Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Microbial and maternal influences on allergic sensitization during childhood: defining a role for monocytes
Stockholm University, Faculty of Science, The Wenner-Gren Institute . (Eva Sverremark-Ekström)
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Allergic diseases are influenced by genetics and the environment. Maternal allergy appears to confer a higher risk for allergic sensitization than paternal allergy, suggesting an in utero influence. A decrease in particular infections or a lower exposure to microbial components during infancy is suggested to contribute to the high allergy prevalence in affluent societies. Toll-like receptors (TLR) 2 and 4 recognize peptidoglycan (PGN) and LPS respectively, are expressed on e.g. monocytes, and have been implicated in modulating the risk of IgE-sensitization. This thesis aimed to study the influence of maternal allergy and early microbial exposure on monocyte function and allergic sensitization during childhood.

Blood samples from children participating in a prospective allergy cohort were used. Two-year old infants with allergic mothers had lower IL-6 production and reduced activation of the TLR-signalling intermediate p38-MAPK in response to PGN than children with non-allergic mothers. In 5-year old children, allergic disease and not maternal allergy influenced monocytic TLR2-regulation. Five-year olds who were seropositive for Epstein-Barr virus (EBV) at 2-years of age had a lower risk of persistent IgE-sensitization while EBV contraction after 2-years of age related to a higher risk of IgE-sensitization. Upon in vitro stimulation, NK cells from EBV+ 2-year olds produced lower IFN-g levels. EBV+ 2-year olds had also lower systemic IFN-g. In comparison to CD14++CD16- monocytes, CD14+CD16+ cells induced NK-cell IFN-g more potently in vitro, and EBV+ infants tended to have lower proportions of these CD14+CD16+ monocytes.

This thesis highlights the importance of early-life microbial (EBV) exposure for a proper allergy-protective immunity. Also, maternal allergic heredity appears to influence monocytic microbial responses in early infancy. All these aspects relate to altered monocyte functionality, which suggest that they could have a role in allergic sensitization.

Place, publisher, year, edition, pages
Stockholm: The Wenner-Gren Institute, Stockholm University , 2009. , 81 p.
Keyword [en]
Monocytes, allergic sensitization, maternal allergy, Toll-like receptor, p38-MAPK, IL-6, Epstein-Barr virus, early-life microbial exposure, NK cells, IFN-γ
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:su:diva-27620ISBN: 978-91-7155-872-5 (print)OAI: oai:DiVA.org:su-27620DiVA: diva2:216587
Public defence
2009-06-12, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8 C, Stockholm, 13:00 (English)
Opponent
Supervisors
Available from: 2009-05-21 Created: 2009-05-11 Last updated: 2012-03-13Bibliographically approved
List of papers
1. 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
Show others...
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
2. 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
Show others...
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
3. Early-life EBV infection protects against persistent IgE sensitization.
Open this publication in new window or tab >>Early-life EBV infection protects against persistent IgE sensitization.
Show others...
2010 (English)In: The Journal of allergy and clinical immunology, ISSN 1097-6825, Vol. 125, no 2, 433-8 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Infection with EBV has previously been implicated in influencing allergic disorders, but its precise role remains contradictory. The timing of primary infection may contribute to the discrepancies. OBJECTIVE: This study aimed at investigating whether the time-point of primary EBV infection during childhood could be of importance in modulating the risk of developing IgE sensitization. METHODS: A total of 219 Swedish infants were followed prospectively to 5 years of age with clinical examinations, skin prick testing, specific IgE analyses, and determination of serostatus against EBV. RESULTS: After analysis of the children's EBV serostatus, we found that 5-year-olds who were infected with EBV before the age of 2 years were at a significantly lower risk of being persistently IgE-sensitized-that is, sensitized at both 2 and 5 years of age (adjusted odds ratio, 0.34; 95% CI, 0.12-0.94). In contrast, contraction of EBV after 2 years of age was highly associated with late-onset IgE sensitization (adjusted odds ratio, 4.64; 95% CI, 1.57-13.69). Persistently sensitized 5-year-olds had higher specific-IgE levels than children with late-onset IgE sensitization (P < .01). CONCLUSION: Our data support the value of early-life microbial exposure for protection against the development of IgE sensitization and underscore the proximate postnatal years as an important period during which EBV could contribute to an allergo-protective immune profile.

National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-33003 (URN)10.1016/j.jaci.2009.09.033 (DOI)19963258 (PubMedID)
Available from: 2009-12-18 Created: 2009-12-18 Last updated: 2012-05-02Bibliographically approved
4. Herpesvirus seropositivity in childhood associates with decreased monocyte-induced NK-cell IFN-γ production
Open this publication in new window or tab >>Herpesvirus seropositivity in childhood associates with decreased monocyte-induced NK-cell IFN-γ production
Show others...
2009 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 182, no 4, 2511-2517 p.Article in journal (Refereed) Published
Abstract [en]

EBV infection is inversely associated with IgE sensitization in children, and this association is further enhanced by CMV coinfection. In mice, herpesvirus latency causes systemic innate activation and protection from bacterial coinfection, implying the importance of herpesviruses in skewing immune responses during latent infection. Early control of viral infections depends on IFN- release by NK cells, which generally requires the presence of accessory cells. We investigated IFN- production by NK cells in PBMCs from children seropositive (SP) for EBV alone, for both EBV and CMV, or seronegative for both viruses. The ability of classical (CD14++CD16–) and proinflammatory (CD14+CD16+) monocytes to induce autologous NK cell IFN- was studied by coculture experiments with enriched CD3–CD56+ cells. Transwell experiments were used to evaluate how monocytes interact with NK cells to induce IFN- synthesis. SP children had a significantly reduced proportion of IFN-+ NK cells and cognate intracellular IFN- levels, which was more pronounced in CMV-coinfected subjects. Also, resting PBMCs of SP children displayed lower proportions of proinflammatory monocytes. IFN- production by NK cells was dependent on interactions with monocytes, with the proinflammatory subset inducing the highest IFN-. Finally, SP children had markedly lower levels of plasma IFN-, concurrent with in vitro findings. Herpesvirus infections could be one contributing factor for maturation toward balanced Th1-Th2 responses. Our data indicate that early infection by herpesviruses may affect NK cell and monocyte interactions and thereby also influence the development of allergies.

National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-25536 (URN)10.4049/jimmunol.0801699 (DOI)000263126300082 ()19201907 (PubMedID)
Available from: 2008-10-16 Created: 2008-10-16 Last updated: 2013-08-30Bibliographically approved

Open Access in DiVA

fulltext(2333 kB)536 downloads
File information
File name FULLTEXT01.pdfFile size 2333 kBChecksum SHA-512
6b70a1be3acb6e24c95a877b0c5e9eeb5ce708e548f3eb91d46c5a9839e412a7e64da96a044b506b55256a736c3b6de478a2ac1074f6c9a303e7f1c6ef2e4eb2
Type fulltextMimetype application/pdf

Search in DiVA

By author/editor
Saghafian Hedengren, Shanie
By organisation
The Wenner-Gren Institute
Immunology in the medical area

Search outside of DiVA

GoogleGoogle Scholar
Total: 536 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 383 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf