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Published on: August 7, 2017
Maternal prenatal immunity, neonatal trained immunity, and early airway microbiota shape childhood asthma development
Avery DeVries1,2, Kathryn McCauley3,4, Douglas Fadrosh3
1Asthma and Airway Disease Research Center, The University of Arizona, Tucson, Arizona, USA.
Insights
Maternal prenatal immune dysfunction, indicated by a low IFN-γ:IL-13 ratio, alters neonatal epigenetics and immune training, increasing childhood asthma risk. This is linked to specific early-life airway microbial colonization patterns.
Area of Science:
- Immunology
- Epigenetics
- Microbiology
Background:
- Childhood asthma development is influenced by prenatal and postnatal exposures, but underlying mechanisms are not fully understood.
- Maternal immune dysfunction during pregnancy, specifically a low interferon-gamma (IFN-γ) to interleukin-13 (IL-13) ratio in the third trimester, is associated with increased childhood asthma risk.
- This study investigates how prenatal maternal immune status impacts neonatal immune programming and early-life microbial exposures.
Purpose of the Study:
- To explore the relationship between maternal prenatal immune status (IFN-γ:IL-13 ratio) and epigenetic, immunologic, and microbial features in neonates.
- To determine if maternal immune status influences neonatal immune training and susceptibility to asthmagenic microbiota.
- To identify specific epigenetic modifications and microbial colonization patterns associated with childhood asthma development.
Main Methods:
- A birth cohort of 155 mother-child dyads was studied, with samples collected prenatally, perinatally, and postnatally.
- Epigenome-wide DNA methylation was assessed in cord blood mononuclear cells (CBMC) using array profiling.
- Cytokine production (IFN-γ, IL-13) was measured by ELISA, and nasopharyngeal microbiome composition was analyzed by 16S rRNA sequencing from ages 2-36 months.
Main Results:
- Maternal prenatal immune status correlated with DNA methylation profiles in neonates born to non-asthmatic mothers.
- A specific set of differentially methylated CpG sites, linked to microbial responses, was associated with childhood asthma.
- Neonates born to mothers with the lowest IFN-γ:IL-13 ratio showed impaired in vitro responsiveness to microbial products in CBMCs, indicating defective innate immunity.
- These infants developed a distinct upper airway microbiota, initially colonized by Haemophilus and later shifting to a Moraxella-dominated community by 36 months.
Conclusions:
- Maternal prenatal immune status significantly influences a child's asthma development trajectory.
- Epigenetic alterations and altered trained innate immunity at birth, driven by maternal immune status, are key mechanisms.
- Pathological upper airway microbial colonization in early life is associated with this process.
Background:
The path to childhood asthma is thought to initiate in utero and be further promoted by postnatal exposures. However, the underlying mechanisms remain underexplored. We hypothesized that prenatal maternal immune dysfunction associated with increased childhood asthma risk (revealed by low IFN-γ:IL-13 secretion during the third trimester of pregnancy) alters neonatal immune training through epigenetic mechanisms and promotes early-life airway colonization by asthmagenic microbiota.
Methods:
We examined epigenetic, immunologic, and microbial features potentially related to maternal prenatal immunity (IFN-γ:IL-13 ratio) and childhood asthma in a birth cohort of mother-child dyads sampled pre-, peri-, and postnatally (N = 155). Epigenome-wide DNA methylation and cytokine production were assessed in cord blood mononuclear cells (CBMC) by array profiling and ELISA, respectively. Nasopharyngeal microbiome composition was characterized at age 2-36 months by 16S rRNA sequencing.
Results:
Maternal prenatal immune status related to methylome profiles in neonates born to non-asthmatic mothers. A module of differentially methylated CpG sites enriched for microbe-responsive elements was associated with childhood asthma. In vitro responsiveness to microbial products was impaired in CBMCs from neonates born to mothers with the lowest IFN-γ:IL-13 ratio, suggesting defective neonatal innate immunity in those who developed asthma during childhood. These infants exhibited a distinct pattern of upper airway microbiota development characterized by early-life colonization by Haemophilus that transitioned to a Moraxella-dominated microbiota by age 36 months.
Conclusions:
Maternal prenatal immune status shapes asthma development in her child by altering the epigenome and trained innate immunity at birth, and is associated with pathologic upper airway microbial colonization in early life.
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