| 1. |
- Dzidic, Majda, et al.
(författare)
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Oral microbiome development during childhood: an ecological succession influenced by postnatal factors and associated with tooth decay
- 2018
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Ingår i: The ISME Journal. - : NATURE PUBLISHING GROUP. - 1751-7362 .- 1751-7370. ; 12:9, s. 2292-2306
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Tidskriftsartikel (refereegranskat)abstract
- Information on how the oral microbiome develops during early childhood and how external factors influence this ecological process is scarce. We used high-throughput sequencing to characterize bacterial composition in saliva samples collected at 3, 6, 12, 24 months and 7 years of age in 90 longitudinally followed children, for whom clinical, dietary and health data were collected. Bacterial composition patterns changed through time, starting with "early colonizers", including Streptococcus and Veillonella; other bacterial genera such as Neisseria settled after 1 or 2 years of age. Dental caries development was associated with diverging microbial composition through time. Streptococcus cristatus appeared to be associated with increased risk of developing tooth decay and its role as potential biomarker of the disease should be studied with species-specific probes. Infants born by C-section had initially skewed bacterial content compared with vaginally delivered infants, but this was recovered with age. Shorter breastfeeding habits and antibiotic treatment during the first 2 years of age were associated with a distinct bacterial composition at later age. The findings presented describe oral microbiota development as an ecological succession where altered colonization pattern during the first year of life may have long-term consequences for childs oral and systemic health.
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| 2. |
- Rodríguez, Juan Miguel, et al.
(författare)
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The composition of the gut microbiota throughout life, with an emphasis on early life
- 2015
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Ingår i: Microbiological Ecology in Health and Disease. - : Taylor & Francis. - 0891-060X .- 1651-2235. ; 26
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Forskningsöversikt (refereegranskat)abstract
- The intestinal microbiota has become a relevant aspect of human health. Microbial colonization runs in parallel with immune system maturation and plays a role in intestinal physiology and regulation. Increasing evidence on early microbial contact suggest that human intestinal microbiota is seeded before birth. Maternal microbiota forms the first microbial inoculum, and from birth, the microbial diversity increases and converges toward an adult-like microbiota by the end of the first 3-5 years of life. Perinatal factors such as mode of delivery, diet, genetics, and intestinal mucin glycosylation all contribute to influence microbial colonization. Once established, the composition of the gut microbiota is relatively stable throughout adult life, but can be altered as a result of bacterial infections, antibiotic treatment, lifestyle, surgical, and a long-term change in diet. Shifts in this complex microbial system have been reported to increase the risk of disease. Therefore, an adequate establishment of microbiota and its maintenance throughout life would reduce the risk of disease in early and late life. This review discusses recent studies on the early colonization and factors influencing this process which impact on health.
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| 3. |
- Abrahamsson, Thomas R, 1968-, et al.
(författare)
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Probiotics in prevention of IgE-associated eczema : a double-blind, randomized, placebo-controlled trial
- 2007
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 119:5, s. 1174-1180
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: An altered microbial exposure may underlie the increase of allergic diseases in affluent societies. Probiotics may alleviate and even prevent eczema in infants. OBJECTIVE: To prevent eczema and sensitization in infants with a family history of allergic disease by oral supplementation with the probiotic Lactobacillus reuteri. METHODS: Double-blind, randomized, placebo-controlled trial, which comprised 232 families with allergic disease, of whom 188 completed the study. The mothers received L reuteri ATCC 55730 (1 x 10(8) colony forming units) daily from gestational week 36 until delivery. Their babies then continued with the same product from birth until 12 months of age and were followed up for another year. Primary outcome was allergic disease, with or without positive skin prick test or circulating IgE to food allergens. RESULTS: The cumulative incidence of eczema was similar, 36% in the treated versus 34% in the placebo group. The L reuteri group had less IgE-associated eczema during the second year, 8% versus 20% (P = .02), however. Skin prick test reactivity was also less common in the treated than in the placebo group, significantly so for infants with mothers with allergies, 14% versus 31% (P = .02). Wheeze and other potentially allergic diseases were not affected. CONCLUSION: Although a preventive effect of probiotics on infant eczema was not confirmed, the treated infants had less IgE-associated eczema at 2 years of age and therefore possibly run a reduced risk to develop later respiratory allergic disease. CLINICAL IMPLICATION: Probiotics may reduce the incidence of IgE-associated eczema in infancy.
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| 4. |
- Björkander, Sofia, et al.
(författare)
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Childhood allergy is preceded by an absence of gut lactobacilli species and higher levels of atopy-related plasma chemokines
- 2020
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 202:3, s. 288-299
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Tidskriftsartikel (refereegranskat)abstract
- Alterations in the composition and reduced diversity of the infant microbiome are associated with allergic disease in children. Further, an altered microbiota is linked to immune dysregulation, including skewing of different T helper (Th) subsets, which is also seen in atopic individuals. The aim of this study was, therefore, to investigate the associations between gut lactobacilli and Th‐related plasma factors in allergy development during childhood. A total of 194 children with known allergy status at 1 year of age were followed to 10 years of age. We used real‐time polymerase chain reaction (PCR) to investigate the presence of three lactobacilli species (Lactobacillus casei, L. paracasei, L. rhamnosus) in infant fecal samples (collected between 1 week and 2 months of age) from a subgroup of children. Plasma chemokines and cytokines were quantified at 6 months and at 1, 2, 5 and 10 years of age with Luminex or enzyme‐linked immunosorbent assay (ELISA). Fractional exhaled nitrogen oxide (FeNO) was measured and spirometry performed at 10 years of age. The data were analysed by non‐parametric testing and a logistic regression model adjusted for parental allergy. An absence of these lactobacilli and higher levels of the chemokines BCA‐1/CXCL13, CCL17/TARC, MIP‐3α/CCL20 and MDC/CCL22 in plasma at 6 months of age preceded allergy development. The presence of lactobacilli associated with lower levels of atopy‐related chemokines during infancy, together with higher levels of interferon (IFN)‐γ and lower FeNO during later childhood. The results indicate that the presence of certain lactobacilli species in the infant gut may influence allergy‐related parameters in the peripheral immune system, and thereby contribute to allergy protection.
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| 5. |
- Böttcher (Fagerås), Malin, et al.
(författare)
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Endotoxin levels in Estonian and Swedish house dust and atopy in infancy
- 2003
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Ingår i: Clinical and Experimental Allergy. - : Wiley. - 1365-2222 .- 0954-7894. ; 33:3, s. 295-300
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Tidskriftsartikel (refereegranskat)abstract
- Background Immune responses, including those to allergens, may be T helper (Th)2 skewed in newborns. In order to redress the fetal Th1/Th2 imbalance, Th1-stimulating factors, such as bacterial endotoxin, may be required. The increasing prevalence and severity of atopic diseases in industrialized countries, which are in marked contrast with the low prevalence of allergy among children in the formerly socialist countries of Europe, have been suggested to be caused by a reduced microbial stimulation.Aim To relate the endotoxin levels in house dust from two countries with a low (Estonia) and a high (Sweden) prevalence of allergy to the development of atopic disease and sensitization in the children during the first 2 years of life.Methods The study included 108 children from Tartu, Estonia and 111 children from Linköping, Sweden. Skin prick tests were performed at 3, 6, 12 and 24 months of age, and questionnaires were distributed to the families. At 24 months, a paediatrician examined the children. Dust samples were collected from mattresses and carpets and the endotoxin concentration was determined by a chromogenic Limulus assay.Results The endotoxin levels were higher in Estonian than in Swedish house dust (median levels 29 (range 0.25–280) and 14 (range 0.25–99) EU/mg dust, respectively, P < 0.001). Furthermore, the levels were inversely related to the development of atopic disease and sensitization in the Swedish, but not in the Estonian, children.Conclusions The low prevalence of atopic disease in Estonia may, at least in part, be related to the high endotoxin levels in this country. The findings support that high levels of endotoxin, or other bacterial products with Th1-stimulating properties, might protect children from developing atopic disease.
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| 6. |
- Dzidic, Majda, et al.
(författare)
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Oral microbiota maturation during the first 7 years of life in relation to allergy development
- 2018
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : WILEY. - 0105-4538 .- 1398-9995. ; 73:10, s. 2000-2011
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Tidskriftsartikel (refereegranskat)abstract
- Background Allergic diseases have become a major public health problem in affluent societies. Microbial colonization early in life seems to be critical for instructing regulation on immune system maturation and allergy development in children. Even though the oral cavity is the first site of encounter between a majority of foreign antigens and the immune system, the influence of oral bacteria on allergy development has not yet been reported. Objective Methods We sought to determine the bacterial composition in longitudinally collected saliva samples during childhood in relation to allergy development. Illumina sequencing of the 16S rDNA gene was used to characterize the oral bacterial composition in saliva samples collected at 3, 6, 12, 24 months, and 7 years of age from children developing allergic symptoms and sensitization (n = 47) and children staying healthy (n = 33) up to 7 years of age. Results Conclusion Children developing allergic disease, particularly asthma, had lower diversity of salivary bacteria together with highly divergent bacterial composition at 7 years of age, showing a clearly altered oral microbiota in these individuals, likely as a consequence of an impaired immune system during infancy. Moreover, the relative amounts of several bacterial species, including increased abundance of Gemella haemolysans in children developing allergies and Lactobacillus gasseri and L. crispatus in healthy children, were distinctive during early infancy, likely influencing early immune maturation. Early changes in oral microbial composition seem to influence immune maturation and allergy development. Future experiments should test the probiotic potential of L. gasseri and L. crispatus isolates.
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| 7. |
- Forsberg, Anna, et al.
(författare)
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Plasticity and flexibility of T cells in human pregnancy in JOURNAL OF REPRODUCTIVE IMMUNOLOGY, vol 90, issue 2, pp 149-149
- 2011
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Ingår i: JOURNAL OF REPRODUCTIVE IMMUNOLOGY. - : Elsevier. - 0165-0378. ; , s. 149-149
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Konferensbidrag (refereegranskat)abstract
- Introduction:Pregnancy challenges the immune system. Thus, tolerance to the semi-allogenic fetus must be supported while the mother and fetus still must be protected against infectious agents. Pregnancy is associated with a Th2 deviated immune system, away from a harmful Th1 associated immunity, although this may be a simplified view. Regulatory T cells (Tregs) are enriched in the uterus, but occur at normal frequency in the circulation. It has become increasingly evident that Tregs and T helper cells are not stably committed lineages but are plastic, showing close relationships between subsets. We hypothesize that an increased T cell flexibility in pregnancy can help to explain the paradox of simultaneous tolerance and strong antimicrobial responses. Our aim was to investigate whether the plasticity concept is applicable for the Treg subset, and if it involves the entire T helper population. Material and methods: Isolated Tregs (CD4dimCD25high) and control cells (CD4+CD25−) from second trimester pregnant (n = 14) and non-pregnant women (n = 14) were stimulated for 24 h with plate-bound anti-CD3/anti-CD28. Signature gene and protein expression of each T cell subset was measured using transcription factor expression by real time-PCR and multiplex bead array of cell culture supernatants, respectively. The whole PBMC fraction is also used in ongoing experiments and either stimulated with plate-bound anti-CD3/anti-CD28 or with the Th1, Th2 and Th17 deviating microbial agents PPD (Th1), TT (Th2) and C. albicans hyphae (Th17). After culturing, the cells are stained for intracellular transcription factors associated with Th1, Th2, Th17 and Treg immunity. Results: Stimulated Tregs from pregnant compared to non-pregnant women showed significantly higher levels of markers for Treg cells (Foxp3 mRNA), Th2 cells (GATA-3 mRNA and IL4 protein) and a tendency to increase in markers of Th17 (RORC mRNA and IL-17 protein), whereas Th1 markers (Tbet mRNA and IFN-γ) showed no difference between pregnant and non-pregnant women. Further, ongoing studies may reveal if the entire T helper population shows a higher degree of responsiveness during pregnancy. Conclusions: Our results imply an increased plasticity of the Treg population during pregnancy, suggesting that Treg cells are able to switch to a Th2/Th17-like phenotype, depending on current demands of tolerance or infectious threats.
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| 8. |
- Furuhjelm, Catrin, et al.
(författare)
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Th1 and Th2 chemokines, vaccine induced 1 immunity and allergic disease in infants after maternal ω-3 fatty acid supplementation during pregnancy and lactation
- 2011
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Ingår i: Pediatric Research. - : Nature Publishing Group. - 0031-3998 .- 1530-0447. ; 69:3, s. 259-264
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Tidskriftsartikel (refereegranskat)abstract
- We investigated whether the previously reported preventive effect of maternal ω-3 fatty acid supplementation on IgE-associated allergic disease in infancy may be mediated by facilitating a balanced circulating Th2/Th1 chemokine profile in the infant. Vaccine-induced immune responses at 2 y of age were also evaluated. Pregnant women, at risk of having an allergic infant, were randomized to daily supplementation with 1.6 g eicosapentaenoic acid and 1.1 g docosahexaenoic acid or placebo from the 25th gestational week through 3.5 mo of breastfeeding. Infant plasma was analyzed for chemokines (cord blood, 3, 12, 24 mo) and anti-tetanus and anti-diphtheria IgG (24 mo). High Th2-associated CC-chemokine ligand 17 (CCL17) levels were associated with infant allergic disease (p < 0.05). In infants without, but not with, maternal history of allergy, the ω-3 supplementation was related to lower CCL17/CXC-chemokine ligand 11 (CXCL11) (Th2/Th1) ratios (p < 0.05). Furthermore, in nonallergic, but not in allergic infants, ω-3 supplementation was linked with higher Th1-associated CXCL11 levels (p < 0.05), as well as increased IgG titers to diphtheria (p = 0.01) and tetanus (p = 0.05) toxins. Thus, the prospect of balancing the infant immune system toward a less Th2-dominated response, by maternal ω-3 fatty acid supplementation, seems to be influenced by allergic status.
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| 9. |
- Humbert, Marion, et al.
(författare)
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Functional SARS-CoV-2 cross-reactive CD4+ T cells established in early childhood decline with age
- 2023
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 120:12
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Tidskriftsartikel (refereegranskat)abstract
- Pre-existing SARS-CoV-2-reactive T cells have been identified in SARS-CoV-2-unexposed individuals, potentially modulating COVID-19 and vaccination outcomes. Here, we provide evidence that functional cross-reactive memory CD4+ T cell immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is established in early childhood, mirroring early seroconversion with seasonal human coronavirus OC43. Humoral and cellular immune responses against OC43 and SARS-CoV-2 were assessed in SARS-CoV-2-unexposed children (paired samples at age two and six) and adults (age 26 to 83). Pre-existing SARS-CoV-2-reactive CD4+ T cell responses targeting spike, nucleocapsid, and membrane were closely linked to the frequency of OC43-specific memory CD4+ T cells in childhood. The functional quality of the cross-reactive memory CD4+ T cell responses targeting SARS-CoV-2 spike, but not nucleocapsid, paralleled OC43-specific T cell responses. OC43-specific antibodies were prevalent already at age two. However, they did not increase further with age, contrasting with the antibody magnitudes against HKU1 (β-coronavirus), 229E and NL63 (α-coronaviruses), rhinovirus, Epstein–Barr virus (EBV), and influenza virus, which increased after age two. The quality of the memory CD4+ T cell responses peaked at age six and subsequently declined with age, with diminished expression of interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor (TNF), and CD38 in late adulthood. Age-dependent qualitative differences in the pre-existing SARS-CoV-2-reactive T cell responses may reflect the ability of the host to control coronavirus infections and respond to vaccination. Copyright © 2023 the Author(s).
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| 10. |
- Huoman, Johanna, et al.
(författare)
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Sublingual immunotherapy alters salivary IgA and systemic immune mediators in timothy allergic children.
- 2019
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Ingår i: Pediatric Allergy and Immunology. - : John Wiley & Sons. - 0905-6157 .- 1399-3038. ; 30:5, s. 522-530
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Immunomodulatory effects of sublingual immunotherapy on systemic and mucosal mediators in allergic children are largely unexplored. The aim of this study was to investigate allergy-related cytokine and chemokine levels, as well as IgA-responses upon a 3-year treatment with timothy grass pollen sublingual immunotherapy in children with allergic rhinoconjunctivitis.METHODS: From children included in the GRAZAX® Asthma Prevention study, blood and saliva samples were analyzed at inclusion, after 3 years of treatment, and 2 years after treatment ending. By means of Luminex and ELISA methodologies, allergy-related cytokines and chemokines were measured in plasma samples and allergen-stimulated peripheral blood mononuclear cell supernatants. Furthermore, studies of total, secretory, and Phl p 1-specific salivary IgA antibodies were performed using the same methods.RESULTS: GRAZAX® -treated children exhibited significantly higher levels of Phl p 1-specific salivary IgA and serum IgG4 , along with significantly lower skin prick test positivity, after 3 years of treatment and 2 years after treatment cessation. Additionally, plasma levels of the Th1-associated chemokines CXCL10 and CXCL11 were significantly higher in treated than untreated children at these time points. Timothy-induced ratios of IL-5/IL-13 over IFN-γ were significantly decreased after 3 years with active treatment, as were symptoms of allergic rhinitis in terms of both severity and visual analogue scale scores. However, no consistent correlations were found between the clinical outcomes and immunologic parameters.CONCLUSION: Phleum pratense sublingual immunotherapy in grass pollen allergic children modulates the immune response in the oral mucosa as well as systemically-by increasing Th1-responses, decreasing Th2-responses, and inducing immunoregulatory responses-all signs of tolerance induction.
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| 11. |
- Jakobsson, Hedvig E., et al.
(författare)
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Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by Caesarean section
- 2014
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Ingår i: Gut. - London : BMJ. - 0017-5749 .- 1468-3288. ; 63:4, s. 559-566
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Tidskriftsartikel (refereegranskat)abstract
- important stimuli for immune development, and a reduced microbial exposure as well as caesarean section (CS) has been associated with the development of allergic disease. Here we address how microbiota development in infants is affected by mode of delivery, and relate differences in colonisation patterns to the maturation of a balanced Th1/Th2 immune response. Design The postnatal intestinal colonisation pattern was investigated in 24 infants, born vaginally (15) or by CS (nine). The intestinal microbiota were characterised using pyrosequencing of 16S rRNA genes at 1 week and 1, 3, 6, 12 and 24 months after birth. Venous blood levels of Th1- and Th2-associated chemokines were measured at 6, 12 and 24 months. Results Infants born through CS had lower total microbiota diversity during the first 2 years of life. CS delivered infants also had a lower abundance and diversity of the Bacteroidetes phylum and were less often colonised with the Bacteroidetes phylum. Infants born through CS had significantly lower levels of the Th1-associated chemokines CXCL10 and CXCL11 in blood. Conclusions CS was associated with a lower total microbial diversity, delayed colonisation of the Bacteroidetes phylum and reduced Th1 responses during the first 2 years of life.
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| 12. |
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| 13. |
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| 14. |
- Jenmalm, Maria C., 1971-
(författare)
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Development of IgG subclass antibodies to allergens in early childhood
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Immune responses to allergens in young children include both Thl and Th2 like immunity, which may regulate the secretion of IgG subclass antibodies differently. The time, route and level of exposure to an allergen, as well as maternally transferred immunity, may be decisive whether sensitisation or tolerance will ensue. To study this, we established sensitive methods and investigated the development of IgG subclass antibodies to food and inhalant allergens during childhood.Material and Methods: The study group comprised a cohort of 96 children participating in a prospective study. IgG subclass antibodies to ß-lactoglobulin, ovalbumin, Bet v 1 and cat dander were analysed at birth, 6 and 18 months and 8 years by ELISA. At 8 years of age, PBMC from 55 of the children were stimulated with birch and ß-lactoglobulin. Production of IL-5, IL-6, IL-10, IL-13 and IFN-y was analysed by ELISA and expression of IL-4 and IL-9 mRNA by semiquantitative RTPCR.Results: High cord blood levels of IgG antibodies to inhalant, but not to food, allergens were associated with less development of atopy in the children during the first eight years of life. IgG subclass antibody responses to allergens were commonly detected during childhood and were largely restricted to the IgG1 subclass. The production of this opsonising and complement activating subclass was associated with Thllike immunity at 8 years of age. IgG subclass antibodies to food allergens peaked in infancy, whereas antibodies to the inhalant perennial allergen cat, but not the inhalant seasonal allergen birch, increased with age. Exposure to cow's milk during the first three months of life was associated with high IgG subclass antibodies to ß-lactoglobulin up to eight years. Exposure to cat and birch tended to be associated with high antibody levels to those allergens, whereas antibody levels to ovalbumin were not related to the introduction of egg in the diet. Atopic symptoms and the presence of positive skin prick tests and circulating IgE antibodies to allergens were associated with high levels of IgG subclass, especially Th2 associated IgG4, antibody responses to allergens. For the food allergens, the differences were mostly marked early in life. Birch induced IL-4 expression may be the major factor determining IgE antibody formation to that allergen, while allergen induced IL-5, IL-6 and IL-10 secretion in PBMC was associated with atopic symptoms.Conclusions: Maternally derived antibodies may modulate immune responses. The tolerance-inducing mechanisms in the intestinal mucosa may be less effective during the first months of life. Responses to food and inhalant allergens show different kinetics. Thl like associated IgG1 antibodies to allergens are commonly observed in both atopic and non-atopic children, whereas Th2 like associated IgG4 responses are more atopy dependent.
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| 15. |
- Lundberg, Anna, et al.
(författare)
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Expression of toll-like receptors and immune-regulatory markers during early infancy and allergy development in Estonian and Swedish infants
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Allergies have increased during the last decades with the highest prevalences in countries with a Westernised lifestyle. As microbial activation might be required for an accurate maturation of the immune system, a reduced or altered microbial exposure during infancy has been suggested as a possible cause for the increase of allergic diseases in affluent countries. Aim: The aim of this study was to investigate the gene expression of TLR2, TLR4, Foxp3, Ebi3 and SOCS3 involved in LPS signaling pathways and immune regulation in two prospectively followed birth cohorts, one from Estonia and one from Sweden, in relation to domestic endotoxin levels and allergy development. Material and methods: Twenty-three children from Estonia and 52 from Sweden were followed from birth to five years of age regarding allergy development using questionnaires, clinical examinations and skin prick tests. RNA was isolated from unstimulated peripheral blood mononuclear cells (PBMC) in samples collected at birth, 3, 6, 12 and 24 months of age. mRNA expression of TLR2, TLR4, SOCS3, Ebi3 and Foxp3 was analysed with real-time RTPCR. The mRNA expression of the genes were compared to previously obtained data of LPS/IFN-γ induced cytokine and chemokine PBMC secretion at the corresponding time-points and also to domestic endotoxin levels. Results: The Estonian infants had higher mRNA expression of the two regulatory T cell (Treg) associated markers Foxp3 and Ebi3 at birth than the Swedish infants. The Foxp3 and Ebi3 expression correlated at all time-points. The mRNA expression of TLR2, TLR4 and SOCS3 was similar in Estonian and Swedish infants at all ages. None of the genes were associated with endotoxin levels.TLR4 mRNA expression correlated positively with cytokines that were upregulated by LPS/IFN- γ stimulation, but was negatively correlated to CCL2 secretion which was downregulated by the stimulation. Low expression of TLR2 mRNA at birth was found in Swedish children who were allergic at 5 years of age. Sensitisation up to 5 years of age was associated with low Ebi3 expression at birth. Conclusion: Estonian children are born with enhanced Ebi3 and Foxp3 expression compared to Swedish children, suggesting an increased capacity for early immune regulation among infants from a country with a low prevalence of allergic disease. An increased early capacity to respond to TLR2 ligands, i.e. Gram positive bacteria, may protect against allergy development.
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| 16. |
- Lundberg, Anna, et al.
(författare)
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Lower LPS responsiveness in Estonian than Swedish infants associates with less allergy development and high endotoxin exposure
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Allergic diseases have increased in the last decades, particularly in countries with an affluent lifestyle, possibly due to a reduced or altered microbial exposure during infancy. Objective: The aim of this study was to follow lipopolysaccharide (LPS) induced immune responses prospectively in infants from Estonia and Sweden, i.e. two countries with different frequencies of allergic disease and a different domestic endotoxin exposure. ' Methods: The study included 14 Estonian and 36 Swedish infants who were followed prospectively from birth up to two years of age regarding development of allergy using questionnaires, clinical examinations and skin prick tests. Isolated cord blood mononuclear cells (birth) and peripheral blood mononuclear cells (obtained at 3, 6, 12 and 24 months) were cultured for 24h with LPS in combination with IFN-γ. The secretion of IL-6, CXCL8 (IL-8), IL-10, IL12p70, IL-17, IL-1β, CCL2 (MCP-1), CCL4 (MIP-1β) and TNF was analysed with a Luminex assay. Results: The Swedish, as compared to Estonian children, had higher levels of LPS/IFN-γ induced CCL4 and IL-6 at birth and of IL-1β, IL-12p70, IL-17 and TNF at 3 months as well as IL-6 at 6 months. Also, the levels of CCL2 at 3 and 6 months of age and CCL4 and TNF at 6 months of age were higher in Swedish than Estonian infants in unstimulated cultures. Sensitised Swedish infants had higher levels of LPS/IFN-γ induced IL-10 at 3 and 12 months of age compared to non-sensitised Swedish infants. Conclusion: The enhanced LPS/IFN-γ induced cytokine and chemokine secretion in Swedish, compared to Estonian infants may support a less rapid induction of immune regulation in an affluent society. This could possibly be due to a reduced microbial pressure on Swedish children during early childhood.
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| 17. |
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| 18. |
- Mai, Xiaomei, 1969-, et al.
(författare)
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Asthma, lung function and allergy in 12-year-old children with very low birth weight : a prospective study
- 2003
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Ingår i: Pediatric Allergy and Immunology. - : Wiley. - 0905-6157 .- 1399-3038. ; 14:3, s. 184-192
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Tidskriftsartikel (refereegranskat)abstract
- We assessed the relationship between very low birth weight (VLBW) (≤1500 g) and the development of asthma, lung function and atopy. The study groups comprised 74 of all 86 (86%) VLBW and 64 of all 86 (74%) matched term children who were prospectively followed for 12 years. A questionnaire on asthmatic and allergic symptoms was completed and skin prick tests, spirometry and hypertonic saline provocation tests were performed at 12 years of age. Cytokine secretion was analysed in stimulated blood leukocyte cultures in 28 VLBW and 23 term children. A history of asthma was more frequent among the VLBW children, as compared with the term children at age 12 (22% vs. 9%, p = 0.046). Among the VLBW children, very preterm birth (gestational age: week 25 to 29) (RR 2.5, 95%CI 1.1–5.8), neonatal mechanical ventilation (RR 2.8, 95%CI 1.2–6.4) and neonatal oxygen supplementation (RR 4.3, 95%CI 1.3–14.0) were significantly associated with a history of asthma by the age of 12 years in univariate analyses. In multivariate logistic regression, neonatal oxygen supplementation ≥ 9 days was the only remaining significant risk factor for a history of asthma (adjusted OR 6.7, 95%CI 1.0–44). The VLBW children who required mechanical ventilation during the neonatal period were more likely to have bronchial hyperresponsiveness than those not requiring mechanical ventilation (60% vs. 28%, p = 0.050). The spirometric values were similar among the VLBW and the term children at 12 years. Very low birth weight was not significantly related to allergic rhinoconjunctivitis, eczema or positive skin prick tests. Furthermore, the levels of IL-4, IL-5 and IFN-γ in stimulated cell cultures were similar in the VLBW and the term children. A history of asthma by 12 years of age was twice as common among the VLBW as the term children, and neonatal oxygen supplementation seemed to be associated with the increased risk. Furthermore, mechanical ventilation during the neonatal period was associated with bronchial hyperresponsiveness at age 12. Very low birth weight per se was not, however, related to atopy.
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| 19. |
- Mjösberg, Jenny, et al.
(författare)
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Circulating CD4dimCD25highFOXP3+ regulatory T cells in severe early-onset preeclampsia
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Preeclampsia is an inflammatory condition suggested to involve regulatory CD4+CD25high T helper cell (Treg) disturbances. However, the importance of Tregs in early-onset preeclampsia, associated with increased disease severity and possibly representing a more distinct placental disease, remains unclear. We recently showed that by defining Tregs as CD4dimCD25high cells, the risk of including activated non-Tregs, being more prominent in the circulation during pregnancy, is avoided. The aim of this study was to determine, using updated Treg markers and flow cytometric gating strategies, the frequency and phenotype of circulating Tregs from women with severe early-onset preeclampsia (n=10) as compared with healthy pregnant (n=20) and nonpregnant (n=20) women. The frequency of CD4dimCD25high cells and the expression of FOXP3 was similar in healthy and preeclamptic pregnancy. However, the occurrence of CTLA-4+ and HLA-DR+ cells in the Treg population from preeclamptic women tended to be higher than in healthy pregnant women, indicating alterations in Treg functionality in preeclampsia. Further, the Treg population from healthy pregnant, but not preeclamptic, women tended to be enriched for CCR4+ and CD45R0+ cells as compared with nonpregnant women. In conclusion, although the findings do not support a role for diminished circulating Treg frequency in severe early-onset preeclampsia, the study suggests functional alterations related to Treg suppression, activation and migration mechanisms in this subgroup of preeclamptic women.
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| 20. |
- Mjösberg, Jenny, et al.
(författare)
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FOXP3+ regulatory T cells, T helper 1, T helper 2 and T helper 17 cells in human early pregnancy decidua
- 2010
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Ingår i: Biology of Reproduction. - : Oxford University Press (OUP). - 0006-3363 .- 1529-7268. ; 82:4, s. 698-705
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Tidskriftsartikel (refereegranskat)abstract
- In pregnancy, the decidua is infiltrated by leukocytes promoting fetal development without causing immunological rejection. Murine regulatory T (Treg) cells are known to be important immune regulators at this site. The aim of the study was to characterize the phenotype and origin of Treg cells and determine the quantitative relationship between Treg, T-helper type 1 (TH1), TH2, and TH17 cells in first-trimester human decidua. Blood and decidual CD4+ T cells from 18 healthy first-trimester pregnant women were analyzed for expression of Treg-cell markers (CD25, FOXP3, CD127, CTLA4, and human leukocyte antigen-DR [HLA-DR]), chemokine receptors (CCR4, CCR6, and CXCR3), and the proliferation antigen MKI67 by six-color flow cytometry. Treg cells were significantly enriched in decidua and displayed a more homogenous suppressive phenotype with more frequent expression of FOXP3, HLA-DR, and CTLA4 than in blood. More decidual Treg cells expressed MKI67, possibly explaining their enrichment at the fetal-maternal interface. Using chemokine receptor expression profiles of CCR4, CCR6, and CXCR3 as markers for TH1, TH2, and TH17 cells, we showed that TH17 cells were nearly absent in decidua, whereas TH2-cell frequencies were similar in blood and decidua. CCR6+ TH1 cells, reported to secrete high levels of interferon gamma (IFNG), were fewer, whereas the moderately IFNG-secreting CCR6− TH1 cells were more frequent in decidua compared with blood. Our results point toward local expansion of Treg cells and low occurrence of TH17 cells. Furthermore, local, moderate TH1 activity seems to be a part of normal early pregnancy, consistent with a mild inflammatory environment controlled by Treg cells.
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| 21. |
- Persson, Marie, et al.
(författare)
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Immunological status in patients undergoing in vitro fertilisation : responses to hormone treatment and relationship to outcome
- 2012
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Ingår i: Journal of Reproductive Immunology. - : Elsevier. - 0165-0378 .- 1872-7603. ; 96:1-2, s. 58-67
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to prospectively investigate the paternal antigen-induced cytokine secretion by peripheral blood mononuclear cells (PBMCs) in response to hormone treatment in women undergoing in vitro fertilisation (IVF) and to examine the predictive value of the cytokine secretion profile in the outcome of IVF treatment, in a pilot study. Twenty-five women were included and IVF treatment was successful for six and unsuccessful for 19 women. Blood samples were collected before IVF treatment, on four occasions during IVF and four weeks after embryo transfer. The numbers of Th1-, Th2- and Th17-associated cytokine-secreting cells and cytokine levels in cell supernatants were analysed by enzyme-linked immunospot-forming (ELISpot), enzyme-linked immune-sorbent (ELISA) or Luminex assay. None of the cytokines (IFN-γ, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17, TNF and GM-CSF) had any predictive value regarding IVF outcome. The majority of the cytokines reached their peak levels at ovum pick-up, suggesting an enhancing influence of the hormonal stimulation. Pregnancy was associated with a high number of IL-4-, IL-5- and IL-13-secreting cells four weeks after ET. In conclusion, the results do not support our hypothesis of a more pronounced peripheral Th1 and Th17 deviation towards paternal antigens in infertile women with an unsuccessful IVF outcome, although this is based on a small number of observations. A larger study is required to confirm this conclusion. Higher numbers of Th2-associated cytokine-secreting cells in pregnant women four weeks after ET do corroborate the hypothesis of a Th2 deviation during pregnancy.
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| 22. |
- Persson, Marie, et al.
(författare)
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Leukocyte populations in patients undergoing in vitro fertilization: responses to hormone treatment and relation to outcome
- 2012
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We aimed to prospectively investigate circulating leukocyte populations in infertile women undergoing IVF treatment and to determine whether any differences in cell proportions were associated with the IVF outcome. We also assessed the effect of IVF-based ovarian stimulation on the leukocyte populations. Twenty-five women were included and IVF treatment was successful in six and unsuccessful in 19 women. Blood samples were collected before IVF treatment, at the time of embryo transfer and four weeks after embryo transfer. The numbers and proportions of lymphocytes, T cells, NK cells, monocytes and granulocytes were analysed by flow cytometry, as well as the following lymphocyte subpopulations: CD3+HLA-DR+, CD4+CD45RA+, CD4+CD45R0+, CD8+CD45RA+, CD8+CD45R0+, CD4+CD25+, CD4dimCD25bright regulatory T cells, CD3-CD56bright and CD3-CD56dim NK cells. The proportions and numbers of leukocytes during IVF treatment were not related to the IVF outcome, although pregnant women (four weeks after ET) had a lower proportion of lymphocytes than the non-pregnant women. The absolute counts of lymphocytes, T cells, granulocytes and monocytes, as well as the proportions of granulocytes and T cells, increased at the time of ET, coinciding with high FSH and hCG levels. In conclusion, the proportions and numbers of leukocyte populations were not associated with the IVF outcome, although a larger study should be conducted to confirm this conclusion. Changes in both proportions and numbers of several leukocyte populations were observed during the course of IVF treatment, suggesting a stimulatory effect of the hormonal influence.
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| 23. |
- Persson, Marie, et al.
(författare)
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Reduced IFN-γ and IL-10 responses to paternal antigens during and after pregnancy in allergic women
- 2012
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Ingår i: Journal of Reproductive Immunology. - : Elsevier. - 0165-0378 .- 1872-7603. ; 95:1-2, s. 50-58
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Tidskriftsartikel (refereegranskat)abstract
- Normal pregnancy and allergy are both characterized by a T helper (Th) 2 deviation. In the current study, we hypothesized that paternal antigen-induced cytokine responses during pregnancy would be deviated toward Th2 and an anti-inflammatory profile, and that the Th2 deviation would be more pronounced in allergic pregnant women. Blood samples were collected longitudinally on three occasions during pregnancy and two occasions post partum (pp). Of the 86 women initially included, 54 women had a normal pregnancy and completed the sampling procedures. Twelve women fulfilled the criteria for allergy (allergic symptoms and circulating immunoglobulin [Ig] E antibodies to inhalant allergens) and 20 were non-allergic (nonsensitized without symptoms). The levels of Th1- and Th2-associated cytokines and chemokines, the Th17 cytokine IL-17 and the anti-inflammatory cytokine IL-10 of the groups were compared. Paternal antigen-induced IL-4 and IL-10 responses increased between the first and the third trimester. Allergy was associated with decreased paternal antigen-induced IFN-γ and CXCL10 secretion in the nonpregnant state (one year pp) and also decreased IFN-γ/IL-4 and IFN-γ/IL-13 ratios during pregnancy. We also observed a decreased paternal antigen-induced IL-10 response in allergic compared with non-allergic women during pregnancy, along with a decreased IL-10/IL-13 ratio. In conclusion, our findings support the hypothesis of lower Th1 responses toward paternal antigens in allergic than in non-allergic women, but also indicate that allergy is associated with a lower capacity to induce anti-inflammatory IL-10 responses after paternal antigen stimulation during pregnancy.
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| 24. |
- Rasmark Roepke, E., et al.
(författare)
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Low-molecular-weight-heparin increases Th1-and Th17-associated chemokine levels during pregnancy in women with unexplained recurrent pregnancy loss: a randomised controlled trial
- 2019
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Low-molecular-weight heparin (LMWH) is widely used to treat recurrent pregnancy loss (RPL) because of its anti-coagulant effects. Although in vitro studies have suggested additional immunological effects, these are debated. We therefore investigated whether LMWH could modulate immune responses in vivo during pregnancy of women with unexplained RPL. A Swedish open multi-centre randomised controlled trial included 45 women treated with tinzaparin and 42 untreated women. Longitudinally collected plasma samples were obtained at gestational weeks (gw) 6, 18, 28 and 34 and analysed by multiplex bead technology for levels of 11 cytokines and chemokines, chosen to represent inflammation and T-helper subset-associated immunity. Mixed linear models test on LMWH-treated and untreated women showed differences during pregnancy of the Th1-associated chemokines CXCL10 (p = 0.01), CXCL11 (p amp;lt; 0.001) and the Th17-associated chemokine CCL20 (p = 0.04), while CCL2, CCL17, CCL22, CXCL1, CXCL8, CXCL12, CXCL13 and IL-6 did not differ. Subsequent Students t-test showed significantly higher plasma levels of CXCL10 and CXCL11 in treated than untreated women at gw 28 and 34. The consistent increase in the two Th1-associated chemokines suggests a potential proinflammatory and unfavourable effect of LMWH treatment during later stages of pregnancy, when Th1 immunity is known to disrupt immunological tolerance.
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| 25. |
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| 26. |
- Sjögren, Ylva Margareta, 1981-, et al.
(författare)
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Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responses
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Among sensitized infants those with high, as compared with low levels, of salivary secretory IgA (SIgA) are less likely to develop allergic symptoms. Also, early colonization with certain gut microbiota, e.g. Lactobacilli and Bifidobacterium species, might be associated with less allergy development. Although animal and in vitro studies emphasize the role of the commensal gut microbiota in the development of the immune system, the influence of the gut microbiota on immune development in infants is unclear. Objective: To assess whether early colonization with certain gut microbiota species associates with mucosal and systemic immune responses i.e. salivary SIgA and the spontaneous toll like receptor (TLR) 2 and TLR4 mRNA expression and LPS-induced cytokine/chemokine responses in peripheral blood mononuclear cells (PBMC). Methods: Faecal samples were collected at one week, one month and two months after birth from 64 Swedish infants, followed prospectively to five years of age. Bacterial DNA was analyzed with real-time PCR using primers binding to Clostridium difficile, four species of bifidobacteria, two lactobacilli groups and Bacteroides fragilis. Saliva was collected at age six and twelve months and at two and five years and SIgA was measured with ELISA. The PBMC, collected twelve months after birth, were analyzed for TLR2 and TLR4 mRNA expression with real-time PCR. Further, the PBMC were stimulated with LPS and cytokine/chemokine responses were measured with Luminex. Results: The number of Bifidobacterium species in the early faecal samples correlated significantly with the total salivary SIgA levels at six months. Early colonization with Bifidobacterium species, lactobacilli groups or C. difficile did not influence TLR2 and TLR4 expression in PBMC. However, PBMC from infants colonized early with high amounts of Bacteroides fragilis expressed lower levels of TLR4 mRNA spontaneously. Furthermore, LPS-induced production of inflammatory cytokines and chemokines, e.g. IL-6 and CCL4 (MIP-1β), were inversely correlated to the relative amounts of Bacteroides fragilis in the early faecal samples. Conclusion: Bifidobacterial diversity may enhance the maturation of the mucosal SIgA system and early high colonization with Bacteroides fragilis might down-regulate LPS responsiveness in infancy.
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| 27. |
- Tomičić, Sara, et al.
(författare)
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High levels of IgG4 antibodies to foods during infancy are associated with tolerance to corresponding foods later in life
- 2009
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Ingår i: Pediatric Allergy and Immunology. - : Wiley. - 0905-6157 .- 1399-3038. ; 5:1, s. 35-41
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Tidskriftsartikel (refereegranskat)abstract
- Children with eczema and sensitization to foods are recommended skin care and, if food allergy is proven by challenge, an elimination diet. For most children the diet period is transient, but the process behind tolerance development and the influence of decreased allergen exposure is not fully known. The aim of the study was to investigate the effect of elimination diet on serum and salivary antibodies and to identify immunological parameters related to the ability to tolerate foods. Eighty-nine children, below 2 yr of age, with eczema and suspected food allergy were included. Recommended treatment was skin care to all children, and 60 children had a period of elimination diet. At 4½ yr of age, the children were divided into two groups, based on if they had been able to introduce the eliminated foods, or not. Serum and salivary antibodies were analyzed with enzyme-linked immunosorbent assay and UniCAP® before and after a 6-wk treatment period and at 4½ yr of age. Children sensitized to egg and/or milk that could eat and drink the offending foods at 4½ yr of age, had higher levels of Immunoglobulin G4 antibodies to ovalbumin and β-lactoglobulin and also higher IgG4/Immunoglobulin E ratios on inclusion in the study, than those who had to eliminate egg and/or milk from their diet, beyond 4½ yr of age. The highest IgG4/IgE ratios were found in children with circulating IgE antibodies to egg and/or milk but negative skin prick test on inclusion. The 6-wk treatment period did not significantly affect the levels of serum and salivary antibodies. In conclusion, eczematous, food sensitized infants with high levels of IgG4 and high ratios of IgG4/IgE antibodies to food allergens are more likely to consume these foods at 4½ yr than infants with low levels and ratios.
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| 28. |
- Wahlberg, Jeanette, 1969-, et al.
(författare)
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Altered Chemokine Th1/Th2 Balance in Addison's Disease: Relationship with Hydrocortisone Dosing and Quality of Life
- 2014
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 46:1, s. 48-53
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Tidskriftsartikel (refereegranskat)abstract
- The adrenalitis found in autoimmune Addison’s disease (AAD) is considered having a Th1-driven pathogenesis. Circulating Th1- and Th2-associated chemokines responsible for the trafficking of leukocytes to inflammatory sites are markers for the Th1/Th2 balance. The aim of the study was to assess if the same daily hydrocortisone dose of 30 mg given in either 2 or 4 doses to patients with AAD could affect the Th1/Th2 balance of circulating chemokines.Fifteen patients (6 women) with AAD were included in this randomised, placebo controlled, double blind cross-over study. Samples for chemokines, Th1-associated (CXCL10, CXCL11) and Th2-associated (CCL17, CCL22), were drawn 5 times during a 24-h period at the end of each treatment period and analysed with Luminex. Seven control subjects did the same diurnal blood sampling once. Subjects with AAD had higher median diurnal levels of the Th1-associated chemokines than controls, CXCL10 [43 (33–56) pg/ml vs. 22 (19–34) pg/ml, p<0.01] and CXCL11 [37 (29–48) pg/ml vs. 16 (9–24) pg/ml, p<0.001], whereas no significant difference was found regarding the Th2-related chemokines. Similar chemokine levels were found when the same hydrocortisone dose of 30 mg was divided in 2 or 4 doses. Levels of CXCL11 correlated negatively with scores of SF-36 domains (high score indicate better health) of General Health (GH) and total score for Physical Component Summary (PCS), and these negative correlations were most pronounced at 04:00 h on the 2-dose regimen. Patients with AAD have a dominant Th1 chemokine profile that partially correlates to reduced quality of life.
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| 29. |
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