RESUMEN
Age-related gut bacterial changes during infancy have been widely studied, but it remains still unknown how these changes are associated with immune cell composition. This study's aim was to explore if the temporal development of gut bacteria during infancy prospectively affects immune cell composition. Faecal bacteria and short-chain fatty acids were analysed from 67 PreventADALL study participants at four timepoints (birth to 12 months) using reduced metagenome sequencing and gas chromatography. Immune cell frequencies were assessed using mass cytometry in whole blood samples at 12 months. The infants clustered into four groups based on immune cell composition: clusters 1 and 2 showed a high relative abundance of naïve cells, cluster 3 exhibited increased abundance of classical- and non-classical monocytes and clusters 3 and 4 had elevated neutrophil levels. At all age groups, we did observe significant associations between the gut microbiota and immune cell clusters; however, these were generally from low abundant species. Only at 6 months of age we observed significant associations between abundant (>8%) species and immune cell clusters. Bifidobacterium adolescentis and Porphyromonadaceae are associated with cluster 1, while Bacteroides fragilis and Bifidobacterium longum are associated with clusters 3 and 4 respectively. These species have been linked to T-cell polarization and maturation. No significant correlations were found between short-chain fatty acids and immune cell composition. Our findings suggest that abundant gut bacteria at 6 months may influence immune cell frequencies at 12 months, highlighting the potential role of gut microbiota in shaping later immune cell composition.
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Heces , Microbioma Gastrointestinal , Humanos , Lactante , Microbioma Gastrointestinal/inmunología , Masculino , Femenino , Heces/microbiología , Recién Nacido , Bacterias/inmunología , Bacterias/clasificación , Ácidos Grasos Volátiles/metabolismo , Metagenoma , Estudios ProspectivosRESUMEN
BACKGROUND: In genetically modified (GM) crops there is a risk that the inserted genes may introduce new allergens and/or adjuvants into the food and feed chain. The MON810 maize, expressing the insecticidal Cry1Ab toxin, is grown in many countries worldwide. In animal models, intranasal and intraperitoneal immunisations with the purified Cry1Ab proteins have induced immune responses, and feeding trials with Cry1Ab-containing feed have revealed some altered immune responses. Previous investigations have primarily measured antibody responses to the protein, while investigations of clinical food allergy symptoms, or allergy promotion (adjuvant effect) associated with the Cry1Ab protein are largely missing. We aimed to investigate immunogenic, allergenic and adjuvant properties of purified Cry1Ab toxin (trypCry1Ab, i.e., trypsin activated Cry1Ab) in a mouse model of food allergy. METHOD: Female C3H/HeJ mice were immunized by intragastric gavage of 10 µg purified, trypsin activated Cry1Ab toxin (trypCry1Ab) alone or together with the food allergen lupin. Cholera toxin was added as a positive control for adjuvant effect to break oral tolerance. Clinical symptoms (anaphylaxis) as well as humoral and cellular responses were assessed. RESULTS: In contrast to results from previous airway investigations, we observed no indication of immunogenic properties of trypCry1Ab protein after repeated intragastric exposures to one dose, with or without CT as adjuvant. Moreover, the results indicated that trypCry1Ab given by the intragastric route was not able to promote allergic responses or anaphylactic reactions against the co-administered allergen lupin at the given dose. CONCLUSION: The study suggests no immunogenic, allergenic or adjuvant capacity of the given dose of trypCry1Ab protein after intragastric exposure of prime aged mice.
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Alérgenos/inmunología , Criptocromos/inmunología , Hipersensibilidad a los Alimentos/inmunología , Proteínas de Insectos/inmunología , Intestinos/inmunología , Extractos Vegetales/inmunología , Zea mays/inmunología , Animales , Toxinas Bacterianas/inmunología , Criptocromos/metabolismo , Grano Comestible , Femenino , Alimentos Modificados Genéticamente , Inmunoglobulina E/metabolismo , Intestinos/microbiología , Lupinus/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Organismos Modificados Genéticamente , Proteolisis , Tripsina/metabolismo , Zea mays/genéticaRESUMEN
Most children are exposed to perfluoroalkyl substances (PFASs) through placental transfer, breastfeeding, and other environmental sources. To date, there are no validated tools to estimate exposure and body burden during infancy and childhood. In this study, we aimed to (i) develop a two-generation pharmacokinetic model of prenatal and postnatal exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonate (PFOS), and perfluorohexanesulfonate (PFHxS); and to (ii) evaluate it against measured children's levels in two studies. We developed a pharmacokinetic model consisting of a maternal and a child compartment to simulate lifetime exposure in women and transfer to the child across the placenta and through breastfeeding. To evaluate the model, we performed simulations for each mother-child dyad from two studies in which maternal PFAS levels at delivery and children's PFAS levels were available. Model predictions based on maternal PFAS levels, sex of child, body weight, and duration of breastfeeding explained between 52% and 60% of the variability in measured children's levels at 6 months of age and between 52% and 62% at 36 months. Monte Carlo simulations showed that the daily intake through breastfeeding and resulting internal PFAS levels can be much higher in nursing infants than in mothers. This pharmacokinetic model shows potential for postnatal exposure assessment in the context of epidemiological studies and risk assessment.
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Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Ambientales/efectos adversos , Contaminantes Ambientales/farmacocinética , Adulto , Ácidos Alcanesulfónicos/efectos adversos , Ácidos Alcanesulfónicos/farmacocinética , Lactancia Materna , Caprilatos/efectos adversos , Caprilatos/farmacocinética , Niño , Preescolar , Contaminantes Ambientales/sangre , Femenino , Fluorocarburos/efectos adversos , Fluorocarburos/farmacocinética , Humanos , Lactante , Recién Nacido , Masculino , Modelos Teóricos , Método de Montecarlo , Madres , Placenta/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ácidos Sulfónicos/efectos adversos , Ácidos Sulfónicos/farmacocinéticaRESUMEN
Epidemiological evidence suggesting that exposure to traffic air pollution may enhance sensitization to common allergens in children is increasing, and animal studies support biological plausibility and causality. The effect of air pollution on respiratory symptoms was suggested to be gender dependent. Previous studies showed that allergy-promoting activity of polystyrene particles (PSP) increased with decreasing particle size after footpad injection of mice. The primary aim of this study was to confirm the influence of particle size on the immunoglobulin E (IgE)-promoting capacity of particles in an airway allergy model. A second aim was to examine whether the allergy-promoting capacity of particles was influenced by gender. Female and male mice were intranasally exposed to the allergen ovalbumin (OVA) with or without ultrafine, fine, or coarse PSP modeling the core of ambient air particles. After intranasal booster immunizations with OVA, serum levels of OVA-specific IgE antibodies, and also markers of airway inflammation and cellular responses in the lung-draining mediastinal lymph nodes (MLN), were determined. PSP of all sizes promoted allergic responses, measured as increased serum concentrations of OVA-specific IgE antibodies. Further, PSP produced eosinophilic airway inflammation and elevated MLN cell numbers as well as numerically reducing the percentage of regulatory T cells. Ultrafine PSP produced stronger allergic responses to OVA than fine and coarse PSP. Although PSP enhanced sensitization in both female and male mice, significantly higher IgE levels and numbers of eosinophils were observed in females than males. However, the allergy-promoting effect of PSP was apparently independent of gender. Thus, our data support the notion that ambient air particle pollution may affect development of allergy in both female and male individuals.
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Hipersensibilidad/patología , Ovalbúmina/efectos adversos , Material Particulado/efectos adversos , Poliestirenos/efectos adversos , Hipersensibilidad Respiratoria/inducido químicamente , Animales , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Femenino , Inmunoglobulina E/sangre , Inflamación/inducido químicamente , Inflamación/patología , Ganglios Linfáticos/citología , Masculino , Ratones , Tamaño de la Partícula , Factores Sexuales , Linfocitos T Colaboradores-Inductores , Linfocitos T ReguladoresRESUMEN
Exposure to the endocrine disruptor (ED) bisphenol A (BPA) used in polycarbonate plastic and epoxy resins appears ubiquitous since BPA can be found in over 90% of analyzed urine samples from all age groups. There is a parallel occurrence of increased prevalence in type 1 diabetes mellitus (T1DM) and an increased exposure to EDs the last decades. T1DM is caused by insulin deficiency due to autoimmune destruction of insulin producing pancreatic beta cells and has been suggested to be induced by various environmental factors acting together with a genetic predisposition. The objective of the present study was to investigate the effect of BPA (0, 1 and 100 mg/l BPA in the drinking water) on T1DM development in nonobese diabetic (NOD) mice, spontaneously developing T1DM. Histological evaluation of pancreas from 12-weeks-old female mice revealed significantly increased insulitis in mice exposed to 1 mg/l BPA, while the insulitis was less severe at the higher BPA exposure. Serum glucose levels in the 1 mg/ml BPA group tended to be hyperglycaemic, also indicating an accelerated onset of T1DM. The high BPA exposure seemed to counteract the diabetes development in females and also in male NOD mice for both BPA concentrations. Prior to insulitis, both BPA concentrations resulted in increased apoptosis and reduced numbers of tissue resident macrophages in pancreatic islets. In conclusion, long-term BPA exposure at a dose three times higher than the tolerable daily intake of 50 µg/kg, appeared to accelerate spontaneous insulitis and diabetes development in NOD mice.
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Compuestos de Bencidrilo/toxicidad , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Tipo 1/inducido químicamente , Disruptores Endocrinos/toxicidad , Predisposición Genética a la Enfermedad , Páncreas/efectos de los fármacos , Fenoles/toxicidad , Animales , Apoptosis/efectos de los fármacos , Autoanticuerpos/sangre , Glucemia/análisis , Citocinas/sangre , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Relación Dosis-Respuesta a Droga , Femenino , Interacción Gen-Ambiente , Insulina/inmunología , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/inmunología , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Ratones , Ratones Endogámicos NOD , Páncreas/inmunología , Páncreas/metabolismo , Páncreas/patologíaRESUMEN
Humans are daily exposed to mineral oil saturated hydrocarbons (MOSH) from the diet. We exposed female Fischer 344 rats to a broad mixture and sub-fractions of MOSH. Chemical characterization of the MOSH mixture used and material accumulated in rat tissues were previously reported (Barp et al. 2017a, 2017b). Rats were exposed to feed containing 0-4000 mg/kg broad MOSH mixture for 30, 60, 90 and 120 days; and for 120 days to feed containing different MOSH fractions: i) mainly molecular masses < C25 (S-C25), ii) dewaxed, mainly molecular masses > C25 (L-C25) and iii) the L-C25 fraction mixed with wax largely consisting of n-alkanes > C25 (L-C25W). Treatments related effects were increased liver and spleen weight, as well as vacuolization and granuloma formation with lymphoid cell clusters in the liver, but effects varied strongly between the MOSH fractions tested. We conclude that increased liver and spleen weights were related to accumulated n-alkanes (wax) above C25, presumably not relevant for humans, but also to MOSH from S-C25, mainly consisting of iso-alkanes and substituted cycloalkanes below C25 with a small proportion of n-alkanes. Induction of liver granuloma appeared to be related to n-alkanes > C25 and not to the accumulated amount of MOSH. Immune responses to an injected antigen were not affected. Iso-alkanes and substituted cycloalkanes accumulating in rat liver and spleen were similar to those accumulating in humans.
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Food allergy is an increasing public health challenge worldwide. It has recently been hypothesized that the increase in exposure to intestinal epithelial barrier-damaging biological and chemical agents contribute to this development. In animal models, exposure to adjuvants with a food allergen has been shown to promote sensitization and development of food allergy, and barrier disrupting capacities have been suggested to be one mechanism of adjuvant action. Here, we investigated how gut barrier disrupting compounds affected food allergy development in a mouse model of peanut allergy. Sensitization and clinical peanut allergy in C3H/HEOuJ mice were assessed after repeated oral exposure to peanut extract together with cholera toxin (CT; positive control), the mycotoxin deoxynivalenol (DON), house dust mite (HDM) or the pesticide glyphosate (GLY). In addition, we investigated early effects 4 to 48â h after a single exposure to the compounds by assessing markers of intestinal barrier permeability, alarmin production, intestinal epithelial responses, and local immune responses. CT and DON exerted adjuvant effects on peanut allergy development assessed as clinical anaphylaxis in mice. Early markers were affected only by DON, observed as increased IL-33 (interleukin 33) and thymic stromal lymphopoietin (TSLP) alarmin production in intestines and IL-33 receptor ST2 in serum. DON also induced an inflammatory immune response in lymph node cells stimulated with lipopolysaccharide (LPS). HDM and GLY did not clearly promote clinical food allergy and affected few of the early markers at the doses tested. In conclusion, oral exposure to CT and DON promoted development of clinical anaphylaxis in the peanut allergy mouse model. DON, but not CT, affected the early markers measured in this study, indicating that DON and CT have different modes of action at the early stages of peanut sensitization.
RESUMEN
Humans are daily exposed to mineral oil saturated hydrocarbons (MOSH) from the diet. We exposed female Fischer 344 rats to a broad mixture and sub-fractions of MOSH. Chemical characterization of the MOSH mixture used and material accumulated in rat tissues were previously reported. Rats were exposed to feed containing 0-4000â¯mg/kg broad MOSH mixture for 30, 60, 90 and 120 days; and for 120 days to feed containing different MOSH fractions: i) mainly molecular massesâ¯<â¯C25 (S-C25), ii) dewaxed, mainly molecular massesâ¯>â¯C25 (L-C25) and iii) the L-C25 fraction mixed with wax largely consisting of n-alkanesâ¯>â¯C25 (L-C25W). Treatments related effects were increased liver and spleen weight, as well as vacuolization and granuloma formation with lymphoid cell clusters in the liver, but effects varied strongly between the MOSH fractions tested. We conclude that increased liver and spleen weights were mainly related to accumulated iso-alkanes and substituted cycloalkanes, but also wax n-alkanes. Induction of liver granuloma appeared to be related to n-alkanesâ¯>â¯C25 and not to the accumulated amount of MOSH. Immune responses to an injected antigen were not affected. MOSH fractions associated with increased liver and spleen weights were similar to those accumulating in humans.
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Hidrocarburos/toxicidad , Hígado/efectos de los fármacos , Aceite Mineral/toxicidad , Animales , Femenino , Granuloma/etiología , Granuloma/metabolismo , Humanos , Hidrocarburos/química , Hidrocarburos/metabolismo , Hígado/metabolismo , Aceite Mineral/química , Aceite Mineral/metabolismo , Ratas , Ratas Endogámicas F344 , Bazo/efectos de los fármacos , Bazo/metabolismoRESUMEN
There is growing evidence that in addition to augmenting the severity of asthma and allergic diseases, particulate air pollution also increases the incidence of allergy and asthma. We studied the adjuvant effect of particles from wood smoke and road traffic on the immune response to the allergen ovalbumin (OVA). OVA with and without particles was injected into one hind footpad of Balb/cA mice. All particles together with OVA significantly increased the level of OVA-specific immunoglobulin E (IgE) in serum, compared to groups given OVA or particles alone. Reference diesel exhaust particles (DEP) with OVA induced the highest levels of IgE, whereas no clear difference was observed between particles from road traffic and wood smoke. Road traffic particles collected in the autumn induced higher IgE values with OVA than corresponding particles collected during the winter season when studded tires are used, suggesting that studded tire-generated road pavement particles have less allergy adjuvant activity than exhaust particles. Compared to OVA or particles alone, all particles with OVA increased popliteal lymph node cell numbers, cell proliferation, ex vivo secretion of IL-4 and IL-10 after ConA stimulation, and the expression of several cell surface molecules (CD19, MHC class II, CD86 and CD23). Wood smoke particles with OVA induced somewhat higher cellular responses than road traffic particles, but less than DEP with OVA which seemed to be the most potent particle in inducing cellular as well as antibody responses. Thus, wood smoke particles had about the same capacity to enhance allergic sensitization as road traffic particles, but less than diesel exhaust particles.
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Adyuvantes Inmunológicos/farmacología , Contaminantes Atmosféricos/farmacología , Alérgenos/farmacología , Inmunoglobulina E/sangre , Animales , Antígenos CD/metabolismo , Recuento de Células , Proliferación Celular/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Combinación de Medicamentos , Femenino , Miembro Posterior , Inmunoglobulina G/sangre , Ensayo del Nódulo Linfático Local , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/inmunología , Tamaño de la Partícula , Humo , Hollín/farmacología , Emisiones de Vehículos , MaderaRESUMEN
Both autoimmune disease prevalence and exposure to immunotoxic chemicals have increased the last decades. As a first screening of immunotoxic chemicals possibly affecting development of autoimmunity through attenuated macrophage function, we demonstrate a promising model measuring macrophage function in isolated peritoneal macrophages (PCM) from Wistar rats and C57Bl/6 mice. Immunotoxic effects of bisphenol A (BPA) and a selection of perfluoroalkyl acids (PFAAs) were analysed in vitro assessing phagocytic function of macrophages from different sources. Phagocytosis was reduced in PCM of C57Bl/6 mice and Wistar rats after BPA and perfluoroundecanoic acid (PFUnDA) exposure, but not in macrophages derived from human and rat monocyte derived macrophages (MDM). On the other hand, in vitro exposure to mixtures of persistent organic pollutants (POPs) showed similar reductions in rat PCM and rat and human MDM phagocytosis. Reduced phagocytosis was partly due to cytotoxicity. PCM isolated from non-obese diabetic (NOD) mice, interleukin 1α/ß knockout (IL-1KO) mice and new-born rats were less sensitive to the xenobiotics than PCM from adult wild type rodents. Finally, in vivo studies with NOD mice verified that POP exposure also decreased the number of pancreatic macrophages in pancreatic islets, reflecting early signs of autoimmunity development, similarly as previously described for BPA.
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Macrófagos Peritoneales/efectos de los fármacos , Macrófagos/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Xenobióticos/toxicidad , Animales , Animales Recién Nacidos , Compuestos de Bencidrilo/toxicidad , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Contaminantes Ambientales/toxicidad , Ácidos Grasos/toxicidad , Femenino , Fluorocarburos/toxicidad , Humanos , Interleucina-1/genética , Macrófagos/inmunología , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Fenoles/toxicidad , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The concentration of mould-specific IgG antibodies in serum may objectively indicate mould exposure and can help identifying exposed individuals. Although inhaled spores probably are the most important source of mould exposure, the commonly used methods for detecting mould-specific IgG antibodies are based on extracts from all mould components, with only low contribution from spores. We have developed a flow cytometric method using surface antigens on mould spores for quantifying mould-specific IgG antibodies in serum. Flow cytometric results were evaluated by comparison with ImmunoCap and ELISA measurements. The flow cytometric assay showed a broad linear dose-dependency and correlated moderately to strongly (r=0.41-0.97) with ImmunoCap and ELISA measurements. The IgG antibody binding was studied in detail by immunolabelling in scanning electron microscopy (SEM), revealing that morphology and IgG antibody binding differed among spores, both within and between mould strains. Germination studies by flow cytometry and SEM showed that IgG antibody binding to mould spores was altered during germination due to loss of coat. The present spore based antibody assay are simple and suitable for quantification of mould-specific IgG antibodies in serum, and includes specificity to other and possibly more relevant antigens than existing methods.
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Antígenos Fúngicos/inmunología , Citometría de Flujo/métodos , Inmunoglobulina G/sangre , Microscopía Electrónica de Rastreo/métodos , Hongos Mitospóricos/inmunología , Esporas Fúngicas/inmunología , Ensayo de Inmunoadsorción Enzimática , Humanos , Hongos Mitospóricos/ultraestructura , Esporas Fúngicas/ultraestructuraRESUMEN
[This corrects the article DOI: 10.1155/2015/343479.]. In the published paper "Genetic and Diet-Induced Obesity Increased Intestinal Tumorigenesis in the Double Mutant Mouse Model Multiple Intestinal Neoplasia X Obese via Disturbed Glucose Regulation and Inflammation" [1] we mistakenly wrote IL-1ß instead of IL-6 in Tables 2 and 3. In addition, IL-6 was not included in the text below the tables stating that it was measured by flow cytometer as was TNFα. The corrected tables are presented here.
RESUMEN
Perfluoralkylated substances (PFAS) are classified as persistent, bioaccumulative and toxic substances and are widespread environmental contaminants. Humans are exposed through food, drinking water and air. We have previously reported that bisphenol A accelerates spontaneous diabetes development in non-obese diabetic (NOD) mice and observed in the present study that perfluoroundecanoic acid, PFUnDA, increased insulitis development, a prerequisite for diabetes development in NOD mice. We exposed NOD mice to PFUnDA in drinking water (3, 30 and 300 µg/l) at mating, during gestation and lactation and until 30 weeks of age. After 300 µg/l PFUnDA exposure, we report (i) increased pancreatic insulitis, (ii) increased number of apoptotic cells in pancreatic islets prior to insulitis and (iii) decreased phagocytosis in peritoneal macrophages. There was also a trend of decreased number of tissue resident macrophages in pancreatic islets prior to insulitis after exposure to 300 µg/l, and altered cytokine secretion in activated splenocytes after exposure to 3 µg/l PFUnDA. Although insulitis is a prerequisite for autoimmune diabetes, the accelerated insulitis was not associated with accelerated diabetes development. Instead, the incidence of diabetes tended to be reduced in the animals exposed to 3 and 30 µg/l PFUnDA, suggesting a non-monotonic dose response. The effects of PFUnDA exposure on increased apoptosis in pancreas and reduced macrophage function as well as accelerated insulitis development in NOD mice, may also be relevant for human insulitis. Further observational autoimmune diabetes clinical cohort studies and animal experiments for PFUnDA as well as other PFASs are therefore encouraged.
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Food allergy is a major health problem of increasing concern. The insufficiency of protein sources for human nutrition in a world with a growing population is also a significant problem. The introduction of new protein sources into the diet, such as newly developed innovative foods or foods produced using new technologies and production processes, insects, algae, duckweed, or agricultural products from third countries, creates the opportunity for development of new food allergies, and this in turn has driven the need to develop test methods capable of characterizing the allergenic potential of novel food proteins. There is no doubt that robust and reliable animal models for the identification and characterization of food allergens would be valuable tools for safety assessment. However, although various animal models have been proposed for this purpose, to date, none have been formally validated as predictive and none are currently suitable to test the allergenic potential of new foods. Here, the design of various animal models are reviewed, including among others considerations of species and strain, diet, route of administration, dose and formulation of the test protein, relevant controls and endpoints measured.
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BACKGROUND: There is increasing epidemiological and experimental evidence for an aggravating effect of particulate air pollution on asthma and allergic symptoms and, to a lesser extent, on allergic sensitization. Genetic factors appear to influence not only the magnitude, but also the quality of the adjuvant effect of particles with respect to allergen-specific IgE (Th2-associated) and IgG2a (Th1-associated) responses. In the present study, we aimed to investigate how the genetic background influences the responses to the allergen and particles alone and in combination. We examined how polystyrene particles (PSP) affected the IgE and IgG2a responses against the model allergen ovalbumin (OVA), after subcutaneous injection into the footpad of BALB/cA, BALB/cJ, NIH and C3H/HeN mice, Further, ex vivo IL-4, IFN-gamma and IL-10 cytokine secretion by Con A-stimulated cells from the draining popliteal lymph node (PLN) five days after injection of OVA and PSP separately or in combination was determined. RESULTS: PSP injected with OVA increased the levels of OVA-specific IgE antibodies in all strains examined. In contrast, the IgG2a levels were significantly increased only in NIH and C3H/HeN mice. PSP in the presence of OVA increased cell numbers and IL-4, IL-10 and IFN-gamma levels in BALB/cA, NIH and C3H/HeN mice, with the exception of IFN-gamma in NIH mice. However, each mouse strain had their unique pattern of response to OVA+PSP, OVA and PSP, and also their unique background cytokine response (i.e. the cytokine response in cells from mice injected with buffer only). CONCLUSION: Genetic factors (i.e. the strain of mice) influenced the susceptibility to the adjuvant effect of PSP on both secondary antibody responses and primary cellular responses in the lymph node, as well as the cellular responses to both OVA and PSP given separately. Interestingly, PSP alone induced cytokine responses in the lymph node in some of the mouse strains. Furthermore, we found that the ex vivo cytokine patterns did not predict the in vivo Th2- and Th1-associated antibody response patterns in the different mouse strains. The results indicate that insoluble particles act by increasing the inherent response to the allergen, and that the genetic background may determine whether an additional Th1-associated component is added to the response.
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Adyuvantes Inmunológicos/toxicidad , Alérgenos/inmunología , Citocinas/metabolismo , Inmunoglobulina E/biosíntesis , Inmunoglobulina G/biosíntesis , Ratones Endogámicos/inmunología , Ovalbúmina/inmunología , Poliestirenos/toxicidad , Adyuvantes Inmunológicos/farmacología , Alérgenos/toxicidad , Animales , Formación de Anticuerpos/genética , Concanavalina A/farmacología , Femenino , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos/genética , Microesferas , Ovalbúmina/toxicidad , Tamaño de la Partícula , Poliestirenos/farmacologíaRESUMEN
Diesel exhaust particles, and polystyrene particles (PSP) as a model for the insoluble particle core, have an adjuvant effect on allergen-specific IgE production in mice. We therefore examined the primary immune response in the draining popliteal lymph node (PLN) to the allergen ovalbumin (OVA) injected together with polystyrene particles into the footpad of BALB/cA mice. Similar numbers of particle-containing cells were observed in the draining lymph node on day 1 after injection of PSP alone or OVA + PSP, the numbers increasing continuously until day 21. The total lymph node cell numbers increased three to four times in the OVA + PSP group compared to both OVA and PSP groups, peaking on day 5. The increase in B cell numbers was twice the increase in T cell numbers. On day 5, OVA + PSP increased the expression of most surface markers measured (MHC class II, CD86, CD23, CD69) compared to OVA and PSP. Further, the ex vivo production of IL-4 and IL-10 by PLN cells from OVA + PSP-injected animals was increased. In conclusion, whereas PSP alone did not influence any of the immunologic markers studied, the adjuvant effect of PSP on the IgE antibody response to OVA was associated with an early increased primary cellular response in the draining lymph node.
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Inmunoglobulina E/sangre , Ganglios Linfáticos/inmunología , Ovalbúmina/inmunología , Poliestirenos/inmunología , Emisiones de Vehículos , Adyuvantes Inmunológicos , Animales , Linfocitos B/citología , Linfocitos B/inmunología , Islas de CpG/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Inmunización , Inmunoglobulina E/biosíntesis , Inmunoglobulina E/inmunología , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunofenotipificación , Cinética , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Linfocitos T/citología , Linfocitos T/inmunologíaRESUMEN
In the RAIAP (respiratory allergy and inflammation due to ambient particles) project, qualitative properties of ambient air particles from Amsterdam, Oslo, Lodz and Rome were investigated in relation to inflammation and allergy. Most collected particle fractions were found to increase the allergen-specific IgE and IgG2a responses after subcutaneous injection of particles with allergen in mice. However, some fractions appeared to skew the antibody response towards more Th1- or Th2-associated antibody isotypes, and the fine fractions were found to be more potent than the coarse fractions with regard to IgE adjuvant activity. In the present study we investigated the cellular response in the draining lymph node 5 days after a subcutaneous injection of selected RAIAP particle fractions. The particles (100 microg) were injected into both hind footpads of BALB/cA mice, in the presence or absence of the allergen ovalbumin (OVA, 50 microg). We also studied if the coarse and fine RAIAP particle fractions affected the cellular responses to OVA differently. The number of lymph node cells, as well as the relative number of B and T lymphocytes and T helper cells were determined. Expression of cell surface molecules (MHC class II, CD86 and CD23) and ex vivo cytokine production (IL-4, IL-10 and IFN-gamma) by the lymph node cells were measured. Overall, particles in the presence of allergen enhanced the levels of the various cellular parameters compared to allergen alone or particles alone. In the absence of allergen, ambient air particles, in contrast to diesel exhaust particles, marginally affected some cellular parameters. By histological examination of the lymph node, the particles appeared to be scattered between the lymphocytes, often localised within macrophage-like (acid phosphatase positive) cells. The cell parameters measured could, for the individual sample, neither predict the degree of a Th2- or Th1-skewed antibody response, nor the stronger antibody adjuvant capacity of the fine than the coarse particle fractions. In conclusion, we have shown that coarse and fine ambient air particles from different European cities enhance the cellular response in the draining lymph node after injection with an allergen. In the absence of allergen, ambient particles only marginally affected the cellular parameters.
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Contaminantes Atmosféricos/toxicidad , Linfocitos B/efectos de los fármacos , Ganglios Linfáticos/efectos de los fármacos , Células TH1/efectos de los fármacos , Células Th2/efectos de los fármacos , Emisiones de Vehículos/toxicidad , Animales , Formación de Anticuerpos , Antígenos CD/análisis , Linfocitos B/inmunología , Antígeno B7-2 , Antígenos CD4/análisis , Células Cultivadas , Ciudades , Europa (Continente) , Femenino , Genes MHC Clase II/inmunología , Inyecciones Subcutáneas , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Glicoproteínas de Membrana/análisis , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Tamaño de la Partícula , Receptores de IgE/análisis , Células TH1/inmunología , Células Th2/inmunologíaRESUMEN
Type 1 diabetes mellitus (T1DM) is an autoimmune disease, where destruction of beta-cells causes insulin deficiency. The incidence of T1DM has increased in the last decades and cannot entirely be explained by genetic predisposition. Several environmental factors are suggested to promote T1DM, like early childhood enteroviral infections and nutritional factors, but the evidence is inconclusive. Prenatal and early life exposure to environmental pollutants like phthalates, bisphenol A, perfluorinated compounds, PCBs, dioxins, toxicants, and air pollutants can have negative effects on the developing immune system, resulting in asthma-like symptoms and increased susceptibility to childhood infections. In this review the associations between environmental chemical exposure and T1DM development is summarized. Although information on environmental chemicals as possible triggers for T1DM is sparse, we conclude that it is plausible that environmental chemicals can contribute to T1DM development via impaired pancreatic beta-cell and immune-cell functions and immunomodulation. Several environmental factors and chemicals could act together to trigger T1DM development in genetically susceptible individuals, possibly via hormonal or epigenetic alterations. Further observational T1DM cohort studies and animal exposure experiments are encouraged.
Asunto(s)
Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/inmunología , Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Ambientales/envenenamiento , Animales , Humanos , Medición de RiesgoRESUMEN
We have studied how spontaneous or carcinogen-induced intestinal tumorigenesis was affected by genetic or diet-induced obesity in C57BL/6J-Apc (Min/+) X C57BL/6J-Lep (ob/+) mice. Obesity was induced by the obese (ob) mutation in the lep gene coding for the hormone leptin, or by a 45% fat diet. The effects of obesity were examined on spontaneous intestinal tumors caused by the multiple intestinal neoplasia (Min) mutation in the adenomatous polyposis coli (Apc) gene and on tumors induced by the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). F1 ob/ob (homozygous mutated) mice had increased body weight (bw) and number of spontaneous and PhIP-induced small intestinal tumors (in Apc (Min/+) mice), versus ob/wt (heterozygous mutated) and wt/wt mice (homozygous wild-type). A 45% fat diet exacerbated bw and spontaneous tumor numbers versus 10% fat, but not PhIP-induced tumors. Except for bw, ob/wt and wt/wt were not significantly different. The obesity caused hyperglucosemia and insulinemia in ob/ob mice. A 45% fat diet further increased glucose, but not insulin. Inflammation was seen as increased TNFα levels in ob/ob mice. Thus the results implicate disturbed glucose regulation and inflammation as mechanisms involved in the association between obesity and intestinal tumorigenesis. Ob/ob mice had shorter lifespan than ob/wt and wt/wt mice.