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

Abstract

Over the last century, the alarming surge in allergy and autoimmune disease has led to the hypothesis that decreasing exposure to microbes, which has accompanied industrialization and modern life in the Western world, has fundamentally altered the immune response. In its current iteration, the "hygiene hypothesis" suggests that reduced microbial exposures during early life restricts the production and differentiation of immune cells suited for immune regulation. Although it is now well-appreciated that the increase in hypersensitivity disorders represents a "perfect storm" of many contributing factors, we argue here that two important considerations have rarely been explored. First, the window of microbial exposure that impacts immune development is not limited to early childhood, but likely extends into the womb. Second, restricted microbial interactions by an expectant mother will bias the fetal immune system toward hypersensitivity. Here, we extend this discussion to hypothesize that the cell types sensing microbial exposures include fetal hematopoietic stem cells, which drive long-lasting changes to immunity.

Keywords: fetal-maternal; hematopoietic stem cell; hygiene hypothesis; immune training; immunity.

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 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.