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BACKGROUND: Since failure in recognition of abnormal cells by the immune system has an important role in bladder cancer development and progression, this study aimed to evaluate whether PD1 (c.627+252C>T) and PD1.5 (c.804C>T) single-nucleotide variants (SNVs) in PDCD1 gene, enrolled in modulation of T lymphocyte activity, influence risk, clinicopathological aspects, and outcome of non-muscle-invasive bladder cancer (NMIBC) patients. MATERIAL AND METHODS: DNA genotyping by real-time polymerase chain reaction was offered to 160 non muscle invasive bladder cancer (NMIBC) patients and 250 controls. One hundred and twenty-seven patients treated with bladder transurethral resection and intravesical bacillus Calmette-Guérin were enrolled in survival analyses. RESULTS: Individuals with PD1.5 CC genotype had 2.3-fold increased risk of developing NMIBC. Similar genotype and haplotype frequencies were seen in patients stratified by clinicopathological aspects. Patients with T allele, CT or TT plus CT or TT genotype and TT haplotype of PD1 and PD1.5 SNVs had up to 4.0-times greater chances of presenting NMIBC relapse and death by any cause than the remaining patients, but analysis of NMIBC specific survival was not possible in study due to the small number of patients evolving to death during follow up. CONCLUSIONS: Our data presented for the first time, preliminary evidence that inherited abnormality in regulation of T lymphocyte activity alters NMIBC risk.
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We aimed to investigate the effects of ethanol and its metabolites (ß-hydroxybutyrate and sodium acetate) in the effector functions of macrophages in response to Paracoccidioides brasiliensis yeast cells and to determine their influence in the development of the adaptive response. Purified peripheral blood monocytes were differentiated into macrophages and were treated with ethanol, ß-hydroxybutyrate, and sodium acetate, and stimulated with P. brasiliensis yeast cells and evaluated for their phenotypic characteristics, functional activity, and capability to induce T cells activation/differentiation. We found that the ethanol treatment diminished the expression of HLA-AB, HLA-DR, CD80, and CD86, modulating the expression of dectin-1, as well as Syk phosphorylation. The ethanol treatment increased the phagocytic activity, expression of CD206, and IL-10 production; however, reduced ROS production, fungicidal activity, caspase-1 cleavage, and IL-1ß and IL-6 production. Our data also showed that the presence of ethanol reduced the differentiation of Th1 and Th17 cells and increased the frequency of Th2 cells. Our results indicated that ethanol exposure could suppress effector function of macrophages, possibly leading to the polarization of M2 macrophages. The ethanol modulates the expression of costimulatory and antigen-presentation molecules and interferes with the NLRP3 inflammasome. Altogether, these alterations affect the development of the adaptive response, decreasing the frequency of IL-17, IL-22, and IFN- γ producing cells, and increasing the frequency of IL-4 producing cells. Therefore, exposure to ethanol can impair the capability of macrophages to exert their effector functions and activate the acquired response related to resistance to P. brasiliensis infection.
Assuntos
Etanol/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Paracoccidioides/fisiologia , Paracoccidioidomicose/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Antifúngicos/farmacologia , Complexo CD3/análise , Caspase 1/análise , Citocinas/análise , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Receptores de Lipopolissacarídeos/análise , Macrófagos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Peróxidos/metabolismo , Fagocitose/efeitos dos fármacosRESUMO
OBJECTIVES: To investigate the involvement of NLRP3 in the effector functions of human dendritic cells (DCs) in response to Paracoccidioides brasiliensis yeast cells (Pb) and to evaluate its role in the modulation of the adaptive immune response. METHODS: DCs were differentiated from purified peripheral blood monocytes and analyzed in relation to the participation of TLR-2, dectin-1, and Syk in Pb recognition, as well as, the indirect mechanisms (Reactive Oxygen Species production, endosome acidification, or K+ efflux) involved in NLRP3 inflammasome activation after the stimulus with Pb. Additionally, we analyzed the role of NLRP3 in the activation of T cells. RESULTS: Our results demonstrated that the NLRP3 inflammasome activation and cytokines production by DCs are dependent on ROS generation, endosome acidification, and K+ efflux and involve the Pb recognition by dectin-1 and Syk phosphorylation. Our data also demonstrate that the NLRP3 inflammasome is essential for the activation/expansion of Th1/Th17 cells and its inhibition leads to an increased frequency of Th2 and Treg cells. CONCLUSION: Altogether our data indicated that activation of NLRP3 presents an important role in both the induction of the initial inflammatory response and in the development of the acquired immune response associated with resistance to infection.
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Células Dendríticas/fisiologia , Inflamassomos/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Paracoccidioides/imunologia , Células Th17/fisiologia , Anticorpos , Diferenciação Celular , Citocinas/genética , Citocinas/metabolismo , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/imunologia , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Fosforilação , Quinase Syk/efeitos dos fármacos , Quinase Syk/genética , Quinase Syk/metabolismoRESUMO
Besides interleukin (IL)-1ß and IL-18, the newly described cytokines of IL-1 family IL-33 and IL-37 can contribute to the differentiation and maintenance of different population of T cells. IL-33 acts as an allarmin and promotes a predominant Th2 inflammatory response, whereas IL-37 plays an important role as an antagonist of inflammation. In paracoccidioidomycosis (PCM), caused by the dimorphic fungi Paracoccidioides brasiliensis and P. lutzii, it has been shown that the acquired immune responses are associated with the diverse clinical manifestations. The severe and disseminated forms (acute form [AF] and multifocal chronic form [CF-MF]) are characterized by high Th2 cytokines and antibody production, impaired cellular immune response, and eosinophilia. In contrast, in the localized form (unifocal chronic form [CF-UF]), the cellular immune response is preserved, with high production of Th1 and Th17 cytokines, and low antibody titers. This study aimed to quantify interleukin-1 family cytokines (IL-1ß, IL-18, IL-37, IL-33, and the soluble IL-33 receptor sST2) in sera of patients presenting different clinical forms of PCM before, during, and after antifungal treatment, as well as to analyze the expression of these cytokines in lesions of PCM patients. We found that AF patients presented high serum levels of IL-1ß, IL-18, IL-33, sST2, and IL-37, and that these cytokines are strongly expressed in lymph nodes lesions. Furthermore, antifungal therapy resulted in the diminution of circulating cytokines and sST2 levels in all groups of patients. These results indicate that, besides IL-1ß and IL-18, IL-33, IL-37, and sST2 can be associated with the disease activity and severity.
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Antifúngicos/uso terapêutico , Interleucina-1/sangue , Paracoccidioidomicose/tratamento farmacológico , Paracoccidioidomicose/imunologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Interleucina-18/sangue , Interleucina-1beta/sangue , Interleucina-33/sangue , Masculino , Pessoa de Meia-Idade , Paracoccidioidomicose/sangue , Paracoccidioidomicose/microbiologia , Índice de Gravidade de Doença , Adulto JovemRESUMO
OBJECTIVES: Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the dimorphic fungus Paracoccidioides brasiliensis that presents two main clinical forms: the adult form (AF) and the juvenile form (JF); and an asymptomatic form denominated PCM-infection (PI). These forms of PCM are related to the immune response developed after infection, which has been associated with Th1 and Th2 responses. However, some PCM characteristics cannot be explained by this balance. In this study we aimed to complement the characterization of the immune response in PCM, including the newly described T cells subpopulations (Th17, Th9 and Th22). METHODS: We analyzed the expression of cytokines and transcription factors characteristics of these different subpopulations of CD4(+) T cells in PBMCs from PCM patients and a PI group. RESULTS: The results showed that the PI group presented a predominant Th1 response; that JF patients were characterized by a mixed Th2/Th9 response; and AF patients were characterized by a predominant Th17/Th22 response, as well as substantial participation of Th1 cells. CONCLUSIONS: These results contribute to the existing knowledge on the immune responses associated with resistance or susceptibility to the P. brasiliensis infection, and thus could lead to the development of new strategies for patient management.