RESUMO
This study explored the correlation between interleukins (IL)-12, IL-18, and IL-21 and the viral load in patients with chronic hepatitis B virus (HBV). A total of 142 patients were consecutively enrolled. All were hepatitis B surface antigen (HBsAg)-positive for >6 months and did not receive drug therapy. An ELISA kit was used to test the IL-12, IL-18, IL-21, and acetylcholinesterase (AchE) levels in serum samples from chronic HBV patients and healthy control groups. The amounts of IL-12 and IL-18 were highest in the 5-6log10 (high viral load) group, while IL-21 was highest in the 3-4log10 (low viral load) group. Also, the IL-21 amount was decreased in the HBsAg+/HBeAg/HBcAb+ group, and IL-12, IL-18, and IL-21 were decreased in the normal alanine aminotransferase (ALT) group compared to the abnormal ALT group. These data suggested that IL-12, IL-18, and IL-21 serum levels were positively correlated with disease progression and could reflect disease severity for different HBV-DNA loads. Detection of IL-12, IL-18, and IL-21 levels was found to be helpful for evaluating the degree of liver cell damage and predicting the progression of hepatitis.
Assuntos
Hepatite B Crônica , Interleucinas , Carga Viral , Humanos , Acetilcolinesterase , Alanina Transaminase , DNA Viral , Antígenos de Superfície da Hepatite B/uso terapêutico , Vírus da Hepatite B/genética , Hepatite B Crônica/diagnóstico , Interleucina-12/sangue , Interleucina-18/sangue , Interleucinas/sangueAssuntos
Quimiocina CXCL10/sangue , Interleucina-18/sangue , Terapia Ultravioleta/métodos , Vitiligo/radioterapia , Adulto , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Pigmentação da Pele/efeitos da radiação , Resultado do Tratamento , Vitiligo/sangue , Vitiligo/diagnóstico , Adulto JovemRESUMO
Activated monocytes/macrophages that produce a cytokine storm play an important role in the pathogenesis of dengue. Interleukin-18 (IL-18) is a proinflammatory cytokine produced by monocyte/macrophages that is increased during dengue. Ferritin is an acute-phase reactant and expressed by cells of the reticulo-endothelial system in response to infection by dengue virus. The aims of this study were to analyze the simultaneous expression of both IL-18 and ferritins in children infected by diverse serotypes of dengue virus (DENV) and determine their association with dengue severity. In this regard, children with dengue (n = 25) and healthy controls with similar age and sex (n = 20) were analyzed for circulating ferritin and cytokines. Monocytes were isolated by Hystopaque gradient and co-cultured with DENV-2. IL-18 and ferritin contents in blood, and IL-18 in culture supernatants were determined by ELISA. Increased levels of ferritin and IL-18 (p < 0.0001) were observed in dengue patients, not associated to NS1expression or type of infection (primary or secondary). Highest values of both molecules (p < 0.001) were observed in dengue with warning signs and severe dengue. Differential effect on IL-18/ferritin production was observed associated to viral serotype infection. There were no correlations between ferritin vs. IL-18 production, ferritin vs. NS1 status, and IL-18 vs. NS1 status. Viral-infected monocyte cultures showed increased production of IL-18 (p < 0.001). In conclusion, increased circulating ferritin and IL-18 are expressed in children infected by different serotypes of DENV associated with dengue severity.
Assuntos
Dengue/sangue , Ferritinas/sangue , Interleucina-18/sangue , Adolescente , Criança , Pré-Escolar , Citocinas/metabolismo , Dengue/diagnóstico , Dengue/metabolismo , Dengue/virologia , Vírus da Dengue/classificação , Vírus da Dengue/genética , Vírus da Dengue/isolamento & purificação , Vírus da Dengue/fisiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Lactente , Macrófagos/metabolismo , Masculino , Monócitos/metabolismo , Sorogrupo , Índice de Gravidade de DoençaRESUMO
INTRODUCTION: The triggering of severe dengue has been associated with an exacerbated inflammatory process characterized by the production of pro-inflammatory cytokines such as IL-1ß/IL-18, which are the product of inflammasome activation. Furthermore, alteration in the levels of high-density (HDL) and low-density lipoproteins (LDL) has been observed; and HDL are known to have immunomodulatory properties, including the regulation of inflammasomes. While HDL would be expected to counteract hyperactivation of the inflammasome, the relationship between HDL and dengue severity, has not previously been explored. METHODOLOGY: We conducted a cross-sectional study of 30 patients with dengue and 39 healthy controls matched by sex and age. Lipid profile and levels of C-reactive protein were quantified. Serum levels of IL-1ß, IL-6, IL-10, IL-18, and TNF-α, were assessed by ELISA. Expression of inflammasome-related genes in PBMC was quantified by qPCR. RESULTS: Dengue patients presented an alteration in the parameters of the lipid profile, with a significant decrease in HDL levels, which was more pronounced in dengue patients with warning signs. Moreover, a decrease in the expression of the inflammasome-related genes NLRP1, NLRC4, caspase-1, IL-1ß and IL-18 was observed, as well as an increase in serum levels of C-reactive protein and IL-10 in dengue patients versus healthy donors. Significant positive correlations between LDL levels and the relative expression of NLRP3, NLRC4, IL-1ß and IL-18, were found. CONCLUSION: The results suggest that there is a relationship between the alteration of LDL and HDL with the imbalance in the inflammatory response, which could be associated with the severity of dengue.
Assuntos
Dengue/sangue , Inflamação/sangue , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Adulto , Proteína C-Reativa/análise , Estudos Transversais , Feminino , Humanos , Interleucina-10/sangue , Interleucina-18/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: Multiple sclerosis (MS) is a neurodegenerative disease of central nervous system (CNS) with autoimmune and inflammatory characteristics, and a still uncertain pathogenesis. Early events as well as evolution of MS are heterogeneous (three main clinical forms) and multifactorial. Genome-wide association studies indicate that MS pathogenesis shares features with both autoimmune and inflammatory diseases. Innate immunity has been recently proved to be an important factor in MS. Genetic variants in inflammasome components have been associated with both autoimmune and neurodegenerative diseases, letting us hypothesize that inflammasome, and related cytokines IL-1ß and IL-18, could represent important contributors in MS pathogenesis, and eventually explain, at least in part, the heterogeneity observed in MS patients. AIM: To evaluate the contribution of inflammasome in MS, in term of (a) genetic effect on development, severity and/or prognosis, and (b) complex activation in peripheral blood as a measure of systemic inflammation. METHODS: Functional genetic variants in inflammasome components were analyzed in a cohort of MS patients, by the use of allele-specific assays and qPCR. Multivariate analysis was performed based on clinical form (recurrent remittent/RR, primary progressive/PP or secondary progressive/SP), severity index (EDSS) and progression index (PI), response to IFN-ß treatment. Peripheral blood monocytes (PBM) of patients were examined for inflammasome activation and expression profile. RESULTS AND DISCUSSION: Variants associated with low serum levels of IL-18 were significantly less frequent in MS patients than in controls, suggesting a protective role of diminished IL-18-mediate inflammation in MS development. On the other hands, gain-of-function variants in NLRP3 (Q705K) and IL1B (-511 C >T) associated with severity and progression of MS, suggesting that a constitutive activation of NLRP3 inflammasome could represent a risk factor for MS clinical presentation. Accordingly, -511C >T SNP resulted more frequent in progressive forms than in RR MS, reinforcing the idea that increased inflammasome activation characterized bad prognosis of MS. Altogether these findings corroborate previous data about the harmful role of NLRP3 inflammasome in experimental autoimmune encephalitis (EAE). Moreover, we reported for the first time the beneficial effect of NLRC4 rs479333 G >C variant in MS progression and in the response to IFN-ß treatment. This intronic polymorphism have been previously associated to decreased NLRC4 transcription and low IL-18 serum level, indicated once more that less activation of inflammasome and IL-18 production are beneficial for MS patients. PBM analysis showed that MS cells express higher level of inflammasome genes than HD ones, and are more prone to respond to a classical NLRP3 stimulus than HD.
Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas de Ligação ao Cálcio/genética , Progressão da Doença , Predisposição Genética para Doença , Inflamassomos/genética , Interleucina-18/sangue , Esclerose Múltipla , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Índice de Gravidade de Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Interleucina-1beta/genética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Esclerose Múltipla/fisiopatologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Human immunodeficiency virus (HIV) promotes an inflammatory process, leading to the progressive loss of the functional capacity of the immune system. The HIV infection induces alterations in several tissues, but mainly in the gut-associated lymphoid tissue (GALT). However, the degree of GALT deterioration varies among infected individuals. In fact, it has been shown that HIV-controllers, who spontaneously control viral replication, exhibit a lower inflammatory response, and a relative normal frequency and function of most of the immune cells. Inflammasomes are molecular complexes involved in the inflammatory response, being NLRP1, NLRP3, NLRC4, AIM2 and Pyrin inflammasomes, the best characterized so far. These complexes regulate the maturation of cytokines of the IL-1 family, including IL-1ß and IL-18. These cytokines have been associated with immune activation and expansion of HIV target cells, promoting viral replication. Interesting, some reports indicate that HIV induces the activation of the NLRP3 inflammasome, but the role of this, and other inflammasomes during HIV infection, especially in GALT, remains unclear. OBJECTIVE: To compare the relative expression of inflammasome components and the proinflammatory response related to their activity, between HIV-progressors and HIV-controllers. METHODS: GALT biopsies and peripheral blood mononuclear cells (PBMCs) from 15 HIV-controllers and 15 HIV-progressors were obtained. The relative expression of the following inflammasome components were evaluated by RT-PCR: NLRP3, NLRC4, NLRP1, AIM2, ASC, Caspase-1, IL-1ß and IL-18. In addition, plasma concentration of IL-18 was evaluated as an indicator of baseline proinflammatory status. Finally, in supernatants of PBMCs in vitro stimulated with inflammasome agonists, the concentrations of IL-1ß and IL-18 were quantified by ELISA. RESULTS: HIV-progressors exhibited higher expression of IL-1ß, IL-18 and caspase-1 genes in GALT and PBMCs compared with HIV-controllers. In addition, HIV-progressors had also increased expression of ASC in PBMCs. When plasma levels were evaluated, IL-18 was increased in HIV-progressors. Interesting, these patients also showed an increased production of IL-1ß in supernatants of PBMCs stimulated in vitro with the agonists of AIM2, NLRP1 and NLRC4 inflammasomes. Finally, the expression of caspase-1, NLRP1, IL-1ß and IL-18 in GALT or peripheral blood was correlated with CD4+ T-cell count and viral load. CONCLUSION: Our results suggest that during HIV-infection, the required signals to induce the expression of different components of the inflammasomes are produced, both in GALT and in periphery. The activation of these molecular complexes could increase the number of target cells, favoring HIV replication and cell death, promoting the disease progression.
Assuntos
Infecções por HIV/etiologia , Inflamassomos/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Tecido Linfoide/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Linfócitos T CD4-Positivos/virologia , Proteínas de Ligação ao Cálcio/metabolismo , Caspase 1/sangue , Caspase 1/genética , Caspase 1/metabolismo , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Interações Hospedeiro-Patógeno , Humanos , Interleucina-18/sangue , Interleucina-18/genética , Interleucina-1beta/sangue , Interleucina-1beta/genética , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Tecido Linfoide/virologia , Proteínas NLR , Reto/metabolismo , Reto/virologia , Carga Viral , Replicação Viral/fisiologiaRESUMO
Objective The present study compares immune and endocrine parameters between HIV-infected patients who underwent the Immune Reconstitution Inflammatory Syndrome (IRIS-P) during antiretroviral therapy (ART) and HIV-patients who did not undergo the syndrome (non-IRIS-P). Materials and methods Blood samples were obtained from 31 HIV-infected patients (15 IRIS-P and 16 non-IRIS-P) before ART (BT) and 48 ± 2 weeks after treatment initiation (AT). Plasma Interleukin-6 (IL-6) and Interleukin-18 (IL-18) were determined by ELISA. Cortisol, dehydroepiandrosterone sulfate (DHEA-S) and thyroxin concentrations were measured using chemiluminescence immune methods. Results Concentrations of IL-6 (7.9 ± 1.9 pg/mL) and IL-18 (951.5 ± 233.0 pg/mL) were significantly higher (p < 0.05) in IRIS-P than in non-IRIS-P (3.9 ± 1.0 pg/mL and 461.0 ± 84.4 pg/mL, respectively) BT. Mean T4 plasma level significantly decreased in both groups of patients after treatment (p < 0.05). In both groups cortisol levels were similar before and after ART (p > 0.05). Levels of DHEA-S in IRIS-P decreased AT (1080.5 ± 124.2 vs. 782.5 ± 123.8 ng/mL, p < 0.05) and they were significantly lower than in non-IRIS-P (782.5 ± 123.8 vs. 1203.7 ± 144.0 ng/mL, p < 0.05). IRIS-P showed higher values of IL-6 and IL-18 BT and lower levels of DHEA-S AT than in non-IRIS-P. Conclusion These parameters could contribute to differentiate IRIS-P from non-IRIS-P. The significant decrease in DHEA-S levels in IRIS-P after ART might suggest a different adrenal response in these patients, which may reflect the severity of the disease.
Assuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Biomarcadores/sangue , Infecções por HIV/sangue , Síndrome Inflamatória da Reconstituição Imune/sangue , Relação CD4-CD8 , Sulfato de Desidroepiandrosterona/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Humanos , Hidrocortisona/sangue , Síndrome Inflamatória da Reconstituição Imune/imunologia , Síndrome Inflamatória da Reconstituição Imune/metabolismo , Interleucina-18/sangue , Interleucina-6/sangue , Luminescência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tiroxina/sangue , Carga ViralRESUMO
ABSTRACT Objective The present study compares immune and endocrine parameters between HIV-infected patients who underwent the Immune Reconstitution Inflammatory Syndrome (IRIS-P) during antiretroviral therapy (ART) and HIV-patients who did not undergo the syndrome (non-IRIS-P). Materials and methods Blood samples were obtained from 31 HIV-infected patients (15 IRIS-P and 16 non-IRIS-P) before ART (BT) and 48 ± 2 weeks after treatment initiation (AT). Plasma Interleukin-6 (IL-6) and Interleukin-18 (IL-18) were determined by ELISA. Cortisol, dehydroepiandrosterone sulfate (DHEA-S) and thyroxin concentrations were measured using chemiluminescence immune methods. Results Concentrations of IL-6 (7.9 ± 1.9 pg/mL) and IL-18 (951.5 ± 233.0 pg/mL) were significantly higher (p < 0.05) in IRIS-P than in non-IRIS-P (3.9 ± 1.0 pg/mL and 461.0 ± 84.4 pg/mL, respectively) BT. Mean T4 plasma level significantly decreased in both groups of patients after treatment (p < 0.05). In both groups cortisol levels were similar before and after ART (p > 0.05). Levels of DHEA-S in IRIS-P decreased AT (1080.5 ± 124.2 vs. 782.5 ± 123.8 ng/mL, p < 0.05) and they were significantly lower than in non-IRIS-P (782.5 ± 123.8 vs. 1203.7 ± 144.0 ng/mL, p < 0.05). IRIS-P showed higher values of IL-6 and IL-18 BT and lower levels of DHEA-S AT than in non-IRIS-P. Conclusion These parameters could contribute to differentiate IRIS-P from non-IRIS-P. The significant decrease in DHEA-S levels in IRIS-P after ART might suggest a different adrenal response in these patients, which may reflect the severity of the disease.
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Biomarcadores/sangue , Infecções por HIV/sangue , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Síndrome Inflamatória da Reconstituição Imune/sangue , Tiroxina/sangue , Ensaio de Imunoadsorção Enzimática , Hidrocortisona/sangue , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Infecções por HIV/tratamento farmacológico , Estudos Prospectivos , Interleucina-6/sangue , Relação CD4-CD8 , Sulfato de Desidroepiandrosterona/sangue , Carga Viral , Interleucina-18/sangue , Luminescência , Síndrome Inflamatória da Reconstituição Imune/imunologia , Síndrome Inflamatória da Reconstituição Imune/metabolismoRESUMO
Considering its role in inflammation and recently described "alternative" roles in epithelial homeostasis and Th1/Th2 balance, we hypothesize that inflammasome genetics could contribute to the development of asthma. Selected functional polymorphisms in inflammasome genes are evaluated in a cohort of asthmatic children and their families. Gain-of-function NLRP1 variants rs11651270, rs12150220 and rs2670660 resulted significantly associated to asthma in trios (TDT) analysis; and rs11651270 and rs2670660 also with asthma severity and total IgE level in asthmatic children. NLRP1 activators in humans are still unknown, however we hypothesized that individuals with gain-of-function SNPs in NLRP1 could be more prone in activating inflammasome in the presence of asthma-related cell stressors (i.e. ER stress or ROS), and this activation contribute to exacerbate inflammatory response and asthma development. Gain-of-function IL1A rs17561 resulted significantly associated with a reduced pulmonary capacity in asthmatic children. IL18 rs5744256 which lead to lower serum level of IL-18 appeared to be associated to a worse response to bronchodilators. Concluding, this work provides evidences about the contribution of inflammasome genetics in the development of paediatric asthma, both considering its inflammatory role in alveolar macrophages (i.e.: NLRP1) or its homeostatic role in lung epithelial cells (i.e.: IL1A, IL18).
Assuntos
Asma/genética , Inflamassomos/genética , Polimorfismo de Nucleotídeo Único , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Alarminas/fisiologia , Proteínas Reguladoras de Apoptose/genética , Asma/epidemiologia , Asma/imunologia , Brasil/epidemiologia , Criança , Células Epiteliais/patologia , Feminino , Mutação com Ganho de Função , Humanos , Imunoglobulina E/análise , Interleucina-18/sangue , Interleucina-1alfa/genética , Interleucina-1beta/genética , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas NLR , RegeneraçãoRESUMO
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.