Philadelphia-negative myeloproliferative neoplasms as disorders marked by cytokine modulation

Background: Cytokines are key immune mediators in physiological and disease processes, whose increased levels have been associated with the physiopathology of hematopoietic malignancies, such as myeloproliferative neoplasms. Methods: This study examined the plasma cytokine profiles of patients with essential thrombocythemia, primary myelofibrosis, polycythemia vera and of healthy subjects, and analyzed correlations with JAK2 V617F status and clinical-hematological parameters. Results: The proinflammatory cytokine levels were increased in myeloproliferative neoplasm patients, and the presence of the JAK2 V617F mutation was associated with high IP-10 levels in primary myelofibrosis patients. Conclusions: Essential thrombocythemia, primary myelofibrosis, and polycythemia vera patients exhibited different patterns of cytokine production, as revealed by cytokine network correlations. Together, these findings suggest that augmented cytokine levels are associated with the physiopathology of myeloproliferative neoplasms.

Effect of hypomethylating agents treatment: modulation of monocyte and macrophage functions and possible therapeutic repercussion

A utilização de estratégias terapêuticas baseadas na manipulação das alterações epigenéticas tem despertado interesse de diferentes grupos de pesquisa. Dentre as epidrugs, os agentes hipometilantes tem um papel bem estabelecido no tratamento de pacientes com síndrome mielodisplásica e outras neoplasias hematológicas. Além dos efeitos diretos sobre as células tumorais, existem várias evidências que indicam que a as células do sistema imune sejam diretamente afetadas pelo tratamento, com efeitos demonstrados sobre a função de células NK, linfócitos e células dendríticas. Porém, pouco foi descrito sobre a modulação exercida pelos agentes hipometilantes sobre a função de monócitos e macrófagos humanos. Nesse contexto, o objetivo deste trabalho foi definir os efeitos do tratamento com Decitabina no fenótipo e funções de monócitos e macrófagos e a possível imunomodulação em pacientes com Síndrome Mielodisplásica (SMD) tratados Azacitidina. Inicialmente, monócitos foram isolados de indivíduos saudáveis (n=30) e tratados com 5?M de Decitabina por 24 horas. Após o tratamento, as células foram infectadas in vitro com Mycobacterium tuberculosis (Mtb) para avaliação dos efeitos sobre as funções celulares importantes no controle da infecção. Os monócitos também foram diferenciados em macrófagos na presença do agente hipometilante para determinação do perfil de polarização celular, através de expressão gênica e de marcadores de superfície. O tratamento com Decitabina induziu aumento na fagocitose e liberação de IL-8, porém prejudicou a atividade microbicida dos monócitos em resposta ao Mtb. Além disso, observou-se que o tratamento favoreceu a polarização de macrófagos para o perfil M2, determinado por alterações morfológicas e aumento da expressão de CD206 e ALOX15. Funcionalmente, essas células demonstraram redução do controle da infecção, apesar de produzirem mediadores inflamatórias de maneira semelhante às células não tratadas. Apesar disso, quando co-cultivados com linfócitos em modelo de granuloma in vitro, Decitabina promoveu redução na produção de IL-1?, TNF-? e IFN-?, com produção semelhante de IL-10, sugerindo um efeito imunomodulador que poderia induzir mecanismos reguladores da resposta imune. Por fim, para avaliação da imunomodulação em pacientes com SMD, foram recrutados 17 indivíduos em tratamento de suporte e 4 pacientes em tratados com o agente hipometilante Azacitidina. A partir de amostras de sangue periférico, o plasma foi separado para quantificação de mediadores imunológicos e a fração celular foi utilizada para da expressão gênica e isolamento de monócitos para avaliações funcionais após infecção por Mtb. Foram observadas alterações na quantificação de mediadores no plasma, com aumento de IL-2, IL-4, IL-12, IL-17, IFN-?, TNF-? e IL-1? nos pacientes em tratamento com azacitidina em relação aos não tratados, restabelecendo níveis semelhantes ao grupo controle, além de aumento de IL-8 e IP-10 quando comparados aos indivíduos saudáveis. Em relação à função dos monócitos, observou-se aumento na produção de IL-8 e IL-12 após a infecção por Mtb, porém nenhuma modulação sobre a função fagocítica e microbicida foi observada nestes pacientes. Assim, os dados sugerem que os agentes hipometilantes exercem modulação importante sobre a função de monócitos e macrófagos, podendo influenciar no padrão de resposta e, desta forma, constituindo uma potencial estratégia terapêutica de manipulação do sistema imuneThe use of therapeutic strategies based on the manipulation of epigenetic alterations has raised interest of different research groups. Among the epidrugs, hypomethylating agents have a well-established role in the treatment of myelodysplastic syndrome and other haematological malignancies. In addition to direct effects on tumor cells, there are several evidences indicating that immune cells are directly affected by treatment, as already demonstrated for NK cell, lymphocyte and dendritic cell function. However, few studies have been developed on human monocytes and macrophages. In this context, we aimed to define the treatment effects of Decitabine on the phenotype and functions of monocytes and macrophages and the possible immunomodulation AZA-treated Myelodysplastic Syndrome (MDS) patients. Initially, monocytes were isolated from healthy subjects (n = 30) and treated with 5?M Decitabine for 24 hours. After treatment, cells were infected in vitro with Mycobacterium tuberculosis (Mtb) to evaluate the effects on cellular functions important to infection control. Monocytes were also differentiated into macrophages in the presence of the hypomethylating agent to determine the cell polarization profile, through gene expression and surface markers. Treatment with Decitabine induced increased phagocytosis and IL-8 release but impaired the microbicidal activity of monocytes in response to Mtb. In addition, it was observed that the treatment favored the polarization of macrophages to the M2 profile, determined by morphological alterations and increased expression of CD206 and ALOX15. Functionally, these cells showed reduced infection control, despite producing inflammatory mediators in a manner similar to untreated cells. However, when co-cultured with lymphocytes during an in vitro granuloma model, Decitabine promotes a reduction in the production of IL-1?, TNF-? and IFN-?, with similar production of IL-10, suggesting an immunomodulatory effect that could lead to mechanisms of immune response regulation. Finally, for evaluation of immunomodulation in MDS patients, 17 individuals undergoing supportive treatment and 4 AZA-treated patients were recruited. From peripheral blood samples, plasma was separated for the quantification of immunological mediators and the cell fraction was used for gene expression and monocyte isolation for functional evaluations following Mtb infection. We identified alteration in the quantification of plasma immune mediators, with increased levels of IL-2, IL-4, IL-12, IL-17, IFN-?, TNF-? and IL-1? in AZA-tretaed patients, to similar levels to the control group, in addition to an increase of IL-8 and IP-10 when compared to healthy individuals. Regarding monocyte function, IL-8 and IL-12 production increased after Mtb infection, but no modulation of phagocytic and microbicidal function was observed in these patients. Thus, the data suggest that hypomethylating agents exert important modulation on the function of monocytes and macrophages, and may influence the response pattern and, thus, constitute a potential therapeutic strategy for the manipulation of the immune syste

Alterations in the inflammatory response and epigenetic changes as indicators of clinical stages of pulmonary tuberculosis

A tuberculose representa um sério problema de Saúde Pública para o Brasil e o mundo. Estima-se que cerca de um terço da população mundial seja infectado pelo bacilo, sendo que 95% destes indivíduos desenvolvem a forma latente da tuberculose. Dessa forma, encontrar um marco entre o que faz o bacilo Mycobacterium tuberculosis (Mtb) induzir no hospedeiro uma doença ativa ou sua forma latente tem sido o objeto de estudo de diferentes grupos de pesquisa. Neste contexto, o objetivo deste estudo foi correlacionar mudanças na resposta imune desenvolvida por monócitos de pacientes em diferentes estágios da tuberculose pulmonar com alterações epigenéticas, e então com aspectos clínicos de cada estágio. Nosso estudo incluiu 17 pacientes com a doença ativa, 14 indivíduos com tuberculose latente e 16 controles não infectados. A partir de sangue periférico, foi coletado plasma para quantificação de citocinas, sCD163 e sCD14. Complementarmente, monócitos foram purificados para avaliação da ativação imune através da quantificação de citocinas e espécies reativas de oxigênio mediante estimulação in vitro com Mtb inativado por calor, bem como PCR array para detectar expressão de enzimas de repressão ou ativação epigenética entre os grupos e avaliação do padrão de metilação global. Pacientes com tuberculose ativa apresentaram níveis plasmáticos elevados de citocinas como IL-6, IP-10, TNF-, IL-12, bem como IL-5. Dentre as citocinas, TNF-, IL-5, IL-6 e IP-10 permitiram diferenciar indivíduos latentes dos pacientes com tuberculose ativa. Também demostramos que maior número de correlações entre as citocinas foi observado nos pacientes com a doença ativa, indicando um estado geral mais ativado do sistema imune. Níveis plasmáticos de sCD163 e sCD14 estavam elevados nos pacientes quando comparados com indivíduos latentes e controles, e poderiam também diferenciar a tuberculose ativa. Tais níveis aumentados correlacionam-se com o estado ativado de monócitos dos pacientes, que produzem maior quantidade de espécies reativas de oxigênio e tendem a produzir mais citocinas inflamatórias, como IL-6 e TNF-. Este perfil parece ser modulado por modificações epigenéticas, uma vez que monócitos de pacientes com tuberculose pareceram mostrar menor expressão de enzimas responsáveis por mudanças relacionadas à repressão e maior expressão de enzimas relacionadas à ativação da expressão gênica, bem como redução no padrão global de metilação do DNA genômico, sugerindo maior atividade destas células. Finalmente, uma vez que pacientes com tuberculose apresentaram níveis elevados de alguns mediadores, correlacionamos estes com o grau de lesão pulmonar, e consequentemente, com a gravidade da doença. Nós mostramos que dentre os marcadores, TNF- e sCD163 correlacionaram-se positivamente com a progressão da tuberculose. Assim, concluímos que em relação aos indivíduos controle e com TB latente, os pacientes com tuberculose ativa apresentam o sistema imune em maior estado de ativação, e ainda, que alterações epigenéticas podem ser as responsáveis pela modulação observada. Dentre os fatores aumentados nos pacientes, TNF-, IL-6, IP-10, IL-5, sCD163 e sCD14 podem diferenciar os pacientes com doença ativa dos demais indivíduos analisados, e ainda sCD163 e TNF- podem atuar como indicativos da gravidade da tuberculose.Tuberculosis is a major public health problem for Brazil and worldwide. It is estimated that about one third of the world population is infected with the bacillus, and 95% of those individuals have the condition in the latent form. Thus, finding a hallmark between what makes the Mycobacterium tuberculosis (Mtb) induces in the host an active disease or its latent form has been the subject of different research groups. In this context, the objective of this study was to correlate changes in the immune response developed by monocytes from patients at different stages of pulmonary tuberculosis with epigenetic alterations and then, with clinical aspects of each stage. Our study included 17 patients with active disease, 14 individuals with latent tuberculosis and 16 uninfected controls. From the peripheral blood, plasma was collected for cytokine and CD163s, sCD14 quantification. In addition, monocytes were purified to evaluation of the immune activation through cytokine and reactive oxygen species quantification upon in vitro stimulation with heat-killed Mtb, as well as PCR array for epigenetic repression or activation enzymes were performed to detect epigenetic changes between the groups and evaluation of the global methylation profile. We have shown that patients with active tuberculosis have increased plasma levels of cytokines such as IL-6, IP-10, TNF-, IL-12, as well as IL-5. Among these cytokines, TNF-, IL-5, IL-6 and IP-10 could differentiate latent-infected from TB patients. We also showed that patients with active disease presented higher number of correlations between plasma cytokines, indicating an activated state of the immune system. The plasma levels of sCD163 and sCD14 were more elevated in patients than latent and control individuals, and might differentiate TB active from these other groups. These increased levels of biomarkers correlate with the activated state of monocytes from patients, which produced raised quantities of reactive oxygen species and tended to produced more pro-inflammatory cytokines, such as IL-6 and TNF-. This profile seems to be modulated by epigenetic modifications, since monocytes from patients with tuberculosis seemed to show reduced expression of enzymes responsible for changes related to repression and enhanced expression of enzymes responsible for activation of gene expression, and in addition, these patients presented reduction in the percentage of global methylation of genomic DNA, suggesting increased activity of these cells when compared to the other groups. Finally, once tuberculosis patients presented increased levels of some mediators, we correlated these with the degree of lung injury, and consequently tuberculosis severity. We have showed that TNF- and sCD163 were correlated with disease progression in tuberculosis. In conclusion, we demonstrated that patients with active tuberculosis are more activated than the other groups, and epigenetic alterations might be responsible for these modulations, indicated by the alteration of the enzymes and methylation pattern analyzed. Among the cytokines/chemokines differentially expressed TNF-, IL-6, IP-10, IL-5 and monocyte activation markers, sCD163 and sCD14 could discriminate between active disease from others, and also sCD163 and TNF- could indicate tuberculosis severity

Efeito das baixas concentrações de agentes antineoplásicos sobre linfócitos humanos de sangue periférico

Our previous studies have shown that low concentrations (noncytotoxics) of antineoplastic agents modulate positively the dendritic cells, favoring their in vitro maturation and improving their antigen presenting function. The effects on colorectal cancer cells (HCT-116) were also investigated and we have observed an increased immunogenicity and susceptibility to cytotoxic T cells. Thereby, this study aimed to investigate the effect of 5-fluorouracil (5-FU) an azacitidine (AZA), in minimum effective and noncytotoxic concentrations on lymphocytes of healthy donors. In this study we have analyzed the cytotoxic effect of drugs at these concentrations as well as the proliferative ability of lymphocytes. In vitro production of IL-10 and IFN-γ has been also evaluated. We have observed that low concentrations of those chemotherapeutic agents are not cytotoxic for lymphocytes. However, the minimum effective concentrations (5-FU: 0,410±0,088 e AZA: 0,757±0,233; p<0, 05) have reduced the cell number. Proliferative activity of allogeneic lymphocytes in a mixed reaction (MLR) was not affected by the treatment. The cytokine production was not affected by the treatments, either. In conclusion, low concentrations of 5-FU and AZA has no deleterious effects on human peripheral blood lymphocytes and seems to be safe for combinatory administration with DC vaccinesEstudos prévios do grupo mostraram que baixas concentrações (não tóxicas) de agentes antineoplásicos modulam positivamente as células dendríticas, favorecendo sua maturação in vitro e melhorando sua função de apresentação de antígenos. Os efeitos sobre células de câncer colorretal (HCT-116) também foram investigados e observou-se aumento da imunogenecidade e suscetibilidade às células T. Dessa forma, o objetivo deste trabalho foi investigar o efeito causado pela administração de 5-fluorouracil (5-FU) e azacitidina (AZA), nas concentrações efetiva mínima e não tóxica sobre linfócitos de doadores saudáveis. Neste estudo, analisamos o efeito citotóxico das drogas nestas concentrações assim como a habilidade proliferativa dos linfócitos . A produção in vitro de IL-10 e IFN- γ também foi avaliada. Observamos que baixas concentrações dos agentes quimioterápicos não são tóxicos para os linfócitos. Entretanto, as concentrações efetivas mínimas (5-FU: 0,410±0,088 e AZA: 0,757±0,233; p<0, 05) reduziram o número de células. A atividade proliferativa de linfócitos alogênicos na reação mista de linfócitos (MLR) não foi afetada pelo tratamento. A produção de citocinas também não foi afetada pela administração das drogas. Em conclusão, baixas concentrações de 5-FU e AZA não apresentaram efeitos deletérios sobre linfócitos humanos de sangue periférico e parecem ser seguras para administração em associação com vacinas de D

Decitabine Promotes Modulation in Phenotype and Function of Monocytes and Macrophages That Drive Immune Response Regulation

Decitabine is an approved hypomethylating agent used for treating hematological malignancies. Although decitabine targets altered cells, epidrugs can trigger immunomodulatory effects, reinforcing the hypothesis of immunoregulation in treated patients. We therefore aimed to evaluate the impact of decitabine treatment on the phenotype and functions of monocytes and macrophages, which are pivotal cells of the innate immunity system. In vitro decitabine administration increased bacterial phagocytosis and IL-8 release, but impaired microbicidal activity of monocytes. In addition, during monocyte-to-macrophage differentiation, treatment promoted the M2-like profile, with increased expression of CD206 and ALOX15. Macrophages also demonstrated reduced infection control when exposed to Mycobacterium tuberculosis in vitro. However, cytokine production remained unchanged, indicating an atypical M2 macrophage. Furthermore, when macrophages were cocultured with lymphocytes, decitabine induced a reduction in the release of inflammatory cytokines such as IL-1β, TNF-α, and IFN-γ, maintaining IL-10 production, suggesting that decitabine could potentialize M2 polarization and might be considered as a therapeutic against the exacerbated immune response

Natural Products from Cyanobacteria with Antimicrobial and Antitumor Activity

Cyanobacteria are an important source of structurally bioactive metabolites, with cytotoxic, antiviral, anticancer, antimitotic, antimicrobial, specific enzyme inhibition and immunosuppressive activities. This study focused on the antitumor and antimicrobial activities of intra and extracellular cyanobacterial extracts. A total of 411 cyanobacterial strains were screened for antimicrobial activity using a subset of pathogenic bacteria as target. The in vitro antitumor assays were performed with extracts of 24 strains tested against two murine cancer cell lines (colon carcinoma CT-26 and lung cancer 3LL). Intracellular extracts inhibited 49 and 35% of Gram-negative and Gram-positive pathogenic bacterial growth, respectively. Furthermore, the methanolic intracellular extract of Cylindrospermopsis raciborskii CYP011K and Nostoc sp. CENA69 showed inhibitory activity against the cancer cell lines. The extracellular extract from Fischerella sp. CENA213 and M. aeruginosa NPJB-1 exhibited inhibitory activity against 3LL lung cancer cells at 0.8 mu g ml(-1) and Oxynema sp. CENA135, Cyanobium sp. CENA154, M. aeruginosa NPJB-1 and M. aeruginosa NPLJ-4 presented inhibitory activity against CT26 colon cancer cells at 0.8 mu g ml(-1). Other extracts were able to inhibit 3LL cell-growth at higher concentrations (20 mu g ml(-1)) such as Nostoc sp. CENA67, Cyanobium sp. CENA154 and M. aeruginosa NPLJ-4, while CT26 cells were inhibited at the same concentration by Nostoc sp. CENA67 and Fischerella sp. CENA213. These extracts presented very low inhibitory activity on human peripheral blood lymphocytes. The results showed that some cyanobacterial strains are a rich source of natural products with potential for pharmacological and biotechnological applications.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Dysregulated Immune Activation in Second-Line HAART HIV+ Patients Is Similar to That of Untreated Patients

Submitted by Nuzia Santos ([email protected]) on 2016-07-08T19:04:08Z No. of bitstreams: 1 ve_Espíndola_Milena_ Dysregulated_CPqRR_2015.PDF: 2923864 bytes, checksum: 446f6e96e03dda9a27eb6b0a5354e683 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2016-07-08T19:23:26Z (GMT) No. of bitstreams: 1 ve_Espíndola_Milena_ Dysregulated_CPqRR_2015.PDF: 2923864 bytes, checksum: 446f6e96e03dda9a27eb6b0a5354e683 (MD5)Made available in DSpace on 2016-07-08T19:23:26Z (GMT). No. of bitstreams: 1 ve_Espíndola_Milena_ Dysregulated_CPqRR_2015.PDF: 2923864 bytes, checksum: 446f6e96e03dda9a27eb6b0a5354e683 (MD5) Previous issue date: 2015Made available in DSpace on 2016-07-22T13:23:08Z (GMT). No. of bitstreams: 3 ve_Espindola_Milena_ Dysregulated_CPqRR_2015.PDF.txt: 54746 bytes, checksum: 58738f3da9d5723ee829eddbd428183b (MD5) ve_Espindola_Milena_ Dysregulated_CPqRR_2015.PDF: 2923864 bytes, checksum: 446f6e96e03dda9a27eb6b0a5354e683 (MD5) license.txt: 2991 bytes, checksum: 5a560609d32a3863062d77ff32785d58 (MD5) Previous issue date: 2015Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil.Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil.Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil.Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil.Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil.Universidade Federal de Uberlândia. Laboratório de Bioinformática e Análises Moleculares. Patos de Minas, MG, Brasil.Universidade Federal de Uberlândia. Laboratório de Bioinformática e Análises Moleculares. Patos de Minas, MG, Brasil.Universidade de São Paulo. Faculdade de Medicina de Ribeirão Preto. Ribeirão Preto, SP, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Rene Rachou. Laboratório de Biomarcadores para Diagnostico e Monitoramento. Belo Horizonte, MG, Brasil.Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil.BACKGROUND: Successful highly active antiretroviral therapy (HAART) has changed the outcome of AIDS patients worldwide because the complete suppression of viremia improves health and prolongs life expectancy of HIV-1+ patients. However, little attention has been given to the immunological profile of patients under distinct HAART regimens. This work aimed to investigate the differences in the immunological pattern of HIV-1+ patients under the first- or second-line HAART in Brazil. METHODS: CD4+ T cell counts, Viral load, and plasma concentration of sCD14, sCD163, MCP-1, RANTES, IP-10, IL-1β, IL-6, TNF-α, IL-12, IFN-α, IFN-γ, IL-4, IL-5, and IL-10 were assessed for immunological characterization of the following clinical groups: Non-infected individuals (NI; n = 66), HIV-1+ untreated (HIV; n = 46), HIV-1+ treated with first-line HAART (HAART 1; n = 15); and HIV-1+ treated with second-line HAART (HAART 2; n = 15). RESULTS: We found that the immunological biosignature pattern of HAART 1 is similar to that of NI individuals, especially in patients presenting slow progression of the disease, while patients under HAART 2 remain in a moderate inflammatory state, which is similar to that of untreated HIV patients pattern. Network correlations revealed that differences in IP-10, TNF-α, IL-6, IFN-α, and IL-10 interactions were primordial in HIV disease and treatment. Heat map and decision tree analysis identified that IP-10>TNF-α>IFN-α were the best respective HAART segregation biomarkers. CONCLUSION: HIV patients in different HAART regimens develop distinct immunological biosignature, introducing a novel perspective into disease outcome and potential new therapies that consider HAART patients as a heterogeneous group

The influence of dehydroepiandrosterone on effector functions of neutrophils

Dehydroepiandrosterone (DHEA) is a steroid hormone secreted by the adrenal glands, gonads and brain. It is a precursor to sex hormones and also is known to have immune modulatory activity. However, little is known about the relationship between DHEA and neutrophils and thus our study evaluates the influence of DHEA in the effector functions of neutrophils. Human neutrophils were treated&nbsp;in vitro&nbsp;with DHEA and further infected with&nbsp;Salmonella enterica&nbsp;serovar Typhimurium. The treatment of neutrophils with 0.01 μM of DHEA increased the phagocytosis of&nbsp;Salmonella&nbsp;independent of TLR4 as the treatment did not modulate the TLR4 expression. Additionally, DHEA caused a decrease in ROS (reactive oxygen species) production and did not influence the formation of the neutrophil extracellular trap (NET). Steroid treated neutrophils, infected or stimulated with LPS (lipopolysaccharide), showed reduced production of IL-8, compared to untreated cells. Also, the protein levels of p-NFκB were decreased in neutrophils treated with DHEA, and this reduction could explain the reduced levels of IL-8. These results led us to conclude that the steroid hormone DHEA has important modulatory functions in neutrophils

Philadelphia-negative myeloproliferative neoplasms as disorders marked by cytokine modulation

Background: Cytokines are key immune mediators in physiological and disease processes, whose increased levels have been associated with the physiopathology of hematopoietic malignancies, such as myeloproliferative neoplasms. Methods: This study examined the plasma cytokine profiles of patients with essential thrombocythemia, primary myelofibrosis, polycythemia vera and of healthy subjects, and analyzed correlations with JAK2 V617F status and clinical-hematological parameters. Results: The proinflammatory cytokine levels were increased in myeloproliferative neoplasm patients, and the presence of the JAK2 V617F mutation was associated with high IP-10 levels in primary myelofibrosis patients. Conclusions: Essential thrombocythemia, primary myelofibrosis, and polycythemia vera patients exhibited different patterns of cytokine production, as revealed by cytokine network correlations. Together, these findings suggest that augmented cytokine levels are associated with the physiopathology of myeloproliferative neoplasms. Keywords: Ph-negative myeloproliferative neoplasms, Inflammation, Plasma cytokines, JAK2 V617

Epigenetic alterations are associated with monocyte immune dysfunctions in HIV-1 infection

Submitted by Nuzia Santos ([email protected]) on 2019-06-27T16:53:13Z No. of bitstreams: 1 Epigenetic alterations are associated.pdf: 2714750 bytes, checksum: 3a70c053abf28c73d1c3781061fcf350 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2019-06-27T16:57:54Z (GMT) No. of bitstreams: 1 Epigenetic alterations are associated.pdf: 2714750 bytes, checksum: 3a70c053abf28c73d1c3781061fcf350 (MD5)Made available in DSpace on 2019-06-27T16:57:54Z (GMT). No. of bitstreams: 1 Epigenetic alterations are associated.pdf: 2714750 bytes, checksum: 3a70c053abf28c73d1c3781061fcf350 (MD5) Previous issue date: 2018Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil.Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil.Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil.Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil.Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil.Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil.Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil.Universidade Federal de Uberlândia. Laboratório de Bioinformática e Análises Moleculares. Patos de Minas, MG, Brasil.Universidade Federal de Uberlândia. Laboratório de Bioinformática e Análises Moleculares. Patos de Minas, MG, Brasil.Fundação Oswaldo Cruz. Instituto Rene Rachou. Laboratório de Biomarcadores para Diagnostico e Monitoramento. Belo Horizonte, MG, Brasil.Universidade de São Paulo. Faculdade de Medicina de Ribeirão Preto. Ribeirão Preto, SP, Brasil.Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil.Monocytes are key cells in the immune dysregulation observed during human immunodeficiency virus (HIV) infection. The events that take place specifically in monocytes may contribute to the systemic immune dysfunction characterized by excessive immune activation in infected individuals, which directly correlates with pathogenesis and progression of the disease. Here, we investigated the immune dysfunction in monocytes from untreated and treated HIV + patients and associated these findings with epigenetic changes. Monocytes from HIV patients showed dysfunctional ability of phagocytosis and killing, and exhibited dysregulated cytokines and reactive oxygen species production after M. tuberculosis challenge in vitro. In addition, we showed that the expression of enzymes responsible for epigenetic changes was altered during HIV infection and was more prominent in patients that had high levels of soluble CD163 (sCD163), a newly identified plasmatic HIV progression biomarker. Among the enzymes, histone acetyltransferase 1 (HAT1) was the best epigenetic biomarker correlated with HIV - sCD163 high patients. In conclusion, we confirmed that HIV impairs effector functions of monocytes and these alterations are associated with epigenetic changes that once identified could be used as targets in therapies aiming the reduction of the systemic activation state found in HIV patients