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Allergy development during the first 10 years of life in a Swedish prospective birth cohort is preceded by a lack of early lactobacilli-colonization and a skewed plasma chemokine-profile
(English)Manuscript (preprint) (Other academic)
Keywords [en]
Allergy, allergic heredity, chemokines, children, cytokines, lactobacilli-colonization, plasma
National Category
Immunology
Research subject
Molecular Bioscience
Identifiers
URN: urn:nbn:se:su:diva-134010OAI: oai:DiVA.org:su-134010DiVA, id: diva2:974579
Available from: 2016-09-27 Created: 2016-09-27 Last updated: 2022-02-23Bibliographically approved
In thesis
1. Immune maturation and lymphocyte characteristics in relation to early gut bacteria exposure
Open this publication in new window or tab >>Immune maturation and lymphocyte characteristics in relation to early gut bacteria exposure
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

At birth, the immune system is immature and the gut microbiota influences immune maturation. Staphylococcus aureus (S. aureus) and lactobacilli are part of the neonatal gut microbiota and have seemingly opposite effects on the immune system. S. aureus is a potent immune activator and early-life colonization associates with higher immune responsiveness later in life. Lactobacilli-colonization associates with reduced allergy-risk and lower immune responsiveness. Further, lactobacilli modulate immune-activation and have probiotic features.

Here, we investigated S. aureus-induced activation of human lymphocytes, including T regulatory cells (Tregs), conventional T-cells (CD4+ and CD8+), unconventional T-cells (γδ T-cells and MAIT-cells) and NK-cells from children and adults, together with the modulatory effect of lactobacilli on immune-activation. Further, early-life colonization with these bacteria was related to lymphocyte-maturation, plasma cytokine- and chemokine-levels and allergy. 

S. aureus cell free supernatant (CFS) and staphylococcal enterotoxin (SE) A induced an increased percentage of FOXP3+ Tregs and of CD161+, IL-10+, IFN-γ+ and IL-17A+ Tregs (Paper I). The same pattern was observed in children with a lower degree of activation, possibly due to lower CD161-expression and poor activation of naive T-cells (Paper II). S. aureus-CFS induced IFN-γ-expression, proliferation and cytotoxic capacity in conventional and unconventional T-cells, and NK-cells. SEA, but not SEH, induced activation of unconventional T-cells and NK-cells by unknown mechanism(s) (Paper III, extended data). Lactobacilli-CFS reduced S. aureus-induced lymphocyte activation without the involvement of IL-10, Tregs or monocytes, but possibly involving lactate (Paper III). Early-life colonization with S. aureus associated with increased percentages of CD161+ and IL-10+ Tregs while lactobacilli-colonization negatively correlated with the percentage of IL-10+ Tregs later in life (Paper II). Allergic disease in childhood associated with double allergic heredity, being born wintertime and with higher plasma levels of TH2-, TH17- and TFH-related chemokines early in life. Lactobacilli-colonization associated with lower prevalence of allergy, reduced chemokine-levels and increased levels of IFN-γ in plasma (Paper IV).   

This thesis provides novel insights into S. aureus- and SE-mediated activation of Tregs, unconventional T-cells and NK-cells and suggests an overall impairment of immune-responsiveness towards this bacterium in children. Further, S. aureus-colonization may influence the maturation of peripheral Tregs. Our data show that lactobacilli potently dampen lymphocyte-activation in vitro and that colonization associates with Treg-responsiveness, altered plasma cytokine- and chemokine-levels and with remaining non-allergic, thereby supporting the idea of lactobacilli as important immune-modulators.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2016. p. 125
Keywords
Allergy, cell-free supernatant, chemokines, colonization, cytokines, FOXP3, immune-maturation, lactobacilli, lymphocytes, NK-cells, Staphylococcus aureus, unconventional T-cells
National Category
Immunology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-134054 (URN)978-91-7649-504-9 (ISBN)978-91-7649-505-6 (ISBN)
Public defence
2016-11-25, sal E306, Arrheniuslaboratorierna, Svante Arrhenius väg 20 C, Stockholm, 09:30 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

 

Available from: 2016-11-01 Created: 2016-09-28 Last updated: 2022-02-23Bibliographically approved

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Björkander, Sophia

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