| 1. |
- Amoudruz, Petra, et al.
(author)
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Impaired Toll-like receptor 2 signaling in monocytes from 5-year-old allergic children
- 2009
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In: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 155:3, s. 387-394
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Journal article (peer-reviewed)abstract
- The relative composition of the two major monocytic subsets CD14+CD16− and CD14+CD16+ is altered in some allergic diseases. These two subsets display different patterns of Toll-like receptor levels, which could have implications for activation of innate immunity leading to reduced immunoglobulin E-specific adaptive immune responses. This study aimed to investigate if allergic status at the age of 5 years is linked to differences in monocytic subset composition and their Toll-like receptor levels, and further, to determine if Toll-like receptor regulation and cytokine production upon microbial stimuli is influenced by the allergic phenotype. Peripheral blood mononuclear cells from 5-year-old allergic and non-allergic children were stimulated in vitro with lipopolysaccharide and peptidoglycan. Cells were analysed with flow cytometry for expression of CD14, Toll-like receptors 2 and 4 and p38-mitogen-activated protein kinase (MAPK). The release of cytokines and chemokines [tumour necrosis factor, interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70] into culture supernatants was measured with cytometric bead array. For unstimulated cells there were no differences in frequency of the monocytic subsets or their Toll-like receptor levels between allergic and non-allergic children. However, monocytes from allergic children had a significantly lower up-regulation of Toll-like receptor 2 upon peptidoglycan stimulation. Further, monocytes from allergic children had a higher spontaneous production of IL-6, but there were no differences between the two groups regarding p38-MAPK activity or cytokine and chemokine production upon stimulation. The allergic subjects in this study have a monocytic population that seems to display a hyporesponsive state as implicated by impaired regulation of Toll-like receptor 2 upon peptidoglycan stimulation.
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| 2. |
- Amoudruz, Petra, et al.
(author)
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Maternal country of birth and previous pregnancies are associated with breast milk characteristics
- 2009
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In: Pediatric Allergy and Immunology. - : Wiley. - 0905-6157 .- 1399-3038. ; 20:1, s. 19-29
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Journal article (peer-reviewed)abstract
- Populations in high infectious exposure countries are at low risk of some immune-mediated diseases such as Crohn’s disease and allergy. This low risk is maintained upon immigration to an industrialized country, but the offspring of such immigrants have a higher immune-mediated disease risk than the indigenous population. We hypothesize that early life exposures in a developing country shape the maternal immune system, which could have implications for the offspring born in a developed country with a low infectious load. The aim of this study was to investigate if exposures in childhood (indicated by country of origin) and subsequent exposures influence immunologic characteristics relevant to stimulation of offspring. Breast milk components among 64 mothers resident in Sweden, 32 of whom immigrated from a developing country, were examined using the ELISA and Cytometric Bead Array methods. Immigrants from a developing country had statistically significantly higher levels of breast milk interleukin-6 (IL-6), IL-8 and transforming growth factor-β1. A larger number of previous pregnancies were associated with down-regulation of several substances, statistically significant for soluble CD14 and IL-8. The results suggest that maternal country of birth may influence adult immune characteristics, potentially relevant to disease risk in offspring. Such a mechanism may explain the higher immune-mediated disease risk among children of migrants from a developing to developed country. Older siblings may influence disease risk through the action of previous pregnancies on maternal immune characteristics.
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| 3. |
- Amoudruz, Petra, 1970-
(author)
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Maternal immune characteristics and innate immune responses in the child in relation to allergic disease
- 2008
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Doctoral thesis (other academic/artistic)abstract
- The mechanistic factors responsible for the increase in allergic diseases are still not fully understood, but a reduced microbial stimulation seems to be one of the key issues. Research is now aiming at investigating the relationship between the innate immune system, involving the toll-like receptors, and allergy development. Further, the maternal influence on the child, possibly through in utero effects, but also through the breast milk, has shown to be of great importance. This thesis aimed at understanding how the maternal immune system is influenced by early exposures and allergic disease, but also to investigate the consequences of the maternal phenotype on the innate immune system of the developing child. The Th1/Th2 cytokine pattern in allergic diseases has been extensively studied. Here we were interested in comparing the innate cytokines in allergic and non-allergic women, and to see if the allergic status was influencing the effect of pregnancy differently. We demonstrate that IL-1β, IL-6, IL-10 and IL-12 production in cells from adult women are not influenced by allergic status, neither during pregnancy nor 2 years after. However, pregnancy had an apparent effect on cytokine levels, regardless of allergic status. Also, total IgE levels in allergic women were significantly lower 2 years after pregnancy in comparison with the levels during pregnancy, pointing to the fact that pregnancy indeed has an immunomodulatory role. We further wanted to investigate the immune system of mothers who had migrated to Sweden in comparison with indigenous mothers. The reason for our interest here was that children born from immigrated mothers have shown to have an increased risk of developing diseases such as allergy and Crohn’s disease. The results showed that immigrants from a developing country had significantly higher levels of breast milk IL-6, IL-8 and TGF-β1. Further, regardless of maternal country of birth, a larger number of previous pregnancies was associated with down-regulation of several substances, statistically significant for soluble CD14 and IL-8. The results suggest that maternal country of birth may indeed influence adult immune characteristics, potentially relevant to disease risk in offspring. The influence of allergic status of the mother on the expression of CD14, TLR2 and TLR4 was further investigated in monocytes from mothers and their newborn babies upon microbial stimulation. We could not find any differences in monocytic TLR levels between the groups. No significant differences regarding cytokine levels between allergic and non-allergic mothers in response to stimuli were found either. However, the cytokine and chemokine release triggered by TLR2 stimulation in CB revealed that CBMC from children with maternal allergic disease released significantly less IL-6, and a trend towards less IL-8. As we could not find differences in TLR levels attributed to maternal allergy, but an impaired IL-6 response, we turned our focus on an intracellular event taking place after TLR ligation. The results confirmed our results of decreased IL-6 levels in CB from children to allergic mothers. At 2 years of age, the children of allergic mothers still displayed a diminished IL-6 response. Additionally, they also had a decreased activity of p38 MAPK. p38 has an important role in driving Th1 responses, suggesting that the p38 pathway could be one of the responsible mechanisms behind the impaired responses correlated to allergic heredity found in CB as well as at 2 years of age. Infancy is a crucial time period for the developing immune system. Further, the relative composition of the two major monocytic subsets CD14++CD16- and CD14+CD16+ is altered in some allergic diseases. TLR levels are different in the two subsets, proposing a possible link to the reduced responding capacity of monocytes from children with allergic heredity. We followed up our earlier studies of children at birth and at 2 years of age by looking at 5 year old children. There were no differences regarding monocytic subsets, nor in TLR levels in unstimulated cells. However, when stimulating the cells with PGN, both monocytic subsets in allergic subjects were less capable of upregulating TLR2 compared to the age-matched controls. Taken together, the work in this thesis suggests that the maternal immune system is affected by the process of pregnancy and childhood exposures. It further suggests that maternal allergy affects the young child, in terms of impaired responses to microbial stimuli, which later in infancy correlates with allergic disease in the child. These impaired innate responses could lead to a diminished Th1 response, or alternatively to a deficiency in regulatory mechanisms, and thereby cause allergic disease.
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| 6. |
- Anchang-Kimbi, Judith K, et al.
(author)
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Diagnostic comparison of malaria infection in peripheral blood, placental blood and placental biopsies in Cameroonian parturient women.
- 2009
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In: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 8, s. 126-
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Journal article (peer-reviewed)abstract
- BACKGROUND: In sub-Saharan Africa, Plasmodium falciparum malaria in pregnancy presents an enormous diagnostic challenge. The epidemiological and clinical relevance of the different types of malaria diagnosis as well as risk factors associated with malaria infection at delivery were investigated. METHOD: In a cross-sectional survey, 306 women reporting for delivery in the Mutenegene maternity clinic, Fako division, South West province, Cameroon were screened for P. falciparum in peripheral blood, placental blood and placental tissue sections by microscopy. Information relating to the use of intermittent preventive treatment in pregnancy with sulphadoxine/pyrimethamine, history of fever attack, infant birth weights and maternal anaemia were recorded. RESULTS: Among these women, P. falciparum infection was detected in 5.6%, 25.5% and 60.5% of the cases in peripheral blood, placental blood and placental histological sections respectively. Placental histology was more sensitive (97.4%) than placental blood film (41.5%) and peripheral blood (8.0%) microscopy. In multivariate analysis, age (< or = 20 years old) (OR = 4.61, 95% CI = 1.47 - 14.70), history of fever attack (OR = 2.98, 95% CI = 1.58 - 5.73) were significant risk factors associated with microscopically detected parasitaemia. The use of > or = 2 SP doses (OR = 0.18, 95% CI = 0.06 - 0.52) was associated with a significant reduction in the prevalence of microscopic parasitaemia at delivery. Age (>20 years) (OR = 0.34, 95% CI = 0.15 - 0.75) was the only significant risk factor associated with parasitaemia diagnosed by histology only in univariate analysis. Microscopic parasitaemia (OR = 2.74, 95% CI = 1.33-5.62) was a significant risk factor for maternal anaemia at delivery, but neither infection detected by histology only, nor past infection were associated with increased risk of anaemia. CONCLUSION: Placenta histological examination was the most sensitive indicator of malaria infection at delivery. Microscopically detected parasitaemia was associated with increased risk of maternal anaemia at delivery, but not low-grade parasitaemia detected by placental histology only.
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| 7. |
- Bachmayer, Nora, 0061-
(author)
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The role of natural killer cells and inflammatory mediators in preeclamptic pregnancies
- 2008
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Doctoral thesis (other academic/artistic)abstract
- The maternal immune system must be able to adjust during pregnancy and accept the foetus that expresses paternal antigens. These changes are found both in placenta and circulation, including a mild inflammatory response. NK cells are abundant during the early part of pregnancy in placenta and are thought to be important for placental development. During preeclampsia the placenta is poorly developed, together with an escalated pro-inflammatory profile noticed in both placenta and circulation. We wanted to study NK cells in placenta and circulation from preeclamptic cases as well as levels of cytokines. HMGB1, an alarmin involved in inflammation, was also measured in preeclamptic placentae.When studying preeclamptic placentae in third trimester we found higher numbers of NK cells as well as a higher expression of CD94+ NK cells. We also found slightly elevated levels of HMGB1 together with significantly lower expression of IL-12 in preeclamptic placentae. Further, the NK cell activating cytokines IL-12/IL-23p40 and IL-15 in sera from preeclamptic women were increased compared to healthy pregnancies. The elevated levels of NK cell activating IL-12/IL-23p40 and IL-15 found in preeclamptic sera, made us investigate the circulating NK cells in preeclampsia. However, no differences were seen between healthy and preeclamptic pregnancies.The main immunological alterations in third trimester preeclamptic pregnancies with regard to NK cells were found in placenta. Altered maternal cytokine levels in placenta could influence decidual NK cells in preeclampsia, noticed by their higher numbers and altered receptor expression. If these alterations also exist during early pregnancy it could result in a poorly developed and dysfunctional placenta.
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| 8. |
- Bachmayer, Nora, et al.
(author)
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Women with pre-eclampsia have an altered NKG2A and NKG2C receptor expression on peripheral blood natural killer cells.
- 2009
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In: American Journal of Reproductive Immunology and Microbiology. - : Wiley. - 8755-8920 .- 1046-7408 .- 1600-0897. ; 62:3, s. 147-57
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Journal article (peer-reviewed)abstract
- PROBLEM: Preeclampsia, a pregnancy disorder, is associated with exaggerated inflammation and increased serum monokines. Uterine natural killer (NK) cells are implicated in preeclampsia pathology, but little is known regarding peripheral NK cells in the disease. METHOD OF STUDY: We examined blood NK cells at delivery in women with preeclampsia, in healthy pregnant women and in healthy non-pregnant blood donors as a reference. RESULTS: Although the percentages of both NKG2A- and NKG2C-positive NK cells were normal in preeclamptic women, the levels of NKG2A and NKG2C on NK cells were significantly up-regulated in these women. In vitro stimulation of PBMCs from healthy pregnant women and blood donors with monokines resulted in increased percentage of NKG2A(+) NK cells and increased NKG2A levels, while levels of NKG2C were decreased. CONCLUSIONS: Our results suggest that the peripheral NK-cell pool is skewed in preeclampsia and possibly under the influence of monokines like interleukin (IL)-15 and IL-12.
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| 9. |
- Gustafsson Lidström, Charlotte, 1978-
(author)
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Local Immune regulation in human pregnancy : with focus on decidual macrophages
- 2007
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Doctoral thesis (other academic/artistic)abstract
- During pregnancy, the woman carries a fetus partly foreign to her immune system, because of the expression of paternal antigens. Despite this, the fetus is normally tolerated and not rejected, as is often the case with organs in allogeneic transplantations. Systemic changes in maternal blood occur during pregnancy but, perhaps of greater importance, are changes in tissues locally in the uterus. The pregnant uterine endometrium, the decidua, is infiltrated by large numbers of leukocytes, mainly natural killer (NK) cells but also macrophages and T lymphocytes. Further, various cytokines are known to be secreted at the fetomaternal interface. However, the functions of these cells and the cytokine networks are not fully understood. The aim of this thesis was to investigate the local immune balance in normal human pregnancy decidua, both in the early phase of pregnancy and at parturition.First trimester decidual mononuclear cells, NK cells and macrophages were all shown to secrete IFN-γ, IL-4 and IL-10, as detected by ELISPOT. The secretion was not mirrored in blood from the same subjects. A significantly larger number of decidual macrophages secreted IL-10 than did their blood counterparts, indicating potential regulatory functions of this cell type.Further examination of early pregnancy decidual macrophages by microarray revealed 120 genes being differentially regulated at the transcriptional level in decidual compared to blood monocytes/macrophages. Several genes were associated with alternative activation/M2 polarization of macrophages, including CCL-18, CD209, IGF-1, MRC-1 and FN-1. Genes connected to immune regulation and tissue remodelling were common, in line with the potential functions for this cell type in utero. In addition, some molecules not previously connected to decidual macrophages, such as TREM-2, A2M and PGDS, were found to be upregulated, gaining new insights into the regulatory functions of decidual macrophages.Term decidual mononuclear cells spontaneously secrete IFN-γ, TNF, IL-4, IL-10, and TGF-β. No differences were seen between tissues obtained before and after the onset of labour, indicating that decidual mononuclear cells are not the main cell population responsible for plausible cytokine regulation in the process of labour induction. Placental and fetal membranes as well as cells in the maternal systemic circulation may instead contribute to a possible shift in immune balance prior to pregnancy termination.In conclusion, decidual leukocytes, including NK cells and macrophages, are potential producers of both Th1-like/pro-inflammatory and Th2-like/anti-inflammatory cytokines in early pregnancy as well as at parturition. Decidual macrophages are of a specialized phenotype with effector functions contributing to a proper invasion of the placenta and to immunological protection of the semi-allogeneic fetus. This thesis adds new knowledge on local immune balance during normal human pregnancy, however, the clinical significance of the presented data needs to be clarified.
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