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BACKGROUND: Several underlying mechanisms potentially account for the link between sleep and attention deficit and hyperactivity disorder (ADHD), including inflammation. However, studies so far have been cross sectional. We investigate (a) the association between early childhood sleep and probable ADHD diagnosis in childhood and (b) whether childhood circulating inflammatory markers mediate these prospective associations. METHODS: Data from the Avon Longitudinal Study of Parents and Children were available for 7,658 10-year-old children. Parent-reported sleep duration, night awakening frequency and regular sleep routines were collected at 3.5 years. The Development and Wellbeing Assessment was administered to capture children with clinically relevant ADHD symptoms, or probable ADHD diagnosis. Blood samples were collected at 9 years, from which two inflammatory markers were obtained [interleukin-6 (IL-6) and C-reactive protein (CRP)]. Logistic regression analyses were applied to investigate the associations between sleep variables at 3.5 years and probable ADHD diagnosis at 10 years. Further, path analysis was applied to examine the potential mediating role of inflammation at 9 years (as measured by CRP and IL-6) in the associations between early sleep and ADHD at 10 years. RESULTS: Less regular sleep routines (OR = 0.51, 95% CI = 0.28-0.93, p = .029), shorter nighttime sleep (OR = 0.70, 95% CI = 0.56-0.89, p = .004) and higher night awakening frequency (OR = 1.27, 95% CI = 1.06-1.52, p = .009) at 3.5 years were associated with higher odds of ADHD at 10 years. Further, IL-6 at 9 years, but not CRP, mediated the association between irregular sleep routines and ADHD (bias-corrected estimate, -0.002; p = .005) and between night awakening and ADHD (bias-corrected estimate, 0.002; p = .003). CONCLUSIONS: Several sleep problems in early childhood constitute a risk factor for probable ADHD diagnosis at 10 years. Further, these associations are partially mediated by IL-6 at 9 years. These results open a new research vista to the pathophysiology of ADHD and highlight sleep and inflammation as potential preventative targets for ADHD.
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Trastorno por Déficit de Atención con Hiperactividad , Trastornos del Sueño-Vigilia , Niño , Preescolar , Humanos , Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Estudios de Cohortes , Estudios Transversales , Inflamación/epidemiología , Interleucina-6 , Estudios Longitudinales , Trastornos del Sueño-Vigilia/diagnóstico , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Chronic inflammation is an important driver in the progression of non-alcoholic steatohepatitis (NASH) and atherosclerosis. The complement system, one of the first lines of defense in innate immunity, has been implicated in both diseases. However, the potential therapeutic value of complement inhibition in the ongoing disease remains unclear. METHODS: After 20 weeks of high-fat diet (HFD) feeding, obese Ldlr-/-.Leiden mice were treated twice a week with an established anti-C5 antibody (BB5.1) or vehicle control. A separate group of mice was kept on a chow diet as a healthy reference. After 12 weeks of treatment, NASH was analyzed histopathologically, and genome-wide hepatic gene expression was analyzed by next-generation sequencing and pathway analysis. Atherosclerotic lesion area and severity were quantified histopathologically in the aortic roots. RESULTS: Anti-C5 treatment considerably reduced complement system activity in plasma and MAC deposition in the liver but did not affect NASH. Anti-C5 did, however, reduce the development of atherosclerosis, limiting the total lesion size and severity independently of an effect on plasma cholesterol but with reductions in oxidized LDL (oxLDL) and macrophage migration inhibitory factor (MIF). CONCLUSION: We show, for the first time, that treatment with an anti-C5 antibody in advanced stages of NASH is not sufficient to reduce the disease, while therapeutic intervention against established atherosclerosis is beneficial to limit further progression.
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Aterosclerosis , Factores Inhibidores de la Migración de Macrófagos , Enfermedad del Hígado Graso no Alcohólico , Animales , Aterosclerosis/metabolismo , Colesterol/metabolismo , Complemento C5/metabolismo , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Hígado/metabolismo , Factores Inhibidores de la Migración de Macrófagos/genética , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismoRESUMEN
Attention-Deficit Hyperactivity Disorder (ADHD) is a complex and heterogeneous neurodevelopmental condition for which curative treatments are lacking. Whilst pharmacological treatments are generally effective and safe, there is considerable inter-individual variability among patients regarding treatment response, required dose, and tolerability. Many of the non-pharmacological treatments, which are preferred to drug-treatment by some patients, either lack efficacy for core symptoms or are associated with small effect sizes. No evidence-based decision tools are currently available to allocate pharmacological or psychosocial treatments based on the patient's clinical, environmental, cognitive, genetic, or biological characteristics. We systematically reviewed potential biomarkers that may help in diagnosing ADHD and/or stratifying ADHD into more homogeneous subgroups and/or predict clinical course, treatment response, and long-term outcome across the lifespan. Most work involved exploratory studies with cognitive, actigraphic and EEG diagnostic markers to predict ADHD, along with relatively few studies exploring markers to subtype ADHD and predict response to treatment. There is a critical need for multisite prospective carefully designed experimentally controlled or observational studies to identify biomarkers that index inter-individual variability and/or predict treatment response.
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BACKGROUND: Diagnostic guidelines recommend using a variety of methods to assess and diagnose ADHD. Applying subjective measures always incorporates risks such as informant biases or large differences between ratings obtained from diverse sources. Furthermore, it has been demonstrated that ratings and tests seem to assess somewhat different constructs. The use of objective measures might thus yield valuable information for diagnosing ADHD. This study aims at evaluating the role of objective measures when trying to distinguish between individuals with ADHD and controls. Our sample consisted of children (n = 60) and adults (n = 76) diagnosed with ADHD and matched controls who completed self- and observer ratings as well as objective tasks. Diagnosis was primarily based on clinical interviews. A popular pattern recognition approach, support vector machines, was used to predict the diagnosis. RESULTS: We observed relatively high accuracy of 79% (adults) and 78% (children) applying solely objective measures. Predicting an ADHD diagnosis using both subjective and objective measures exceeded the accuracy of objective measures for both adults (89.5%) and children (86.7%), with the subjective variables proving to be the most relevant. CONCLUSIONS: We argue that objective measures are more robust against rater bias and errors inherent in subjective measures and may be more replicable. Considering the high accuracy of objective measures only, we found in our study, we think that they should be incorporated in diagnostic procedures for assessing ADHD.
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Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Pruebas Neuropsicológicas/normas , Máquina de Vectores de Soporte/normas , Evaluación de Síntomas/métodos , Evaluación de Síntomas/normas , Adulto , Trastorno por Déficit de Atención con Hiperactividad/psicología , Niño , Humanos , Persona de Mediana EdadRESUMEN
Several diffusion tensor imaging (DTI) studies in attention deficit hyperactivity disorder (ADHD) have shown a delay in brain white matter (WM) development. Because these studies were mainly conducted in children and adolescents, these WM abnormalities have been assumed, but not proven to progress into adulthood. To provide further insight in the natural history of WM maturation delay in ADHD, we here investigated the modulating effect of age on WM in children and adults. 120 stimulant-treatment naive male ADHD children (10-12 years of age) and adults (23-40 years of age) with ADHD (according to DSM-IV; all subtypes) were included, along with 23 age and gender matched controls. Fractional anisotropy (FA) values were compared throughout the WM by means of tract-based spatial statistics (TBSS) and in specific regions of interest (ROIs). On both TBSS and ROI analyses, we found that stimulant-treatment naive ADHD children did not differ in FA values from control children, whereas adult ADHD subjects had reduced FA values when compared to adult controls in several regions. Significant age × group interactions for whole brain FA (p = 0.015), as well as the anterior thalamic radiation (p = 0.015) suggest that ADHD affects the brain WM age-dependently. In contrast to prior studies conducted in medicated ADHD children, we did not find WM alterations in stimulant treatment naïve children, only treatment-naïve adults. Thus, our findings suggest that the reported developmental delay in WM might appear after childhood, and that previously reported differences between ADHD children and normal developing peers could have been attributed to prior ADHD medications, and/or other factors that affect WM development, such as age and gender.
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Trastorno por Déficit de Atención con Hiperactividad/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/crecimiento & desarrollo , Imagen de Difusión Tensora , Sustancia Blanca/diagnóstico por imagen , Adulto , Factores de Edad , Análisis de Varianza , Anisotropía , Estudios de Casos y Controles , Niño , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica , Adulto JovenRESUMEN
Plasmacytoid dendritic cells (pDCs) are antigen presenting cells specialized in viral recognition through Toll-like receptor (TLR)7 and TLR9, and produce vast amounts of interferon alpha upon ligation of these TLRs. We had previously demonstrated a strong influx of pDCs in the tubulointerstitium of renal biopsies at the time of acute rejection. However, the role of human pDCs in mediating acute or chronic allograft rejection remains elusive. pDCs are thought to have a limited capacity to ingest apoptotic cells, critical for inducing CD4+ T cell activation via indirect antigen presentation and subsequent activation of antibody producing B cells. Here we tested whether the function of pDCs is affected by their presence within the graft. Maturation and interferon alpha production by pDCs was enhanced when cells were activated in the presence of viable HK2 renal epithelial cells. Importantly, soluble factors produced by cytomegalovirus-infected (primary) epithelial or endothelial cells enhanced pDC activation and induced their capacity to phagocytose apoptotic cells. Phagocytosis was not induced by free virus or soluble factors from non-infected cells. Activated pDCs showed an enhanced CD4+ and CD8+ T cell allostimulatory capacity as well as a potent indirect alloantigen presentation. Granulocyte Macrophage-Colony Stimulating Factor is one of the soluble factors produced by renal epithelial cells that, combined with TLR9 ligation, induced this functional capacity. Thus, pDCs present in the rejecting allograft can contribute to alloimmunity and potentially act as important orchestrators in the manifestation of acute and chronic rejection.
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Células Dendríticas/metabolismo , Células Epiteliales/metabolismo , Rechazo de Injerto/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Trasplante de Riñón/efectos adversos , Túbulos Renales Proximales/metabolismo , Comunicación Paracrina , Fagocitosis , Receptor Toll-Like 9/metabolismo , Presentación de Antígeno , Apoptosis , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular , Técnicas de Cocultivo , Citomegalovirus/inmunología , Citomegalovirus/patogenicidad , Células Dendríticas/inmunología , Células Epiteliales/inmunología , Células Epiteliales/patología , Células Epiteliales/virología , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Rechazo de Injerto/virología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Interacciones Huésped-Patógeno , Humanos , Interferón-alfa/metabolismo , Isoantígenos/inmunología , Isoantígenos/metabolismo , Túbulos Renales Proximales/inmunología , Túbulos Renales Proximales/patología , Túbulos Renales Proximales/virología , Activación de Linfocitos , Fenotipo , Transducción de Señal , Receptor Toll-Like 9/inmunologíaRESUMEN
BACKGROUND: Kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are promising biomarkers for monitoring delayed graft function (DGF) after kidney transplantation. Here we investigated localization and distribution of KIM-1 and NGAL staining in renal allograft biopsies and studied their association with histological features, functional DGF (fDGF) and the tubular function slope (TFS), a functioning proximal tubular epithelial cell (PTEC) marker. METHODS: Day 10 protocol biopsies of 64 donation after circulatory death recipients were stained for KIM-1 and NGAL and the positive area was quantified using ImageJ software. Biopsies were scored according to Banff and acute tubular necrosis (ATN) criteria. A 99mtechnetium-mercaptoacetyltriglycine (99mTc-MAG3)-renography was performed to calculate TFS. RESULTS: KIM-1 staining was located on the brush border of tubular epithelial cells (TECs) and correlated with denudation, while NGAL was present more focally in a cytoplasmic distribution. KIM-1 and NGAL staining were not correlated and no co-localization was observed. Quantitative stainings were not associated with fDGF, but KIM-1 tended to be higher in patients with prolonged fDGF (≥21 days; P = 0.062). No correlation was observed between the quantitative tissue stainings and urinary KIM-1 or NGAL. Quantitative KIM-1 staining was inversely correlated with the TFS (Spearman's ρ = -0.53; P < 0.001), whereas NGAL was not. The latter finding might be because cortical NGAL staining is dependent on filtration and subsequent reabsorption by functioning PTECs. Staining of NGAL was indeed restricted to PTECs, as shown by co-localization with a PTEC-specific lectin. CONCLUSIONS: KIM-1 and NGAL staining showed different localization and distribution. Quantitative KIM-1 staining was inversely correlated with functioning PTECs.
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Biomarcadores/metabolismo , Moléculas de Adhesión Celular/metabolismo , Funcionamiento Retardado del Injerto/diagnóstico , Células Epiteliales/patología , Receptor Celular 1 del Virus de la Hepatitis A/metabolismo , Trasplante de Riñón/efectos adversos , Túbulos Renales Proximales/patología , Anciano , Animales , Biopsia , Funcionamiento Retardado del Injerto/metabolismo , Células Epiteliales/metabolismo , Femenino , Humanos , Túbulos Renales Proximales/lesiones , Túbulos Renales Proximales/metabolismo , Lipocalina 2/metabolismo , Masculino , Persona de Mediana Edad , Ratas , Ratas Endogámicas Lew , Coloración y Etiquetado , Trasplante HomólogoRESUMEN
IL-35 is a cytokine of the IL-12 family, existing as a heterodimer of IL-12p35 and Ebi3. IL-35 has anti-inflammatory properties and is produced by regulatory T cells in humans and mice, where it is required for optimal suppression of immune responses. Distinct from other IL-12 cytokines, the expression of IL-35 has not been described in antigen-presenting cells. In view of the immune-regulatory properties of IL-35, we investigated the expression, regulation, and function of IL-12p35 and Ebi3 in human monocyte-derived dendritic cells and tolerogenic DCs (tolDCs). These tolDCs do not produce IL-12p70 or the homodimer IL-12p40. We demonstrate that tolDCs completely lack transcriptional expression of IL-12p40. However, tolDCs maintain mRNA expression of IL-12p35 and Ebi3. Using intracellular flow cytometry and Western blot analysis, we show that tolDCs produce Ebi3 and IL-12p35, and both can be enhanced upon stimulation with IFN-γ, LPS, or CD40L. tolDCs supernatants have the capacity to suppress T-cell activation. Using IL12A silencing, we demonstrate that IL-12p35 is required for tolDCs to reach their full suppressive potential. Taken together, our results indicate that tolDCs produce IL-35, providing an additional novel mechanism by which tolDCs elicit their tolerogenic potential.
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Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Tolerancia Inmunológica , Interleucinas/biosíntesis , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Antígenos B7/metabolismo , Antígeno B7-2/metabolismo , Antígeno B7-H1/metabolismo , Células Dendríticas/efectos de los fármacos , Dexametasona/farmacología , Expresión Génica , Humanos , Tolerancia Inmunológica/efectos de los fármacos , Interleucina-12/biosíntesis , Subunidad p35 de la Interleucina-12/genética , Subunidad p35 de la Interleucina-12/metabolismo , Interleucina-27/genética , Interleucina-27/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Lipopolisacáridos/inmunología , Antígenos de Histocompatibilidad Menor , FenotipoRESUMEN
Uptake of apoptotic cells by DCs is considered to contribute to induction and maintenance of immunological tolerance. TolDCs are sought after as cellular therapy in transplantation and autoimmunity and can be generated in vitro using GCs. In this study, we investigated how uptake of dead cells affects the production and expression of different members of the IL-12 family by immature DCs or TolDCs. We show that compared to regular immature DCs, TolDCs display elevated levels of PS-recognizing bridge molecule receptors αvß5 and CD36, and have enhanced phagocytic abilities with accelerated uptake of apoptotic cells. We confirm that apoptotic cell uptake results in diminished production of IL-12p40 and IL-12p70 by DCs. We now show that this also results in increased expression of IL-12p35 and Ebi3. TolDCs completely lack expression of IL-12p40 yet have enhanced levels of Ebi3 and IL-12p35. Uptake by TolDCs of apoptotic or necrotic cells does not affect the expression of Ebi3/IL-12p35 and also does not increase IL-12p40. This is distinct from the culture of immature DCs with necrotic cells, which is sufficient to induce IL-12p40 secretion. Conversely, ingestion of apoptotic cells by DCs leads to increased expression of IL-12p35 and Ebi3 without affecting IL-12p40. In conclusion, we have shown that uptake of apoptotic versus necrotic cells by DCs differentially regulates members of the IL-12 family. Apoptotic cells favor expression of Ebi3 and IL-12p35, and we propose that differential regulation of the IL-12 family is an additional mechanism in determining the immune response to dying cells.
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Apoptosis/inmunología , Células Dendríticas/inmunología , Regulación de la Expresión Génica/inmunología , Interleucina-12/inmunología , Fagocitosis/inmunología , Células Cultivadas , Humanos , Necrosis/inmunologíaRESUMEN
Reactive oxygen species (ROS) produced by macrophages have recently been shown to have immunosuppressive properties and induce regulatory T cells. Here we investigated the ROS producing capacity of well-defined human Mph2 subsets and studied the contribution of ROS in the Mph-T cell interaction. Mph were generated from monocytes using M-CSF (Mph2), IL-4 (Mph2a), or IL-10 (Mph2c). Upon PMA stimulation, Mph2 and Mph2c showed a high ROS producing capacity, whereas this was low for Mph2a. Mph2 and Mph2c displayed a reduced T cell stimulatory capacity compared to Mph2a. Addition of the ROS inhibitor DPI decreased the T cell proliferation and IFN-γ production. When testing directly on Mph, DPI dose-dependently decreased the IL-10 and IL-12p40 production of CD40L-stimulated Mph2 subsets. In conclusion, the ROS producing capacity is different among human Mph type-2 subsets. In all cases, DPI suppressed T cell proliferation and cytokine production, indicating a ROS-dependent mechanism of T cell activation.
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Macrófagos/inmunología , Especies Reactivas de Oxígeno/inmunología , Linfocitos T Reguladores/inmunología , Citometría de Flujo , Humanos , Activación de Linfocitos/inmunología , Factor Estimulante de Colonias de Macrófagos/inmunología , Macrófagos/metabolismo , Compuestos Onio/farmacología , Reacción en Cadena de la Polimerasa , ARN Mensajero/química , ARN Mensajero/genética , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Macrophages have been demonstrated to suppress T cell responses by producing reactive oxygen species (ROS) leading to the subsequent induction of T regulatory cells in a ROS-dependent manner. Macrophages may therefore be instrumental in downregulating T cell responses in situations of exacerbated immune responses. Here we investigated the effect of immunosuppressive drugs on ROS production by macrophage subsets and the subsequent effects on T cell activation. Macrophage types 1 and 2 were differentiated with GM-CSF or M-CSF, in presence or absence of dexamethasone, cyclosporine A, FK506, rapamycin, or mycophenolic acid. The ROS producing capacity of fully differentiated Mph was highest in anti-inflammatory Mph2 and not affected by exposure to immunosuppressive drugs. However, presence of rapamycin during Mph2 differentiation decreased the ROS production of these cells. In contrast, other immunosuppressive drugs, with dexamethasone being the most potent, increased the ROS producing capacity of Mph2. Intriguingly although the ROS producing ability of Mph1 was unaffected, dexamethasone strongly increased the ROS producing capabilities of dendritic cells. Both at the mRNA and protein level we found that dexamethasone enhanced the expression of NOX2 protein p47(phox). Functionally, dexamethasone further enhanced the capacity of Mph2 to suppress T cell mediated IFN-γ and IL-4 production. In vivo, only in rats with normal ROS production (congenic DA.Ncf1(E3/E3)) it was observed that dexamethasone injection resulted in long-lasting upregulation of ROS production by macrophages and induced higher levels of Treg in a ROS-dependent manner. In conclusion, we show that the anti-inflammatory drug dexamethasone increases the ROS producing capacity of macrophages.
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Dexametasona/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Especies Reactivas de Oxígeno/metabolismo , Linfocitos T/inmunología , Animales , Células Cultivadas , NADPH Oxidasas/inmunología , NADPH Oxidasas/metabolismo , Unión Proteica , RatasRESUMEN
The plastic role of dendritic cells (DCs) in the regulation of immune responses has made them interesting targets for immunotherapy, but also for pathogens or tumors to evade immunity. Functional alterations of DCs are often ascribed to manipulation of canonical NF-κB activity. However, though this pathway has been linked to murine myeloid DC biology, a detailed analysis of its importance in human myeloid DC differentiation, survival, maturation, and function is lacking. The myeloid DC subsets include interstitial DCs and Langerhans cells. In this study, we investigated the role of canonical NF-κB in human myeloid DCs generated from monocytes (monocyte-derived DCs [mo-DCs]) or CD34(+) progenitors (CD34-derived myeloid DCs [CD34-mDCs]). Inhibition of NF-κB activation during and after mo-DC, CD34-interstitial DC, or CD34-Langerhans cell differentiation resulted in apoptosis induction associated with caspase 3 activation and loss of mitochondrial transmembrane potential. Besides regulating survival, canonical NF-κB activity was required for the acquisition of a DC phenotype. Despite phenotypic differences, however, Ag uptake, costimulatory molecule and CCR7 expression, as well as T cell stimulatory capacity of cells generated under NF-κB inhibition were comparable to control DCs, indicating that canonical NF-κB activity during differentiation is redundant for the development of functional APCs. However, both mo-DC and CD34-mDC functionality were reduced by NF-κB inhibition during activation. In conclusion, canonical NF-κB activity is essential for the development and function of mo-DCs as well as CD34-mDCs. Insight into the role of this pathway may help in understanding how pathogens and tumors escape immunity and aid in developing novel treatment strategies aiming to interfere with human immune responses.
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Antígenos CD34 , Diferenciación Celular/inmunología , Células de Langerhans/inmunología , Células Mieloides/inmunología , FN-kappa B/inmunología , Antígenos/inmunología , Antígenos/metabolismo , Apoptosis/inmunología , Caspasa 3/inmunología , Caspasa 3/metabolismo , Células Cultivadas , Regulación de la Expresión Génica/inmunología , Humanos , Células de Langerhans/citología , Células de Langerhans/metabolismo , Células Mieloides/citología , Células Mieloides/metabolismo , FN-kappa B/metabolismo , Receptores CCR7/biosíntesis , Receptores CCR7/inmunología , Células Madre/citología , Células Madre/inmunología , Células Madre/metabolismoRESUMEN
The phagocyte NAPDH-oxidase complex consists of several phagocyte oxidase (phox) proteins, generating reactive oxygen species (ROS) upon activation. ROS are involved in the defense against microorganisms and also in immune regulation. Defective ROS formation leads to chronic granulomatous disease (CGD) with increased incidence of autoimmunity and disturbed resolution of inflammation. Because regulatory T cells (Tregs) suppress autoimmune T-cell responses and are crucial in down-regulating immune responses, we hypothesized that ROS deficiency may lead to decreased Treg induction. Previously, we showed that in p47(phox)-mutated mice, reconstitution of macrophages (Mph) with ROS-producing capacity was sufficient to protect the mice from arthritis. Now, we present evidence that Mph-derived ROS induce Tregs. In vitro, we showed that Mph ROS-dependently induce Treg, using an NADPH-oxidase inhibitor. This finding was confirmed genetically: rat or human CGD Mph with mutated p47(phox) or gp91(phox) displayed hampered Treg induction and T-cell suppression. However, basal Treg numbers in these subjects were comparable to those in controls, indicating a role for ROS in induction of peripheral Tregs. Induction of allogeneic delayed-type hypersensitivity with p47(phox)-mutated Mph confirmed the importance of Mph-derived ROS in Treg induction in vivo. We conclude that NAPDH oxidase activity in Mph is important for the induction of Tregs to regulate T cell-mediated inflammation.
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Macrófagos/metabolismo , NADPH Oxidasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Linfocitos T Reguladores/inmunología , Animales , Cartilla de ADN/genética , Citometría de Flujo , Enfermedad Granulomatosa Crónica/inmunología , Humanos , Glicoproteínas de Membrana/inmunología , NADPH Oxidasa 2 , NADPH Oxidasas/antagonistas & inhibidores , NADPH Oxidasas/inmunología , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estadísticas no Paramétricas , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismoRESUMEN
BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that persists into adulthood in the majority of cases. The evidence on persistence poses several difficulties for adult psychiatry considering the lack of expertise for diagnostic assessment, limited treatment options and patient facilities across Europe. METHODS: The European Network Adult ADHD, founded in 2003, aims to increase awareness of this disorder and improve knowledge and patient care for adults with ADHD across Europe. This Consensus Statement is one of the actions taken by the European Network Adult ADHD in order to support the clinician with research evidence and clinical experience from 18 European countries in which ADHD in adults is recognised and treated. RESULTS: Besides information on the genetics and neurobiology of ADHD, three major questions are addressed in this statement: (1) What is the clinical picture of ADHD in adults? (2) How can ADHD in adults be properly diagnosed? (3) How should ADHD in adults be effectively treated? CONCLUSIONS: ADHD often presents as an impairing lifelong condition in adults, yet it is currently underdiagnosed and treated in many European countries, leading to ineffective treatment and higher costs of illness. Expertise in diagnostic assessment and treatment of ADHD in adults must increase in psychiatry. Instruments for screening and diagnosis of ADHD in adults are available and appropriate treatments exist, although more research is needed in this age group.
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Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/terapia , Consenso , Adolescente , Adulto , Estimulantes del Sistema Nervioso Central/uso terapéutico , Niño , Terapia Combinada , Progresión de la Enfermedad , Europa (Continente) , Femenino , Humanos , Masculino , Guías de Práctica Clínica como Asunto/normas , Psicoterapia/métodosRESUMEN
Several studies have evaluated the association between individual polymorphisms and response to methylphenidate (MPH) in subjects with attention-deficit/hyperactivity disorder (ADHD). There are few replication studies for each polymorphism of interest and results are sometimes inconsistent in this field. Although data collection from multiple international sites would allow large sample sizes, this approach has been criticized for introducing sampling variability due to differences in ethnicity and methodology between studies. To examine these issues, we aggregated nine pharmacogenetic studies from four different continents and conducted a two stage analysis: (a) we evaluated the role of methodological aspects in the variability of ADHD symptom improvement between studies using meta-regression analysis; (b) we assessed the role of individual characteristics of the subjects in the variability of ADHD symptoms improvement using multivariate regression analysis in the same data sets. At the study level, from five evaluated factors, only the design of the study (open studies vs. randomized controlled trials) was significantly associated with heterogeneity of results (P = 0.001). At the individual level, age (P < 0.001), comorbid oppositional defiant disorder (P < 0.001), and pre-treatment scores (P < 0.001) were associated with change of ADHD scores with treatment in the final multivariate model. Our results suggest that joint analyses of pharmacogenetic studies are feasible and promising, since fixed variables, such as the site where the study was conducted, were not related to results. Nevertheless, stratified analyses according to the design of the study must be preferentially conducted and the role of individual factors such as demographic data and comorbid profile as confounders should be assessed.
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Trastorno por Déficit de Atención con Hiperactividad , Estimulantes del Sistema Nervioso Central/uso terapéutico , Metilfenidato/uso terapéutico , Farmacogenética/métodos , Adolescente , Adulto , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/genética , Estimulantes del Sistema Nervioso Central/farmacología , Niño , Comorbilidad , Demografía , Femenino , Humanos , Masculino , Metilfenidato/farmacología , Persona de Mediana Edad , Análisis Multivariante , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de Regresión , Proyectos de Investigación , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Renal tubular epithelial cells (TECs) play an active role in renal inflammation. Previous studies have demonstrated the capacity of TECs to modulate T-cell responses both positively and negatively. Recently, new costimulatory molecules [inducible T cell costimulator-L (ICOS-L) and B7-H1] have been described, which appear to be involved in peripheral T-cell activation. METHODS: We characterized expression and regulation of costimulatory molecules on primary human TECs and the TEC line human kidney-2 (HK-2) with reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry. Immunohistochemistry was performed on human kidney biopsies. The capacity of TECs to modulate T-cell activation was studied in TEC/T-cell cultures. RESULTS: We demonstrate that TECs express ICOS-L and B7-H1 in vitro and in vivo. Stimulation with interferon-gamma (IFN-gamma) resulted in increased expression of B7-H1, whereas ICOS-L expression was marginally increased upon stimulation with CD40L, with no effect of interleukin (IL-1), IL-17, or tumor necrosis factor-alpha (TNF-alpha). Furthermore, we show that TECs are able to costimulate T cells that have received signal-1 using alphaCD3 antibodies, inducing strong IL-10 production, which was partially mediated by ICOS-L. In contrast, B7-H1 appeared to be involved in inhibition of proliferation and cytokine synthesis. In addition, TECs were able to alter the cytokine profile of fully activated T cells, which were incubated with alphaCD3 and alphaCD28 antibodies, resulting in low IFN-gamma and high IL-10 production. This activity appeared to be independent of ICOS-L and B7-H1. CONCLUSION: Interaction of tubular epithelial cells and kidney infiltrating T cells via ICOS-L and B7-H1 may change the balance of positive and negative signals to the T cells, leading to IL-10 production and limitation of local immune responses.
Asunto(s)
Antígeno B7-1/genética , Túbulos Renales/citología , Túbulos Renales/inmunología , Glicoproteínas de Membrana/genética , Péptidos/genética , Proteínas/genética , Linfocitos T/citología , Linfocitos T/inmunología , Antígenos CD , Antígeno B7-H1 , Comunicación Celular/inmunología , Línea Celular Transformada , Células Epiteliales/citología , Células Epiteliales/fisiología , Expresión Génica/inmunología , Humanos , Ligando Coestimulador de Linfocitos T Inducibles , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Activación de Linfocitos/fisiología , Transducción de Señal/inmunología , Linfocitos T/metabolismoRESUMEN
Graft-infiltrating dendritic cells (DC) and alloreactive T lymphocytes play a critical role in renal allograft rejection. Renal proximal tubular epithelial cells (TEC) are considered as active players in the attraction of leukocytes during renal inflammatory responses. Macrophage inflammatory protein (MIP)-3alpha/CCL20 is a major chemokine expressed by epithelial cells that attracts immature DC. In the present study, we present evidence that also the transplanted kidney can be a major source of MIP-3alpha/CCL20. Renal transplant recipients with rejection showed significantly increased excretion of urinary MIP-3alpha/CCL20 that correlated with transplant function. The tubular staining for MIP-3alpha/CCL20 in renal biopsies of patients with rejection as well as in vitro studies with primary human TEC indicated that TEC might be responsible for the increased urinary MIP-3alpha/CCL20. Furthermore, MIP-3alpha/CCL20 produced by activated TEC was highly potent in the attraction of CD1a+CD34+-derived DC precursors. These data suggest a role for MIP-3alpha/CCL20 in amplification of the immune response during renal allograft rejection by attraction of CCR6+ inflammatory cells, which may include DC, to the site of inflammation.
Asunto(s)
Quimiocinas CC/biosíntesis , Células Dendríticas/citología , Trasplante de Riñón/métodos , Proteínas Inflamatorias de Macrófagos/biosíntesis , Trasplante Homólogo/métodos , Adulto , Antígenos CD1/biosíntesis , Antígenos CD34/biosíntesis , Biopsia , Ligando de CD40/biosíntesis , Movimiento Celular , Quimiocina CCL20 , Quimiocina CCL5/biosíntesis , Quimiocinas/metabolismo , Factores Quimiotácticos , Células Dendríticas/metabolismo , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/patología , Femenino , Citometría de Flujo , Regulación de la Expresión Génica , Rechazo de Injerto , Humanos , Inmunohistoquímica , Inflamación , Interleucina-1/biosíntesis , Riñón/patología , Túbulos Renales/patología , Leucocitos/citología , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Receptores CCR6 , Receptores de Quimiocina/biosíntesis , Factores de TiempoRESUMEN
Sanglifehrin A (SFA) is a recently developed immunosuppressant that belongs to the family of immunophilin-binding ligands. SFA is a cyclophilin A-binding immunosuppressive drug with a novel, but unidentified, mechanism of action. Several reports exist about the effect of SFA on T cells, but its effect on the initiators of the immune response, i.e., dendritic cells (DCs), is relatively unknown. Therefore, we examined the effect of SFA on the differentiation and function of human monocyte-derived DCs. Unlike the well-known cyclophilin A-binding immunosuppressant cyclosporin A, which did not affect DC phenotype, differentiation of DCs in the presence of SFA resulted in CD14-CD1a DCs with normal DC morphology, viability, and a proper capacity to activate allogeneic T cells. However, DCs generated in the presence of SFA demonstrated reduced macropinocytosis and lectin-mediated endocytosis, which was in line with a decreased expression of C-type lectins, including mannose receptor, C1qRP, DC-ASGPR, and especially, DC-SIGN. In contrast, FcalphaRI (CD89) and FcgammaRII (CD32) were increased by SFA. The explicit effect of SFA on the expression of Ag uptake receptors and Ag capture by DCs makes SFA unique among immunophilin-binding immunosuppressive drugs.