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Training the Fetal Immune System Through Maternal Inflammation—A Layered Hygiene Hypothesis

Apostol, April C., Jensen, Kirk D. C., Beaudin, Anna E.·2020·Frontiers in Immunology
DOI 10.3389/fimmu.2020.00123PMC PMC7026678
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Figure 1 Understanding the mechanisms that impact fetal immune development in response to maternal immune perturbation. The maternal immune response to infection and inflammation is necessarily perceived by the fetus at the fetal-maternal interface. The fetus may perceive the maternal immune response through: I. Direct transfer and exposure to maternal antigen (i) via antibody-antigen complexes mediated by neonatal Fc receptor (FcRn); II. Receptors on the maternal side responding to PAMPs (Pathogen-Associated Molecular Patterns) produced by pathogens and maternal cytokines that signal to the fetal side (ii) through TLRs (Toll-Like Receptors) and specific cytokine receptors, respectively; III. Direct passage of cytokines across the fetal-maternal interface interacting directly with receptors on the fetal side that may evoke a different cellular response on the fetal side (iii); or IV. Vertical transmission of infection from mother to fetus, causing immune cells to directly perceive and respond to infection (iv). Fetal HSCs can respond to these signals of maternal infection and inflammation by direct changes to their function, including changes in cell proliferation or quiescence that alter the persistence of progenitors, and changes to differentiation potential and cellular output. Such changes at the HSC level can alter the trajectory of the immune system in a way that impacts immune homeostasis and function throughout the lifespan. Figure created using Biorender.com.
Figure 1 Understanding the mechanisms that impact fetal immune development in response to maternal immune perturbation. The maternal immune response to infection and inflammation is necessarily perceived by the fetus at the fetal-maternal interface. The fetus may perceive the maternal immune response through: I. Direct transfer and exposure to maternal antigen (i) via antibody-antigen complexes mediated by neonatal Fc receptor (FcRn); II. Receptors on the maternal side responding to PAMPs (Pathogen-Associated Molecular Patterns) produced by pathogens and maternal cytokines that signal to the fetal side (ii) through TLRs (Toll-Like Receptors) and specific cytokine receptors, respectively; III. Direct passage of cytokines across the fetal-maternal interface interacting directly with receptors on the fetal side that may evoke a different cellular response on the fetal side (iii); or IV. Vertical transmission of infection from mother to fetus, causing immune cells to directly perceive and respond to infection (iv). Fetal HSCs can respond to these signals of maternal infection and inflammation by direct changes to their function, including changes in cell proliferation or quiescence that alter the persistence of progenitors, and changes to differentiation potential and cellular output. Such changes at the HSC level can alter the trajectory of the immune system in a way that impacts immune homeostasis and function throughout the lifespan. Figure created using Biorender.com.CC BY · PubMed Central
Figure 2 In utero perturbation shapes adult immunity by altering the establishment of the fetal hematopoietic and immune systems. (A) Factors such as maternal diet, infection, inflammation, environmental insult, and stress can influence fetal growth in utero. (B) In utero perturbations impact fetal hematopoietic stem and progenitor cells (HSPCs), thereby altering the composition or function of the fetal-derived immune cells they generate during development. The function and cell composition of fetal-derived immune cell compartments can also be impinged upon directly by in utero perturbation. Maternal perturbation can also drive changes (red arrows) to the adult hematopoietic stem cell (HSC) compartment. Transient fetal hematopoietic progenitors can fail to appear normally during ontogeny, or be induced to persist abnormally, driven by persistent epigenetic reprogramming. Such changes will ultimately impact heterogeneity and function of the adult HSC compartment. Perturbing the composition and function of the adult HSC compartment will alter adult immune output and the trajectory of the immune system. Similarly, as fetal-derived immune cells play critical roles in tissue development and homeostasis, disturbing their establishment or function can impact tissue-specific immunity and disease-risk across the lifespan. Figure created using Biorender.com.
Figure 2 In utero perturbation shapes adult immunity by altering the establishment of the fetal hematopoietic and immune systems. (A) Factors such as maternal diet, infection, inflammation, environmental insult, and stress can influence fetal growth in utero. (B) In utero perturbations impact fetal hematopoietic stem and progenitor cells (HSPCs), thereby altering the composition or function of the fetal-derived immune cells they generate during development. The function and cell composition of fetal-derived immune cell compartments can also be impinged upon directly by in utero perturbation. Maternal perturbation can also drive changes (red arrows) to the adult hematopoietic stem cell (HSC) compartment. Transient fetal hematopoietic progenitors can fail to appear normally during ontogeny, or be induced to persist abnormally, driven by persistent epigenetic reprogramming. Such changes will ultimately impact heterogeneity and function of the adult HSC compartment. Perturbing the composition and function of the adult HSC compartment will alter adult immune output and the trajectory of the immune system. Similarly, as fetal-derived immune cells play critical roles in tissue development and homeostasis, disturbing their establishment or function can impact tissue-specific immunity and disease-risk across the lifespan. Figure created using Biorender.com.CC BY · PubMed Central

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Metadata

Authors
Apostol, A. C., Jensen, K. D. C., & Beaudin, A. E.
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2020-02-11
Volume
11
ISSN
1664-3224
DOI
10.3389/fimmu.2020.00123
PMC
PMC7026678
Cited by
96
References
22
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
University of California Merced

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CoChat. (2026). Citation check: Training the Fetal Immune System Through Maternal Inflammation—A Layered Hygiene Hypothesis. https://app.cochat.ai/papers/10.3389/fimmu.2020.00123
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Apostol, A. C., Jensen, K. D. C., & Beaudin, A. E. (2020). Training the Fetal Immune System Through Maternal Inflammation—A Layered Hygiene Hypothesis. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2020.00123