcium mobilization, which confirms its functionality. Regulation of CCR1 on ASMC was also assessed using proinflammatory, Th1 and Th2 cytokines. We found that TNF-alpha and to a lesser extent, IFN-gamma, upregulated CCR1 mRNA and protein expression, while Th2 cytokines had no effect. The effect of these two cytokines was totally suppressed by either dexamethasone or mithramycin.
Collectively, our results demonstrate the expression of functional C-C chemokine receptors by ASMC. Interestingly, we have shown that CCR3 activation mediates ASMC migration and provides a new possible mechanism for the increased smooth muscle mass observed in asthmatic patients. Although the exact function of the CCR1 expressed by ASMC is unknown, our results suggest an involvement in asthma pathogenesis, possibly through airway remodelling.

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4

Fulkerson, Patricia C. "A Critical Role for Eosinophils and CCR3 Signal Transduction in Allergic Airway Disease". University of Cincinnati / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1120337075.

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5

Hablot, Julie. "Liens entre inflammations articulaire et digestive : étude expérimentale chez la souris et contribution de l’immunité mucosale". Thesis, Université de Lorraine, 2018. http://www.theses.fr/2018LORR0095/document.

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Des cellules immunitaires appartenant à l’immunité de type 3 sont localisées dans muqueuse digestive. Les micro-organismes du microbiote stimulent le système immunitaire pour le maintenir en veille face à de potentiels agents infectieux, tout en ayant une tolérance pour les micro-organismes commensaux. Des études montrent des anomalies du microbiote intestinal chez les patients arthritiques. Ceci suggère une dérégulation de l’immunité mucosale digestive dans la survenue de l’inflammation articulaire. Des cellules de l’immunité mucosale pourraient migrer vers les sites articulaires, notamment grâce à des récepteurs aux chimiokines. Le facteur RORγt, indispensable à la différenciation des cellules de l’immunité de type 3, est régulé négativement par le récepteur PPARγ. A l’aide de modèle murins, nous avons étudié l’impact de l’invalidation de PPARγ et de l’inhibition du récepteur aux chimiokines CCR3 sur les relations entre sphères digestive et articulaire. Nous avons montré que l’induction d’une colite au cours d’une arthrite au collagène modifie le microbiote intestinal, retarde l’apparition et diminue la sévérité des lésions articulaires. Nous avons démontré que les souris PPARγ-/- développent spontanément une inflammation articulaire associées à des anomalies dans la répartition des cellules immunitaires de type 3 de la muqueuse digestive. Ces souris sont dysbiotiques avec une flore enrichie notamment en entérobactéries, mais non-arthritogène. Enfin, l’inhibition de CCR3 au cours du développement d’une arthrite au collagène retarde et diminue la sévérité de la pathologie et altère la répartition des leucocytes dans les articulations et de la muqueuse digestive
Numerous type 3 immune cells (Th17 and ILC3) are physiologically located in lamina propria of the intestine. Microbial agents within the gut shape the immune system to make it efficient against threats but peaceful with commensals. Recent studies demonstrated changes in gut microbiota composition (dysbiosis) in chronic inflammatory rheumatism. These results suggest a role for mucosal immunity alteration in articular inflammation occurrence. Indeed, some type 3 immune cells once activated by microbiota, are thought to migrate to joints, involving notably chemokines receptors. Transcription factor RORγt, the master regulator of type 3 immune cells, could be negatively regulated by nuclear receptor PPARγ. Using experimental murine models, we studied the consequence of PPARγ deficiency and consequence of the chemokine receptor CCR3 inhibition on the joint-gut axis. Firstly, we demonstrated that experimental colitis induces microbiota changes, delays and reduces collagen-induced arthritis severity. Secondly, we showed that PPARγ deficient mice display spontaneous joint inflammation associated with abnormal type 3 distribution within the gut. Dysbiosis with enrichment in facultative anaerobic Enterobacteriaceae was found in these mice. Fecal microbiota transfer demonstrated this microbiota is non-arthritogenic. Finally, we demonstrated that CCR3 inhibition has profound anti-arthritic potencies associated with changes in leukocytes distribution within the joint-gut axis

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6

Kirchem, Antje. "Investigation of the signalling pathways coupled to the eotaxin receptor CCR3 in human eosinophils". Thesis, Imperial College London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406094.

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Araújo, Jéssica Maria Dantas. "Participação do receptor CCR3 na migração de eosinófilos induzida por estrogênio para o útero de camundongos C57/BL6 ovariectomizados". Pós-Graduação em Ciências Fisiológicas, 2017. https://ri.ufs.br/handle/riufs/6889.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
Eosinophils are commonly described as cells from innate immunity that act on parasitic infections and lung diseases. However, in recent years, new functions are being added to these cells, among them, the maintenance of reproductive homeostasis. In addition, since the 1960s, studies have shown the estrogen relationship and the selective eosinophils migration to the uterus of castrated rats. The elucidation of the mechanism for the migration of these cells appears to be based on findings showing that the CCR3 receptor and its CCL11 chemokine are expressed in the human endometrium. Objective: The objective of this study was to evaluate the CCR3 participation in the eosinophils migration to the uterus of castrated mice, induced by 17-β-estradiol (E2). Methods: C57/BL6 mice, which received subcutaneous E2 injection, were used to determine the time and dose response of E2 (times 6, 12, 24 and 48 hours and doses of 0.1, 1, 3, 10, 30, 100 and 300 μg/kg) that promotes uterine weight gain and eosinophil migration. Subsequently, using the air bubble model, we sought to standardize CCL11- induced eosinophil recruitment, and the dose of the CCR3 antagonist (SB 328437 at doses of 1, 3 and 10 mg/kg) which promotes reduction in eosinophils migration. In addition, in the same model, the effect of the uterine extract with and without the administration of E2 (at the times of 6, 12 and 24 h) on the leukocyte migration was evaluated. Finally, an investigation was carried out on the effect of SB 328437 on uterine weight and eosinophil recruitment. The eosinophil peroxidase (EPO) absorbance and histology were used to evaluate the eosinophil migration, in which the uterus was stained with orcein specific for eosinophils. Results: The results demonstrated that the dose of 100 μg/kg E2 in the 24 hour period promoted a 40% increase in uterine weight, accompanied by eosinophil migration. In the air bubble model, it was observed that CCL11 recruited eosinophils, and SB 328437 promoted a 55% reduction in migration of these cells. The extract of the uterus caused the migration of total and eosinophilic leukocytes, but there was no difference between the groups with and without the administration of E2. Corroborating the results of SB 328437 in the air bubble experiment, the evaluation of its effect on uterine weight and eosinophils recruitment demonstrated that dose of 3 mg/kg reduced both parameters (approximately 45% and 56%, respectively) when stimulated with E2. The results were analyzed using ANOVA with Tukey post-test (more than two groups), and t test (two groups). Conclusion: Based on the results, it was possible to confirm the hypothesis that the CCR3 receptor participates in the eosinophils migration to the uterus of C57/BL6 mice after E2 induction. Furthermore, it represents an important pathway to be considered in studies aimed at elucidating mechanisms in in physiological and pathological processes involving the eosinophils recruitment.
Os eosinófilos são comumente descritos como células pertencentes à imunidade inata que agem em infecções parasitárias e nas doenças pulmonares. Porém, nos últimos anos, novas funções estão sendo acrescidas a essas células, dentre as quais, de manutenção da homeostase reprodutiva. Além disso, desde a década de 60, estudos demonstraram a relação do estrogênio com a migração seletiva de eosinófilos para o útero de ratas castradas. A elucidação do mecanismo para a migração dessas células baseia-se em achados evidenciando que o receptor CCR3 e sua quimiocina CCL11 estão expressos no endométrio humano. Objetivo: Diante do exposto, o estudo objetivou avaliar a participação do CCR3 na migração de eosinófilos para o útero de camundongos castrados, induzida por 17-β-estradiol (E2). Metodologia: Camundongos C57/BL6 receberam a injeção de E2 subcutânea, objetivando determinar o tempo e a dose resposta do E2 (tempos de 6, 12, 24 e 48 horas e doses de 0,1, 1, 3, 10, 30, 100 e 300 μg/kg) que promove aumento do peso do útero e migração de eosinófilos. Posteriormente, utilizando o modelo de bolha de ar, buscou-se padronizar o recrutamento de eosinófilos induzido por CCL11, e a dose do antagonista do CCR3 (SB 328437, nas doses de 1, 3 e 10 mg/kg) que promove redução da migração de eosinófilos. Ademais, no mesmo modelo, avaliou-se o efeito do extrato do útero com e sem a administração de E2 (nos tempos de 6, 12 e 24 h), na migração de leucócitos. Por último, foi realizada uma investigação sobre o efeito do SB 328437 no peso do útero e no recrutamento de eosinófilos. Para avaliação da migração de eosinófilos foi utilizada a absorbância da Peroxidase de Eosinófilos (EPO) e a histologia, no qual, os úteros foram corados com orceína, específico para eosinófilos. Resultados: Os resultados demonstraram que a dose de 100 μg/kg de E2 no tempo de 24 horas promoveu aumento de 40% no peso do útero, acompanhado da migração de eosinófilos. No modelo de bolha de ar, observou-se que a CCL11 recrutou os eosinófilos, e o SB 328437 promoveu redução de 55% na migração dessas células. O extrato do útero provocou a migração de leucócitos totais e de eosinófilos, porém não houve diferença entre os grupos com ou sem a administração de E2. Corroborando os resultados do SB 328437 no experimento da bolha de ar, a avaliação do efeito do antagonista no peso do útero e no recrutamento de eosinófilos, demonstrou que a dose de 3 mg/kg reduziu ambos os parâmetros (aproximadamente em 45% e 56%, respectivamente) quando estimulados com E2. Os resultados foram analisados utilizando o ANOVA com pós- teste de Tukey (mais de dois grupos), e o teste t (em dois grupos). Conclusão: Perante os resultados encontrados, foi possível confirmar a hipótese de que o receptor CCR3 participa da migração de eosinófilos para o útero de camundongos C57/BL6, após indução com E2. Outrossim, representa uma importante via a ser considerada em estudos que visam a elucidação de mecanismos em processos fisiológicos e patológicos envolvendo o recrutamento de eosinófilos.
São Cristóvão, SE

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8

Pope, Samuel M. "Specific Role of Eotaxin-1 and Eotaxin-2 in Allergic Pulmonary Eosinophilia". Cincinnati, Ohio : University of Cincinnati, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=ucin1098472372.

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SANTUCCI, MARILINA BENEDETTA. "Ruolo della sfingosina 1-fosfato nella risposta immunitaria all’ infezione da mycobacterium tuberculosis". Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2004. http://hdl.handle.net/2108/208530.

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In questa tesi è stato studiato il ruolo della sfingosina 1-fosfato (S1P) nella risposta immunitaria durante l’infezione da M. tuberculosis. La S1P è un lipide bioattivo che regola diverse funzioni biologiche cellulari. In questo contesto, è stata analizzata l’attività anti-micobatterica in cellule della linea monocito/macrofagica, THP-1 ed in una linea tumorale di cellule dell’epitelio alveolare, A549 infettate con il ceppo patogeno di M. tuberculosis H37Rv e stimolate con S1P. La crescita di M. tuberculosis è stata valutata tramite il saggio delle unità formanti colonia ed i risultati di questa analisi mostrano che la stimolazione con S1P determina un incremento dell’attività micobattericida di queste cellule. La S1P potrebbe rappresentare un componente della mucosa polmonare importante nel mantenere la sterilità al livello degli alveoli e nel regolare la risposta infiammatoria locale. In questo ambito, il passo successivo è stato quello di quantificare la S1P al livello del lavaggio broncoalveolare tramite saggio di competizione con 3HS1P. Questa analisi ha evidenziato che il contenuto di S1P al livello della mucosa polmonare di pazienti con tubercolosi polmonare attiva è più basso di quello osservato nei soggetti sani; inoltre il trattamento con S1P di cellule di lavaggio broncoalveolare (BAL) provenienti da pazienti con tubercolosi polmonare attiva, ha messo in evidenza una riduzione della crescita intracellulare dei micobatteri endogeni. Questo risultato dimostra l’efficacia dell’azione svolta dalla S1P in un sistema cellulare che riflette quello presente nel polmone profondo in corso di malattia. Al fine di analizzare se la mucosa polmonare rappresentasse un sito di accumulo dei linfociti T CD4+CCR5+ e dei linfociti TCD4+CCR3+, entrambe queste sottopopolazioni cellulari sono state studiate nel BAL e nel sangue periferico di pazienti con tubercolosi, di soggetti con malattie polmonari non correlate alla tubercolosi e di soggetti sani. Questo studio ha messo in evidenza che i linfociti T CD4+ che esprimono il recettore CCR5 o CCR3 si raccolgono 4 maggiormente nel basso tratto respiratorio rispetto al sangue periferico e che, in accordo con l’osservazione che i linfociti T CD4 del polmone di pazienti con tubercolosi polmonare sono principalmente di tipo Th1, i linfociti T CD4+CCR5+ si accumulano in maggior misura nel polmone di pazienti con tubercolosi polmonare attiva. L’obiettivo successivo di questo lavoro è stato quello di determinare se una migliore uccisione intracellulare di M. tuberculosis, dopo la stimolazione con S1P, fosse associata ad una più efficiente risposta immunitaria, vista in termini di incremento della frequenza dei linfociti T CD4+CCR5+, specifici per M. tuberculosis. A questo scopo i PBMC provenienti da pazienti con tubercolosi polmonare attiva, da soggetti con tubercolosi latente (PPD+) e da donatori sani (PPD-), sono stati infettati con M. tuberculosis e trattati con S1P. La risposta immunitaria specifica verso M. tuberculosis è stata valutata determinando la frequenza dell’espressione del CD69 su linfociti T CD4+CCR5+ del sangue periferico, dopo infezione con M. tuberculosis. I risultati di questa tesi mostrano che dopo la stimolazione con S1P dei PBMC provenienti da pazienti con tubercolosi polmonare, si assiste ad un aumento della percentuale di linfociti T specifici per M. tuberculosis senza un concomitante aumento della produzione di IFN-γ da parte delle stesse cellule. Questo risultato potrebbe essere spiegato con il fatto che nei pazienti con tubercolosi polmonare, la presenza delle cellule T regolatorie inibirebbe l’attivazione dei linfociti T specifici per M. tuberculosis, indotti dalla stimolazione con S1P, e quindi anche la produzione di IFN-γ. La mancata attivazione dei linfociti T specifici per M. tuberculosis si riflette anche in una mancata capacità di controllo della crescita intracellulare di M. tuberculosis nei PBMC di pazienti con tubercolosi polmonare dopo stimolazione con S1P; al contrario, in tre soggetti con tubercolosi latente, la stimolazione dei PBMC con S1P determina una diminuzione della crescita intracellulare di M. tuberculosis.

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10

Apel, Anna-Katharina [Verfasser]. "Biophysical and structural analysis of the chemokine receptors CCR2A and CCR3, leading to a 2.7 Å resolution structure of CCR2A / Anna-Katharina Apel". Ulm : Universität Ulm, 2019. http://d-nb.info/1188320963/34.

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Titz, Tiago de Oliveira. "Avaliação fenotípica e funcional dos eosinófilos da dermatite atópica do adulto". Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/5/5133/tde-20052015-121525/.

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Introdução: A dermatite atópica (DA) é uma doença cutânea inflamatória de caráter crônico, recidivante, em que o prurido intenso e a xerose cutânea são frequentes. A etiopatogenia da DA é multifatorial, envolvendo fatores genéticos, ambientais e imunológicos. Eosinófilos são leucócitos polimorfonucleares multifuncionais que estão implicados na patogênese de diversos processos inflamatórios, incluindo a DA. Além da produção e secreção de diversas proteínas presentes nos grânulos citoplasmáticos, os eosinófilos também apresentam potencial para secretar metaloproteinases, enzimas proteolíticas que degradam vários componentes da matriz extracelular, e estão presentes em diversos processos fisiológicos e patológicos. Objetivo: Avaliar: 1) o perfil fenotípico dos eosinófilos na dermatite atópica do adulto, através da expressão das moléculas CCR3, CD23, CD38, CD69 e CD62L; 2) o perfil funcional, a partir da secreção de metaloproteinases, inibidores teciduais de metaloproteinases e RANTES por eosinófilos purificados. Métodos: Foram incluídos 41 adultos diagnosticados com DA, de acordo com os critérios de Hanifin & Rajka e 45 controles adultos sadios. A gravidade da doença foi mensurada através do escore de gravidade EASI (Eczema Area and Severity Index). Eosinófilos (LIN 1- CCR3+) do sangue periférico foram analisados para os marcadores CCR3, CD38, CD69, CD23 e CD62L através da citometria de fluxo (LSRFortessa, BD Biosciences) a análise foi realizada com o FlowJo 7.5.6 software. Eosinófilos purificados de indivíduos com DA e indivíduos controles foram estimulados com enterotoxina de Staphylococcus aureus B (SEB) e FSL-1 (agonista de receptores Toll-like 2 e 6), e os sobrenadantes foram coletados para dosagem de metaloproteinases (MMPs), inibidores teciduais de metaloproteinases 1 e 2 (TIMP-1 e TIMP-2) e RANTES por ELISA e por Cytometric bead array. Resultados: Indivíduos com DA apresentaram maior frequência de eosinófilos (LIN1- CCR3+), relacionada à gravidade da doença. Observou-se também, que a frequência de CD62L (L-selectina) e de CD23 (receptor de baixa afinidade para IgE) em eosinófilos (LIN1- CCR3+) diminui em pacientes com DA. Os receptores de ativação precoce (CD69) e tardio (CD38) não mostraram diferença estatística entre os grupos analisados. Os níveis séricos de MMPs e de TIMPs foram similares entre os controles e pacientes. Ao analisarmos a secreção de MMPs e de (TIMPs), a partir de eosinófilos purificados de pacientes com dermatite atópica, observamos diminuição dos níveis basais de TIMP-1 e TIMP-2 e de RANTES. Conclusões: Na DA do adulto, o perfil fenotípico e funcional dos eosinófilos mostrou: perfil de ativação da fase aguda, com expressão aumentada de CCR3; potencial de migração elevado, em decorrência da diminuição da expressão de CD62L; falhas no processo de ativação dos eosinófilos via CD23, bem como, no remodelamento tecidual mediado por TIMP-1 e TIMP-2 e na quimotaxia mediada por RANTES
Introduction: Atopic dermatitis (AD) is an inflammatory, chronic and recurrent skin disease characterized by intense pruritus and xerosis. AD has a complex etiopathogenesis, which involves the influence of genetics, environment, and immunological disorders, among others. Eosinophils are multifunctional polymorphonuclear leukocytes that contribute to the pathogenesis of several inflammatory processes, such as AD. In addition to the production and secretion of diverse proteins of the cytoplasmic granules, eosinophils have also the potential to secrete metalloproteinases (MMPs), proteolytic enzymes with a primary role for degrading several extracellular matrix components, present in distinct physiological and pathological processes. Objective: To evaluate:1) the phenotypic profile of eosinophils in adults with atopic dermatitis through the expression of CCR3, CD23, CD38, CD69 and CD62L molecules; 2) the functional profile through secretion of MMPs, tissue inhibitors of metalloproteinases 1 and 2 ( TIMP-1 and TIMP-2) and RANTES by purified eosinophils. Methods: This work enrolled 41 patients with AD, diagnosed according to Hanifin & Rajka\'s criteria) and 45 healthy controls. Severity of the disease was established utilizing EASI (Eczema Area and Severity Index). Eosinophils (Lineage cocktail 1- CCR3+) from peripheral blood were analyzed for CCR3, CD38, CD69, CD23 and CD62L by flow cytometry (LSRFortessa, BD Biosciences), and analysis was performed using the FlowJo 7.5.6 software. Purified eosinophils were stimulated with Staphylococcus aureus enterotoxin B (SEB) FSL-1 (Toll-like receptor 2/6 agonist), and supernatants were collected for MMPs, TIMPs and RANTES secretion, evaluated by ELISA and cytometric bead array (CBA). Results: Patients with AD have a higher frequency of eosinophils (LIN1- CCR3+), related to disease severity. Moreover, the frequency of CD62L (L-selectin) and CD23 (low-affinity receptor for IgE) in (LIN1- CCR3+) eosinophils was reduced in individuals with AD. CD69 and CD38 (early and late activation receptors) did not show significant difference in the studied groups. Serum levels of MMPs and of TIMP-1 and TIMP-2 were similar in healthy controls and AD patients. When analyzing secretion of MMPs and TIMPs by purified eosinophils from AD individuals, we detected a decrease in baseline levels of TIMP-1, TIMP-2, and reduced RANTES-mediated chemotaxis. Conclusions: Eosinophils in AD exhibit an activation profile of acute phase, with enhanced CCR3 expression, high potential for migration due to reduced expression of CD62, defective activation mechanisms via CD23, altered tissue remodeling process mediated by TIMP-1 and TIMP-2 and reduced RANTES-mediated chemotaxis

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Schauren, Juliana da Silveira. "Estudo dos polimorfismos CCR2-64I, CCR5-59353, CCR5-59356, CCR5-59402 e CCR5-59653 em pacientes com lúpus eritematoso sistêmico do sul do Brasil". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2013. http://hdl.handle.net/10183/78127.

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O Lúpus Eritematoso Sistêmico (LES) é uma doença autoimune inflamatória crônica que possui uma etiopatogênese complexa. Diversos fatores participam da patogênese da doença, dentre eles alterações no balanço de citocinas e quimiocinas. As quimiocinas e seus receptores são fundamentais na regulação da migração de leucócitos durante a inflamação e acredita-se que elas possam ter um papel importante na patogênese de doenças autoimunes, inclusive no LES. Diversos estudos abordaram o papel de quimiocinas e seus receptores no LES, porém, principalmente se tratando dos receptores de quimiocinas CCR5 e CCR2, não existe um consenso. Devido à falta de consenso em relação ao papel dos receptores de quimiocinas na patogênese do LES e considerando a necessidade de mais estudos nesta área, o presente trabalho tem por objetivo investigar o possível papel de polimorfismos na região promotora do CCR5 no desenvolvimento do LES, comparando as frequências dos genótipos e haplótipos entre pacientes e controles, e analisar o possível envolvimento destes polimorfismos nas manifestações clínicas/laboratoriais da doença. O estudo incluiu 382 pacientes com LES (289 Euro-descendentes e 93 Afro-descendentes) e 375 controles (243 Euro-descendentes e 132 Afro-descendentes) genotipados para os polimorfismos CCR2-64I G>A (rs1799864), CCR5-59353 C>T (rs1799988), CCR5-59356 C>T (rs41469351), CCR5-59402 A>G (rs1800023) e CCR5-59653 C>T (rs1800024) através de PCR-RFLP e sequenciamento, respectivamente. Dados prévios de nosso grupo em relação ao CCR5delta32 foram incluídos no estudo para a inferência dos haplótipos e como um possível fator de confusão na regressão binária logística. Os resultados obtidos indicam que, em pacientes Euro-descendentes, as frequências reduzidas o polimorfismo CCR5delta32 e o haplótipo HHG*2 observadas em pacientes quando comparados com controles foram associadas com a doença (p=0,001; OR 3,5; 95%CI 1,6-7,5 e 2,0% vs. 7,2%; presidual=2,9E-5; respectivamente). Em pacientes Afrodescendentes, as frequências dos haplótipos HHA/HHB, HHC e HHG*2 foram diferentes em pacientes e controles (10% vs. 20,5%, presidual = 0,003; 29,4% vs. 17,4%; presidual=0,003 e 3,9% vs. 0,8%; presidual=0,023; respectivamente). Em relação às manifestações clínicas da doença, a presença do CCR5delta32 foi confirmada como um fator de susceptibilidade para nefrite classe IV em pacientes Afro-descendentes e no grupo de pacientes como um todo (pcorrigido=0,012; OR 3,0; 95%CI 3,0-333,3 e pcorrigido=0,0006; OR 6,8; 95%CI 1,9-2,48; respectivamente). Em conclusão, o presente estudo indica que polimorfismos na região promotora do CCR5 podem atuar como modificadores no LES. Os resultados observados reforçam o papel do polimorfismo CCR5delta32 como um fator de proteção para o desenvolvimento do LES em Euro-descendentes e como um fator de susceptibilidade à nefrite classe IV em pacientes Afro-descendentes. Além disto, também foram descritos a redução da frequência dos haplótipos HHA/HHB e o aumento da frequência dos haplótipos HHC e HHG*2 em pacientes Afro-descendentes, que possivelmente podem estar associados com uma maior expressão do CCR5 em subtipos específicos celulares e com uma menor expressão deste receptor de maneira geral.
Systemic Lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease, characterized by a complex etiopathogenesis. Many factors are known to participate in the pathogenesis of SLE, including alterations in the cytokines or chemokines balance. Chemokines and their receptors are central players in the regulation of leucocytes chemotaxis in inflammation and they are thought to have an important role in the pathogenesis of autoimmune diseases, including SLE. Several studies have addressed the role of chemokines and their receptors in SLE, however there is no consensus regarding their involvement on the pathogenesis of the disease. Given the lack of consensus considering the role of chemokine receptors in SLE pathogenesis and the need for more studies in this area, the present work aims to investigate a possible role of the CCR5 promoter region polymorphisms in the development of SLE comparing the frequencies of the genotypes and haplotypes with ethnically matched controls and analyze if there is a possible involvement of the polymorphisms in the clinical outcome of the disease. This study included 388 SLE patients (289 classified as Europeanderived and 93 as African-derived) and 375 controls (243 European-derived and 132 African-derived) genotyped for the CCR2-64I G>A (rs1799864), CCR5-59353 C>T (rs1799988), CCR5-59356 C>T (rs41469351), CCR5-59402 A>G (rs1800023) and CCR5-59653 C>T (rs1800024) polymorphisms though PCRRFLP and direct sequencing, respectively. Previous data from CCR5delta32 were included in the study to infer the haplotypes and also as a possible confounding factor in the binary logistic regression. Our results indicated that, in Europeanderived patients, CCR5delta32 and the HHG*2 haplotype reduced frequencies in patients when compared to controls were associated with the disease (p=0.001; OR 3.5; 95%CI 1.6-7.5 and 2.0%, vs. 7.2% residual p= 2.9E-5, respectively). In African-derived patients, the HHA/HHB, HHC and HHG*2 haplotype frequencies differed between patients and controls (10% vs. 20.5%, residual p= 0.003; 29.4% vs. 17.4%, residual p=0.003 and 3.9% vs. 0.8%, residual p=0.023; respectively). Considering the clinical manifestations of the disease, CCR5delta32 presence was confirmed as a susceptibility factor to class IV nephritis in the African-derived group and when patients were considered together (pcorrected=0.012; OR 3.0; 95%CI 3.0-333.3 and pcorrected= 0.0006; OR 6.8; 95%CI 1.9-2.48, respectively). In conclusion, this study indicates that CCR5 promoter polymorphisms are important disease modifiers in SLE. Present data reinforces CCR5delta32 polymorphism as a protective factor for the development of the disease in European-derived patients and as a susceptibility factor for class IV nephritis in African-derived patients. Furthermore, we also describe a reduced frequency of HHA/HHB and an enhanced frequency of HHC and HHG*2 haplotypes in our African-derived patients, which potentially could reflect in a higher expression of CCR5 in specific cell subsets and in a lower expression of CCR5 overall.

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13

Sato, Wakiro. "Human Th17 Cells Are Identified as Bearing CCR2+CCR5- Phenotype". Kyoto University, 2008. http://hdl.handle.net/2433/124335.

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14

Sohy, Denis. "Etude de la dimérisation des récepteurs aux chimiokines CCR2, CCR5 et CXCR4". Doctoral thesis, Universite Libre de Bruxelles, 2008. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210282.

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La dimérisation des récepteurs couplés aux protéines G est un nouveau concept apparu dans la littérature au cours des quelques années qui ont précédé le début de notre travail. Bien qu’il soit clairement établi que les récepteurs sont capables de former des homo et des hétérodimères, les conséquences fonctionnelles de telles interactions demeurent souvent peu claires. Dans une étude précédente, le laboratoire d’accueil a montré que les récepteurs aux chimiokines CCR2 et CCR5 forment des homo et des hétérodimères de manière constitutive et identifié une coopérativité négative de liaison de nature allostérique entre les deux sites de liaison de CCR2 et CCR5 dans des cellules co-exprimant les deux récepteurs. Dans ce travail, nous avons étendu cette étude au récepteur CXCR4, structurellement plus éloigné que CCR2 et CCR5 entre eux. Nous montrons par une méthode biophysique se basant sur le transfert d’énergie de bioluminescence (le BRET) que CCR2, CCR5 et CXCR4 forment des homodimères et des hétérodimères de manière constitutive. De plus nous démontrons une coopérativité négative de liaison de nature allostérique des deux sites de liaisons pour les hétérodimères CCR2/CXCR4 et CCR5/CXCR4. lorsque CXCR4 est co-exprimé avec CCR2 ou CCR5, la chimiokine spécifique de CXCR4 (SDF-1α) inhibe la liaison du traceur spécifique de CCR2 (MCP-1) ou du traceur spécifique de CCR5 (MIP-1β), et vice-versa. La nature allostérique de ces interactions est démontrée par des expériences mesurant la dissociation de traceurs en présence ou non de compétiteurs. La coopérativité négative de liaison de nature allostérique des deux sites de liaisons est montrée également dans des cellules primaires, excluant tout effet indésirable dû à la surexpression de récepteurs. Nous montrons également que l’antagoniste spécifique de CXCR4 (AMD3100) inhibe la liaison du traceur spécifique de CCR2 (MCP-1) ou du traceur spécifique de CCR5 (MIP-1β), et vice-versa (TAK-779 vs SDF-1α), uniquement quand CXCR4 est co-exprimé respectivement avec CCR2 ou CCR5. Il s’agit là de la première preuve montrant que les interactions allostériques au sein d’hétérodimères de récepteurs aux chimiokines impliquent aussi des antagonistes, et qu’un antagoniste de récepteur aux chimiokines influence la réponse fonctionnelle d’un autre récepteur aux chimiokines auquel il ne se lie pas. De tels effets fonctionnels ont été montré dans des expériences de mobilisation de Ca++, de chimiotactisme sur lymphoblastes et dans des expériences d’air pouch in vivo.
Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished

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15

Longden, James. "Quantitative approaches to the study of the trafficking of CCR1 and CCR5". Thesis, University of Nottingham, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437076.

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16

Zambra, Francis Maria Báo. "Influência dos genes CCR2 e CCR5 em hiperplasia e câncer de próstata". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2012. http://hdl.handle.net/10183/69706.

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A hiperplasia prostática benigna (HPB) e o câncer de próstata (CaP) são duas condições crônicas muito comuns em homens com idade avançada e têm sido relacionadas a processos inflamatórios. As quimiocinas são reconhecidas como mediadores críticos da resposta inflamatória por regular a migração das células imunológicas através da ativação de receptores de quimiocinas na superfície destas células. As quimiocinas estão relacionadas à patogênese tumoral, embora não seja claro de que modo afetam a progressão tumoral humana. O objetivo desse estudo foi investigar a associação de dois polimorfismos de receptores de quimiocinas, CCR2-64I e CCR5-delta32, com HPB e CaP. Neste trabalho foram genotipadas 385 amostras de DNA genômico de homens do sul do Brasil, predominantemente euro-descendentes, incluindo 130 casos de HPB, 136 casos de CaP e 119 indivíduos controle saudáveis. Para o polimorfismo CCR2-64I a genotipagem foi realizada por PCR-RFLP e para o CCR5-delta32 foi por PCR convencional. As frequências alélicas do CCR2-64I foram 14,0%; 15,8% e 11,1% nos grupos controle, HPB e CaP, respectivamente; enquanto as do CCR5-delta32 foram 5,1%; 7,1% e 6,2%, respectivamente. A mediana referente aos níveis de PSA foi de 0,79; 1,45 e 6,91 ng/mL nos grupos controle, HPB e CaP, respectivamente; diferindo significativamente entre estes (todos p<0,001). A mediana do volume da próstata foi 20,00 cm3 no grupo controle, portanto, menor que dos grupos HPB (35,35 cm3) e CaP (35,80 cm3) (ambos p<0,001); no entanto, não foi observada diferença entre pacientes com HPB e CaP (p=0,172). Algo interessante observado foi CCR2-64I como um fator protetor para CaP quando comparado com HPB (OR=0,550; IC95%=0,311–0,975), mas não quando comparado com o grupo controle (p=0,448). Não foi observada associação do CCR2-64I com os estados clinicopatológicos do CaP (estadiamento tumoral e escore de Gleason) (todos p≥0,308). Não foi observada associação significativa da variante CCR5-delta32 com HPB ou CaP (todos p≥0,072), ou com os estados clinicopatológicos do CaP (todos p≥0,253). Assim, nossos dados sugerem a influência da variante CCR2-64I, observada como fator protetor para CaP quando comparada com HPB, no desenvolvimento do câncer de próstata.
Benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are two chronic conditions very common in aged men and have been related to inflammatory process. Chemokines are recognized as critical mediators of inflammatory responses by regulating the migration of immune cells through the activation of chemokine receptors on the surface of these cells. Chemokines are implicated in tumor pathogenesis, although it is not clear how it affects human tumor progression. The aim of this study was to investigate the association of two chemokine receptor gene polymorphisms, CCR2-64I and CCR5-delta32, with BPH and PCa. In this study were genotyped 385 genomic DNA samples from southernmost Brazilian men, predominantly euro-descendants, including 130 BPH, 136 PCa and 119 healthy control subjects. To CCR2-64I polymorphism the genotyping was performed by PCR-RFLP and to CCR5-delta32 by conventional PCR. The allele frequencies of CCR2-64I were 14.0%, 15.8% and 11.1% in control, BPH and PCa, respectively; while of CCR5-delta32 were 5.1%, 7.1% and 6.2%, respectively. Median of serum PSA levels were 0.79, 1.45 and 6.91 ng/mL in control, BPH and PCa group, respectively (all p<0.001). The prostate volume median was 20.00 cm3 in the control group, thus, lower than BPH (35.35 cm3) and PCa (35.80 cm3) group (both p<0.001), nevertheless no difference was observed between BPH and PCa patients (p=0.172). Interestingly, CCR2-64I was detected as a protective factor to PCa when compared with BPH (OR=0.550; 95%CI=0.311–0.975), but not when compared with control group (p=0.448). No significant associations of the CCR2-64I were observed with PCa clinicopathologic states (tumor stage and Gleason score) (all p≥0.308). No significant associations of the CCR5-delta32 variant were observed with BPH or PCa (all p≥0.072), or with PCa clinicopathologic status (all p≥0.253). Thus, our data suggest a influence of the CCR2-64I variant, that was observed as a protective factor in PCa when compared with BPH, in prostate cancer development.

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17

Manin, Graziele Zenaro. "Identificação dos componentes do Sistema Imune que participam na resistência de camundongos em modelo de infecção letal por Legionella longbeachae". Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/17/17147/tde-21052014-153321/.

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A doença dos legionários consiste em uma broncopneumonia severa e atípica, que acomete de 2 a 7% das pessoas infectadas com Legionella spp e que apresenta taxa de mortalidade que varia de 5 a 30%, sendo considerada uma importante causa de morbidade e mortalidade mundial. A patologia causada pela espécie L. pneumophila tem sido amplamente estudada em modelos experimentais e suas características clínicas foram extensivamente descritas. No entanto, este modelo não representa adequadamente a doença que acomete seres humanos, pois L. pneumophila não é letal aos camundongos como é para humanos. Recentemente, uma nova espécie de bactéria do gênero Legionella, denominada Legionella longbeachae, foi descrita como importante agente de doença dos legionários em países do hemisfério sul. A pneumonia induzida por L. longbeachae em humanos não difere da induzida por L. pneumophila. No entanto, L. longbeachae é letal para camundongos em doses baixas, o que torna esse modelo murino de doença dos legionários mais fidedigno ao que ocorre com humanos. Com a acentuada mudança dos hábitos de nossa sociedade, há o aumento do número de pessoas com fatores que predispõe a doença, como idade elevada ou tratamento imunossupressor. Assim, entender melhor a relação patógeno-hospedeiro no curso da doença dos legionários por meio da utilização de um modelo experimental adequado é importante para a descoberta de novos meios de combater este patógeno. Neste trabalho, geramos uma cepa de L. longbeachae mutante para rpsL, que se torna resistente à estreptomicina. Essa cepa pode ser utilizada para infecções in vivo nas quais a quantificação da CFU foi estimada em placas contendo antibiótico, o que culmina em maior eficiência experimental e menor quantidade de contaminações. Essa cepa foi utilizada em experimentos in vivo para avaliar os componentes do sistema imune que operam na resistência diante de uma dose letal bacteriana administrada pela via intranasal. Demonstramos que camundongos deficientes para as citocinas IFN ou TNF e para o receptor de quimiocinas CCR2 são mais susceptíveis à infecção do que os camundongos selvagens. No entanto, camundongos deficientes para o receptor de quimiocinas CCR5, para o receptor de IL-17, para a citocina IL-6 ou para o receptor citoplasmático NOD2 são mais resistentes à infecção quando comparados com animais selvagens. A descoberta destas moléculas em um modelo de infecção letal in vivo ressalta a importância de alguns componentes da imunidade para a resistência durante a doença dos legionários experimental e possíveis alvos terapêuticos para essa doença.
Legionnaires disease is a severe and atypical bronchopneumonia, which affects 2-7% people infected with Legionella spp and has a mortality rate of 5 to 30%, therefore it is considered an important cause of mortality and morbidity worldwide. Disease caused by Legionella pneumophila has been largely studied in experimental models and its clinical characteristics was extensively described. However this model does not adequately represent the disease that affects humans, because L. pneumophila is not lethal to mice, as it is to humans. Recently, a new species of bacterium from Legionella genus, called Legionella longbeachae, was described as an important agent of Legionnaires disease in the southern hemisphere. The pneumonia induced by L. longbeachae in humans is not different from pneumonia induced by L. pneumophila. However, a low dose of L. longbeachae is lethal to mice, which makes this murine infection model of Legionnaires disease more reliable than that which occurs in humans. Because our society is changing, there is an increase in the number of persons with predisposing factors, like higher age or immunosuppressive treatment. So, a better understanding of host-pathogen relationship by using a suitable experimental model is important to find new ways to fight this pathogen. Here, we generated a strain of rpsL mutant L. longbeachae, which becomes resistant to streptomycin. This strain could be used in in vivo infections, when CFU quantification was estimated in plates with antibiotic, culminating in greater experimental efficiency and lower contamination. This strain was used in in vivo experiments to evaluate components of the immune system that participates in resistance against lethal dose of bacteria administered intranasally. We showed that Tnf-/-, Ifn-/- or Ccr2-/- mice are more susceptible to infection than wild type mice. However Ccr5-/-, Il17r-/-, Il6-/- or Nod2-/- mice are more resistant to infection than wild type animals. The discovery of these molecules in a lethal infection model in vivo highlights the importance of some components of immunity to resistance during experimental Legionnaires disease and potential therapeutic targets to disease.

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18

Opalek, Judy Marcus. "I. Differential gene expression in human peripheral blood monocytes and alveolar macrophages II. Macrophage colony-stimulating factor is important in the development of pulmonary fibrosis". Columbus, Ohio : Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1075754091.

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Thesis (Ph. D.)--Ohio State University, 20043.
Title from first page of PDF file. Document formatted into pages; contains xiv, 115 p.; also includes graphics. Includes abstract and vita. Advisor: Clay B. Marsh, Dept.of Pathology. Includes bibliographical references (p. 102-115).

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19

Simonis, Christopher. "Molekulare Klonierung, stabile Transfektion und funktionelle Expression der murinen Chemokinrezeptoren Ccr2 und Ccr5". Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-99950.

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20

Leach, Katie. "Pharmacological analysis of the CC chemokine receptors, CCR4 and CCR5 signalling properties and receptor-drug interactions". Thesis, University of Reading, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.427859.

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21

Su, Yung-Chang University of New South Wales &amp Garvan Institute of Medical Research St Vincent's Clinical School UNSW. "Immune regulation in mouse models of allergic asthma". Awarded by:University of New South Wales & Garvan Institute of Medical Research. St. Vincent's Clinical School, 2006. http://handle.unsw.edu.au/1959.4/26978.

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Allergic asthma is an immunological disease, mediated by CD4+ Th2 cells, and its prevalence has increased over recent decades. Features of allergic asthma include airway hyperresponsiveness (AHR), airway eosinophilia, excessive airway mucus production, and increased IgE and Th2 cytokine levels. Airway remodeling with pulmonary fibrosis is noted in the progress of asthma. In this thesis, a murine model of allergic asthma was used to investigate the effect of cyclophosphamide (CY) on asthma and the involvement of regulatory T cells (Treg), and the role of Granulocyte-macrophage colony stimulating-factor (GM-CSF) in allergic asthma by using GM-CSF knockout mice. CY is a cytotoxic agent, which paradoxically augments several immune responses. The first part of this thesis was aimed to study the effects of CY in a murine model of allergic airway inflammation. BALB/c mice were immunized with ovalbumin (OVA) on days 0 and 14, and challenged with aerosolized OVA from days 21 to 27. Some mice additionally received CY on days -2 and 12. In the CY-treated animals, pronounced worsening of inflammatory features was noted, including increases in eosinophil infiltration, epithelial thickness, mucus occlusion and eosinophil numbers in bronchoalveolar lavage fluid (BALF). Increased total and OVA-specific serum IgE were also noted in the CY-treated animals. In cell cultures from peritracheal lymph nodes, the Th2 cytokines IL-4 and IL-5 were elevated in animals treated with CY. It was hypothesized that the effects of CY could be caused by reduced immunosuppression mediated by Treg. mRNA expression of the immunosuppressive cytokines IL-10 and TGF-beta was reduced in the lungs of CY-treated mice. The expression of FoxP3, a marker of naturally occurring Treg, was significantly reduced in spleens, thymuses and peritracheal lymph nodes after the second injection of CY, and in the lung tissue after allergen challenge in CY-treated mice. Furthermore, lung IL-10-producing CD4+ T cells and CTLA-4+-bearing CD4+ T cells were reduced after allergen aerosol challenge in CY-treated mice. Thus CY worsened the features of allergic pulmonary inflammation in this model, in association with increased production of IgE and Th2 cytokines. The reduction in expression of FoxP3 and immunosuppressive cytokines by CY suggests that toxicity to Treg may contribute to the increased inflammation. GM-CSF plays a role in the growth, development, and maturation of bone marrow hemopoietic cells into mature blood cells, and has been proposed to be involved in potentiating the function of inflammatory cells in allergic inflammation. In the second part of this thesis, GM-CSF knockout (KO) mice were used to investigate the role of GM-CSF. In allergic KO mice, airway eosinophils were only shown in the perivascular, but not peribronchial areas in the lung, compared to the allergic wild-type (WT) mice in which eosinophil infiltration appeared in both areas. Eosinophil numbers were drastically reduced in the bronchoalveolar lavage fluid (BALF) of KO mice. IL-5 production in the lung tissue and BALF in allergic KO mice was reduced; similar results were also found in peritracheal draining lymph nodes after in vitro stimulation assays. However, IL-4 and IL-13 production, airway hyperresponsiveness (AHR), and serum IgE production were not affected in allergic KO mice. Surprisingly, lung IFN-gamma mRNA and BALF levels were increased in allergic KO mice. Lung mRNA levels of CCR3, a key chemokine receptor on eosinophils, were significantly reduced in allergic KO mice, whereas expression of the chemokines eotaxin and RANTES were at similar levels in allergic KO and WT mice. Lung mRNA levels of the IFN-gamma-inducible chemokines Mig (CXCL9) and IP-10 (CXCL10), which are antagonists of CCR3, and their receptor CXCR3 were increased in allergic KO mice, compared with allergic WT mice. Data obtained from flow cytometry showed more eosinophils survived in the lung of WT mice than KO mice. Another allergy model, a peritoneal allergy model was performed to investigate inflammation in a different model. Leukocyte subpopulations such as neutrophils, eosinophils, macrophages, and lymphocytes were reduced in the peritoneal lavage fluid of allergic KO mice. The findings revealed that GM-CSF is essential for IL-5 production, pulmonary airway eosinophilia and eosinophil survival. In the absence of GM-CSF, over-production of IFN-???? may induce chemokines, including Mig and IP-10, which are antagonists for CCR3 and may reduce airway eosinophil infiltration. In this thesis, a murine model of allergic asthma has been used to obtain novel findings on the regulation of allergic inflammation. The results with CY are relevant to the treatment of asthma patients with CY and other cytotoxic agents. The findings in the GM-CSF KO mice suggest that GM-CSF is a potential therapeutic target in asthma, and that in assessment of new therapeutic agents for asthma, effects on GM-CSF should be considered.

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22

Buson, Genny. "Studio di polimorfismi in geni coinvolti in patologie oculari angioproliferative". Doctoral thesis, Università degli studi di Padova, 2011. http://hdl.handle.net/11577/3422745.

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The ocular angioproliferative diseases are multifactorial diseases, characterized by a progressive degeneration of cells in the macular region of the retina which permit distinct and central vision. This means that people with these diseases gradually lose their "high definition" vision guaranteed by the macula. The most frequent cause of macular degeneration is the age-related macular degeneration (AMD), which usually affects people older than 50 years and is the leading cause of legal blindness in the elderly population. The macula may also be affected by pathology in diabetic retinopathy (DR); the presence of exudates and accumulation of fluid leaking from the capillaries, causing a condition called macular edema, are the most common cause of loss of visual function in diabetic patients. VEGF (Vascular Endothelial Growth Factor) and the receptor KDR (kinase insert domain receptor) regulate angiogenesis and therefore considered important factors involved in the pathological process that leads to the onset of ocular angioproliferative disease. In the first part, an association study between polymorphisms in the VEGF and its receptor KDR genes and onset of ocular diseases such as AMD and DR, has been performed. For this purpose we analyzed 16 polymorphisms (11 in the VEGF gene and 5 on the gene KDR) in a population of 226 patients with AMD, 177 patients with diabetic retinopathy and a control population of 240 healthy subjects. All the SNPs were analyzed by GenomeLab SNPStream DNA microarray technology (Beckman Coulter) that allows a large-scale genotyping. The results obtained in this first part showed a strong association between some polymorphisms of VEGF-A and, for the first time, KDR with susceptibility to the onset of ocular angioproliferative disease. A recent study showed that the CCR3 (CC chemokine receptor type 3) and corresponding ligands eotaxin 1,2,3 are expressed only in the endothelial cells lining the abnormal blood vessels of CNV from people with wet AMD and not in choroidal endothelium from people without AMD, or from those with dry AMD or other types of choroidal or retinal disorder. Therefore, in the second part of the study we have analyzed, for the first time, if single nucleotide polymorphisms in the genes CCR3 and eotaxin 1 (CCL11), eotaxin 2 (CCL24), eotaxin 3 (CCL26) are associated with the onset of AMD and DR. For this purpose we selected 46 polymorphisms (14 in the CCR3 gene, 8 in the gene CCL11, 4 in the CCL26 gene, 11 in the VEGF-A gene and 4 in the KDR gene) in 283 patients with AMD, 175 patients with diabetic retinopathy and control population of 262 healthy subjects. Genotyping analysis was performed using the Illumina BeadXpress, a high-throughput, dual-color laser detection system that enables scanning of a broad range of multiplexed assays developed using the VeraCode digital microbead technology. This technology was also used to confirm the association of VEGF-KDR pathway with AMD and DR extending the number of SNPs studied in these two genes. The analysis of allele and genotype frequencies of the CCR3 and eotaxins genes between groups of patients AMD and DR and the control group did not show any statistically significant difference. Instead, we again confirmed the importance of VEGF / KDR pathway, expanding the current knowledge on the role of this growth factor in pathophysiology of these diseases and demonstrating a genetic contribution in susceptibility to the onset of AMD and DR. The in-depth knowledge of these mechanisms could provide the basis to determine the risk of developing the disease and understand its entirety to allow the identification and synthesis of new drugs. In fact, carriers of risk alleles or non-risk may respond differently to therapy or may require different amounts of anti-VEGF (currently used in the treatment of these diseases) to increase its effectiveness.
Le patologie oculari angioproliferative sono malattie multifattoriali, tutte caratterizzate da una progressiva degenerazione delle cellule della regione maculare della retina, quella che permette la visione centrale e distinta. Ciò comporta che le persone affette da queste patologie perdano gradualmente la visione ad “alta definizione” garantita dalla macula. La causa più frequente di degenerazione maculare è la patologia detta degenerazione maculare legata all’età (AMD) che interessa solitamente persone al di sopra dei 50 anni ed è la principale causa di cecità legale nella popolazione anziana. La macula può essere interessata da patologia anche nell’ambito della retinopatia diabetica (DR); la presenza di essudati e l’accumulo di liquido che fuoriesce dai capillari, determinando una condizione chiamata edema maculare, costituiscono la più comune causa di perdita della funzione visiva nei pazienti diabetici. VEGF (Vascular Endothelial Growth Factor) ed il recettore KDR (kinase insert domain receptor) regolano l’angiogenesi e quindi sono considerati importanti fattori coinvolti nel processo patologico che porta all’insorgenza delle patologie oculari di origine angioproliverative. Nella prima parte dello studio è stato eseguito un’analisi di associazione tra polimorfismi presenti nei geni VEGF ed il suo recettore KDR e insorgenza di patologie angioproliferative come l’AMD e DR. Per questo scopo abbiamo analizzato 16 polimorfismi (11 sul gene VEGF e 5 sul gene KDR) in una popolazione di 226 pazienti affetti da AMD, una popolazione di 177 pazienti affetti da DR e una popolazione di controllo di 240 soggetti sani. L’analisi dei polimorfismi è stata effettuata mediante GenomeLab SNPstream (Beckman Coulter) che permette una genotipizzazione su larga scala. I risultati ottenuti in questa prima parte hanno evidenziato una forte associazione tra alcuni polimorfismi di VEGF-A e, per la prima volta, KDR con la suscettibilità all’insorgenza alle patologie oculari di origine neovascolare. Uno studio recente ha dimostrato che il CCR3 (C-C chemokine receptor type 3) e i corrispettivi ligandi eotassina 1,2,3 sono espressi a livello oculare solo in soggetti affetti da AMD di tipo neovascolare (AMD-CNV) e non in altri tipi di patologie oculari e in soggetti sani. Pertanto, nella seconda parte dello studio abbiamo analizzato, per la prima volta, se polimorfismi a singolo nucleotide nei geni CCR3 ed eotassina 1 (CCL11), eotassina 2 (CCL24), eotassina 3 (CCL26) sono associati all’insorgenza di AMD e DR. Per questo scopo abbiamo analizzato 46 polimorfismi (14 sul gene CCR3, 8 sul gene CCL11, 4 sul gene CCL26, 11 sul gene VEGF-A e 4 sul gene KDR) in 283 pazienti affetti da AMD, 175 pazienti affetti da DR e una popolazione di controllo di 262 soggetti sani. L’analisi dei polimorfismi è stata effettuata mediante BeadXpress di Illumina, un sistema high-throughput a scansione laser dual-color che consente di analizzare un'ampia varietà di saggi in multiplex sviluppati usando la tecnologia digitale a microbeads VeraCode. Quest’ultima tecnologia è stata inoltre utilizzata per confermare l’associazione del pathway VEGF-KDR con l’AMD e DR ampliando il numero di SNP studiati in questi due geni. L’analisi delle frequenze alleliche e genotipiche dei geni CCR3, eotassine 1,2,3 tra i gruppi dei pazienti AMD e DR ed il gruppo di controllo non ha evidenziato nessuna differenza statisticamente significativa. Questi risultati portano ad ipotizzare che il pathway CCR3/eotassina 1,2,3, svolga un ruolo secondario nei processi fisiopatologici che portano all’insorgenza delle patologie oculari angioproliferative. Abbiamo invece confermato nuovamente l’associazione del pathway VEGF/KDR allargando le attuali conoscenze sul ruolo di questo fattore di crescita nella fisiopatologia di tali patologie e dimostrando un contributo genetico nella suscettibilità all’insorgenza dell’AMD e DR. L’approfondita conoscenza di tali meccanismi potrebbe costituire la base per poter determinare il rischio di sviluppare la patologia e comprenderla nel suo insieme per permettere l’identificazione e la sintesi di farmaci innovativi. Infatti soggetti portatori di alleli di rischio o non di rischio potrebbero rispondere in maniera diversa alla terapia o potrebbero essere necessarie diverse quantità di farmaco anti-VEGF (attualmente utilizzato nella terapia di queste patologie) per aumentarne l’efficacia.

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SANTOS, Erinaldo Ubirajara Damasceno dos. "Estudo de associação de polimorfismos nos genes CCR2 e CCR5 com o desenvolvimento de lesões cervicais induzidas pelo HPV". Universidade Federal Rural de Pernambuco, 2016. http://www.tede2.ufrpe.br:8080/tede2/handle/tede2/4811.

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Cervical cancer (CC) affects about half a million women each year worldwide. The main etiological agent that can lead to the development of the CC is the human papillomavirus (HPV). However, not all women infected with HPV will have a progression to cancer, since the neoplastic development involves immune, genetic and environmental factors. Chemokine receptors play an important role in immune response, and progression of cervical intraepithelial neoplasia (CIN) for CC. Genetic variations related to the genes of these receptors may lead to the formation of cervical neoplasia. This study aimed to associate polymorphisms in genes of CCR2-64I chemokine receptor (rs1799864) and CCR5-Δ32 (rs333) with susceptibility to the development of cervical lesions (CIN or CC) in women from the State of Pernambuco, Brazil. The study population consisted of 139 women with cervical lesions (patients) and 151 healthy women (controls). The CCR2-64I and CCR5-Δ32 polymorphisms were analyzed by the technique of PCR-RFLP. The HPV detection was performed using the standard PCR technique. A protective effect for individuals carriers of a mutant genotypes (GA or AA) for individuals with cervical injury to the polymorphism in CCR2-64I gene (OR = 0.37, p = 0.0008). The same was observed for the A allele (OR = 0.39, P = 0.0002). In contrast, no association to the polymorphism in the CCR5-Δ32 gene was observed (p> 0.05). The prevalence of HPV types showed that 38.8% of patients were infected with HPV16; 22.3% HPV 18; HPV31 2.9%; 3.6% HPV 33; and 14.4% for other types of HPV. For multiple infection 18% of patients were co-infected with types 16 and 18. When we analyzed the association of HPV type with CCR2-64I polymorphism in the gene between individuals of the group of patients there is an effect protector of infection for HPV 16 (OR = 0.35, p = 0.0184). Moreover, when patients were stratified according to the severity of cervical lesions, 28.78% (40/139) had CIN I (low grade lesion), 62.58% (87/139) had CIN II or III (high-grade lesions) and 8.63% (12/139) had CC. In summary, our study showed CCR2-64I polymorphism protective effect of both susceptibility to infection with HPV 16 and for the development of cervical lesions (CIN and CC).
O câncer cervical (CC) afeta cerca de meio milhão de mulheres a cada ano em todo o mundo. O principal agente etiológico que pode levar ao desenvolvimento do CC é a infecção por Papillomavírus humano (HPV). Porém, nem todas as mulheres infectadas pelo HPV terão uma progressão para o câncer, visto que, o desenvolvimento neoplásico envolve fatores imunológicos, genéticos e ambientais. Os receptores de quimiocinas desempenham um importante papel na resposta imunológica e progressão de neoplasia intraepitelial cervical (NIC) para o CC. Variações genéticas relacionados com os genes destes receptores podem levar a formação de neoplasia cervical. O presente estudo teve como objetivo associar polimorfismos nos genes receptores das quimiocinas CCR2-64I (rs1799864) and CCR5-Δ32 (rs333) com a susceptibilidade para o desenvolvimento de lesão cervical (NIC ou CC) em mulheres residentes no Estado Pernambuco-Brasil. A população de estudo consistiu de 139 mulheres com lesões cervicais (pacientes) e 151 mulheres saudáveis (controles). Os polimorfismos CCR2-64I e CCR5-Δ32 foram analisados pela técnica da PCR-RFLP. A detecção do HPV foi realizada através da técnica de PCR convencional. Um efeito protetor foi observado para indivíduos carreadores de um dos genótipos mutantes (GA ou AA) em relação aos indivíduos com lesão cervical para o polimorfismo no gene CCR2-64I (OR = 0,37, p= 0,0008). O mesmo foi observado para o alelo A (OR = 0,39, P = 0,0002). Contrariamente, nenhuma associação para o polimorfismo no gene CCR5-Δ32 foi observada (p> 0,05). A prevalência dos tipos de HPV mostrou que 38,8% dos pacientes estavam infectados pelo HPV16; 22,3% HPV 18; 2,9% HPV31; 3,6% HPV 33; e 14,4% por outros tipos de HPV. Em relação a infecção múltipla, 18% dos pacientes foram co-infectados pelos tipos 16 e 18. Quando analisada a associação do tipo de HPV com o polimorfismo no gene CCR2-64I, entre os indivíduos do grupo de pacientes, observou-se um efeito protetor da infecção para o HPV 16 (OR = 0,35, p = 0,0184). Além disso, quando os pacientes foram estratificados de acordo com a gravidade das lesões cervicais, 28,78% (40/139) apresentaram NIC I (lesão de baixo grau), 62,58% (87/139) tinham NIC II ou III (lesão de alto grau) e 8,63% (12/139) tiveram CC. Em resumo, nosso estudo mostrou um efeito protetor do polimorfismo CCR2-64I tanto para susceptibilidade para a infecção pelo HPV 16 como para o desenvolvimento de lesões cervicais (CIN e CC).

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Kramp, Birgit [Verfasser]. "Establishing the interaction between the CC chemokine ligand 5 and the receptors CCR1 and CCR / Birgit Kramp". Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2014. http://d-nb.info/1049557794/34.

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Hirata, Bruna Karina Banin. "Estudo de associação dos polimorfismos genéticos CCR2-V64I e CCR5-Delta32 com suscetibilidade e parâmetros clinicopatológicos do câncer de mama". Universidade Estadual de Londrina. Programa de Pós- Graduação em Patologia Experimental, 2014. http://www.bibliotecadigital.uel.br/document/?code=vtls000190140.

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Entre os diversos tipos de cânceres, o de mama representa um grave problema de saúde pública correspondendo ao segundo tipo mais freqüente no mundo e o primeiro na população feminina. As células tumorais podem expressar receptores de quimiocinas, tais como o CCR2 e o CCR5, que estão implicados na progressão tumoral, podendo modular não apenas o recrutamento leucocitário, mas também a angiogênese, invasão e proliferação de células tumorais. Polimorfismos em muitos destes receptores são considerados fatores de risco para o desenvolvimento de diferentes tipos de câncer. A proposta deste estudo foi investigar o impacto dos polimorfismos CCR2-V64I (rs1799864) e CCR5-Delta32 (rs333) sobre a suscetibilidade e características clinicopatológicas do câncer de mama. A genotipagem foi realizada por PCR convencional e por PCR-RFLP em 118 pacientes com diagnóstico confirmado histologicamente e 180 controles livres de neoplasia de mama. O estudo de associação caso-controle foi analisado pelo cálculo da Odds Ratio (OR) com intervalo de confiança a 95% (IC=95%). E as análises de correlação entre os dados de genotipagem e os parâmetros histopatológicos (tamanho tumoral, comprometimento de linfonodos, estadiamento e grau nuclear) e subtipos tumorais do câncer de mama (triplo negativo, HER2+ e receptor hormonal positivo) foram realizadas pelo teste de Spearman rho. Nenhuma associação positiva ou negativa entre as variantes polimórficas de CCR2-V64I e CCR5-Delta32 e a suscetibilidade ao câncer de mama foi encontrada (CCR2-V64I: OR=1.32; IC95%=0.57-3.06; CCR5-Delta32: OR=1.04; IC95%=0.60-1.81). Entretanto, a análise de correlação mostrou significância entre o polimorfismo CCR2-V64I e os tumores que apresentavam a superexpressão do oncogene HER2 (p=0.026). Este estudo mostrou que os polimorfismos CCR2-V64I e CCR5-Delta32 não conferem suscetibilidade e também não estão correlacionados a um pior prognóstico no câncer de mama, em uma amostra da população brasileira da região sul. Contudo, uma vez que a freqüência dos alelos Delta32 (do gene CCR5) e A (do gene CCR2) foram baixas na população estudada (4% e 5% para o alelo Delta32 em controles e pacientes com câncer de mama, respectivamente e 12% para o alelo A em controles e pacientes), pode ser necessária a inclusão de um número maior de indivíduos com o intuito de confirmar a ausência de associação entre estes polimorfismos e a suscetibilidade ao câncer de mama. Adicionalmente, a correlação observada entre a variante alélica do gene CCR2 com o subtipo molecular HER2+ ressalta a importância de se estudar marcadores moleculares especificamente dentro dos subgrupos do câncer de mama, dadas a heterogeneidade e variabilidade de resposta desta doença.
Among the various types of cancer, breast cancer presents as a serious public health problem, being the second most common type in the world and first in the female population. The tumor cells can express chemokine receptors, such as CCR2 and CCR5, wich are implicated in tumor progression, can modulate not only leucocyte recruitment, but also the angiogenesis, invasion and proliferation of tumor cells. Polymorphisms of several receptors were found to be risk factors for development of different types of cancer. The purpose of this study was to investigate the impact of CCR2-V64I (rs1799864) and CCR5-Delta32 (rs333) polymorphisms on the susceptibility and clinicopathological characteristics of breast cancer. The genotyping was done by conventional PCR and PCR-RFLP methods in 118 histologically confirmed patients and 180 controls. The case-control association study was analyzed by Odds Ratio (OR) with a 95% confidence interval (IC=95%). The correlation analysis between the genotyping data and the histopathological parameters (tumor size, lymph nodes commitment, staging and nuclear grade) and breast cancer subtypes (triple negative, HER2+ and hormonal receptors positive) were realized by Spearman rho test. No association between polymorphic variants of CCR2-V64I and CCR5-Delta32 and breast cancer susceptibility was found (CCR2-V64I: OR=1.32; CI95%=0.57-3.06; CCR5-Delta32: OR=1.04; CI95%=0.60-1.81). However, the correlation analysis showed significance between the CCR2 polymorphism and tumors with overexpression of the oncogene HER2+ (p=0.026). This study shows that CCR2-V64I and CCR5-Delta32 polymorphisms does not confers susceptibility and also are not correlated with poor prognosis in breast cancer in Southern Brazilian population sample. However, since the frequency of the Delta32 (CCR5 gene) and A (CCR2 gene) allele were low in the studied population (4 and 5% of Delta32 allele in controls and breast cancer patients, respectively and 12% to A allele in both groups, there may be a need the inclusion of a greater number of individuals in order to confirm the absence of association between these polymorphisms and breast cancer susceptibility in Brazilian population. Additionally, the correlation observed between the variant allele of the CCR2 gene with the molecular subtype HER2+ highlights the importance of studying molecular markers specifically within subgroups of breast cancer, given the high heterogeneity and variability of response in this disease.

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Domínguez, Hernández Francisco. "Implicación de las quimoquinas IL-8, MCP-1, rantes, los receptores CXCR1, CXCR4, CCr2, CCr5 y el factor IGFBP-rP1 en la interfase materno-embrionaria". Doctoral thesis, Universitat de València, 2003. http://hdl.handle.net/10803/10135.

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La implantación embrionaria es la fijación del blastocisto al endometrio materno. El conocimiento de los factores moleculares implicados en su regulación es crucial para comprender los mecanismos que controlan la reproducción humana Las quimoquinas y sus receptores participan activamente en este proceso así como otros factores como IGFBP-rP1.Los objetivos principales de la tesis doctoral fueron los siguientes - Investigar la expresión y localización de la quimoquinas IL-8, MCP-1, RANTES y SDF-1 en el endometrio humano.- Estudiar la expresión y localización de los receptores de las quimoquinas antes citadas CXCR1, CCR2b, CCR5 y CXCR4 en el endometrio humano.- Determinar la presencia de dichos receptores en el blastocisto humano.- Analizar la expresión de qué genes están regulados en el endometrio durante la ventana de implantación y establecer su implicación en la receptividad endometrial humana.- Evaluar la expresión y localización de IGFBP-rP1 en el endometrio humano.Las conclusiones de la tesis doctoral fueron las siguientes- IL-8 y MCP-1 a nivel de proteína se localizan en el epitelio luminal y glandular así como en células endoteliales. RANTES fue localizada principalmente en células del estroma y endoteliales.- Los niveles de IL-8 y MCP-1 aumentaron debido a la administración de progesterona durante la fase receptiva del ciclo menstrual.- El blastocisto humano no produce cantidades medibles de IL-8, MCP-1 y RANTES, pero induce un aumento en el ARN mensajero de IL-8 en células epiteliales endometriales en cultivo.- Los receptores de quimoquinas CXCR1 (IL-8), CCR5 (RANTES) y CCR2b (MCP-1) a nivel de ARNm esta aumentado en el endometrio premenstrual, mientras que CXCR4 (SDF-1) se encontró aumentado ligeramente durante la ventana de implantación (fase secretora media). El blastocisto humano posee los receptores CCR5 (RANTES) y CCR2b (MCP-1) a nivel de proteína. - Las células endometriales epiteliales en cultivo poseen los receptores CXCR1 (IL-8), CCR5 (RANTES) y CCRb (MCP-1). El embrión humano induce una polarización de dichos receptores endometriales.- IGFBP-rP1 fue la segunda molécula más expresada tanto por el endometrio receptivo (LH+7) como en la línea celular RL95-A (receptiva) entre más de 375 genes analizados de citoquinas, quimoquinas, factores de crecimiento y sus receptores.- El ARN mensajero de IGFBP-rP1 aumentó unas 35 veces durante la fase receptiva comparado con el endometrio pre-receptivo, mostrando además un pico de expresión en la fase lútea tardía. La separación de estroma, y epitelio demostró que la expresión de IGFBP-rP1 aumentaba principalmente en células del estroma.- La localización del ARNm de IGFBP-rP1 por hibridación in situ confirmó la localización de dicha molécula en células del estroma aunque también se observó en epitelio y células endoteliales. La localización de la proteína se concentró en la superficie apical del endometrio, sugiriendo su posible función en la fisiología de la receptividad endometrial. Concluimos por todo ello que algunas quimoquinas secretadas por el endometrio de forma local como IL-8, RANTES, MCP-1 u otras pueden activar sus receptores en la superficie del blastocisto, lo que supondría su heterodimerización y con ello, se provocaría un fenotipo adhesivo en el blastocisto y su posterior implantación.
Human implantation is the process of the adhesion of the blastocyst to the human endometrium. The knowledge of the biochemical factors involved in this process is crucial for the understanding of the mechanisms of the human reproduction.Chemokines, a subfamily of cytokines, and their receptors are actively implicated in this process. Another factor, IGFBP-rP1, is also related to the molecular basis of implantation. Our objectives in this doctoral thesis are: - To investigate the localization and expression of IL-8, MCP-1, RANTES and SDF-1 in the human endometrium. - To study the localization and expression of the chemokine receptors CXCR1, CCR2b, CCR5 and CXCR4 in the human endometrium. - To determine the presence of these receptors in the human blastocyst - To analyze the expression of genes expressed differentially in human receptive endometrium versus pre-receptive endometrium. - To evaluate the expression and localization of IGFBP-rP1 in the human endometrium. The major conclusions of this doctoral thesis are: - IL-8 and MCP-1 are localized in the luminal and glandular epithelium. RANTES was localized in stroma and endothelial cells. The levels of IL-8 and MCP-1 were up-regulated with the administration of progesterone. - The human blastocyst doesn't produce IL-8, MCP-1 nor RANTES, but induces an up-regulation of IL-8 mRNA in endometrial epithelial cells in culture. - The chemokine receptors CXCR1, CCR5, CCR2 are up-regulated in the premenstrual endometrium, whereas CXCR4 is up-regulated in the implantation window. The human blastocyst expresses the CCR5 and CCR2 receptors. - The epithelial endometrial cells in culture express the CXCR1, CCR5 and CCR2 receptors. The human blastocyst produces an up-regulation and polarization of these receptors in this culture. - IGFBP-rP1 was the second most up-regulated molecule in receptive endometrium and in RL95A (receptive) cell line, among more than 375 genes analyzed. - IGFBP-rP1 mRNA was up-regulated more than 35 times during receptive phase compared to pre-receptive one. Stromal cells were responsible for the expression of this molecule. mRNA of IGFBP-rP1 was localized by in situ hybridization in luminal and glandular epithelium and stromal cells. The protein was localized in the apical zone of the luminal epithelium, suggesting a possible role in endometrial receptivity.

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John, Bangan. "Association Among CCR5 Genotypes, CCR5 Expression, And In Vitro HIV Infection". Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1365888090.

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Giongo, Cíntia de Oliveira. "Caracterização imunogenética de variantes dos genes CCR2, CCR5 e HLA-G como potenciais alvos para diagnóstico, prognóstico e tratamento do câncer de mama feminino esporádico e familial". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2012. http://hdl.handle.net/10183/78137.

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O câncer de mama é a neoplasia mais comum entre as mulheres. Sua etiologia é complexa, onde tanto fatores ambientais como genéticos podem contribuir para o desenvolvimento tumoral. Estima-se que 5 a 10% dos casos de carcinomas de mama sejam representados pelos carcinomas de mama familial e 90 a 95% sejam representados pelos carcinomas de mama esporádicos. Independente da etiologia, um dos principais agravantes é consequência da habilidade das células tumorais metastizar. Mutações podem levar a mudança ou perda de expressão de diferentes genes e isto possibilita que as células adquiram particularidades genéticas e fenotípicas que contribuem para a progressão do tumor através da aquisição de vantagens que medeiam a sua sobrevivência. Dentre estas vantagens adquiridas está a capacidade das células tumorais de escaparem da destruição pelas células imunológicas ou, até mesmo, utilizarem estas células a seu favor, na promoção de um microambiente tumoral inflamatório que pode auxiliar o desenvolvimento da angiogênese que posteriormente facilitará a metástase. As características dos carcinomas de mama são as principais ferramentas para avaliação do diagnóstico e prognóstico da doença. Portanto, o objetivo de nosso trabalho foi a análise de quatro variantes polimórficas de genes que codificam importantes moléculas do sistema imunológico, duas relacionadas aos genes que codificam os receptores de quimiocinas, CCR2 e CCR5, e duas relacionadas ao gene HLA-G em 188 mulheres com carcinoma de mama (105 com câncer de mama familial e 83 com câncer de mama esporádico) e em 151 mulheres sem carcinoma e sem história familiar de câncer (grupo controle), como possíveis marcadores de diagnóstico e prognóstico do carcinoma de mama. Para a análise da variante do CCR2, denominada CCR264I, e para a análise de uma das variantes que codifica a molécula de HLA-G, denominada +3142, utilizou-se a técnica PCR-RFLP. Para a análise da variante do gene CCR5, denominada CCR5delta32 e para a análise da outra variante do HLA-G, caracterizada pela inserção de 14pb na região 3’UTR do gene, utilizou-se a técnica PCR. As frequências alélicas, genotípicas e haplotípicas foram estimadas e comparadas entre os grupos de mulheres, usando o Teste Qui-Quadrado ou o Teste Exato de Fisher e, posteriormente, foram relacionadas a fatores de diagnóstico e prognóstico. Observou-se maiores frequências dos alelos selvagens do CCR2, Val (p=0,040, OR 0,61, IC 95% = 0,38 – 0,98) e do CCR5, Wt (p=0,032, OR 0,46, IC 95% = 0,23 – 0,94) e maior frequência do haplótipo duplo selvagem Wt/Val destas mesmas variantes gênicas dos genes CCR2 e CCR5, nas mulheres do grupo controle (p=0,030) em relação às mulheres com câncer de mama familial. Quando as variantes foram avaliadas em conjunto com os parâmetros clínicos, observou-se que as mulheres com carcinoma de mama esporádico apresentavam a doença em idade mais elevada (57,29 ± 8,457 anos e 44,23 ± 12,092 anos para mulheres com câncer de mama esporádico e familial, respectivamente, p < 0.001) e de forma mais agressiva, com maior frequência dos carcinomas invasores (p = 0,001) que as mulheres com carcinoma de mama familial. Além disso, as variantes de inserção/deleção de 14 pb do HLA-G e CCR264I, mostraram relação positiva com a agressividade tumoral nestas mulheres (p = 0,039 e p = 0,005). Nossos dados sugerem que os carcinomas invasores possam estar relacionados a uma maior infiltração de células imunológicas e com o aumento da inflamação no microambiente tumoral, mediados pelo receptor CCR2 e pela molécula HLA-G, respectivamente.
Breast cancer is the most common cancer among women. Its etiology is complex, where genetic, environmental and endocrine factors contribute to tumor development. It is estimated that 5 to 10% of the breast cancers are represented by familial breast cancers and 90 to 95% are represented by sporadic breast cancers. Independent of the etiology, the major aggravating consequence is the ability of tumor cells to metastasize. Mutations can lead to a change or loss of expression a different genes and this allows the appearance of genetic and phenotypic features which contribute to tumor progression. Among these features is the ability of tumor cells to evade from the immune cells or even use immune cells in the promotion of a inflammatory microenvironment promotion which may help angiogenesis and, later, metastasis. The aim of our study was to evaluate four important polymorphic variants of genes which encode important immune system molecules, two related genes encoding chemokine receptors, CCR2 and CCR5, and two related to HLA-G gene in 188 women with breast cancer (105 women with familial breast cancer and 83 with sporadic breast cancer) and 151 women without cancer and family history of cancer (control group), such as potential markers for diagnosis and prognosis of breast cancer. CCR2 polymorphism, CCR264I, and one HLA-G polymorphism, +3142, were genotyped by PCR-RFLP. CCR5delta32 and 14pb HLA-G polymorphism were genotyped by PCR. Allelic, genotypic and haplotypic frequencies were estimated and compared between the groups using the Chi-square test or Fisher's exact test and subsequently were associated to diagnostic and prognostic factors. We observed a higher allelic frequency of the CCR2 wild type allele, Val (p = 0.040, OR 0.61, 95% CI = 0.38 - 0.98) e CCR5 wild type allele, Wt (p = 0.032, OR 0.46, CI 95% = 0.23 - 0.94) and higher haplotype frequency of the double wild type variants (Wt/Val) of these same genes (CCR2 and CCR5) in women in the control group (p = 0.030) compared to women with familial breast cancer. All polymorphisms were evaluated together with the clinical parameters and it was observed that women with breast cancer showed sporadic cancer latter (57.29 ± 8.457 years and 44.23 ± 12.092 years for women with sporadic breast cancer and familial breast cancer, respectively, p < 0.001) and more invasiveness (p = 0.001) as compared to women with familial breast cancer. Moreover, the HLA-G 14pb and CCR264I polymorphism, showed a positive association with tumor aggressiveness in women with sporadic breast cancer (p = 0.039 and p = 0.005, respectively). Our data suggest that invasive cancers may be associated with increased immune cells infiltration and inflammation in the tumor microenvironment mediated by both CCR2 receptor and HLA-G molecule.

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29

Fish, Richard James. "RANTES derivatives and CCR5". Thesis, University of York, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.369362.

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30

Müller, Christine [Verfasser] y Gernot [Akademischer Betreuer] Zissel. "Charakterisierung CCR6-positiver T-Zellen". Freiburg : Universität, 2011. http://d-nb.info/1123463107/34.

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31

Arnatt, Christopher Kent. "DEVELOPMENT OF ANTAGONISTS TARGETING CHEMOKINE RECEPTOR CCR5 AND THE CHEMOKINE RECEPTOR CCR5 – MU OPIOID RECEPTOR HETERODIMER". VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/517.

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The chemokine receptor CCR5 (CCR5) plays an integral role within the inflammatory network of cells. Importantly, CCR5 is a mediator in several disease states and can be targeted using small molecule antagonists. Within this work, CCR5’s role in prostate cancer and HIV/AIDS has been exploited in order to develop potential therapeutics and probes. First, a series of novel compounds was designed by using pharmacophore-based drug design based upon known CCR5 antagonists and molecular modeling studies of the CCR5 receptor’s three-dimensional conformation. Once synthesized, these compounds were tested for their CCR5 antagonism and their anti-proliferative effects in several prostate cancer cell lines. The data from both the calcium mobilization studies and the anti-proliferation studies suggests that the compounds synthesized have activity as CCR5 antagonists and as anti-proliferative agents in certain prostate cancer cell lines. In addition, a bivalent ligand containing both a mu opioid receptor (MOR) and a CCR5 antagonist pharmacophore was designed and synthesized in order to study the pharmacological profile of the putative CCR5-MOR heterodimer and its relation with NeuroAIDS. The structural-activity relationship between the bivalent ligand and the heterodimer was studied with radio-ligand binding assays, functional assays, HIV-1 fusion assays, cell fusion assays, and in silico molecular dynamics. The subsequent bivalent ligand was proven to be a potent inhibitor in both an artificial cell fusion assay mimicking HIV invasion and a native HIV-1 invasion assay using live virus. In all, two novel sets of compounds were synthesized that targeted either CCR5 or the CCR5-MOR heterodimer. For the CCR5 antagonists, as leads for prostate cancer therapeutics, further work needs to be done to ascertain and develop their structure-activity-relationship. This library of novel compounds was shown as promising leads as CCR5 and anti-prostate cancer agents. The bivalent ligand targeting the CCR5-MOR heterodimer proved to be a potent and tissue-specific inhibitor for neuroAIDS where the known treatment, maraviroc, is less efficacious and fails to inhibit virus entry in the presence of morphine. Both projects illustrate the roles that CCR5 plays in these two unique diseases.

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32

Basquin, Jérôme. "Etude structurale du complexe CCR4-NOT". Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ084/document.

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Le recyclage des ARN débute par un étape de déadenylation ou la queue poly (A) est enzymatiquement clivée. La deadenylation est l’étape limitante dans le processus de dégradation des ARN. In vivo la deadenylation s’effectue successivement par les complexes multi-protéiques Pan2-Pan3 et Ccr4-Not. Le complexe Ccr4-not est conservé chez les eucaryotes et considéré comme le complexe prédominant responsable de l’activité de déadenylation dans la cellule. Le complexe est compose de neuf protéines organisées autour de la protéine d’échafaudage Not1. Le complexe comprend quatre modules distincts ; le module de déadenylation, la module Caf40, le module N-terminal et le module C-terminal. Mon mémoire de thèse regroupe les études structurales qui ont contribuées à caractériser les structures des différents modules à la fois chez la levure et chez l’humain
MRNA turnover begins with deadenylation where in the poly(A) tail at the 3’ end of the mRNA is removed. Deadenylation is the rate-limiting step of the decay pathway. In vivo, deadenylation is carried out by two major macromolecular complexes, the Pan2-Pan3 complex and the Ccr4-Not complex. The Ccr4-Not complex is a multi-protein complex that is evolutionarily conserved in all eukaryotes and is considered to be the major deadenylase complex in the cell. In S. cerevisiae, the Ccr4-Not complex is composed of nine subunits and is built around the scaffolding protein Not1. Structurally, the Ccr4-Not complex assembles into four separate modules with distinct domains of Not1 acting as a scaffold for individual modules. The four modules include the N-terminal module, the deadenylase module, the Caf40 module and the C-terminal module. With the exception of the C-terminal module, the architecture and biochemical role of all other modules of the yeast Ccr4-Not complex has been characterized. My doctoral thesis is focused on the elucidation of the architecture of the human of the yeast Ccr4-Not complex

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33

Maier, Corinna. "Expressionsanalyse des Chemokinrezeptors CCR6 auf Fibroblasten". [S.l. : s.n.], 2007. http://nbn-resolving.de/urn:nbn:de:bsz:25-opus-60178.

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34

José, de Pessoa Saldanha Carlos. "Avaliação da mutação ccr532 do receptor da quimiocina como marcador genético-histórico na população de Triunfo Pernambuco". Universidade Federal de Pernambuco, 2008. https://repositorio.ufpe.br/handle/123456789/6316.

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Made available in DSpace on 2014-06-12T18:04:10Z (GMT). No. of bitstreams: 2 arquivo3738_1.pdf: 896817 bytes, checksum: 7cd3fad40aa580f879fae31cec4ad007 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2008
O gene ccr5 codifica o receptor b-quimiocina 5 (CCR5), uma proteína transmembrânica que age como principal co-receptor para os vírus HIV-1, Variola major e para a bactéria Yersinia pestis, nos macrófagos e monócitos humanos. Uma deleção de 32 pares de bases neste gene dá origem ao alelo mutante ccr532 cuja presença, em homozigose, tem sido relatada em indivíduos resistentes à AIDS. A mutação ccr532 tem uma origem recente e se deu na Europa, e atinge suas maiores freqüências nas populações do norte (16% na Finlândia). Ocorrências isoladas foram descritas no resto do globo, entretanto resultariam de fluxo gênico recente para essas populações. Segundo informação verbal popular, Triunfo não se constitui numa cidade atrativa para imigrações e apresentaria certo grau de consangüinidade entre os seus 14 mil habitantes, por isso esta população tornou-se objeto de estudos das freqüências dos alelos ccr5 e ccr532 para que se pudesse determinar se essas freqüências divergem ou não das encontradas nos demais Estados Nordestinos. Foram analisados 345 indivíduos não aparentados desta população, e após extração por mini salting-out o DNA genômico foi amplificado por PCR e a partir da eletroforese por PAGE a 5% suas bandas foram visualizadas por impregnação com AgNO3. As freqüências genotípicas observadas foram 89,28% (ccr5/ccr5), 10,72% (ccr5/$32) e 0,0% ($32/$32). As freqüências alélicas foram 94,64% para o ccr5 e 5,36% para o ccr5Q32. A população encontrase em equilíbrio de Hardy-Weinberg (p= 0,61). A freqüência um pouco elevada do ccr532 encontrada na população de Triunfo pode ser resultado da ocorrência de efeito fundador nessa cidade, ou de um processo de deriva genética

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35

Dorman, Klara [Verfasser] y Sebastian [Akademischer Betreuer] Kobold. "Kombinierte Expression von epithelial cell adhesion molecule (EpCAM)-spezifischem chimärem Antigenrezeptor mit den Chemokinrezeptoren CCR4, CCR8 und CXCR6 in der T-Zell-basierten Immuntherapie von murinen Tumormodellen / Klara Dorman ; Betreuer: Sebastian Kobold". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2021. http://d-nb.info/1232645435/34.

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36

Knipfer, Lisa [Verfasser], Stefan [Akademischer Betreuer] Wirtz y Falk [Gutachter] Nimmerjahn. "The role of the C-C type chemokine receptors CCR4 and CCR8 in migration and effector function of innate lymphoid cells type 2 (ILC2s) / Lisa Knipfer ; Gutachter: Falk Nimmerjahn ; Betreuer: Stefan Wirtz". Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2020. http://d-nb.info/1224356195/34.

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37

Barmania, Fatima. "Analysis of CCR5 diversity in the South African population". Diss., University of Pretoria, 2011. http://hdl.handle.net/2263/31127.

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Infection with the human immunodeficiency virus (HIV) constitutes a global pandemic, and South Africa forms part of the region known to house over two-thirds of HIV infected individuals worldwide. In the early stages of infection, the C-C chemokine receptor type five (CCR5) is the major HIV-1 co-receptor. The importance of this receptor in HIV infection and disease progression was recognised with the discovery of the CCR5 delta 32 (Δ32) allele. Individuals homozygous for this mutation lack functional CCR5 receptors. Consequently, they are almost completely resistant to HIV infection, while the absence of CCR5 has minimal effects on health. Heterozygous individuals display decreased cell surface CCR5 which slows disease progression. Phenotypic expression of CCR5 is heterogeneous and its relation to genetic mutations in the CCR5 gene is not currently known for the South African population. This together with the effect of CCR5 expression on HIV infection provided the rationale for investigating both the phenotypic and genotypic distribution of CCR5. The aim of this study was therefore 1) to investigate CCR5 phenotypic expression on cluster differentiation four (CD4) T-lymphocytes in a group of South African individuals and 2) to analyse the genetic variation in a South African cohort. Flow cytometric methods were used to measure the phenotypic distribution of CCR5 in 245 individuals by assessing both the percentage of CD4+CCR5+ T-cells and CCR5 density. Sixty five individuals, mostly found within the lower CCR5 receptor density range were selected for DNA sequencing. The study found considerable variability in CCR5 expression with South African individuals expressing relatively high CD4+CCR5+ T-cell percentages. Ethnicity was established as a significant variable affecting CCR5 expression with Black African individuals displaying higher (p <0.05) CD4+CCR5+ T-cell percentages and densities than Caucasians. Genotypic data revealed 70 single nucleotide polymorphisms (SNPs), four insertions and the ∆32 deletion. Results showed that Black African individuals have greater genetic diversity with 39 mutations exclusive to this group. The ∆32 mutation was not detected in the Black African group but was identified in the Caucasian group at a frequency of 18.6 %. Twelve novel mutations were identified in this study with two in the open reading frame (ORF). It is evident from the data that the variability in CCR5 phenotypic expression is difficult to correlate with specific mutations in the gene. This thesis provides information on CCR5 distribution and diversity in the South African population which will be of value to patients, clinicians and health policy officials.
Dissertation (MSc)--University of Pretoria, 2011.
Immunology
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38

Rodrigues, Erika Cruz Vicente. "Avaliação de empresas: CCR". reponame:Repositório Institucional do BNDES, 2014. https://web.bndes.gov.br/bib/jspui/handle/1408/7028.

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Valuation é o termo em inglês para o método utilizado para determinar o preço justo a ser pago por um ativo. Existem três métodos mais conhecidos para avaliação: a avaliação pelo método de fluxo de caixa descontado, avaliação relativa e avaliação por direitos contingentes (opções reais). Este trabalho é baseado na avaliação pelo método de fluxo de caixa descontado na análise da empresa CCR, uma das maiores empresas de concessão de infraestrutura do mundo. Após analisar os demonstrativos financeiros da companhia e, efetuar uma análise do panorama do setor de exploração de rodovias, serão realizadas projeções do fluxo de caixa e, com base nestas projeções iremos elaborar a avaliação da empresa CCR visando precificar valor justo para a empresa.
Valuation is the word in english for the method used to determine the fair price to be paid for an asset. There are three methods most popular assessment: the assessment by the method of discounted cash flow, evaluation and assessment by rights quotas (real options). This work is based on the assessment by the method of discounted cash flow analysis of the company CCR, one of the largest companies to grant infrastructure of the world. After reviewing the financial statements of the company and perform an analysis of the industry landscape exploitation of highways, shall be carried out projections of cash flow and, with basenestas projections we will draw up the valuation of the company CCR aiming at establishing the fair value for the company.
MBA Executivo (especialização em Finanças) - Ibmec Business School, Rio de Janeiro, 2014.
Bibliografia: p. 23.

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39

Martinelli, Roberta. "Molecular characterisation of the chemokine receptor CCR2". Thesis, Imperial College London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398841.

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40

Bryce, Steven Alan. "Regulation of the bioavailability of CCR7 ligands". Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5904/.

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The efficient functioning of the immune system is dependent on the coordinated movement and positioning of immune cells. These cells patrol the body and facilitate the clearance of pathogens, whilst maintaining self-tolerance and inducing adaptive immunity. The coordinated migration of cells into and within tissues is mediated by chemokines, a family of small chemotactic cytokines that are potent inducers of cellular movement. Chemokines and their cognate receptors have been shown to play key roles in health, and in a broad spectrum of diseases. After their secretion, chemokines can be controlled by proteases and interactions with atypical chemokine receptors that structurally resemble conventional chemokine receptors but cannot couple to the signaling pathways that they use. Instead, they are thought to degrade, transport or buffer extracellular chemokines to regulate their access to cells bearing conventional chemokine receptors. However, their functions in vivo remain to be fully defined. CCRL1, a member of the atypical chemokine receptor family, binds to CCL19, CCL21 and CCL25 and is proposed to be a scavenger of these chemokines. Post-translational regulation of these chemokines is important because their interactions with cognate, conventional receptors CCR7 and CCR9, are critical for the development and functioning of the immune system. The work in this thesis primarily explores the importance of CCRL1 in regulating CCR7 ligands, but also considers the impact of protease-mediated ‘clipping’ on the function of CCL21 and other extended chemokines. Whilst in vitro evidence, and a growing body of in vivo evidence, supports the idea that CCRL1 serves an important role in the chemokine control, the true biological function of CCRL1 remains unclear. Therefore, the principal aim of this thesis was to further our understanding of the biology of CCRL1, mainly through the characterisation of CCRL1-deficient mice. Firstly, the effect of CCRL1 deletion on dendritic cell (DC) migration from the skin was investigated. Four distinct subsets of migratory DCs were examined in skin-draining lymph nodes at steady state and after induction of cutaneous inflammation. Under inflammatory conditions, skin-derived DCs were identified by FITC painiting or by photoconverting the skin of Kaede transgenic mice. CCRL1 deficiency was found to result in a specific reduction in the abundance of Langerin+ skin-derived DCs in inguinal lymph nodes at rest, and although the initial inflammation-driven arrival of DCs at skin-draining lymph nodes showed no requirement for CCRL1, DCs that took longer to reach these organs were substantially reduced in CCRL1-deficient mice. All DC subsets were affected, but overall it was epidermal Langerhans cells that showed the greatest requirement for CCRL1. Defective DC arrival at lymph nodes was accompanied by DC retention in resting and inflamed skin, and these cells struggled to leave CCRL1 deficient skin in ex vivo ‘crawl out’ assays. Further experiments demonstrated that, as expected, DC arrival at lymph nodes draining inflamed skin was heavily dependent on CCR7 in the models being used, and that increased levels of bioavailable CCL19 and CCL21 accompanied CCRL1 deficiency in inflamed skin. This suggested CCRL1 regulates chemokine to prevent DCs from becoming disorientated in the skin and failing to efficiently egress this tissue. I hypothesised that dysregulation of CCL19 rather than CCL21 may be particularly significant because of its greater diffusivity, and strikingly, inflammation-driven DC migration defects observed in CCRL1 deficient mice were completely reversed by genetic deletion of CCL19 in the same animals. To place these findings in an anatomical context, expression of CCRL1 in skin and lymph node was explored using CCRL1+/gfp ‘knock-in’ receptor mice and anti-CCRL1 antibodies. In skin, CCRL1 was abundantly expressed by keratinocytes, and found on lymphatic endothelial cells (LECs) that are traversed by migrating DC as they leave the skin. In lymph nodes draining the skin, LECs in the supcapsular sinus (SCS) were strongly CCRL1+. Although some leukocytes were found to express very low levels of eGFP in CCRL1+/gfp, the data suggested that CCRL1-mediated scavenging of CCL19 by keratinocytes and LECs facilitates CCR7-driven DC migration from resting and inflamed skin. CCRL1 expression in other secondary lymphoid tissues was examined and its role in regulating leukocyte populations residing in or around the SCS was explored. As in the inguinal lymph node, CCRL1 was restricted to the SCS LECs in other lymph nodes, such as the mesenteric lymph nodes that drains the intestine. In the spleen, endothelial cells lining venules adjacent to the white pulp marginal zone specifically expressed CCRL1. The overall cellularity and microanatomy of lymph nodes and the spleen appeared normal in CCRL1-deficient mice, as was the recruitment of CCR7+ cells into the spleen two hours after adoptive transfer. However, NK cells, iNKT cells and γδ T cells, which are thought to reside in intrafollicular regions, were less abundant in CCRL1-deficient inguinal and mesenteric lymph nodes, although they were present at normal frequency in the spleen. CD169+ macrophages are intimately associated with CCRL1+ endothelial cells in the spleen. CCRL1 deficiency had no clear impact on these cells in the inguinal lymph nodes, and only resulted in a small increase in the abundance of these cells in the spleen, without obviously affecting their position. Strikingly, however, in mesenteric lymph nodes, CD169+ macrophages, and LECs with which they associate, were far more abundant when CCRL1 had been deleted and were aberrantly distributed throughout the lymph node parenchyma. The reason this phenotype is restricted to the mesenteric lymph node is unclear, but it might be related to the fact the intestine, unlike other non-lymphoid tissues, is an abundant source of CCL25. This, along with the immunological implications of these observations, requires further investigation. There is a lot of evidence that macrophages regulate lymphangiogenesis. The close association between LECs and CD169+ macrophages in lymph nodes, and the phenotype in CCRL1-deficient mesenteric lymph nodes, stimulated experiments to explore functional interactions between these cells. Inflammation in the footpad induced lymphangiogenesis in draining popliteal and inguinal lymph nodes. When clodronated liposomes were used to specifically deplete macrophages from the popliteal lymph node of WT mice, lymphangiogenesis appeared suppressed while it continued unabated in the inguinal lymph node where the CD169+ macrophage population was intact. WT and CCRL1-deficient mice responded similarly, and although preliminary, these data suggest that CD169+ macrophages play an important role in stimulating lymph node lymphangiogenesis. In addition to the CCRL1 studies above, other mechanisms that might regulate chemokines after their secretion were explored. Work published at the beginning of my PhD showed that CCL21, which carries an extended C-terminus that anchors it to the extracellular matrix, can be cleaved by bone marrow-derived DCs (BMDCs) to release a more freely diffusible version. These findings were reproduced here using in vitro-derived human or mouse DCs. DCs were far better at cleaving CCL21 than other leukocytes, and they could also cleave CCL2, a pro-inflammatory chemokine with an extended C-terminus. Interestingly, a truncated version of CCL21 was detected in mouse secondary lymphoid tissues. It was larger than the version generated by BMDCs in vitro, and the nature of its truncation is not clear, but this shows that CCL21 processing occurs in vivo. If this form of CCL21 is more diffusible than the full-length protein, then it might be more available for regulation by CCRL1.
However, neither forms of CCL21 were more abundant in CCRL1-deficient secondary lymphoid tissues than equivalent tissues from WT mice. CCR7 plays a critical role in directing DC egress from tissues, their entry into lymph nodes, and their movement within these tissues. The work presented in this thesis provides evidence of two mechanisms that regulate CCR7 ligands: CCRL1-mediated CCL19 scavenging and DC-mediated CCL21 cleavage. It reveals that, under certain circumstances, CCRL1 is critical for facilitating DC egress from peripheral tissues to the lymph nodes, and plays an indispensible role in regulating LECs and CD169+ macrophages in lymph nodes. These studies extend our understanding of CCRL1 and the chemokine networks at work in lymph nodes and other tissues, and form the foundation on which to explore the immunological importance of the regulation of extracellular chemokines.

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41

Sax, Michael John. "The CCL5-CCR5 Axis in Breast Cancer". Thesis, Griffith University, 2015. http://hdl.handle.net/10072/365646.

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Cancer is one of the leading underlying causes of death worldwide. Despite decades of research, cancer is predicted to be the leading cause of death by the year 2020. Anti angiogenic therapies that target the key signalling molecule, vascular endothelial growth factor (VEGF) have shown promise in the treatment of some solid tumours, resulting in increased progression-free survival times in patients. However, there are several significant problems with current anti-angiogenic therapies, such as the phenomenon of resistance. Tumours can be divided into those that are intrinsically nonresponsive to therapy, and those that do respond. However, for those tumours that do respond to therapy, an initial positive response (tumour regression) is followed by tumour re-vascularisation and rapid relapse. Secondly, anti-angiogenic therapies target normal physiological processes, including vascular homeostasis, wound healing and the immune system, leading to a range of potentially negative side effects, including death. Thus unravelling the biology of angiogenesis and developing new drug targets is a priority of current research. The C-C chemokine receptor 5 (CCR5) has been the subject of extensive research in the last few years. This is primarily because of its association with the pathology of disease, viral infection, and the immune response. However, while the main ligand for CCR5, C C chemokine ligand 5 (CCL5) is known to be upregulated in malignant breast cancer, little has been done to unravel the CCL5-CCR5 axis in breast cancer and its potential role as a driver of malignancy. Furthermore, while experimental evidence, including data from CCR5 knockout mouse, suggests a role for CCL5-CCR5 in neovascularisation, little has been done to study the potential role of CCL5-CCR5 in tumour angiogenesis, as well as implications CCL5-CCR5 signalling may have on clinical course in breast cancer.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
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42

De, Poorter Cédric. "Mécanismes d'activation et interactions fonctionnelles hétérologues des récepteurs aux chimiokines". Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209589.

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Mécanismes d’activation et conséquences fonctionnelles de la dimérisation des récepteurs aux chimiokines

Les chimiokines sont de petites protéines qui régulent la migration des cellules immunitaires. Elles exercent leur action en se liant à des récepteurs appartenant à la famille des récepteurs couplés aux protéines G (RCPG) dont la fonction est intimement liée à la régulation des cellules immunitaires. Notre laboratoire étudie depuis plusieurs années les relations reliant la structure et la fonction des récepteurs aux chimiokines. Ces dernières années, un nouveau concept est venu révolutionner le mode de fonctionnement des RCPGs. En effet, des travaux ont montré que la plupart des RCPGs sont capables de former des dimères. Le but de cette thèse de doctorat est d’étudier de manière systématique la dimérisation des récepteurs aux chimiokines et d’analyser les conséquences fonctionnelles de la dimérisation.

Dimérisation des récepteurs humains aux chimiokines et conséquences fonctionnelles

En utilisant une technique biophysique basée sur un transfert d’énergie de luminescence (BRET) nous avons montré au cours de ce travail de thèse que les récepteurs CCR1, CCR2, CCR5, CCR7 et CXCR4 sont capables de former des homodimères et des hétérodimères. De plus, une dimérisation entre ChemR23, dont le ligand naturel, la chémérine, est structurellement différent des chimiokines, et les récepteurs CCR7 et CXCR4, a également été identifiée.

D’un point de vue fonctionnel, des expériences réalisées au laboratoire dans le cadre d’un autre travail de thèse ont identifié une forme de compétition croisée entre CCR2, CCR5 et CXCR4 où la liaison de ligands (agonistes ou antagonistes) spécifiques de l'un des deux récepteurs inhibe la liaison des ligands spécifiques de l’autre. Ces effets ont été démontrés sur des cellules recombinantes mais aussi sur des cellules immunes et dans un modèle in vivo. (El-Asmar, 2005; Springael, 2006; Sohy, 2007; Sohy, 2009). Au cours de ce travail, nous nous sommes dans un premier temps focalisés sur les

hétéromères de ChemR23 avec CXCR4 et CCR7 et nous avons ensuite étudié plus en profondeur les hétéromères de CCR7. Concernant la dimérisation de ChemR23 avec les récepteurs aux chimiokines CCR7 et CXCR4, nous avons pu mettre en évidence une coopérativité négative de liaison entre les agonistes des récepteurs comme cela avait pu être démontré pour CCR2/CCR5/CXCR4. Par contre, nous n’avons observé aucun effet de compétition hétérologue ou d’inhibition fonctionnelle croisée de l’AMD3100 sur ChemR23 quand il est coexprimé avec CXCR4. De manière additionnelle, nous avons pu observer cette compétition croisée sur des cellules dendritiques murines immatures, démontrant l’existence des effets de l’hétérodimérisation lorsque les récepteurs sont exprimés à un niveau physiologique. Lors de l’étude approfondie des hétéromères de CCR7, nous avons montré que les conséquences fonctionnelles de l’hétérodimérisation de CCR7 sont différentes suivant le récepteur avec lequel il interagit. Pour l’hétérodimère CCR7/CCR2, nous avons identifié une forme de compétition croisée, où la liaison de ligands spécifiques de l'un des deux récepteurs inhibe la liaison des ligands spécifiques de l’autre, rejoignant les effets mis en évidence pour les hétéromères CCR2/CCR5/CXCR4. Ensuite, nous avons montré pour l’hétérodimère CCR7/CCR5 que les ligands de CCR7 sont capables d’inhiber la liaison des ligands spécifiques sur CCR5 mais que l’inverse n’est pas vrai. Enfin, pour l’hétérodimère CCR7/CXCR4, nous n’avons pas pu mettre en évidence d’inhibition croisée, que ce soit dans un sens ou dans l’autre. D’autre part, un effet inhibiteur de CCR7 a également été identifié pour les hétéromères CCR7/CCR5 et CCR7/CXCR4. Nous avons pu montrer que l’expression de CCR7 exerce un effet négatif sur la réponse fonctionnelle de certains récepteurs hétérologues comme CCR5 et CXCR4 mais pas CCR2 ou ChemR23.

L’ensemble de ces données permet de mieux comprendre les interactions entre récepteurs et pourrait mener à l’identification de nouvelles cibles pour les programmes de recherche de molécules thérapeutiques, qui, jusqu’à présent, ciblaient presque exclusivement un seul et unique récepteur.

Etude du mécanisme d’activation du récepteur CCR5 et étude de la relation entre activité constitutive et dimérisation.

De nombreux travaux ont été menés ces dernières années afin de mieux comprendre les mécanismes moléculaires à la base de l’activation des récepteurs couplés aux protéines G (RCPG). Il apparaît que les RCPGs peuvent se trouver dans plusieurs états conformationnels, dont certains sont favorisés par la présence d’agonistes ou d’antagonistes, ou encore d’anticorps reconnaissant des épitopes conformationnels. Certaines mutations peuvent également induire la stabilisation de certaines conformations, actives ou inactives. Pour les RCPGs appartenant à la famille de la rhodopsine, il en a résulté un modèle selon lequel les récepteurs sont maintenus dans une conformation inactive par un ensemble d’interactions ioniques impliquant l’arginine (R3.50) d’un motif DRY conservé, présent à l’extrémité cytosolique du troisième segment transmembranaire. Les interactions responsables de ce qu’on appelle le « DRY-lock » feraient intervenir notamment l’aspartate (D3.49) adjacent de l’arginine et un aspartate ou glutamate (D/E6.30) localisé au sein de l’hélice 6. Selon ce modèle, la liaison d’un agoniste, ainsi que certaines mutations, favoriseraient la rupture de ces interactions ioniques, et une conformation permettant aux récepteurs de se coupler plus efficacement aux protéines G. Des résultats du laboratoire indiquent cependant que ce modèle ne serait pas transposable complètement au récepteur CCR5.

CCR5 possède intrinsèquement une activité constitutive en absence d'agoniste. Cette activité peut être mise en évidence par l'action d'un des antagonistes de CCR5, le TAK-779, qui s'est révélé posséder une activité de type agoniste inverse. D'autre part, CCR5 possède au sein de l'hélice 6 une arginine en position 6.30 et non pas un glutamate ou un aspartate. Une arginine à cette position ne peut donc contribuer au maintien d’une conformation inactive par interaction avec R3.50 .Dans le but de tester le modèle de « DRY-lock » sur CCR5 et de mieux comprendre les interactions moléculaires impliquées dans l’activation du récepteur, plusieurs récepteurs mutants ont été construits au laboratoire. Tout d’abord, l’arginine 3.50 du motif DRY a été mutée en Asn (R3.50N) afin de rompre les interactions ioniques de ce résidu. L’aspartate 3.49 a été muté en Asn (D3.49N) ou en Val (D3.49V), afin de neutraliser une des interactions du « DRY-lock » (Lagane, 2005). L’arginine 6.30 a été mutée d’une part en Asp (R6.30D) ou en Glu (R6.30E), afin de rétablir une possibilité d’interaction avec R3.50, d’autre part en Ala (R6.30A) et en Gln (R6.30Q) afin de mieux cerner le rôle de la charge de l’arginine. Afin de tester l’hypothèse d’interaction entre le résidu 6.30 et le résidu 2.40, l’aspartate 2 .40 a été mutée en Ala (D2.40A) ou en Arg (D2.40R) et des récepteurs présentant les deux mutations ont également construits (D2.40A/R6.30A et D2.40R/R6.30D). L’ensemble des résultats obtenus par l’analyse de ces mutants a permis de montrer que la nature des interactions entre l’extrémité cytosolique des hélices 3 et 6 influence l’activité du récepteur CCR5 (Springael, 2007). Une interaction forte conduit à une forme de récepteur inactif alors qu’une interaction faible s’accompagne d’une augmentation d’activité constitutive. Cette propriété de CCR5 serait donc partagée avec d’autres récepteurs appartenant à la famille de la rhodopsine. Cependant les interactions inter-hélice stabilisant ces conformations seraient différentes pour CCR5. D’autre part, l’étude de la position 2.40 laisse supposer l'importance du résidu aspartate 2.40 dans le maintien d'une conformation permettant l'activité constitutive du récepteur. Nous avons également testé s’il existait une corrélation entre activité constitutive et capacité du récepteur CCR5 à former des dimères, mais les résultats ne nous ont pas permis de mettre en évidence une quelconque relation entre activité et dimérisation.

Doctorat en Sciences biomédicales et pharmaceutiques
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Yamamoto, Takamasa. "Loss of SMAD4 Promotes Lung Metastasis of Colorectal Cancer by Accumulation of CCR1+ Tumor-associated Neutrophils through CCL15-CCR1 Axis". 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225454.

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Guo, Yanping. "The mechanism of Nov (CCN3) function in haematopoiesis". Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:5785f3b9-3206-4bb4-b486-d90cded680f8.

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Haematopoietic stem cells (HSC) are strictly regulated by intrinsic regulators and extrinsic signals from the microenvironment. Nov (CCN3), a matricellular protein of the CCN family, has been reported as a suppressor gene in solid tumours and chronic myeloid leukaemia (CML). Recent study identified Nov as a positive regulator in human cord blood CD34+ stem cells. However, the functions of Nov in haematopoiesis and adult HSC remain largely unknown.

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45

Castan, Laure. "De l'allergie alimentaire à l'asthme : rôle de CCR9". Thesis, Nantes, 2017. http://www.theses.fr/2017NANT1018/document.

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Aujourd’hui, l’allergie est classée 4ème maladie mondiale en termes de morbidité par l’OMS. Les allergies et leur évolution naturelle (marche atopique) sont devenues un problème majeur de santé publique particulièrement dans les pays industrialisés. La marche atopique se manifeste par l’évolution de la dermatite atopique et/ou des allergies alimentaires chez le jeune enfant vers des allergies respiratoires comme l’asthme ou la rhinite allergique plus tard dans l’adolescence. Ce passage pourrait impliquer un chimiotactisme contrôlé par le système chimiokine/récepteurs de chimiokine. A l’aide d’un modèle murin mimant la marche atopique composé d’un modèle d’allergie alimentaire au gluten et d’un modèle aigu d’asthme aux acariens, nous avons pu caractériser le rôle du récepteur de chimiokine CCR9 dans la maladie. Ainsi, des souris déficientes pour le gène de CCR9 montrent un phénotype atténué de la maladie démontrant une implication de ce récepteur dans la pathogénèse. De plus nous avons démontré que CCR9 agirait sur la balance TH17/Treg car sa délétion entraine une augmentation des T régulateurs. En parallèle, dans un modèle d’allergie alimentaire au gluten par sensibilisation cutanée, nous avons analysé l’inflammation intestinale en réponse à plusieurs allergènes. Ces derniers travaux ont été réalisés en collaboration avec un laboratoire du National Food Institute au Danemark. Ainsi, nos résultats démontrent donc l’importance de l’axe intestin-poumon et l’importance d’aborder l’allergie comme une maladie de l’ensemble de l’organisme et non pas comme une maladie d’organe
Allergic diseases are now considered as the fourth worldwide diseases in terms of morbidity, according to the World Health Organization. Allergic diseases and their natural evolution (atopic march) are a major health issue, particularly among developed countries. Indeed, the atopic march is characterized by an evolution from atopic dermatitis and/or food allergies in young children (6 months to 2 years) to respiratory allergies such as asthma and rhinitis later in life. This natural history could involve the chemotaxis, controlled by the chemokine/chemokine receptor system. Using a murine model of atopic march combining a food allergy model to gluten and a model of acute asthma to house dust mite, we analyzed the role of the chemokine receptor CCR9 in the evolution of the disease. Using knock-out mice for CCR9, we observed a decrease of the symptoms of the disease, suggesting a role for this receptor in the pathology. Moreover, we showed that CCR9 seems to act on the Treg/TH17 balance; indeed its deletion induces an increase of the T regulators cell level. Meanwhile, using a food allergy model to gluten based on cutaneous sensitizations, we analyzed the intestinal inflammation to different gluten products. This work was done in collaboration with a lab of the National Food Institute, in Denmark. Our results prove the great significance of the gutlung axis and more generally the importance of approaching the allergy as a whole disease and not as an organ-specific disease

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Castanheira, Fernanda Vargas e. Silva. "Papel protetor do receptor quimiotático CCR5 durante a sepse experimental". Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/17/17133/tde-10012017-100344/.

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A sepse é uma resposta inflamatória sistêmica resultante da inabilidade do sistema imune em controlar uma infecção, onde a taxa de sobrevida está associada ao recrutamento de neutrófilos para o local da infecção. Tem sido demonstrado que a expressão de receptores quimiotáticos pode ser alterada durante a sepse. Neutrófilos de animais naives respondem às quimiocinas CXC, mas são irresponsivos às quimiocinas CC. Entretanto, dados do nosso laboratório mostram que a expressão de CXCR2 é reduzida na sepse, prejudicando a migração de neutrófilos para o foco da infecção. Além disso, ocorre o aparecimento do receptor CCR2 nos neutrófilos, levando à infiltração dessas células no pulmão e outros órgãos. Nesse contexto, o nosso objetivo foi investigar a possível expressão do receptor CCR5 em neutrófilos e seu papel na evolução da sepse. Demostramos que animais sham-operados expressam baixos níveis de CCR5 e altos níveis de CXCR2. Entretanto, sob a condição de sepse experimental induzida por ligação e perfuração do ceco (CLP), neutrófilos circulantes e que migraram para a cavidade peritoneal expressam altos níveis de CCR5 em paralelo com a internalização de CXCR2. Além disso, animais deficientes para CCR5 (CCR5-/-), submetidos à CLP, apresentam diminuição na taxa de sobrevida, redução na migração de neutrófilos para o foco da infecção, aumento da disseminação bacteriana, aumento no infiltrado de neutrófilos no pulmão e aumento nos níveis de marcadores de lesão do coração e rim, quando comparados com animais selvagens (WT). Adicionalmente, a incubação de neutrófilos isolados da medula óssea com LPS aumentou a expressão de CCR5 e os tornou responsivos à MIP-1? (ligante de CCR5), induzindo quimiotaxia. Também demonstramos que o receptor CCR5 possui importante papel durante a adesão de neutrófilos ao endotélio vascular para posterior migração. Em conjunto, esses resultados indicam que durante a CLP, o aumento da expressão de CCR5 em neutrófilos tem um papel protetor, visto que animais CCR5-/- sépticos apresentam reduzida migração de neutrófilos para o foco infeccioso, inflamação sistêmica acentuada e baixa taxa de sobrevivência.
Sepsis is a systemic inflammatory response resulted from the inability of the innate immune system to control infections, being the survival rate associated to the recruitment of neutrophils to the infection site. It has been demonstrated that chemokine receptors expression profile can be altered under sepsis conditions. Neutrophils from naïve mice respond to CXC chemokines, but are usually unresponsive to CC chemokines. However, data from our laboratory show that CXCR2 expression is down regulated, impairing the neutrophil migration to infection focus. In addition, CCR2 appears on the surface of neutrophils, mediating the accumulation of these cells in the lung and other organs. In this context, we aimed to investigate the possible expression of CCR5 receptor on neutrophils and its role on sepsis evolution. We showed that neutrophils from sham mice express high levels of CXCR2 and low levels of CCR5. However, during experimental sepsis, induced by cecal ligation and puncture (CLP), in parallel with CXCR2 internalization, neutrophils from the circulation or from the peritoneal cavity express higher levels of CCR5. Interestingly, deficient mice for the CCR5 receptor (CCR5-/-), undergone to CLP show decreased survival rate, reduction in the neutrophil migration to the site of infection, increase in the numbers of bacteria, increase in the neutrophil infiltration in lung and heart and increase in the levels of markers of injuries in heart and kidney, when compared to wild type mice (WT).In addition, the incubation of bone marrow derivedneutrophils with LPS enhances the expression of CCR5 and renders them responsive to CCL4 (a ligant of CCR5)-induced chemotaxis. Moreover, we demonstrated that CCR5 receptor has an important role during neutrophil adhesion to the vascular endothelium before transmigration. Together, these results indicate that during CLP-induced sepsis, the increase of the expression of CCR5 on neutrophils plays a host protective role, since CCR5-/- mice under sepsis present reduced neutrophil migration to infection focus, high systemic inflammation and low survival rate.

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Costa, Giselle Calasans de Souza. "Investigação de mutações nos genes da CCR5 e langerina e suas associações com a infecção pelo HIV-1". reponame:Repositório Institucional da FIOCRUZ, 2012. https://www.arca.fiocruz.br/handle/icict/4243.

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Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2012-07-25T20:46:06Z No. of bitstreams: 1 Giselle Calasans Investigação de mutacçoes nos genes....pdf: 17299730 bytes, checksum: b9919577a31cf080e622e852dc432578 (MD5)
Made available in DSpace on 2012-07-25T20:46:06Z (GMT). No. of bitstreams: 1 Giselle Calasans Investigação de mutacçoes nos genes....pdf: 17299730 bytes, checksum: b9919577a31cf080e622e852dc432578 (MD5) Previous issue date: 2012
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, Bahia, Brasil
O HIV-1 é o agente etiológico da AIDS. Sabe-se que fatores virais e do hospedeiro podem influenciar na susceptibilidade à infecção pelo vírus e na progressão para a AIDS. Em relação aos fatores intrínsecos ao hospedeiro, tem sido demonstrado que algumas alterações na CCR5 podem afetar sua ligação com a gp120 do HIV-1, influenciando na infecção pelo vírus. Além disso, a proteína Langerina, encontrada na superfície das Células de Langerhans (LCs), apresenta um papel importante em relação à infecção pelo HIV-1, por ter a capacidade de se ligar à gp120 viral através de seu Domínio de Reconhecimento de Carboidrato (CRD). Esta interação permite que as LCs internalizem o vírus em Grânulos de Birbeck, os quais degradam a partícula viral, inibindo a apresentação do HIV-1 para os linfócitos T. Desta forma, diferenças na função da langerina, devido a mutações no promotor do gene Langerina e na região codificante do CRD, por exemplo, podem influenciar a susceptibilidade à infecção pelo HIV-1. Sendo assim, o objetivo principal deste trabalho foi verificar a existência de mutações nas regiões do gene CCR5 que codificam para os domínios N e Cterminal da proteína, no promotor do gene da Langerina e na região codificante do CRD, bem como verificar a existência de possíveis associações entre as mutações encontradas e a infecção pelo HIV-1. Para tal, através de sequenciamento, foi analisado um total de 128 amostras de DNA de indivíduos infectados pelo HIV-1 de Feira de Santana, Bahia e 197 amostras de DNA de indivíduos não-infectados de Salvador, Bahia. Os possíveis sítios de ligação para fatores de transcrição da região promotora do gene da Langerina foram analisados pela ferramenta MatInspector implementada no software Genomatix. Análises físico-químicas, de domínios protéicos potenciais, de predição da estrutura proteica secundária e de modelagem tridimensional proteica foram também realizadas, utilizando diferentes ferramentas de bioinformática. Os estudos na região N-terminal da CCR5 revelaram a existência de uma mutação de sentido trocado no aminoácido 55 (p.L55Q) apenas em indivíduos não-infectados, com uma frequência do alelo mutante de 1,8%. Análises físico-químicas demonstraram que esta mutação aumentou a flexibilidade e a acessibilidade da CCR5 e a modelagem protéica demonstrou que a mutação levou a um pequeno desvio para a direita, bem como alterou levemente a carga eletrostática dessa região da proteína. Foi observada diferença estatisticamente significante entre as frequências alélicas (p=0,039) e genotípicas (p=0,038) da mutação p.L55Q quando os indivíduos infectados e não-infectados foram comparados. Os estudos na região C-terminal da CCR5 demonstraram a existência de três mutações silenciosas em indivíduos infectados pelo HIV- 1: c.3,765C>T, c.3,777A>T e c.3,831A>G. Em relação à análise da região promotora do gene da Langerina, foram observadas três mutações (-577T>C, -517T>C e -160T>C) que, segundo o MatInspector, criaram novos sítios de ligação para fatores de transcrição, tais como: NFAT5, HOXB9.01 e STAT6.01. Entretanto, comparando as frequências alélicas e genotípicas dessas mutações entre os indivíduos infectados e não-infectados, não foi observada diferença estatisticamente significante. Já as análises realizadas na região gênica que codifica o CRD da Langerina demonstraram a existência de três mutações: p.K313I (c.937T>A), c.941C>T (g.4728C>T) e c.983C>T (g.4770C>T) As análises físico-químicas revelaram que a mutação p.K313I aumentou a hidrofobicidade e as hélices transmembranares e diminuiu a hidrofilicidade, a acessibilidade e a antigenicidade da proteína. Entretanto, a presença do alelo mutante não alterou a predição da estrutura secundária da Langerina e não foi observada diferença estatisticamente significante nas frequências alélicas e genotípicas quando os dois grupos estudados foram comparados. Estes resultados sugerem que a mutação p.L55Q, encontrada no domínio N-terminal da CCR5, pode afetar a entrada do HIV-1 na célula. Foi possível, também, observar que as mutações encontradas no gene da Langerina não apresentam associação com a infecção pelo HIV-1. No entanto, é importante que novos estudos sejam realizados com o intuito de compreender melhor o verdadeiro papel da mutação p.L55Q na infecção pelo HIV-1, assim como, novas análises voltadas para a busca de variações no gene da Langerina também devam ser conduzidas, uma vez que este é o primeiro estudo que investiga mutações na Langerina em indivíduos infectados pelo HIV-1.
HIV-1 is the etiologic agent of AIDS. It has been demonstrated that the mechanisms underlying HIV-1 infection and pathogenesis require a combination of viral and host factors. Concerned to the host intrinsic factors, some mutations at CCR5 human gene can affect the interaction between CCR5 protein and HIV-1 gp120, influencing the virus infection. Besides, the Langerin protein, located exclusively on Langerhans cells surface, has an important role in HIV-1 infection due to its ability of binding to gp120 through its Carbohydrate Recognition Domain (CRD). This interaction ables HIV-1 internalization into Birbeck granules, which degrade the virus and prevent LC infection and viral dissemination. So, differences in Langerin function due to mutations at promoter and CRD encoding regions of the human Langerin gene, for example, might influence the susceptibility to HIV-1 infection. Thus, the main purpose of this study is to investigate the existence of mutations at the regions of CCR5 gene that encodes the N- and C-terminal protein domains and at promoter and CRD encoding regions of the human Langerin gene, and finally to stablish possible associations among the observed mutations and HIV-1 infection. Using DNA sequencing, it was studied a total of 128 DNA samples of HIV-1 infected individuals from Feira de Santana, Bahia and 197 DNA samples of HIV-1 non-infected individuals from Salvador, Bahia. The transcription factors binding sites were analyzed using the MatInspector tool implemented in the Genomatix software. Physico-chemical, potential protein domain, prediction of protein secondary structure and protein modeling analyses were also performed, using Bioinformatic tools. The studies into the N-terminal protein domain revealed a new missense mutation at aminoacid 55 (p.L55Q), only in HIV-1 non-infected individuals, with allelic frequency of 1.8%. Physico-chemical analysis revealed that this mutation magnified the flexibility and accessibility profiles and the modeling of CCR5 structures showed that this mutation resulted in a small deviation to the right, as well as, a hydrophobic to hydrophilic property alteration. When HIV-1 infected and non-infected groups were compared, the allelic and genotypic frequencies of the p.L55Q mutation were statistically significant (p=0.039 and 0.038, respectively). Three novel silent mutations were found at encoding region of C-terminal protein domain in the HIV-1 infected individuals: c.3,765C>T, c.3,777A>T and c.3,831A>G. Concerned to the analyses at promoter Langerin region, the studies revealed three mutations: -577T>C, -517T>C and -160T>C. The search for possible transcription factors binding sites using MatInspector demonstrated that these promoter mutations created new binding sites to some transcription factors, such as NFAT5, HOXB9.01 and STAT6.01. However, when HIV- 1 infected and non-infected groups were compared, the allelic and genotypic frequencies of the analyzed promoter sites were not statistically significant. It was observed three mutations at Langerin gene region that encodes to the protein CRD: p.K313I (c.937T>A), c.941C>T (g.4728C>T) and c.983C>T (g.4770C>T). The physico-chemical analysis revealed that the p.K313I polymorphism magnified the hydropathy and transmembrane profiles and reduced the hydrophilicity, accessibility and anitigenicity profiles. However, this mutation did not modify the protein secondary structure prediction and when HIV-1 infected and non-infected individuals were compared, it was not observed a statistically significant difference in the allelic and genotypic frequencies from the p.K313I polymorphism. These results suggest that the p.L55Q mutation can affect HIV-1 infection through CCR5 entry. It was also observed that the mutations detected at the promoter and CRD encoding regions of the human Langerin gene are not associated with HIV-1 infection susceptibility. However, it is important to accomplish future studies in order to better understand the role of the p.L55Q mutation at HIV-1 infection, as well as, conduct new search for variations at Langerin gene that could influence HIV-1 infection, since this is the first study that analyzes mutations at promoter and encoding regions of Langerin gene in a HIV-1 infected population.

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Le, Dréau Gwenvaël. "NOV/CCN3 et système nerveux central : étude du rôle de NOV/CCN3 dans les précurseurs de neurones granulaires et des astrocytes". Paris 6, 2008. http://www.theses.fr/2008PA066063.

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NOV/CCN3 est une protéine sécrétée et multifonctionnelle impliquée dans le développement de différents tissus. Le système nerveux central représentant l’un de ses sites majeurs d’expression au cours du développement, nous avons ainsi émis l’hypothèse que NOV participe au développement de ce tissu. Les résultats obtenus en étudiant le rôle potentiel de NOV durant la phase postnatale de développement du cervelet chez le rat suggèrent que NOV participe à la mise en place des neurones granulaires en inhibant la prolifération et stimulant la migration de leurs précurseurs. Par ailleurs, nous avons observé in vitro que l’expression de NOV est induite au cours de la différenciation de lignées de précurseurs astrocytaires mais que NOV ne semble pas réguler ce processus. Ces résultats soutiennent l’hypothèse que NOV soit impliquée dans le développement du système nerveux central, en particulier dans le devenir de populations neuronales.

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Frank, Sunna [Verfasser]. "Die Bedeutung der Chemokinrezeptoren CCR7 und CXCR4 sowie des CCR7-Liganden CCL21 für die Ausbreitung des duktalen Adenokarzinoms des Pankreas / Sunna Frank". Kiel : Universitätsbibliothek Kiel, 2010. http://d-nb.info/1019984872/34.

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Durkin, Kesta. "The role of CCR4 and CRTI-I2 in asthma". Thesis, University of Southampton, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.484851.

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Chemokine receptors CCR4 and CRTH2, both expressed preferentially on Th2 cells, have been proposed to play an important role in the recruitment of T cells in asthma. The aim of this thesis was to see if fu.rther evidence of the role of CCR4 and its ligands CCLl7 and CCL22 in allergic asthma could be obtained in a combination of descriptive and functional studies. Differences in the expression ofCCR4 and CRTH2 on peripheral blood T cells from healthy non-atopic subjects and mild atopic asthmatic patients were looked for. Also the expression of a selection of activation/memory markers on CD4+ T cells were studied to determine whether there are any differences in the co-expression ofthese markers on CCR4+ T cells between the two subject groups. In order to try and confirm or deny findings in peripheral blood, immunohistochemistry was used to look for any differences in the expression of CCR4 in bronchial biopsy tissue sections of healthy control and asthmatic subjects. A bronchial explant model was used to look for differences in the production of a selection of. cytokines and chemokines (the main focus being on CCLl7 and CCL22) between healthy and house dust mite allergic asthmatics. Bronchial biopsies from healthy and asthmatic subjects were cultured for 24 hr with/without allergen and supernatants were assessed for cytokines and chemokines. The chemotactic responses of a CCR4+ T cell line and peripheral blood T cells, polarised in vitro torwards a Th2 phenotype were assessed; to recombinant chemokines and bronchial biopsy supernatants from asthmatic and healthy subjects stimulated ex vivo with allergen. A final aim, using peripheral blood mononuclear cells from allergic asthmatics was to elucidate whether CCR4+ cells contain allergen specific T cells by assessing lL-5 production following stimulation with allergen of whole PBMC and PBMC depleted of CCR4+ cells. There were no significant differences between healthy subjects and asthmatic patients in levels of expression of CCR4 and CRTH2 on CD4+ T cells and expression of . activation/memory markers on either CD4+ or CCR4+ICD4+ T cells. Sections of bronchial biopsies from healthy or asthmatic subjects were found not to contain any CCR4 positive cells. Analysis of bronchial explant supernatants showed significantly decreased lL-2 production in allergen-challenged when compared to unchallenged explants in healthy controls. Allergen induced a significant increase in IL-5 (p=<0.001) in asthmatic explants; this was significantly higher when compared to lL-5 measured in stimulated explants from healthy controls (p=

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