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Maternal immune characteristics and innate immune responses in the child in relation to allergic disease
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
Responsible organisation
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Stockholm: Wenner-Grens institut för experimentell biologi , 2008. , 174 p.
National Category
Immunology
Research subject
Immunology
Identifiers
URN: urn:nbn:se:su:diva-7818ISBN: 978-91-7155-655-4 (print)OAI: oai:DiVA.org:su-7818DiVA: diva2:199097
Public defence
2008-06-13, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8 C, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2008-05-22 Created: 2008-05-20 Last updated: 2010-01-13Bibliographically approved
List of papers
1. Pregnancy, but not the allergic status, influences spontaneous and induced IL-1beta, IL-6, IL-10 and IL-12 responses
Open this publication in new window or tab >>Pregnancy, but not the allergic status, influences spontaneous and induced IL-1beta, IL-6, IL-10 and IL-12 responses
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2006 In: Immunology, ISSN 0019-2805, Vol. 119, no 1, 18-26 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25184 (URN)
Note
Part of urn:nbn:se:su:diva-7818Available from: 2008-05-22 Created: 2008-05-20Bibliographically approved
2. Maternal country of birth and previous pregnancies are associated with breast milk characteristics
Open this publication in new window or tab >>Maternal country of birth and previous pregnancies are associated with breast milk characteristics
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2009 (English)In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 20, no 1, 19-29 p.Article in journal (Refereed) Published
Abstract [en]

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.

Keyword
allergy, breast milk, cytometric bead array, cytokines;exposures, inflammatory bowel disease, immigrants, lipopolysaccharide, soluble CD14, siblings
National Category
Pediatrics
Identifiers
urn:nbn:se:su:diva-25185 (URN)10.1111/j.1399-3038.2008.00754.x (DOI)
Available from: 2008-05-22 Created: 2008-05-20 Last updated: 2011-05-16Bibliographically approved
3. Neonatal immune responses to microbial stimuli - is there an influence of maternal allergy?
Open this publication in new window or tab >>Neonatal immune responses to microbial stimuli - is there an influence of maternal allergy?
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2005 In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, Vol. 115, no 6, 1304-1310 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25186 (URN)
Note
Part of urn:nbn:se:su:diva-7818Available from: 2008-05-22 Created: 2008-05-20Bibliographically approved
4. Maternal allergy influences p38-mitogen-activated protein kinase activity upon microbial challenge in CD14+ monocytes from 2-year-old children
Open this publication in new window or tab >>Maternal allergy influences p38-mitogen-activated protein kinase activity upon microbial challenge in CD14+ monocytes from 2-year-old children
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2008 (English)In: Clinical and Experimental Allergy, ISSN 0954-7894, ISSN 1365-2222, Vol. 38, no 3, 449-57 p.Article in journal (Refereed) Published
Keyword
Adult, Aging/*blood, Antigens; CD14/*metabolism, Child; Preschool, Enzyme Activation, Female, Fetal Blood, Humans, Hypersensitivity, Infant; Newborn, Interleukin-6/metabolism, Lipopolysaccharides/pharmacology, Monocytes/drug effects/*metabolism, Mothers, Peptidoglycan/pharmacology, Phosphorylation/drug effects, Polysaccharides; Bacterial/*pharmacology, p38 Mitogen-Activated Protein Kinases/*metabolism
Identifiers
urn:nbn:se:su:diva-15811 (URN)10.1111/j.1365-2222.2007.02917.x (DOI)000252966600009 ()18177491 (PubMedID)
Available from: 2008-12-10 Created: 2008-12-10 Last updated: 2010-01-13Bibliographically approved
5. Impaired Toll-like receptor 2 signaling in monocytes from 5-year-old allergic children
Open this publication in new window or tab >>Impaired Toll-like receptor 2 signaling in monocytes from 5-year-old allergic children
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2009 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 155, no 3, 387-394 p.Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:su:diva-25188 (URN)10.1111/j.1365-2249.2008.03792.x (DOI)000262950100003 ()
Available from: 2009-05-11 Created: 2008-05-20 Last updated: 2012-02-09Bibliographically approved

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