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Pregnancy and the Hygiene Hypothesis

Pregnancy and the Hygiene Hypothesis - 1 Pregnancy and...

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Unformatted text preview: 1 Pregnancy and the Hygiene Hypothesis Both the placenta and the chorionic villi are entirely fetal tissue. Maternal blood "spills" from open endometrial arteries (the spiral arteries) into the intervillous space, and returns into endometrial veins. Thus the chorionic villi are surrounded and bathed by "lakes" of maternal blood. Within the intervillous space, maternal blood is not contained by blood vessels. The surface of the chorionic villi is an epithelial layer, the fetal syncytiotrophoblast, which has the ability to grow invasively into the maternal endometrium. The syncytiotrophoblast also has microvilli on the surface for absorbing nutrients from maternal blood. Forming the core of each chorionic villus is mesenchymal stroma containing fetal blood vessels. Fetal circulation is entirely closed, confined to vessels within the chorionic villi. Maternal blood flow though the placenta is open. "Lakes" of maternal blood fill the intervillous space, uncontained by any endothelial lining. Between maternal blood and fetal blood lies the thin fetal syncytiotrophoblast epithelium and the fetal capillary endothelium, across which all exchange of gases, nutrients, hormones, and wastes occurs. The fetal allograft is exposed to the maternal immune system at the placenta and fetal membranes (the amnion and chorion), collectively described as the maternal ­fetal interface. On the fetal side of the interface, the placenta and membranes enclose the fetus and are derived entirely from fetal tissue. Forming a specialized epithelial surface within the placenta, fetal syncytiotrophoblast cells directly contact maternal blood for nutrient exchange. On the maternal side of the interface, the uterine tissue in contact with the placenta and fetal membranes, the decidua, is rich in specialized maternal immune cells including lymphocytes and macrophages. Despite the prolonged direct exposure of decidual leukocytes and maternal blood to fetal antigens, the immune system does not recognize the fetus as foreign. Several mechanisms underlie this maternal tolerance of fetal tissues. T ­Helper Cells and the Th1 ­Th2 Shift Emphasis on cell ­mediated immunity versus humoral immunity changes according to the type of T helper lymphocytes responding to an infectious threat. Multiple factors, including the cytokine environment and costimulatory molecules present during activation of the T ­helper cell, determine the development of either Th1 ­ or Th2 ­helper phenotype. One hypothesis is that, in addition to hormonal factors that affect the Th1 ­Th2 balance, macrophages present at the maternal ­fetal interface release predominantly Th2 ­stimulating cytokines and contribute to the overall dominance of humoral immunity during pregnancy. In addition to stimulating B lymphocytes, Th2 cells suppress the cytotoxic T lymphocyte response, decreasing the robustness of cell ­mediated immunity. In the uterine decidua, the Th2 cytokine environment favors activation of B lymphocytes, resulting in stimulation of antibody secretion and suppression of cell ­mediated immunity. 2 This phenomenon is often referred to as the Th1 ­Th2 shift of pregnancy and is thought to contribute to maternal tolerance of the fetus by suppressing the anti ­fetal cell ­mediated immune response. The local Th1 ­Th2 shift may also influence the systemic maternal immune response during pregnancy as evidenced in pregnant patients with autoimmune disorders. Women with rheumatoid arthritis, a predominantly cell ­mediated autoimmune disorder, tend to experience remissions during pregnancy. Similarly, patients with multiple sclerosis have fewer exacerbations while pregnant but worsening symptoms during the postpartum period. Systemic lupus erythematosis, however, a predominantly antibody ­mediated autoimmune disorder, often worsens during pregnancy, perhaps due to increased immunoglobulin synthesis and decreased clearance of immune complexes resulting from robust Th2 activity. Systemic suppression of cell ­mediated immunity may contribute to increased susceptibility to some intracellular pathogens—including viruses, bacteria, and parasites—during pregnancy. In 1989, David Strachan proposed the hygiene hypothesis. He suggested that the rising incidence of allergic disease, such as asthma or allergies, was actually linked to reduced exposure to germs through declining family sizes, more limited exposure to animals, and higher general standards of cleanliness. Strachan reasoned that repeated exposure to microbes at an early age, for example as a result of having siblings, owning a pet, living on a farm, or attending day care, actually helped our immune systems to properly adapt so they would not overreact to routine environmental stimuli, such as potential allergens. Possibly the most famous and clear cut example of the hygiene hypothesis comes from comparing the prevalence of allergies in the East and West German populations before and after unification. Before unification, East Germany had more children growing up on farms and in larger families than West Germany; the population also had much lower rates of allergies and asthma than West Germany. After unification, however, when East Germany developed a more western culture, its rates of allergies and asthma increased to the degree that they now resemble those of West Germany. East Germany also had a quite highly developed health care system, so it is perhaps less likely that the observed differences in asthma diagnosis were due to different patterns of medical diagnosis rather than true differences in disease prevalence. The immunological explanation has been put into the context of the functional T cell subsets known as T helper 1 (TH1) and T helper 2 (TH2) that display polarized cytokine profiles. It has been argued that bacterial and viral infections during early life direct the maturing immune system toward TH1, which counterbalance proallergic responses of TH2 cells. Thus, a reduction in the overall microbial burden will result in weak TH1 imprinting and unrestrained TH2 responses that allow an increase in allergy. This notion is contradicted by 3 observations that the prevalence of TH1 ­autoimmune diseases is also increasing and that TH2 ­ skewed parasitic worm (helminth) infections are not associated with allergy. More recently, elevations of anti ­inflammatory cytokines, such as interleukin ­10, that occur during long ­term helminth infections have been shown to be inversely correlated with allergy. The induction of a robust anti ­inflammatory regulatory network by persistent immune challenge offers a unifying explanation for the observed inverse association of many infections with allergic disorders. ...
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