RESUMEN
BACKGROUND: The prevalence of peanut allergy has increased in developed countries, but little is known about developing countries with high peanut consumption and widespread parasitic infections. OBJECTIVE: We sought to investigate peanut allergy in Ghana. METHODS: In a cross-sectional survey among Ghanaian schoolchildren (n = 1604), data were collected on reported adverse reactions to peanut, peanut sensitization (serum specific IgE and skin reactivity), consumption patterns, and parasitic infections. In a subset (n = 43) IgE against Ara h 1, 2, 3, and 9 as well as cross-reactive carbohydrate determinants (CCDs) was measured by using ImmunoCAP. Cross-reactivity and biological activity were investigated by means of ImmunoCAP inhibition and basophil histamine release, respectively. RESULTS: Adverse reactions to peanut were reported in 1.5%, skin prick test reactivity in 2.0%, and IgE sensitization (≥0.35 kU/L) in 17.5% of participants. Moreover, 92.4% of those IgE sensitized to peanut (≥0.35 kU/L) had negative peanut skin prick test responses. Schistosoma haematobium infection was positively associated with IgE sensitization (adjusted odds ratio, 2.29; 95% CI, 1.37-3.86). In the subset IgE titers to Ara h 1, 2, 3, and 9 were low (<1.3 kU/L), except for 6 moderately strong reactions to Ara h 9. IgE against peanut was strongly correlated with IgE against CCDs (r = 0.89, P < .0001) and could be almost completely inhibited by CCDs, as well as S haematobium soluble egg antigen. Moreover, IgE to peanut showed poor biological activity. CONCLUSIONS: Parasite-induced IgE against CCDs might account largely for high IgE levels to peanut in our study population of Ghanaian schoolchildren. No evidence of IgE-mediated peanut allergy was found.
Asunto(s)
Arachis/inmunología , Carbohidratos/inmunología , Inmunoglobulina E/sangre , Hipersensibilidad al Cacahuete/inmunología , Esquistosomiasis Urinaria/inmunología , Alérgenos/inmunología , Antígenos de Plantas/inmunología , Basófilos/inmunología , Niño , Reacciones Cruzadas , Femenino , Ghana/epidemiología , Liberación de Histamina , Humanos , Masculino , Hipersensibilidad al Cacahuete/epidemiología , Esquistosomiasis Urinaria/epidemiología , Pruebas CutáneasRESUMEN
Viruses use a wide range of strategies to modulate the host immune response. The human gammaherpesvirus EBV, causative agent of infectious mononucleosis and several malignant tumors, encodes proteins that subvert immune responses, notably those mediated by T cells. Less is known about EBV interference with innate immunity, more specifically at the level of TLR-mediated pathogen recognition. The viral dsDNA sensor TLR9 is expressed on B cells, a natural target of EBV infection. Here, we show that EBV particles trigger innate immune signaling pathways through TLR9. Furthermore, using an in vitro system for productive EBV infection, it has now been possible to compare the expression of TLRs by EBV(-) and EBV(+) human B cells during the latent and lytic phases of infection. Several TLRs were found to be differentially expressed either in latently EBV-infected cells or after induction of the lytic cycle. In particular, TLR9 expression was profoundly decreased at both the RNA and protein levels during productive EBV infection. We identified the EBV lytic-phase protein BGLF5 as a protein that contributes to downregulating TLR9 levels through RNA degradation. Reducing the levels of a pattern-recognition receptor capable of sensing the presence of EBV provides a mechanism by which the virus could obstruct host innate antiviral responses.
Asunto(s)
Desoxirribonucleasas/fisiología , Regulación hacia Abajo/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/inmunología , Receptor Toll-Like 9/antagonistas & inhibidores , Receptor Toll-Like 9/biosíntesis , Proteínas Virales/fisiología , Latencia del Virus/inmunología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/patología , Subgrupos de Linfocitos B/virología , Linfoma de Burkitt/inmunología , Linfoma de Burkitt/patología , Linfoma de Burkitt/virología , Línea Celular Tumoral , Células Cultivadas , Regulación hacia Abajo/genética , Infecciones por Virus de Epstein-Barr/metabolismo , Regulación Viral de la Expresión Génica/inmunología , Células HEK293 , Herpesvirus Humano 4/patogenicidad , Humanos , ARN Viral/antagonistas & inhibidores , ARN Viral/metabolismo , Receptor Toll-Like 9/genética , Virión/inmunología , Activación Viral/inmunologíaRESUMEN
BACKGROUND: Epidemiological data on food allergy are scarce in African countries. We studied the prevalence of food sensitization in Ghanaian schoolchildren. METHODS: Children (5-16 years; n = 1,714) from 9 Ghanaian schools were given parental consent to participate in the study. Adverse reactions and food consumption were determined by a questionnaire and atopy by skin prick testing (SPT) to peanut and 6 fruits. Subjects with positive SPTs were considered cases (n = 43) and matched with at least 1 control (n = 84), using age, sex, and school as matching criteria. Serum samples from case-control sets were analyzed for specific IgE (sIgE) to foods that elicited a positive SPT response in cases. RESULTS: Overall, 11% of 1,407 children reported adverse reactions to foods, and 5% of 1,431 children showed a positive SPT reaction mostly directed against peanut and pineapple (both 2%). Although there was a positive association between adverse reactions and SPT responses to any food allergen in the urban children (adjusted OR = 3.6, 95% CI 1.2-10.8), most of the reported adverse reactions were not in children showing an SPT reaction to the specific food item. sIgE sensitization was very variable for the different foods, ranging from 0 to 100% in cases, and from 0 to 25% among controls. High IgE levels for a food item significantly increased the risk of SPT positivity to any food item in the urban, but not in the rural, schoolchildren. CONCLUSIONS: Specific foods were identified to be allergenic in Ghana. We show a good association between SPT and sIgE in urban, but not in rural, schoolchildren. However, there was no clear association between reported adverse reactions to food and SPT or sIgE.
Asunto(s)
Hipersensibilidad a los Alimentos/epidemiología , Hipersensibilidad a los Alimentos/inmunología , Adolescente , Ananas/inmunología , Niño , Preescolar , Estudios Transversales , Ingestión de Alimentos/inmunología , Conducta Alimentaria , Femenino , Alimentos/efectos adversos , Hipersensibilidad a los Alimentos/sangre , Frutas/inmunología , Ghana/epidemiología , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Estilo de Vida , Masculino , Hipersensibilidad al Cacahuete/sangre , Hipersensibilidad al Cacahuete/epidemiología , Hipersensibilidad al Cacahuete/inmunología , Prevalencia , Población Rural/estadística & datos numéricos , Pruebas Cutáneas , Encuestas y Cuestionarios , Población Urbana/estadística & datos numéricosRESUMEN
Developed countries are suffering from an epidemic rise in immunologic disorders, such as allergy-related diseases and certain autoimmunities. Several studies have demonstrated a negative association between helminth infections and inflammatory diseases (eg, allergy), providing a strong case for the involvement of helminth infections in this respect. However, some studies point in the opposite direction. The discrepancy may be explained by differences in frequency, dose, time, and type of helminth. In this review, new studies are discussed that may support the concept that chronic helminth infections in particular-but not acute infections-are associated with the expression of regulatory networks necessary for downmodulating allergic immune responses to harmless antigens. Furthermore, different components of regulatory networks are highlighted, such as the role of regulatory T and B cells, modulation of dendritic cells, early innate signals from structural cells (eg, epithelial cells), and their individual contributions to protection against allergic diseases. It is of great interest to define and characterize specific helminth molecules that have profound immunomodulatory capacities as targets for therapeutic application in the treatment or prophylaxis of allergic manifestations.
Asunto(s)
Helmintiasis/inmunología , Helmintos/inmunología , Hipersensibilidad/inmunología , Inmunidad Innata , Inmunomodulación , Animales , Linfocitos B/inmunología , Enfermedad Crónica , Células Dendríticas/inmunología , Regulación hacia Abajo , Células Epiteliales/inmunología , Helmintiasis/parasitología , Humanos , Hipersensibilidad/parasitología , Ratones , Transducción de Señal/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
BACKGROUND: Recognition of pathogens by dendritic cells (DCs) through interaction with pattern recognition receptors, including Toll like receptors (TLR), is crucial for the initiation of appropriate polarized T helper (Th) cell responses. Yet, the characteristics and differences in molecular profiles of DCs with different T cell polarizing capacities are still poorly defined. To address this issue, the molecular profile of human monocyte derived DCs was characterized after exposure to TLR4 ligand LPS in combination with the Th1 promoting bacterial extracts from Listeria monocytogenes and Escherichia coli or the Th2 promoting helminth derived phospholipids from Schistosoma mansoni and Ascaris lumbricoides, all with TLR2 activating capacity. RESULTS: With regard to the signalling pathways activated upon exposure to LPS and the TLR2 activating compounds, we find that the ratio of activated Mitogen Activated Protein Kinases (MAPK) p-ERK/p-p38 is lower in DCs stimulated with the bacterial products compared to DCs stimulated with the helminth products, which correlates with the Th1 and Th2 polarizing capacity of these compounds. Furthermore, analysis of the mRNA expression levels of a set of 25 carefully selected genes potentially involved in modulation of T cell polarization revealed that the mRNA expression of notch ligand delta-4 and transcription factor c-fos are differentially regulated and show a strong correlation with Th1 and Th2 polarization, respectively. CONCLUSION: This study shows that combined TLR2 and TLR4 activation in the context of different antigen sources can induce very distinct molecular profiles in DCs and suggests that the Th1/Th2 polarizing capacity of compounds can be predicted with the molecular signature they induce in DCs.
Asunto(s)
Células Dendríticas/inmunología , Células TH1/inmunología , Células Th2/inmunología , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 4/inmunología , Animales , Antígenos Bacterianos/inmunología , Antígenos Helmínticos/inmunología , Ascaris lumbricoides/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/microbiología , Activación Enzimática/inmunología , Escherichia coli/inmunología , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Listeria monocytogenes/inmunología , Proteínas Quinasas Activadas por Mitógenos/inmunología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Monocitos/citología , Monocitos/inmunología , Monocitos/metabolismo , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Schistosoma mansoni/inmunología , Transducción de Señal/inmunología , Células TH1/metabolismo , Células Th2/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
Acute Plasmodium falciparum infection is associated with strongly upregulated cytokine responses that are at least partly the result of activation of Toll-like receptors (TLRs). Whether and how TLR expression/responsiveness changes upon malarial infection is, however, currently not well understood. To assess this, we examined expression of TLRs and used the TLR ligand lipopolysaccharide (LPS) and Pam(3)Cys to stimulate peripheral blood mononuclear cells (PBMCs) from Ghanaian schoolchildren who live in a rural area where P. falciparum is endemic. Expression of TLR2 was higher, and responses to its ligand, Pam(3)Cys, were enhanced in P. falciparum-infected children compared to their uninfected counterparts. In cells from the same children, stimulation by Pam(3)Cys resulted in higher p38 mitogen-activated protein kinase activation and higher cytokine production. In vitro experiments confirmed that preincubation of PBMCs with P. falciparum-infected red blood cells enhanced responsiveness to TLR ligands. Taken together, the data indicate that P. falciparum-infected children in areas where malaria is endemic have an altered innate immune system, which might be important for the balance between immunity and pathology when new infections are encountered or when novel vaccines are introduced.
Asunto(s)
Activación Enzimática/inmunología , Malaria Falciparum/inmunología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 4/inmunología , Adolescente , Animales , Antígenos de Protozoos/inmunología , Niño , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Citometría de Flujo , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Malaria Falciparum/enzimología , Masculino , Proteínas Quinasas Activadas por Mitógenos/inmunología , Plasmodium falciparum/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
BACKGROUND: The statistical analysis of immunological data may be complicated because precise quantitative levels cannot always be determined. Values below a given detection limit may not be observed (nondetects), and data with nondetects are called left-censored. Since nondetects cannot be considered as missing at random, a statistician faced with data containing these nondetects must decide how to combine nondetects with detects. Till now, the common practice is to impute each nondetect with a single value such as a half of the detection limit, and to conduct ordinary regression analysis. The first aim of this paper is to give an overview of methods to analyze, and to provide new methods handling censored data other than an (ordinary) linear regression. The second aim is to compare these methods by simulation studies based on real data. RESULTS: We compared six new and existing methods: deletion of nondetects, single substitution, extrapolation by regression on order statistics, multiple imputation using maximum likelihood estimation, tobit regression, and logistic regression. The deletion and extrapolation by regression on order statistics methods gave biased parameter estimates. The single substitution method underestimated variances, and logistic regression suffered loss of power. Based on simulation studies, we found that tobit regression performed well when the proportion of nondetects was less than 30%, and that taken together the multiple imputation method performed best. CONCLUSION: Based on simulation studies, the newly developed multiple imputation method performed consistently well under different scenarios of various proportion of nondetects, sample sizes and even in the presence of heteroscedastic errors.
Asunto(s)
Técnicas Inmunológicas , Modelos Teóricos , Proyectos de Investigación , Animales , Sesgo , Interpretación Estadística de Datos , Humanos , Inmunidad Innata , Análisis de Regresión , Tamaño de la Muestra , Estadística como AsuntoRESUMEN
Malaria and helminth infections have a shared geographical distribution and therefore co-infections are frequent in tropical areas of the world. Human populations of helminth and malaria co-infection have shown contradictory results for the course of malarial infection and disease, possibly depending on the type of helminth studied, the intensity of helminth infection and the age of the study population. Although immunological studies might clarify the underlying mechanisms of protection or increased susceptibility, there are very few studies that have looked at immunological parameters in helminth and malaria co-infection. After discussing the available immunological data on co-infection, we describe a pilot study performed in Ghanaian school children where we compare anti-malarial responses in children living in an urban area, where the prevalence of helminth and Plasmodium falciparum infections was low, with that of children living in a rural area with high prevalence of helminth and Plasmodium falciparum infections.
Asunto(s)
Helmintiasis/epidemiología , Helmintiasis/inmunología , Malaria/epidemiología , Malaria/inmunología , Adolescente , Animales , Niño , Preescolar , Comorbilidad , Femenino , Ghana/epidemiología , Humanos , Inmunidad Celular , Malaria Falciparum/epidemiología , Malaria Falciparum/inmunología , Masculino , Proyectos PilotoRESUMEN
Worldwide, more than a billion people are infected with helminths. These worm infections generally do not lead to mortality, however, they are chronic in nature and can lead to considerable morbidity. Immunologically these infections are interesting; chronic helminth infections are characterized by skewing towards a T helper 2 type response as well as regulatory responses. The regulatory network is associated with chronic helminth infections and is thought to prevent strong immune responses against parasitic worms, allowing their long-term survival and restricting pathology. This regulatory network is thought to also temper responses to non-helminth antigens, like allergens or self-antigens, possibly leading to lower prevalence of allergies and autoimmune diseases in subjects that are chronically infected with helminths. This raises the interesting idea that helminths may bear molecules that have potential therapeutic action against allergies and possibly other inflammatory diseases. However, on the other side of the coin, this would predict that helminth infected subjects might not respond strongly to third party antigens like vaccines. This is an important issue, since most vaccines that are being developed against diseases such as HIV, tuberculosis or malaria will be introduced in areas where helminth infections are highly prevalent. Moreover, these vaccines are proving difficult to develop and are often weak, thus any confounder that would affect their efficacy needs to be taken into consideration. Helminth derived molecules have been identified that induce T helper 2 and regulatory responses via modulation of dendritic cells and some appear to do so via Toll like receptor (TLR) signaling. New insights into these pathways could be useful to antagonize suppression and hence boost vaccine efficacy or to optimize suppression induced by helminth derived molecules and control inflammatory diseases.
Asunto(s)
Helmintiasis/inmunología , Helmintos/inmunología , Factores Inmunológicos/inmunología , Transducción de Señal/inmunología , Linfocitos T Reguladores/inmunología , Células Th2/inmunología , Alérgenos/inmunología , Animales , Autoantígenos/inmunología , Enfermedad Crónica , Enfermedades Transmisibles/inmunología , Células Dendríticas/inmunología , Helmintiasis/mortalidad , Interacciones Huésped-Parásitos/inmunología , Humanos , Hipersensibilidad/inmunología , Prevalencia , Receptores Toll-Like/inmunología , Vacunas/inmunología , Vacunas/farmacologíaRESUMEN
Dendritic cell-specific transcript (DC-SCRIPT) is a putative DC zinc (Zn) finger-type transcription factor described recently in humans. Here, we illustrate that DC-SCRIPT is highly conserved in evolution and report the initial characterization of the murine ortholog of DC-SCRIPT, which is also preferentially expressed in DC as shown by real-time quantitative polymerase chain reaction, and its distribution resembles that of its human counterpart. Studies undertaken in human embryonic kidney 293 cells depict its nuclear localization and reveal that the Zn finger domain of the protein is mainly responsible for nuclear import. The human and the mouse genes are located in syntenic chromosomal regions and exhibit a similar genomic organization with numerous common transcription factor-binding sites in their promoter region, including sites for many factors implicated in haematopoiesis and DC biology, such as Gfi, GATA-1, Spi-B, and c-Rel. Taken together, these data show that DC-SCRIPT is well-conserved in evolution and that the mouse homologue is more than 80% homologous to the human protein. Therefore, mouse models can be used to elucidate the function of this novel DC marker.
Asunto(s)
Proteínas de Unión al ADN/genética , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Proteínas Nucleares/química , Proteínas Represoras/química , Factores de Transcripción/genética , Transporte Activo de Núcleo Celular/fisiología , Animales , Animales Recién Nacidos , Sitios de Unión/genética , Proteínas Portadoras , Línea Celular , Núcleo Celular/genética , Núcleo Celular/metabolismo , Células Cultivadas , Mapeo Cromosómico , Cromosomas Humanos Par 5/genética , Secuencia Conservada , Proteínas de Unión al ADN/biosíntesis , Humanos , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Proteínas Nucleares/biosíntesis , Proteínas Nucleares/genética , Proteínas Nucleares/aislamiento & purificación , Proteínas Nucleares/metabolismo , Regiones Promotoras Genéticas/genética , Unión Proteica/genética , Proteínas Represoras/genética , Proteínas Represoras/aislamiento & purificación , Proteínas Represoras/metabolismo , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido Nucleico , Factores de Transcripción/biosíntesis , Factores de Transcripción/metabolismo , Dedos de Zinc/fisiologíaRESUMEN
Helminth infections have profound effects on the immune system. Here, recent insights in the molecular interactions between schistosomes and the host are described with respect to adaptive but also with respect to innate immune responses. Furthermore, the different mechanisms of immune hyporesponsiveness are depicted with emphasis on regulatory T cells. Finally, the relationship between downregulatory responses and allergy is discussed.
Asunto(s)
Hipersensibilidad/inmunología , Inmunidad Innata/inmunología , Esquistosomiasis/inmunología , Animales , Enfermedad Crónica , Humanos , Tolerancia Inmunológica/inmunología , Schistosoma/inmunología , Esquistosomiasis/parasitologíaRESUMEN
Expression of the transcription factor Foxp3 (forkhead box P3) has been implicated as a key element for CD25(+) T regulatory cell function in mice. However, literature over similar involvement of FOXP3 expression in human T regulatory cells is limited. We found that, unlike murine cells, FOXP3 mRNA expression could be induced in human CD25(-) and CD8(+) peripheral blood mononuclear cells, which were both negative for FOXP3 mRNA expression after isolation. Expression of FOXP3 mRNA began as soon as 24-40 hours after stimulation, demonstrating a correlation between activation and FOXP3 mRNA expression in human cells. In order to determine whether FOXP3 expression is confined to CD4(+)CD25(+) T cells with a regulatory phenotype, we analyzed several well-defined T-cell clones and lines with various specificities. Surprisingly, expression of FOXP3 mRNA was detected in all clones and limited to the CD25(hi) populations. Nonetheless, the CD25(hi) fraction did not display regulatory properties because both the CD25(hi) and CD25(low) populations exhibited a similar proliferative- and interferon-gamma-secreting potential after antigenic stimulation. These results indicate that FOXP3 expression in humans, unlike mice, may not be specific for cells with a regulatory phenotype and may be only a consequence of activation status.
Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Proteínas de Unión al ADN/biosíntesis , Regulación de la Expresión Génica/fisiología , Leucocitos Mononucleares/metabolismo , Linfocitos T/metabolismo , Animales , Linfocitos T CD4-Positivos/inmunología , Proteínas de Unión al ADN/inmunología , Factores de Transcripción Forkhead , Regulación de la Expresión Génica/inmunología , Humanos , Interferón gamma/inmunología , Interferón gamma/metabolismo , Células Jurkat , Leucocitos Mononucleares/inmunología , Activación de Linfocitos/inmunología , Activación de Linfocitos/fisiología , Ratones , Mycobacterium leprae/metabolismo , ARN Mensajero/inmunología , ARN Mensajero/metabolismo , Receptores de Interleucina-2 , Linfocitos T/inmunologíaRESUMEN
Cathelicidins are effector molecules of the innate host defense system that establish an antimicrobial barrier at epithelial interfaces. The human cathelicidin LL-37, in addition to its antimicrobial activity, also exhibits immunomodulatory effects, such as inhibition of pro-inflammatory responses to bacterial LPS in human monocytic cells. In this report, we demonstrate that LL-37 almost completely prevents the pro-inflammatory cytokine release by human peripheral blood mononuclear cells (PBMCs) following stimulation with Toll-like receptor (TLR)4 and TLR2/1 agonists while leaving TLR2/6, TLR5, TLR7 and TLR8 responses unchanged. Modulation of the TLR response by LL-37 occurred at least partly through the MAP kinase pathway via inhibition of p38 phosphorylation. By using an LL-37 library with overlapping sequences, we identified the mid-region of LL-37, comprising amino acids 13-31, as the active domain for the modulation of TLR responses. The mechanism of immunomodulation of LL-37 and LL-37 fragments is lipopoly-saccharide binding. Correlations between the capacity of LL-37 fragments to modulate TLR responses and their physico-chemical properties revealed that cationicity and hydrophobicity are essential for the modulation of LL-37-mediated TLR responses.
Asunto(s)
Péptidos Catiónicos Antimicrobianos/química , Receptores Toll-Like/química , Secuencia de Aminoácidos , Péptidos Catiónicos Antimicrobianos/metabolismo , Péptidos Catiónicos Antimicrobianos/farmacología , Catelicidinas , Células Cultivadas , Cromatografía Líquida de Alta Presión , Dicroismo Circular , Humanos , Ligandos , Datos de Secuencia Molecular , Transducción de Señal , Relación Estructura-Actividad , Receptores Toll-Like/agonistas , Receptores Toll-Like/efectos de los fármacos , Receptores Toll-Like/metabolismoRESUMEN
Malaria and helminth infections often coincide in the same tropical regions. Studies of the consequences of helminth and malaria coinfection in humans have been few and are mainly epidemiological, with little information on cellular immune responses. In this study, we investigated the antimalarial immune responses of Ghanaian children living in a rural area with a high prevalence of both helminth infection and Plasmodium falciparum infection. Whole blood specimens were cultured with P. falciparum-infected red blood cells (iRBCs), and pro- and anti-inflammatory cytokines and immune regulatory molecules were measured. In response to iRBCs, levels of interleukin (IL)-10, but not tumor necrosis factor-alpha,were higher in samples from helminth-infected children than in those from uninfected children, as was expression of the regulatory molecules suppressor of cytokine signaling (SOCS)-3, Foxp3, and programmed death (PD)-1. Furthermore, a significant correlation was found between SOCS-3 gene expression and IL-10 production. These results indicate that the presence of helminth infection modulates the immune response to malarial parasites, making it more anti-inflammatory.
Asunto(s)
Antígenos de Protozoos/inmunología , Malaria/inmunología , Animales , Niño , Femenino , Ghana , Helmintiasis , Humanos , Interferón gamma/sangre , Interleucina-10/sangre , Interleucina-6/sangre , Malaria/complicaciones , Masculino , Plasmodium falciparum , Esquistosomiasis mansoni/complicaciones , Esquistosomiasis mansoni/inmunología , Linfocitos T/inmunología , Clima Tropical , Factor de Necrosis Tumoral alfa/sangreRESUMEN
BACKGROUND: Helminth infections are prevalent in rural areas of developing countries and have in some studies been negatively associated with allergic disorders and atopy. In this context little is known of the molecular mechanisms of modulation involved. We have characterized the innate immune responses, at the molecular level, in children according to their helminth infection status and their atopic reactivity to allergens. METHODOLOGY/PRINCIPAL FINDINGS: The mRNA expression of several genes of the innate immune system that have been associated with microbial exposure and allergy was examined in 120 school children in a rural area in Ghana. Helminth infections were common and atopy rare in the study area. The analysis of gene expression in ex vivo whole blood samples reflected the levels of corresponding proteins. Using this approach in a population of school children in whom the presence of Schistosoma haematobium infection was associated with protection from atopic reactivity, we found that the level of TLR2 and SOCS-3, genes associated with atopy in the children, were significantly downregulated by presence of S. haematobium infection. CONCLUSIONS: S. haematobium infections modulate the expression of genes of the innate immune system (TLR2 and SOCS-3); these are genes that are associated with increased allergic inflammatory processes, providing a molecular link between the negative association of this infection and atopy in rural children in Ghana.
Asunto(s)
Hipersensibilidad/inmunología , Pyroglyphidae/inmunología , Esquistosomiasis Urinaria/inmunología , Proteínas Supresoras de la Señalización de Citocinas/genética , Animales , Niño , Preescolar , Femenino , Citometría de Flujo , Ghana/epidemiología , Humanos , Hipersensibilidad/sangre , Inmunoglobulina E/sangre , Masculino , Reacción en Cadena de la Polimerasa , Esquistosomiasis Urinaria/epidemiología , Esquistosomiasis Urinaria/genética , Piel/inmunología , Proteína 1 Supresora de la Señalización de Citocinas , Proteína 3 Supresora de la Señalización de CitocinasRESUMEN
To determine mechanisms of neonatal parasite antigen (Ag)-specific immune suppression associated with placental Plasmodium falciparum infection, we isolated cord blood mononuclear cells (CBMCs) from Gabonese neonates born to mothers with differing histories of P. falciparum infection and performed ex vivo and in vitro studies to evaluate immune regulatory activity. We found increased ex vivo percentages of CD4(+)CD25(hi) and CD4(+)CD25(+)CTLA-4(+) cells and increased interleukin (IL)-10 responses to parasite Ag in vitro in CBMCs from neonates born to mothers with placental P. falciparum infection at delivery. Depleting CBMCs of CD4(+)CD25(+) cells before cell culture led to the abrogation of parasite Ag-specific IL-10 responses, to enhanced interferon- gamma responses, and to enhanced expression of CD25 on CD8(+) T cells and of major histocompatibility complex class I and II on monocytes. These data demonstrate that parasite Ag-specific CD4(+) regulatory cells are generated in utero as a consequence of placental P. falciparum infection.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Sangre Fetal/inmunología , Malaria Falciparum/inmunología , Placenta/parasitología , Complicaciones Parasitarias del Embarazo/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Animales , Femenino , Sangre Fetal/citología , Humanos , Recién Nacido , Malaria Falciparum/parasitología , Placenta/inmunología , Enfermedades Placentarias/inmunología , Enfermedades Placentarias/parasitología , Plasmodium falciparum/inmunología , Embarazo , Complicaciones Parasitarias del Embarazo/parasitologíaRESUMEN
Dendritic cells (DC) compose a heterogeneous population of cells that hold a leading role in initiating and directing immune responses. Although their function in recognizing, capturing, and presenting Ags is well defined, the molecular mechanisms that control their differentiation and immune functions are still largely unknown. In this study, we report the isolation and characterization of DC-SCRIPT, a novel protein encoded by an 8-kb mRNA that is preferentially expressed in DC. DC-SCRIPT is expressed in multiple DC subsets in vivo, including myeloid DC, plasmacytoid DC, and Langerhans cells. At the protein level, DC-SCRIPT consists of a proline-rich region, 11 C2H2-type zinc fingers, and an acidic region. Localization studies reveal that DC-SCRIPT resides in the nucleus and that nuclear localization is critically dependent on the zinc fingers. The protein displays no transcriptional activation properties according to assorted transactivation assays, but interacts with the corepressor C-terminal binding protein 1. Taken together, our results show that we have isolated a novel DC marker that could be involved in transcriptional repression. In contrast to other DC molecules, DC-SCRIPT identifies all DC subsets tested to date.
Asunto(s)
Células Dendríticas/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Represoras/metabolismo , Oxidorreductasas de Alcohol , Secuencia de Aminoácidos , Secuencia de Bases , Proteínas Portadoras , ADN Complementario/genética , Proteínas de Unión al ADN/metabolismo , Células Dendríticas/inmunología , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Técnicas In Vitro , Datos de Secuencia Molecular , Proteínas Nucleares/química , Proteínas Nucleares/genética , Fosfoproteínas/metabolismo , Unión Proteica , ARN Mensajero/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Represoras/química , Proteínas Represoras/genética , Homología de Secuencia de Aminoácido , Técnicas del Sistema de Dos Híbridos , Dedos de Zinc/genéticaRESUMEN
Westernized countries are suffering from an epidemic rise in immunologic disorders, such as childhood allergy. A popular explanation is that the increased prevalence in allergy is due to a diminished or altered exposure to gut-dwelling microbes, resulting in a disordered immunoregulation. Various population studies have provided a strong case for the involvement of helminth infections in this respect. Detailed analysis of helminth-induced immune responses showed that helminths not only prime for polarized Th2 responses but also potently induce T-cell hyporesponsiveness. Recently, it has been demonstrated that helminths induce suppressed host immune responses by the priming for regulatory T cells. It is proposed that this regulatory T cell-inducing activity accounts for the protection observed in the development of allergic disorders. It would be interesting to define and characterize particular helminth molecules that have profound immunomodulatory capacities as a target for therapeutic application in the treatment or prophylaxis of allergic manifestations.