| 1. |
- Amoudruz, Petra, et al.
(författare)
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Impaired Toll-like receptor 2 signaling in monocytes from 5-year-old allergic children
- 2009
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 155:3, s. 387-394
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Maternal country of birth and previous pregnancies are associated with breast milk characteristics
- 2009
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Ingår i: Pediatric Allergy and Immunology. - : Wiley. - 0905-6157 .- 1399-3038. ; 20:1, s. 19-29
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Tidskriftsartikel (refereegranskat)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. |
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| 4. |
- Holmlund, Ulrika
(författare)
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Influence of maternal allergy on the intra uterine environment and on immune functions of the neonate
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The prevalence of IgE mediated allergic diseases has drastically increased during the past few decades and there is no satisfactory explanation. A family history of allergic disease is clearly a strong risk factor, bin in view of the rapidity of the increase in allergy prevalence environmental factors are likely to have played a crucial role. This thesis aimed at elucidating the impact of maternal allergy on the in utero environment and on innate immune functions of the newborn baby. Allergic symptoms usually appear early in life. This implies an early priming for allergic disease, possibly even at the fetal level. We therefore compared the presence and production of IgE in placenta from allergic and non-allergic women. Surprisingly, numerous IgE+ cells, located primarily in the fetal villous stroma, were detected immunohistochemically in a majority of the investigated placentas irrespective of maternal allergy, maternal or fetal total scrum IgE levels. The placental IgE could not be demonstrated to be bound to IgE receptors, but was shown to be bound to fetal macrophages, possibly via FcgammaRI. No evidence was found for local fetal IgE production. The novel finding of numerous IgE+ cells in the placenta irrespective of maternal allergy could indicate a physiological role of IgE in utero during pregnancy. The placenta has been suggested to be a pregnancy-specific component of the innate immune system. We describe the novel findings of expression of Toll-like receptors 2 and 4 (TLR2 and TLR4) on villous trophoblast, whereas no immune reactivity was present in the villous core. The intermediate trophoblast was also found to express both TLR2 and TLR4. Regulation of TLR2 and TLR4 was investigated by stimulating placental explants with LPS and zymosan. Stimulation readily induced a release of IL-6 and IL-8 in the placental cultures, whereas TLR2 and TLR4 mRNA and protein expression remained at the same high level as in unstimulated explants. We believe that the TLRs and the trophoblast are important components of the innate immune system with a crucial role in the defense against placental infection, but they might also influence the cytokine environment in utero, something that could have impact on the baby's immune system. The newborn child's ability to respond to microbial stimuli in the environment is believed to be important for maturation of the neonatal immune system. We investigated how cord blood mononuclear blood cells (CBMC) from children of allergic and non-allergic women respond to microbial stimuli. Cord blood (CB) monocytes from children with allergic mothers had significantly lower expression of TLR2 and TLR4 compared to maternal peripheral blood mononuclear cells (PBMC) both before and after microbial stimulation, in contrast to CB monocytes from children with non-allergic mothers. Further, CBMCs from children with allergic mothers had a lower (p=0.03) IL-6 response after microbial stimulation than CBMCs from children with non-allergic mothers. Our results imply that CB monocytes and CBMC immune responses are influenced by maternal allergy. Based on these findings we speculate that monocytes from children with allergic mothers have a reduced capacity to respond to microbial stimuli. The soluble form of the endotoxin receptor CD14 has been shown to be negatively associated with total serum IgE levels. We investigated the levels of soluble (s) and membrane bound (m) CD14 in cord blood and at two years of age from children with allergic or non-allergic mothers and related these parameters with allergy development at two years of age. Children with allergic mothers had significantly higher sCD14 levels in CB compared to children with non-allergic mothers. At two years of age no significant differences in sCD14 levels were observed between the two groups of children and no association between sCD14 and allergic disease was found. Further, we observed large differences in sCD14 and mCD14 with respect to age. These findings highlight the complexity of the interaction between innate and adaptive immune responses. CD14 might be involved in the regulation of IgE production, but we suggest that CD14 could also be important for the maturation and development of the neonatal immune system. In conclusion, the work presented in this thesis has increased our knowledge on the in utero environment in allergic and non-allergic mothers and suggests that maternal allergy influences innate immune functions of the newborn baby.
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| 5. |
- Nyström, Anna-Maja, et al.
(författare)
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Noonan and cardio-facio-cutanenous syndromes : two clinically and genetically overlapping disorders
- 2008
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 45:8, s. 500-506
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Tidskriftsartikel (refereegranskat)abstract
- Background: Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFC) are related disorders associated with disrupted RAS/RAF/MEK/ERK signalling. NS, characterised by facial dysmorphism, congenital heart defects and short stature, is caused by mutations in the genes PTPN11, SOS1, KRAS and RAF1. CFC is distinguished from NS by the presence of ectodermal abnormalities and more severe mental retardation in addition to the NS phenotype. The genetic aetiology of CFC was recently assigned to four genes: BRAF, KRAS, MEK1 and MEK2. Methods: A comprehensive mutation analysis of BRAF, KRAS, MEK1, MEK2 and SOS1 in 31 unrelated patients without mutations in PTPN11 is presented. Results: Mutations were identified in seven patients with CFC (two in BRAF, one in KRAS, one in MEK1, two in MEK2 and one in SOS1). Two mutations were novel: MEK1 E203Q and MEK2 F57L. The SOS1 E433K mutation, identified in a patient diagnosed with CFC, has previously been reported in patients with NS. In one patient with NS, we also identified a mutation, BRAF K499E, that has previously been reported in patients with CFC. We thus suggest involvement of BRAF in the pathogenesis of NS also. Conclusions: Taken together, our results indicate that the molecular and clinical overlap between CFC and NS is more complex than previously suggested and that the syndromes might even represent allelic disorders. Furthermore, we suggest that the diagnosis should be refined to, for example, NS–PTPN11-associated or CFC–BRAF-associated syndromes after the genetic defect has been established, as this may affect the prognosis and treatment of the patients.
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