RESUMEN
Mucopolysaccharidosis type II (MPS II) is an inborn error of the metabolism resulting from several possible mutations in the gene coding for iduronate-2-sulfatase (IDS), which leads to a great clinical heterogeneity presented by these patients. Many studies demonstrate the involvement of oxidative stress in the pathogenesis of inborn errors of metabolism, and mitochondrial dysfunction and oxidative stress can be related since most of reactive oxygen species come from mitochondria. Cellular models have been used to study different diseases and are useful in biochemical research to investigate them in a new promising way. The aim of this study is to develop a heterozygous cellular model for MPS II and analyze parameters of oxidative stress and mitochondrial dysfunction and investigate the in vitro effect of genistein and coenzyme Q10 on these parameters for a better understanding of the pathophysiology of this disease. The HP18 cells (heterozygous c.261_266del6/c.259_261del3) showed almost null results in the activity of the IDS enzyme and presented accumulation of glycosaminoglycans (GAGs), allowing the characterization of this knockout cellular model by MPS II gene editing. An increase in the production of reactive species was demonstrated (p < .05 compared with WT vehicle group) and genistein at concentrations of 25 and 50 µm decreased in vitro its production (p < .05 compared with HP18 vehicle group), but there was no effect of coenzyme Q10 in this parameter. There was a tendency for lysosomal pH change in HP18 cells in comparison to WT group and none of the antioxidants tested demonstrated any effect on this parameter. There was no increase in the activity of the antioxidant enzymes superoxide dismutase and catalase and oxidative damage to DNA in HP18 cells in comparison to WT group and neither genistein nor coenzyme q10 had any effect on these parameters. Regarding mitochondrial membrane potential, genistein induced mitochondrial depolarization in both concentrations tested (p < .05 compared with HP18 vehicle group and compared with WT vehicle group) and incubation with coenzyme Q10 demonstrated no effect on this parameter. In conclusion, it is hypothesized that our cellular model could be compared with a milder MPS II phenotype, given that the accumulation of GAGs in lysosomes is not as expressive as another cellular model for MPS II presented in the literature. Therefore, it is reasonable to expect that there is no mitochondrial depolarization and no DNA damage, since there is less lysosomal impairment, as well as less redox imbalance.
Asunto(s)
Iduronato Sulfatasa , Enfermedades Mitocondriales , Mucopolisacaridosis II , Ubiquinona/análogos & derivados , Humanos , Mucopolisacaridosis II/tratamiento farmacológico , Mucopolisacaridosis II/genética , Genisteína/farmacología , Potencial de la Membrana Mitocondrial , Estrés Oxidativo , Iduronato Sulfatasa/metabolismo , Iduronato Sulfatasa/farmacología , Antioxidantes/farmacología , Antioxidantes/metabolismoRESUMEN
Mucopolysaccharidosis type II (MPS II or Hunter Syndrome) is a lysosomal disease caused by deficient degradation of glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate due to the deficiency of the enzyme iduronate-2-sulfatase. The main treatment for MPS II is the administration of the recombinant form of the enzyme, in a process known as enzyme replacement therapy (ERT). Oxidative damage can contribute to the pathophysiology of MPS II and treatment with ERT can reduce the effects of oxidative stress. For a better understanding of pathophysiology of MPS II, we evaluated biomarkers of mitochondrial dysfunction, DNA (Deoxyribonucleic acid) damage, antioxidant defenses, reactive species production and lysosomal size in IDS-deficient HEK 293 cells and investigate the in vitro effect of genistein and coenzyme Q10 (CoQ) on these biomarkers. An increase in the production of reactive species was demonstrated, as well as an increase in the activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). Also, an increase in lysosomal volume and oxidative damage to DNA were verified. There was no evidence of a change in mitochondrial function in this cell model. In the HEK 293 (human embryonic kidney 293) knockout (KO) HP10 cell model we found that genistein at concentrations of 25 and 50 µm decreased in vitro the production of reactive species and the activity of the SOD enzyme, showing an antioxidant protective effect. Still, in these cells we verified that the coenzyme Q10 in the concentrations of 5 and 10 µm decreased in vitro the activity of the SOD enzyme and in the concentration of 10 µm decreased in vitro the DNA damage, also demonstrating antioxidant protection. In conclusion, MPS II knockout cells demonstrated oxidative stress and DNA damage and genistein, as well as coenzyme Q10, have been shown to have an important protective effect in vitro against these oxidative damages.
Asunto(s)
Mucopolisacaridosis II , Humanos , Mucopolisacaridosis II/tratamiento farmacológico , Genisteína/farmacología , Células HEK293 , Antioxidantes/farmacología , Antioxidantes/metabolismo , Estrés Oxidativo , Glicosaminoglicanos/metabolismo , Mitocondrias/metabolismo , Biomarcadores/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
The therapeutic targeting of the immune system, for example in vaccinology and cancer treatment, is a challenging task and the subject of active research. Several in silico tools used for predicting immunogenicity are based on the analysis of peptide sequences binding to the Major Histocompatibility Complex (pMHC). However, few of these bioinformatics tools take into account the pMHC three-dimensional structure. Here, we describe a new bioinformatics tool, MatchTope, developed for predicting peptide similarity, which can trigger cross-reactivity events, by computing and analyzing the electrostatic potentials of pMHC complexes. We validated MatchTope by using previously published data from in vitro assays. We thereby demonstrate the strength of MatchTope for similarity prediction between targets derived from several pathogens as well as for indicating possible cross responses between self and tumor peptides. Our results suggest that MatchTope can enhance and speed up future studies in the fields of vaccinology and cancer immunotherapy.
Asunto(s)
Complejo Mayor de Histocompatibilidad , Péptidos , Antígenos de Histocompatibilidad , Reacciones Cruzadas , Secuencia de AminoácidosRESUMEN
This research communication addresses the impact of the addition of Lactobacillus casei and/or carbonation (CO2) on the chemical composition, physicochemical characteristics, probiotic survival, and sensory acceptance of passion-fruit flavored whey dairy beverages (70% milk/30% whey) during storage (30 d/4°C). The addition of Lactobacillus casei and/or carbonation did not impact on the chemical composition, pH values, and acceptance (flavor and overall impression) of the products, but increased the acidity, and decreased the aroma acceptance. The carbonation process did not affect the probiotic survival but decreased the acidity of the products during storage. It can be concluded that it is possible to develop a probiotic passion-fruit flavored carbonated whey dairy beverage with suitable chemical composition, acidity, sensory acceptance (>6 in 9-point hedonic scale) and probiotic viability (>7 log cfu/ml) that could be refrigerated stored for 30 d. This is the first report considering a probiotic non-fermented carbonated whey dairy beverage.
Asunto(s)
Bebidas Gaseosas/análisis , Bebidas Gaseosas/microbiología , Lacticaseibacillus casei/fisiología , Leche/química , Leche/microbiología , Probióticos/administración & dosificación , Animales , Fenómenos Químicos , Almacenamiento de Alimentos/métodos , Frutas , Concentración de Iones de Hidrógeno , Passiflora , Refrigeración , Olfato , Suero Lácteo/química , Suero Lácteo/microbiologíaRESUMEN
The aim of the present study was to evaluate the impact of SEMA4A genetic variants on expression of sema4A protein and its relation to autoimmunity development in Systemic Lupus Erythematosus and Rheumatoid Arthritis patients. A total of 541 SLE patients, 390 RA patients and 607 healthy individuals were genotyped. We also assessed SEMA4A mRNA expression from whole blood cells and the in vitro protein production from resting and activated T lymphocytes as well as mature dendritic cells from healthy individuals stratified according to their genotypes for SLE/RA associated SEMA4A variants. Our results showed that T/T genotype for rs3738581 SNP is associated with both RA and SLE development (p = .000053, OR = 2.35; p = .0019, OR = 2.07, respectively; statistical power = 100%) and also to an increased in vitro sema4A production in active T lymphocytes. Our findings are indicative of a T cell-specific upregulation of sema4A in the presence of T/T genotype, being a risk factor for SLE and RA.
Asunto(s)
Artritis Reumatoide/genética , Autoinmunidad/genética , Lupus Eritematoso Sistémico/genética , Semaforinas/genética , Linfocitos T/inmunología , Adulto , Anciano , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Brasil , Estudios de Casos y Controles , Estudios de Cohortes , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Semaforinas/metabolismo , Linfocitos T/metabolismo , Regulación hacia ArribaRESUMEN
The search for epitopes that will effectively trigger an immune response remains the "El Dorado" for immunologists. The development of promising immunotherapeutic approaches requires the appropriate targets to elicit a proper immune response. Considering the high degree of HLA/TCR diversity, as well as the heterogeneity of viral and tumor proteins, this number will invariably be higher than ideal to test. It is known that the recognition of a peptide-MHC (pMHC) by the T-cell receptor is performed entirely in a structural fashion, where the atomic interactions of both structures, pMHC and TCR, dictate the fate of the process. However, epitopes with a similar composition of amino acids can produce dissimilar surfaces. Conversely, sequences with no conspicuous similarities can exhibit similar TCR interaction surfaces. In the last decade, our group developed a database and in silico structural methods to extract molecular fingerprints that trigger T-cell immune responses, mainly referring to physicochemical similarities, which could explain the immunogenic differences presented by different pMHC-I complexes. Here, we propose an immunoinformatic approach that considers a structural level of information, combined with an experimental technology that simulates the presentation of epitopes for a T cell, to improve vaccine production and immunotherapy efficacy.
Asunto(s)
Inmunoterapia , Complejo Mayor de Histocompatibilidad/inmunología , Péptidos/química , Linfocitos T/inmunología , Vacunas Virales/inmunología , Animales , Epítopos/inmunología , Humanos , Péptidos/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Reproducibilidad de los ResultadosRESUMEN
PURPOSE: Idiopathic recurrent pregnancy loss (RPL) is a multifactorial reproductive disorder where an impaired control of apoptosis is likely involved. Triggering the cell death mechanism occurs in a spatiotemporal manner and is strongly related to a healthy pregnancy. Single nucleotide polymorphisms (SNPs) at the regulatory regions of genes are known to influence the expression patterns of apoptosis-related molecules. METHODS: A total of 296 unrelated female Brazilian patients were evaluated for clinical-demographic variables and genetic factors: 140 women who had experienced an unexplained RPL (with at least two consecutive abortions) and 156 healthy multiparous women. In all patients, six SNPs were evaluated in genes of apoptosis-related pathways: FAS (rs2234767, rs1800682), FAS-L (rs763110, rs5030772), BAX (rs4645878), and BCL-2 (rs2279115) by PCR followed by a restriction fragment length polymorphism (RFLP)-based analysis. RESULTS: The BAX-248GA genotype is independently associated with idiopathic RPL [adjusted OR = 0.30, 95% CI 0.13-0.70, P = 0.005] susceptibility. In the same multivariate model, the variables ethnicity, smoking, and alcohol consumption were statistically associated with RPL susceptibility (P < 0.05). No association with RPL susceptibility was reported for the remaining SNPs. CONCLUSION: Our study is the first to evaluate the role of the main SNPs from both the extrinsic and intrinsic apoptosis pathways in RPL susceptibility. The association of BAX-248G/A with RPL susceptibility suggests that maternal predisposition for RPL has an essential contribution from genes involved in the delicate balance of endometrium cell turnover (cell death/proliferation). Therefore, apoptotic genes may represent promising targets for future studies on healthy pregnancies and the spectrum of pregnancy disorders.
Asunto(s)
Aborto Habitual/genética , Proteína Ligando Fas/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteína X Asociada a bcl-2/genética , Receptor fas/genética , Adolescente , Adulto , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Embarazo , Pronóstico , Adulto JovenRESUMEN
In transplantation, donor dendritic cells (do-DCs) initiate the alloimmune response either by direct interaction with host T cells or by transferring intact donor MHC to host DCs. However, how do-DCs can be targeted for improving allograft survival is still unclear. Here we show CD103+ DCs are the major do-DC subset involved in the acute rejection of murine skin transplants. In the absence of CD103+ do-DCs, less donor MHC-II is carried to host lymph nodes, fewer allogenic T cells are primed and allograft survival is prolonged. Incubation of skin grafts with the anti-inflammatory mycobacterial protein DnaK reduces donor MHC-II on CD103+DCs and prolongs graft survival. This effect is mediated through IL-10-induced March1, which ubiquitinates and decreases MHC-II levels. Importantly, in vitro pre-treatment of human DCs with DnaK reduces their ability to prime alloreactive T cells. Our findings demonstrate a novel therapeutic approach to dampen alloimmunity by targeting donor MHC-II on CD103+DCs.
Asunto(s)
Antígenos CD/metabolismo , Células Dendríticas/metabolismo , Cadenas alfa de Integrinas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Antígenos CD/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Cadenas alfa de Integrinas/genética , Interleucina-10/genética , Interleucina-10/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Plantago australis is a popular plant found to be widely spread in Latin America. In folk medicine, the seeds and leaves are used mainly for anti-inflammatory, wound healing, among others. The verbascoside, a phenolic glycoside, is an active chemical component described in this species of plant, which has antioxidant, anti-inflammatory and healing effects. PURPOSE: The aim of the present study was to evaluate whether P. australis hydroethanolic extract (PAHE) standardized in verbascoside could promote wound healing associated with anti-inflammatory action within both in vitro and in vivo models. METHODS: For the wound healing activity, we used a Scratch Test, an assay capable of evaluating the migratory ability of keratinocyte cells (HaCat) in vitro and thereby confirming the activity in rats. For the anti-inflammatory activity, the inflammation was induced with LPS in microglial murine cells (N9). Inflammatory mediators (IL-6, IL-10, IL-12p70, INFγ, MCP-1 and TNFα) were measured and the activity of superoxide dismutase (SOD), catalase (CAT), and mitochondrial membrane potential were evaluated. In addition, using paw edema induced by carrageenan in rats, the anti-inflammatory activity in vivo was analyzed. RESULTS: The PAHE and verbascoside, induced a significant increase in migration of keratinocytes, at all concentrations tested when compared to the negative control. The wound healing activity in vivo showed that the PAHE accelerated the process. The treatments with PAHE and verbascoside induce increases in the antioxidants enzymes, suggesting a possible activation of these enzymes. However, this did not result in an increase in the expression of inflammatory mediators in microglial cells. In LPS activated cells the verbascoside displayed a significant reduction of TNFα, IL-6, IL-12p70, MCP-1 and INFγ, while the PAHE only displayed statistically significant reduction in TNFα. Interestingly, both the compounds could reduce the oxidative parameters in N9 cells activated by LPS. Additionally, pretreatment with PAHE inhibited the paw edema in rats. CONCLUSION: The results suggest that PAHE has wound healing activity, improving cells migration and, as well as was able to reverse the oxidation effect in LPS-activated N9 cells. The wound-healing and anti-inflammatory activities of PAHE were confirmed in vivo. In addition, the presence of verbascoside can be related to PAHE effects, since this compound was capable of increase keratinocytes migration and inhibiting inflammation mediators.
Asunto(s)
Antiinflamatorios/uso terapéutico , Extractos Vegetales/uso terapéutico , Plantago , Cicatrización de Heridas/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Carragenina , Catalasa/metabolismo , Línea Celular , Citocinas/inmunología , Citocinas/metabolismo , Edema/tratamiento farmacológico , Glucósidos/farmacología , Glucósidos/uso terapéutico , Humanos , Lipopolisacáridos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos CBA , Fenoles/farmacología , Fenoles/uso terapéutico , Fitoterapia , Extractos Vegetales/farmacología , Ratas Wistar , Superóxido Dismutasa/metabolismoRESUMEN
Cytokines are essential to maintain and coordinate the correct activity of immune cells during human pregnancy. IL-17 is a pro-inflammatory cytokine that induces the expression of many inflammatory mediators. The aim of this study was to compare the levels of Th1, Th2 and Th17 cytokines of women ongoing normal pregnancy with those found in women who suffered spontaneous abortion. IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, and IFN-γ peripheral blood levels were measured in women who suffered spontaneous abortion (n = 13, blood collected up to 24 h after abortion), and were compared with healthy successful pregnancies (n = 16). Cytokine levels were measured using a cytometric bead array (CBA analysis). Similar cytokine levels were observed between spontaneous abortion and healthy pregnant women excepted to IL-17, which levels were increased in the healthy pregnant women (p = 0.0232). Our results show high IL-17 levels in the peripheral blood of women at late stages of healthy pregnancy, although low IL-17 levels were detected in the peripheral blood of women just after spontaneous abortion. In line with recent studies, this finding highlights IL-17 as a regulatory cytokine essential to the maintenance of a successful pregnancy.
Asunto(s)
Aborto Espontáneo/sangre , Interleucina-17/sangre , Embarazo/sangre , Adulto , Citocinas/sangre , Femenino , Humanos , Embarazo/inmunología , Células TH1/metabolismo , Células Th17/metabolismo , Células Th2/metabolismoRESUMEN
Diabetes is a chronic metabolic disease associated with oxidative stress, damage to biomolecules such as DNA, and neuroinflammation. Taurine, a sulfur-containing amino acid widespread in the brain, has neuroprotective properties that might prevent tissue injury and DNA damage induced by chronic hyperglycemia. We evaluated the effects of chronic taurine treatment on oxidative stress parameters, DNA damage and inflammatory markers in the frontal cortex, and hippocampus of streptozotocin-induced diabetic rats. Diabetic rats displayed increased levels of reactive oxygen species (ROS) and DNA damage in both areas, evidencing the pro-oxidant effects of diabetes in the brain. Moreover, this condition increased levels of several inflammatory mediators, such as IL-6, IL-12, TNF-γ, and IFN-α, more pronouncedly in the hippocampus. Supporting our hypothesis, taurine treatment reduced ROS, DNA damage, and inflammatory cytokine levels, providing evidence of its beneficial effects against genotoxicity and neuroinflammation associated with diabetes. Our data endorse the necessary clinical trials to evaluate the efficacy and safety of taurine supplementation in the prevention and treatment of neurochemical and metabolic alterations related to diabetes.
Asunto(s)
Encéfalo/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Taurina/farmacología , Animales , Antioxidantes/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Citocinas/análisis , Daño del ADN/efectos de los fármacos , Diabetes Mellitus Experimental/patología , Masculino , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Taurina/uso terapéuticoRESUMEN
The recent outbreak of the Zika virus (ZIKV) and the discovery that perinatal Zika exposure can lead to the Congenital Zika Syndrome has promoted a call for prevention measures. Due to the increased number of babies born with microcephaly, structural brain abnormalities, and neurological alterations in regions affected by ZIKV, investigations were carried out in order to better understand this process. The maternal immune system directly influences the fetal central nervous system, and complications during pregnancy have been associated with neurodevelopmental disorders. Autism spectrum disorder (ASD), a neurodevelopmental disorder commonly manifested in the first years of life, is a disease with multifactorial etiology and is manifested typically by social and communication impairments, as well as stereotyped behaviors. Brain abnormalities, including both anatomically and functionally, can be observed in this disorder, suggesting delays in neuronal maturation and altered brain connectivity. It is known that some viral congenital infections, such as rubella, and cytomegalovirus can interfere with brain development, being associated with brain calcification, microcephaly, and ASD. Here, we reviewed a range of studies evaluating the aspects concerning brain development, immunological status during pregnancy, and neuroimmunomodulation in congenital viral infections, and we discuss if the fetal brain infection caused by ZIKV could predispose to ASD. Finally, we suggest a mechanism encompassing neurological and immunological pathways that could play a role in the development of ASD in infants after ZIKV infection in pregnancy.
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Trastorno del Espectro Autista/inmunología , Trastorno del Espectro Autista/virología , Neuroinmunomodulación/inmunología , Complicaciones Infecciosas del Embarazo/inmunología , Infección por el Virus Zika/complicaciones , Femenino , Humanos , Embarazo , Complicaciones Infecciosas del Embarazo/virologíaRESUMEN
This study aimed to evaluate the immune profile of lean and overweight-obese COPD patients. Forty patients with moderate to very severe COPD were divided into lean group (n=20; aged 62.00±8.91years; BMI 22.26±1.65kg/m2) or overweight-obese group (n=20; aged 65.40±6.69years; BMI 29.19±3.55kg/m2). The cytokine profile (IL-2, IL-4, IL-6, IL-10, INF-γ, and TNF-α) was evaluated through the Cytometric Bead Array technique, and the expression of CD4, CD8, CD25, CD45ra, CD45ro, CD69, CD195(CCr5) and HLA-DR were evaluated in CD3+ T-cells. Overweight-obese COPD group had lower levels of IL-2 (p=0.01) and higher INF-γ levels (p=0.02) and IL-6 (p=0.003) than lean COPD. Lean COPD patients had higher CD25+ (p=0.01), CCr5 (p=0.04) and HLA-DR (p=0.007) expression on T cell surface compared to overweight-obese COPD participants. These changes are related to immune dysfunction of obesity, and excess of fat mass in COPD can be a key factor to low T-cells activation.
Asunto(s)
Citocinas/sangre , Sobrepeso/sangre , Sobrepeso/inmunología , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Linfocitos T/inmunología , Anciano , Femenino , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Prueba de PasoRESUMEN
During pregnancy, the maternal immune system is tolerant to foetal antigens via the engagement of immune regulatory mechanisms. Failure in regulating the maternal immunity to foetal antigens may lead to pre-eclampsia (PE). We addressed the role of HLA-G gene polymorphisms and protein expression as well as regulatory T cells and Th1/Th2/Th17 cytokines in healthy and pathological pregnancies. Blood samples from 26 pregnant women with PE, 25 non-PE and 7 strictly healthy pregnant women were assessed. PBMCs were phenotyped for early activation markers (CD25 and CD69), regulatory T-cell markers (CD8+CD28- and CD4+CD25highFoxp3+), ILT-2 (HLA-G receptor) and HLA-G. Lymphocyte proliferation was estimated and levels of IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α and IL-17 were measured. HLA-G polymorphisms (rs66554220 and rs1063320) were genotyped by PCR. PE women exhibited low levels of HLA-G in PBMCs and low frequency of regulatory CD8+CD28- T cells. High amounts of the pro-inflammatory cytokines IL-17, IL-2 and TNF-α as well as IL-4 and IL-10 and an increased proliferative cell activation profile were observed in PE. The allelic and genotypic frequencies of the HLA-G gene polymorphisms and the frequency of CD4+CD25highFoxp3+ T cells did not vary among the groups. Our data suggest that the cytokine imbalance presented in PE is associated with a deficient immune regulatory profile, contributing to an impaired immune tolerance between mother and foetus.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Antígenos HLA-G/inmunología , Inflamación/inmunología , Preeclampsia/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Células Cultivadas , Citocinas/genética , Femenino , Humanos , Tolerancia Inmunológica , Preeclampsia/genética , EmbarazoRESUMEN
HLA-G is a molecule essential to the maintenance of the maternal-fetal interface tolerance, thus contributing to a healthy pregnancy. Here we investigate the role of HLA-G single nucleotide polymorphisms (SNPs) and whether a specific HLA-G haplotype influence or not recurrent pregnancy loss (RPL) risk. A total of 296 DNA samples from RPL (N=140) and controls (N=156) were evaluated. The HLA-G 3'UTR region was sequenced and eight major SNPs were evaluated (14pb insertion/deletion, +3003T/C, +3010C/G, +3027C/A, +3035C/T, +3142G/C, +3187A/G, +3196C/G). A high linkage disequilibrium (LD) among all pairs and a perfect LD between +3010C/G and +3142G/A (D'=1.0, r(2)=1.0) were observed. Our data showed an increased risk to +3010CC genotype carriers in comparison with control [odds ratio (OR) 2.05 95% confidence interval (CI) 1.05-4.00, p=0.035] and to a decreased risk of RPL in +3142CC genotype carriers (OR=0.49 95%CI 0.25-0.95, p=0.035) and +3187AG genotype carriers (OR=0.58 95%CI 0.35-0.94, p=0.029). A total of eight haplotypes were observed in the sample, being UTR-1 and UTR-2 the most represented. An association between UTR-1 haplotype carriers with a reduced risk of both RPL and secondary RPL was observed. Our results indicate that the HLA-G 3'UTR plays important roles in RPL and might be an important marker of susceptibility to this, and possible to other, pregnancy disorders.
Asunto(s)
Regiones no Traducidas 3'/genética , Aborto Habitual/genética , Rechazo de Injerto/genética , Antígenos HLA-G/genética , Tolerancia al Trasplante , Adolescente , Adulto , Población Negra , Brasil , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Polimorfismo de Nucleótido Simple , Embarazo , Tolerancia al Trasplante/genética , Población Blanca , Adulto JovenRESUMEN
Cytokines are intrinsically related to disease progression in HIV infection. We evaluated the plasma levels of Th1/Th2/Th17 cytokines in extreme progressors, including slow (SPs) and rapid (RPs) progressors, who were thus classified based on clinical and laboratory follow-up covering a period of time before the initiation of HAART, ranging from 93-136.5 months for SPs and 7.5-16.5 months for RPs. Analyses were also performed based on the different stages of HIV infection (chronic, pre-HAART individuals-subjects sampled before initiating HAART but who initiated therapy from 12 to 24 months-and those receiving HAART). The plasma cytokine levels of 16 HIV-infected rapid progressors and 25 slow progressors were measured using a Human Th1/Th2/Th17 CBA kit. The IL-6 and IL-10 plasma levels differed significantly between the stages of HIV infection. The IL-6 levels were higher in slow progressors pre-HAART than in chronically infected SPs and HIV-seronegative individuals. The IL-10 levels were higher in slow progressors pre-HAART than in slow progressors receiving HAART and HIV-seronegative controls, and in rapid progressors, the IL-10 levels were higher in pre-HAART subjects than in HIV-seronegative controls. The results reflect the changes in the cytokine profile occurring during different clinical stages in HIV+ subjects. Our results suggest an association between increased IL-6 and IL-10 levels and pre-HAART stages independent of the slow or rapid progression status of the subjects. Thus, increased IL-6 and IL-10 levels could indicate a global inflammatory status and could be used as markers of the disease course in HIV-infected individuals.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/sangre , Infecciones por VIH/sangre , Interleucina-10/sangre , Interleucina-6/sangre , Síntomas Prodrómicos , Adulto , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Infecciones por VIH/patología , VIH-1 , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de TiempoRESUMEN
BACKGROUND AND AIM: Physical exercise is a key part of rehabilitation programs in chronic obstructive pulmonary disease (COPD) patients, although it could modulates immune system responses by altering the cytokine profile of such individuals. Furthermore, the degree of severity of COPD could influence the inflammatory response induced by exercise. To evaluate the cytokine profile of individuals with different degrees of COPD in response to a 6-min walk test (6MWT). METHODS: Forty-one patients with COPD were classified according to the severity of the disease by Global Initiative for Chronic Obstructive Lung Disease method: moderate = 14 individuals; severe = 14 individuals; very severe = 13 individuals. Blood sample collection was performed in the subjects pre and post a 6MWT. Cytokine plasma levels were analyzed to determine the cytokine profile using a Cytometric Bead Array technique (Becton Dickinson, San Jose, CA, USA) assay in flow cytometry. RESULTS: A significant difference was observed in the interleukin (IL)-6 levels after test between very severe and severe groups (P = 0.036). Also, lower levels of IL-4 were observed in the severe group compared with the very severe and the moderate groups in the pretest (P = 0.029; P = 0.003, respectively), and different values between the moderate and severe groups in the post-test (P = 0.044). A significant time pre-post effect was found in the IL-4 levels on the very severe group (P = 0.046). CONCLUSION: After the 6MWT, a discrete inflammatory response was observed in COPD patients, independent of the degree of severity. The results concerning IL-4 and IL-6 levels can be indicative of an attempt to control inflammation after the 6MWT in COPD patients.
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Interleucina-4/sangre , Interleucina-6/sangre , Enfermedad Pulmonar Obstructiva Crónica/sangre , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Prueba de PasoRESUMEN
PROBLEM: Augmented levels of IL-1ß have been pointed out as an important pathogenic factor for preeclampsia development. Inflammasome is the cytoplasmic complex responsible for pro-IL1ß cleavage and IL-1ß secretion. Aim of the study was to evaluate the association between polymorphisms in inflammasome' genes and preeclampsia. METHOD OF STUDY: Selected polymorphisms in inflammasome genes (NLRP1, NLRP3, CARD8, and IL1B) were analyzed in 286 Brazilian women with and 309 without preeclampsia. RESULTS AND CONLCLUSIONS: The NLRP1 variant rs12150220 (L155H) was associated with the development of preeclampsia (OR = 1.58), suggesting a role of this inflammasome receptor in the pathogenesis of this multifactorial disorder.
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Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Reguladoras de la Apoptosis/genética , Polimorfismo de Nucleótido Simple , Preeclampsia/genética , Proteínas Adaptadoras Transductoras de Señales/inmunología , Adulto , Proteínas Reguladoras de la Apoptosis/inmunología , Brasil , Femenino , Humanos , Inflamasomas/genética , Inflamasomas/inmunología , Proteínas NLR , Preeclampsia/inmunología , Embarazo , Factores de RiesgoRESUMEN
OBJECTIVE: This study aimed to investigate the role of Human Leukocyte Antigen (HLA)-G in the susceptibility to HIV-1 infection through the analysis of the HLA-G 3' untranslated region (UTR) polymorphisms 14 bp insertion/deletion (rs66554220) and +3142C>G (rs1063320). DESIGN: We analyzed 582 HIV-1 infected patients and 626 uninfected individuals from Brazil and Italy in a case-control study. METHODS: HLA-G polymorphisms were genotyped using PCR, PCR-RFLP assays or direct sequencing. All analyses were stratified by ethnicity. Genotypic, allelic and diplotypic frequencies were compared between HIV-1 infected subjects and controls using Chi-square or Fischer exact tests. Also, haplotypic frequencies were estimated using MLocus software. RESULTS: African-derived HIV-infected individuals presented a higher frequency of the 14 bp insertion allele as compared to non-infected individuals (0.468 versus 0.373, respectively; p(Bonf) = 0.010). A higher frequency of the 14 bp insertion +3142G (insG) haplotype (0.456 versus 0.346, p<0.001) and the insG/insG diplotype (OR=1.88, 95%CI = 1.08-3.23, p=0.021) was observed among African-derived patients as compared to uninfected controls. Also, we observed a higher frequency of the ins/ins genotype among African-derived HIV patients co-infected with HCV (OR=2.78, 95%CI = 1.20-6.49, p = 0.008). CONCLUSIONS: Our data point out to an increased frequency of alleles and genotypes associated with low HLA-G expression among African-derived patients, suggesting a potential role for HLA-G in the susceptibility to HIV-1 infection and HCV co-infection in those individuals.